Thiobenzimidazole derivative or pharmaceutically acceptable salt thereof and application of thiobenzimidazole derivative or pharmaceutically acceptable salt 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 comprising the derivative as an active ingredient, the chromene-benzimidazole derivative of the present invention being activated in cancer cells, being capable of inhibiting tubulin polymerization and inhibiting a C-terminal domain of Hsp90, and being capable of preventing or treating cancer, or a pharmaceutically acceptable salt thereof, and a composition for preventing or treating cancer comprising the derivative as an active ingredient. When the compound is administered to a subject, cancer cell cycle arrest can be caused to induce cell apoptosis and hinder the activity of onco-protein, and the compound can be used as a novel double-targeting anti-cancer drug to prevent or treat cancers, preferably to prevent or treat triple negative breast cancer.

Description

Technical Field

[0001] This invention relates to thiobenzimidazole derivatives or pharmaceutically acceptable salts thereof and their uses. Background Technology

[0002] Triple-negative breast cancer (TNBC, ER-, PR-, HER2-) accounts for 10% to 15% of all breast cancer patients. These patients lack hormone receptors (ER (estrogen receptor), PR (progesterone receptor)) and the HER2 protein, and therefore cannot benefit from hormone therapy or HER2-targeted therapy. Currently, standard treatment for triple-negative breast cancer relies entirely on conventional cytotoxic anticancer drugs (taxanes or anthracyclines). Due to the lack of clearly defined targeted therapies, treatment strategies for other subtypes are very limited compared to breast cancer. More seriously, most patients experience recurrence within 2 to 3 years after surgery or chemotherapy, and the disease is prone to metastasis to other organs such as the lungs, liver, brain, and bones, reducing patient survival rates.

[0003] The 5-year overall survival rate for patients diagnosed with stage III cancer is less than 55%, and the 5-year survival rate for patients with metastatic cancer (advanced-stage) is less than 30%, which is extremely low. This disease is a very serious condition in which most patients will die within a few years.

[0004] Microtubules are major components of the cytoskeleton, composed of heteromeric tubulin molecules based on α and β subunits. Microtubules perform numerous cellular functions, including intracellular transport, polarity maintenance, intracellular signal transduction, cell migration, and proliferation. During mitosis, they form spindle fibers, enabling chromosomes to separate at the poles after aligning at the cell center. If spindle fibers malfunction, cell division is inhibited, inducing apoptosis; therefore, they have attracted considerable attention as targets for anticancer drugs.

[0005] Drugs targeting microtubules can be broadly categorized into those that stabilize microtubules and those that disrupt their stability. First, microtubule stabilizers include taxane, paclitaxel (Taxol), and docetaxel, which prevent microtubule depolymerization and promote polymerization. Most microtubule stabilizers bind to taxane binding sites or overlapping sites of β-tubulin. Second, microtubule destabilizers include colchicine and vinca alkaloids, which bind to colchicine binding sites or vinca binding sites. Compared to drugs that affect microtubule polymerization, drugs targeting the microtubules themselves can be effective at lower drug concentrations, ultimately inhibiting cell mitosis. Therefore, there is a need to develop potential microtubule polymerization inhibitors as anticancer drugs.

[0006] On the other hand, commercially available anthelmintics contain flubendazole and abendazole, which are tubulin polymerization inhibitors. These have been found to induce cell death through cell cycle arrest and also have apoptotic effects on slow-growing cancer cells, thus attracting attention as a potential cancer treatment. However, due to their low solubility in water, they are difficult to absorb in the body, and large doses can cause side effects such as elevated liver enzymes. Therefore, there is a need to develop a derivative with a novel structure.

[0007] Therefore, the inventors have demonstrated that novel thiobenzimidazole derivatives or pharmaceutically acceptable salts thereof can act as microtubule polymerization inhibitors to achieve cell cycle arrest in cancer cells, thereby inducing apoptosis, thus completing this invention.

[0008] The relevant prior art is found in the Indian Journal of Chemistry, Vol. 52B, April 2013, pp. 535-545. Summary of the Invention

[0009] Technical problems to be solved

[0010] The purpose of this invention is to provide a thiobenzimidazole derivative or a pharmaceutically acceptable salt thereof.

[0011] Another object of the present invention is to provide a method for preparing the thiobenzimidazole derivative or its pharmaceutically acceptable salt.

[0012] Furthermore, another object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of cancer, comprising the thiobenzimidazole derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

[0013] However, the technical problem to be solved by the present invention is not limited to the above-mentioned problems, and other problems not mentioned will be clearly understood by those skilled in the art through the following description.

[0014] Technical methods for solving problems

[0015] To address the aforementioned issues, the present invention provides a thiobenzimidazole derivative or its racemate, isomer, solvate or pharmaceutically acceptable salt thereof represented by the following [Formula 1]: [Formula 1] ; In Equation 1, X is selected from either C or N. R 1 It is selected from C3 to C3, whether substituted or unsubstituted. 20 cycloalkyl, substituted or unsubstituted C3 to C4 20 Heterocyclic alkyl groups, substituted or unsubstituted C3 to C4 20 Aryl groups and substituted or unsubstituted C3 to C4 groups 20 Any of the heteroaryl groups If the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is substituted, it is by any one or more substitutions selected from heterocycloalkyl, C1 to C6 alkyl, hydroxyl, alkylacyl, -CF3, and dimethylamino. R 2 It is hydrogen or halogen.

[0016] According to an embodiment of the present invention, in [Formula 1], R 1 It is selected from any one of the group consisting of substituted or unsubstituted piperidine, substituted or unsubstituted morpholine, substituted or unsubstituted piperazine, and substituted or unsubstituted thiophene. If the piperidine, morpholine, piperazine, or thiophene is substituted, it is substituted by one or more of the following: morpholino, methyl, hydroxy, isobutyryl, -CF3, and dimethylamino.

[0017] According to another embodiment of the present invention, the thiobenzimidazole derivative represented by [Formula 1] may be any one selected from the group consisting of the following compounds: [Equation 1-1] ; [Equation 1-2] ; [Equation 1-3] ; [Equations 1-4] ; [Equations 1-5] ; [Equations 1-6] ; [Equations 1-7] ; [Equations 1-8] ; [Equations 1-9] ; [Equation 1-10] .

[0018] According to another embodiment of the present invention, the thiobenzimidazole derivative has the effect of inhibiting tubulin polymerization.

[0019] According to another embodiment of the present invention, the pharmaceutically acceptable salt of the thiobenzimidazole derivative is selected from one or more of the group consisting of hydrochloride, bromate, sulfate, phosphate, nitrate, citrate, acetate, lactate, tartrate, maleate, gluconate, succinate, formate, trifluoroacetate, oxalate, fumarate, glutarate, adipate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, camphorsulfonate, sodium salt, potassium salt, lithium salt, calcium salt, and magnesium salt, preferably hydrochloride.

[0020] In addition, the present invention provides a composition for the prevention or treatment of cancer comprising the thiobenzimidazole derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

[0021] In addition, the present invention provides a method for preventing or treating cancer, comprising the step of administering the thiobenzimidazole derivative or a pharmaceutically acceptable salt thereof to a subject.

[0022] In addition, the present invention provides the use of the thiobenzimidazole derivative thereof or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention or treatment of cancer.

[0023] In addition, the present invention provides a cancer diagnosis method comprising the step of administering the thiobenzimidazole derivative or a pharmaceutically acceptable salt thereof to a subject.

[0024] In addition, the present invention provides the use of the thiobenzimidazole derivative thereof or a pharmaceutically acceptable salt thereof in the preparation of a medicament for diagnosing cancer.

[0025] According to one embodiment of the present invention, the pharmaceutical composition can induce cell cycle arrest in cancer cells, thereby inducing apoptosis.

[0026] According to another embodiment of the present invention, the cancer is selected from one or more of the group consisting of skin cancer, breast cancer, uterine cancer, esophageal cancer, gastric cancer, brain tumor, colon cancer, rectal cancer, colorectal cancer, lung cancer, ovarian cancer, cervical cancer, endometrial cancer, vulvar cancer, kidney cancer, hematologic malignancies, 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, preferably breast cancer, more preferably HER-2 positive breast cancer or triple-negative breast cancer.

[0027] Invention Effects

[0028] This invention relates to a thiobenzimidazole derivative or a pharmaceutically acceptable salt thereof, and compositions containing said derivative as an active ingredient for the prevention or treatment of cancer. The thiobenzimidazole derivative of this invention is activated in cancer cells, inhibits tubulin polymerization, and, when administered to a subject, can block the cancer cell cycle and induce apoptosis, thereby exhibiting cytotoxicity. It can be used for the prevention or treatment of cancer, preferably for the prevention or treatment of HER-2 positive breast cancer or triple-negative breast cancer.

[0029] The effects of this invention are not limited thereto, and those skilled in the art will clearly understand from the following description other effects not mentioned. Attached Figure Description

[0030] Figure 1 The experimental results of treating human breast cancer cell lines MDA-MB-231 and JIMT-1 with thiobenzimidazole derivatives of formulas 1-1 to 1-10 are shown.

[0031] Figure 2 The IC50 values ​​derived from treatment of MDA-MB-231 and JIMT-1 cell lines with the thiobenzimidazole derivatives of the present invention (Formulas 1-1 to 1-4) are shown.

[0032] The best form of implementing an invention

[0033] The inventors of this invention studied thiobenzimidazole derivatives or their pharmaceutically acceptable salts and confirmed that the derivatives have anticancer activity, thereby completing this invention.

[0034] More specifically, the thiobenzimidazole derivative or a pharmaceutically acceptable salt thereof, when activated in cancer cells, can inhibit tubulin polymerization to block the cancer cell cycle and induce apoptosis, thereby exhibiting cytotoxicity.

[0035] Based on the above results, the present invention provides a thiobenzimidazole derivative or a pharmaceutically acceptable salt thereof represented by the following [Formula 1]: [Formula 1] ; In Equation 1, X is selected from either C or N. R 1 It is selected from C3 to C3, whether substituted or unsubstituted. 20 cycloalkyl, substituted or unsubstituted C3 to C4 20 Heterocyclic alkyl groups, substituted or unsubstituted C3 to C4 20 Aryl groups and substituted or unsubstituted C3 to C4 groups 20 Any of the heteroaryl groups If the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is substituted, it is by any one or more substitutions selected from heterocycloalkyl, C1 to C6 alkyl, hydroxyl, alkylacyl, -CF3, and dimethylamino. R 2 It is hydrogen or halogen.

[0036] In this invention, the term "substitution" refers to a reaction in which one atom or group of atoms in a compound molecule is replaced by another atom or group of atoms.

[0037] In this invention, the term "chain-like" refers to a molecule with a chain-like structure. A chain-like structure is a chemical structure in which carbon atoms are connected in a chain-like manner, and can be linear or branched.

[0038] In this invention, the term "cyclic" refers to a ring structure formed by connecting the two ends of an organic compound skeleton.

[0039] In this invention, the term "chain or cyclic alkyl" refers to a monovalent straight-chain, branched, or cyclic saturated hydrocarbon residue having 1 to 20 carbon atoms and consisting only of carbon and hydrogen 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, etc.

[0040] In this invention, the term "heterocyclic alkyl" generally refers to a saturated or unsaturated (but not aromatic) cyclic hydrocarbon, which may optionally be unsubstituted, monosubstituted or polysubstituted, and has at least one heteroatom selected from N, O or S in its structure, preferably any one of piperidine, piperazine or morpholine.

[0041] In this invention, the term "aryl" refers to an unsaturated aromatic ring compound having 3 to 12 carbon atoms, which has a monocyclic ring (e.g., phenyl) or multiple fused rings (e.g., naphthyl). Examples of such aryl groups include, but are not limited to, phenyl, naphthyl, etc.

[0042] In this invention, the term "heteroaryl" refers to a monocyclic or multiple fused rings in which at least one of the atoms constituting the ring is a heteroatom of N, O, or S. Examples of such heteroaryl groups include, but are not limited to, pyridinyl, pyrazinyl, oxazolyl, furanyl, thiophenyl, etc.

[0043] In this invention, the "halogen group" can be fluorine (F), chlorine (Cl), bromine (Br) or iodine (I), etc.

[0044] In this invention, "carbonyl" refers to -C(=O)- group, "sulfonyl" refers to -S(=O)2- group, "sulfonamide" refers to -S(=O)2-NH- group, "acyl" refers to -C(=O)-R group, and "alkylacyl" refers to an acyl group where R is an alkyl group.

[0045] According to a preferred embodiment of the present invention, the compound represented by Formula 1 is preferably one or more selected from the group consisting of the following compounds: [Equation 1-1] ; [Equation 1-2] ; [Equation 1-3] ; [Equations 1-4] ; [Equations 1-5] ; [Equations 1-6] ; [Equations 1-7] ; [Equations 1-8] ; [Equations 1-9] ; [Equation 1-10] .

[0046] The thiobenzimidazole derivative or a pharmaceutically acceptable salt thereof of the present invention has specific activity in cancer cells, can inhibit microtubule polymerization and induce apoptosis, and can be used in pharmaceutical compositions for the prevention or treatment of cancer containing the thiobenzimidazole derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

[0047] In this invention, the term "pharmaceutically acceptable salt" refers to a dosage form of the compound that will not cause severe irritation to the organism administering the compound and will not impair the compound's biological activity and physical properties. Pharmaceutically acceptable salts can be prepared by reacting the compounds of this invention with inorganic acids such as hydrochloric acid, bromic acid, sulfuric acid, nitric acid, and phosphoric acid; sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, and p-toluenesulfonic acid; and organic carboxylic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, decanoic acid, isobutyric acid, malonic acid, succinic acid, phthalic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, and salicylic acid. Furthermore, the compounds of this invention can be prepared by reacting them with a base to form salts of alkali metals such as ammonium, sodium, and potassium salts; salts of alkaline earth metals such as calcium and magnesium salts; salts of organic bases such as dicyclohexylamine, N-methyl-D-glucosamine, and tris(hydroxymethyl)methylamine; and salts of amino acids such as arginine and lysine.

[0048] Furthermore, the thiobenzimidazole derivative or its pharmaceutically acceptable salt includes not only pharmaceutically acceptable salts, but also all salts, hydrates and solvates that can be prepared by conventional methods.

[0049] Furthermore, the present invention can provide a method for the prevention, treatment and / or diagnosis of cancer, comprising the step of administering the thiobenzimidazole derivative or a pharmaceutically acceptable salt thereof to a subject.

[0050] In this invention, the term "prevention" refers to all actions that inhibit or delay the occurrence, spread, or recurrence of cancer by applying the composition of this invention; "treatment" refers to all actions that improve or benefit cancer symptoms by applying the composition of this invention.

[0051] In this invention, the term "pharmaceutical composition" is intended for the prevention or treatment of diseases and can be formulated into various forms for use according to conventional methods. For example, it can be formulated into oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, and syrups, or into external preparations, suppositories, and sterile injections.

[0052] In this invention, "comprising as an active ingredient" means that the content of the ingredient is sufficient or necessary to achieve the desired biological effect. In practical applications, the content of the active ingredient is determined according to the purpose of treating the disease and should not cause other toxicities. For example, it can be varied based on various factors such as the disease or condition being treated, the type of composition being administered, the size of the subject, or the severity of the disease or condition. Those skilled in the art to which this invention pertains can determine the effective content of a single composition empirically without requiring extensive experimentation.

[0053] Furthermore, in addition to the active ingredients of the above-mentioned dosage forms, the pharmaceutical compositions of the present invention may also contain one or more pharmaceutically acceptable carriers.

[0054] The pharmaceutically acceptable carrier may be saline, sterile water, Ringer's solution, buffered saline, glucose solution, maltodextrin solution, glycerol, ethanol, and at least one mixture of these components, and may further include, as needed, other conventional additives such as antioxidants, buffers, and antibacterial agents. Furthermore, diluents, dispersants, surfactants, binders, and lubricants may be added to formulate aqueous solutions, suspensions, emulsions, or other injectable preparations, pills, capsules, granules, or tablets. Additionally, formulation may preferably be carried out using appropriate methods in the art or methods disclosed in Remington's Pharmaceutical Science (Mack Publishing Company, Easton PA) to suit different diseases or ingredients.

[0055] The compositions of the present invention can be administered orally or parenterally in pharmaceutically effective amounts according to desired methods. The term "pharmaceutically effective amount" in the present invention refers to a content that can adequately treat a disease without causing side effects within a reasonable benefit / risk ratio of applicable drug treatment. The level of the effective amount can be determined based on many factors as well as other factors known in the medical field. Factors to be considered may include the patient's health status, disease severity, drug activity, drug sensitivity, method of administration, time of administration, route of administration and excretion rate, treatment duration, and drugs taken in combination or concurrently.

[0056] Furthermore, the pharmaceutical compositions of the present invention can be administered to subjects to prevent, treat, and / or diagnose cancers, including skin cancer, breast cancer, uterine cancer, esophageal cancer, gastric cancer, brain tumors, colon cancer, rectal cancer, colorectal cancer, lung cancer, ovarian cancer, cervical cancer, endometrial cancer, vulvar cancer, kidney cancer, hematologic malignancies, pancreatic cancer, prostate cancer, testicular cancer, laryngeal cancer, head and neck cancer, thyroid cancer, liver cancer, bladder cancer, osteosarcoma, lymphoma, hematologic malignancies, thymic cancer, urethral cancer, or bronchial cancer, preferably cancers with acidity higher than normal cells and whose cytotoxicity can be inhibited by microtubule polymerization inhibitors. Non-limiting examples include breast cancer, preferably HER-2 positive breast cancer or triple-negative breast cancer.

[0057] In this invention, the term "subject" can be any mammal, such as livestock or humans, that requires prevention, treatment, and / or diagnosis of cancer, without particular limitation, but is preferably human.

[0058] The pharmaceutical compositions of the present invention can be formulated into various dosage forms for administration to subjects. A representative parenteral dosage form is an injectable dosage form, preferably an isotonic aqueous solution or suspension. Injectable dosage forms can be prepared using suitable dispersants or wetting agents and suspending agents according to techniques known in the art. For example, the components can be dissolved in physiological saline or buffer solution to prepare an injection. Furthermore, dosage forms for oral administration include ingestible tablets, sublingual tablets, lozenges, capsules, elixirs, suspensions, syrups, and rice paper capsules, etc. These dosage forms, in addition to the active ingredient, may include diluents (e.g., lactose, glucose, sucrose, mannitol, sorbitol, cellulose, and / or glycine) and lubricants (e.g., silica, talc, stearic acid and its magnesium or calcium salts, and / or polyethylene glycol). The tablets may contain binders such as magnesium aluminum silicate, starch paste, gelatin, astragalus gum, methylcellulose, sodium carboxymethyl cellulose, and / or polyvinylpyrrolidone, and may further include disintegrants, absorbents, colorants, flavoring agents, and / or sweeteners such as starch, agar, alginate, or their sodium salts. The formulation can be prepared by conventional mixing, granulation, or coating methods.

[0059] Furthermore, the pharmaceutical composition of the present invention may also include preservatives, hydrating agents, emulsification promoters, salts or buffers for controlling osmotic pressure, and other substances that can be used for treatment, and may be formulated according to conventional methods.

[0060] The pharmaceutical compositions of the present invention can be administered via various routes, including oral, transdermal, subcutaneous, intravenous, or intramuscular administration. The appropriate dosage of the active ingredient can be determined based on factors such as the route of administration, the patient's age, sex, weight, and disease severity. Furthermore, the compositions of the present invention can be used in combination with known compounds that can enhance the desired effect.

[0061] The pharmaceutical compositions according to the present invention can be administered to humans or animals via oral administration or parenteral administration, such as intravenous, subcutaneous, intranasal, or intraperitoneal administration. Oral administration also includes sublingual administration. Parenteral administration includes injection methods such as subcutaneous injection, intramuscular injection, and intravenous injection, as well as infusion methods.

[0062] In the pharmaceutical compositions of the present invention, the total effective amount of the thiobenzimidazole derivative or a pharmaceutically acceptable salt thereof can be administered to the patient via a single dose or via a fractionated treatment protocol with multiple doses over a prolonged period. The content of the active ingredient in the pharmaceutical compositions of the present invention can be varied according to the severity of the disease, but generally, based on an adult, the effective dose per administration can be from 100 μg to 3000 mg, administered multiple times a day. However, the concentration of the thiobenzimidazole derivative or a pharmaceutically acceptable salt thereof depends on various factors, such as the patient's age, weight, health status, sex, disease severity, diet, and excretion rate, and these factors can be taken into account when determining the patient's dosage.

[0063] Furthermore, as long as the pharmaceutical composition of the present invention achieves the effects of the present invention, there are no particular limitations on its dosage form, route of administration, or method of administration. In addition to the thiobenzimidazole derivative or its pharmaceutically acceptable salt as the active ingredient, the pharmaceutical composition of the present invention may further include known anticancer agents and may be used in combination with other known treatment methods.

[0064] The terminology used in the embodiments is for illustrative purposes only and is not intended to limit the scope. Unless the context clearly indicates that they have different meanings, the singular form encompasses the plural form. In this specification, terms such as "comprising" or "having" are used to express the presence of the features, numbers, steps, operations, constituent elements, accessories, or combinations thereof described in the specification, and do not exclude the possibility of the presence or additional addition of one or more other features, numbers, steps, operations, constituent elements, accessories, or combinations thereof.

[0065] Unless otherwise defined, all terms used herein, including technical or scientific terms, shall have their ordinary meanings as understood by one of ordinary skill in the art. Terms commonly used, such as those defined in dictionaries, shall be understood as having their meanings in the relevant technical context and shall not be interpreted as idealized or overly formalized meanings unless explicitly defined in this specification.

[0066] This invention can be modified in many ways and has many implementations. Specific embodiments are illustrated with reference to the accompanying drawings and are described in detail below. However, this specification is not intended to limit the invention to specific embodiments, but rather to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the invention. In describing exemplary embodiments, detailed descriptions of well-known structures or functions are omitted where it is determined that such detailed descriptions would unnecessarily obscure this disclosure.

[0067] Methods of implementing the present invention

[0068] Preparation Example. Synthesis of Methyl (5-(phenylthio)-1H-benzo[d]imidazol-2-yl)carbamate derivative.

[0069] The compounds of the present invention are prepared by the reaction shown in the following reaction formula:

[0070] 1-1. Synthesis of methyl (5-((4-(4-morpholinopiperidin-1-yl)phenyl)thio)-1H-benzo[d]imidazol-2-yl)carbamate 5 (Formula 1-1)

[0071] Add 1,3-bis(methoxycarbonyl)-S-methylisothiourea (2.5 eq) to a 5% acetic acid in EtOH solution of 4-((4-morpholinopiperidin-1-yl)phenyl)thio)benzene-1,2-diamine (0.241 g, 1.07 mmol), heat the mixture and stir at 90 °C for 20 hours, then remove the solvent by evaporation under reduced pressure.

[0072] The reactants were cooled thoroughly and placed at room temperature to form a solid, which was then filtered and washed with MeOH. The washing continued with MeOH until the sulfurous odor of the remaining urea was completely removed. After drying, 0.250 g of methyl 5-((4-(4-morpholinopiperidin-1-yl)phenyl)thio)-1H-benzo[d]imidazol-2-yl)carbamate was obtained as a white solid.

[0073] Yield 85%

[0074] 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)

[0075] 1-2. Synthesis of (5-((3-fluoro-4-morpholinophenyl)thio)-1H-benzo[d]imidazol-2-yl)carbamate (Formula 1-2)

[0076] 1,3-bis(methoxycarbonyl)-S-methylisothiourea (2.5 eq) was added to a 5% acetic acid in EtOH solution of 4-((3-fluoro-4-morpholinophenyl)thio)benzene-1,2-diamine (0.230 g, 0.72 mmol). The mixture was heated and stirred at 90 °C for 5 hours, followed by evaporation under reduced pressure to remove the solvent.

[0077] The reactants were cooled thoroughly and placed at room temperature to form a solid, which was then filtered and washed with MeOH. The mixture was then washed with MeOH until the sulfurous odor of the remaining urea was completely removed. After drying, a white solid (5-((3-fluoro-4-morpholinophenyl)thio)-1H-benzo[d]imidazol-2-yl)carbamate (0.230 g) was obtained.

[0078] Yield 79%

[0079] 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), 1-3. Synthesis of (5-((3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)thio)-1H-benzo[d]imidazol-2-yl)carbamate (Formula 1-3) 1,3-bis(methoxycarbonyl)-S-methylisothiourea (0.234 g, 1.13 mmol) was added to a 5% acetic acid in EtOH solution of 4-((3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)thio)benzene-1,2-diamine (0.150 g, 0.45 mmol), the mixture was heated and stirred at 90 °C for 5 hours, and then the solvent was removed by evaporation under reduced pressure.

[0080] The reactants were cooled thoroughly and placed at room temperature to form a solid, which was then filtered and washed with MeOH. The washing continued with MeOH until the sulfurous odor of the remaining urea was completely removed. Separation was performed by silica gel column chromatography using chloromethane and methanol (9:1, v / v) as the developing solvent. After drying, a white solid (0.110 g) of methyl 5-((3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)thio)-1H-benzo[d]imidazol-2-yl)carbamate was obtained.

[0081] Yield 59%

[0082] 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)

[0083] 1-4. Synthesis of (5-((6-(4-hydroxypiperidin-1-yl)pyridin-3-yl)thio)-1H-benzo[d]imidazol-2-yl)carbamate (Formula 1-4)

[0084] 1-(5-((3,4-diaminophenyl)thio)pyridin-2-yl)piperidin-4-ol (1-(5-((3,4-diaminophenyl)thio)pyridin-2-yl)piperidin-4-ol) and 1,3-bis(methoxycarbonyl)-S-methylisothiourea were reacted according to the above method to obtain methyl (5-((6-(4-hydroxypiperidin-1-yl)pyridin-3-yl)thio)-1H-benzo[d]imidazol-2-yl)carbamate.

[0085] Yield 84%

[0086] 1H 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)

[0087] 1-5. Synthesis of (5-((4-(4-isobutyrylpiperazin-1-yl)phenyl)thio)-1H-benzo[d]imidazol-2-yl)carbamate (Formula 1-5)

[0088] 1-(4-(4-((3,4-diaminophenyl)thio)phenyl)piperazin-1-yl)-2-methylpropan-1-one (1-(4-(4-((3,4-diaminophenyl)thio)phenyl)piperazin-1-yl)-2-methylpropan-1-one) and 1,3-bis(methoxycarbonyl)-S-methylisothiourea were reacted according to the above method to obtain methyl (5-((4-(4-isobutyrylpiperazin-1-yl)phenyl)thio)-1H-benzo[d]imidazol-2-yl)carbamate.

[0089] Yield 74%

[0090] 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)

[0091] 1-6. Synthesis of (5-((4-(4-isobutyryl-3,5-dimethylpiperazin-1-yl)phenyl)thio)-1H-benzo[d]imidazol-2-yl)carbamate (Formula 1-6)

[0092] 1-(4-(4-((3,4-diaminophenyl)thio)phenyl)-2,6-dimethylpiperazin-1-yl)-2-methylpropan-1-one (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 according to the above method to obtain methyl (5-((4-(4-isobutyryl-3,5-dimethylpiperazin-1-yl)phenyl)thio)-1H-benzo[d]imidazol-2-yl)carbamate.

[0093] Yield 87%

[0094] 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)

[0095] 1-7. Synthesis of methyl(5-((4-(1-methylpiperidin-4-yl)phenyl)thio)-1H-benzo[d]imidazol-2-yl)carbamate (Formula 1-7)

[0096] 4-((4-(1-methylpiperidin-4-yl)phenyl)thio)benzene-1,2-diamine and 1,3-bis(methoxycarbonyl)-S-methylisothiourea were reacted according to the above method to obtain methyl (5-((4-(1-methylpiperidin-4-yl)phenyl)thio)-1H-benzis[d]imidazol-2-yl)carbamate.

[0097] Yield 61%

[0098] 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)

[0099] 1-8. Synthesis of (5-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)thio)-1H-benzo[d]imidazol-2-yl)carbamate (Formula 1-8)

[0100] 4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)thio)benzene-1,2-diamine (4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)thio)benzene-1,2-diamine) and 1,3-bis(methoxycarbonyl)-S-methylisothiourea were reacted according to the above method to obtain methyl (5-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)thio)-1H-benzis[d]imidazol-2-yl)carbamate.

[0101] Yield 68%

[0102] 1H 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)

[0103] 1-9. Synthesis of methyl(5-((4-(4-(dimethylamino)piperidin-1-yl)phenyl)thio)-1H-benzo[d]imidazol-2-yl)carbamate (Formula 1-9)

[0104] 4-((4-(4-(dimethylamino)piperidin-1-yl)phenyl)thio)benzene-1,2-diamine (4-((4-(4-(dimethylamino)piperidin-1-yl)phenyl)thio)benzene-1,2-diamine) and 1,3-bis(methoxycarbonyl)-S-methylisothiourea were reacted according to the above method to obtain methyl (5-((4-(4-(dimethylamino)piperidin-1-yl)phenyl)thio)-1H-benzis[d]imidazol-2-yl)carbamate.

[0105] Yield 73%

[0106] 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)

[0107] 1-10. Synthesis of (5-((3-fluoro-4-(thiophen-3-yl)phenyl)thio)-1H-benzo[d]imidazol-2-yl)carbamate (Formula 1-10)

[0108] 4-((3-fluoro-4-(thiophen-3-yl)phenyl)thio)benzene-1,2-diamine and 1,3-bis(methoxycarbonyl)-S-methylisothiourea were reacted according to the above method to obtain methyl (5-((3-fluoro-4-(thiophen-3-yl)phenyl)thio)-1H-benzis[d]imidazol-2-yl)carbamate.

[0109] Yield 83%

[0110] 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)

[0111] 1-11. Synthesis of (5-((6-(4-hydroxypiperidin-1-yl)pyridin-3-yl)thio)-1H-benzo[d]imidazol-2-yl)carbamate hydrochloride salt (hydrochloride salts of formulas 1-4)

[0112] Hydrogen chloride gas was injected at 2-minute intervals into a methanol (35 mL) 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) until the pH dropped below 1. The reaction mixture was evaporated under reduced pressure to give an oily product, which was then immediately dissolved in isopropanol (IPA, 20 mL) and cooled to room temperature to obtain a solid suspension. Isopropyl ether (20 mL) was added in portions while stirring for 2 hours, followed by filtration. The mixture was washed with a mixture of isopropanol and isopropyl ether (IPE), dried in hot air at 50 °C for 1 hour, and then dried under vacuum at 40 °C for 2 hours to give a white solid (90 mg).

[0113] Yield 82%

[0114] 1H NMR (D2O, 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).

[0115] Example 1. Confirmation of the cell viability of breast cancer cell lines by thiobenzimidazole derivatives.

[0116] This experiment used MDA-MB-231, a human triple-negative breast cancer (TNBC) cell line (cell seeding rate: 0.8 (M231) x 10⁻⁶). 4 Cells / well (confluence ≥ 25%) and JIMT-1 as a HER2-positive breast cancer (HER2+BC) cell line (cell seeding density: 0.8 (JIMT) x 10⁻⁶). 4 Cells / well (confluence ≥ 25%).

[0117] The cell lines were cultured at 5% CO2 and 37°C in Dulbecco's modified Eagle's medium (DMEM) containing 10% fetal bovine serum (FBS), streptomycin-penicillin (100 U / mL), and fungizone (0.625 μg / mL).

[0118] The human breast cancer cell lines MDA-MB-231 and JIMT-1 were treated with thiobenzimidazole derivatives of formulas 1-1 to 1-10 at concentrations of 0, 0.5, 1, and 5 μM, respectively, for 72 hours. Cell viability was then determined using the MTS assay. The MTS assay method was as follows: Cells were seeded in 96-well plates and adhered for 24 hours. After treatment with the thiobenzimidazole derivatives for 72 hours, the cells were developed with MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazole) for 4 hours. The absorbance was then measured at 490 nm using a Spectramax Plus 384 microplate analyzer. The results are shown below. Figure 1 As shown in the accompanying drawings, it can be confirmed that the thiobenzimidazole derivatives of formulas 1-1 to 1-10 exhibit a concentration-dependent inhibitory effect on the cell survival of human breast cancer cell lines MDA-MB-231 and JIMT-1.

[0119] Example 2. Confirmation of the cell viability and IC50 of thiobenzimidazole derivatives against breast cancer cell lines. 50 value

[0120] MDA-MB-231 and JIMT-1 cell lines were treated with the thiobenzimidazole derivatives of the present invention (formulas 1-1 to 1-4) at concentrations of 0, 0.01, 0.05, 0.1, 0.25, 0.5, 1, 5, and 10 μM, respectively, and cell viability and IC50 values ​​were confirmed. The cell line preparation method and experimental methods were the same as in Example 1. The results are as follows. Figure 2 As shown, the IC50 values ​​of thiobenzimidazole derivatives of formulas 1-1 to 1-4 in the MDA-MB-231 cell line were confirmed. 50 The values ​​were 0.592 μM, 0.174 μM, 0.583 μM, and 0.135 μM, respectively, indicating low IC50 values. 50 value.

[0121] The embodiments have been described above with reference to the accompanying drawings. Those skilled in the art should understand that various modifications and equivalent embodiments can be implemented based on these drawings. Suitable results can also be obtained if the described techniques are performed in a different order, and / or if the constituent elements of the described systems, architectures, devices, or circuits are combined in different ways, and / or replaced or substituted by other components or their equivalents.

[0122] Therefore, other embodiments, examples, and equivalents of the claims should be interpreted as being included within the scope of protection of the claims.

Claims

1. A thiobenzimidazole derivative or a pharmaceutically acceptable salt thereof represented by the following [Formula 1]: [Formula 1] ； In Equation 1, X is selected from either C or N. R 1 It is selected from C3 to C3, whether substituted or unsubstituted. 20 cycloalkyl, substituted or unsubstituted C3 to C4 20 Heterocyclic alkyl groups, substituted or unsubstituted C3 to C4 20 Aryl groups and substituted or unsubstituted C3 to C4 groups 20 Any of the heteroaryl groups If the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is substituted, it is by any one or more substitutions selected from heterocycloalkyl, C1 to C6 alkyl, hydroxyl, alkylacyl, -CF3, and dimethylamino. R 2 It is hydrogen or halogen.

2. The thiobenzimidazole derivative or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, In the above [Equation 1], R 1 It is selected from any one of the group consisting of substituted or unsubstituted piperidine, substituted or unsubstituted morpholine, substituted or unsubstituted piperazine, and substituted or unsubstituted thiophene. If the piperidine, morpholine, piperazine, or thiophene is substituted, it is substituted by one or more of the following: morpholino, methyl, hydroxy, isobutyryl, -CF3, and dimethylamino.

3. The thiobenzimidazole derivative or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, The thiobenzimidazole derivative represented by [Formula 1] is selected from any one of the following groups of compounds: [Equation 1-1] ； [Equation 1-2] ； [Equation 1-3] ； [Equations 1-4] ； [Equations 1-5] ； [Equations 1-6] ； [Equations 1-7] ； [Equations 1-8] ； [Equations 1-9] ； [Equation 1-10] 。 4. The thiobenzimidazole derivative or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, The thiobenzimidazole derivative represented by [Formula 1] is selected from any one of the following groups of compounds: [Equation 1-1] ； [Equation 1-2] ； [Equation 1-3] ； [Equations 1-4] 。 5. The thiobenzimidazole derivative or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, The thiobenzimidazole derivative inhibits microtubule polymerization.

6. The thiobenzimidazole derivative or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, The pharmaceutically acceptable salt of the thiobenzimidazole derivative is selected from any one or more of the group consisting of hydrochloride, bromate, sulfate, phosphate, nitrate, citrate, acetate, lactate, tartrate, maleate, gluconate, succinate, formate, trifluoroacetate, oxalate, fumarate, glutarate, adipate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, camphorsulfonate, sodium salt, potassium salt, lithium salt, calcium salt, and magnesium salt.

7. The thiobenzimidazole derivative or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, The pharmaceutically acceptable salt of the thiobenzimidazole derivative is a hydrochloride salt.

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

9. The pharmaceutical composition for preventing or treating cancer according to claim 8, characterized in that, The pharmaceutical composition induces apoptosis by causing cell cycle arrest in cancer cells.

10. The pharmaceutical composition for preventing or treating cancer according to claim 8, characterized in that, The cancer is selected from any one or more of the following groups: skin cancer, breast cancer, uterine cancer, esophageal cancer, stomach cancer, brain tumor, colon cancer, rectal cancer, colorectal cancer, lung cancer, ovarian cancer, cervical cancer, endometrial cancer, vulvar cancer, kidney cancer, hematologic malignancies, pancreatic cancer, prostate cancer, testicular cancer, laryngeal cancer, head and neck cancer, thyroid cancer, liver cancer, bladder cancer, osteosarcoma, lymphoma, hematologic malignancies, thymic cancer, urethral cancer, and bronchial cancer.

11. The pharmaceutical composition for preventing or treating cancer according to claim 8, characterized in that, The cancer in question is either HER-2 positive breast cancer or triple-negative breast cancer.

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