WO2024162814A1 - Novel bicyclic compound and use thereof - Google Patents

Novel bicyclic compound and use thereof Download PDF

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WO2024162814A1
WO2024162814A1 PCT/KR2024/001580 KR2024001580W WO2024162814A1 WO 2024162814 A1 WO2024162814 A1 WO 2024162814A1 KR 2024001580 W KR2024001580 W KR 2024001580W WO 2024162814 A1 WO2024162814 A1 WO 2024162814A1
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cancer
carboxamide
disease
dodecyl
compound
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PCT/KR2024/001580
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French (fr)
Korean (ko)
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박석주
유지훈
김다롱
전희전
곽윤나
홍기범
도현주
김성환
이정열
Original Assignee
프라비바이오 주식회사
재단법인 대구경북첨단의료산업진흥재단
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Publication of WO2024162814A1 publication Critical patent/WO2024162814A1/en

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    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
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Definitions

  • the present invention relates to a novel bicyclic compound and uses thereof, and more particularly, to uses of the compound of formula 1 and its salts for treating or preventing cancer or autoimmune diseases.
  • the present invention relates to a composition comprising the compound and its salts as active ingredients for treating, preventing or improving cancer or autoimmune diseases.
  • the present invention relates to a method for treating, preventing or improving cancer or autoimmune diseases by administering the compound and its salts to a subject.
  • cancer is still a major cause of death worldwide.
  • cancer treatments such as targeted anticancer drugs and immunotherapy drugs, are being developed, there is still a very high demand for drugs that are safe for the human body and have excellent cancer treatment properties.
  • Autoimmunity refers to an inappropriate response of the immune system to autoantigens, causing damage to cells or tissues through humoral immunity, cell-mediated immunity, or both.
  • Autoimmune diseases are related to molecules, cells, and tissues targeted by the autoimmune response, and can be systemic or specific to specific organs depending on the distribution of the target antigen.
  • SLE systemic lupus erythematosus
  • RA rheumatoid arthritis
  • MS multiple sclerosis
  • autoimmune anemia insulin-dependent diabetes mellitus
  • Graves' disease are organ-specific autoimmune diseases.
  • the inventors of the present invention recognized the problems of the above-mentioned prior art and conducted numerous trials and errors to find a compound having excellent treatment, prevention or improvement effects on cancer or autoimmune diseases. As a result, they developed a bicyclic compound of chemical formula 1 and completed the present invention.
  • the purpose of the present invention is to provide a compound or a salt thereof having excellent treatment, prevention or improvement effects on cancer or autoimmune diseases.
  • X1, X2, X3 and X4 are each independently carbon or nitrogen.
  • the term "each independently" as used in the present invention means that two or more substituents are individually defined and may be different from each other or may be the same.
  • X1, X2, X3 and X4 may be the same or different from each other.
  • X1, X2, X3 and X4 may all be carbon.
  • X1 may be nitrogen
  • X2, X3 and X4 may be carbon.
  • X2 may be nitrogen
  • X1, X3 and X4 may be carbon.
  • Y is -CO- or -CH 2 CO-.
  • -CO- represents a ketone group.
  • R1, R2, R3, R4 and R5 are each independently H, -OH, -SH, halogen, -NO 2 , -NH 2 , -CF 3 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 arylalkyl, C5-C10 aryl, C3-C10 alkylaryl, C3-C10 cycloalkyl, C3-C10 heteroaryl, C3-C10 heterocycloalkyl, -OR6, -COR6, -SR6 or -NHR6.
  • R1, R2, R3, R4 and R5 may be the same or different.
  • R1 and R2, R2 and R3, R3 and R4, or R4 and R5 may be combined with each other to form a C5-C10 aryl or a C2-C10 heteroaryl.
  • R1 and R2 may be combined with each other to form a C5-C10 aryl or a C2-C10 heteroaryl.
  • R2 and R3 may be combined with each other to form a C5-C10 aryl or a C2-C10 heteroaryl.
  • R3 and R4 may be combined with each other to form a C5-C10 aryl or a C2-C10 heteroaryl.
  • R4 and R5 may be combined with each other to form a C5-C10 aryl or a C2-C10 heteroaryl.
  • the heteroaryl formed by combining R1 and R2, R2 and R3, R3 and R4, or R4 and R5 preferably has a nitrogen atom.
  • R6 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 arylalkyl, C5-C10 aryl, C3-C10 alkylaryl, C3-C10 cycloalkyl, C3-C10 heteroaryl or C3-C10 heterocycloalkyl.
  • R7 is C8-C12 alkyl, C8-C12 alkenyl or C8-C12 alkynyl.
  • R1 to R7 may be independently substituted with C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C5-C10 aryl, C3-C10 cycloalkyl, C3-C10 heteroaryl, or C3-C10 heterocycloalkyl.
  • alkyl, alkenyl, and alkynyl are intended to include both straight-chain (also referred to as linear) and branched-chain (also referred to as branched).
  • halogen as used in the present invention means fluorine, chlorine, bromine or iodine.
  • alkoxy as used in the present invention means O-alkyl.
  • hetero as used in the present invention means a hetero atom selected from oxygen, nitrogen and sulfur.
  • cycloalkyl as used in the present invention means alkyl forming a ring.
  • heterocycloalkyl as used in the present invention means cycloalkyl in which a heteroatom is contained within the ring.
  • arylalkyl used in the present invention means alkyl having an aryl group.
  • alkylaryl used in the present invention means aryl having an alkyl group.
  • salt used in the present invention can be prepared by a method conventional in the art, and for example, can be formed by forming a salt of an inorganic acid such as hydrochloric acid, hydrogen bromide, sulfuric acid, sodium bisulfate, phosphoric acid, or carbonic acid, or a salt of these acids together with an organic acid such as formic acid, acetic acid, oxalic acid, benzoic acid, citric acid, tartaric acid, gluconic acid, gestic acid, fumaric acid, lactobionic acid, salicylic acid, or acetylsalicylic acid (aspirin), or can form a metal salt thereof by reacting with an alkali metal ion such as sodium or potassium, or can form another type of salt by reacting with an ammonium ion, but is not limited thereto.
  • an inorganic acid such as hydrochloric acid, hydrogen bromide, sulfuric acid, sodium bisulfate, phosphoric acid, or carbonic acid
  • organic acid such as
  • the compound according to the present invention or its salt includes isomers, solvates or crystalline forms.
  • the term "isomer” as used in the present invention includes stereoisomers, enantiomers, diastereomers, tautomers, geometric isomers, etc.
  • solvate as used in the present invention means an aggregate or complex of the compound of the present invention and one or more solvent molecules, wherein the solvent includes, but is not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and ethanolamine.
  • the term “hydrate” as used in the present invention means a solvate in which the solvent molecule is water.
  • crystal form as used in the present invention means a form in which identical molecules form different crystal structures.
  • the compound of formula 1 according to the present invention may be selected from the group consisting of:
  • Another aspect of the present invention provides a pharmaceutical composition for treating or preventing cancer or an autoimmune disease, comprising a compound represented by chemical formula 1 or a pharmaceutically acceptable salt thereof.
  • treatment means all cases in which cancer or an autoimmune disease is improved, reversed, or cured by administration of a composition according to the present invention.
  • prevention used in the present invention means all things that suppress, delay, prevent, etc. the occurrence or recurrence of cancer or autoimmune disease by administration of the composition according to the present invention.
  • the cancer may be, but is not limited to, liver cancer, colon cancer, pancreatic cancer, colon cancer, small intestine cancer, stomach cancer, lung cancer, brain cancer, bone cancer, melanoma, breast cancer, sclerosing adenoma, uterine cancer, cervical cancer, head and neck cancer, esophageal cancer, thyroid cancer, parathyroid cancer, kidney cancer, sarcoma, prostate cancer, urethral cancer, bladder cancer, blood cancer, lymphoma, or fibroadenoma.
  • the above autoimmune diseases include systemic lupus erythematosus (SLE), glomerulitis, ankylosing spondylitis, myastenia gravis, rheumatoid arthritis (RA), multiple sclerosis (MS), systemic sclerosis, pernicious anemia, autoimmune anemia, inflammatory bowel disease, insulin-dependent diabetes mellitus (IDDM), type 1 diabetes, Graves' disease, Graves' hyperthyroidism, Kikuchi's disease, hemophagocytic lymphohistiocytosis, adult onset Still's disease, Behcet's disease. disease), IgG4-associated diseases, psoriasis, asthma, or transplant rejection, but are not limited to these.
  • SLE systemic lupus erythematosus
  • glomerulitis glomerulitis
  • ankylosing spondylitis myastenia gravis
  • RA rheumatoid arthritis
  • MS multiple sclerosis
  • the pharmaceutical composition of the present invention comprises an effective amount of the compound, an isomer thereof, a solvate, a hydrate, a crystal form thereof, or a salt thereof, and can be administered to a subject in need of prevention or treatment of cancer or an autoimmune disease.
  • the term "administration" means physically introducing a composition into a subject using any of a variety of methods and delivery systems known to those of ordinary skill in the art.
  • the administration may be, for example, oral, or intravenous, intramuscular, subcutaneous, intraperitoneal, spinal or other parenteral administration, such as injection or infusion, but is not limited thereto.
  • the number of times the administration may be performed may be, for example, single, multiple, and over one or more extended periods of time.
  • the pharmaceutical composition of the present invention may be formulated as a preparation for oral or parenteral administration according to the route of administration as described above.
  • subject as used herein includes a human or any non-human animal, which non-human animal may be a vertebrate, such as a primate, dog, cow, horse, pig, rodent, such as a mouse, rat, guinea pig, and the like. As used herein, the “subject” is used interchangeably with “individual” and “patient”.
  • the subject to whom the compound or composition according to the present invention is administered may be a cancer patient, or a cancer patient suffering from an autoimmune disease or at a high risk of developing an autoimmune disease.
  • the subject to whom the compound or composition according to the present invention is administered may be a patient suffering from an autoimmune disease, or a patient suffering from cancer or at a high risk of developing an autoimmune disease.
  • the effective amount may be a "therapeutically effective amount” or a “prophylactically effective amount.”
  • therapeutically effective amount means any amount that, when the drug or therapeutic agent is used alone or in combination with other therapeutic agents, can exhibit a decrease in the severity of disease symptoms, an increase in the frequency and duration of disease symptom-free periods, or a prevention of impairment or disability due to disease affliction.
  • prophylactically effective amount means any amount that inhibits the occurrence or recurrence of a disease in a subject.
  • the level of the effective amount can be determined depending on factors such as the severity of the disease, age, sex, activity of the drug, sensitivity to the drug, time of administration, route of administration and excretion rate, duration of treatment, concomitant medications, and other factors well known in the medical field.
  • the dosage of the pharmaceutical composition may vary depending on the age, sex, weight, administration route, severity of disease, etc. of the subject, and specifically, depending on the symptoms of the subject, 0.1 to 100 mg/kg of the composition of the present invention may be administered once or several times a day, or at intervals of several days to several months.
  • the pharmaceutical composition may further comprise suitable carriers, excipients and diluents commonly used in the manufacture of pharmaceutical compositions.
  • Carriers, excipients and diluents that may be included in the composition may be, but are not limited to, for example, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
  • the pharmaceutical composition may be administered in combination with other therapeutic agents.
  • the pharmaceutical composition of the present invention and the other therapeutic agents may be administered simultaneously, sequentially, or individually.
  • the other therapeutic agents may be drugs such as compounds, proteins, etc. that have preventive, therapeutic, and improving effects on cancer or autoimmune diseases, but are not limited thereto.
  • the pharmaceutical composition may be formulated to be administered simultaneously, sequentially, or separately with another therapeutic agent.
  • the compound, its isomer, solvate, hydrate, crystalline form, or salt thereof and the other therapeutic agent may be administered simultaneously in one formulation, or may be administered simultaneously, sequentially, or separately in separate formulations.
  • the compound, its isomer, solvate, hydrate, crystalline form, or salt thereof and the other therapeutic agent included in the pharmaceutical composition of the present invention may be formulated separately in separate containers, or may be formulated together in the same container.
  • the compound, its isomer, solvate, hydrate, crystalline form, or salt thereof and the other therapeutic agent included in the pharmaceutical composition of the present invention may be the same or different from each other in terms of pharmaceutically effective amount, administration time, administration interval, administration route, treatment period, etc.
  • Another aspect of the present invention provides a method for treating or preventing cancer or an autoimmune disease, comprising administering to a subject a compound represented by chemical formula 1 or a salt thereof.
  • the compound or its salt may be administered to the subject simultaneously, sequentially, or separately with other agents.
  • spontaneous administration means administering the compound or its salt and the other therapeutic agent at the same time as one preparation, or means administering the compound or its salt and the other therapeutic agent at the same time as separate preparations, in which case the routes of administration may be different.
  • the above “sequential" administration means administering the compound or its salt and the other therapeutic agent relatively sequentially, allowing for the shortest possible time between administrations.
  • the above “separate” administration means administering the compound or its salt and other therapeutic agents at regular intervals of time.
  • Another aspect of the present invention provides a food composition for improving or preventing cancer or an autoimmune disease, comprising a compound represented by chemical formula 1 or a food-chemically acceptable salt thereof.
  • each term has the same meaning as described above in the composition unless specifically mentioned.
  • improvement means any act in which the degree of cancer or autoimmune disease is reduced, improved, or progression is delayed by administration of the composition according to the present invention.
  • the above food may be a health functional food.
  • health functional food refers to a food manufactured and processed in the form of tablets, capsules, powders, granules, liquids, and pills using raw materials or ingredients that have functionality useful to the human body.
  • functionality refers to obtaining a useful effect for health purposes such as regulating nutrients or physiological actions for the structure and function of the human body.
  • the food composition according to the present invention can be manufactured by a method commonly used in the art, and can be manufactured by adding raw materials and ingredients commonly added in the art during the manufacturing process.
  • it has the advantage of not having side effects that may occur when taking drugs for a long period of time because it uses food as a raw material, and since it is highly portable, the food composition of the present invention can be taken as a supplement to enhance or improve the therapeutic effect of cancer.
  • the amount of the compound, its isomer, solvate, hydrate, crystal form or its food-wise acceptable salt included as an effective ingredient in the food composition according to the present invention may be suitably determined depending on the intended use (prevention, improvement or therapeutic treatment).
  • the compound of the present invention or its food-wise acceptable salt may be included in an amount of 0.001 to 20 wt%, 0.001 to 15 wt% or 0.001 to 10 wt% in the composition.
  • 0.01 to 2 g, specifically 0.02 to 2 g, more specifically 0.3 to 1 g may be added based on 100 mL.
  • the amount may be used below the above range.
  • the content of the compound according to the present invention or a food-wise acceptable salt thereof added to the food composition can be appropriately increased or decreased as needed.
  • the food composition of the present invention may further contain additional ingredients in addition to the compound or a food-wise acceptable salt thereof to enhance efficacy.
  • the above food composition may be in any one dosage form selected from the group consisting of a pill, a tablet, a granule, a powder, a capsule, and a liquid solution.
  • the type of the food is not particularly limited.
  • foods to which the substance can be added include meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, dairy products including ice cream, various soups, beverages, tea, drinks, alcoholic beverages, and vitamin complexes, and include all foods in the conventional sense.
  • the food composition of the present invention may contain various flavoring agents or natural carbohydrates as additional ingredients, like conventional foods.
  • the natural carbohydrates are monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, polysaccharides such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol and erythritol.
  • a natural sweetener such as thaumatin and stevia extract, or a synthetic sweetener such as saccharin and aspartame can be used.
  • the food composition of the present invention is a beverage composition
  • the liquid component other than containing the compound or a food-wise acceptable salt thereof as an essential component in the indicated ratio there is no special limitation on the liquid component other than containing the compound or a food-wise acceptable salt thereof as an essential component in the indicated ratio, and various flavoring agents or natural carbohydrates, etc. may be contained as additional components like a conventional beverage.
  • the bicyclic compound of chemical formula 1 or a salt thereof according to the present invention has an excellent effect of killing cancer cells or inhibiting tumor growth and proliferation, and is highly safe for the human body. Therefore, it can be usefully utilized for the prevention, treatment, or improvement of cancer.
  • the bicyclic compound of chemical formula 1 or a salt thereof according to the present invention exhibits a strong immunosuppressive function by not only inhibiting the proliferation of T cells but also inducing the death of B cells, and therefore can be usefully used for the treatment or prevention of autoimmune diseases that form autoantibodies in addition to transplant rejection.
  • Figure 1 shows the level of apoptosis when the compound of the present invention was treated at a concentration of 30 ⁇ M in the B cell lymphoma cell line SU-DLH-8. On the X-axis, C indicates the control (DMSO).
  • Figure 2 shows the level of apoptosis when the cervical cancer cell line HeLa was treated with the compound of the present invention at a concentration of 30 ⁇ M.
  • C indicates the control group (DMSO).
  • the compounds of the present invention were prepared according to the following reaction scheme. Compounds having different substituents were also prepared through similar steps, but are not all specified in this specification. Those skilled in the art can easily prepare compounds having different substituents by referring to the representative examples below.
  • Benzoic acid (1 eq), amine (1.1 eq), EDCI (1.1 eq), DMAP (0.1 eq), and TEA (2.2 eq) having various substituents were added to 1 ml of dichloromethane (DCM) and stirred at room temperature for 6 hours. 50 ml of water was added and dichloromethane (60 ml) was added to separate the organic layer, which was dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. Then, the residue was purified using column chromatography (EA 5%) to obtain the target compound as a result.
  • DCM dichloromethane
  • the human B-cell lymphoma cell line SU-DLH-8 (ATCC, Cat. # CRL-2961) purchased from ATCC was cultured in RPMI-1640 medium containing 10% FBS, 100 U/mL penicillin, and 100 ⁇ g/mL streptomycin. Each cell culture was collected, centrifuged at 1,300 rpm for 5 minutes, the supernatant was removed, and the cells were resuspended in the same medium. 90 ⁇ L per well was dispensed into a 96-well plate (Costar 96 well cell culture plate, Corning) and finally treated to obtain the conditions shown in Table 1.
  • Each plate was treated with 10 ⁇ L of the compound according to the present invention or the control (DMSO) at various concentrations (0, 10, 30, 50 ⁇ M), and then cultured in a 5% CO 2 incubator at 37°C for 48 hours. Thereafter, 10 ⁇ L of CCK-8 was added to each well, and cultured again in a 5% CO 2 incubator at 37°C for 4 hours, and the absorbance was measured at 450 nm to show the relative cell viability (%) for cells not treated with the drug, as shown in Table 2.
  • the values listed in Table 2 indicate the relative cell viability in the groups treated with each compound at various concentrations, when the cell viability in the group treated with the control (DMSO) is 100%.
  • the human prostate cancer cell line LNCaP the human breast cancer cell line MCF-7, the human lung cancer cell line A549, and the human colon cancer cell line HCT-116 were provided from the Korea Cell Line Bank and cultured in RPMI-1640 medium containing 10% FBS.
  • the human cervical cancer cell line HeLa and the human liver cancer cell line SK-HEP-1 both provided from the Korea Cell Line Bank, were cultured in MEM and DMEM medium containing 10% FBS, 100 U/mL penicillin, and 100 ⁇ g/mL streptomycin, respectively.
  • each stabilized cell was recovered through Trypsin-EDTA treatment, centrifuged at a speed of 1,200 rpm for 3 minutes, the supernatant was removed, resuspended in the same medium, and dispensed at 100 ⁇ L per well into a 96-well plate (Costar 96 well cell culture plate, Corning) to finally achieve the conditions in Table 3.
  • SK-HEP-1 Human Hepatic Adenocarcinoma
  • DMEM with 10% FBS, 100U/mL penicillin, 100 ⁇ g/mL streptomycin 1 ⁇ 10 4 cells/well
  • HeLa Human Cervical Carcinoma
  • MEM with 10% FBS, 100U/mL penicillin, 100 ⁇ g/mL streptomycin 5 ⁇ 10 3 cells/well
  • LNCaP Human Prostate Adenocarcinoma
  • RPMI 10% FBS 2.5 ⁇ 10 4 cells/well MCF-7 (Human Breast Cancer) 2 ⁇ 10 4 cells/well A549 (Human Lung Carcinoma) 1.5 ⁇ 10 4 cells/well HCT-116 (Human Colorectal Carcinoma) 3.5 ⁇ 10 4 cells/well
  • Human B-cell lymphoma cell line SU-DLH-8 (ATCC, Cat. # CRL-2961) purchased from ATCC was cultured in RPMI-1640 medium containing 10% FBS, 100 U/mL penicillin, and 100 ⁇ g/mL streptomycin. Each cell culture was collected, centrifuged at 1,300 rpm for 5 minutes, and the supernatant was removed. The cells were resuspended in the same medium and dispensed into 6-well plates at 1.5 mL per well to achieve the final conditions of Table 10. The plates were treated with 30 ⁇ M compounds 50, 110, 114, and 119 or the control group (DMSO), and then cultured at 37°C for 48 hours in a 5% CO 2 incubator.
  • DMSO control group
  • control or compound-treated cells were collected and fluorescent stained for Annexin V/PI, and the results were analyzed via flow cytometry.
  • the degree of apoptosis occurrence was analyzed via flow cytometry, and the sum of the percentages (%) of cells located at Annexin V High /PI High , Annexin V High /PI Low , and Annexin V Low /PI High in the data is represented as a bar graph in Figure 1.
  • the human cervical cancer cell line HeLa obtained from the Korea Cell Line Bank was cultured in MEM medium containing 10% FBS, 100 U/mL penicillin, and 100 ⁇ g/mL streptomycin. After that, each stabilized cell was recovered through Trypsin-EDTA treatment, centrifuged at a speed of 1,200 rpm for 3 minutes, the supernatant was removed, resuspended in the same medium, and dispensed into 6-well plates at 1.5 mL per well to achieve the final conditions of Table 10. After treating the plate with 30 ⁇ M of compounds 50, 110, 114, and 119 or the control group (DMSO), the plate was cultured at 37°C for 48 hours in a 5% CO2 incubator.
  • MEM medium containing 10% FBS, 100 U/mL penicillin, and 100 ⁇ g/mL streptomycin.
  • control or compound-treated cells were recovered through Trypsin-EDTA treatment, fluorescent staining for Annexin V/PI (Propidium Iodide) was performed, and the results were analyzed through flow cytometry.
  • Annexin V/PI Propidium Iodide
  • the degree of apoptosis occurrence was analyzed through flow cytometry, and the sum of the ratios (%) of cells located at Annexin V High /PI High , Annexin V High /PI Low , and Annexin V Low /PI High in the data is represented as a bar graph in Figure 2.
  • Figures 1 and 2 demonstrate that the compound according to the present invention has anticancer efficacy by inducing apoptosis of cancer cells.
  • the spleen was removed from 7-week-old C57BL/6 mice, mashed, and separated into single cells using a strainer (40 ⁇ M pore size, SPL). Red blood cells were removed with ACK (Ammonium-Chloride-Potassium) lysis buffer to isolate only white blood cells. CD90.2 microbeads (130-121-278, Miltenyi Biotec.) were added, and the mixture was incubated at 4°C for 20 minutes. Then, T cells in the spleen were finally isolated using the MACS Magnetic Stand and LS column.
  • ACK Ammonium-Chloride-Potassium
  • T cells isolated from the spleen were resuspended in 1 mL of free media (RPMI-1640 + 200 U/mL penicillin + 200 ⁇ g/mL streptomycin), 0.3 ⁇ L of CFSE (10 mM) was added, and the mixture was incubated at 37°C for 5 minutes. After that, 10 mL of Free media was added to stop the reaction, and the cell pellet was obtained by centrifugation.
  • free media RPMI-1640 + 200 U/mL penicillin + 200 ⁇ g/mL streptomycin
  • T cell proliferation inhibition rate (%) is shown in Table 11.
  • Adaptive immunity exhibits a stronger immune response than innate immunity, and can be divided into immune responses mediated by T cells and immune responses mediated by B cells.
  • the compound according to the present invention exhibits a strong immunosuppressive function by inhibiting the proliferation of T cells as shown in Table 11, and inducing the death of B cells as shown in Table 2, and therefore can be usefully used for the treatment or prevention of autoimmune diseases that form autoantibodies in addition to transplant rejection.

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Abstract

The present invention relates to a novel bicyclic compound and use thereof and, in particular, to use of a compound of chemical formula 1 and a salt thereof for the treatment or prevention of cancer or an autoimmune disease. Also, the present invention relates to a composition for the treatment, prevention or amelioration of cancer or an autoimmune disease, the composition comprising the compound and a salt thereof as an active ingredient. Also, the present invention relates to a method for treating, preventing or ameliorating cancer or an autoimmune disease by administering the compound and a salt thereof to a subject.

Description

신규 바이사이클릭 화합물 및 이의 용도Novel bicyclic compounds and their uses
본 발명은 신규 바이사이클릭 화합물 및 이의 용도에 관한 것으로서, 구체적으로는 화학식 1의 화합물 및 이의 염을 암 또는 자가면역질환의 치료 또는 예방을 위해 사용하는 용도에 관한 것이다. 또한, 본 발명은 상기 화합물 및 이의 염을 유효성분으로 포함하는 암 또는 자가면역질환의 치료, 예방 또는 개선용 조성물에 관한 것이다. 또한, 본 발명은 상기 화합물 및 이의 염을 대상체에게 투여하여 암 또는 자가면역질환을 치료, 예방 또는 개선하기 위한 방법에 관한 것이다.The present invention relates to a novel bicyclic compound and uses thereof, and more particularly, to uses of the compound of formula 1 and its salts for treating or preventing cancer or autoimmune diseases. In addition, the present invention relates to a composition comprising the compound and its salts as active ingredients for treating, preventing or improving cancer or autoimmune diseases. In addition, the present invention relates to a method for treating, preventing or improving cancer or autoimmune diseases by administering the compound and its salts to a subject.
지난 수년간 암에 대한 집중적인 연구가 이루어졌음에도 불구하고 여전히 암은 전세계적으로 주요한 사망 원인이다. 표적항암제, 면역항암제 등 다수의 암 치료법이 개발되고 있으나 인체에 대한 안전성이 높으면서 암 치료능이 우수한 약물에 대한 요구는 여전히 매우 높다.Despite the intensive research on cancer over the past years, cancer is still a major cause of death worldwide. Although many cancer treatments, such as targeted anticancer drugs and immunotherapy drugs, are being developed, there is still a very high demand for drugs that are safe for the human body and have excellent cancer treatment properties.
자가면역이란 체액성 면역, 세포성 면역 또는 양쪽 모두에 의해 세포나 조직에 손상을 초래하는 것으로서 면역계의 자가항원(autoantigen)에 대한 부적절한 반응을 가리킨다. 자가면역질환은 자가면역 반응이 표적으로 삼는 분자, 세포 및 조직들과 관련이 있으며, 표적 항원의 분포에 따라 전신성으로 나타나거나 또는 특정 장기에 특이적으로 나타날 수 있다. 예를 들면, 전신홍반성낭창(systemic lupus erythematosus; SLE), 류마티스 관절염(rheumatoid arthritis; RA), 다발성 경화증(multiple sclerosis; MS) 등은 전신성 자가면역질환에 속하며, 자가 면역성 빈혈, 인슐린 의존성 당뇨(insulin-dependent diabetes mellitus; IDDM), 그레이브스 병(grave’s disease) 등은 장기 특이적 자가면역질환에 속한다.Autoimmunity refers to an inappropriate response of the immune system to autoantigens, causing damage to cells or tissues through humoral immunity, cell-mediated immunity, or both. Autoimmune diseases are related to molecules, cells, and tissues targeted by the autoimmune response, and can be systemic or specific to specific organs depending on the distribution of the target antigen. For example, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and multiple sclerosis (MS) are systemic autoimmune diseases, while autoimmune anemia, insulin-dependent diabetes mellitus (IDDM), and Graves' disease are organ-specific autoimmune diseases.
특히, 암 치료제 또는 자가면역질환 치료제가 개발된 것은 있어도, 암 환자가 자가면역질환에 걸린 경우, 또는 반대로 자가면역질환 환자가 암에 걸린 경우, 적절한 치료제가 없다. 따라서, 이에 대한 개발 필요성은 당 업계에서 여전히 크게 존재한다.In particular, although cancer treatment drugs or autoimmune disease treatment drugs have been developed, there is no appropriate treatment for cancer patients with autoimmune diseases, or conversely, for autoimmune disease patients with cancer. Therefore, there is still a great need for development of such drugs in the industry.
본 발명자들은 상기 종래 기술의 문제점을 인지하고, 암 또는 자가면역질환에 대해 우수한 치료, 예방 또는 개선 효과를 가지는 화합물을 발견하기 위해 수많은 시행착오를 거치며 연구를 거듭하였다. 그 결과, 화학식 1의 바이사이클릭 화합물을 개발하고 본 발명을 완성하기에 이르렀다. 본 발명은 암 또는 자가면역질환의 치료, 예방 또는 개선 효과가 우수한 화합물 또는 이의 염을 제공하는 것을 목적으로 한다.The inventors of the present invention recognized the problems of the above-mentioned prior art and conducted numerous trials and errors to find a compound having excellent treatment, prevention or improvement effects on cancer or autoimmune diseases. As a result, they developed a bicyclic compound of chemical formula 1 and completed the present invention. The purpose of the present invention is to provide a compound or a salt thereof having excellent treatment, prevention or improvement effects on cancer or autoimmune diseases.
본 발명의 목적을 달성하기 위한 본 발명에 따른 화합물은 하기 화학식 1로 표시된다:The compound according to the present invention for achieving the purpose of the present invention is represented by the following chemical formula 1:
[화학식 1][Chemical Formula 1]
Figure PCTKR2024001580-appb-img-000001
Figure PCTKR2024001580-appb-img-000001
상기 화학식 1에서, X1, X2, X3 및 X4는 서로 독립적으로 탄소 또는 질소이다. 본 발명에서 사용되는 용어 "서로 독립적으로"는, 2개 이상의 치환기가 개별적으로 정의되어 서로 상이할 수도 있고 동일할 수도 있다는 것을 의미한다. 상기 화학식 1에서, X1, X2, X3 및 X4는 서로 동일하거나 상이할 수 있다. 예를 들어, X1, X2, X3 및 X4가 모두 탄소일 수 있다. 또다른 예로서, X1이 질소이고, X2, X3 및 X4가 탄소일 수 있다. 또다른 예로서, X2가 질소이고, X1, X3 및 X4가 탄소일 수 있다. In the chemical formula 1, X1, X2, X3 and X4 are each independently carbon or nitrogen. The term "each independently" as used in the present invention means that two or more substituents are individually defined and may be different from each other or may be the same. In the chemical formula 1, X1, X2, X3 and X4 may be the same or different from each other. For example, X1, X2, X3 and X4 may all be carbon. As another example, X1 may be nitrogen, and X2, X3 and X4 may be carbon. As another example, X2 may be nitrogen, and X1, X3 and X4 may be carbon.
상기 화학식 1에서, Y는 -CO- 또는 -CH2CO-이다. 여기서, -CO-는 케톤기를 나타낸다.In the above chemical formula 1, Y is -CO- or -CH 2 CO-. Here, -CO- represents a ketone group.
상기 화학식 1에서, R1, R2, R3, R4 및 R5는 서로 독립적으로 H, -OH, -SH, 할로겐, -NO2, -NH2, -CF3, C1-C6 알킬, C2-C6 알케닐, C2-C6 알키닐, C3-C10 아릴알킬, C5-C10 아릴, C3-C10 알킬아릴, C3-C10 사이클로알킬, C3-C10 헤테로아릴, C3-C10 헤테로사이클로알킬, -OR6, -COR6, -SR6 또는 -NHR6이다. R1, R2, R3, R4 및 R5는 서로 동일하거나 상이할 수 있다. 화학식 1에서, X1이 질소인 경우, R1은 부재(absent)이다.In the above chemical formula 1, R1, R2, R3, R4 and R5 are each independently H, -OH, -SH, halogen, -NO 2 , -NH 2 , -CF 3 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 arylalkyl, C5-C10 aryl, C3-C10 alkylaryl, C3-C10 cycloalkyl, C3-C10 heteroaryl, C3-C10 heterocycloalkyl, -OR6, -COR6, -SR6 or -NHR6. R1, R2, R3, R4 and R5 may be the same or different. In the chemical formula 1, when X1 is nitrogen, R1 is absent.
상기 화학식 1에서, R1 및 R2, R2 및 R3, R3 및 R4, 또는 R4 및 R5는 서로 결합하여 C5-C10 아릴 또는 C2-C10 헤테로아릴을 형성한다. 예를 들어, R1 및 R2가 서로 결합하여 C5-C10 아릴 또는 C2-C10 헤테로아릴을 형성할 수 있다. 또다른 예로서, R2 및 R3이 서로 결합하여 C5-C10 아릴 또는 C2-C10 헤테로아릴을 형성할 수 있다. 또다른 예로서, R3 및 R4가 서로 결합하여 C5-C10 아릴 또는 C2-C10 헤테로아릴을 형성할 수 있다. 또다른 예로서, R4 및 R5가 서로 결합하여 C5-C10 아릴 또는 C2-C10 헤테로아릴을 형성할 수 있다. R1 및 R2, R2 및 R3, R3 및 R4, 또는 R4 및 R5가 서로 결합하여 형성하는 헤테로아릴은 바람직하게는 질소 원자를 갖는다. In the above chemical formula 1, R1 and R2, R2 and R3, R3 and R4, or R4 and R5 may be combined with each other to form a C5-C10 aryl or a C2-C10 heteroaryl. For example, R1 and R2 may be combined with each other to form a C5-C10 aryl or a C2-C10 heteroaryl. As another example, R2 and R3 may be combined with each other to form a C5-C10 aryl or a C2-C10 heteroaryl. As another example, R3 and R4 may be combined with each other to form a C5-C10 aryl or a C2-C10 heteroaryl. As another example, R4 and R5 may be combined with each other to form a C5-C10 aryl or a C2-C10 heteroaryl. The heteroaryl formed by combining R1 and R2, R2 and R3, R3 and R4, or R4 and R5 preferably has a nitrogen atom.
상기 화학식 1에서, R6은 H, C1-C6 알킬, C2-C6 알케닐, C2-C6 알키닐, C3-C10 아릴알킬, C5-C10 아릴, C3-C10 알킬아릴, C3-C10 사이클로알킬, C3-C10 헤테로아릴 또는 C3-C10 헤테로사이클로알킬이다.In the above chemical formula 1, R6 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 arylalkyl, C5-C10 aryl, C3-C10 alkylaryl, C3-C10 cycloalkyl, C3-C10 heteroaryl or C3-C10 heterocycloalkyl.
상기 화학식 1에서, R7은 C8-C12 알킬, C8-C12 알케닐 또는 C8-C12 알키닐이다.In the above chemical formula 1, R7 is C8-C12 alkyl, C8-C12 alkenyl or C8-C12 alkynyl.
R1 내지 R7은 서로 독립적으로 C1-C6 알킬, C2-C6 알케닐, C2-C6 알키닐, C5-C10 아릴, C3-C10 사이클로알킬, C3-C10 헤테로아릴, 또는 C3-C10 헤테로사이클로알킬로 치환된 것일 수 있다.R1 to R7 may be independently substituted with C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C5-C10 aryl, C3-C10 cycloalkyl, C3-C10 heteroaryl, or C3-C10 heterocycloalkyl.
본 발명에서, 알킬, 알케닐, 알키닐과 같은 용어는 직쇄(또는 선형이라고도 지칭함) 또는 측쇄(또는 분지형이라고도 지칭함)를 모두 포함하는 것으로 의도된다.In the present invention, terms such as alkyl, alkenyl, and alkynyl are intended to include both straight-chain (also referred to as linear) and branched-chain (also referred to as branched).
본 발명에서 사용되는 용어 "할로겐"은 플루오르, 염소, 브롬 또는 요오드를 의미한다.The term "halogen" as used in the present invention means fluorine, chlorine, bromine or iodine.
본 발명에서 사용되는 용어 "알콕시"는 O-알킬을 의미한다.The term “alkoxy” as used in the present invention means O-alkyl.
본 발명에서 사용되는 용어 "헤테로"는 산소, 질소 및 황 중에서 선택된 헤테로 원자를 의미한다.The term "hetero" as used in the present invention means a hetero atom selected from oxygen, nitrogen and sulfur.
본 발명에서 사용되는 용어 "사이클로알킬"은 고리를 형성하는 알킬을 의미한다. 본 발명에서 사용되는 용어 "헤테로사이클로알킬"은 헤테로 원자가 고리 내에 포함된 사이클로알킬을 의미한다.The term "cycloalkyl" as used in the present invention means alkyl forming a ring. The term "heterocycloalkyl" as used in the present invention means cycloalkyl in which a heteroatom is contained within the ring.
본 발명에서 사용되는 용어 "아릴알킬"은 아릴기를 갖는 알킬을 의미한다. 본 발명에서 사용되는 용어 "알킬아릴"은 알킬기를 갖는 아릴을 의미한다.The term "arylalkyl" used in the present invention means alkyl having an aryl group. The term "alkylaryl" used in the present invention means aryl having an alkyl group.
본 발명에서 사용되는 용어 "염"은, 당해 기술 분야에서 통상적인 방법에 의해 제조될 수 있는 것으로서, 예를 들면, 염산, 브롬화수소, 황산, 황산수소나트륨, 인산, 탄산 등의 무기산과의 염 또는 개미산, 초산, 옥살산, 벤조산, 시트르산, 타르타르산, 글루콘산, 게스티스산, 푸마르산, 락토비온산, 살리실릭산, 또는 아세틸살리실릭산(아스피린)과 같은 유기산과 함께 이들의 산의 염을 형성하거나, 또는 나트륨, 칼륨 등의 알칼리금속 이온과 반응하여 이들의 금속염을 형성하거나, 또는 암모늄 이온과 반응하여 또 다른 형태의 염을 형성할 수도 있으며, 이에 한정되는 것은 아니다.The term "salt" used in the present invention can be prepared by a method conventional in the art, and for example, can be formed by forming a salt of an inorganic acid such as hydrochloric acid, hydrogen bromide, sulfuric acid, sodium bisulfate, phosphoric acid, or carbonic acid, or a salt of these acids together with an organic acid such as formic acid, acetic acid, oxalic acid, benzoic acid, citric acid, tartaric acid, gluconic acid, gestic acid, fumaric acid, lactobionic acid, salicylic acid, or acetylsalicylic acid (aspirin), or can form a metal salt thereof by reacting with an alkali metal ion such as sodium or potassium, or can form another type of salt by reacting with an ammonium ion, but is not limited thereto.
본 발명에 따른 화합물 또는 이의 염에는 이성질체, 용매화물 또는 결정형이 포함된다. 본 발명에서 사용되는 용어 "이성질체"에는 입체 이성질체, 거울상 이성질체, 부분입체 이성질체, 호변 이성질체, 기하 이성질체 등이 포함된다. 본 발명에서 사용되는 용어 "용매화물"은 본 발명의 화합물과 1종 이상의 용매 분자와의 응집체 또는 복합체를 의미하며, 여기서 용매에는 물, 이소프로판올, 에탄올, 메탄올, 디메틸설폭사이드, 에틸 아세테이트, 아세트산 및 에탄올아민 등이 포함되지만 이에 한정되는 것은 아니다. 본 발명에서 사용되는 용어 "수화물"은 용매 분자가 물인 용매화물을 의미한다. 본 발명에서 사용되는 용어 "결정형"은 동일한 분자들이 서로 다른 결정 구조를 이루고 있는 형태를 의미한다.The compound according to the present invention or its salt includes isomers, solvates or crystalline forms. The term "isomer" as used in the present invention includes stereoisomers, enantiomers, diastereomers, tautomers, geometric isomers, etc. The term "solvate" as used in the present invention means an aggregate or complex of the compound of the present invention and one or more solvent molecules, wherein the solvent includes, but is not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and ethanolamine. The term "hydrate" as used in the present invention means a solvate in which the solvent molecule is water. The term "crystal form" as used in the present invention means a form in which identical molecules form different crystal structures.
본 발명에 따른 화학식 1의 화합물은 하기로 이루어진 군으로부터 선택될 수 있다:The compound of formula 1 according to the present invention may be selected from the group consisting of:
N-운데실-2,3-디하이드로-1H-벤조[d][1,2,3]트리아졸-5-카복스아마이드,N-undecyl-2,3-dihydro-1H-benzo[d][1,2,3]triazole-5-carboxamide,
N-도데실-1H-벤조[d][1,2,3]트리아졸-5-카복스아마이드,N-dodecyl-1H-benzo[d][1,2,3]triazole-5-carboxamide,
N-운데실-1H-벤조[d]이미다졸-5-카복스아마이드,N-undecyl-1H-benzo[d]imidazole-5-carboxamide,
1-메틸-N-운데실-1H-인돌-7-카복스아마이드,1-Methyl-N-undecyl-1H-indole-7-carboxamide,
N-운데실퀴놀린-2-카복스아마이드,N-undecylquinoline-2-carboxamide,
N-도데실퀴놀린-2-카복스아마이드,N-dodecylquinoline-2-carboxamide,
8-하이드록시-N-운데실퀴놀린-7-카복스아마이드,8-hydroxy-N-undecylquinoline-7-carboxamide,
N-도데실-8-하이드록시퀴놀린-7-카복스아마이드,N-dodecyl-8-hydroxyquinoline-7-carboxamide,
6-하이드록시-N-운데실-2-나프타마이드,6-hydroxy-N-undecyl-2-naphthamide,
N-도데실-6-하이드록시-2-나프타마이드,N-dodecyl-6-hydroxy-2-naphthamide,
N-도데실-1H-벤조[d]이미다졸-5-카복스아마이드,N-dodecyl-1H-benzo[d]imidazole-5-carboxamide,
6-브로모-N-운데실-2-나프타마이드,6-Bromo-N-undecyl-2-naphthamide,
6-브로모-N-도데실-2-나프타마이드,6-Bromo-N-dodecyl-2-naphthamide,
2-클로로-N-도데실-3-메틸벤즈아마이드,2-chloro-N-dodecyl-3-methylbenzamide,
N-도데실-1-하이드록시-2-나프타마이드,N-dodecyl-1-hydroxy-2-naphthamide,
N-운데실이미다조[1,5-a]피리딘-6-카복스아마이드,N-undecylimidazo[1,5-a]pyridine-6-carboxamide,
N-도데실이미다조[1,5-a]피리딘-6-카복스아마이드,N-dodecylimidazo[1,5-a]pyridine-6-carboxamide,
N-운데실퀴놀린-5-카복스아마이드,N-undecylquinoline-5-carboxamide,
N-도데실퀴놀린-5-카복스아마이드,N-dodecylquinoline-5-carboxamide,
2-(퀴놀린-5-일)-N-운데실아세트아마이드,2-(quinolin-5-yl)-N-undecylacetamide,
N-도데실-2-(퀴놀린-5-일)아세트아마이드,N-dodecyl-2-(quinolin-5-yl)acetamide,
N-운데실-1H-인돌-6-카복스아마이드,N-undecyl-1H-indole-6-carboxamide,
N-도데실-1H-인돌-6-카복스아마이드,N-dodecyl-1H-indole-6-carboxamide,
1-브로모-N-운데실-2-나프타마이드,1-Bromo-N-undecyl-2-naphthamide,
1-브로모-N-도데실-2-나프타마이드,1-Bromo-N-dodecyl-2-naphthamide,
2-(나프탈렌-1-일)-N-운데실아세트아마이드, 및2-(naphthalen-1-yl)-N-undecylacetamide, and
N-도데실-2-(나프탈렌-1-일)아세트아마이드.N-Dodecyl-2-(naphthalen-1-yl)acetamide.
본 발명의 다른 하나의 양태는 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 포함하는, 암 또는 자가면역질환 치료 또는 예방용 약학 조성물을 제공한다.Another aspect of the present invention provides a pharmaceutical composition for treating or preventing cancer or an autoimmune disease, comprising a compound represented by chemical formula 1 or a pharmaceutically acceptable salt thereof.
본 발명에 따른 약학 조성물에서, 특별히 달리 언급되지 않는 한, 관련 용어들은 앞서 설명된 용어들과 동일한 의미를 갖는 것으로 이해된다.In the pharmaceutical composition according to the present invention, unless specifically stated otherwise, related terms are understood to have the same meaning as the terms described above.
본 발명에서 사용되는 용어, "치료"는 본 발명에 따른 조성물의 투여에 의해 암 또는 자가면역질환이 호전, 역전, 완치 등이 되는 모든 것을 의미한다.The term "treatment" used in the present invention means all cases in which cancer or an autoimmune disease is improved, reversed, or cured by administration of a composition according to the present invention.
본 발명에서 사용되는 용어, "예방"은 본 발명에 따른 조성물의 투여에 의해 암 또는 자가면역질환의 발생 또는 재발의 억제, 지연, 방지 등이 되는 모든 것을 의미한다.The term "prevention" used in the present invention means all things that suppress, delay, prevent, etc. the occurrence or recurrence of cancer or autoimmune disease by administration of the composition according to the present invention.
또한, 상기 암은 간암, 대장암, 췌장암, 결장암, 소장암, 위암, 폐암, 뇌암, 골암, 흑색종, 유방암, 경화성선증, 자궁암, 자궁경부암, 두경부암, 식도암, 갑상선암, 부갑상선암, 신장암, 육종, 전립선암, 요도암, 방광암, 혈액암, 림프종, 또는 섬유선종일 수 있으나, 이에 제한되지 않는다.Additionally, the cancer may be, but is not limited to, liver cancer, colon cancer, pancreatic cancer, colon cancer, small intestine cancer, stomach cancer, lung cancer, brain cancer, bone cancer, melanoma, breast cancer, sclerosing adenoma, uterine cancer, cervical cancer, head and neck cancer, esophageal cancer, thyroid cancer, parathyroid cancer, kidney cancer, sarcoma, prostate cancer, urethral cancer, bladder cancer, blood cancer, lymphoma, or fibroadenoma.
상기 자가면역질환에는 상기 자가면역질환에는 전신홍반성낭창(systemic lupus erythematosus; SLE), 사구체염, 강직성 척추염(Ankylosing spondylitis), 중증근무력증(Myastenia gravis) 류마티스 관절염(rheumatoid arthritis; RA), 다발성 경화증(multiple sclerosis; MS), 전신성 경화증(systemic sclerosis), 악성 빈혈(Pernicious anemia) 자가 면역성 빈혈, 염증성장질환(Infammatory bowel disease), 인슐린 의존성 당뇨(insulin-dependent diabetes mellitus; IDDM), 제1형 당뇨병, 그레이브스 병(grave’s disease), 그레이브스 갑상선 항진증(Graves hyperthyroidism), 기쿠치(Kikuchi) 병, 혈구탐식성 림프조직구증(Hemophagocytic lymphohistiocytosis), 성인 스틸 병(Adult onset Still's disease), 베체트 병(Behcet disease), IgG4-연관성 질환, 건선, 천식 또는 이식거부반응 등이 포함될 수 있으나, 이에 제한되는 것은 아니다.The above autoimmune diseases include systemic lupus erythematosus (SLE), glomerulitis, ankylosing spondylitis, myastenia gravis, rheumatoid arthritis (RA), multiple sclerosis (MS), systemic sclerosis, pernicious anemia, autoimmune anemia, inflammatory bowel disease, insulin-dependent diabetes mellitus (IDDM), type 1 diabetes, Graves' disease, Graves' hyperthyroidism, Kikuchi's disease, hemophagocytic lymphohistiocytosis, adult onset Still's disease, Behcet's disease. disease), IgG4-associated diseases, psoriasis, asthma, or transplant rejection, but are not limited to these.
본 발명의 약학 조성물은 상기 화합물, 이의 이성질체, 용매화물, 수화물, 결정형 또는 이의 염을 유효량으로 포함하여, 암 또는 자가면역질환 예방 또는 치료를 필요로 하는 대상체에게 투여될 수 있다. The pharmaceutical composition of the present invention comprises an effective amount of the compound, an isomer thereof, a solvate, a hydrate, a crystal form thereof, or a salt thereof, and can be administered to a subject in need of prevention or treatment of cancer or an autoimmune disease.
본 명세서에서 사용되는 용어, "투여"는 관련 기술분야의 통상의 기술자에게 공지된 다양한 방법 및 전달 시스템 중 임의의 것을 사용하여 조성물을 대상체에게 물리적으로 도입하는 것을 의미한다. 상기 투여는 예를 들어, 경구 투여, 또는 정맥내, 근육내, 피하, 복강내, 척수 또는 다른 비경구 투여, 예컨대 주사 또는 주입에 의한 투여 등으로 수행될 수 있으나, 이에 제한되지 않는다. 상기 투여의 횟수는 예를 들어 단회, 복수 회, 및 하나 이상의 연장된 기간에 걸쳐 수행될 수 있다. 본 발명의 약학 조성물은 상술한 바와 같은 투여 경로에 따라 경구 투여용 또는 비경구 투여용 제제로 제형화 할 수 있다. As used herein, the term "administration" means physically introducing a composition into a subject using any of a variety of methods and delivery systems known to those of ordinary skill in the art. The administration may be, for example, oral, or intravenous, intramuscular, subcutaneous, intraperitoneal, spinal or other parenteral administration, such as injection or infusion, but is not limited thereto. The number of times the administration may be performed may be, for example, single, multiple, and over one or more extended periods of time. The pharmaceutical composition of the present invention may be formulated as a preparation for oral or parenteral administration according to the route of administration as described above.
본 명세서에서 사용되는 용어, "대상체"는 인간 또는 임의의 비인간 동물을 포함하며, 상기 비인간 동물은 척추동물, 예컨대 영장류, 개, 소, 말, 돼지, 설치류, 예컨대 마우스, 래트, 기니피그 등일 수 있다. 본 명세서에서, 상기 "대상체"는 "개체" 및 "환자"와 상호교환적으로 사용된다. The term "subject" as used herein includes a human or any non-human animal, which non-human animal may be a vertebrate, such as a primate, dog, cow, horse, pig, rodent, such as a mouse, rat, guinea pig, and the like. As used herein, the "subject" is used interchangeably with "individual" and "patient".
특히, 본 발명에 따른 화합물 또는 조성물이 투여되는 대상체는 암 환자, 또는 자가면역질환을 앓고 있거나 자가면역질환 발병 위험도가 높은 암 환자일 수 있다. 또한, 본 발명에 따른 화합물 또는 조성물이 투여되는 대상체는 자가면역질환 환자, 또는 암을 앓고 있거나 암 발병 위험도가 높은 자가면역질환 환자일 수 있다. In particular, the subject to whom the compound or composition according to the present invention is administered may be a cancer patient, or a cancer patient suffering from an autoimmune disease or at a high risk of developing an autoimmune disease. In addition, the subject to whom the compound or composition according to the present invention is administered may be a patient suffering from an autoimmune disease, or a patient suffering from cancer or at a high risk of developing an autoimmune disease.
또한, 상기 유효량은 "치료 유효량" 또는 "예방 유효량"일 수 있다. 용어, "치료 유효량"은 약물 또는 치료제가 단독으로 또는 다른 치료제와 조합되어 사용되는 경우에, 질환 증상의 중증도 감소, 질환 증상이 없는 기간의 빈도 및 지속기간의 증가, 또는 질환 고통으로 인한 손상 또는 장애의 방지를 나타낼 수 있는 임의의 양을 의미한다. 용어, "예방 유효량"은 대상체에서 질환의 발생 또는 재발을 억제하는 임의의 양을 의미한다. 상기 유효량의 수준은 대상체의 중증도, 연령, 성별, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출 비율, 치료기간, 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소 등에 따라 결정될 수 있다.Additionally, the effective amount may be a "therapeutically effective amount" or a "prophylactically effective amount." The term "therapeutically effective amount" means any amount that, when the drug or therapeutic agent is used alone or in combination with other therapeutic agents, can exhibit a decrease in the severity of disease symptoms, an increase in the frequency and duration of disease symptom-free periods, or a prevention of impairment or disability due to disease affliction. The term "prophylactically effective amount" means any amount that inhibits the occurrence or recurrence of a disease in a subject. The level of the effective amount can be determined depending on factors such as the severity of the disease, age, sex, activity of the drug, sensitivity to the drug, time of administration, route of administration and excretion rate, duration of treatment, concomitant medications, and other factors well known in the medical field.
또한, 상기 약학 조성물의 투여량은 대상체의 나이, 성별, 체중, 투여 경로, 질병의 중증도 등에 따라 달라질 수 있으며, 구체적으로 대상체의 증상에 따라 본 발명의 조성물 0.1 내지 100 mg/kg을 일일 단회 내지 수회 투여하거나, 또는 수일 내지 수개월 간격으로 투여할 수 있다. In addition, the dosage of the pharmaceutical composition may vary depending on the age, sex, weight, administration route, severity of disease, etc. of the subject, and specifically, depending on the symptoms of the subject, 0.1 to 100 mg/kg of the composition of the present invention may be administered once or several times a day, or at intervals of several days to several months.
또한, 상기 약학 조성물은 약학 조성물의 제조에 통상적으로 사용하는 적절한 담체, 부형제 및 희석제를 더 포함할 수 있다. 조성물에 포함될 수 있는 담체, 부형제 및 희석제는 예를 들면 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유일 수 있으나, 이에 제한되지 않는다.In addition, the pharmaceutical composition may further comprise suitable carriers, excipients and diluents commonly used in the manufacture of pharmaceutical compositions. Carriers, excipients and diluents that may be included in the composition may be, but are not limited to, for example, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
또한, 상기 약학 조성물은 다른 치료제와 병용하여 투여될 수 있다. 이 경우, 본 발명의 약학 조성물과 다른 치료제는 동시에, 순차적으로, 또는 개별적으로 투여될 수 있다. 상기 다른 치료제는 암 또는 자가면역질환의 예방, 치료 및 개선 효과를 갖는 화합물, 단백질 등의 약물일 수 있으나, 이에 제한되는 것은 아니다.In addition, the pharmaceutical composition may be administered in combination with other therapeutic agents. In this case, the pharmaceutical composition of the present invention and the other therapeutic agents may be administered simultaneously, sequentially, or individually. The other therapeutic agents may be drugs such as compounds, proteins, etc. that have preventive, therapeutic, and improving effects on cancer or autoimmune diseases, but are not limited thereto.
또한, 상기 약학 조성물은 다른 치료제와 동시에, 순차적으로 또는 개별적으로 투여되도록 제형화될 수 있다. 예를 들어, 상기 화합물, 이의 이성질체, 용매화물, 수화물, 결정형 또는 이의 염과 다른 치료제는 하나의 제제로 동시에 투여될 수 있으며, 또는 별개의 제제로 동시에, 순차적으로 또는 개별적으로 투여될 수 있다. 동시에, 순차적으로 또는 개별적으로 투여하기 위해, 본 발명의 약학 조성물에 포함되는 상기 화합물, 이의 이성질체, 용매화물, 수화물, 결정형 또는 이의 염과 다른 치료제는 각각 별도의 용기로 분리시켜 제형화되거나, 동일한 용기에서 함께 제형화될 수 있다. 또한, 본 발명의 약학 조성물에 포함되는 상기 화합물, 이의 이성질체, 용매화물, 수화물, 결정형 또는 이의 염과 다른 치료제는 약학적 유효량, 투여 시간, 투여 간격, 투여 경로, 치료 기간 등이 서로 동일하거나 상이할 수 있다.In addition, the pharmaceutical composition may be formulated to be administered simultaneously, sequentially, or separately with another therapeutic agent. For example, the compound, its isomer, solvate, hydrate, crystalline form, or salt thereof and the other therapeutic agent may be administered simultaneously in one formulation, or may be administered simultaneously, sequentially, or separately in separate formulations. In order to be administered simultaneously, sequentially, or separately, the compound, its isomer, solvate, hydrate, crystalline form, or salt thereof and the other therapeutic agent included in the pharmaceutical composition of the present invention may be formulated separately in separate containers, or may be formulated together in the same container. In addition, the compound, its isomer, solvate, hydrate, crystalline form, or salt thereof and the other therapeutic agent included in the pharmaceutical composition of the present invention may be the same or different from each other in terms of pharmaceutically effective amount, administration time, administration interval, administration route, treatment period, etc.
본 발명의 다른 하나의 양태는 화학식 1로 표시되는 화합물 또는 이의 염을 대상체에게 투여하는 단계를 포함하는, 암 또는 자가면역질환 치료 또는 예방 방법을 제공한다.Another aspect of the present invention provides a method for treating or preventing cancer or an autoimmune disease, comprising administering to a subject a compound represented by chemical formula 1 or a salt thereof.
본 발명에 따른 암 또는 자가면역질환 치료 또는 예방 방법에서, 특별히 달리 언급되지 않는 한, 관련 용어들은 앞서 설명된 용어들과 동일한 의미를 갖는 것으로 이해된다.In the method for treating or preventing cancer or autoimmune disease according to the present invention, unless specifically stated otherwise, related terms are understood to have the same meaning as the terms described above.
또한, 본 발명에 따른 암 또는 자가면역질환 치료 또는 예방 방법에서, 상기 화합물 또는 이의 염은 다른 제제와 동시에, 순차적으로 또는 개별적으로 대상체에게 투여될 수 있다. In addition, in the method for treating or preventing cancer or autoimmune disease according to the present invention, the compound or its salt may be administered to the subject simultaneously, sequentially, or separately with other agents.
상기 "동시" 투여는 상기 화합물 또는 이의 염과 다른 치료제를 하나의 제제로 한 번에 투여하는 것을 의미하거나, 또는 상기 화합물 또는 이의 염과 다른 치료제를 별도의 제제로 한 번에 투여하는 것을 의미하며, 이 경우 투여경로는 서로 상이할 수 있다. The above “simultaneous” administration means administering the compound or its salt and the other therapeutic agent at the same time as one preparation, or means administering the compound or its salt and the other therapeutic agent at the same time as separate preparations, in which case the routes of administration may be different.
상기 "순차적" 투여는 화합물 또는 이의 염과 다른 치료제를 비교적 연속적으로 투여하는 것을 의미하며, 투여 간격에 소모되는 시간으로 가능한 최소한의 시간을 허락한다. The above "sequential" administration means administering the compound or its salt and the other therapeutic agent relatively sequentially, allowing for the shortest possible time between administrations.
상기 "개별적" 투여는 일정 시간 간격을 두고 화합물 또는 이의 염과 다른 치료제를 투여하는 것을 의미한다. The above "separate" administration means administering the compound or its salt and other therapeutic agents at regular intervals of time.
본 발명의 다른 하나의 양태는 화학식 1로 표시되는 화합물 또는 이의 식품학적으로 허용가능한 염을 포함하는, 암 또는 자가면역질환 개선 또는 예방용 식품 조성물을 제공한다.Another aspect of the present invention provides a food composition for improving or preventing cancer or an autoimmune disease, comprising a compound represented by chemical formula 1 or a food-chemically acceptable salt thereof.
본 발명에 따른 식품 조성물에서 각 용어는 특별히 언급하지 않는 한 상기 조성물에서 상기한 바와 동일한 의미를 갖는다.In the food composition according to the present invention, each term has the same meaning as described above in the composition unless specifically mentioned.
본 발명에서 사용되는 용어 "개선"은 본 발명에 따른 조성물의 투여로 암 또는 자가면역질환의 정도가 감소되거나 호전되거나 진행이 지연되는 모든 행위를 의미한다.The term “improvement” as used in the present invention means any act in which the degree of cancer or autoimmune disease is reduced, improved, or progression is delayed by administration of the composition according to the present invention.
상기 식품은 건강기능성 식품일 수 있다. 용어 "건강기능성 식품"이란, 인체에 유용한 기능성을 가진 원료나 성분을 사용하여 정제, 캅셀, 분말, 과립, 액상 및 환 등의 형태로 제조 및 가공한 식품을 의미한다. 여기서 "기능성"이라 함은 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학적 작용 등과 같은 보건용도에 유용한 효과를 얻는 것을 의미한다.The above food may be a health functional food. The term "health functional food" refers to a food manufactured and processed in the form of tablets, capsules, powders, granules, liquids, and pills using raw materials or ingredients that have functionality useful to the human body. Here, "functionality" refers to obtaining a useful effect for health purposes such as regulating nutrients or physiological actions for the structure and function of the human body.
본 발명에 따른 식품 조성물은 당업계에서 통상적으로 사용되는 방법에 의하여 제조가능하며, 상기 제조 시에는 당업계에서 통상적으로 첨가하는 원료 및 성분을 첨가하여 제조할 수 있다. 또한, 일반 약품과는 달리 식품을 원료로 하여 약품의 장기 복용 시 발생할 수 있는 부작용 등이 없는 장점이 있고, 휴대성이 뛰어나므로, 본 발명의 식품 조성물은 암의 치료 효과를 증진 또는 개선시키기 위한 보조제로 섭취가 가능하다. The food composition according to the present invention can be manufactured by a method commonly used in the art, and can be manufactured by adding raw materials and ingredients commonly added in the art during the manufacturing process. In addition, unlike general drugs, it has the advantage of not having side effects that may occur when taking drugs for a long period of time because it uses food as a raw material, and since it is highly portable, the food composition of the present invention can be taken as a supplement to enhance or improve the therapeutic effect of cancer.
본 발명에 따른 식품 조성물에 유효성분으로서 포함되는 화합물, 이의 이성질체, 용매화물, 수화물, 결정형 또는 이의 식품학적으로 허용가능한 염의 양은 사용 목적(예방, 개선 또는 치료적 처치)에 따라 적합하게 결정될 수 있다. 일반적으로, 식품의 제조 시에 본 발명의 화합물 또는 이의 식품학적으로 허용가능한 염은 조성물 중 0.001 내지 20 중량%, 0.001 내지 15 중량% 또는 0.001 내지 10 중량%의 양으로 포함될 수 있다. 건강음료의 경우 100 mL를 기준으로 0.01 내지 2 g, 구체적으로 0.02 내지 2 g, 보다 구체적으로 0.3 내지 1 g을 가할 수 있다. 그러나, 건강 및 위생을 목적으로 하거나 또는 건강 조절을 목적으로 하는 장기간의 섭취의 경우에는 상기 양은 상기 범위 이하로도 사용될 수 있다.The amount of the compound, its isomer, solvate, hydrate, crystal form or its food-wise acceptable salt included as an effective ingredient in the food composition according to the present invention may be suitably determined depending on the intended use (prevention, improvement or therapeutic treatment). Generally, when manufacturing a food, the compound of the present invention or its food-wise acceptable salt may be included in an amount of 0.001 to 20 wt%, 0.001 to 15 wt% or 0.001 to 10 wt% in the composition. In the case of a health drink, 0.01 to 2 g, specifically 0.02 to 2 g, more specifically 0.3 to 1 g may be added based on 100 mL. However, in the case of long-term intake for the purpose of health and hygiene or health control, the amount may be used below the above range.
상기 식품 조성물을 제조하는 과정에서 식품 조성물에 첨가되는 본 발명에 따른 화합물 또는 이의 식품학적으로 허용가능한 염은 필요에 따라 그 함량을 적절히 가감할 수 있다.In the process of manufacturing the above food composition, the content of the compound according to the present invention or a food-wise acceptable salt thereof added to the food composition can be appropriately increased or decreased as needed.
본 발명의 식품 조성물은 효능 증진을 위해 상기 화합물 또는 이의 식품학적으로 허용가능한 염 외에 추가 성분을 더 포함할 수 있다. The food composition of the present invention may further contain additional ingredients in addition to the compound or a food-wise acceptable salt thereof to enhance efficacy.
상기 식품 조성물은 환제, 정제, 과립, 분말, 캡슐, 액상의 용액으로 이루어진 군으로부터 선택된 어느 하나의 제형일 수 있다.The above food composition may be in any one dosage form selected from the group consisting of a pill, a tablet, a granule, a powder, a capsule, and a liquid solution.
또한, 상기 식품의 종류는 특별한 제한되지 않는다. 상기 물질을 첨가할 수 있는 식품의 예로는 육류, 소세지, 빵, 쵸코렛, 캔디류, 스넥류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알콜 음료 및 비타민 복합제 등이 있으며, 통상적인 의미에서의 식품을 모두 포함한다.In addition, the type of the food is not particularly limited. Examples of foods to which the substance can be added include meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, dairy products including ice cream, various soups, beverages, tea, drinks, alcoholic beverages, and vitamin complexes, and include all foods in the conventional sense.
본 발명의 식품 조성물은 통상의 식품과 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 상기 천연 탄수화물은 포도당, 과당과 같은 모노사카라이드, 말토스, 수크로스와 같은 디사카라이드, 및 덱스트린, 사이클로덱스트린과 같은 폴리사카라이드, 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이다. 감미제로서는 타우마틴, 스테비아 추출물과 같은 천연 감미제나, 사카린, 아스파르탐과 같은 합성 감미제 등을 사용할 수 있다. The food composition of the present invention may contain various flavoring agents or natural carbohydrates as additional ingredients, like conventional foods. The natural carbohydrates are monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, polysaccharides such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol and erythritol. As a sweetener, a natural sweetener such as thaumatin and stevia extract, or a synthetic sweetener such as saccharin and aspartame can be used.
본 발명의 식품 조성물이 음료 조성물일 경우 필수 성분으로서 상기 화합물 또는 이의 식품학적으로 허용가능한 염을 지시된 비율로 함유하는 외에는 액체 성분에 특별한 제한은 없으며, 통상의 음료와 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다.When the food composition of the present invention is a beverage composition, there is no special limitation on the liquid component other than containing the compound or a food-wise acceptable salt thereof as an essential component in the indicated ratio, and various flavoring agents or natural carbohydrates, etc. may be contained as additional components like a conventional beverage.
본 발명에 따른 화학식 1의 바이사이클릭 화합물 또는 이의 염은 암세포를 사멸시키는 효과 또는 종양 성장 및 증식 억제 효과가 매우 우수하며, 인체에 대한 안전성이 뛰어나다. 따라서, 암의 예방, 치료 또는 개선을 위하여 유용하게 활용될 수 있다.The bicyclic compound of chemical formula 1 or a salt thereof according to the present invention has an excellent effect of killing cancer cells or inhibiting tumor growth and proliferation, and is highly safe for the human body. Therefore, it can be usefully utilized for the prevention, treatment, or improvement of cancer.
또한, 본 발명에 따른 화학식 1의 바이사이클릭 화합물 또는 이의 염은 T 세포의 증식을 억제할 뿐만 아니라 B 세포의 사멸을 유도할 수 있어 강력한 면역억제 기능을 나타내므로, 이식 거부반응 외에 자가 항체를 형성하는 자가면역질환 치료 또는 예방을 위해 유용하게 사용할 수 있다.In addition, the bicyclic compound of chemical formula 1 or a salt thereof according to the present invention exhibits a strong immunosuppressive function by not only inhibiting the proliferation of T cells but also inducing the death of B cells, and therefore can be usefully used for the treatment or prevention of autoimmune diseases that form autoantibodies in addition to transplant rejection.
도 1은 B 세포 림프종 세포주 SU-DLH-8에 본 발명의 화합물을 30μM 농도로 처리하였을 때 세포사멸사(Apoptosis) 수준을 나타낸다. X축에서 C는 대조군(DMSO)을 가리킨다.Figure 1 shows the level of apoptosis when the compound of the present invention was treated at a concentration of 30 μM in the B cell lymphoma cell line SU-DLH-8. On the X-axis, C indicates the control (DMSO).
도 2는 자궁경부암 세포주 HeLa에 본 발명의 화합물을 30μM 농도로 처리하였을 때 세포사멸사(Apoptosis) 수준을 나타낸다. X축에서 C는 대조군(DMSO)을 가리킨다.Figure 2 shows the level of apoptosis when the cervical cancer cell line HeLa was treated with the compound of the present invention at a concentration of 30 μM. On the X-axis, C indicates the control group (DMSO).
이하 본 발명을 실시예에 의해 보다 상세하게 설명한다. 그러나 이들 실시예는 본 발명을 예시적으로 설명하기 위한 것으로, 본 발명의 범위가 이들 실시예에 의해 제한되는 것은 아니다. 또한, 당해 기술분야에서 통상의 지식을 가진 자라면 본 발명의 취지를 해하지 않는 범위 내에서 본 발명에 대해 다양한 변형 및 수정을 가할 수 있을 것이다. 본 명세서에서 특별히 정의되지 않은 용어들에 대해서는 본 발명이 속하는 기술 분야에서 통상적으로 사용되는 의미를 갖는 것으로 이해되어야 할 것이다. 또한, 문맥상 특별히 정의하지 않은 경우라면, 단수는 복수를 포함하며, 복수는 단수를 포함한다.Hereinafter, the present invention will be described in more detail by way of examples. However, these examples are provided for illustrative purposes only, and the scope of the present invention is not limited by these examples. In addition, those skilled in the art will be able to make various modifications and changes to the present invention without detracting from the spirit of the present invention. It should be understood that terms not specifically defined herein have the meanings commonly used in the technical field to which the present invention belongs. In addition, unless specifically defined in the context, the singular includes the plural, and the plural includes the singular.
제조예Manufacturing example
본 발명의 화합물들이 하기 반응식에 따라 제조되었다. 치환기가 다른 화합물들의 경우에도 유사한 단계를 통해 실제 제조하였으나, 본 명세서에 모두 명시하지는 않았다. 당해 기술분야에서 통상의 지식을 가진 자라면 하기의 대표적인 예들을 참조하여 치환기가 다른 화합물들을 용이하게 제조할 수 있다.The compounds of the present invention were prepared according to the following reaction scheme. Compounds having different substituents were also prepared through similar steps, but are not all specified in this specification. Those skilled in the art can easily prepare compounds having different substituents by referring to the representative examples below.
[반응식][Reaction formula]
Figure PCTKR2024001580-appb-img-000002
Figure PCTKR2024001580-appb-img-000002
디클로로메탄(DCM) 1ml에 다양한 치환기가 결합되어 있는 벤조익산 (1 eq), 아민 (1.1 eq), EDCI (1.1 eq), DMAP (0.1 eq), TEA (2.2 eq)를 넣고 상온에서 6시간 동안 교반하였다. 물 50 ml를 첨가하고 디클로로메탄 (60 ml)을 첨가하여 유기물질 층을 분리하였으며, 이를 Na2SO4에서 건조시키고, 여과한 후 감압하에서 농축시켰다. 이어서, 컬럼크로마토그래피를 사용하여 정제하고 (EA 5%) 그 결과 목적 화합물을 수득하였다.Benzoic acid (1 eq), amine (1.1 eq), EDCI (1.1 eq), DMAP (0.1 eq), and TEA (2.2 eq) having various substituents were added to 1 ml of dichloromethane (DCM) and stirred at room temperature for 6 hours. 50 ml of water was added and dichloromethane (60 ml) was added to separate the organic layer, which was dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. Then, the residue was purified using column chromatography (EA 5%) to obtain the target compound as a result.
수득한 화합물과 이의 화학구조, 순도, 성상, 수율 및 식별 데이터를 대표적으로 나타내면 다음과 같다.The obtained compounds and their chemical structures, purity, properties, yields and identification data are presented as follows.
화합물 46: N-운데실-2,3-디하이드로-1H-벤조[d][1,2,3]트리아졸-5-카복스아마이드Compound 46: N-undecyl-2,3-dihydro-1H-benzo[d][1,2,3]triazole-5-carboxamide
Figure PCTKR2024001580-appb-img-000003
Figure PCTKR2024001580-appb-img-000003
순도: 100%, 연한 갈색 고체, 수율: 30%, 1H NMR (400 MHz, DMSO) δ 8.61 (t, J = 5.2 Hz, 1H), 8.43 (s, 1H), 7.93 (s, 2H), 3.29 (d, J = 6.3 Hz, 2H), 1.62 - 1.49 (m, 2H), 1.27 (d, J = 25.8 Hz, 16H), 0.84 (t, J = 6.8 Hz, 3H)., MS calcd for C18H28N4O(M+H)+:316, found 317.Purity: 100%, light brown solid, yield: 30%, 1 H NMR (400 MHz, DMSO) δ 8.61 (t, J = 5.2 Hz, 1H), 8.43 (s, 1H), 7.93 (s, 2H), 3.29 (d, J = 6.3 Hz, 2H), 1.62 - 1.49 (m, 2H), 1.27 (d, J = 25.8 Hz, 16H), 0.84 (t, J = 6.8 Hz, 3H)., MS calcd for C 18 H 28 N 4 O(M+H) + :316, found 317.
화합물 47: N-도데실-1H-벤조[d][1,2,3]트리아졸-5-카복스아마이드Compound 47: N-Dodecyl-1H-benzo[d][1,2,3]triazole-5-carboxamide
Figure PCTKR2024001580-appb-img-000004
Figure PCTKR2024001580-appb-img-000004
순도: 98%, 백색 고체, 수율: 29%, 1H NMR (400 MHz, DMSO) δ 8.61 (t, J = 5.4 Hz, 1H), 8.43 (s, 1H), 7.93 (s, 2H), 3.27 (d, J = 7.0 Hz, 2H), 1.59 - 1.50 (m, 2H), 1.26 (d, J = 28.8 Hz, 18H), 0.84 (t, J = 6.8 Hz, 3H)., MS calcd for C19H30N4O(M+H)+:330, found 331.Purity: 98%, white solid, yield: 29%, 1H NMR (400 MHz, DMSO) δ 8.61 (t, J = 5.4 Hz, 1H), 8.43 (s, 1H), 7.93 (s, 2H), 3.27 (d, J = 7.0 Hz, 2H), 1.59 - 1.50 (m, 2H), 1.26 (d, J = 28.8 Hz, 18H), 0.84 (t, J = 6.8 Hz, 3H)., MS calcd for C 19 H 30 N 4 O(M+H) + :330, found 331.
화합물 50: N-운데실-1H-벤조[d]이미다졸-5-카복스아마이드Compound 50: N-Undecyl-1H-benzo[d]imidazole-5-carboxamide
Figure PCTKR2024001580-appb-img-000005
Figure PCTKR2024001580-appb-img-000005
순도: 100%, 황색 고체, 수율: 47%, 1H NMR (400 MHz, DMSO) δ 12.63 (s, 1H), 8.39 (s, 1H), 8.31 (s, 1H), 8.13 (s, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.61 (s, 1H), 3.26 (dd, J = 13.0, 6.8 Hz, 2H), 1.52 (dd, J = 13.6, 6.7 Hz, 2H), 1.26 (d, J = 22.2 Hz, 16H), 0.84 (t, J = 6.8 Hz, 3H)., MS calcd for C19H29N3O(M+H)+:315, found 316.Purity: 100%, yellow solid, yield: 47%, 1H NMR (400 MHz, DMSO) δ 12.63 (s, 1H), 8.39 (s, 1H), 8.31 (s, 1H), 8.13 (s, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.61 (s, 1H), 3.26 (dd, J = 13.0, 6.8 Hz, 2H), 1.52 (dd, J = 13.6, 6.7 Hz, 2H), 1.26 (d, J = 22.2 Hz, 16H), 0.84 (t, J = 6.8 Hz, 3H)., MS calcd for C 19 H 29 N 3 O(M+H) + :315, found 316.
화합물 85: 1-메틸-N-운데실-1H-인돌-7-카복스아마이드Compound 85: 1-Methyl-N-undecyl-1H-indole-7-carboxamide
Figure PCTKR2024001580-appb-img-000006
Figure PCTKR2024001580-appb-img-000006
순도: 99%, 백색 고체, 수율: 10%, 1H NMR (400 MHz, CDCl3) δ 7.68 (dd, J = 7.9, 1.1 Hz, 1H), 7.20 (dd, J = 7.2, 0.9 Hz, 1H), 7.07 - 7.03 (m, 2H), 6.51 (d, J = 3.1 Hz, 1H), 6.00 (s, 1H), 3.85 (s, 3H), 3.49 (dd, J = 13.1, 7.0 Hz, 2H), 1.69 - 1.58 (m, 2H), 1.46 - 1.22 (m, 16H), 0.88 (t, J = 6.8 Hz, 3H)., MS calcd for C21H32N2O (M+H)+: 328, found 329.Purity: 99%, white solid, yield: 10%, 1H NMR (400 MHz, CDCl 3 ) δ 7.68 (dd, J = 7.9, 1.1 Hz, 1H), 7.20 (dd, J = 7.2, 0.9 Hz, 1H), 7.07 - 7.03 (m, 2H), 6.51 (d, J = 3.1 Hz, 1H), 6.00 (s, 1H), 3.85 (s, 3H), 3.49 (dd, J = 13.1, 7.0 Hz, 2H), 1.69 - 1.58 (m, 2H), 1.46 - 1.22 (m, 16H), 0.88 (t, J = 6.8 Hz, 3H)., MS calcd for C 21 H 32 N 2 O (M+H) + : 328, found 329.
화합물 94: N-운데실퀴놀린-2-카복스아마이드Compound 94: N-undecylquinoline-2-carboxamide
Figure PCTKR2024001580-appb-img-000007
Figure PCTKR2024001580-appb-img-000007
순도: 99%, 황색 고체, 수율: 75%, 1H NMR (400 MHz, CDCl3) δ 8.31 (s, 2H), 8.28 (s, 1H), 8.11 (d, J = 8.5 Hz, 1H), 7.88 (dd, J = 8.2, 0.8 Hz, 1H), 7.77 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.62 (ddd, J = 8.1, 7.0, 1.1 Hz, 1H), 3.53 (dd, J = 13.5, 7.1 Hz, 2H), 1.70 (dt, J = 14.9, 7.3 Hz, 2H), 1.48 - 1.22 (m, 16H), 0.87 (t, J = 6.9 Hz, 3H)., MS calcd for C21H30N2O (M+H)+: 326, found 327.Purity: 99%, yellow solid, yield: 75%, 1 H NMR (400 MHz, CDCl 3 ) δ 8.31 (s, 2H), 8.28 (s, 1H), 8.11 (d, J = 8.5 Hz, 1H), 7.88 (dd, J = 8.2, 0.8 Hz, 1H), 7.77 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.62 (ddd, J = 8.1, 7.0, 1.1 Hz, 1H), 3.53 (dd, J = 13.5, 7.1 Hz, 2H), 1.70 (dt, J = 14.9, 7.3 Hz, 2H), 1.48 - 1.22 (m, 16H), 0.87 (t, J = 6.9 Hz, 3H)., MS calcd for C 21 H 30 N 2 O (M+H) + : 326, found 327.
화합물 95: N-도데실퀴놀린-2-카복스아마이드Compound 95: N-Dodecylquinoline-2-carboxamide
Figure PCTKR2024001580-appb-img-000008
Figure PCTKR2024001580-appb-img-000008
순도: 100%, 황색 고체, 수율: 79%, 1H NMR (400 MHz, CDCl3) δ 8.31 (s, 2H), 8.28 (s, 1H), 8.11 (d, J = 8.5 Hz, 1H), 7.88 (d, J = 8.2 Hz, 1H), 7.77 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.62 (ddd, J = 8.1, 7.0, 1.1 Hz, 1H), 3.53 (dd, J = 13.5, 7.1 Hz, 2H), 1.79 - 1.63 (m, 2H), 1.49 - 1.17 (m, 18H), 0.87 (t, J = 6.8 Hz, 3H)., MS calcd for C22H32N2O (M+H)+: 340, found 341.Purity: 100%, yellow solid, yield: 79%, 1 H NMR (400 MHz, CDCl 3 ) δ 8.31 (s, 2H), 8.28 (s, 1H), 8.11 (d, J = 8.5 Hz, 1H), 7.88 (d, J = 8.2 Hz, 1H), 7.77 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.62 (ddd, J = 8.1, 7.0, 1.1 Hz, 1H), 3.53 (dd, J = 13.5, 7.1 Hz, 2H), 1.79 - 1.63 (m, 2H), 1.49 - 1.17 (m, 18H), 0.87 (t, J = 6.8 Hz, 3H)., MS calcd for C 22 H 32 N 2 O (M+H) + : 340, found 341.
화합물 110: 8-하이드록시-N-운데실퀴놀린-7-카복스아마이드Compound 110: 8-Hydroxy-N-undecylquinoline-7-carboxamide
Figure PCTKR2024001580-appb-img-000009
Figure PCTKR2024001580-appb-img-000009
순도: 100%, 갈색 고체, 수율: 27%, 1H NMR (400 MHz, CDCl3) δ 8.89 (dd, J = 4.3, 1.4 Hz, 1H), 8.21 (dd, J = 8.3, 1.4 Hz, 1H), 8.13 (d, J = 8.8 Hz, 1H), 7.81 (s, 1H), 7.55 (dd, J = 8.3, 4.3 Hz, 1H), 7.38 (d, J = 8.8 Hz, 1H), 3.53 (dd, J = 12.8, 7.1 Hz, 2H), 1.73 - 1.60 (m, 2H), 1.47 - 1.20 (m, 16H), 0.87 (t, J = 6.8 Hz, 3H)., MS calcd for C21H30N2O2(M+H)+:342, found 343.Purity: 100%, brown solid, yield: 27%, 1 H NMR (400 MHz, CDCl 3 ) δ 8.89 (dd, J = 4.3, 1.4 Hz, 1H), 8.21 (dd, J = 8.3, 1.4 Hz, 1H), 8.13 (d, J = 8.8 Hz, 1H), 7.81 (s, 1H), 7.55 (dd, J = 8.3, 4.3 Hz, 1H), 7.38 (d, J = 8.8 Hz, 1H), 3.53 (dd, J = 12.8, 7.1 Hz, 2H), 1.73 - 1.60 (m, 2H), 1.47 - 1.20 (m, 16H), 0.87 (t, J = 6.8 Hz, 3H)., MS calcd for C 21 H 30 N 2 O 2 (M+H) + :342, found 343.
화합물 111: N-도데실-8-하이드록시퀴놀린-7-카복스아마이드Compound 111: N-Dodecyl-8-hydroxyquinoline-7-carboxamide
Figure PCTKR2024001580-appb-img-000010
Figure PCTKR2024001580-appb-img-000010
순도: 97%, 갈색 오일, 수율: 2%, 1H NMR (400 MHz, CDCl3) δ 8.95 - 8.73 (m, 1H), 8.16 (t, J = 9.2 Hz, 2H), 7.80 (s, 1H), 7.52 (dd, J = 8.3, 4.2 Hz, 1H), 7.38 (d, J = 8.8 Hz, 1H), 3.54 (dd, J = 12.9, 6.9 Hz, 2H), 1.68 (dt, J = 14.7, 7.2 Hz, 2H), 1.28 (d, J = 22.2 Hz, 18H), 0.88 (dd, J = 7.7, 5.9 Hz, 3H)., MS calcd for C22H32N2O2(M+H)+:356, found 357.Purity: 97%, brown oil, yield: 2%, 1 H NMR (400 MHz, CDCl 3 ) δ 8.95 - 8.73 (m, 1H), 8.16 (t, J = 9.2 Hz, 2H), 7.80 (s, 1H), 7.52 (dd, J = 8.3, 4.2 Hz, 1H), 7.38 (d, J = 8.8 Hz, 1H), 3.54 (dd, J = 12.9, 6.9 Hz, 2H), 1.68 (dt, J = 14.7, 7.2 Hz, 2H), 1.28 (d, J = 22.2 Hz, 18H), 0.88 (dd, J = 7.7, 5.9 Hz, 3H)., MS calcd for C 22 H 32 N 2 O 2 (M+H) + :356, found 357.
화합물 112: 6-하이드록시-N-운데실-2-나프타마이드Compound 112: 6-Hydroxy-N-undecyl-2-naphthamide
Figure PCTKR2024001580-appb-img-000011
Figure PCTKR2024001580-appb-img-000011
순도: 97%, 갈색 고체, 수율: 3%, 1H NMR (400 MHz, CDCl3) δ 8.20 (s, 1H), 7.82 (d, J = 8.5 Hz, 1H), 7.76 (dd, J = 8.6, 1.7 Hz, 1H), 7.70 (d, J = 8.6 Hz, 1H), 7.20 - 7.12 (m, 2H), 6.21 (s, 1H), 3.50 (dd, J = 13.1, 7.1 Hz, 2H), 1.70 - 1.65 (m, 2H), 1.38 - 1.21 (m, 16H), 0.88 (t, J = 6.8 Hz, 3H)., MS calcd for C22H31NO2(M+H)+:341, found 342.Purity: 97%, brown solid, yield: 3%, 1 H NMR (400 MHz, CDCl 3 ) δ 8.20 (s, 1H), 7.82 (d, J = 8.5 Hz, 1H), 7.76 (dd, J = 8.6, 1.7 Hz, 1H), 7.70 (d, J = 8.6 Hz, 1H), 7.20 - 7.12 (m, 2H), 6.21 (s, 1H), 3.50 (dd, J = 13.1, 7.1 Hz, 2H), 1.70 - 1.65 (m, 2H), 1.38 - 1.21 (m, 16H), 0.88 (t, J = 6.8 Hz, 3H)., MS calcd for C 22 H 31 NO 2 (M+H) + :341, found 342.
화합물 113: N-도데실-6-하이드록시-2-나프타마이드Compound 113: N-dodecyl-6-hydroxy-2-naphthamide
Figure PCTKR2024001580-appb-img-000012
Figure PCTKR2024001580-appb-img-000012
순도: 100%, 백색 고체, 수율: 29%, 1H NMR (400 MHz, CDCl3) δ 8.20 (s, 1H), 7.80 (d, J = 8.5 Hz, 1H), 7.76 (dd, J = 8.6, 1.7 Hz, 1H), 7.68 (d, J = 8.6 Hz, 1H), 7.21 - 7.11 (m, 2H), 6.24 (s, 1H), 6.05 (s, 1H), 3.51 (dd, J = 13.1, 7.0 Hz, 2H), 1.71 - 1.64 (m, 2H), 1.45 - 1.19 (m, 18H), 0.88 (t, J = 6.8 Hz, 3H)., MS calcd for C23H33NO2(M+H)+:355, found 356.Purity: 100%, white solid, yield: 29%, 1 H NMR (400 MHz, CDCl 3 ) δ 8.20 (s, 1H), 7.80 (d, J = 8.5 Hz, 1H), 7.76 (dd, J = 8.6, 1.7 Hz, 1H), 7.68 (d, J = 8.6 Hz, 1H), 7.21 - 7.11 (m, 2H), 6.24 (s, 1H), 6.05 (s, 1H), 3.51 (dd, J = 13.1, 7.0 Hz, 2H), 1.71 - 1.64 (m, 2H), 1.45 - 1.19 (m, 18H), 0.88 (t, J = 6.8 Hz, 3H)., MS calcd for C 23 H 33 NO 2 (M+H) + :355, found 356.
화합물 114: N-도데실-1H-벤조[d]이미다졸-5-카복스아마이드Compound 114: N-Dodecyl-1H-benzo[d]imidazole-5-carboxamide
Figure PCTKR2024001580-appb-img-000013
Figure PCTKR2024001580-appb-img-000013
순도: 96%, 황색 고체, 수율: 30%, 1H NMR (400 MHz, DMSO) δ 12.64 (s, 1H), 8.39 (s, 1H), 8.31 (s, 1H), 8.11 (d, J = 55.9 Hz, 1H), 7.71 (s, 1H), 7.57 (s, 1H), 3.26 (dd, J = 12.9, 6.4 Hz, 2H), 1.57 - 1.48 (m, 2H), 1.26 (d, J = 23.3 Hz, 18H), 0.85 (t, J = 6.8 Hz, 3H)., MS calcd for C20H31N3O(M+H)+:329, found 330.Purity: 96%, yellow solid, yield: 30%, 1 H NMR (400 MHz, DMSO) δ 12.64 (s, 1H), 8.39 (s, 1H), 8.31 (s, 1H), 8.11 (d, J = 55.9 Hz, 1H), 7.71 (s, 1H), 7.57 (s, 1H), 3.26 (dd, J = 12.9, 6.4 Hz, 2H), 1.57 - 1.48 (m, 2H), 1.26 (d, J = 23.3 Hz, 18H), 0.85 (t, J = 6.8 Hz, 3H)., MS calcd for C 20 H 31 N 3 O(M+H) + :329, found 330.
화합물 115: 6-브로모-N-운데실-2-나프타마이드Compound 115: 6-Bromo-N-undecyl-2-naphthamide
Figure PCTKR2024001580-appb-img-000014
Figure PCTKR2024001580-appb-img-000014
순도: 98%, 백색 고체, 수율: 44%, 1H NMR (400 MHz, CDCl3) δ 8.23 (s, 1H), 8.04 (s, 1H), 7.84 (dd, J = 8.6, 1.6 Hz, 1H), 7.78 (dd, J = 8.7, 4.6 Hz, 2H), 7.60 (dd, J = 8.7, 1.8 Hz, 1H), 6.25 (s, 1H), 3.50 (dd, J = 13.1, 7.0 Hz, 2H), 1.72 - 1.61 (m, 2H), 1.49 - 1.16 (m, 16H), 0.88 (t, J = 6.8 Hz, 3H)., MS calcd for C22H30BrNO(M+H)+:404, found 406.Purity: 98%, white solid, yield: 44%, 1H NMR (400 MHz, CDCl 3 ) δ 8.23 (s, 1H), 8.04 (s, 1H), 7.84 (dd, J = 8.6, 1.6 Hz, 1H), 7.78 (dd, J = 8.7, 4.6 Hz, 2H), 7.60 (dd, J = 8.7, 1.8 Hz, 1H), 6.25 (s, 1H), 3.50 (dd, J = 13.1, 7.0 Hz, 2H), 1.72 - 1.61 (m, 2H), 1.49 - 1.16 (m, 16H), 0.88 (t, J = 6.8 Hz, 3H)., MS calcd for C 22 H 30 BrNO(M+H) + :404, found 406.
화합물 116: 6-브로모-N-도데실-2-나프타마이드Compound 116: 6-Bromo-N-dodecyl-2-naphthamide
Figure PCTKR2024001580-appb-img-000015
Figure PCTKR2024001580-appb-img-000015
순도: 97%, 백색 고체, 수율: 37%, 1H NMR (400 MHz, CDCl3) δ 8.23 (s, 1H), 8.03 (d, J = 1.5 Hz, 1H), 7.84 (dd, J = 8.6, 1.7 Hz, 1H), 7.78 (dd, J = 8.6, 4.6 Hz, 2H), 7.60 (dd, J = 8.8, 1.9 Hz, 1H), 6.26 (s, 1H), 3.50 (dd, J = 13.1, 7.1 Hz, 2H), 1.70 - 1.61 (m, 2H), 1.45 - 1.21 (m, 18H), 0.88 (t, J = 6.8 Hz, 3H)., MS calcd for C23H32BrNO(M+H)+:418, found 419.Purity: 97%, white solid, yield: 37%, 1 H NMR (400 MHz, CDCl 3 ) δ 8.23 (s, 1H), 8.03 (d, J = 1.5 Hz, 1H), 7.84 (dd, J = 8.6, 1.7 Hz, 1H), 7.78 (dd, J = 8.6, 4.6 Hz, 2H), 7.60 (dd, J = 8.8, 1.9 Hz, 1H), 6.26 (s, 1H), 3.50 (dd, J = 13.1, 7.1 Hz, 2H), 1.70 - 1.61 (m, 2H), 1.45 - 1.21 (m, 18H), 0.88 (t, J = 6.8 Hz, 3H)., MS calcd for C 23 H 32 BrNO(M+H) + :418, found 419.
화합물 119: 2-클로로-N-도데실-3-메틸벤즈아마이드Compound 119: 2-Chloro-N-dodecyl-3-methylbenzamide
Figure PCTKR2024001580-appb-img-000016
Figure PCTKR2024001580-appb-img-000016
순도: 100%, 백색 고체, 수율: 33%, 1H NMR (400 MHz, CDCl3) δ 13.89 (s, 1H), 8.42 (d, J = 8.2 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.54 (dtd, J = 16.3, 6.9, 1.2 Hz, 2H), 7.27 (q, J = 8.8 Hz, 2H), 6.35 (s, 1H), 3.48 (dd, J = 13.1, 7.1 Hz, 2H), 1.66 (dd, J = 14.4, 7.1 Hz, 2H), 1.43 - 1.19 (m, 16H), 0.88 (t, J = 6.8 Hz, 3H)., MS calcd for C22H31NO2(M+H)+:341, found 342.Purity: 100%, white solid, yield: 33%, 1 H NMR (400 MHz, CDCl 3 ) δ 13.89 (s, 1H), 8.42 (d, J = 8.2 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.54 (dtd, J = 16.3, 6.9, 1.2 Hz, 2H), 7.27 (q, J = 8.8 Hz, 2H), 6.35 (s, 1H), 3.48 (dd, J = 13.1, 7.1 Hz, 2H), 1.66 (dd, J = 14.4, 7.1 Hz, 2H), 1.43 - 1.19 (m, 16H), 0.88 (t, J = 6.8 Hz, 3H)., MS calcd for C 22 H 31 NO 2 (M+H) + :341, found 342.
화합물 120: N-도데실-1-하이드록시-2-나프타마이드Compound 120: N-Dodecyl-1-hydroxy-2-naphthamide
Figure PCTKR2024001580-appb-img-000017
Figure PCTKR2024001580-appb-img-000017
순도: 100%, 백색 고체, 수율: 291H NMR (400 MHz, CDCl3) δ 13.88 (d, J = 0.7 Hz, 1H), 8.42 (d, J = 8.2 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.55 (dt, J = 22.9, 7.3 Hz, 2H), 7.33 - 7.24 (m, 2H), 6.32 (s, 1H), 3.49 (dd, J = 13.1, 7.0 Hz, 2H), 1.66 (dd, J = 14.3, 7.2 Hz, 2H), 1.43 - 1.23 (m, 18H), 0.88 (t, J = 6.7 Hz, 3H)., MS calcd for C23H33NO2(M+H)+:355, found 356.Purity: 100%, white solid, yield: 29 1 H NMR (400 MHz, CDCl 3 ) δ 13.88 (d, J = 0.7 Hz, 1H), 8.42 (d, J = 8.2 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.55 (dt, J = 22.9, 7.3 Hz, 2H), 7.33 - 7.24 (m, 2H), 6.32 (s, 1H), 3.49 (dd, J = 13.1, 7.0 Hz, 2H), 1.66 (dd, J = 14.3, 7.2 Hz, 2H), 1.43 - 1.23 (m, 18H), 0.88 (t, J = 6.7 Hz, 3H)., MS calcd for C 23 H 33 NO 2 (M+H) + :355, found 356.
화합물 121: N-운데실이미다조[1,5-a]피리딘-6-카복스아마이드Compound 121: N-undecylimidazo[1,5-a]pyridine-6-carboxamide
Figure PCTKR2024001580-appb-img-000018
Figure PCTKR2024001580-appb-img-000018
순도: 98%, 황색 고체, 수율: 27%, 1H NMR (400 MHz, CDCl3) δ 8.59 (d, J = 0.9 Hz, 1H), 8.17 (s, 1H), 7.44 (t, J = 4.7 Hz, 2H), 6.94 (dd, J = 9.5, 1.3 Hz, 1H), 6.45 (s, 1H), 3.45 (dd, J = 13.1, 7.1 Hz, 2H), 1.67 - 1.55 (m, 2H), 1.41 - 1.23 (m, 16H), 0.88 (t, J = 6.8 Hz, 3H)., MS calcd for C19H29N3O(M+H)+:315, found 316.Purity: 98%, yellow solid, yield: 27%, 1H NMR (400 MHz, CDCl 3 ) δ 8.59 (d, J = 0.9 Hz, 1H), 8.17 (s, 1H), 7.44 (t, J = 4.7 Hz, 2H), 6.94 (dd, J = 9.5, 1.3 Hz, 1H), 6.45 (s, 1H), 3.45 (dd, J = 13.1, 7.1 Hz, 2H), 1.67 - 1.55 (m, 2H), 1.41 - 1.23 (m, 16H), 0.88 (t, J = 6.8 Hz, 3H)., MS calcd for C 19 H 29 N 3 O(M+H) + :315, found 316.
화합물 122: N-도데실이미다조[1,5-a]피리딘-6-카복스아마이드Compound 122: N-Dodecylimidazo[1,5-a]pyridine-6-carboxamide
Figure PCTKR2024001580-appb-img-000019
Figure PCTKR2024001580-appb-img-000019
순도: 100%, 황색 고체, 수율: 28%, 1H NMR (400 MHz, CDCl3) δ 8.59 (d, J = 0.8 Hz, 1H), 8.19 (s, 1H), 7.46 (t, J = 4.7 Hz, 2H), 6.92 (dd, J = 9.5, 1.3 Hz, 1H), 6.25 (s, 1H), 3.46 (dd, J = 13.1, 7.1 Hz, 2H), 1.67 - 1.56 (m, 2H), 1.36 - 1.25 (m, 18H), 0.88 (t, J = 6.8 Hz, 3H)., MS calcd for C20H31N3O(M+H)+:329, found 330.Purity: 100%, yellow solid, yield: 28%, 1 H NMR (400 MHz, CDCl 3 ) δ 8.59 (d, J = 0.8 Hz, 1H), 8.19 (s, 1H), 7.46 (t, J = 4.7 Hz, 2H), 6.92 (dd, J = 9.5, 1.3 Hz, 1H), 6.25 (s, 1H), 3.46 (dd, J = 13.1, 7.1 Hz, 2H), 1.67 - 1.56 (m, 2H), 1.36 - 1.25 (m, 18H), 0.88 (t, J = 6.8 Hz, 3H)., MS calcd for C 20 H 31 N 3 O(M+H) + :329, found 330.
화합물 129: N-운데실퀴놀린-5-카복스아마이드Compound 129: N-undecylquinoline-5-carboxamide
Figure PCTKR2024001580-appb-img-000020
Figure PCTKR2024001580-appb-img-000020
순도: 100%, 백색 고체, 수율: 48%, 1H NMR (400 MHz, CDCl3) δ 8.94 (dd, J = 4.2, 1.7 Hz, 1H), 8.74 (dd, J = 8.6, 0.7 Hz, 1H), 8.17 (dd, J = 7.5, 1.7 Hz, 1H), 7.72 - 7.62 (m, 2H), 7.46 (dd, J = 8.6, 4.2 Hz, 1H), 3.53 (dd, J = 13.1, 7.1 Hz, 2H), 1.65 (dd, J = 14.8, 7.6 Hz, 2H), 1.46 - 1.24 (m, 16H), 0.88 (t, J = 6.8 Hz, 3H)., MS calcd for C21H30N2O (M+H)+:326, found 327.Purity: 100%, white solid, yield: 48%, 1 H NMR (400 MHz, CDCl 3 ) δ 8.94 (dd, J = 4.2, 1.7 Hz, 1H), 8.74 (dd, J = 8.6, 0.7 Hz, 1H), 8.17 (dd, J = 7.5, 1.7 Hz, 1H), 7.72 - 7.62 (m, 2H), 7.46 (dd, J = 8.6, 4.2 Hz, 1H), 3.53 (dd, J = 13.1, 7.1 Hz, 2H), 1.65 (dd, J = 14.8, 7.6 Hz, 2H), 1.46 - 1.24 (m, 16H), 0.88 (t, J = 6.8 Hz, 3H)., MS calcd for C 21 H 30 N 2 O (M+H) + :326, found 327.
화합물 130: N-도데실퀴놀린-5-카복스아마이드Compound 130: N-dodecylquinoline-5-carboxamide
Figure PCTKR2024001580-appb-img-000021
Figure PCTKR2024001580-appb-img-000021
순도: 100%, 백색 고체, 수율: 10%, 1H NMR (400 MHz, CDCl3) δ 8.95 (dd, J = 4.2, 1.7 Hz, 1H), 8.79 - 8.69 (m, 1H), 8.18 (dd, J = 7.7, 1.4 Hz, 1H), 7.72 - 7.64 (m, 2H), 7.47 (dd, J = 8.6, 4.2 Hz, 1H), 6.04 (s, 1H), 3.54 (dd, J = 13.1, 7.1 Hz, 2H), 1.71 - 1.65 (m, 2H), 1.41 - 1.23 (m, 18H), 0.88 (t, J = 6.8 Hz, 3H)., MS calcd for C22H32N2O(M+H)+:340, found 341.Purity: 100%, white solid, yield: 10%, 1 H NMR (400 MHz, CDCl 3 ) δ 8.95 (dd, J = 4.2, 1.7 Hz, 1H), 8.79 - 8.69 (m, 1H), 8.18 (dd, J = 7.7, 1.4 Hz, 1H), 7.72 - 7.64 (m, 2H), 7.47 (dd, J = 8.6, 4.2 Hz, 1H), 6.04 (s, 1H), 3.54 (dd, J = 13.1, 7.1 Hz, 2H), 1.71 - 1.65 (m, 2H), 1.41 - 1.23 (m, 18H), 0.88 (t, J = 6.8 Hz, 3H)., MS calcd for C 22 H 32 N 2 O(M+H) + :340, found 341.
화합물 131: 2-(퀴놀린-5-일)-N-운데실아세트아마이드Compound 131: 2-(quinolin-5-yl)-N-undecylacetamide
Figure PCTKR2024001580-appb-img-000022
Figure PCTKR2024001580-appb-img-000022
순도: 100%, 연한 갈색 고체, 수율: 39%, 1H NMR (400 MHz, CDCl3) δ 8.92 (dd, J = 4.2, 1.7 Hz, 1H), 8.20 (dd, J = 8.3, 1.7 Hz, 1H), 7.82 - 7.65 (m, 2H), 7.51 (dd, J = 8.2, 7.1 Hz, 1H), 7.44 (dd, J = 8.3, 4.2 Hz, 1H), 7.15 (d, J = 5.8 Hz, 1H), 4.16 (s, 2H), 3.12 (dd, J = 12.7, 6.9 Hz, 2H), 1.37 - 1.03 (m, 18H), 0.88 (t, J = 7.0 Hz, 3H)., MS calcd for C22H32N2O(M+H)+:340, found 341.Purity: 100%, light brown solid, yield: 39%, 1 H NMR (400 MHz, CDCl 3 ) δ 8.92 (dd, J = 4.2, 1.7 Hz, 1H), 8.20 (dd, J = 8.3, 1.7 Hz, 1H), 7.82 - 7.65 (m, 2H), 7.51 (dd, J = 8.2, 7.1 Hz, 1H), 7.44 (dd, J = 8.3, 4.2 Hz, 1H), 7.15 (d, J = 5.8 Hz, 1H), 4.16 (s, 2H), 3.12 (dd, J = 12.7, 6.9 Hz, 2H), 1.37 - 1.03 (m, 18H), 0.88 (t, J = 7.0 Hz, 3H)., MS calcd for C 22 H 32 N 2 O(M+H) + :340, found 341.
화합물 132: N-도데실-2-(퀴놀린-5-일)아세트아마이드Compound 132: N-dodecyl-2-(quinolin-5-yl)acetamide
Figure PCTKR2024001580-appb-img-000023
Figure PCTKR2024001580-appb-img-000023
순도: 100%, 백색 고체, 수율: 12%, 1H NMR (400 MHz, CDCl3) δ 8.92 (dd, J = 4.2, 1.7 Hz, 1H), 8.20 (dd, J = 8.3, 1.7 Hz, 1H), 7.76 (dd, J = 6.9, 5.5 Hz, 2H), 7.51 (dd, J = 8.2, 7.1 Hz, 1H), 7.45 (dd, J = 8.3, 4.2 Hz, 1H), 7.21 (s, 1H), 4.16 (s, 2H), 3.12 (dd, J = 12.7, 6.9 Hz, 2H), 1.38 - 1.08 (m, 20H), 0.88 (t, J = 6.9 Hz, 3H)., MS calcd for C23H34N2O(M+H)+:354, found 355.Purity: 100%, white solid, yield: 12%, 1 H NMR (400 MHz, CDCl 3 ) δ 8.92 (dd, J = 4.2, 1.7 Hz, 1H), 8.20 (dd, J = 8.3, 1.7 Hz, 1H), 7.76 (dd, J = 6.9, 5.5 Hz, 2H), 7.51 (dd, J = 8.2, 7.1 Hz, 1H), 7.45 (dd, J = 8.3, 4.2 Hz, 1H), 7.21 (s, 1H), 4.16 (s, 2H), 3.12 (dd, J = 12.7, 6.9 Hz, 2H), 1.38 - 1.08 (m, 20H), 0.88 (t, J = 6.9 Hz, 3H)., MS calcd for C 23 H 34 N 2 O(M+H) + :354, found 355.
화합물 133: N-운데실-1H-인돌-6-카복스아마이드Compound 133: N-undecyl-1H-indole-6-carboxamide
Figure PCTKR2024001580-appb-img-000024
Figure PCTKR2024001580-appb-img-000024
순도: 100%, 황색 고체, 수율: 51%, 1H NMR (400 MHz, DMSO) δ 11.33 (s, 1H), 8.30 (t, J = 5.5 Hz, 1H), 7.92 (s, 1H), 7.59 - 7.41 (m, 3H), 6.47 (s, 1H), 3.27 - 3.21 (m, 2H), 1.57 - 1.47 (m, 2H), 1.26 (d, J = 19.4 Hz, 16H), 0.85 (t, J = 6.8 Hz, 3H)., MS calcd for C20H30N2O(M+H)+:314, found 315.Purity: 100%, yellow solid, yield: 51%, 1 H NMR (400 MHz, DMSO) δ 11.33 (s, 1H), 8.30 (t, J = 5.5 Hz, 1H), 7.92 (s, 1H), 7.59 - 7.41 (m, 3H), 6.47 (s, 1H), 3.27 - 3.21 (m, 2H), 1.57 - 1.47 (m, 2H), 1.26 (d, J = 19.4 Hz, 16H), 0.85 (t, J = 6.8 Hz, 3H)., MS calcd for C 20 H 30 N 2 O(M+H) + :314, found 315.
화합물 134: N-도데실-1H-인돌-6-카복스아마이드Compound 134: N-Dodecyl-1H-indole-6-carboxamide
Figure PCTKR2024001580-appb-img-000025
Figure PCTKR2024001580-appb-img-000025
순도: 100%, 황색 고체, 수율: 56%, 1H NMR (400 MHz, DMSO) δ 11.33 (s, 1H), 8.30 (t, J = 5.6 Hz, 1H), 7.92 (s, 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.52 - 7.41 (m, 2H), 6.47 (s, 1H), 3.25 (dd, J = 11.4, 5.5 Hz, 2H), 1.58 - 1.48 (m, 2H), 1.26 (d, J = 21.0 Hz, 18H), 0.85 (t, J = 6.8 Hz, 3H)., MS calcd for C21H32N2O (M+H)+:328, found 329.Purity: 100%, yellow solid, yield: 56%, 1H NMR (400 MHz, DMSO) δ 11.33 (s, 1H), 8.30 (t, J = 5.6 Hz, 1H), 7.92 (s, 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.52 - 7.41 (m, 2H), 6.47 (s, 1H), 3.25 (dd, J = 11.4, 5.5 Hz, 2H), 1.58 - 1.48 (m, 2H), 1.26 (d, J = 21.0 Hz, 18H), 0.85 (t, J = 6.8 Hz, 3H)., MS calcd for C 21 H 32 N 2 O (M+H) + :328, found 329.
화합물 135: 1-브로모-N-운데실-2-나프타마이드Compound 135: 1-Bromo-N-undecyl-2-naphthamide
Figure PCTKR2024001580-appb-img-000026
Figure PCTKR2024001580-appb-img-000026
순도: 98%, 황색 고체, 수율: 24%, 1H NMR (400 MHz, CDCl3) δ 8.34 (d, J = 8.5 Hz, 1H), 7.83 (dd, J = 8.0, 3.1 Hz, 2H), 7.69 - 7.55 (m, 2H), 7.55 - 7.44 (m, 1H), 5.95 (s, 1H), 3.51 (dd, J = 13.1, 7.1 Hz, 2H), 1.67 (dd, J = 14.5, 7.1 Hz, 2H), 1.49 - 1.11 (m, 18H), 0.88 (t, J = 6.8 Hz, 3H)., MS calcd for C22H30BrNO 404, found 404.Purity: 98%, yellow solid, yield: 24%, 1 H NMR (400 MHz, CDCl 3 ) δ 8.34 (d, J = 8.5 Hz, 1H), 7.83 (dd, J = 8.0, 3.1 Hz, 2H), 7.69 - 7.55 (m, 2H), 7.55 - 7.44 (m, 1H), 5.95 (s, 1H), 3.51 (dd, J = 13.1, 7.1 Hz, 2H), 1.67 (dd, J = 14.5, 7.1 Hz, 2H), 1.49 - 1.11 (m, 18H), 0.88 (t, J = 6.8 Hz, 3H)., MS calcd for C 22 H 30 BrNO 404, found 404.
화합물 136: 1-브로모-N-도데실-2-나프타마이드Compound 136: 1-Bromo-N-dodecyl-2-naphthamide
Figure PCTKR2024001580-appb-img-000027
Figure PCTKR2024001580-appb-img-000027
순도: 100%, 황색 고체, 수율: 12%, 1H NMR (400 MHz, CDCl3) δ 8.35 (d, J = 8.3 Hz, 1H), 7.84 (d, J = 8.3 Hz, 2H), 7.70 - 7.54 (m, 2H), 7.50 (d, J = 8.4 Hz, 1H), 5.93 (s, 1H), 3.52 (dd, J = 13.1, 7.0 Hz, 2H), 1.68 (dd, J = 14.4, 7.1 Hz, 2H), 1.48 - 1.19 (m, 20H), 0.88 (t, J = 6.8 Hz, 3H)., MS calcd for C23H32BrNO 418, found 418.Purity: 100%, yellow solid, yield: 12%, 1H NMR (400 MHz, CDCl 3 ) δ 8.35 (d, J = 8.3 Hz, 1H), 7.84 (d, J = 8.3 Hz, 2H), 7.70 - 7.54 (m, 2H), 7.50 (d, J = 8.4 Hz, 1H), 5.93 (s, 1H), 3.52 (dd, J = 13.1, 7.0 Hz, 2H), 1.68 (dd, J = 14.4, 7.1 Hz, 2H), 1.48 - 1.19 (m, 20H), 0.88 (t, J = 6.8 Hz, 3H)., MS calcd for C 23 H 32 BrNO 418, found 418.
화합물 137: 2-(나프탈렌-1-일)-N-운데실아세트아마이드 Compound 137: 2-(naphthalen-1-yl)-N-undecylacetamide
Figure PCTKR2024001580-appb-img-000028
Figure PCTKR2024001580-appb-img-000028
순도: 100%, 백색 고체, 수율: 20%, 1H NMR (400 MHz, CDCl3) δ 7.98 - 7.94 (m, 1H), 7.91 - 7.86 (m, 1H), 7.83 (d, J = 8.2 Hz, 1H), 7.58 - 7.50 (m, 2H), 7.49 - 7.43 (m, 1H), 7.40 (d, J = 6.4 Hz, 1H), 5.24 (s, 1H), 4.02 (s, 2H), 3.11 (dd, J = 13.1, 6.9 Hz, 2H), 1.35 - 1.03 (m, 18H), 0.88 (t, J = 7.0 Hz, 3H)., MS calcd for C23H33NO (M+H)+:339, found 340.Purity: 100%, white solid, yield: 20%, 1 H NMR (400 MHz, CDCl 3 ) δ 7.98 - 7.94 (m, 1H), 7.91 - 7.86 (m, 1H), 7.83 (d, J = 8.2 Hz, 1H), 7.58 - 7.50 (m, 2H), 7.49 - 7.43 (m, 1H), 7.40 (d, J = 6.4 Hz, 1H), 5.24 (s, 1H), 4.02 (s, 2H), 3.11 (dd, J = 13.1, 6.9 Hz, 2H), 1.35 - 1.03 (m, 18H), 0.88 (t, J = 7.0 Hz, 3H)., MS calcd for C 23 H 33 NO (M+H) + :339, found 340.
화합물 138: N-도데실-2-(나프탈렌-1-일)아세트아마이드Compound 138: N-dodecyl-2-(naphthalen-1-yl)acetamide
Figure PCTKR2024001580-appb-img-000029
Figure PCTKR2024001580-appb-img-000029
순도: 100%, 백색 고체, 수율: 23%, 1H NMR (400 MHz, CDCl3) δ 7.98 - 7.93 (m, 1H), 7.89 (dd, J = 6.7, 2.7 Hz, 1H), 7.83 (d, J = 8.2 Hz, 1H), 7.58 - 7.50 (m, 2H), 7.49 - 7.43 (m, 1H), 7.40 (d, J = 6.3 Hz, 1H), 5.24 (s, 1H), 4.02 (s, 2H), 3.11 (dd, J = 13.1, 7.0 Hz, 2H), 1.34 - 1.13 (m, 16H), 1.11 (s, 4H), 0.88 (t, J = 6.9 Hz, 3H)., MS calcd for C24H35NO(M+H)+:353, found 354.Purity: 100%, white solid, yield: 23%, 1 H NMR (400 MHz, CDCl 3 ) δ 7.98 - 7.93 (m, 1H), 7.89 (dd, J = 6.7, 2.7 Hz, 1H), 7.83 (d, J = 8.2 Hz, 1H), 7.58 - 7.50 (m, 2H), 7.49 - 7.43 (m, 1H), 7.40 (d, J = 6.3 Hz, 1H), 5.24 (s, 1H), 4.02 (s, 2H), 3.11 (dd, J = 13.1, 7.0 Hz, 2H), 1.34 - 1.13 (m, 16H), 1.11 (s, 4H), 0.88 (t, J = 6.9 Hz, 3H)., MS calcd for C 24 H 35 NO(M+H) + :353, found 354.
실험예 1. 항암 효능 실험 (1)Experimental Example 1. Anticancer Efficacy Experiment (1)
본 실험예에서는 본 발명에 따른 화합물의 암 세포주에 대한 항암 효능을 평가하였다.In this experimental example, the anticancer efficacy of the compound according to the present invention against cancer cell lines was evaluated.
ATCC에서 구매한 인간 유래 B 세포 림프종 세포주 SU-DLH-8(ATCC, Cat. # CRL-2961)을 10% FBS, 100U/mL penicillin, 100μg/mL streptomycin이 포함된 RPMI-1640 배지에서 배양하였다. 이후 각 세포 배양액을 회수하여 1,300rpm의 속도로 5분간 원심분리하고, 상층액을 제거한 세포를 동일 배지에 재현탁하여 96-웰 플레이트(Costar 96 well cell culture plate, Corning)에 웰 당 90μL씩 분주해 최종적으로 표 1의 조건이 되도록 처리해주었다. The human B-cell lymphoma cell line SU-DLH-8 (ATCC, Cat. # CRL-2961) purchased from ATCC was cultured in RPMI-1640 medium containing 10% FBS, 100 U/mL penicillin, and 100 μg/mL streptomycin. Each cell culture was collected, centrifuged at 1,300 rpm for 5 minutes, the supernatant was removed, and the cells were resuspended in the same medium. 90 μL per well was dispensed into a 96-well plate (Costar 96 well cell culture plate, Corning) and finally treated to obtain the conditions shown in Table 1.
세포주Cell line 배양액 조건Culture conditions 최종 세포 수Final cell count
SU-DHL-8
(Human B lymphocyte)SU-DHL-8
(Human B lymphocyte) 		RPMI with 10% FBS,
100U/mL penicillin,
100μg/mL streptomycinRPMI with 10% FBS,
100U/mL penicillin,
100μg/mL streptomycin 		2×104cells/well2×10 4 cells/well
각 플레이트에 본 발명에 따른 화합물 또는 대조군(DMSO)을 농도별(0, 10, 30, 50μM)로 10μL씩 처리한 후, 5% CO2 항온배양기에서 37℃로 48시간 배양하였다. 이후 각 웰에 10μL의 CCK-8을 첨가하여 다시 5% CO2 항온배양기에서 37℃로 4시간 배양한 후, 450nm에서 흡광도를 측정하여 약물을 처리하지 않은 세포에 대한 상대적인 세포 생존율(Relative cell viability, %)을 표 2에 나타내었다. 표 2에 기재되어 있는 값은 대조군(DMSO)을 처리한 그룹에서 세포의 생존율을 100%라 했을 때 각 화합물을 농도별로 처리한 그룹에서 상대적인 세포의 생존율을 의미한다.Each plate was treated with 10 μL of the compound according to the present invention or the control (DMSO) at various concentrations (0, 10, 30, 50 μM), and then cultured in a 5% CO 2 incubator at 37°C for 48 hours. Thereafter, 10 μL of CCK-8 was added to each well, and cultured again in a 5% CO 2 incubator at 37°C for 4 hours, and the absorbance was measured at 450 nm to show the relative cell viability (%) for cells not treated with the drug, as shown in Table 2. The values listed in Table 2 indicate the relative cell viability in the groups treated with each compound at various concentrations, when the cell viability in the group treated with the control (DMSO) is 100%.
Human B Lymphocyte cell line, SU-DHL-8Human B Lymphocyte cell line, SU-DHL-8
화합물 번호Compound number None (%)None (%) 50 μM (%)50 μM (%) 30 μM (%)30 μM (%) 10 μM (%)10 μM (%)
4646 100100 7.41 7.41 12.12 12.12 12.66 12.66
4747 100100 17.66 17.66 19.07 19.07 23.87 23.87
5050 100100 7.85 7.85 10.34 10.34 12.07 12.07
8585 100100 2.79 2.79 2.04 2.04 4.63 4.63
9494 100100 1.60 1.60 2.21 2.21 3.90 3.90
9595 100100 6.43 6.43 4.94 4.94 14.73 14.73
110110 100100 2.24 2.24 4.08 4.08 6.13 6.13
112112 100100 12.54 12.54 30.88 30.88 27.07 27.07
114114 100100 5.74 5.74 9.82 9.82 8.51 8.51
119119 100100 5.62 5.62 12.06 12.06 17.58 17.58
120120 100100 11.16 11.16 9.74 9.74 15.58 15.58
121121 100100 1.06 1.06 5.64 5.64 8.40 8.40
122122 100100 1.41 1.41 3.73 3.73 2.39 2.39
129129 100100 1.76 1.76 0.49 0.49 3.90 3.90
130130 100100 2.63 2.63 4.12 4.12 6.41 6.41
131131 100100 4.59 4.59 4.13 4.13 3.81 3.81
132132 100100 4.15 4.15 2.88 2.88 2.95 2.95
133133 100100 6.61 6.61 3.29 3.29 2.58 2.58
134134 100100 5.06 5.06 4.93 4.93 8.90 8.90
135135 100100 8.45 8.45 18.61 18.61 30.10 30.10
136136 100100 9.83 9.83 15.69 15.69 22.99 22.99
B 세포 림프종 세포주 SU-DLH-8와 유사하게 다른 암종에 대해서도 항암 효능을 확인하기 위하여, 한국세포주은행으로부터 인간 유래 전립선암 세포주 LNCaP, 인간 유래 유방암 세포주 MCF-7, 인간 유래 폐암 세포주 A549, 인간 유래 대장암 세포주 HCT-116을 분양받은 후, 10% FBS가 포함된 RPMI-1640 배지에서 배양하였다. 또한, 한국세포주은행으로부터 분양받은 인간 유래 자궁경부암 세포주 HeLa, 인간 유래 간암 세포주 SK-HEP-1를 각각 10% FBS, 100U/mL penicillin, 100μg/mL streptomycin이 포함된 MEM 및 DMEM 배지에서 배양하였다. 이후 안정화된 각 세포를 Trypsin-EDTA 처리를 통해 회수하여 1,200rpm의 속도로 3분간 원심분리하고, 상층액을 제거한 뒤 동일 배지에 재현탁하여 96-웰 플레이트(Costar 96 well cell culture plate, Corning)에 웰 당 100μL씩 분주해 최종적으로 표 3의 조건이 되도록 처리해주었다. To confirm the anticancer efficacy against other cancers similar to the B cell lymphoma cell line SU-DLH-8, the human prostate cancer cell line LNCaP, the human breast cancer cell line MCF-7, the human lung cancer cell line A549, and the human colon cancer cell line HCT-116 were provided from the Korea Cell Line Bank and cultured in RPMI-1640 medium containing 10% FBS. In addition, the human cervical cancer cell line HeLa and the human liver cancer cell line SK-HEP-1, both provided from the Korea Cell Line Bank, were cultured in MEM and DMEM medium containing 10% FBS, 100 U/mL penicillin, and 100 μg/mL streptomycin, respectively. Afterwards, each stabilized cell was recovered through Trypsin-EDTA treatment, centrifuged at a speed of 1,200 rpm for 3 minutes, the supernatant was removed, resuspended in the same medium, and dispensed at 100 μL per well into a 96-well plate (Costar 96 well cell culture plate, Corning) to finally achieve the conditions in Table 3.
세포주Cell line 배양액 조건Culture conditions 최종 세포 수Final cell count
SK-HEP-1
(Human Hepatic Adenocarcinoma)SK-HEP-1
(Human Hepatic Adenocarcinoma) 		DMEM with 10% FBS,
100U/mL penicillin,
100μg/mL streptomycinDMEM with 10% FBS,
100U/mL penicillin,
100μg/mL streptomycin 		1×104cells/well1×10 4 cells/well
HeLa
(Human Cervical Carcinoma)HeLa
(Human Cervical Carcinoma) 		MEM with 10% FBS,
100U/mL penicillin,
100μg/mL streptomycinMEM with 10% FBS,
100U/mL penicillin,
100μg/mL streptomycin 		5×103cells/well5×10 3 cells/well
LNCaP
(Human Prostate Adenocarcinoma) LNCaP
(Human Prostate Adenocarcinoma) 		RPMI with 10% FBSRPMI with 10% FBS 2.5×104cells/well2.5×10 4 cells/well
MCF-7
(Human Breast Cancer)MCF-7
(Human Breast Cancer) 		2×104cells/well2×10 4 cells/well
A549
(Human Lung Carcinoma)A549
(Human Lung Carcinoma) 		1.5×104cells/well1.5×10 4 cells/well
HCT-116
(Human Colorectal Carcinoma)HCT-116
(Human Colorectal Carcinoma) 		3.5×104cells/well3.5×10 4 cells/well
해당 세포를 5% CO2 항온배양기에서 37℃로 배양 후 24시간이 경과한 시점에서 각 세포의 안정화를 확인한 뒤, 각 플레이트를 200μL/well의 PBS로 세척하고 웰 당 50μL의 배양액을 처리하였다. 해당 플레이트에 본 발명에 따른 화합물 또는 대조군(DMSO)을 농도별(0, 10, 30, 50μM)로 50μL씩 처리한 후, 5% CO2 항온배양기에서 37℃로 48시간 배양하였다. 이후 각 웰에 10μL의 CCK-8을 첨가하여 다시 5% CO2 항온배양기에서 37℃로 2시간 배양한 후, 450nm에서 흡광도를 측정하여 약물을 처리하지 않은 세포에 대한 상대적인 세포 생존율을 표 4 내지 9에 나타내었다. 표 4 내지 9에 기재되어 있는 값은 대조군(DMSO)을 처리한 그룹에서 세포의 생존율을 100%라 했을 때 각 화합물을 농도별로 처리한 그룹에서 상대적인 세포의 생존율을 의미한다.After culturing the cells in a 5% CO 2 incubator at 37°C, stabilization of each cell was confirmed after 24 hours, and each plate was washed with 200 μL/well of PBS, and 50 μL of the culture solution was treated per well. The plates were treated with 50 μL of the compound according to the present invention or the control group (DMSO) at various concentrations (0, 10, 30, 50 μM), and then cultured in a 5% CO 2 incubator at 37°C for 48 hours. Thereafter, 10 μL of CCK-8 was added to each well, and cultured again in a 5% CO 2 incubator at 37°C for 2 hours, and the absorbance was measured at 450 nm to show the relative cell viability to cells not treated with the drug, as shown in Tables 4 to 9. The values listed in Tables 4 to 9 represent the relative cell survival rates in the groups treated with each compound at different concentrations, when the cell survival rate in the group treated with the control group (DMSO) is considered 100%.
Human Hepatic Adenocarcinoma cell line, SK-HEP-1Human Hepatic Adenocarcinoma cell line, SK-HEP-1
화합물 번호Compound number None (%)None (%) 50 μM (%)50 μM (%) 30 μM (%)30 μM (%) 10 μM (%)10 μM (%)
9494 100100 30.4130.41 52.8252.82 106.89106.89
110110 100100 3.343.34 13.8113.81 27.2127.21
120120 100100 26.7326.73 33.8433.84 43.8243.82
132132 100100 22.2222.22 37.1637.16 83.8183.81
136136 100100 50.9550.95 62.8962.89 83.3183.31
Human Cervical Carcinoma cell line, HeLaHuman Cervical Carcinoma cell line, HeLa
화합물 번호Compound number None (%)None (%) 50 μM (%)50 μM (%) 30 μM (%)30 μM (%) 10 μM (%)10 μM (%)
4646 100100 26.00 26.00 32.00 32.00 37.00 37.00
4747 100100 13.00 13.00 21.00 21.00 30.00 30.00
5050 100100 1.00 1.00 1.00 1.00 1.00 1.00
9494 100100 32.00 32.00 42.00 42.00 42.00 42.00
112112 100100 25.00 25.00 27.00 27.00 50.00 50.00
114114 100100 12.00 12.00 28.00 28.00 58.00 58.00
116116 100100 0.00 0.00 0.00 0.00 1.00 1.00
122122 100100 7.00 7.00 9.00 9.00 22.00 22.00
130130 100100 3.00 3.00 6.00 6.00 11.00 11.00
132132 100100 5.00 5.00 7.00 7.00 9.00 9.00
134134 100100 9.00 9.00 19.00 19.00 48.00 48.00
136136 100100 5.00 5.00 13.00 13.00 18.00 18.00
138138 100100 36.00 36.00 57.00 57.00 79.00 79.00
Human Prostate Adenocarcinoma cell line, LNCaPHuman Prostate Adenocarcinoma cell line, LNCaP
화합물 번호Compound number None (%)None (%) 50 μM (%)50 μM (%) 30 μM (%)30 μM (%) 10 μM (%)10 μM (%)
110110 100100 10.98 10.98 14.54 14.54 24.43 24.43
119119 100100 29.77 29.77 38.98 38.98 54.49 54.49
121121 100100 24.28 24.28 28.14 28.14 50.47 50.47
Human Breast Cancer cell line, MCF-7Human Breast Cancer cell line, MCF-7
화합물 번호Compound number None (%)None (%) 50 μM (%)50 μM (%) 30 μM (%)30 μM (%) 10 μM (%)10 μM (%)
8585 100100 19.50 19.50 25.23 25.23 62.46 62.46
110110 100100 1.75 1.75 8.79 8.79 42.76 42.76
119119 100100 4.13 4.13 7.80 7.80 25.01 25.01
120120 100100 10.73 10.73 11.66 11.66 39.88 39.88
121121 100100 5.62 5.62 6.98 6.98 16.06 16.06
122122 100100 8.15 8.15 14.17 14.17 48.23 48.23
129129 100100 46.63 46.63 76.16 76.16 92.13 92.13
131131 100100 24.29 24.29 28.31 28.31 88.33 88.33
132132 100100 13.40 13.40 23.58 23.58 74.52 74.52
Human Lung Carcinoma cell line, A549Human Lung Carcinoma cell line, A549
화합물 번호Compound number None (%)None (%) 50 μM (%)50 μM (%) 30 μM (%)30 μM (%) 10 μM (%)10 μM (%)
8585 100100 60.21 60.21 79.23 79.23 104.02 104.02
110110 100100 1.94 1.94 9.86 9.86 51.52 51.52
119119 100100 15.19 15.19 18.69 18.69 43.48 43.48
120120 100100 22.04 22.04 33.12 33.12 61.25 61.25
121121 100100 53.00 53.00 64.79 64.79 92.76 92.76
132132 100100 48.08 48.08 76.20 76.20 85.31 85.31
133133 100100 31.60 31.60 48.89 48.89 83.94 83.94
135135 100100 43.00 43.00 79.30 79.30 88.66 88.66
Human Colorectal Carcinoma cell line, HCT-116Human Colorectal Carcinoma cell line, HCT-116
화합물 번호Compound number None (%)None (%) 50 μM (%)50 μM (%) 30 μM (%)30 μM (%) 10 μM (%)10 μM (%)
110110 100100 1.63 1.63 3.06 3.06 14.40 14.40
114114 100100 8.20 8.20 2.00 2.00 39.69 39.69
120120 100100 0.000.00 0.28 0.28 25.40 25.40
121121 100100 0.84 0.84 1.57 1.57 114.24 114.24
상기 표 2, 4 내지 9는 본 발명에 따른 화합물이 다양한 암종에 대해 성장 및 증식을 억제하고 암세포를 사멸시키는 효능을 갖는다는 것을 보여준다. 이에 따라 본 발명에 따른 화합물은 암의 예방, 치료 또는 개선을 위하여 유용하게 활용될 수 있다는 것이 입증되었다.The above Tables 2, 4 to 9 show that the compound according to the present invention has the effect of inhibiting the growth and proliferation of various cancers and killing cancer cells. Accordingly, it has been proven that the compound according to the present invention can be usefully utilized for the prevention, treatment or improvement of cancer.
실험예 2. 항암 효능 실험 (2)Experimental Example 2. Anticancer Efficacy Experiment (2)
본 실험예에서는 본 발명에 따른 화합물을 암 세포주에 처리하였을 때 세포사멸사(Apoptosis)를 확인하고자 하였으며, 이를 위해 10∼15 passage 내의 암 세포주에 대해 하기 실험을 수행하였다.In this experimental example, we attempted to confirm apoptosis when a compound according to the present invention was treated to a cancer cell line. To this end, the following experiment was performed on a cancer cell line within 10 to 15 passages.
ATCC에서 구매한 인간 유래 B 세포 림프종 세포주 SU-DLH-8(ATCC, Cat. # CRL-2961)을 10% FBS, 100U/mL penicillin, 100μg/mL streptomycin이 포함된 RPMI-1640 배지에서 배양하였다. 이후 각 세포 배양액을 회수하여 1,300rpm의 속도로 5분간 원심분리하고, 상층액을 제거한 세포를 동일 배지에 재현탁하여 6-웰 플레이트에 웰 당 1.5mL씩 분주해 최종적으로 표 10의 조건이 되도록 처리해주었다. 해당 플레이트에 30μM의 50번 화합물, 110번 화합물, 114번 화합물, 119번 화합물 또는 대조군(DMSO)을 처리한 후, 5% CO2 항온배양기에서 37℃로 48시간 배양하였다. 이후 대조군 또는 화합물이 처리된 세포를 회수하여 Annexin V/PI에 대한 형광 염색을 진행하고 Flow cytometry를 통해 결과를 분석하였다. 세포사멸사(Apoptosis)의 발생 정도는 Flow cytometry를 통해 분석한 결과 데이터 상 Annexin VHigh/PIHigh, Annexin VHigh/PILow 및 Annexin VLow/PIHigh에 위치하는 세포의 비율(%)에 대한 합을 막대그래프로 도 1에 나타내었다.Human B-cell lymphoma cell line SU-DLH-8 (ATCC, Cat. # CRL-2961) purchased from ATCC was cultured in RPMI-1640 medium containing 10% FBS, 100 U/mL penicillin, and 100 μg/mL streptomycin. Each cell culture was collected, centrifuged at 1,300 rpm for 5 minutes, and the supernatant was removed. The cells were resuspended in the same medium and dispensed into 6-well plates at 1.5 mL per well to achieve the final conditions of Table 10. The plates were treated with 30 μM compounds 50, 110, 114, and 119 or the control group (DMSO), and then cultured at 37°C for 48 hours in a 5% CO 2 incubator. Afterwards, control or compound-treated cells were collected and fluorescent stained for Annexin V/PI, and the results were analyzed via flow cytometry. The degree of apoptosis occurrence was analyzed via flow cytometry, and the sum of the percentages (%) of cells located at Annexin V High /PI High , Annexin V High /PI Low , and Annexin V Low /PI High in the data is represented as a bar graph in Figure 1.
또한, 한국세포주은행으로부터 분양받은 인간 유래 자궁경부암 세포주 HeLa를 10% FBS, 100U/mL penicillin, 100μg/mL streptomycin이 포함된 MEM 배지에서 배양하였다. 이후 안정화된 각 세포를 Trypsin-EDTA 처리를 통해 회수하여 1,200rpm의 속도로 3분간 원심분리하고, 상층액을 제거한 뒤 동일 배지에 재현탁하여 6-웰 플레이트에 웰 당 1.5mL씩 분주해 최종 표 10의 조건이 되도록 처리해주었다. 해당 플레이트에 30μM의 50번 화합물, 110번 화합물, 114번 화합물, 119번 화합물 또는 대조군(DMSO)을 처리한 후, 5% CO2 항온배양기에서 37℃로 48시간 배양하였다. 이후 대조군 또는 화합물이 처리된 세포를 Trypsin-EDTA 처리를 통해 회수하여 Annexin V/PI(Propidium Iodide)에 대한 형광 염색을 진행하고 Flow cytometry를 통해 결과를 분석하였다. 세포사멸사(Apoptosis)의 발생 정도는 Flow cytometry를 통해 분석한 결과 데이터 상 Annexin VHigh/PIHigh, Annexin VHigh/PILow 및 Annexin VLow/PIHigh에 위치하는 세포의 비율(%)에 대한 합을 막대그래프로 도 2에 나타내었다.In addition, the human cervical cancer cell line HeLa obtained from the Korea Cell Line Bank was cultured in MEM medium containing 10% FBS, 100 U/mL penicillin, and 100 μg/mL streptomycin. After that, each stabilized cell was recovered through Trypsin-EDTA treatment, centrifuged at a speed of 1,200 rpm for 3 minutes, the supernatant was removed, resuspended in the same medium, and dispensed into 6-well plates at 1.5 mL per well to achieve the final conditions of Table 10. After treating the plate with 30 μM of compounds 50, 110, 114, and 119 or the control group (DMSO), the plate was cultured at 37°C for 48 hours in a 5% CO2 incubator. Thereafter, control or compound-treated cells were recovered through Trypsin-EDTA treatment, fluorescent staining for Annexin V/PI (Propidium Iodide) was performed, and the results were analyzed through flow cytometry. The degree of apoptosis occurrence was analyzed through flow cytometry, and the sum of the ratios (%) of cells located at Annexin V High /PI High , Annexin V High /PI Low , and Annexin V Low /PI High in the data is represented as a bar graph in Figure 2.
세포주Cell line 배양액 조건Culture conditions 최종 세포 수Final cell count
SU-DHL-8
(Human B lymphocyte)SU-DHL-8
(Human B lymphocyte) 		RPMI with 10% FBSRPMI with 10% FBS 3×106cells/well3×10 6 cells/well
HeLa
(Human Cervical Carcinoma)HeLa
(Human Cervical Carcinoma) 		MEM with 10% FBS,
100U/mL penicillin,
100μg/mL streptomycinMEM with 10% FBS,
100U/mL penicillin,
100μg/mL streptomycin 		3.6×105cells/well3.6×10 5 cells/well
도 1 및 도 2는 본 발명에 따른 화합물이 암세포의 세포사멸사를 유도함으로써 항암 효능을 갖는다는 것을 입증한다.Figures 1 and 2 demonstrate that the compound according to the present invention has anticancer efficacy by inducing apoptosis of cancer cells.
실험예 3. T 세포 증식억제능 실험Experimental Example 3. Experiment on T cell proliferation inhibition ability
본 발명에 따른 화합물의 T 세포 증식억제 효과 검증을 위하여, 세포 내 분자와 공유결합으로 결합하는 형광염료인 ‘carboxyfluorescein diacetate succinimidyl ester(CFSE)’를 이용한 Flow cytometry 분석을 기반으로 하는 실험을 수행하였다.In order to verify the T cell proliferation inhibitory effect of the compound according to the present invention, an experiment was performed based on flow cytometry analysis using ‘carboxyfluorescein diacetate succinimidyl ester (CFSE)’, a fluorescent dye that covalently binds to intracellular molecules.
7주령 C57BL/6 생쥐에서 비장을 적출하여 으깬 후 strainer(40 μM pore size, SPL)로 단세포만 분리한 후 ACK(Ammonium-Chloride-Potassium) lysis 완충용액으로 적혈구를 제거하여 백혈구만 분리하였다. 여기에 CD90.2 microbead(130-121-278, Miltenyi Biotec.)를 첨가하고 4℃에서 20분 반응시킨 후 MACS Magnetic Stand와 LS column을 이용하여 최종적으로 비장의 T 세포만 분리하였다. 비장세포에서 분리한 T 세포는 Free media(RPMI-1640+200 U/mL penicillin+200μg/mL Streptomycin) 1mL로 재현탁한 후, CFSE(10mM) 0.3 μL를 첨가하고 37℃에서 5분간 반응시켰다. 이후 Free media 10 mL을 첨가하여 반응을 정지하고 원심분리하여 세포 침전물을 얻었다. 여기에 10% FBS와 100 U/mL penicillin, 100 μg/mL streptomycin이 들어있는 RPMI 1640 배지를 첨가하여 세포를 부유시키고, 96-웰 플레이트에 웰 당 2 x105 cell의 세포를 분주하고 CD3, CD28 항체를 각각 0.5 μg/mL로 처리하여 T 세포를 활성화하였다. DMSO에 희석된 화합물을 10 μM, 30 μM, 50 μM의 농도로 각각 3개의 웰씩 처리하고 37℃, 5% CO2 항온배양기에서 3일간 배양한 후 FACS canto 기기로 Reading 하였다. 그 결과 수득된 T 세포의 증식억제율(%)은 표 11에 나타내었다.The spleen was removed from 7-week-old C57BL/6 mice, mashed, and separated into single cells using a strainer (40 μM pore size, SPL). Red blood cells were removed with ACK (Ammonium-Chloride-Potassium) lysis buffer to isolate only white blood cells. CD90.2 microbeads (130-121-278, Miltenyi Biotec.) were added, and the mixture was incubated at 4°C for 20 minutes. Then, T cells in the spleen were finally isolated using the MACS Magnetic Stand and LS column. The T cells isolated from the spleen were resuspended in 1 mL of free media (RPMI-1640 + 200 U/mL penicillin + 200 μg/mL streptomycin), 0.3 μL of CFSE (10 mM) was added, and the mixture was incubated at 37°C for 5 minutes. After that, 10 mL of Free media was added to stop the reaction, and the cell pellet was obtained by centrifugation. RPMI 1640 medium containing 10% FBS, 100 U/mL penicillin, and 100 μg/mL streptomycin was added to suspend the cells, and 2 x 10 5 cells per well were dispensed into a 96-well plate, and CD3 and CD28 antibodies were treated at 0.5 μg/mL each to activate T cells. The compounds diluted in DMSO were treated in 3 wells each at a concentration of 10 μM, 30 μM, and 50 μM, and cultured for 3 days in a 37°C, 5% CO 2 incubator, and then read using a FACS canto instrument. The resulting T cell proliferation inhibition rate (%) is shown in Table 11.
화합물 번호Compound number 50 μM50 μM 30 μM30 μM 10 μM10 μM
4646 77.04 77.04 11.83 11.83 0.000.00
4747 89.20 89.20 52.70 52.70 0.000.00
5050 95.88 95.88 96.24 96.24 25.22 25.22
8585 48.22 48.22 32.05 32.05 0.000.00
9494 75.07 75.07 63.42 63.42 4.25 4.25
9595 93.36 93.36 33.42 33.42 13.01 13.01
110110 100.00 100.00 100.00 100.00 97.03 97.03
111111 100.00 100.00 100.00 100.00 98.41 98.41
114114 73.42 73.42 75.62 75.62 53.42 53.42
119119 100.00 100.00 17.12 17.12 0.000.00
120120 86.03 86.03 4.66 4.66 0.000.00
121121 86.60 86.60 1.78 1.78 0.000.00
122122 98.64 98.64 73.91 73.91 2.24 2.24
131131 96.36 96.36 11.99 11.99 6.19 6.19
132132 37.81 37.81 4.22 4.22 3.03 3.03
133133 47.17 47.17 13.97 13.97 2.11 2.11
136136 68.51 68.51 43.74 43.74 0.000.00
적응면역은 선천면역에 비해 강력한 면역반응을 나타내며 T 세포에 의한 면역반응과 B 세포에 의한 면역반응으로 나눌 수 있다. 본 발명에 따른 화합물은 표 11에서 보는 바와 같이 T 세포의 증식을 억제할 뿐만 아니라 표 2에서 보는 바와 같이 B 세포의 사멸을 유도 할 수 있어 강력한 면역억제 기능을 나타내므로, 이식 거부반응 외에 자가 항체를 형성하는 자가면역질환 치료 또는 예방을 위해 유용하게 사용할 수 있다.Adaptive immunity exhibits a stronger immune response than innate immunity, and can be divided into immune responses mediated by T cells and immune responses mediated by B cells. The compound according to the present invention exhibits a strong immunosuppressive function by inhibiting the proliferation of T cells as shown in Table 11, and inducing the death of B cells as shown in Table 2, and therefore can be usefully used for the treatment or prevention of autoimmune diseases that form autoantibodies in addition to transplant rejection.

Claims (8)

  1. 하기 화학식 1로 표시되는 화합물 또는 이의 염:A compound represented by the following chemical formula 1 or a salt thereof:
    [화학식 1][Chemical Formula 1]
    Figure PCTKR2024001580-appb-img-000030
    Figure PCTKR2024001580-appb-img-000030
    상기 화학식 1에서,In the above chemical formula 1,
    X1, X2, X3 및 X4는 서로 독립적으로 탄소 또는 질소이고,X1, X2, X3 and X4 are independently carbon or nitrogen,
    Y는 -CO- 또는 -CH2CO-이고,Y is -CO- or -CH 2 CO-,
    R1, R2, R3, R4 및 R5는 서로 독립적으로 H, -OH, -SH, 할로겐, -NO2, -NH2, -CF3, C1-C6 알킬, C2-C6 알케닐, C2-C6 알키닐, C3-C10 아릴알킬, C5-C10 아릴, C3-C10 알킬아릴, C3-C10 사이클로알킬, C3-C10 헤테로아릴, C3-C10 헤테로사이클로알킬, -OR6, -COR6, -SR6 또는 -NHR6이고,R1, R2, R3, R4 and R5 are independently H, -OH, -SH, halogen, -NO 2 , -NH 2 , -CF 3 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 arylalkyl, C5-C10 aryl, C3-C10 alkylaryl, C3-C10 cycloalkyl, C3-C10 heteroaryl, C3-C10 heterocycloalkyl, -OR6, -COR6, -SR6 or -NHR6,
    R6은 H, C1-C6 알킬, C2-C6 알케닐, C2-C6 알키닐, C3-C10 아릴알킬, C5-C10 아릴, C3-C10 알킬아릴, C3-C10 사이클로알킬, C3-C10 헤테로아릴 또는 C3-C10 헤테로사이클로알킬이고,R6 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 arylalkyl, C5-C10 aryl, C3-C10 alkylaryl, C3-C10 cycloalkyl, C3-C10 heteroaryl or C3-C10 heterocycloalkyl,
    R7은 C8-C12 알킬, C8-C12 알케닐 또는 C8-C12 알키닐이고,R7 is C8-C12 alkyl, C8-C12 alkenyl or C8-C12 alkynyl,
    R1 및 R2, R2 및 R3, R3 및 R4, 또는 R4 및 R5는 서로 결합하여 C5-C10 아릴 또는 C2-C10 헤테로아릴을 형성함.R1 and R2, R2 and R3, R3 and R4, or R4 and R5 are combined with each other to form C5-C10 aryl or C2-C10 heteroaryl.
  2. 제1항에 있어서,In the first paragraph,
    화학식 1로 표시되는 화합물이 하기로 이루어진 군으로부터 선택되는 것인, 화합물 또는 이의 염:A compound or a salt thereof, wherein the compound represented by the chemical formula 1 is selected from the group consisting of:
    N-운데실-2,3-디하이드로-1H-벤조[d][1,2,3]트리아졸-5-카복스아마이드,N-undecyl-2,3-dihydro-1H-benzo[d][1,2,3]triazole-5-carboxamide,
    N-도데실-1H-벤조[d][1,2,3]트리아졸-5-카복스아마이드,N-dodecyl-1H-benzo[d][1,2,3]triazole-5-carboxamide,
    N-운데실-1H-벤조[d]이미다졸-5-카복스아마이드,N-undecyl-1H-benzo[d]imidazole-5-carboxamide,
    1-메틸-N-운데실-1H-인돌-7-카복스아마이드,1-Methyl-N-undecyl-1H-indole-7-carboxamide,
    N-운데실퀴놀린-2-카복스아마이드,N-undecylquinoline-2-carboxamide,
    N-도데실퀴놀린-2-카복스아마이드,N-dodecylquinoline-2-carboxamide,
    8-하이드록시-N-운데실퀴놀린-7-카복스아마이드,8-hydroxy-N-undecylquinoline-7-carboxamide,
    N-도데실-8-하이드록시퀴놀린-7-카복스아마이드,N-dodecyl-8-hydroxyquinoline-7-carboxamide,
    6-하이드록시-N-운데실-2-나프타마이드,6-hydroxy-N-undecyl-2-naphthamide,
    N-도데실-6-하이드록시-2-나프타마이드,N-dodecyl-6-hydroxy-2-naphthamide,
    N-도데실-1H-벤조[d]이미다졸-5-카복스아마이드,N-dodecyl-1H-benzo[d]imidazole-5-carboxamide,
    6-브로모-N-운데실-2-나프타마이드,6-Bromo-N-undecyl-2-naphthamide,
    6-브로모-N-도데실-2-나프타마이드,6-Bromo-N-dodecyl-2-naphthamide,
    2-클로로-N-도데실-3-메틸벤즈아마이드,2-chloro-N-dodecyl-3-methylbenzamide,
    N-도데실-1-하이드록시-2-나프타마이드,N-dodecyl-1-hydroxy-2-naphthamide,
    N-운데실이미다조[1,5-a]피리딘-6-카복스아마이드,N-undecylimidazo[1,5-a]pyridine-6-carboxamide,
    N-도데실이미다조[1,5-a]피리딘-6-카복스아마이드,N-dodecylimidazo[1,5-a]pyridine-6-carboxamide,
    N-운데실퀴놀린-5-카복스아마이드,N-undecylquinoline-5-carboxamide,
    N-도데실퀴놀린-5-카복스아마이드,N-dodecylquinoline-5-carboxamide,
    2-(퀴놀린-5-일)-N-운데실아세트아마이드,2-(quinolin-5-yl)-N-undecylacetamide,
    N-도데실-2-(퀴놀린-5-일)아세트아마이드,N-dodecyl-2-(quinolin-5-yl)acetamide,
    N-운데실-1H-인돌-6-카복스아마이드,N-undecyl-1H-indole-6-carboxamide,
    N-도데실-1H-인돌-6-카복스아마이드,N-dodecyl-1H-indole-6-carboxamide,
    1-브로모-N-운데실-2-나프타마이드,1-Bromo-N-undecyl-2-naphthamide,
    1-브로모-N-도데실-2-나프타마이드,1-Bromo-N-dodecyl-2-naphthamide,
    2-(나프탈렌-1-일)-N-운데실아세트아마이드, 및2-(naphthalen-1-yl)-N-undecylacetamide, and
    N-도데실-2-(나프탈렌-1-일)아세트아마이드.N-Dodecyl-2-(naphthalen-1-yl)acetamide.
  3. 제1항에 따른 화합물 또는 이의 염을 유효성분으로 포함하는, 암 또는 자가면역질환 치료 또는 예방용 약학 조성물.A pharmaceutical composition for treating or preventing cancer or an autoimmune disease, comprising a compound according to claim 1 or a salt thereof as an active ingredient.
  4. 제3항에 있어서, In the third paragraph,
    상기 암은 간암, 대장암, 췌장암, 결장암, 소장암, 위암, 폐암, 뇌암, 골암, 흑색종, 유방암, 경화성선증, 자궁암, 자궁경부암, 두경부암, 식도암, 갑상선암, 부갑상선암, 신장암, 육종, 전립선암, 요도암, 방광암, 혈액암, 림프종 또는 섬유선종인, 약학 조성물.A pharmaceutical composition wherein the cancer is liver cancer, colon cancer, pancreatic cancer, colon cancer, small intestine cancer, stomach cancer, lung cancer, brain cancer, bone cancer, melanoma, breast cancer, sclerosing adenoma, uterine cancer, cervical cancer, head and neck cancer, esophageal cancer, thyroid cancer, parathyroid cancer, kidney cancer, sarcoma, prostate cancer, urethral cancer, bladder cancer, blood cancer, lymphoma or fibroadenoma.
  5. 제3항에 있어서, In the third paragraph,
    상기 자가면역질환은 전신홍반성낭창(systemic lupus erythematosus; SLE), 사구체염, 강직성 척추염(Ankylosing spondylitis), 중증근무력증(Myastenia gravis) 류마티스 관절염(rheumatoid arthritis; RA), 다발성 경화증(multiple sclerosis; MS), 전신성 경화증(systemic sclerosis), 악성 빈혈(Pernicious anemia) 자가 면역성 빈혈, 염증성장질환(Infammatory bowel disease), 인슐린 의존성 당뇨(insulin-dependent diabetes mellitus; IDDM), 제1형 당뇨병, 그레이브스 병(grave’s disease), 그레이브스 갑상선 항진증(Graves hyperthyroidism), 기쿠치(Kikuchi) 병, 혈구탐식성 림프조직구증(Hemophagocytic lymphohistiocytosis), 성인 스틸 병(Adult onset Still's disease), 베체트 병(Behcet disease), IgG4-연관성 질환, 건선, 천식 또는 이식거부반응인, 약학 조성물.The above autoimmune diseases include systemic lupus erythematosus (SLE), glomerulitis, ankylosing spondylitis, Myastenia gravis, rheumatoid arthritis (RA), multiple sclerosis (MS), systemic sclerosis, pernicious anemia, autoimmune anemia, inflammatory bowel disease, insulin-dependent diabetes mellitus (IDDM), type 1 diabetes, Graves' disease, Graves' hyperthyroidism, Kikuchi's disease, hemophagocytic lymphohistiocytosis, adult onset Still's disease, Behcet's disease, A pharmaceutical composition for use in the treatment of an IgG4-associated disease, psoriasis, asthma or transplant rejection.
  6. 제1항에 따른 화합물 또는 이의 염을 유효성분으로 포함하는, 암 또는 자가면역질환 개선 또는 예방용 식품 조성물.A food composition for improving or preventing cancer or autoimmune disease, comprising a compound according to Article 1 or a salt thereof as an effective ingredient.
  7. 제6항에 있어서, In Article 6,
    상기 암은 간암, 대장암, 췌장암, 결장암, 소장암, 위암, 폐암, 뇌암, 골암, 흑색종, 유방암, 경화성선증, 자궁암, 자궁경부암, 두경부암, 식도암, 갑상선암, 부갑상선암, 신장암, 육종, 전립선암, 요도암, 방광암, 혈액암, 림프종 또는 섬유선종인, 식품 조성물.The above cancer is liver cancer, colon cancer, pancreatic cancer, colon cancer, small intestine cancer, stomach cancer, lung cancer, brain cancer, bone cancer, melanoma, breast cancer, sclerosing adenoma, uterine cancer, cervical cancer, head and neck cancer, esophageal cancer, thyroid cancer, parathyroid cancer, kidney cancer, sarcoma, prostate cancer, urethral cancer, bladder cancer, blood cancer, lymphoma or fibroadenoma, food composition.
  8. 제6항에 있어서, In Article 6,
    상기 자가면역질환은 전신홍반성낭창(systemic lupus erythematosus; SLE), 사구체염, 강직성 척추염(Ankylosing spondylitis), 중증근무력증(Myastenia gravis) 류마티스 관절염(rheumatoid arthritis; RA), 다발성 경화증(multiple sclerosis; MS), 전신성 경화증(systemic sclerosis), 악성 빈혈(Pernicious anemia) 자가 면역성 빈혈, 염증성장질환(Infammatory bowel disease), 인슐린 의존성 당뇨(insulin-dependent diabetes mellitus; IDDM), 제1형 당뇨병, 그레이브스 병(grave’s disease), 그레이브스 갑상선 항진증(Graves hyperthyroidism), 기쿠치(Kikuchi) 병, 혈구탐식성 림프조직구증(Hemophagocytic lymphohistiocytosis), 성인 스틸 병(Adult onset Still's disease), 베체트 병(Behcet disease), IgG4-연관성 질환, 건선, 천식 또는 이식거부반응인, 식품 조성물.The above autoimmune diseases include systemic lupus erythematosus (SLE), glomerulitis, ankylosing spondylitis, Myastenia gravis, rheumatoid arthritis (RA), multiple sclerosis (MS), systemic sclerosis, pernicious anemia, autoimmune anemia, inflammatory bowel disease, insulin-dependent diabetes mellitus (IDDM), type 1 diabetes, Graves' disease, Graves' hyperthyroidism, Kikuchi's disease, hemophagocytic lymphohistiocytosis, adult onset Still's disease, Behcet's disease, Food composition for use in IgG4-related diseases, psoriasis, asthma or transplant rejection.
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