Thiobenzimidazole derivative or pharmaceutically acceptable salt thereof, and use thereof

Abstract

The present invention relates to: a chromene-benzimidazole derivative or a pharmaceutically acceptable salt thereof; and a composition for preventing or treating cancer, the composition containing said derivative as an active ingredient. The chromene-benzimidazole derivative of the present invention is activated in cancer cells to inhibit tubulin polymerization, and suppresses the C-terminal domain of Hsp90, and thus can arrest the cell cycle of the cancer cells and induce apoptosis as well as inhibit the activity of oncoproteins when administered to a subject. Therefore, the chromene-benzimidazole derivative of the present invention can be used as a new dual-target anticancer drug for preventing or treating cancer, preferably for preventing or treating triple-negative breast cancer.

Description

Thiobenzimidazole derivatives or pharmaceutically acceptable salts thereof and uses thereof

[0001] The present invention relates to a thiobenzimidazole derivative or a pharmaceutically acceptable salt thereof and its use.

[0002] Patients with triple-negative breast cancer (TNBC; ER-, PR-, HER2-) account for 10-15% of all breast cancer patients and lack hormone receptors (ER (estrogen receptor), PR (progesterone receptor)) and the HER2 protein, making them ineligible for hormonal therapy or HER2-targeted therapies. Currently, the standard treatment for triple-negative breast cancer relies entirely on conventional cytotoxic chemotherapy (taxanes or anthracyclines). Because there are no established targeted therapies, treatment strategies for other subtypes are less diverse than for breast cancer. Furthermore, most patients experience recurrence within 2-3 years after surgery or chemotherapy, and metastases easily develop in other organs such as the lungs, liver, brain, and bones, reducing patient survival rates.

[0003] The five-year overall survival rate for patients diagnosed with stage III (stage-III) cancer is less than 55%, and for patients with advanced metastases, the five-year survival rate is even lower, at less than 30%. Most of these patients ultimately suffer from a very serious disease that ultimately leads to death within several years.

[0004] Microtubules, a key component of the cytoskeleton, are composed of tubulin heteropolymers composed of α and β subunits. Microtubules perform various cellular functions, including intracellular transport, maintaining polarity, intracellular signaling, cell migration, and proliferation. During mitosis, microtubules form a spindle, which aligns chromosomes at the center of the cell and then separates them toward the poles. Failure of the spindle to function properly inhibits cell division, leading to apoptosis. Therefore, microtubules are attracting attention as potential targets for anticancer drugs.

[0005] Drugs that target microtubules are broadly divided into two groups: those that stabilize them and those that destabilize them. First, microtubule stabilizers, such as taxanes, paclitaxel (Taxol), and docetaxel, prevent microtubule depolymerization and enhance microtubule polymerization. Most microtubule-stabilizing agents bind to the taxane-binding site or the overlapping site on β-tubulin. Second, microtubule destabilizing agents, such as colchicine and vinca alkaloids, bind to the colchicine-binding site or the vinca-binding site. These microtubule-targeting agents are effective at lower concentrations than those that affect microtubule polymerization, and both inhibit mitosis. Therefore, there is a pressing need to develop potential tubulin polymerization inhibitors as anticancer agents.

[0006] Meanwhile, flubendazole and albendazole are tubulin polymerization inhibitors marketed as anthelmintics. However, they have been shown to induce cell death through cell cycle arrest, and their killing effects on slow-growing cancer cells have been confirmed, attracting attention as treatments for various cancers. However, their low solubility in water limits their absorption in the body, and ingestion in large doses can cause side effects such as elevated liver enzyme levels. Therefore, the development of derivatives with novel structures is required.

[0007] Accordingly, the inventors of the present invention have confirmed that a novel thiobenzimidazole derivative or a pharmaceutically acceptable salt thereof acts as a tubulin polymerization inhibitor to induce cell cycle arrest and apoptosis in cancer cells, thereby completing the present invention.

[0008] Related prior art includes Indian Journal of Chemistry, Vol. 52B, April 2013, pp 535-545.

[0009] The technical problem to be achieved by the present invention is to provide a thiobenzimidazole derivative or a pharmaceutically acceptable salt thereof.

[0010] The technical problem to be achieved by the present invention is to provide a method for producing the above thiobenzimidazole derivative or a pharmaceutically acceptable salt thereof.

[0011] In addition, another object of the present invention is to provide a pharmaceutical composition for preventing or treating cancer, comprising the thiobenzimidazole derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

[0012] However, the technical problems to be solved by the present invention are not limited to the problems mentioned above, and other problems not mentioned can be clearly understood by those skilled in the art from the description below.

[0013] In order to solve the above problem, the present invention provides a thiobenzimidazole derivative represented by the following [chemical formula 1], a racemate, an isomer, a solvate thereof, or a pharmaceutically acceptable salt thereof:

[0014] [Chemical Formula 1]

[0015]

[0016] In the above chemical formula 1,

[0017] X is either C or N,

[0018] R 1 Silver is substituted or unsubstituted C3 to C 20 Cycloalkyl, substituted or unsubstituted C3 to C 20 Heterocycloalkyl, substituted or unsubstituted C3 to C 20 Aryl and substituted or unsubstituted C3 to C 20 Any one selected from the heteroaryls of

[0019] When the above cycloalkyl, heterocycloalkyl, aryl or heteroaryl is substituted, it is substituted with at least one selected from a heterocycloalkyl group, a C1 to C6 alkyl group, a hydroxy group, an alkylacyl group, -CF3 and a dimethylamino group,

[0020] R 2 is hydrogen or halogen.

[0021] As one embodiment of the present invention, in the above [chemical formula 1],

[0022] R 1is any one selected from the group consisting of substituted or unsubstituted piperidine, substituted or unsubstituted morpholine, substituted or unsubstituted piperazine and substituted or unsubstituted thiophene,

[0023] When the above piperidine, morpholine, piperazine or thiophene is substituted, it may be substituted with one or more selected from a morpholine group, a methyl group, a hydroxyl group, an isobutyl acyl group, -CF3 and a dimethyl amino group.

[0024] As another embodiment of the present invention, the thiobenzimidazole derivative represented by the above [chemical formula 1] may be any one selected from the group consisting of the following compounds:

[0025] [Chemical Formula 1-1]

[0026]

[0027] [Chemical Formula 1-2]

[0028]

[0029] [Chemical Formula 1-3]

[0030]

[0031] [Chemical Formula 1-4]

[0032]

[0033] [Chemical Formula 1-5]

[0034]

[0035] [Chemical Formula 1-6]

[0036]

[0037] [Chemical Formula 1-7]

[0038]

[0039] [Chemical Formula 1-8]

[0040]

[0041] [Chemical Formula 1-9]

[0042]

[0043] [Chemical Formula 1-10]

[0044]

[0045]

[0046] As another embodiment of the present invention, the thiobenzimidazole derivative may inhibit tubulin polymerization.

[0047] In another embodiment of the present invention, the pharmaceutically acceptable salt of the thiobenzimidazole derivative may be at least one selected from the group consisting of hydrochloride, bromate, sulfate, phosphate, nitrate, citrate, acetate, lactate, tartrate, maleate, gluconate, succinate, formate, trifluoroacetate, oxalate, fumarate, glutarate, adipate, methanesulfonate, benzenesulfonate, paratoluenesulfonate, camphorsulfonate, sodium salt, potassium salt, lithium salt, calcium salt, and magnesium salt, and preferably may be hydrochloride.

[0048] In addition, the present invention provides a composition for preventing or treating cancer, comprising the thiobenzimidazole derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

[0049] In addition, the present invention provides a method for preventing or treating cancer, comprising a step of administering the thiobenzimidazole derivative or a pharmaceutically acceptable salt thereof to a subject.

[0050] In addition, the present invention provides the use of the thiobenzimidazole derivative or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention or treatment of cancer.

[0051] In addition, the present invention provides a method for diagnosing cancer, comprising a step of administering the thiobenzimidazole derivative or a pharmaceutically acceptable salt thereof to a subject.

[0052] In addition, the present invention provides the use of the thiobenzimidazole derivative or a pharmaceutically acceptable salt thereof for the manufacture of a drug for cancer diagnosis.

[0053] As one embodiment of the present invention, the pharmaceutical composition may induce apoptosis by arresting the cell cycle of cancer cells.

[0054] In another embodiment of the present invention, the cancer may be at least one selected from the group consisting of skin cancer, breast cancer, uterine cancer, esophageal cancer, stomach cancer, brain tumor, colon cancer, rectal cancer, large intestine cancer, lung cancer, ovarian cancer, cervical cancer, endometrial cancer, vulvar cancer, kidney cancer, blood cancer, pancreatic cancer, prostate cancer, testicular cancer, laryngeal cancer, head and neck cancer, thyroid cancer, liver cancer, bladder cancer, osteosarcoma, lymphoma, leukemia, thymic cancer, urethral cancer, and bronchial cancer, and preferably may be breast cancer, and more preferably HER-2 positive breast cancer or triple negative breast cancer.

[0055] The present invention relates to a thiobenzimidazole derivative or a pharmaceutically acceptable salt thereof and a composition for preventing or treating cancer comprising the derivative as an active ingredient. The thiobenzimidazole derivative of the present invention is activated in cancer cells to inhibit tubulin polymerization, and exhibits cytotoxicity by blocking the cancer cell cycle and inducing apoptosis when administered to a subject. Therefore, it can be used for preventing or treating cancer, preferably preventing or treating HER-2 positive breast cancer or triple-negative breast cancer.

[0056] The effects of the present invention are not limited to those mentioned above, and other effects not mentioned will be clearly understood by those skilled in the art from the description below.

[0057] Figure 1 shows the experimental results of treating the human breast cancer cell lines MDA-MB-231 and JIMT-1 with thiobenzimidazole derivatives of chemical formulas 1-1 to 1-10.

[0058] Figure 2 shows the treatment of MDA-MB-231 and JIMT-1 cell lines with thiobenzimidazole derivatives (chemical formulae 1-1 to 1-4) of the present invention and the derivation of IC50 values.

[0059] The present inventors conducted extensive research on thiobenzimidazole derivatives or pharmaceutically acceptable salts thereof, and confirmed the anticancer activity of the derivatives, thereby completing the present invention.

[0060] More specifically, it was confirmed that the thiobenzimidazole derivative or a pharmaceutically acceptable salt thereof is activated in cancer cells, inhibits tubulin polymerization, blocks the cancer cell cycle, and induces apoptosis, thereby exhibiting cytotoxicity.

[0061] From the above results, the present invention can provide a thiobenzimidazole derivative represented by the following [chemical formula 1] or a pharmaceutically acceptable salt thereof.

[0062] [Chemical Formula 1]

[0063]

[0064] In the above chemical formula 1,

[0065] X is either C or N,

[0066] R 1 Silver is substituted or unsubstituted C3 to C 20 Cycloalkyl, substituted or unsubstituted C3 to C 20 Heterocycloalkyl, substituted or unsubstituted C3 to C 20 Aryl and substituted or unsubstituted C3 to C 20 Any one selected from the heteroaryls of

[0067] When the above cycloalkyl, heterocycloalkyl, aryl or heteroaryl is substituted, it is substituted with at least one selected from a heterocycloalkyl group, a C1 to C6 alkyl group, a hydroxy group, an alkylacyl group, -CF3 and a dimethylamino group,

[0068] R 2 is hydrogen or halogen.

[0069] In the present invention, the term “substitution” refers to a reaction in which an atom or atomic group included in a molecule of a compound is replaced with another atom or atomic group.

[0070] In the present invention, the term “chain-like” refers to a molecule having a chain-like structure, and the chain-like structure is a chemical structure in which carbon atoms are connected in a chain shape, and there are straight chain-like structures and branched structures.

[0071] In the present invention, the term “cyclo or ring” refers to a structure in which both ends of the skeleton of an organic compound are connected to form a ring.

[0072] In the present invention, the term “chain or cyclic alkyl group” means a monovalent linear or branched or cyclic saturated hydrocarbon residue consisting solely of carbon and hydrogen atoms, having 1 to 20 carbon atoms. Examples of such alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 2-butyl, 3-butyl, pentyl, n-hexyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0073] In the present invention, the term "heterocycloalkyl group" typically refers to a saturated or unsaturated (but not aromatic) cyclohydrocarbon, which may be optionally unsubstituted, monosubstituted or polysubstituted, in the structure of which at least one heteroatom is selected from N, O or S, and preferably any one of piperidine, piperazine or morpholine.

[0074] In the present invention, the term "aryl group" means an unsaturated aromatic ring compound having 3 to 12 carbon atoms, having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl). Examples of such aryl groups include, but are not limited to, phenyl, naphthyl, and the like.

[0075] In the present invention, the term “heteroaryl group” refers to a single ring or multiple condensed rings in which at least one of the atoms constituting the ring has a heteroatom of N, O, or S. Examples of such heteroaryl groups include, but are not limited to, a pyridyl group, a pyrimidinyl group, a pyrazinyl group, an oxazolyl group, a furyl group, a thiophenyl group, and the like.

[0076] In the present invention, the “halogen group” may be fluorine (F), chloride (Cl), bromine (Br), or iodine (I).

[0077] In the present invention, “carbonyl group” means a -C(=O)- group, “sulfonyl group” means a -S(=O)2- group, “sulfonamide group” means a -S(=O)2-NH- group, “acyl group” means a -C(=O)-R group, and “alkylacyl group” means that R of the acyl group is alkyl.

[0078] As a preferred embodiment of the present invention, the compound represented by the above chemical formula 1 is preferably at least one selected from the group consisting of the following compounds:

[0079] [Chemical Formula 1-1]

[0080]

[0081] [Chemical Formula 1-2]

[0082]

[0083] [Chemical Formula 1-3]

[0084]

[0085] [Chemical Formula 1-4]

[0086]

[0087] [Chemical Formula 1-5]

[0088]

[0089] [Chemical Formula 1-6]

[0090]

[0091] [Chemical Formula 1-7]

[0092]

[0093] [Chemical Formula 1-8]

[0094]

[0095] [Chemical Formula 1-9]

[0096]

[0097] [Chemical Formula 1-10]

[0098]

[0099]

[0100] The thiobenzimidazole derivative or pharmaceutically acceptable salt thereof of the present invention is specifically activated in cancer cells, inhibits tubulin polymerization, and induces cell death, and thus can be used as a pharmaceutical composition for preventing or treating cancer, which includes the thiobenzimidazole derivative or pharmaceutically acceptable salt thereof as an active ingredient.

[0101] In the present invention, the term “pharmaceutically acceptable salt” means a formulation of a compound that does not cause serious irritation to an organism to which the compound is administered and does not impair the biological activity and physical properties of the compound. The pharmaceutically acceptable salt can be obtained by reacting the compound of the present invention with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., a sulfonic acid such as methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, etc., an organic carboxylic acid such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, capric acid, isobutanoic acid, malonic acid, succinic acid, phthalic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicylic acid, etc. In addition, the compound of the present invention can be obtained by reacting it with a base to form a salt such as an alkali metal salt such as an ammonium salt, a sodium or potassium salt, an alkaline earth metal salt such as a calcium or magnesium salt, a salt of an organic base such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and a salt of an amino acid such as arginine or lysine.

[0102] In addition, the thiobenzimidazole derivative or a pharmaceutically acceptable salt thereof may include not only a pharmaceutically acceptable salt, but also all salts, hydrates, and solvates that can be prepared by a conventional method.

[0103] In addition, the present invention can provide a method for preventing, treating, and / or diagnosing cancer, comprising a step of administering the thiobenzimidazole derivative or a pharmaceutically acceptable salt thereof to a subject.

[0104] In the present invention, the term "prevention" means any act of inhibiting or delaying the occurrence, spread or recurrence of cancer by administering the composition of the present invention, and "treatment" means any act of improving or beneficially changing the symptoms of the disease by administering the composition of the present invention.

[0105] The term "pharmaceutical composition" in the present invention refers to a composition manufactured for the purpose of preventing or treating a disease, and may be formulated and used in various forms according to conventional methods. For example, it may be formulated in oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, and syrups, and may be formulated and used in the form of topical preparations, suppositories, and sterile injectable solutions.

[0106] In the present invention, "including as an active ingredient" means that the ingredient is included in an amount necessary or sufficient to realize a desired biological effect. In actual application, the amount included as an active ingredient can be determined by considering the amount for treating the target disease and not causing other toxicity, and may vary depending on various factors such as the disease or condition being treated, the form of the composition being administered, the size of the subject, or the severity of the disease or condition. A person of ordinary skill in the art to which the present invention pertains can empirically determine the effective amount of an individual composition without undue experimentation.

[0107] In addition, the pharmaceutical composition of the present invention may, depending on each formulation, additionally include one or more pharmaceutically acceptable carriers in addition to the above-described effective ingredients.

[0108] The pharmaceutically acceptable carrier may be saline solution, sterile water, Ringer's solution, buffered saline solution, dextrose solution, maltodextrin solution, glycerol, ethanol, or a mixture of one or more of these components, and may further include other conventional additives such as antioxidants, buffers, and bacteriostatic agents, if necessary. In addition, diluents, dispersants, surfactants, binders, and lubricants may be additionally added to formulate the composition into an injectable formulation such as an aqueous solution, suspension, or emulsion, or into a pill, capsule, granule, or tablet. Furthermore, the composition may be preferably formulated according to each disease or component using an appropriate method in the art or a method disclosed in Remington's Pharmaceutical Science (Mack Publishing Company, Easton PA).

[0109]

[0110] The composition of the present invention can be administered orally or parenterally in a pharmaceutically effective amount depending on the intended method, and the term “pharmaceutically effective amount” of the present invention means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment and not causing side effects, and the effective dosage level can be determined based on factors including the patient’s health condition, severity, activity of the drug, sensitivity to the drug, administration method, administration time, administration route and excretion rate, treatment period, drugs used in combination or simultaneously, and other factors well known in the medical field.

[0111] Accordingly, the pharmaceutical composition of the present invention can be administered to a subject to prevent, treat, and / or diagnose cancer, and the cancer may be skin cancer, breast cancer, uterine cancer, esophageal cancer, stomach cancer, brain tumor, colon cancer, rectal cancer, large intestine cancer, lung cancer, ovarian cancer, cervical cancer, endometrial cancer, vulvar cancer, kidney cancer, blood cancer, pancreatic cancer, prostate cancer, testicular cancer, laryngeal cancer, head and neck cancer, thyroid cancer, liver cancer, bladder cancer, osteosarcoma, lymphoma, blood cancer, thymic cancer, urethral cancer, or bronchial cancer, and is not limited thereto, but preferably, it may be a cancer having a characteristic of higher acidity than normal cells and cytotoxicity being inhibited by a tubulin polymerization inhibitor, and non-limiting examples thereof include breast cancer, preferably HER-2 positive breast cancer or triple-negative breast cancer.

[0112] In the present invention, the term “subject” is not limited to a mammal such as a livestock or a human that requires prevention, treatment, and / or diagnosis of cancer, but may preferably be a human.

[0113] The pharmaceutical composition of the present invention can be formulated in various forms for administration to a subject, and a representative form of a parenteral administration form is an injectable form, preferably an isotonic aqueous solution or suspension. The injectable form can be prepared using a suitable dispersing or wetting agent and a suspending agent according to a technique known in the art. For example, each component can be dissolved in saline or a buffer to be formulated for injection. In addition, oral administration forms include, for example, ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, and wafers, and these formulations may contain, in addition to the active ingredient, a diluent (e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and / or glycine) and a lubricant (e.g., silica, talc, stearic acid and its magnesium or calcium salts, and / or polyethylene glycol). The above tablets may contain a binder such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine, and optionally may further contain a disintegrating agent such as starch, agar, alginic acid or its sodium salt, an absorbent, a coloring agent, a flavoring agent and / or a sweetening agent. The above formulations may be prepared by conventional mixing, granulating or coating methods.

[0114] In addition, the pharmaceutical composition of the present invention may further include auxiliary agents such as preservatives, wetting agents, emulsifying agents, salts for osmotic pressure control or buffers, and other therapeutically useful substances, and may be formulated according to conventional methods.

[0115] The pharmaceutical composition according to the present invention can be administered via various routes, including oral, transdermal, subcutaneous, intravenous, or intramuscular. The dosage of the active ingredient can be appropriately selected based on various factors, such as the route of administration, the patient's age, sex, weight, and severity of the condition. Furthermore, the composition of the present invention can be administered in combination with known compounds capable of enhancing the desired effect.

[0116] The pharmaceutical composition according to the present invention may be administered to humans or animals orally or parenterally, such as intravenously, subcutaneously, intranasally, or intraperitoneally. Oral administration also includes sublingual administration. Parenteral administration includes injection methods such as subcutaneous injection, intramuscular injection, and intravenous injection, as well as drip methods.

[0117] In the pharmaceutical composition of the present invention, the total effective amount of the thiobenzimidazole derivative or the pharmaceutically acceptable salt thereof according to the present invention can be administered to a patient as a single dose, or can be administered by a fractionated treatment protocol in which multiple doses are administered over a long period of time. The pharmaceutical composition of the present invention may vary the content of the active ingredient depending on the severity of the disease, but can typically be administered repeatedly several times a day at an effective dose of 100 ㎍ to 3,000 mg per administration for an adult. However, the concentration of the thiobenzimidazole derivative or the pharmaceutically acceptable salt thereof can be determined by taking into consideration various factors such as the route of administration and the number of treatments as well as the patient's age, weight, health status, sex, severity of the disease, diet, and excretion rate.

[0118] In addition, the pharmaceutical composition according to the present invention is not particularly limited in its formulation, administration route, and administration method as long as it exhibits the effects of the present invention, and the pharmaceutical composition of the present invention may additionally include a known anticancer agent in addition to the thiobenzimidazole derivative or a pharmaceutically acceptable salt thereof as an active ingredient, and may be used in combination with other known treatments for the treatment of these diseases.

[0119]

[0120] The terms used in the examples are for illustrative purposes only and should not be construed as limiting. Singular expressions include plural expressions unless the context clearly dictates otherwise. In this specification, terms such as "comprise" or "have" are intended to specify the presence of a feature, number, step, operation, component, part, or combination thereof described in the specification, but should be understood to not preclude the presence or addition of one or more other features, numbers, steps, operations, components, parts, or combinations thereof.

[0121] Unless otherwise defined, all terms used herein, including technical or scientific terms, have the same meaning as commonly understood by a person of ordinary skill in the art to which the embodiments pertain. Terms defined in commonly used dictionaries should be interpreted as having a meaning consistent with their meaning in the context of the relevant technology, and shall not be interpreted in an idealized or overly formal sense unless explicitly defined herein.

[0122] The present invention is susceptible to various modifications and embodiments. Specific embodiments are illustrated in the drawings and described in detail in the following detailed description. However, this is not intended to limit the present invention to specific embodiments, but rather to encompass all modifications, equivalents, and alternatives falling within the spirit and technical scope of the present invention. In describing the present invention, detailed descriptions of related known technologies will be omitted if they are deemed to obscure the gist of the present invention.

[0123] Manufacturing example. Synthesis of methyl (5-(phenylthio)-1H-benzo[d]imidazol-2-yl)carbamate derivatives.

[0124] The compound of the present invention was prepared by a reaction represented by the following reaction formula:

[0125]

[0126] 1-1. Synthesis of Methyl (5-((4-(4-morpholinopiperidin-1-yl)phenyl)thio)-1H-benzo[d]imidazol-2-yl)carbamate 5 (Chemical Formula 1-1)

[0127]

[0128] 1,3-Bis(methoxycarbonyl)-S-methylisothiourea (2.5 eq) was added to a solution of 4-((4-(4-morpholinopiperidin-1-yl)phenyl)thio)benzene-1,2-diamine (0.241 g, 1.07 mmol) in 5% acetic acid in EtOH (5 mL), and the mixture was heated and stirred at 90 °C for 20 h, after which the solvent was removed by evaporation under reduced pressure.

[0129] The reaction mixture was sufficiently cooled and left at room temperature to produce a solid, which was filtered and washed with MeOH at the same time. At this time, the remaining urea was washed with MeOH until the sulfur odor was completely removed, and dried to obtain methyl (5-((4-(4-morpholinopiperidin-1-yl)phenyl)thio)-1H-benzo[d]imidazol-2-yl)carbamate (0.250 g) as a white solid.

[0130] Yield 85%

[0131] 1 H NMR (400 MHz, DMSO-d6) δ 11.72(m, 2H), 7.34(d, J=8.0Hz, 1H), 7.289s, 1H), 7.21(d, J=8.8Hz, 2H), 7.02(m, 1H), 6.93(d, J=8.8Hz, 2H), 3.74(s, 3H), 3.72(m, 2H), 3.56(m, 4H), 2.70(t, 2H), 2.47(m, 4H), 2.26(m, 1H), 1.85(d, J=10.8Hz, 2H), 1.45(m, 2H)

[0132]

[0133] 1-2. Synthesis of Methyl (5-((3-fluoro-4-morpholinophenyl)thio)-1H-benzo[d]imidazol-2-yl)carbamate (Chemical Formula 1-2)

[0134] 1,3-Bis(methoxycarbonyl)-S-methylisothiourea (2.5 eq) was added to a solution of 4-((3-fluoro-4-morpholinophenyl)thio)benzene-1,2-diamine (0.230 g, 0.72 mmol) in 5% acetic acid in EtOH (5 mL), and the mixture was stirred at 90 °C for 5 h while warming, and then the solvent was removed by evaporation under reduced pressure.

[0135] The reaction mixture was sufficiently cooled and left at room temperature to form a solid, which was filtered and washed with MeOH at the same time. At this time, the remaining urea was washed with MeOH until the sulfur odor was completely removed, and dried to obtain methyl (5-((3-fluoro-4-morpholinophenyl)thio)-1H-benzo[d]imidazol-2-yl)carbamate (0.230 g) as a white solid.

[0136] Yield 79%

[0137] 1 H NMR (400 MHz, DMSO-d6) δ 11.82(m, 1H), 11.64(m, 1H), 7.46(s, 1H), 7.43(d, J=8.0Hz, 1H), 7.16(d, J=8.4Hz, 1H), 6.97(m, 3H), 3.75(s, 3H), 3.71(m, 4H), 2.97(m, 4H),

[0138]

[0139] 1-3. Synthesis of Methyl (5-((3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)thio)-1H-benzo[d]imidazol-2-yl)carbamate (Chemical Formula 1-3)

[0140] 1,3-Bis(methoxycarbonyl)-S-methylisothiourea (0.234 g, 1.13 mmol) was added to a solution of 4-((3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)thio)benzene-1,2-diamine (0.150 g, 0.45 mmol) in 5% acetic acid in EtOH (3 mL), and the mixture was heated and stirred at 90 °C for 5 h, after which the solvent was removed by evaporation under reduced pressure.

[0141] The reaction mixture was sufficiently cooled and left at room temperature to generate a solid, which was filtered and washed with MeOH at the same time. At this time, the sulfur smell of the remaining urea was completely removed, and the residue was separated using column chromatography with methylene chloride and methanol (9:1, v / v / ) as an eluent using silica gel, and dried to obtain Methyl (5-((3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)thio)-1H-benzo[d]imidazol-2-yl)carbamate (0.110 g) as a white solid.

[0142] Yield 59%

[0143] 1 H NMR (400 MHz, DMSO-d6) δ 11.95(m, 1H), 11.40(m, 1H), 7.45(m, 2H), 7.15(d, J=8.4Hz, 1H), 6.96(s, 2H), 6.93(m, 1H), 3.75(s, 3H), 3.65(m, 4H), 2.97(m, 4H), 2.20(s, 3H)

[0144]

[0145] 1-4. Synthesis of Methyl (5-((6-(4-hydroxypiperidin-1-yl)pyridin-3-yl)thio)-1H-benzo[d]imidazol-2-yl)carbamate (Chemical Formula 1-4)

[0146] 1-(5-((3,4-diaminophenyl)thio)pyridin-2-yl)piperidin-4-ol and 1,3-Bis(methoxycarbonyl)-S-methylisothiourea were reacted as described above to obtain Methyl (5-((6-(4-hydroxypiperidin-1-yl)pyridin-3-yl)thio)-1H-benzo[d]imidazol-2-yl)carbamate.

[0147] Yield 84%

[0148] 1 H NMR (400 MHz, DMSO-d6) δ 11.82(m, 1H), 11.33(m, 1H), 8.18(s, 1H), 7.55(d, J=8.8Hz, 1H), 7.33(d, J=8.4Hz, 1H), 7.24(s, 1H), 7.01(d, J=8.4Hz, 1H), 6.87(d, J=8.8Hz, 1H), 4.72(s, 1H), 4.02(m, 2H), 3.73(s, 3H), 3.70(m, 1H), 3.12(m, 2H), 1.78(m, 2H), 1.35(m, 2H)

[0149]

[0150] 1-5 Methyl (5-((4-(4-isobutyrylpiperazin-1-yl)phenyl)thio)-1H-benzo[d]imidazol-2-yl)carbamate (1-5)

[0151] 1-(4-(4-((3,4-diaminophenyl)thio)phenyl)piperazin-1-yl)-2-methylpropan-1-one was prepd Methyl (5-((4-(4-isobutyrylpiperazin-1-yl)phenyl)thio)-1H-benzo[d]imidazol-2-yl)carbamate was used.

[0152] Like 74 %

[0153] 1 H NMR (400 MHz, DMSO-d6) δ 11.73(m, 2H), 7.35(m, 2H), 7.23(d, J=8.8Hz, 2H), 7.04(m, 1H), 6.96(d, J=8.8Hz, 2H), 3.74(s, 3H), 3.62(d, J=18.0Hz, 4H), 3.16(d, J=21.6Hz, 4H), 2.90(q, 1H), 1.01(d, J=6.8Hz, 6H)

[0154]

[0155] 1-6. Synthesis of Methyl (5-((4-(4-isobutyryl-3,5-dimethylpiperazin-1-yl)phenyl)thio)-1H-benzo[d]imidazol-2-yl)carbamate (Formula 1-6)

[0156] 1-(4-(4-((3,4-diaminophenyl)thio)phenyl)-2,6-dimethylpiperazin-1-yl)-2-methylpropan-1-one and 1,3-Bis(methoxycarbonyl)-S-methylisothiourea were reacted as described above to obtain methyl (5-((4-(4-isobutyryl-3,5-dimethylpiperazin-1-yl)phenyl)thio)-1H-benzo[d]imidazol-2-yl)carbamate.

[0157] Yield 87%

[0158] 1 H NMR (400 MHz, DMSO-d6) δ 11.72(m, 2H), 7.33(d, J=9.6Hz, 2H), 7.25(d, J=8.8Hz, 2H), 7.04(d, J=8.0Hz, 1H), 6.97(d, J=8.8Hz, 2H), 4.52(bs, 1H), 4.19(bs, 1H), 3.74(s, 3H), 3.54(m, 2H), 2.85(m, 3H), 1.32(bs, 3H), 1.19(bs, 3H), 1.04((d, J=6.8Hz, 6H)

[0159]

[0160] 1-7. Synthesis of Methyl (5-((4-(1-methylpiperidin-4-yl)phenyl)thio)-1H-benzo[d]imidazol-2-yl)carbamate (Formula 1-7)

[0161] 4-((4-(1-methylpiperidin-4-yl)phenyl)thio)benzene-1,2-diamine and 1,3-Bis(methoxycarbonyl)-S-methylisothiourea were reacted as described above to obtain Methyl (5-((4-(1-methylpiperidin-4-yl)phenyl)thio)-1H-benzo[d]imidazol-2-yl)carbamate.

[0162] Yield 61%

[0163] 1 H NMR (400 MHz, DMSO-d6) δ 11.82(m, 2H), 7.48(s, 1H), 7.43(d, J=8.0Hz, 1H), 7.18(d, J=8.4Hz, 3H), 7.09(d, J=8.0Hz, 2H), 3.75(s, 3H), 2.84(d, J=11.2Hz, 2H), 2.35(m, 1H), 2.16(s, 3H), 1.91(m, 2H), 1.68(m, 2H), 1.60(m, 2H)

[0164]

[0165] 1-8. Synthesis of Methyl (5-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)thio)-1H-benzo[d]imidazol-2-yl)carbamate (Formula 1-8)

[0166] 4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)thio)benzene-1,2-diamine and 1,3-Bis(methoxycarbonyl)-S-methylisothiourea were reacted as described above to obtain methyl (5-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)thio)-1H-benzo[d]imidazol-2-yl)carbamate.

[0167] Yield 68%

[0168] 1 H NMR (400 MHz, DMSO-d6) δ 11.90(m, 1H), 11.33(m, 1H), 7.35(m, 1H), 7.30(d, J=9.2Hz, 2H), 7.04(d, J=8.0Hz, 1H), 6.96(d, J=8.0Hz, 2H), 3.81(d, J=12.8Hz, 2H), 3.74(s, 3H), 2.72(t, 2H), 2.70(m, 1H), 1.88(d, J=12.4Hz, 2H), 1.53(m, 2H)

[0169]

[0170] 1-9 Methyl (5-((4-(4-(dimethylamino)piperidin-1-yl)phenyl)thio)-1H-benzo[d]imidazol-2-yl)carbamate (1-9) .

[0171] 4-((4-(4-(dimethylamino)piperidin-1-yl)phenyl)thio)benzene-1,2-diamine 과 1,3-Bis(methoxycarbonyl)-S-methylisothiourea (5-((4-(4-(dimethylamino)piperidin-1-yl)phenyl)thio)-1H-benzo[d]imidazol-2-yl)carbamate.

[0172] Like 73 %

[0173] 1 H NMR (400 MHz, DMSO-d6) δ 11.63(m, 2H), 7.34(d, J=8.0Hz, 1H), 7.28(s, 1H), 7.21(d, J=8.8Hz, 2H), 7.02(d, J=6.8Hz, 1H), 6.93(d, J=9.2Hz, 2H), 3.73(s, 3H), 3.70(m, 2H), 2.70(t, 2H), 2.17(s, 6H), 2.16(m, 1H), 1.82(d, J=12.4Hz, 2H), 1.43(q, 2H)

[0174]

[0175] 1-10. Synthesis of Methyl (5-((3-fluoro-4-(thiophen-3-yl)phenyl)thio)-1H-benzo[d]imidazol-2-yl)carbamate (Formula 1-10)

[0176] 4-((3-fluoro-4-(thiophen-3-yl)phenyl)thio)benzene-1,2-diamine and 1,3-Bis(methoxycarbonyl)-S-methylisothiourea were reacted as described above to obtain methyl (5-((3-fluoro-4-(thiophen-3-yl)phenyl)thio)-1H-benzo[d]imidazol-2-yl)carbamate.

[0177] Yield 83%

[0178] 1 H NMR (400 MHz, DMSO-d6) δ 11.99(bs, 1H), 11.55(bs, 1H), 7.79(s, 1H), 7.78(m, 3H), 7.65(d, J=8.4Hz, 1H), 7.52(d, J=8.0Hz, 1H), 7.44(d, J=4.8Hz, 1H), 7.28(d, J=8.0Hz, 1H), 6.95(s, 2H), 3.77(s, 3H)

[0179]

[0180] 1-11. Synthesis of Methyl (5-((6-(4-hydroxypiperidin-1-yl)pyridin-3-yl)thio)-1H-benzo[d]imidazol-2-yl)carbamate hydrochloride salt (hydrochloride salt of chemical formula 1-4)

[0181] To a suspension of methyl (5-((6-(4-hydroxypiperidin-1-yl)pyridin-3-yl)thio)-1H-benzo[d]imidazol-2-yl)carbamate (100 mg, 0.25 mmol) in methanol (35 mL) was injected hydrogen chloride gas at 2-minute intervals until the pH became below 1. The reactant was evaporated under reduced pressure to obtain an oily product. Isopropyl alcohol (IPA, 20 mL) was added again, heated to dissolve, and cooled to room temperature to produce a solid suspension. Isopropyl ether (20 mL) was added portionwise, stirred for 2 hours, and then filtered. At this time, the product was washed with a mixed solvent of IPA and Isopropyl ether (IPE), dried with hot air at 50 oC for 1 hour, and then dried under vacuum at 40 oC for 2 hours to obtain a white solid (90 mg).

[0182] Yield 82%

[0183] 1H NMR (DO, 400 MHz) δ 7.81-6.80 (m, 6H), 3.71 (s, 3H), 3.90 (m, 2H), 3.69 (m, 1H), 3.20 (m, 2H), 1.84 (m, 2H), 1.37 (m, 2H).

[0184]

[0185] Example 1. Confirmation of cell viability of thiobenzimidazole derivatives in breast cancer cell lines.

[0186] MDA-MB-231, a human triple-negative breast cancer (TNBC) cell line (Cell seeding numbers: 0.8(M231) x 10 4 cells / wells (confluency 25%) and HER2 positive breast cancer (HER2+ BC) cell line JIMT-1 (Cell seeding numbers: 0.8(JIMT) x 10 4cells / wells (confluency 25%)) was used in the experiment.

[0187] The above cell lines were cultured in Dulbecco's modified Eagle's medium (DMEM) containing 10% fetal bovine serum (FBS), streptomycin-penicillin (100 U / mL), and Fungizone (0.625 ㎍ / mL) at 5% CO2 and 37°C.

[0188] The human breast cancer cell lines MDA-MB-231 and JIMT-1 were treated with the thiobenzimidazole derivatives of Chemical Formulas 1-1 to 1-10 at concentrations of 0, 0.5, 1, and 5 μM, respectively, for 72 hours, and then cell viability was measured using the MTS assay technique. In the MTS assay, cells were allowed to attach to a 96-well plate for 24 hours, treated with the thiobenzimidazole derivatives for 72 hours, and then color was developed with MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) for 4 hours, and then the absorbance was measured at 490 nm using a Spectramax Plus384 microplate analyzer. This is shown in Figure 1, and as shown in the figure, it was confirmed that the thiobenzimidazole derivatives of the chemical formulas 1-1 to 1-10 inhibited cell viability in a concentration-dependent manner in human breast cancer cell lines MDA-MB-231 and JIMT-1.

[0189]

[0190] Example 2. Cell viability and IC of thiobenzimidazole derivatives against breast cancer cell lines 50 Check value

[0191] For MDA-MB-231 and JIMT-1 cell lines, the thiobenzimidazole derivatives (chemical formulae 1-1 to 1-4) of the present invention were treated at concentrations of 0, 0.01, 0.05, 0.1, 0.25, 0.5, 1, 5 and 10 μM, respectively, and then cell viability and IC were measured accordingly. 50 The values ​​were confirmed. The preparation method and experimental method of the cell line were the same as those performed in Example 1. The results are shown in Fig. 2, and in the MDA-MB-231 cell line, the thiobenzimidazole derivatives of Chemical Formula 1-1 to Chemical Formula 1-4 had low IC of 0.592 μM, 0.174 μM, 0.583 μM, and 0.135 μM, respectively. 50 It was confirmed that it has a value.

[0192]

[0193] Although the embodiments described above have been described with limited drawings, those skilled in the art will appreciate that various technical modifications and variations can be applied based on the above. For example, appropriate results can still be achieved even if the described techniques are performed in a different order than described, and / or components of the described systems, structures, devices, circuits, etc. are combined or combined in a different manner than described, or are replaced or substituted with other components or equivalents.

[0194] Therefore, other implementations, other manufacturing examples and equivalents to the patent claims also fall within the scope of the claims described below.

Claims

1. A thiobenzimidazole derivative represented by the following [chemical formula 1] or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] In the above chemical formula 1, X is either C or N, R 1 Silver is substituted or unsubstituted C3 to C 20 Cycloalkyl, substituted or unsubstituted C3 to C 20 Heterocycloalkyl, substituted or unsubstituted C3 to C 20 Aryl and substituted or unsubstituted C3 to C 20 Any one selected from the heteroaryls of When the above cycloalkyl, heterocycloalkyl, aryl or heteroaryl is substituted, it is substituted with at least one selected from a heterocycloalkyl group, a C1 to C6 alkyl group, a hydroxy group, an alkylacyl group, -CF3 and a dimethylamino group, R 2 is hydrogen or halogen.

2. In paragraph 1, In the above [chemical formula 1], R 1 is any one selected from the group consisting of substituted or unsubstituted piperidine, substituted or unsubstituted morpholine, substituted or unsubstituted piperazine and substituted or unsubstituted thiophene, A thiobenzimidazole derivative or a pharmaceutically acceptable salt thereof, characterized in that the piperidine, morpholine, piperazine or thiophene is substituted with at least one selected from a morpholine group, a methyl group, a hydroxyl group, an isobutyl acyl group, -CF3 and a dimethyl amino group.

3. In paragraph 1, A thiobenzimidazole derivative represented by the above [chemical formula 1] is characterized in that it is one selected from the group consisting of the following compounds, or a pharmaceutically acceptable salt thereof: [Chemical Formula 1-1] [Chemical Formula 1-2] [Chemical Formula 1-3] [Chemical Formula 1-4] [Chemical Formula 1-5] [Chemical Formula 1-6] [Chemical Formula 1-7] [Chemical Formula 1-8] [Chemical Formula 1-9] [Chemical Formula 1-10] 4. In paragraph 1, A thiobenzimidazole derivative represented by the above [chemical formula 1] is characterized in that it is one selected from the group consisting of the following compounds, or a pharmaceutically acceptable salt thereof: [Chemical Formula 1-1] [Chemical Formula 1-2] [Chemical Formula 1-3] [Chemical Formula 1-4] 5. In paragraph 1, The above thiobenzimidazole derivative is a thiobenzimidazole derivative or a pharmaceutically acceptable salt thereof, characterized in that it inhibits tubulin polymerization.

6. In paragraph 1, A thiobenzimidazole derivative or a pharmaceutically acceptable salt thereof, characterized in that the pharmaceutically acceptable salt of the above thiobenzimidazole derivative is at least one selected from the group consisting of hydrochloride, bromate, sulfate, phosphate, nitrate, citrate, acetate, lactate, tartrate, maleate, gluconate, succinate, formate, trifluoroacetate, oxalate, fumarate, glutarate, adipate, methanesulfonate, benzenesulfonate, paratoluenesulfonate, camphorsulfonate, sodium salt, potassium salt, lithium salt, calcium salt, and magnesium salt.

7. In paragraph 1, A thiobenzimidazole derivative or a pharmaceutically acceptable salt thereof, characterized in that the pharmaceutically acceptable salt of the above thiobenzimidazole derivative is a hydrochloride.

8. A pharmaceutical composition for preventing or treating cancer, comprising a thiobenzimidazole derivative according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, as an active ingredient.

9. In paragraph 8, A pharmaceutical composition for preventing or treating cancer, characterized in that the pharmaceutical composition induces apoptosis by arresting the cancer cell cycle.

10. In paragraph 8, A pharmaceutical composition for preventing or treating cancer, characterized in that the cancer is at least one selected from the group consisting of skin cancer, breast cancer, uterine cancer, esophageal cancer, stomach cancer, brain tumor, colon cancer, rectal cancer, large intestine cancer, lung cancer, ovarian cancer, cervical cancer, endometrial cancer, vulvar cancer, kidney cancer, blood cancer, pancreatic cancer, prostate cancer, testicular cancer, laryngeal cancer, head and neck cancer, thyroid cancer, liver cancer, bladder cancer, osteosarcoma, lymphoma, blood cancer, thymic cancer, urethral cancer, and bronchial cancer.

11. In paragraph 8, A pharmaceutical composition for preventing or treating cancer, characterized in that the cancer is HER-2 positive breast cancer or triple negative breast cancer.

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