KR20230169573A - Benzimidazole derivatives, preparation method thereof, and pharmaceutical composition for the prevention or treatment of cancer or infectious diseases containing the same as an active ingredient - Google Patents

Abstract

The present invention relates to a benzimidazole derivative, a method for producing the same, and a pharmaceutical composition containing the same as an active ingredient for the prevention or treatment of cancer or infection. The compound represented by Formula 1 described herein has excellent inhibition against cancer cell lines. It is expected to be useful as a treatment for cancer and parasitic infections due to its effectiveness and inhibition of parasite invasion and infection.

Description

Benzimidazole derivatives, preparation method thereof, and pharmaceutical composition for the prevention or treatment of cancer or infectious diseases containing the same as an active ingredient as an active ingredient}

The present invention relates to a novel benzimidazole derivative, a method for producing the same, and a pharmaceutical composition for preventing or treating cancer or infectious diseases containing the same as an active ingredient.

Worldwide, millions of people suffer from bone, bladder, blood (leukemia), brain, breast, colon, cervix, esophagus, intestines, kidneys, lungs, liver, mouth, nasal cavity, nerves, ovaries, pancreas, skin, stomach, prostate, neck, and uterus. , die from a variety of cancers, including vaginal ones. Over the years, several methods, including radiation and chemotherapy, have been used to treat cancer, but the number of cancer patients is still increasing.

Accordingly, the present inventors completed the present invention by confirming that the novel benzimidazole derivative had excellent anticancer effect. In addition, we invented a new benzimidazole derivative that improved the pharmacokinetic properties of existing benzimididazole-based compounds such as fenbendazole, mebendazole, and oxybendazole, which were used as anthelmintics, and developed systemic hookworm infections that are difficult to treat with existing anthelmintics. We want to expand the scope of its use as a treatment.

One object of the present invention is to provide novel benzimidazole derivatives.

Another object of the present invention is to provide a method for producing novel benzimidazole derivatives.

Another object of the present invention is to provide a pharmaceutical composition for preventing or treating cancer or infectious diseases.

Another object of the present invention is to provide a health functional food for preventing or improving cancer or infectious diseases.

In order to achieve the above purpose,

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

[Formula 1]

In Formula 1,

A is O or CH ₂ ;

R ¹ is C1-C5 alkyl;

R ² is hydrogen or halogen;

R ³ is C1-C5 alkyl.

In another aspect, the present invention is as shown in Scheme 1 below,

Provided is a method for producing a compound represented by Formula 1, which includes preparing a compound represented by Formula 1 by reacting a compound represented by Formula 2 with a compound represented by Formula 3.

[Scheme 1]

In Scheme 1 above,

A, R ¹ , R ² and R ³ are as defined in Formula 1 of Clause 1.

In another aspect, the present invention provides a method for preventing or treating cancer or infectious diseases, comprising a compound represented by Formula 1 described herein, a tautomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. Provides a pharmaceutical composition for use.

In another aspect, the present invention provides a method for preventing cancer or infectious diseases, containing a compound represented by Formula 1 described herein, a tautomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. We provide health functional foods for improvement.

The compound represented by Formula 1 described herein is expected to be useful as a treatment for cancer and parasitic infections by exhibiting an excellent inhibitory effect on cancer cell lines and an inhibitory effect on parasite invasion and infection.

Hereinafter, the present invention will be described in detail.

Meanwhile, the embodiments of the present invention may be modified into various other forms, and the scope of the present invention is not limited to the embodiments described below. Additionally, the embodiments of the present invention are provided to more completely explain the present invention to those with average knowledge in the relevant technical field.

Furthermore, “including” a certain element throughout the specification means that other elements may be further included, rather than excluding other elements, unless specifically stated to the contrary.

The terms “alkylene”, “alkenyl” or “alkyl” include straight or branched chain hydrocarbon moieties, unless otherwise specified. For example, “C1-C5alkyl” means alkyl with a skeleton of 1 to 5 carbons. Specifically, C1-C5 alkyl is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, sec-pentyl, neopentyl, etc. may include.

One embodiment of the present invention,

Provided is a compound represented by the following formula (1), a tautomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

[Formula 1]

In Formula 1,

A is O or CH ₂ ;

R ¹ is C1-C5 alkyl;

R ² is hydrogen or halogen;

R ³ is C1-C5 alkyl.

One embodiment of the present invention,

In Formula 1,

A is O or CH ₂ ;

R ¹ is C1-C2alkyl;

R ² is hydrogen or halogen;

R ³ provides a compound wherein C1-C4alkyl, a tautomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

One embodiment of the present invention,

The compound represented by Formula 1 provides a compound selected from the group of compounds below, a tautomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

<1> N-(6-propoxy-1H-benzo[d]imidazol-2-yl)propionamide;

<2> N-(6-butoxy-1H-benzo[d]imidazol-2-yl)acetamide;

<3> N-(6-butoxy-1H-benzo[d]imidazol-2-yl)propionamide;

<4> N-(5-fluoro-6-propoxy-1H-benzo[d]imidazol-2-yl)acetamide;

<5> N-(5-fluoro-6-propoxy-1H-benzo[d]imidazol-2-yl)propionamide;

<6> N-(5-chloro-6-propoxy-1H-benzo[d]imidazol-2-yl)acetamide;

<7> N-(5-chloro-6-propoxy-1H-benzo[d]imidazol-2-yl)propionamide;

<8> N-(6-butoxy-5-fluoro-1H-benzo[d]imidazol-2-yl)propionamide;

<9> N-(6-butoxy-5-fluoro-1H-benzo[d]imidazol-2-yl)acetamide;

<10> N-(6-butoxy-5-chloro-1H-benzo[d]imidazol-2-yl)propionamide;

<11> N-(6-butoxy-5-chloro-1H-benzo[d]imidazol-2-yl)acetamide; and

<12> N-(6-butyl-1H-benzo[d]imidazol-2-yl)propionamide.

One embodiment of the present invention,

As shown in Scheme 1 below,

Provided is a method for producing a compound represented by Formula 1, which includes preparing a compound represented by Formula 1 by reacting a compound represented by Formula 2 with a compound represented by Formula 3.

[Scheme 1]

In Scheme 1 above,

A, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and Z are as defined in Formula 1 of claim 1.

One embodiment of the present invention,

Provided is a pharmaceutical composition for the prevention or treatment of cancer or infection, containing the compound represented by Formula 1, a tautomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

The above cancers include pseudomyxoma, intrahepatic biliary tract cancer, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, oral cavity cancer, mycosis fungoides, acute myeloid leukemia, acute lymphocytic leukemia, basal cell carcinoma, Ovarian epithelial cancer, ovarian germ cell cancer, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, biliary tract cancer, colon cancer, chronic myeloid leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, ampulla of Vater cancer, bladder cancer, peritoneal cancer. , parathyroid cancer, adrenal cancer, sinonasal cancer, non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, pediatric brain cancer, pediatric lymphoma, childhood leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, renal pelvis cancer, kidney cancer, heart cancer, Duodenal cancer, malignant soft tissue cancer, malignant bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureteral cancer, urethral cancer, cancer of unknown primary site, gastric lymphoma, stomach cancer, gastric carcinoid, gastrointestinal stromal cancer, Wilms Breast cancer, breast cancer, sarcoma, penile cancer, pharynx cancer, gestational trophoblastic disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoid, vaginal cancer, spinal cancer, acoustic neuroma A group consisting of pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsillar cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, lung squamous cell carcinoma, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleura cancer, and thymic cancer. It may be one or more types selected from.

The infection may be an infection caused by parasites. Animals, including domestic animals such as cats and dogs, and humans are susceptible to parasitic infections/infestations. These parasites may be ectoparasites and endoparasites such as filarial parasites and other larvae. The present invention can be used to control or treat ectoparasites and endoparasites in animals, and to prevent or treat parasite invasion and infection in animals.

Animals and humans also suffer from endoparasitic infestations, including, for example, helminthiasis, which is most often caused by a group of parasites classified as tapeworms (tapeworms), nematodes (roundworms) and trematodes (flatworms or flukes). These parasites negatively affect the nutritional status of animals and cause serious economic losses in pigs, sheep, horses and cattle, as well as affecting livestock and poultry. Other parasites that occur in the gastrointestinal tract of animals and humans include hookworms, hookworms, roundworms, glandular worms, trichinella, Trichinella, Toxocara, Toxascaris, whipworms, pinworms, and parasites found in the blood or other tissues and organs, such as filarial and extraintestinal stages. Includes T. nematodes, Toxocara, and Trichinella.

In addition, by using the new benzimidazole derivative of the present invention with improved pharmacokinetic properties, it is used to treat systemic infectious diseases such as brain-eating amoeba, which eats brain cells that are difficult to treat with existing anthelmintics and causes death, and acanthomaeba, which causes keratitis. Improvement of treatment effect can be expected.

In the present invention, the term “containing as an active ingredient” means containing in a dosage range that brings about the effect of preventing, improving, or treating cancer or infectious diseases, and the dosage range may vary depending on the severity and formulation. , the number of applications may also vary depending on the age, weight, and constitution of the subject.

The pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount.

In the present invention, the term “pharmaceutically effective amount” means an amount sufficient to treat a disease with a reasonable benefit/risk ratio applicable to medical treatment or improvement, and the effective dose level is determined by the type and severity of the individual, age, It can be determined based on factors including gender, drug activity, sensitivity to the drug, time of administration, route of administration and excretion rate, duration of treatment, concurrently used drugs, and other factors well known in the medical field. For example, effective amounts of 0.001 mg/kg to 100 mg/kg, 0.01 mg/kg to 10 mg/kg, or 0.1 mg/kg to 1 mg/kg are included. The upper quantitative limit of the pharmaceutical composition of the present invention can be selected and implemented by a person skilled in the art within an appropriate range.

The pharmaceutical composition according to the present invention may contain an effective amount of the compound represented by Formula 1 alone or may include one or more pharmaceutically acceptable carriers, excipients, or diluents.

The pharmaceutically acceptable carrier, excipient, or diluent refers to a substance that is physiologically acceptable and does not typically cause gastrointestinal upset, allergic reactions such as dizziness, or similar reactions when administered to humans. Examples of the carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, Examples include, but are not limited to, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil. In addition, fillers, anti-coagulants, lubricants, wetting agents, fragrances, emulsifiers and preservatives may be additionally included.

The compound represented by Formula 1 or a pharmaceutically acceptable salt thereof may be administered in various oral and parenteral dosage forms during clinical administration. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc. These solid preparations contain one or more compounds and at least one excipient, such as starch, calcium carbonate, sucrose, or lactose ( It is prepared by mixing lactose, gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspensions, oral solutions, emulsions, and syrups. In addition to the commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. there is. Preparations for parenteral administration include sterilized aqueous solutions, non-aqueous solvents, suspensions, and emulsions. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable esters such as ethyl oleate.

A pharmaceutical composition containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient can be administered parenterally, and parenteral administration can be done by subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection. It depends on how you do it.

At this time, in order to formulate a formulation for parenteral administration, the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof is mixed with water along with a stabilizer or buffer to prepare a solution or suspension, which is administered in ampoule or vial unit dosage form. It can be manufactured with The composition may be sterilized and/or contain auxiliaries such as preservatives, stabilizers, wetting agents or emulsification accelerators, salts and/or buffers for adjusting osmotic pressure, and other therapeutically useful substances, and may be mixed, granulated, etc. using conventional methods. It can be formulated according to the coating or coating method.

In the present invention, the term “prevention” refers to the prevention of cancer by suppressing or blocking the symptoms of cancer or infectious disease by administering, ingesting, or applying the pharmaceutical composition or health functional food of the present invention to an individual who is not suffering from cancer or infectious disease. Or, it means preventing symptoms of infection from occurring in advance.

In the present invention, the term “treatment” includes complete cure of symptoms of cancer or infectious disease as well as partial cure, improvement, and relief of symptoms of cancer or infectious disease as a result of administering the pharmaceutical composition of the present invention to an individual suffering from cancer.

Furthermore, the compound represented by Formula 1 can be used not only in the form of its pharmaceutically acceptable salt, but also in the form of tautomers, solvates, hydrates, etc. that can be prepared therefrom.

The term “isomer” refers to a compound of the present invention or a salt thereof that has the same chemical or molecular formula but is structurally or sterically different. These isomers include structural isomers such as tautomers resulting from changes in the position of the hydrogen atom, and stereoisomers. Stereoisomers include R or S isomers (optical isomers, enantiomers) with an asymmetric carbon center, and geometric isomers. All isomers (trans, cis) are included. In the present invention, tautomers of the compound represented by Formula 1 and mixtures thereof are also included within the scope of the present invention.

The term “hydrate” refers to a compound of the present invention containing a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. or its salt. The hydrate of the compound represented by Formula 1 of the present invention may contain a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. The hydrate may contain more than 1 equivalent of water, preferably 1 to 5 equivalents of water. Such hydrates can be prepared by crystallizing the compound represented by Formula 1 of the present invention, a tautomer, or a pharmaceutically acceptable salt thereof from water or a solvent containing water.

The term “solvate” refers to a compound of the invention or a salt thereof containing a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. Preferred solvents therefor are solvents that are volatile, non-toxic, and/or suitable for administration to humans.

The compound represented by Formula 1 of the present invention can be used in the form of a pharmaceutically acceptable salt, and an acid addition salt formed by a pharmaceutically acceptable free acid is useful as the salt. Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, etc., aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanedio acids. Non-toxic organic acids such as ate, aromatic acids, aliphatic and aromatic sulfonic acids, organic acids such as trifluoroacetic acid, acetate, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid, etc. get These pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, and nitrate. Odide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, sube. Latex, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycol Includes nitrate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, etc.

The acid addition salt according to the present invention can be prepared by conventional methods, for example, the precipitate produced by dissolving the derivative of Formula 1 in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, etc. and adding an organic acid or inorganic acid. It can be prepared by filtering and drying, or by distilling the solvent and excess acid under reduced pressure, drying it, and crystallizing it in an organic solvent.

In addition, pharmaceutical compositions for the prevention or treatment of cancer or infections containing the compound represented by Formula 1, its tautomer, its solvate, its hydrate, or its pharmaceutically acceptable salt as an active ingredient can be administered as an individual therapeutic agent. Alternatively, it can be used in combination with other treatments in use, and the effect can be enhanced by combined administration.

One embodiment of the present invention,

Provided is a health functional food for preventing or improving cancer or infectious diseases, containing the compound represented by Formula 1, a tautomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

In the present invention, the term “improvement” means reducing or alleviating the symptoms of cancer or infectious disease by administering, ingesting, or applying the pharmaceutical composition or food composition of the present invention to an individual suffering from cancer.

The term “health functional food” refers to food manufactured and processed using raw materials or ingredients with functionality useful to the human body in accordance with the Health Functional Food Act, and the term “functional” refers to food that is related to the structure and function of the human body. It means ingestion for the purpose of controlling nutrients or obtaining useful health effects such as physiological effects. The health functional food or health supplement food of the present invention obtained in this way is very useful because it can be consumed on a daily basis.

There is no particular limitation on the type of food, and it includes all health functional foods in the conventional sense.

Matters mentioned in the pharmaceutical composition and health functional food of the present invention apply equally unless they contradict each other.

One embodiment of the present invention is to treat cancer or infectious disease, comprising the step of administering a compound represented by Formula 1 described herein, a tautomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof to a subject in need. Provides a prevention or treatment method.

One embodiment of the present invention is a compound represented by Formula 1 described herein for use in the manufacture of a medicament for use in the prevention or treatment of cancer or infection, a tautomer thereof, a solvate thereof, a hydrate or The use of a pharmaceutically acceptable salt thereof is provided.

For the above method or use, the detailed description of the pharmaceutical composition described above may be applied.

Hereinafter, the present invention will be described in detail through production examples, examples and experimental examples.

However, the following Preparation Examples, Examples and Experimental Examples are merely illustrative of the present invention, and the content of the present invention is not limited to the following Preparation Examples, Examples and Experimental Examples.

[Scheme 1]

<Preparation Example 1> Preparation of 2-nitro-4-propoxyaniline

Lithium hydroxide monohydrate (2.7 g, 64.8 mmol) and n-propyl bromide (4.1 ml, 45.4 mmol) were added to a solution of 4-amino-3-nitrophenol (5.0 g, 32.4 mmol) in ethanol (50 ml). The reaction mixture was then heated at 70°C for 12 hours. After cooling to room temperature, the solvent was removed under reduced pressure and the solution was partitioned into water and ethyl acetate. The organic layer was washed with 1% aqueous lithium hydroxide solution, water and brine, dried over MgSO ₄ , filtered and concentrated. The residue was purified by silica gel flash column chromatography (hexane/ethyl acetate 100/0 -> 60/40) to obtain the desired compound (6.0 g, 94% yield).

^1H NMR (300 MHz, DMSO- d6 ) δ 7.36 (d, J = 2.9 Hz _, 1H), 7.25 (s, 2H), 7.17 (dd, J = 9.2, 3.0 Hz, 1H), 6.99 (d, J = 9.2 Hz, 1H), 3.87 (t, J = 6.5 Hz, 2H), 1.71 (h, J = 13.8, 7.4, 6.5 Hz, 2H), 0.97 (t, J = 7.4 Hz, 3H); MS: 197.3 [M+H ⁺ ].

<Preparation Example 2> Preparation of 4-propoxybenzene-1,2-diamine

Pd/C was added to a solution of 2-nitro-4-propoxyaniline (Preparation Example 1, 1.0 g, 5.10 mmol) in methanol (25 ml). The reaction mixture was then stirred under H ₂ gas at room temperature for 12 hours. Pd/C was filtered through Celite® 545, and the filtrate was concentrated under reduced pressure to obtain the desired compound (847 mg, yield 100%).

^1H NMR (300 MHz, DMSO- d ₆ ) δ 6.40 (d, J = 8.3 Hz, 1H), 6.16 (d, J = 2.8 Hz, 1H), 5.97 (dd, J = 8.3, 2.8 Hz, 1H) , 4.46 (s, 2H), 3.97 (s, 2H), 3.72 (t, J = 6.5 Hz, 2H), 1.64 (h, 2H), 0.94 (t, J = 7.4 Hz, 3H); MS: 167.3 [M+H ⁺ ].

<Preparation Example 3> Preparation of 4-propoxybenzene-1,2-diamine

Pyridine (26 ml) was added to a solution of S-methylisothiourea hemisulfate (9.0 g, 64.6 mmol) in dichloromethane (130 ml), and the mixture was cooled to 0°C in an ice bath. Propionyl chloride (17 ml, 194 mmol) was then added and the reaction mixture was stirred at room temperature for 2 hours before quenched with water (60 ml). The layers were separated and the aqueous layer was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the desired compound (13.0 g, yield 99%).

¹ H NMR (500 MHz, DMSO- d ₆ ) δ 2.43 - 2.30 (m, 4H), 2.27 (s, 3H), 1.05 - 0.96 (m, 6H).

<Example 1> Preparation of N-(6-propoxy-1H-benzo[d]imidazol-2-yl)propionamide

4-propoxybenzene-1,2-diamine (Preparation Example 2, 150 mg, 0.902 mmol) and methyl (Z)-N, N'-dipropionylcarbamidothioate (Preparation Example 3, 219 mg, 1.08 mmol) A mixture of 1,2-dimethoxyethane (3 ml) and methanol (2 ml) was heated at 80°C for 15 hours. After cooling to room temperature, the solvent was removed under reduced pressure. The residue was purified by silica gel flash column chromatography (hexane/ethyl acetate 100/0 -> 80/20) and then recrystallized with diethyl ether to obtain the desired compound (80 mg, yield 36%).

^1H NMR (300 MHz, chloroform- d ) δ 7.37 (d, J = 8.8 Hz, 1H), 6.99 (d, J = 2.3 Hz, 1H), 6.93 (dd, J = 8.8, 2.3 Hz, 1H), 3.95 (t, J = 6.6 Hz, 2H), 2.70 (q, J = 7.6 Hz, 2H), 1.85 (h, J = 6.9 Hz, 2H), 1.32 (t, J = 7.5 Hz, 3H), 1.07 ( t, J = 7.4 Hz, 3H); MS: 248.1 [M+H ⁺ ].

[Scheme 2]

<Preparation Example 4> Preparation of 4-butoxy-2-nitroaniline

The desired compound (yield 86%) was obtained in a similar manner to Preparation Example 1.

^1H NMR (300 MHz, DMSO- d6 ) δ 7.36 (d, J = 2.9 Hz _, 1H), 7.25 (s, 2H), 7.16 (dd, J = 9.2, 3.0 Hz, 1H), 6.99 (d, J = 9.2 Hz, 1H), 3.91 (t, J = 6.4 Hz, 2H), 1.68 (p, J = 8.1, 6.2 Hz, 2H), 1.43 (h, 2H), 0.93 (t, J = 7.4 Hz, 3H); MS: 211.3 [M+H ⁺ ].

<Preparation Example 5> Preparation of 4-butoxybenzene-1,2-diamine

The desired target compound (yield 100%) was obtained in a similar manner to Preparation Example 2.

^1H NMR (500 MHz, DMSO- d6 ) δ 6.40 (d, J = 8.3 Hz, 1H), 6.16 (d, J = 2.7 Hz, 1H), 5.97 (dd _, J = 8.3, 2.7 Hz, 1H) , 4.47 (s, 2H), 3.98 (s, 2H), 3.76 (t, J = 6.5 Hz, 2H), 1.61 (p, J = 8.1, 6.5 Hz, 2H), 1.40 (h, 2H), 0.92 ( t, J = 7.4 Hz, 3H); MS: 181.3 [M+H ⁺ ].

<Preparation Example 6> Preparation of methyl (Z)-N,N'-diacetylcarbamidothioate

The desired compound (yield 89%) was obtained in a similar manner to Preparation Example 3.

¹ H NMR (500 MHz, DMSO- d ₆ ) δ 2.26 (s, 3H), 2.05 (s, 6H).

<Example 2> Preparation of N-(6-butoxy-1H-benzo[d]imidazol-2-yl)acetamide

The desired compound (yield 32%) was obtained in a similar manner to Example 1.

^1H NMR (300 MHz, DMSO- d ₆ ) δ 7.33 (d, J = 8.7 Hz, 1H), 7.01 (d, J = 2.4 Hz, 1H), 6.74 (dd, J = 8.7, 2.4 Hz, 1H) , 3.95 (t, J = 6.4 Hz, 2H), 2.17 (s, 3H), 1.70 (p, J = 8.3, 6.5 Hz, 2H), 1.46 (h, 2H), 0.95 (t, J = 7.4 Hz, 3H); MS: 248.3 [M+H ⁺ ].

[Scheme 3]

<Example 3> Preparation of N-(6-butoxy-1H-benzo[d]imidazol-2-yl)propionamide

The desired compound (yield 30%) was obtained in a similar manner to Example 1.

^1H NMR (300 MHz, DMSO- d6 ) δ 11.85 (s, 1H), 11.38 (s, 1H), _7.29 (d, 1H), 6.97 (s, 1H), 6.69 (d, J = 8.7 Hz, 1H), 3.94 (t, J = 6.4 Hz, 2H), 2.42 (q, J = 7.5 Hz, 2H), 1.69 (p, J = 6.8 Hz, 2H), 1.45 (h, J = 7.4 Hz, 2H) , 1.11 (t, J = 7.5 Hz, 3H), 0.94 (t, J = 7.4 Hz, 3H); MS: 262.3 [M+H ⁺ ].

[Scheme 4]

<Preparation Example 7> Preparation of 4-fluoro-2-nitro-5-propoxyaniline

A mixture of potassium tert-butoxide (9.0 g, 74.7 mmol) and n-propanol (35 ml, 460 mmol) in anhydrous THF (200 ml) was stirred at 0° C. for 30 minutes. A solution of 4,5-difluoro-2-nitroaniline (10.0 g, 57.4 mmol) dissolved in anhydrous THF (50 ml) was added over 30 minutes using a dropping funnel while maintaining the temperature at 0°C. The reaction mixture was heated at 70° C. for 12 hours. After cooling to room temperature, the mixture was partitioned into water and ethyl acetate. The pH was adjusted to 4 by adding 2N HCl while stirring the mixture vigorously at 0°C. The aqueous layer from the separated layers was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (hexane/ethyl acetate 100/0 -> 60/40) to obtain the desired compound (9.8 g, yield 80%).

^1H NMR (300 MHz, chloroform- d ) δ 7.87 (d, J = 11.5 Hz, 1H), 6.21 (d, J = 7.2 Hz, 1H), 6.16 (s, 2H), 4.01 (t, J = 6.6) Hz, 2H), 1.91 (h, J = 7.1 Hz, 2H), 1.08 (t, J = 7.4 Hz, 3H); MS: 215.3 [M+H ⁺ ].

<Preparation Example 8> Preparation of 4-fluoro-5-propoxybenzene-1,2-diamine

Iron powder (6.0 g, 106.4 mmol) and ammonium chloride (5.7 g, 106.4 mmol) were added to a 1:1 THF/H2O (80 ml) solution of 4-fluoro-2-nitro-5-propoxyaniline (3.8 g, 17.7 mmol). mmol) was added. The reaction mixture was heated at 65°C for 3 hours. After cooling to room temperature, iodine and ammonium chloride were filtered through Celite® 545. The layers were separated and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the desired target compound (3.3 g, yield 100%).

^1H NMR (500 MHz, chloroform- d ) δ 6.52 (d, J = 12.0 Hz, 1H), 6.42 (d, J = 8.0 Hz, 1H), 3.92 (t, J = 6.8 Hz, 2H), 3.27 ( s, 4H), 1.80 (h, J = 7.3 Hz, 2H), 1.04 (t, J = 7.5 Hz, 3H); MS: 185.3 [M+H ⁺ ].

<Example 4> Preparation of N-(5-fluoro-6-propoxy-1H-benzo[d]imidazol-2-yl)acetamide

The desired compound (yield 24%) was obtained in a similar manner to Example 1.

^1H NMR (400 MHz, methanol- d ₄ ) δ 7.32 (d, J = 10.6 Hz, 1H), 7.24 (d, J = 7.3 Hz, 1H), 4.05 (t, J = 6.5 Hz, 2H), 2.30 (s, 3H), 1.87 (h, J = 7.0 Hz, 2H), 1.10 (t, J = 7.4 Hz, 3H); MS: 252.5 [M+H ⁺ ].

[Scheme 5]

<Example 5> Preparation of N-(5-fluoro-6-propoxy-1H-benzo[d]imidazol-2-yl)propionamide

The desired compound (yield 40%) was obtained in a similar manner to Example 1.

^1H NMR (300 MHz, DMSO- d ₆ ) δ 11.95 (s, 1H), 11.45 (s, 1H), 7.24 (d, J = 11.5 Hz, 1H), 7.16 (d, J = 7.7 Hz, 1H) , 3.96 (t, J = 6.5 Hz, 2H), 2.43 (q, J = 7.5 Hz, 2H), 1.75 (h, J = 7.1 Hz, 2H), 1.11 (t, J = 7.5 Hz, 3H), 1.00 (t, J = 7.4 Hz, 3H); MS: 266.1 [M+H ⁺ ].

[Scheme 6]

<Preparation Example 9> Preparation of 4-chloro-2-nitro-5-propoxyaniline

The desired compound (yield 40%) was obtained in a similar manner to Preparation Example 7.

^1H NMR (300 MHz, DMSO- d6 ) δ 7.99 (s, 1H), 7.60 (s, 2H), 6.62 ( _s , 1H), 4.01 (t, J = 6.5 Hz, 2H), 1.79 (h, 2H), 1.00 (t, J = 7.4 Hz, 3H); MS: 231.3 [M+H ⁺ ].

<Preparation Example 10> Preparation of 4-chloro-5-propoxybenzene-1,2-diamine

The desired compound (yield 100%) was obtained in a similar manner to Preparation Example 8.

^1H NMR (300 MHz, DMSO- d6 ) δ 6.51 (s, 1H), _6.34 (s, 1H), 4.47 (s, 4H), 3.77 (t, J = 6.5 Hz, 2H), 1.67 (h, 2H), 0.97 (t, J = 7.4 Hz, 3H); MS: 201.2 [M+H ⁺ ].

<Example 6> Preparation of N-(5-chloro-6-propoxy-1H-benzo[d]imidazol-2-yl)acetamide

The desired compound (yield 31%) was obtained in a similar manner to Example 1.

^1H NMR (400 MHz, DMSO- d6 ) δ 7.45 (s, 1H), _7.16 (s, 1H), 3.97 (t, J = 6.4 Hz, 2H), 2.15 (s, 3H), 1.76 (h, 2H), 1.02 (t, J = 7.4 Hz, 3H); MS: 268.2 [M+H ⁺ ].

[Scheme 7]

<Example 7> Preparation of N-(5-chloro-6-propoxy-1H-benzo[d]imidazol-2-yl)propionamide

The desired compound (yield 27%) was obtained in a similar manner to Example 1.

^1H NMR (400 MHz, methanol- d ₄ ) δ 7.63 (s, 1H), 7.24 (s, 1H), 4.07 (t, J = 6.3 Hz, 2H), 2.62 (q, J = 7.5 Hz, 2H) , 1.90 (h, J = 6.9 Hz, 2H), 1.27 (t, J = 7.5 Hz, 3H), 1.13 (t, J = 7.4 Hz, 3H); MS: 282.2 [M+H ⁺ ].

[Scheme 8]

<Preparation Example 11> Preparation of 5-butoxy-4-fluoro-2-nitroaniline

The desired compound (yield 89%) was obtained in a similar manner to Preparation Example 7.

^1H NMR (500 MHz, DMSO- d6 ) δ 7.75 (d, J = 12.1 Hz, 1H), 7.51 (s, 2H), _6.64 (d, J = 7.8 Hz, 1H), 4.06 (t, J = 6.5 Hz, 2H), 1.75 (p, J = 8.5, 6.6 Hz, 2H), 1.44 (h, 2H), 0.95 (t, J = 7.4 Hz, 3H); MS: 229.3 [M+H ⁺ ].

<Preparation Example 12> Preparation of 4-butoxy-5-fluorobenzene-1,2-diamine

The desired target compound (yield 99%) was obtained in a similar manner to Preparation Example 8.

¹ H NMR (500 MHz, DMSO- d ₆ ) δ 6.37 - 6.32 (m, 2H), 4.31 (d, J = 9.1 Hz, 4H), 3.82 (t, J = 6.5 Hz, 2H), 1.62 (p, 2H), 1.41 (h, 2H), 0.92 (t, J = 7.4 Hz, 3H); MS: 199.2 [M+H ⁺ ].

<Example 8> Preparation of N-(6-butoxy-5-fluoro-1H-benzo[d]imidazol-2-yl)propionamide

The desired compound (yield 31%) was obtained in a similar manner to Example 1.

^1H NMR (500 MHz, methanol- d ₄ ) δ 7.25 (d, J = 10.9 Hz, 1H), 7.19 (d, J = 7.5 Hz, 1H), 4.08 (t, J = 6.4 Hz, 2H), 2.55 (q, J = 7.5 Hz, 2H), 1.83 (p, 2H), 1.57 (h, 2H), 1.26 (t, J = 7.5 Hz, 3H), 1.03 (t, J = 7.4 Hz, 3H); MS: 280.2 [M+H ⁺ ].

[Scheme 9]

<Example 9> Preparation of N-(6-butoxy-5-fluoro-1H-benzo[d]imidazol-2-yl)acetamide

The desired compound (yield 21%) was obtained in a similar manner to Example 1.

^1H NMR (300 MHz, methanol- d ₄ ) δ 7.26 (d, J = 10.9 Hz, 1H), 7.20 (d, J = 7.5 Hz, 1H), 4.08 (t, J = 6.4 Hz, 2H), 2.27 (s, 3H), 1.82 (p, 2H), 1.57 (h, J = 7.3 Hz, 2H), 1.03 (t, J = 7.4 Hz, 3H); MS: 266.2 [M+H ⁺ ].

[Scheme 10]

<Preparation Example 13> Preparation of 5-butoxy-4-chloro-2-nitroaniline

The desired target compound (yield 99%) was obtained in a similar manner to Preparation Example 7.

^1H NMR (300 MHz, DMSO- d6 ) δ 7.99 (s, 1H), _7.59 (s, 2H), 6.62 (s, 1H), 4.05 (t, J = 6.4 Hz, 2H), 1.75 (p, J = 8.5, 6.5 Hz, 2H), 1.46 (h, 2H), 0.95 (t, J = 7.4 Hz, 3H); MS: 245.4 [M+H ⁺ ].

<Preparation Example 14> Preparation of 4-butoxy-5-chlorobenzene-1,2-diamine

The desired target compound (yield 99%) was obtained in a similar manner to Preparation Example 8.

^1H NMR (500 MHz, DMSO- d6 ) δ 6.51 (s, 1H), 6.35 (s, 1H), _4.51 (s, 4H), 3.82 (t, 2H), 1.64 (p, 2H), 1.43 ( h, 3H), 0.93 (t, 4H); MS: 215.3 [M+H ⁺ ].

<Example 10> Preparation of N-(6-butoxy-5-chloro-1H-benzo[d]imidazol-2-yl)propionamide

The desired compound (yield 26%) was obtained in a similar manner to Example 1.

^1H NMR (500 MHz, methanol- d ₄ ) δ 7.61 (s, 1H), 7.23 (s, 1H), 4.11 (t, J = 6.3 Hz, 2H), 2.62 (q, J = 7.5 Hz, 2H) , 1.86 (p, J = 7.9, 6.3 Hz, 2H), 1.60 (h, 2H), 1.27 (t, J = 7.5 Hz, 3H), 1.04 (t, J = 7.4 Hz, 3H); MS: 296.2 [M+H ⁺ ].

[Scheme 11]

<Example 11> Preparation of N-(6-butoxy-5-chloro-1H-benzo[d]imidazol-2-yl)acetamide

The desired compound (yield 41%) was obtained in a similar manner to Example 1.

^1H NMR (300 MHz, DMSO- d- ₆ ) δ 11.95 (d, J = 12.3 Hz, 1H), 11.53 (d, J = 15.5 Hz, 1H), 7.46 (s, 1H), 7.17 (d, J) = 19.7 Hz, 1H), 4.01 (t, J = 6.9 Hz, 2H), 2.15 (s, 3H), 1.74 (p, J = 7.1 Hz, 2H), 1.49 (h, J = 7.3 Hz, 2H), 0.95 (t, J = 7.4 Hz, 3H); MS: 282.2 [M+H ⁺ ].

[Scheme 12]

<Preparation Example 15> Preparation of 4-butylbenzene-1,2-diamine

The desired target compound (yield 98%) was obtained in a similar manner to Preparation Example 2.

^1H NMR (300 MHz, DMSO- d ₆ ) δ 6.40 (d, J = 7.7 Hz, 1H), 6.34 (d, J = 2.0 Hz, 1H), 6.19 (dd, J = 7.7, 2.0 Hz, 1H) , 4.28 (s, 4H), 2.32 (t, J = 7.5 Hz, 2H), 1.44 (p, 2H), 1.27 (h, 2H), 0.87 (t, J = 7.3 Hz, 3H); MS: 165.3 [M+H ⁺ ].

<Example 12> Preparation of N-(6-butyl-1H-benzo[d]imidazol-2-yl)propionamide

The desired compound (yield 23%) was obtained in a similar manner to Example 1.

^1H NMR (500 MHz, DMSO- d ₆ ) δ 11.89 (s, 1H), 11.41 (s, 1H), 7.36 - 7.17 (m, 2H), 6.91 (d, J = 8.1 Hz, 1H), 2.63 ( t, 2H), 2.44 (q, J = 7.5 Hz, 2H), 1.57 (p, 2H), 1.32 (h, J = 7.4 Hz, 2H), 1.12 (t, J = 7.6 Hz, 3H), 0.91 ( t, J = 7.3 Hz, 3H); MS: 246.2 [M+H ⁺ ].

The structural formulas and compound names of Examples 1 to 12 are shown in Table 1 below.

Example compound structural formula Compound name One N-(6-propoxy-1H-benzo[d]imidazol-2-yl)propionamide 2 N-(6-butoxy-1H-benzo[d]imidazol-2-yl)acetamide 3 N-(6-butoxy-1H-benzo[d]imidazol-2-yl)propionamide 4 N-(5-fluoro-6-propoxy-1H-benzo[d]imidazol-2-yl)acetamide 5 N-(5-fluoro-6-propoxy-1H-benzo[d]imidazol-2-yl)propionamide 6 N-(5-chloro-6-propoxy-1H-benzo[d]imidazol-2-yl)acetamide 7 N-(5-chloro-6-propoxy-1H-benzo[d]imidazol-2-yl)propionamide 8 N-(6-butoxy-5-fluoro-1H-benzo[d]imidazol-2-yl)propionamide 9 N-(6-butoxy-5-fluoro-1H-benzo[d]imidazol-2-yl)acetamide 10 N-(6-butoxy-5-chloro-1H-benzo[d]imidazol-2-yl)propionamide 11 N-(6-butoxy-5-chloro-1H-benzo[d]imidazol-2-yl)acetamide 12 N-(6-Butyl-1H-benzo[d]imidazol-2-yl)propionamide

<Experimental Example 1> Evaluation of survival inhibition of cancer cell lines (A549, H460 and H1299)

A549, H460, and H1299 lung cancer cell lines (American Type Culture Collection) were grown in RPMI-1640 medium (Thermo Fisher Scientific) supplemented with 10% fetal bovine serum (Invitrogen) and 1% penicillin-streptomycin (Thermo Fisher Scientific) at 37°C. Cultured in a 5% CO ₂ incubator. A549, H460, and H1299 cells (10,000 cells per well) were seeded in 96-well plates in 100 μL of RPMI-1640 1 day before drug treatment. The next day, the compounds of Examples 1 to 12 and Comparative Example 1 (paclitaxel) were administered at 1 μM (final concentration). After 48 hours, 10 μL of CCK-8 reagent (Dojindo) was added and the rate of inhibition of survival of cancer cell lines was assessed by measuring the absorbance signal at 450 nm from formazan by-products using a SpectraMax Minimax 300 imaging cytometer (Molecular Devices). did.

The results measured in Experimental Example 1 are summarized and shown in Table 2 below.

Example % inhibition @ 1 μM A549 H460 H1299 One 64 56 65 2 64 62 64 3 25 34 41 4 68 56 57 5 63 53 49 6 54 50 38 7 54 51 47 8 57 55 56 9 54 56 46 10 57 57 58 11 51 54 53 12 58 47 56 Comparative Example 1
(Paclitaxel) 67 64 67

As shown in Table 2, it can be seen that the compounds of Examples 1 to 12 of the present invention exhibit excellent inhibitory effects similar to paclitaxel in lung cancer cell lines (A549, H460, and H1299).

Claims (8)

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

In Formula 1,
A is O or CH ₂ ;
R ¹ is C1-C5 alkyl;
R ² is hydrogen or halogen;
R ³ is C1-C5 alkyl.
According to paragraph 1,
A is O or CH ₂ ;
R ¹ is C1-C2alkyl;
R ² is hydrogen or halogen;
R ³ is a C1-C4alkyl compound, a tautomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.
According to paragraph 1,
A is O or CH ₂ ;
R ¹ is methyl or ethyl;
R ² is hydrogen, F or Cl;
R ³ is propyl or butyl, a tautomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.
According to paragraph 1,
The compound represented by Formula 1 is any one compound selected from the following compound group, a tautomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof:
<1>N-(6-propoxy-1H-benzo[d]imidazol-2-yl)propionamide;
<2>N-(6-butoxy-1H-benzo[d]imidazol-2-yl)acetamide;
<3>N-(6-butoxy-1H-benzo[d]imidazol-2-yl)propionamide;
<4>N-(5-fluoro-6-propoxy-1H-benzo[d]imidazol-2-yl)acetamide;
<5>N-(5-fluoro-6-propoxy-1H-benzo[d]imidazol-2-yl)propionamide;
<6>N-(5-chloro-6-propoxy-1H-benzo[d]imidazol-2-yl)acetamide;
<7>N-(5-chloro-6-propoxy-1H-benzo[d]imidazol-2-yl)propionamide;
<8>N-(6-butoxy-5-fluoro-1H-benzo[d]imidazol-2-yl)propionamide;
<9>N-(6-butoxy-5-fluoro-1H-benzo[d]imidazol-2-yl)acetamide;
<10>N-(6-butoxy-5-chloro-1H-benzo[d]imidazol-2-yl)propionamide;
<11>N-(6-butoxy-5-chloro-1H-benzo[d]imidazol-2-yl)acetamide; and
<12> N-(6-butyl-1H-benzo[d]imidazol-2-yl)propionamide.
As shown in Scheme 1 below,
A method for producing a compound represented by Formula 1, comprising the step of preparing a compound represented by Formula 1 by reacting a compound represented by Formula 2 with a compound represented by Formula 3:
[Scheme 1]

In Scheme 1 above,
A, R ¹ , R ² and R ³ are as defined in Formula 1 of Clause 1.
A pharmaceutical composition for the prevention or treatment of cancer or infection, containing the compound represented by Formula 1 of claim 1, its tautomer, its solvate, its hydrate, or its pharmaceutically acceptable salt as an active ingredient.
According to clause 6,
The above cancers include pseudomyxoma, intrahepatic biliary tract cancer, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, oral cavity cancer, mycosis fungoides, acute myeloid leukemia, acute lymphocytic leukemia, basal cell carcinoma, Ovarian epithelial cancer, ovarian germ cell cancer, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, biliary tract cancer, colon cancer, chronic myeloid leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, ampulla of Vater cancer, bladder cancer, peritoneal cancer. , parathyroid cancer, adrenal cancer, sinonasal cancer, non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, pediatric brain cancer, pediatric lymphoma, childhood leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, renal pelvis cancer, kidney cancer, heart cancer, Duodenal cancer, malignant soft tissue cancer, malignant bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureteral cancer, urethral cancer, cancer of unknown primary site, gastric lymphoma, stomach cancer, gastric carcinoid, gastrointestinal stromal cancer, Wilms Breast cancer, breast cancer, sarcoma, penile cancer, pharynx cancer, gestational trophoblastic disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoid, vaginal cancer, spinal cancer, acoustic neuroma A group consisting of pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsillar cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, lung squamous cell carcinoma, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleura cancer, and thymic cancer. A pharmaceutical composition, characterized in that it is one or more selected from.
A health functional food for preventing or improving cancer or infectious diseases, containing the compound represented by Formula 1 of claim 1, its tautomer, its solvate, its hydrate, or its pharmaceutically acceptable salt as an active ingredient.