WO2018135918A1 - Pharmaceutical composition comprising compound having blt inhibiting activity as effective ingredient for preventing or treating chronic obstructive pulmonary disease - Google Patents

Pharmaceutical composition comprising compound having blt inhibiting activity as effective ingredient for preventing or treating chronic obstructive pulmonary disease Download PDF

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WO2018135918A1
WO2018135918A1 PCT/KR2018/000957 KR2018000957W WO2018135918A1 WO 2018135918 A1 WO2018135918 A1 WO 2018135918A1 KR 2018000957 W KR2018000957 W KR 2018000957W WO 2018135918 A1 WO2018135918 A1 WO 2018135918A1
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prop
methyl
phenyl
ynyl
fluorophenyl
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PCT/KR2018/000957
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French (fr)
Korean (ko)
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최용석
김재홍
이경
한효경
위준동
권진선
구자일
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동국대학교 산학협력단
고려대학교 산학협력단
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Priority claimed from KR1020180006634A external-priority patent/KR20180087157A/en
Application filed by 동국대학교 산학협력단, 고려대학교 산학협력단 filed Critical 동국대학교 산학협력단
Publication of WO2018135918A1 publication Critical patent/WO2018135918A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine

Definitions

  • the present invention relates to a pharmaceutical composition for preventing or treating chronic obstructive pulmonary disease. More specifically, the present invention relates to a pharmaceutical composition for preventing or treating chronic obstructive pulmonary disease, comprising as an active ingredient a compound exhibiting inhibitory activity of Leukotriene B4 receptor 2. It relates to a composition.
  • Chronic obstructive pulmonary disease is a disease in which airflow restriction or obstruction is caused by chronic bronchitis or emphysema, and it is mainly a lung disease in which the airway is narrowed as a result of abnormal inflammatory reaction of the lung.
  • Chronic obstructive pulmonary disease is mainly caused by inhalation of harmful particles or gases, and smoking is known as a major cause.
  • Smoking acts as a powerful stimulant in lung tissue, increasing the production of various proinflammatory, growth, oxidative and chemotactic factors, and activating the inflammatory signaling system to induce inflammatory cells, including neutrophils and macrophages. To promote lung aggravation. Especially.
  • Chronic obstructive pulmonary disease is referred to collectively as chronic bronchitis with cough with chronic sputum and emphysema with abnormal increase in alveoli below terminal bronchiole and destruction of alveolar septum, which is difficult to distinguish between them.
  • COPD chronic obstructive pulmonary disease
  • COPD causes symptoms of airway disease such as dyspnea, cough, and sputum, which worsen lung function and lead to death. It is known that more than 90% of the causes are due to smoking, and pollution, congenital diseases and respiratory infections. Therefore, chronic obstructive pulmonary disease is a disease that causes the limitation of daily life and lowers the quality of life by gradually progressing the respiratory distress and eventually depends on others to the daily life, thereby lowering the productivity and quality of life of the people around.
  • leukotriene B4 is a group of inflammatory lipid mediators synthesized from arachidonic acid (AA) by the 5-lipoxygenase pathway that mediates acute and chronic inflammation.
  • LTB 4 is known to have a biological effect by binding to two types of receptors, BLT1 and BLT2.
  • Leukotriene B4 receptor 2 (BLT2) is a group of G protein-coupled receptors (GPCRs) that has low affinity for LTB 4 and is a lipid mediator of arachidonic acid (AA) induced through a 5-lipoxygenase dependent pathway. to be.
  • the present inventors while continuing to research to develop a more effective treatment for chronic obstructive pulmonary disease in order to solve the above-mentioned problems, the inventors prepared a compound that exhibits a BLT2 inhibitory activity, including the compound The first drug to treat obstructive pulmonary disease was designed.
  • the present invention has been made to solve the above problems, the present inventors have confirmed the effects of the treatment of chronic obstructive pulmonary disease of the compound showing the BLT2 inhibitory activity and based on this, to complete the present invention.
  • an object of the present invention is a pharmaceutical composition for preventing or treating chronic obstructive pulmonary disease (COPD), comprising as an active ingredient a compound, an isomer thereof, or a pharmaceutically acceptable salt thereof exhibiting BLT2 inhibitory activity.
  • COPD chronic obstructive pulmonary disease
  • the present invention comprises a compound exhibiting BLT2 inhibitory activity, an isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient, chronic obstructive pulmonary disease (COPD) ) Provides a pharmaceutical composition for prophylaxis or treatment.
  • COPD chronic obstructive pulmonary disease
  • the compound is tert -butyl 4- (4- (3- ( N -phenylpentaneamido) prop-1-ynyl) benzoyl) piperazine-1-carboxylate; N -phenyl- N- (3- (4- (piperazin-1-carbonyl) phenyl) prop-2-ynyl) pentaneamide; N- (3- (4-methylpiperazin-1-carbonyl) phenyl) prop-2-ynyl) -N -phenylpentanamide; N- (3- (4- (4-ethylpiperazin-1-carbonyl) phenyl) prop-2-ynyl) -N -phenylpentanamide; N- (3- (4- (4-isopropylpiperazin-1-carbonyl) phenyl) prop-2-ynyl) -N -phenylpentaneamide; N- (3- (4- (4- (2-hydroxy
  • the composition may inhibit Leukotriene B4 receptor 2 (BLT2) activity.
  • BLT2 Leukotriene B4 receptor 2
  • It provides a method of treating chronic obstructive pulmonary disease comprising administering the pharmaceutical composition to a subject.
  • the present invention provides a therapeutic use for chronic obstructive pulmonary disease of a composition comprising the compound, an isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a pharmaceutical for the prevention or treatment of chronic obstructive pulmonary disease (COPD), comprising as an active ingredient a compound, an isomer thereof, or a pharmaceutically acceptable salt thereof, which exhibits Leukotriene B4 receptor 2 (BLT2) inhibitory activity.
  • COPD chronic obstructive pulmonary disease
  • BLT2 Leukotriene B4 receptor 2
  • the present inventors have experimentally confirmed the excellent chemotactic inhibitory effect and the treatment effect of chronic obstructive pulmonary disease of the compound showing the BTL2 inhibitory activity, the compound of the present invention can be usefully used as a pharmaceutical composition for treating chronic obstructive pulmonary disease It is expected to be able.
  • 1A to 1E and 2A to 2D are results of confirming the growth inhibitory effect of the compound treatment of the present invention in cells expressing BLT2 (CHO-BLT2).
  • 3A and 3B show the results of confirming chemotaxis inhibitory effect and IC 50 (50% inhibitory concentration) of cells by the compound treatment of the present invention in cells expressing BLT2 (CHO-BLT2 cells).
  • 4A and 4B show the results of confirming the chemotaxis inhibitory effect of cells treated with the compound of the present invention in cells expressing BLT2 (CHO-BLT2 cells) or cells expressing BLT1 (CHO-BLT1).
  • 5A to 5D show results of confirming chemotaxis inhibitory effect and IC 50 (50% inhibitory concentration) of cells by treatment with a compound of the present invention in cells expressing BLT2 (CHO-BLT2 cells).
  • 6A to 6C show the results of confirming the chemotaxis inhibitory effect of cells treated with the compound of the present invention in cells expressing BLT2 (CHO-BLT2 cells) or cells expressing BLT1 (CHO-BLT1).
  • 7A to 7C show the results of confirming the effect of inhibiting the binding of LTB4 and BLT2 by the compound treatment of the present invention in BLT2-expressing cells (CHO-BLT2 cells).
  • Figure 8a is a result confirming the inhibitory effect of TNF- ⁇ production by the compound treatment of the present invention in an animal model of chronic obstructive pulmonary disease.
  • Figure 8c is a result confirming the inhibitory effect of ROS production by the compound treatment of the present invention in an animal model of chronic obstructive pulmonary disease.
  • Figure 9 is a result of confirming the degree of infiltration of inflammatory cells by treatment of LMT-886 and LMT-1013 compounds of the present invention in animal models of chronic obstructive pulmonary disease induced by tobacco smoke and lipopolysaccharide.
  • FIG. 13 shows the results of measuring IL-6 by treatment with the compounds LMT-886 and LMT-1013 of the present invention in an animal model of chronic obstructive pulmonary disease induced by tobacco smoke and lipopolysaccharide.
  • Figure 14 shows the results confirmed by H & E staining lung tissue animal models of chronic obstructive pulmonary disease induced by tobacco smoke and lipopolysaccharide.
  • the present inventors based on the fact that the treatment of the compound prepared in Example can significantly inhibit the growth of BLT2 expressing cells, specific effects of BLT2-dependent chemotaxis and the effect of treating chronic obstructive pulmonary disease, etc. It confirmed with and based on this, this invention was completed.
  • the present invention provides a pharmaceutical composition for preventing or treating chronic obstructive pulmonary disease (COPD), comprising a compound represented by the following formula (1), an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • COPD chronic obstructive pulmonary disease
  • R 1 is C 1 -C 10 is alkyl
  • R 2 is , , , , or Is
  • R a is , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , Or hydroxy,
  • R b is , , , or ego
  • R C is , , or ego
  • R d is hydrogen or ego
  • R e is or ego
  • R 3 is hydrogen or fluorine.
  • Preferred examples of the compound represented by Formula 1 according to the present invention are as follows:
  • the present invention also provides a pharmaceutical composition for preventing or treating chronic obstructive pulmonary disease (COPD) comprising a compound represented by the following formula (2), an isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient. do.
  • COPD chronic obstructive pulmonary disease
  • R 1 is C 1 -C 10 alkyl, , or ego,
  • R 2 is hydrogen, , or ego
  • R 3 is hydrogen, , or ego
  • R 4 is hydrogen, , or ego
  • R a is hydrogen, C 1 -C 10 alkyl, C 1 -C 5 carboxyl,
  • R 5 , R 6 , and R 7 are each independently hydrogen, halogen, nitro, methyl, trifluoromethyl or methoxy,
  • R 1 is C 1 -C 10 alkyl and R a is hydrogen or C 1 -C 10 alkyl; And when R 2 , R 3 , and R 4 are all hydrogen at the same time.
  • Preferred examples of the compound represented by Formula 2 according to the present invention are as follows:
  • the term "pharmaceutically acceptable” is suitable for use in contact with the tissues of a subject (eg, a human being) because the benefit / risk ratio is reasonable without excessive toxicity, irritation, allergic reactions or other problems or complications.
  • a compound or composition is within the scope of sound medical judgment.
  • Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid and aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. Obtained from non-toxic organic acids such as dioates, aromatic acids, aliphatic and aromatic sulfonic acids.
  • Such pharmaceutically nontoxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, and iodide.
  • the acid addition salt according to the present invention is dissolved in a conventional method, for example, the compound represented by the formula (1) or (2) in an excess of aqueous acid solution, and the salt is water-miscible organic solvent such as methanol, ethanol, acetone Or by precipitation with acetonitrile. It may also be prepared by evaporating the solvent or excess acid from the mixture and then drying or by suction filtration of the precipitated salt.
  • a conventional method for example, the compound represented by the formula (1) or (2) in an excess of aqueous acid solution
  • the salt is water-miscible organic solvent such as methanol, ethanol, acetone Or by precipitation with acetonitrile. It may also be prepared by evaporating the solvent or excess acid from the mixture and then drying or by suction filtration of the precipitated salt.
  • Bases can also be used to make pharmaceutically acceptable metal salts.
  • Alkali metal or alkaline earth metal salts are obtained, for example, by dissolving the compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare sodium, potassium or calcium salt as the metal salt.
  • the corresponding silver salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable negative salt (eg silver nitrate).
  • a compound showing BLT2 inhibitory activity was prepared (see Example 1), and the growth inhibition of BLT2 expressing cells by the compound treatment was confirmed (see Experimental Example 2).
  • the chemotaxis of the BLT2 expressing cells can be inhibited (see Experimental Example 3)
  • using the compound of the present invention confirmed the inhibitory effect of LTB4 and BLT2 binding (see Experimental Example 4), chronic obstructive pulmonary disease
  • TNF- ⁇ , IL-6 and ROS production in bronchoalveolar lavage fluid see Experimental Example 5
  • the animal models of chronic obstructive pulmonary disease induced by tobacco smoke and lipopolysaccharide were prepared to confirm the efficacy of the compounds LMT-886 and LMT-1013 exhibiting BLT2 inhibitory activity (see Experimental Example 6). .
  • the inventors of the present invention to determine the effect of reducing the production of TNF- ⁇ and IL-6 to activate the inflammatory signaling system as an inflammatory cytokine in bronchoalveolar lavage fluid for chronic obstructive pulmonary disease-induced mice of the present invention, Changes in the production of TNF- ⁇ 2 and IL-6 in the bronchoalveolar lavage fluid of the experimental group to which the normal control group, the negative control group, the compound of the present invention and the comparative drug (ROF; Roflumilast PDE4 inhibitor) were administered were measured.
  • ROF Roflumilast PDE4 inhibitor
  • the tumor necrosis factor (TNF- ⁇ ) of the present invention is a kind of cytokinin produced by macrophages and the like, and interleukin-6 of the present invention produces B-cell antibody.
  • B-cell stimulating factor 2 (BSF-2) which induces final differentiation into cells, wherein the glycoprotein has an isolated molecular weight of 210,000. It is a cytokine produced by several cells such as T lymphocytes, B lymphocytes, macrophages and fibroblasts.
  • the reactive oxygen species (ROS) of the present invention are oxygen-containing chemical reaction molecules, which are formed as natural by-products of normal metabolism of oxygen and play an important role in cellular signaling and homeostasis. However, during environmental stress, ROS levels can increase significantly, which can lead to significant damage to cellular structure.
  • the compound of the present invention effectively inhibits the inflammatory response in the lung tissue through the inhibition of the inflammatory mediators, and thus can be usefully used as an active ingredient in the pharmaceutical composition for the prevention and treatment of chronic obstructive pulmonary disease.
  • prevention means any action that inhibits or delays the development of chronic obstructive pulmonary disease by administration of a pharmaceutical composition according to the present invention.
  • treatment means any action that improves or advantageously changes the symptoms for chronic obstructive pulmonary disease by administration of the pharmaceutical composition according to the present invention.
  • chronic obstructive pulmonary disease is an abnormal inflammatory reaction occurs in the lungs by inhalation of harmful particles such as smoking or industrial gases, thereby gradually limiting airflow and thus lowering lung function.
  • a respiratory disorder that causes respiratory distress More specifically, if a substance that stimulates the airways, such as cigarette smoke, repeatedly stimulates the airways and bronchus, the secretion of bronchial mucus secreted to remove foreign substances in the bronchus increases. Causes partial or complete closure. When the bronchus is closed, the alveoli expand and become damaged, and the ability to exchange oxygen and carbon dioxide is impaired. The closed alveoli are easily infected with bacteria.
  • chronic obstructive pulmonary disease When bacteria are infected by patients with chronic obstructive pulmonary disease, arterial oxygen pressure is a serious disorder of gas exchange. This rapidly decreasing situation may occur, and carbon dioxide coma may occur when the arterial blood carbon dioxide pressure increases due to respiratory failure.
  • chronic obstructive pulmonary disease may include, but is not limited to, emphysema, chronic bronchitis, and the like.
  • the chronic obstructive pulmonary disease of the present invention may be a disease due to overexpression of Leukotriene B4 receptor 2 (BLT2). More specifically, leukotriene is an immune mediator that causes bronchial contraction, and overexpression of Leukotriene B4 receptor 2 (BLT2) may cause chronic obstructive pulmonary disease.
  • BLT2 Leukotriene B4 receptor 2
  • BLT2 Leukotriene B4 receptor 2 is one of the group of G protein-coupled receptors (GPCR), which has a low affinity for LTB 4 ( Leukotriene B4; LTB 4 ), and the composition of the present invention is a cell growth by BLT2.
  • GPCR G protein-coupled receptors
  • the term “inhibition” means inhibiting any step of transcription, mRNA processing, translation, translocation, and maturation of a gene, or inhibition of protein-to-protein binding, activation of a protein, or signaling through it. .
  • the pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier in addition to the active ingredient.
  • the pharmaceutically acceptable carrier is commonly used in the formulation, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose , Polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate and mineral oil, and the like.
  • it may further include a lubricant, a humectant, a sweetener, a flavoring agent, an emulsifier, a suspending agent, a preservative, and the like.
  • compositions of the present invention can be administered orally or parenterally (eg, applied intravenously, subcutaneously, intraperitoneally or topically) according to the desired method, and the dosage is determined by the condition and weight of the patient, Depending on the extent, drug form, route of administration, and time, it may be appropriately selected by those skilled in the art.
  • the pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount.
  • pharmaceutically effective amount means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level refers to the type of disease, the severity, the activity of the drug, It may be determined according to the sensitivity to the drug, the time of administration, the route of administration and the rate of release, the duration of treatment, factors including the drug used concurrently and other factors well known in the medical field.
  • the pharmaceutical compositions according to the present invention may be administered as individual therapeutic agents or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be single or multiple administrations. Taking all of the above factors into consideration, it is important to administer an amount that can obtain the maximum effect in a minimum amount without side effects, which can be easily determined by those skilled in the art.
  • the effective amount of the pharmaceutical composition of the present invention may vary depending on the age, sex, condition, weight of the patient, the absorption of the active ingredient in the body, the inactivation rate and excretion rate, the type of disease, the drug used in general 0.001 to 150 mg, preferably 0.01 to 100 mg per 1 kg of body weight may be administered daily or every other day, or divided into 1 to 3 times a day.
  • the dosage may be increased or decreased depending on the route of administration, the severity of obesity, sex, weight, age, etc., and the above dosage does not limit the scope of the present invention in any way.
  • the present invention also provides a method of treating chronic obstructive pulmonary disease comprising administering the pharmaceutical composition to a subject.
  • subject means a subject in need of treatment for a disease, and more specifically, a mammal, such as a primate, mouse, dog, cat, horse and cow, which is human or non-human. .
  • non-limiting compounds to be used as active ingredients of the pharmaceutical composition according to the present invention include the following compounds, isomers thereof and pharmaceutically acceptable salts thereof.
  • the following compounds according to the invention were synthesized and the yield and 1 H NMR measurement results are described below.
  • N -Phenyl- N -(3- (4- (4- ( Prof -2- Inil Piperazine-1- Carbonyl ) Phenyl) Prof -2-ynyl) pentaneamide N -phenyl- N -(3- (4- (4- (prop-2- ynyl ) piperazine -1-carbonyl) phenyl) prop-2-ynyl) pentanamide) ( LMT -833)
  • N -(3- Fluorophenyl )- N -(3- (4- (4- Isopropyl piperazine -One- Carbonyl ) Phenyl) prop-2-ynyl) pentaneamide N -(3- fluorophenyl )- N -(3- (4- (4-isopropylpiperazine-1-carbonyl) phenyl) prop-2-ynyl) pentanamide
  • N -(4- Fluorophenyl )- N -(3- (4- (4- Isopropyl piperazine -One- Carbonyl ) Phenyl) prop-2-ynyl) pentaneamide N -(4- fluorophenyl )- N -(3- (4- (4-isopropylpiperazine-1-carbonyl) phenyl) prop-2-ynyl) pentanamide
  • Benzamide N , N -diethyl-4- (3- ( N -phenylpentanamido) prop-1-ynyl) benzamide) ( LMT -883)
  • N -(3- (3- (4-methylpiperazin-1-carbonyl) phenyl) prop-2-ynyl)- N -Phenylpentaneamide N -(3- (3- (4-methylpiperazine-1-carbonyl) phenyl) prop-2-ynyl)- N -phenylpentanamide
  • N -(4- Fluorophenyl )- N -(3- (3- (4- Isopropyl piperazine -One- Carbonyl ) Phenyl) prop-2-ynyl) pentaneamide N -(4- fluorophenyl )- N -(3- (3- (4-isopropylpiperazine-1-carbonyl) phenyl) prop-2-ynyl) pentanamide
  • tert -Butyl 4- (5- (3-(( N - Phenylpentaneamido ) Prof -1-yn-1-yl) Picolinoyl Piperazine-1-carboxylate ( tert -butyl 4- (5- (3- ( N - phenylpentanamido prop-1- yn -1-yl) picolinoyl) piperazine-1-carboxylate) ( LMT -834)
  • N -(3- (6- (4- Isopropyl piperazine -One- Carbonyl Pyridin-3-yl) Prof -2-yn-1-yl)- N -Phenylpentaneamide N -(3- (6- (4- isopropylpiperazine -1-carbonyl) pyridin -3-yl) prop-2-yn-1-yl)- N -phenylpentanamide
  • N, N -Diethyl-4- (3- ( N -(4-fluorophenyl) pentaneamido) prop-1-yn-1-yl) benzamide N, N -diethyl-4- (3- ( N -(4-fluorophenyl) pentanamido) prop-1-yn-1-yl) benzamide) ( LMT -927)
  • N -Ethyl-4- (3- ( N - Phenylpentaneamido ) Prof -1-yn-1-yl) Benzamide
  • N -ethyl-4- (3- ( N -phenylpentanamido) prop-1-yn-1-yl) benzamide
  • BLT2 is Expressed cells or BLT2 is Preparation of Unexpressed Cells
  • cells without BLT2 expression and cells with BLT2 expression were prepared in the following manner.
  • CHO cells were obtained from the Korea Cell Line Bank (KCLB, 10061), which contained 10% FBS (fetal bovine serum; Life technologies, Inc.), penicillin (50 units / ml), and antibiotic antimycotic solution (Life technologies, Inc.). It was incubated at 37 °C, 5% CO 2 conditions in RPMI 1640 medium (Invitrogen) containing the. The cells were maintained in the growth phase by splitting with Trypsin-EDTA for 3 days, respectively, with PBS (phosphate-buffered saline; 137 mM NaCl, 2.7 mM KCl, 10 mM Na 2 HPO 4 , 2m MKH 2 PO 4 ) And then added to fresh medium to prepare cells without BLT2 expression.
  • FBS fetal bovine serum
  • penicillin 50 units / ml
  • antibiotic antimycotic solution Life technologies, Inc.
  • CHO-K1 cells were transformed with pcDNA3-long form BLT2 encoding HA-tagged human BLT2, and 0.4 mg / ml of G418 (Invitrogen). , Carlsbad, CA, USA).
  • G418 Invitrogen
  • the selected clones were analyzed by RT-PCR using human-specific BLT2 primers, and representative clones were used in the experiments with cells expressing BLT2 (CHO-BLT2).
  • LTB 4 which is a ligand of BLT2 to BLT2-expressing cells (CHO-BLT2 cells) (300 nM) treated (DMSO +) and ethanol treated (DMSO-) cell growth increased from 20% to 35%, and in BLT2 expressed cells (CHO-BLT2), positive control Phosphorus LY255283 pre-treated, showed about 90% cell growth compared to the control group treated with DMSO, confirming the effect of inhibiting cell growth according to the compound treatment of the Example.
  • LTB 4 which is a ligand of BLT2 to BLT2-expressing cells (CHO-BLT2 cells) (300 nM) treated (DMSO +) and ethanol treated (DMSO-) cell growth increased from 20% to 35%, and in BLT2 expressed cells (CHO-BLT2), positive control Phosphorus LY255283 pre-treated, showed about 90% cell growth compared to the control group treated with DMSO, confirming the effect of inhibiting cell growth according to the compound treatment of the Example. Specifically, the growth inhibitory effect of the compounds of the present invention AC-1632 (78.7%), AC-1635 (71.6%), AC-1646 (72.1%) and AC-1650 (82.2%) was confirmed.
  • the compounds of the present invention can inhibit BLT2-induced cell proliferation with excellent efficiency, and the compound is used as a therapeutic agent for BLT2-related chronic obstructive pulmonary disease. It can be used as a possible pharmaceutical ingredient (BLT2-blocking pharmacological molecules).
  • Chemotactic motility was analyzed using a Transwell chamber equipped with a 6.5-mm diameter polycarbonate filter (8- ⁇ m pore size, Corning Costar). Specifically, the bottom surface of the filter was coated with 10 ⁇ g / ml fibronectin in serum free RPMI 1640 medium at 37 ° C. for 1 hour. A dry, coated filter with RPMI 1640 medium containing varying amounts of LTB 4 is placed in the bottom well of the Transwell chamber and finally 2 ⁇ 10 4 cells of CHO cells stably expressing BLT1 and BLT2 in serum-free RPMI 1640 medium. Experiments were performed by loading the upper wells with / 100 ⁇ l.
  • the cells were pretreated with each inhibitor for 30 minutes before dispensing. After 3 hours of incubation at 37 ° C., 5% CO 2 , the filters were fixed with methanol for 3 minutes and stained with hematoxylin and eosin for 10 minutes.
  • the cells used BLT2-expressing cells (CHO-BLT2 cells) and BLT1-expressing cells (CHO-BLT1), LY255283 and U75302 as the positive control, respectively, and LTB 4 , the ligand of BLT2 as the control. , (300 nM), LTB 4 , the ligand of BLT1 (10nM) and LPA (lysophosphatidic acid; 100nM) were used. Chemotaxis was quantified by counting cells on the lower side of the filter under an optical microscope (magnification, x 200). Six fields were counted in each assay, each sample analyzed twice, and the assay was repeated three times.
  • LTB 4 which is a ligand of BLT2 to BLT2-expressing cells (CHO-BLT2 cells)
  • DMSO + DMSO +
  • DMSO- ethanol treated
  • cell chemotaxis was 2.4-fold increased
  • LY255283 used as a positive control pretreated (10 ⁇ M)
  • the ligand LTB Compared to the case of 4 treated, it was confirmed that the coinability of 90%.
  • the ligand LTB 4 (10 nM) treated (DMSO +), ethanol treated compared to (DMSO-), the cell chemotaxis increased 2.2 times, the pretreatment (10 ⁇ M) of U75302 used as a positive control, the ligand LTB It was confirmed that 90% of chemotaxis was shown in comparison with the case where 4 was treated.
  • LTB 4 is a ligand Compared with treatment (DMSO +), chemotaxis was 66%, 90%, and 70.3% inhibited, whereas LTB 4 , a ligand, was expressed in BLT1-expressing cells (CHO-BLT1). It was confirmed that chemotaxis was not suppressed compared to treatment (DMSO +).
  • LTB 4 which is a ligand of BLT2 in BLT2-expressing cells (CHO-BLT2 cells) (300 nM) treated (DMSO +) and ethanol treated (DMSO-), compared to 2.9-fold increase in cell chemotaxis, 10 ⁇ M pretreated LY255283 used as a positive control, the ligand LTB 4 To It showed 90% chemotaxis compared to the treatment, and when the compound of the present invention (AC-1074) was pretreated with 10 ⁇ M of cells expressing BLT2, the ligand was treated with LTB 4 (DMSO +). It was confirmed that 53% inhibition of chemotaxis.
  • LTB 4 which is a ligand of BLT1 in BLT1-expressing cells (CHO-BLT1 cells)
  • 10 nM DMSO +
  • DMSO- DMSO-
  • the cell chemotaxis was increased by 2.8-fold
  • the compound (AC-1074) of the present invention was added to cells expressing BLT2 10.
  • pretreatment with M it was confirmed that there was no change in chemotaxis compared to (DMSO +) when the ligand LTB 4 was treated.
  • chemotactic activity was LTB 4 in cells stably expressing BLT2 (CHO-BLT2).
  • the compounds of the present invention LMT-692, LMT-696, LMT-1013, and AC-1074
  • LMT-692, LMT-696, LMT-1013, and AC-1074 can significantly inhibit this chemotaxis, as the BLT2-dependent strain induced by LTB 4 It can be used as a pharmaceutical component to inhibit Mars.
  • LTB 4 and BLT2 binding (ligand binding affinity) inhibition was analyzed using the isotope tritium (H3) label LTB 4 ([3H] LTB 4, ARC) (specific activity 160.0 Ci / mmol).
  • Experimental method is to put 2 ⁇ 10 6 CHO-BLT2 cells in a 100 mm culture dish and incubate for 48 hours before proceeding. The harvested cells are used five times for one minute in a homogenizer to separate the proteins of the cell membrane. Thereafter, centrifugation was performed for 40 minutes at 45,000 RPM at 4 ° C. to harvest only protein of the cell membrane and quantify it at a concentration of 40 ⁇ g / 45 ⁇ l.
  • the concentration of the compound (AC-1074) of the present invention increases (10 -9 , 10 -8 , 10 -7 , 10 -6 and 10 -5 ) the binding of LTB 4 and BLT2 was inhibited, the IC 50 (50% binding inhibition concentration) of the AC-1074 compound was 140.35 nM.
  • COPD Chronic obstructive pulmonary disease
  • Toxic smoke-induced chronic obstructive pulmonary disease (COPD) animal model experiments were conducted by the Korea Institute of Bioscience and Biotechnology (KRIBB). More specifically, standard tobacco extract (Cigarette smoking, CS) was prepared as follows to cause chronic obstructive pulmonary disease caused by tobacco extract in experimental mice. In accordance with ISO 3402, 60 cigarette smoke condensate collections were carried out in a smoking room maintained at a temperature of 22 ⁇ 2 ° C and a relative humidity of 60 ⁇ 5%, according to the ISO 3402 standard, Coresta Monitering Cigarette 7, Heinr Borgwaldt, Germany.
  • ISO 3402 60 cigarette smoke condensate collections were carried out in a smoking room maintained at a temperature of 22 ⁇ 2 ° C and a relative humidity of 60 ⁇ 5%, according to the ISO 3402 standard, Coresta Monitering Cigarette 7, Heinr Borgwaldt, Germany.
  • Cigarette cigarettes were burned using an automatic smoking machine (Automatic smoking machine, RM20, Heinr Borgwaldt, ISO 3308 standard) with a smoking volume of 35.0 ⁇ 0.3 ml, a smoking cycle of 60 ⁇ 0.5 seconds and a smoking time of 2.00 ⁇ 0.02 seconds.
  • the length of the butts was set to tip paper length + 3 mm (overwrap + 3 mm), and the smoke smoke condensate was collected by a 92 mm cambridge filter (ISO 3308 standard product).
  • the filter cartridge which collected the smoke smoke condensate, was separated from the cigaratte holder and placed in a 100 ml Erlenmeyer flask, and then shaken well by adding 50 ml of extraction solvent isopropanol, followed by extraction at room temperature for at least 8 hours. . After extraction, the resultant was filtered, concentrated with a vacuum filter concentrator, and the concentrates contained in three Erlenmeyer flasks were collected in scintillation vials and completely concentrated with nitrogen gas.
  • mice Male 8-week-old mice (BALB / c, SPF, 18-20 g) supplied by Orient Biotech Co., Ltd. (Korea) were thoroughly fed with solid feed (no antibiotics, Samyang Feed Co.) and water until the day of the experiment. It was supplied and used for experiments after 1 week of adaptation in a temperature of 22 ⁇ 2 ° C., a humidity of 55 ⁇ 15% and a light-dark cycle of 12 hours. After 8-week-old BALB / c mice were anesthetized with 7% chloral hydrate, the mouse's incisors were fixed with rubber bands when there was no movement, and then standard tobacco extract was added to 100 ⁇ g / ml of lipopolysaccharide (LPS).
  • LPS lipopolysaccharide
  • the COPD-induced negative control group significantly increased the production of TNF- ⁇ in bronchoalveolar lavage fluid compared to the normal control group, the experimental group administered the compound of the present invention AC-1013 negative control group It was confirmed that the production of TNF- ⁇ is inhibited as compared with that of.
  • COPD Chronic obstructive pulmonary disease
  • the COPD-induced negative control group significantly increased the production of IL-6 in bronchoalveolar lavage fluid compared with the normal control group
  • the experimental group administered the compound of the present invention AC-1013 negative control group It was confirmed that the production of IL-6 is inhibited compared with that of.
  • ROS reactive oxygen species
  • mice were exposed to a total of 8 cigarette smokes for 1 hour per day, and LPS was intranasally administered at 5 ⁇ g / 50 ⁇ l / mouse.
  • Compounds of the invention (LMT-886 and LMT-1013) were administered orally 1 hour before exposure to tobacco smoke.
  • Tobacco smoke acts as a powerful stimulant in the lung tissue and activates the inflammatory signaling system, which further exacerbates pulmonary inflammation. Therefore, suppressing inflammation can be used as an index for improving chronic obstructive pulmonary disease.
  • Infiltration of inflammatory cells (Neutrophils, Macrophages, etc.) was confirmed. Therefore, in order to confirm the number of inflammatory cells in the bronchial alveolar lavage fluid of the COPD mouse described in Example 6-1, 700ul (total volume 1.4 ml) of saline (PBS: phosphate buffered saline) was added to the lungs of the mouse using bronchial implantation.
  • PBS phosphate buffered saline
  • centrifugation (14,000 rpm, 4 ° C, 5 min) was carried out by tapping 1 ml of PBS into a 1.5 ml tube from which cells were separated, and then 100 ⁇ l of each sample was obtained for cytospin (Hanil). Science, Korea) was attached to the slide by rotating for 5 minutes at 1000rpm. Thereafter, the nucleus and cytoplasm of the cells were stained using a Diff-Quik staining kit to distinguish inflammatory cells, and the number of cells was calculated by microscopic examination.
  • the compounds of the present invention LMT-886 and LMT-1013 significantly reduced the infiltration of inflammatory cells (neutrophils) of COPD mice.
  • Toxic agents that cause emphysema include neutrophil elastase (NE) and reactive oxygen species (ROS).
  • NE neutrophil elastase
  • ROS reactive oxygen species
  • DCFDA Dichlorofluorescin diacetate
  • NE see FIG. 10
  • ROS see FIG. 11
  • saline PBS: phosphate buffered
  • saline 700ul total volume 1.4 ml
  • ELISA kit (BD Bioscience, San Diego, Calif.) was used to measure the levels of TNF- ⁇ and IL-6 in the supernatant, and was performed according to the protocol of each manufacturer.
  • the supernatant was dispensed on a 96 well plate to which TNF- ⁇ or IL-6 antibody was attached and attached for 2 hours, followed by washing with a washing solution, and the detection antibody was attached with HRP for 1 hour and then washed again.
  • the reaction was stopped with sulfuric acid solution, and the absorbance was measured at 450 nm using a SPARK TM 10 M multimode microplate reader (Tecan system inc., CA, USA).
  • TNF- ⁇ (see FIG. 12) and IL-6 (see FIG. 13) were significantly increased in COPD mouse bronchial alveolar lavage fluid, but the compounds LMT-886 and LMT of the present invention.
  • Oral administration of -1013 was found to significantly reduce the production of cytokines such as TNF- ⁇ and IL-6.
  • lungs were removed, immediately fixed in 10% formaldehyde solution, rinsed and washed with running water for 8 hours, embedded in epoxy, and sections were made of microtome.
  • staining was performed with hematoxylin and eosin (H & E), and then fixed with Histomount solution (invitrogen, USA), and pathological changes of lung tissue were examined using an optical microscope. .
  • the compounds LMT-886 and LMT-1013 of the present invention is shown to improve the inflammation of the lungs in animal models of chronic obstructive pulmonary disease caused by tobacco smoke and lipopolysaccharide, and may be able to restore the reduced lung function. Judging.
  • Compounds exhibiting BTL2 inhibitory activity of the present invention exhibits an excellent chemotactic inhibitory effect and a treatment effect for chronic obstructive pulmonary disease, whereby the compounds of the present invention are for preventing or treating chronic obstructive pulmonary disease (COPD). It is expected that it may be usefully used as an active ingredient of a pharmaceutical composition.
  • COPD chronic obstructive pulmonary disease

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Abstract

The present invention relates to a novel compound exhibiting inhibitory activity against Leukotriene B4 receptor 2(BLT2) and a composition comprising the same as an effective ingredient for preventing or treating inflammatory diseases. In the present invention, a novel compound exhibiting a BTL2-inhibiting activity was investigated. The compound was experimentally identified to have excellent effects such as enhancement of cancer cell death, suppression of metastasis, suppression of chemotaxis, anti-asthmatic activity, etc. and is expected to more fundamentally approach and treat a target, with respect to the prevention or treatment of inflammatory diseases.

Description

BLT 저해 활성을 갖는 화합물을 유효성분으로 포함하는 만성 폐쇄성 폐질환 예방 또는 치료용 약학적 조성물Pharmaceutical composition for preventing or treating chronic obstructive pulmonary disease comprising a compound having a BLT inhibitory activity as an active ingredient
본 발명은 만성 폐쇄성 폐질환 예방 또는 치료용 약학적 조성물에 관한 것으로서, 보다 구체적으로는 BLT2 (Leukotriene B4 receptor 2) 억제 활성을 나타내는 화합물을 유효성분으로 포함하는 만성 폐쇄성 폐질환 예방 또는 치료용 약학적 조성물에 관한 것이다.The present invention relates to a pharmaceutical composition for preventing or treating chronic obstructive pulmonary disease. More specifically, the present invention relates to a pharmaceutical composition for preventing or treating chronic obstructive pulmonary disease, comprising as an active ingredient a compound exhibiting inhibitory activity of Leukotriene B4 receptor 2. It relates to a composition.
만성 폐쇄성 폐질환(COPD; chronic obstructive pulmonary disease)은 만성 기관지염이나 폐기종 등에 의해서 기도를 통과하는 공기의 기류 제한 혹은 폐쇄가 나타나는 질병으로, 주로 폐의 비정상적인 염증반응 결과, 기도가 좁아지는 폐질환이다. 만성 폐쇄성 폐질환은 주로 유해입자나 가스의 흡입에 의해 발생하게 되며, 특히 흡연이 주요 원인으로 알려져 있다. 흡연은 폐조직내 강력한 자극물질로 작용하여, 다양한 전염증 인자, 성장인자, 산화물질 및 화학 주성 인자들의 생성을 증가시키며, 염증성 신호전달체계를 활성화시켜 호중구 및 대식세포를 비롯한 많은 염증세포의 유주를 촉진시켜 폐 염증을 더욱 악화시키게 된다. 특히. 담배 연기와 같이 기도를 자극하는 물질이 기도와 기관지를 반복적으로 자극하면, 기관지 내의 이물질을 제거하기 위하여 분비되는 기관지 점액의 분비가 증가함으로 기관지의 부분적 또는 전체적 폐쇄를 일으킨다. 기관지가 폐쇄되면 폐포는 확장되고 손상되어 산소와 이산화탄소의 교환능력이 손상 받게 된다. 폐쇄된 폐포는 세균이 쉽게 감염되는데, 만성 폐쇄성 폐질환 환자에게 세균이 감염되면 가스교환의 심각한 장애로 동맥혈 산소압이 급격히 감소하는 상황이 발생하며, 호흡부전에 의하여 동맥혈 이산화탄소압이 상승하면 이산화탄소 혼수가 발생할 수도 있다. 또한, 담배연기 및 염증세포들에서 유래된 기질금속단백질분해효소 (metalloproteinase)와 같은 단백분해 효소가 활성화되어 폐 간질 조직 내 구성물을 파괴하게 된다. 이는 결국 폐 조직의 비정상적인 변화 즉 기도벽의 비후, 폐섬유화를 야기하여 폐기능 저하를 야기하게 된다. 만성 폐쇄성 폐질환은 임상적으로 만성적 객담을 동반하는 기침을 하는 만성기관지염과 종말세기관지(terminal bronchiole) 이하의 폐포들이 비정상적으로 늘어나고 폐포격벽이 파괴되는 폐기종이 혼합되어 양자간의 구분이 힘든 경우, 이들을 총칭하여 COPD라고 한다. COPD는 호흡곤란, 기침, 가래 등의 기도 질환 증상을 나타내다가 폐 기능을 악화시켜 사망에 이르게 한다. 발병 원인은 90% 이상이 흡연 때문인 것으로 알려져 있고 이외에 공해와 선천적 질환, 호흡기 감염증 등이 있다. 따라서, 만성 폐쇄성 폐질환은 서서히 진행하는 호흡곤란에 의해 일상생활의 제한, 삶의 질 저하를 초래하고 결국에는 일상생활까지 타인에게 의존하게 되어 주위사람들의 생산성과 삶의 질까지도 저하시키는 질환이다.Chronic obstructive pulmonary disease (COPD) is a disease in which airflow restriction or obstruction is caused by chronic bronchitis or emphysema, and it is mainly a lung disease in which the airway is narrowed as a result of abnormal inflammatory reaction of the lung. Chronic obstructive pulmonary disease is mainly caused by inhalation of harmful particles or gases, and smoking is known as a major cause. Smoking acts as a powerful stimulant in lung tissue, increasing the production of various proinflammatory, growth, oxidative and chemotactic factors, and activating the inflammatory signaling system to induce inflammatory cells, including neutrophils and macrophages. To promote lung aggravation. Especially. Repeated stimulation of the airway and bronchus, such as tobacco smoke, causes partial or total obstruction of the bronchus by increasing the secretion of bronchial mucus secreted to remove foreign bodies in the bronchus. When the bronchus is closed, the alveoli expand and damage, impairing the exchange capacity of oxygen and carbon dioxide. Closed alveoli are easily infected with bacteria. When bacteria are infected by patients with chronic obstructive pulmonary disease, arterial oxygen pressure decreases rapidly due to severe gas exchange, and when arterial carbon dioxide pressure rises due to respiratory failure, carbon dioxide coma May occur. In addition, proteolytic enzymes such as metalloproteinases derived from tobacco smoke and inflammatory cells are activated to destroy components in lung interstitial tissue. This in turn causes abnormal changes in lung tissue, that is, thickening of the airway wall, pulmonary fibrosis, leading to decreased lung function. Chronic obstructive pulmonary disease is referred to collectively as chronic bronchitis with cough with chronic sputum and emphysema with abnormal increase in alveoli below terminal bronchiole and destruction of alveolar septum, which is difficult to distinguish between them. This is called COPD. COPD causes symptoms of airway disease such as dyspnea, cough, and sputum, which worsen lung function and lead to death. It is known that more than 90% of the causes are due to smoking, and pollution, congenital diseases and respiratory infections. Therefore, chronic obstructive pulmonary disease is a disease that causes the limitation of daily life and lowers the quality of life by gradually progressing the respiratory distress and eventually depends on others to the daily life, thereby lowering the productivity and quality of life of the people around.
이에, 만성 폐쇄성 폐질환을 치료하고자 하는 시도가 다양하게 진행되고 있으나 (한국공개특허 10-2017-0003601), 현재까지 개발된 만성 폐쇄성 폐질환을 치료하고자 하는 약물은 주로 흡입성 스테로이드 호르몬 제제로서, 이러한 스테로이드제는 구강진균증, 목소리 쉼, 피부의 멍, 폐렴 등의 발생위험을 높일 수 있어 장기간 단독 사용하는 것은 권장되지 않는 문제점을 가지고 있다.Therefore, various attempts to treat chronic obstructive pulmonary disease are progressing (Korea Patent Publication No. 10-2017-0003601), but the drugs to treat chronic obstructive pulmonary disease developed until now are mainly inhaled steroid hormone preparations, Such steroids can increase the risk of oral fungal disease, voice rest, bruising of the skin, pneumonia, etc. and therefore, long-term use alone is not recommended.
한편, 류코트리엔 (Leukotriene B4; LTB4)은 급성 및 만성염증을 매개하는 5-리폭시제나제 경로에 의해 아라키돈산(AA)으로부터 합성되는 염증성 리피드 매개체 군이다. LTB4는 BLT1과 BLT2 의 두 가지 형태의 수용체들에 결합함으로써 생물학적 영향을 주는 것으로 알려져 있다. BLT2(Leukotriene B4 receptor 2)는 GPCR(G protein-coupled receptor) 군 중 하나로 LTB4에 대해 낮은 친화력을 갖는 수용체이며, 5-리폭시제나제 의존성 경로를 통해 유도된 아라키돈산(AA)의 리피드 매개체이다.On the other hand, leukotriene B4 (LTB 4 ) is a group of inflammatory lipid mediators synthesized from arachidonic acid (AA) by the 5-lipoxygenase pathway that mediates acute and chronic inflammation. LTB 4 is known to have a biological effect by binding to two types of receptors, BLT1 and BLT2. Leukotriene B4 receptor 2 (BLT2) is a group of G protein-coupled receptors (GPCRs) that has low affinity for LTB 4 and is a lipid mediator of arachidonic acid (AA) induced through a 5-lipoxygenase dependent pathway. to be.
이에, 본 발명자들은 상기와 같은 종래의 문제점을 해결하기 위하여, 보다 효과적인 만성 폐쇄성 폐질환 치료 물질을 개발하기 위한 연구를 계속하던 중, BLT2 억제 활성을 나타내는 화합물을 제조하였으며, 상기 화합물을 포함하는 만성 폐쇄성 폐질환 치료제를 최초로 고안하였다.Accordingly, the present inventors, while continuing to research to develop a more effective treatment for chronic obstructive pulmonary disease in order to solve the above-mentioned problems, the inventors prepared a compound that exhibits a BLT2 inhibitory activity, including the compound The first drug to treat obstructive pulmonary disease was designed.
본 발명은 상기와 같은 문제점을 해결하기 위해 안출된 것으로서, 본 발명자들은 BLT2 억제 활성을 나타내는 화합물의 만성 폐쇄성 폐질환 치료 효과를 확인하고 이에 기초하여 본 발명을 완성하게 되었다.The present invention has been made to solve the above problems, the present inventors have confirmed the effects of the treatment of chronic obstructive pulmonary disease of the compound showing the BLT2 inhibitory activity and based on this, to complete the present invention.
이에, 본 발명의 목적은 BLT2 억제 활성을 나타내는 화합물, 이의 이성질체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는, 만성 폐쇄성 폐질환(COPD; chronic obstructive pulmonary disease) 예방 또는 치료용 약학적 조성물을 제공하는 것이다.Accordingly, an object of the present invention is a pharmaceutical composition for preventing or treating chronic obstructive pulmonary disease (COPD), comprising as an active ingredient a compound, an isomer thereof, or a pharmaceutically acceptable salt thereof exhibiting BLT2 inhibitory activity. To provide.
또한, 본 발명의 목적은 BLT2 억제 활성을 나타내는 화합물, 이의 이성질체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는, 만성 폐쇄성 폐질환 예방 또는 개선용 건강기능식품 조성물을 제공하는 것이다.It is also an object of the present invention to provide a health functional food composition for preventing or improving chronic obstructive pulmonary disease, comprising as an active ingredient a compound, an isomer thereof, or a pharmaceutically acceptable salt thereof, which exhibits BLT2 inhibitory activity.
그러나 본 발명이 이루고자 하는 기술적 과제는 이상에서 언급한 과제에 제한되지 않으며, 언급되지 않은 또 다른 과제들은 아래의 기재로부터 당업자에게 명확하게 이해될 수 있을 것이다.However, the technical problem to be achieved by the present invention is not limited to the above-mentioned problem, another task that is not mentioned will be clearly understood by those skilled in the art from the following description.
상기와 같은 본 발명의 목적을 달성하기 위하여, 본 발명은 BLT2 억제 활성을 나타내는 화합물, 이의 이성질체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는, 만성 폐쇄성 폐질환(COPD; chronic obstructive pulmonary disease) 예방 또는 치료용 약학적 조성물을 제공한다.In order to achieve the above object of the present invention, the present invention comprises a compound exhibiting BLT2 inhibitory activity, an isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient, chronic obstructive pulmonary disease (COPD) ) Provides a pharmaceutical composition for prophylaxis or treatment.
본 발명의 일 구현예로서, 상기 화합물은 tert-부틸 4-(4-(3-(N-페닐펜탄아미도)프로프-1-이닐)벤조일)피페라진-1-카복실레이트; N-페닐-N-(3-(4-(피페라진-1-카보닐)페닐)프로프-2-이닐)펜탄아마이드; N-(3-(4-(4-메틸피페라진-1-카보닐)페닐)프로프-2-이닐)-N-페닐펜탄아마이드; N-(3-(4-(4-에틸피페라진-1-카보닐)페닐)프로프-2-이닐)-N-페닐펜탄아마이드; N-(3-(4-(4-아이소프로필피페라진-1-카보닐)페닐)프로프-2-이닐)-N-페닐펜탄아마이드; N-(3-(4-(4-(2-하이드록시에틸)피페라진-1-카보닐)페닐)프로프-2-이닐)-N-페닐펜탄아마이드; N-(3-(4-(4-(사이클로프로필메틸)피페라진-1-카보닐)페닐)프로프-2-이닐)-N-페닐펜탄아마이드; N-(3-(4-(4-사이클로헥실피페라진-1-카보닐)페닐)프로프-2-이닐)-N-페닐펜탄아마이드; N-(3-(4-(4-(사이클로헥실메틸)피페라진-1-카보닐)페닐)프로프-2-이닐)-N-페닐펜탄아마이드; N-(3-(4-(4-아이소부틸피페라진-1-카보닐)페닐)프로프-2-이닐)-N-페닐펜탄아마이드; N-페닐-N-(3-(4-(4-(프로프-2-이닐)피페라진-1-카보닐)페닐)프로프-2-이닐)펜탄아마이드; N-(3-(4-(4-시아노피페라진-1-카보닐)페닐)프로프-2-이닐)-N-페닐펜탄아마이드; tert-부틸 4-(4-(3-(N-(3-플루오로페닐)펜탄아미도)프로프-1-이닐)벤조일)피페라진-1-카복실레이트; N-(3-플루오로페닐)-N-(3-(4-(피페라진-1-카보닐)페닐)프로프-2-이닐)펜탄아마이드; N-(3-플루오로페닐)-N-(3-(4-(4-아이소프로필피페라진-1-카보닐)페닐)프로프-2-이닐)펜탄아마이드; tert-부틸 4-(4-(3-(N-(4-플루오로페닐)펜탄아미도)프로프-1-이닐)벤조일)피페라진-1-카복실레이트; N-(4-플루오로페닐)-N-(3-(4-(피페라진-1-카보닐)페닐)프로프-2-이닐)펜탄아마이드; N-(4-플루오로페닐)-N-(3-(4-(4-아이소프로필피페라진-1-카보닐)페닐)프로프-2-이닐)펜탄아마이드; N-(3-(4-(몰폴린-4-카보닐)페닐)프로프-2-이닐)-N-페닐펜탄아마이드; N-페닐-N-(3-(4-(피페리딘-1-카보닐)페닐)프로프-2-이닐)펜탄아마이드; N,N-다이에틸-4-(3-(N-페닐펜탄아미도)프로프-1-이닐)벤즈아마이드; N-페닐-N-(3-(3-(피페라진-1-카보닐)페닐)프로프-2-이닐)펜탄아마이드; N-(3-(3-(4-메틸피페라진-1-카보닐)페닐)프로프-2-이닐)-N-페닐펜탄아마이드; N-(3-(3-(4-아이소프로필피페라진-1-카보닐)페닐)프로프-2-이닐)-N-페닐펜탄아마이드; tert-부틸-4-(3-(3-(N-(4-플루오로페닐)펜탄아미도)프로프-1-이닐)벤조일)피페라진-1-카복실레이트; N-(4-플루오로페닐)-N-(3-(3-(피페라진-1-카보닐)페닐)프로프-2-이닐)펜탄아마이드; N-(4-플루오로페닐)-N-(3-(3-(4-아이소프로필피페라진-1-카보닐)페닐)프로프-2-이닐)펜탄아마이드; N-(3-(4-하이드록시페닐)프로프-2-이닐)-N-페닐펜탄아마이드; 2-(4-(3-(N-페닐펜탄아미도)프로프-1-이닐)페녹시)아세트산; tert-부틸 4-(5-(3-((N-페닐펜탄아미도)프로프-1-인-1-일)피콜리노일)피페라진-1-카복실레이트; N-페닐-N-(3-(6-(피페라진-1-카보닐)피리딘-3-일)프로프-2-인-1-일)펜탄아마이드; N-(3-(6-(4-아이소프로필피페라진-1-카보닐)피리딘-3-일)프로프-2-인-1-일)-N-페닐펜탄아마이드; N,N-다이에틸-4-(3-(N-(3-플루오로페닐)펜탄아미도)프로프-1-인-1-일)벤즈아마이드; N,N-다이에틸-4-(3-(N-(4-플루오로페닐)펜탄아미도)프로프-1-인-1-일)벤즈아마이드; N-(3-(4-(N,N-다이에틸설파모일)페닐)프로프-2-이닐)-N-페닐펜탄아마이드; N-(3-(4-(N-아이소프로필설파모일)페닐)프로프-2-이닐)-N-페닐펜탄아마이드; tert-부틸 4-(3-(N-페닐펜탄아미도)프로프-1-인-1-일)벤조에이트; 4-(3-(N-페닐펜탄아미도)프로-1-핀-1-일)벤조익산; N-에틸-4-(3-(N-페닐펜탄아미도)프로프-1-인-1-일)벤즈아마이드; N-(2-(다이메틸아미노)에틸)-4-(3-(N-페닐펜탄아미도)프로프-1-인-1-일)벤즈아마이드; 에틸 2-(4-(3-(N-페닐펜탄아미도)프로프-1-인-1-일)벤즈아미도)아세테이트; 2-(4-(3-(N-페닐펜탄아미도)프로프-1-인-1-일)벤즈아미도)아세틱산; 메틸 2-(4-(3-(N-페닐펜탄아미도)프로프-1-인-1-일)벤즈아미도)프로파노에이트; 2-(4-(3-(N-페닐펜탄아미도)프로프-1-인-1-일)벤즈아미도)프로피오닉산; 2-(4-(3-(N-(3-플루오로페닐)펜탄아미도)프로프-1-이닐)페녹시)아세트산; 2-(4-(3-(N-(4-플루오로페닐)펜탄아미도)프로프-1-이닐)페녹시)아세트산; N-((3'-(4-메틸페닐설폰아미도)바이페닐-4-일)메틸)-N-페닐펜탄아마이드; N-(4'-((N-페닐펜탄아미도)메틸)바이페닐-3-일)-4-(트리플루오로메틸)벤즈아마이드; N-(3-플루오로페닐)-N-((3'-(4-메틸페닐설폰아미도)바이페닐-4-일)메틸)펜탄아마이드; N-(4'-((N-3-플루오로페닐)펜탄아미도)메틸)바이페닐-3-일)-4-(트리플루오로메틸)벤즈아마이드; 1-(3-플루오로페닐)-1-((4'-메톡시바이페닐-4-일)메틸)-3-(3-(트리플루오로메틸)페닐)유레아; N-(3-플루오로페닐)-N-((4'-메톡시바이페닐-4-일)메틸)-1-(4-메톡시페닐설폰일)메탄아마이드; 1-(3-플루오로페닐)-1-((4'-하이드록시바이페닐-4-일)메틸)-3-(3-(트리플루오로메틸)페닐)유레아; 2-(4'-((1-(3-플루오로페닐)-3-(3-(트리플루오로메틸)페닐)유레이도)메틸)바이페닐-4-일옥시)아세트산; 4-(4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)부탄산; 2-(4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)-2-메틸프로판산; (E)-3-(4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아크릴산; 3-(4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)프로판산; N-(3-플루오로페닐)-N-((4'-(2-(4-메틸피페라진-1-일)-2-옥소에톡시)바이페닐-4-일)메틸)펜탄아마이드; 프로프-2-인일 2-(4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세테이트; N-(3-플루오로페닐)-N-((4'-(프로프-2-이닐옥시)바이페닐-4-일)메틸)펜탄아마이드; N-((2'-(1H-테트라졸-5-일)바이페닐-4-일)메틸)-N-페닐펜탄아마이드; 2-(4'-((N-페닐펜탄아미도)메틸)바이페닐-4-일옥시)아세트산; 2-(4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세트산; 2-(4'-((N-(3-클로로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세트산; 2-(4'-((N-(3-브로모페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세트산; 2-(4'-((N-(3-(트리플루오로메틸)페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세트산; 2-(4'-((N-m-톨릴펜탄아미도)메틸)바이페닐-4-일옥시)아세트산; N-((4'-하이드록시바이페닐-4-일)메틸)-N-(3-니트로페닐)펜탄아마이드; 2-(4'-((N-(3-니트로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세트산; 2-(4'-((N-(3-아이오도페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세트산; 2-((4'-((N-(3-플루오로페닐)아세트아미도)메틸)-[1,1'-바이페닐]-4-일)옥시)아세트산; N-((4'-(4-아이소프로필피페라진-1-카보닐)바이페닐-4-일)메틸)-N-페닐펜탄아마이드; N-(4-플루오로페닐)-N-((4'-(4-아이소프로필피페라진-1-카보닐)바이페닐-4-일)메틸)펜탄아마이드; N-((3'-(4-아이소프로필피페라진-1-카보닐)바이페닐-4-일)메틸)-N-페닐펜탄아마이드; 및 N-(4-플루오로페닐)-N-((3'-(4-아이소프로필피페라진-1-카보닐)바이페닐-4-일)메틸)펜탄아마이드로 이루어진 군으로부터 선택될 수 있다.In one embodiment of the present invention, the compound is tert -butyl 4- (4- (3- ( N -phenylpentaneamido) prop-1-ynyl) benzoyl) piperazine-1-carboxylate; N -phenyl- N- (3- (4- (piperazin-1-carbonyl) phenyl) prop-2-ynyl) pentaneamide; N- (3- (4- (4-methylpiperazin-1-carbonyl) phenyl) prop-2-ynyl) -N -phenylpentanamide; N- (3- (4- (4-ethylpiperazin-1-carbonyl) phenyl) prop-2-ynyl) -N -phenylpentanamide; N- (3- (4- (4-isopropylpiperazin-1-carbonyl) phenyl) prop-2-ynyl) -N -phenylpentaneamide; N- (3- (4- (4- (2-hydroxyethyl) piperazin-1-carbonyl) phenyl) prop-2-ynyl) -N -phenylpentaneamide; N- (3- (4- (4- (cyclopropylmethyl) piperazin-1-carbonyl) phenyl) prop-2-ynyl) -N -phenylpentaneamide; N- (3- (4- (4-cyclohexylpiperazine-1-carbonyl) phenyl) prop-2-ynyl) -N -phenylpentaneamide; N- (3- (4- (4- (cyclohexylmethyl) piperazin-1-carbonyl) phenyl) prop-2-ynyl) -N -phenylpentanamide; N- (3- (4- (4-isobutylpiperazin-1-carbonyl) phenyl) prop-2-ynyl) -N -phenylpentaneamide; N -phenyl- N- (3- (4- (4- (prop-2-ynyl) piperazin-1-carbonyl) phenyl) prop-2-ynyl) pentaneamide; N- (3- (4- (4-cyanopiperazin-1-carbonyl) phenyl) prop-2-ynyl) -N -phenylpentanamide; tert -butyl 4- (4- (3- ( N- (3-fluorophenyl) pentaneamido) prop-1-ynyl) benzoyl) piperazine-1-carboxylate; N - (3-fluorophenyl) - N - (3- (4- ( piperazine-1-carbonyl) phenyl) prop-2-ynyl) pentane amide; N - (3-fluorophenyl) - N - (3- (4- (4- isopropyl-piperazine-1-carbonyl) phenyl) prop-2-ynyl) pentane amide; tert -butyl 4- (4- (3- ( N- (4-fluorophenyl) pentaneamido) prop-1-ynyl) benzoyl) piperazine-1-carboxylate; N - (4-fluorophenyl) - N - (3- (4- ( piperazine-1-carbonyl) phenyl) prop-2-ynyl) pentane amide; N - (4-fluorophenyl) - N - (3- (4- (4-isopropyl-piperazine-1-carbonyl) phenyl) prop-2-ynyl) pentane amide; N- (3- (4- (morpholin-4-carbonyl) phenyl) prop-2-ynyl) -N -phenylpentanamide; N -phenyl- N- (3- (4- (piperidine-1-carbonyl) phenyl) prop-2-ynyl) pentaneamide; N , N -diethyl-4- (3- ( N -phenylpentaneamido) prop-1-ynyl) benzamide; N -phenyl- N- (3- (3- (piperazin-1-carbonyl) phenyl) prop-2-ynyl) pentaneamide; N- (3- (3- (4-methylpiperazin-1-carbonyl) phenyl) prop-2-ynyl) -N -phenylpentanamide; N- (3- (3- (4-isopropylpiperazin-1-carbonyl) phenyl) prop-2-ynyl) -N -phenylpentaneamide; tert -butyl-4- (3- (3- ( N- (4-fluorophenyl) pentaneamido) prop-1-ynyl) benzoyl) piperazine-1-carboxylate; N - (4-fluorophenyl) - N - (3- (3- ( piperazine-1-carbonyl) phenyl) prop-2-ynyl) pentane amide; N - (4- fluorophenyl) - N - (3- (3- (4- isopropyl-piperazine-1-carbonyl) phenyl) prop-2-ynyl) pentane amide; N- (3- (4-hydroxyphenyl) prop-2-ynyl) -N -phenylpentanamide; 2- (4- (3- ( N -phenylpentaneamido) prop-1-ynyl) phenoxy) acetic acid; tert -butyl 4- (5- (3-(( N -phenylpentaneamido) prop-1-yn-1-yl) picolinoyl) piperazin-1-carboxylate; N -phenyl- N- ( 3- (6- (piperazin-1-carbonyl) pyridin-3-yl) prop-2-yn-1-yl) pentaneamide; N- (3- (6- (4-isopropylpiperazin- 1-carbonyl) pyridin-3-yl) prop-2-yn-1-yl) -N -phenylpentanamide; N, N -diethyl-4- (3- ( N- (3-fluorophenyl ) Pentaneamido) prop-1-yn-1-yl) benzamide; N, N -diethyl-4- (3- ( N- (4-fluorophenyl) pentaneamido) prop-1- In-1-yl) benzamide; N- (3- (4- ( N, N -diethylsulfamoyl) phenyl) prop-2-ynyl) -N -phenylpentanamide; N- (3- (4 -( N -isopropylsulfamoyl) phenyl) prop-2-ynyl) -N -phenylpentaneamide; tert -butyl 4- (3- ( N -phenylpentaneamido) prop-1-yn-1- Yl) benzoate; 4- (3- ( N -phenylpentaneamido) prop-1-pin-1-yl) benzoic acid; N -ethyl-4- (3- ( N -phenylpentaneamido) prop -1-yn-1-yl) benzamide; N -(2- (dimethylamino) ethyl) -4- (3- ( N -phenylpentaneamido) prop-1-yn-1-yl) benzamide; ethyl 2- (4- (3- ( N -Phenylpentaneamido) prop-1-yn-1-yl) benzamido) acetate; 2- (4- (3- ( N -phenylpentaneamido) prop-1-yn-1-yl) Benzamido) acetic acid; methyl 2- (4- (3- ( N -phenylpentaneamido) prop-1-yn-1-yl) benzamido) propanoate; 2- (4- (3 -( N -phenylpentaneamido) prop-1-yn-1-yl) benzamido) propionic acid; 2- (4- (3- ( N- (3-fluorophenyl) pentaneamido) Prop-1-ynyl) phenoxy) acetic acid 2- (4- (3- ( N- (4-fluorophenyl) pentaneamido) prop-1-ynyl) phenoxy) acetic acid; N -((3 '-(4-methylphenylsulfonamido) biphenyl-4-yl) methyl) -N -phenylpentanamide; N- (4 '-(( N -phenylpentaneamido) methyl) biphenyl-3-yl) -4- (trifluoromethyl) benzamide; N- (3-fluorophenyl) -N -((3 '-(4-methylphenylsulfonamido) biphenyl-4-yl) methyl) pentaneamide; N- (4 '-(( N- 3-fluorophenyl) pentaneamido) methyl) biphenyl-3-yl) -4- (trifluoromethyl) benzamide; 1- (3-fluorophenyl) -1-((4'-methoxybiphenyl-4-yl) methyl) -3- (3- (trifluoromethyl) phenyl) urea; N- (3-fluorophenyl) -N -((4'-methoxybiphenyl-4-yl) methyl) -1- (4-methoxyphenylsulfonyl) methaneamide; 1- (3-fluorophenyl) -1-((4'-hydroxybiphenyl-4-yl) methyl) -3- (3- (trifluoromethyl) phenyl) urea; 2- (4 '-((1- (3-fluorophenyl) -3- (3- (trifluoromethyl) phenyl) ureido) methyl) biphenyl-4-yloxy) acetic acid; 4- (4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) butanoic acid; 2- (4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) -2-methylpropanoic acid; ( E ) -3- (4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acrylic acid; 3- (4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) propanoic acid; N- (3-fluorophenyl) -N -((4 '-(2- (4-methylpiperazin-1-yl) -2-oxoethoxy) biphenyl-4-yl) methyl) pentaneamide; Prop-2-ynyl 2- (4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetate; N- (3-fluorophenyl) -N -((4 '-(prop-2-ynyloxy) biphenyl-4-yl) methyl) pentaneamide; N -((2 '-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl) -N -phenylpentanamide; 2- (4 '-(( N -phenylpentaneamido) methyl) biphenyl-4-yloxy) acetic acid; 2- (4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetic acid; 2- (4 '-(( N- (3-chlorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetic acid; 2- (4 '-(( N- (3-bromophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetic acid; 2- (4 '-(( N- (3- (trifluoromethyl) phenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetic acid; 2- (4 '-(( Nm -tolylpentaneamido) methyl) biphenyl-4-yloxy) acetic acid; N - ((4'- hydroxy-biphenyl-4-yl) methyl) - N - (3- nitrophenyl) pentane amide; 2- (4 '-(( N- (3-nitrophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetic acid; 2- (4 '-(( N- (3-iodophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetic acid; 2-((4 '-(( N- (3-fluorophenyl) acetamido) methyl)-[1,1'-biphenyl] -4-yl) oxy) acetic acid; N -((4 '-(4-isopropylpiperazin-1-carbonyl) biphenyl-4-yl) methyl) -N -phenylpentaneamide; N- (4-fluorophenyl) -N -((4 '-(4-isopropylpiperazin-1-carbonyl) biphenyl-4-yl) methyl) pentaneamide; N -((3 '-(4-isopropylpiperazin-1-carbonyl) biphenyl-4-yl) methyl) -N -phenylpentaneamide; And N- (4-fluorophenyl) -N -((3 '-(4-isopropylpiperazin-1-carbonyl) biphenyl-4-yl) methyl) pentaneamide .
본 발명의 다른 구현예로서, 상기 조성물은 BLT2 (Leukotriene B4 receptor 2) 활성을 저해시킬 수 있다. In another embodiment of the present invention, the composition may inhibit Leukotriene B4 receptor 2 (BLT2) activity.
상기 약학적 조성물을 개체에 투여하는 단계를 포함하는 만성 폐쇄성 폐질환의 치료방법을 제공한다.It provides a method of treating chronic obstructive pulmonary disease comprising administering the pharmaceutical composition to a subject.
본 발명은 상기 화합물, 이의 이성질체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 조성물의 만성 폐쇄성 폐질환의 치료용도를 제공한다.The present invention provides a therapeutic use for chronic obstructive pulmonary disease of a composition comprising the compound, an isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명은 BLT2 (Leukotriene B4 receptor 2) 억제 활성을 나타내는 화합물, 이의 이성질체 또는 이의 약학적 허용가능한 염을 유효성분으로 포함하는, 만성 폐쇄성 폐질환(COPD; chronic obstructive pulmonary disease)의 예방 또는 치료용 약학적 조성물에 관한 것이다. 본 발명자들은 BTL2 억제 활성을 나타내는 화합물의 우수한 주화성 억제 효과 및 만성 폐쇄성 폐질환 치료 효과 등을 실험적으로 확인하였는바, 본 발명의 화합물은 만성 폐쇄성 폐질환을 치료하기 위한 약학적 조성물로 유용하게 사용될 수 있을 것으로 기대된다.The present invention provides a pharmaceutical for the prevention or treatment of chronic obstructive pulmonary disease (COPD), comprising as an active ingredient a compound, an isomer thereof, or a pharmaceutically acceptable salt thereof, which exhibits Leukotriene B4 receptor 2 (BLT2) inhibitory activity. To a red composition. The present inventors have experimentally confirmed the excellent chemotactic inhibitory effect and the treatment effect of chronic obstructive pulmonary disease of the compound showing the BTL2 inhibitory activity, the compound of the present invention can be usefully used as a pharmaceutical composition for treating chronic obstructive pulmonary disease It is expected to be able.
도 1a 내지 도 1e 및 도 2a 내지 도 2d는 BLT2가 발현된 세포 (CHO-BLT2)에서, 본 발명의 화합물 처리에 의한 성장 억제 효과를 확인한 결과이다.1A to 1E and 2A to 2D are results of confirming the growth inhibitory effect of the compound treatment of the present invention in cells expressing BLT2 (CHO-BLT2).
도 3a 및 도 3b는 BLT2가 발현된 세포 (CHO-BLT2 cells)에서, 본 발명의 화합물 처리에 의한 세포의 주화성 억제 효과 및 IC50 (50% 억제 농도)를 확인한 결과이다.3A and 3B show the results of confirming chemotaxis inhibitory effect and IC 50 (50% inhibitory concentration) of cells by the compound treatment of the present invention in cells expressing BLT2 (CHO-BLT2 cells).
도 4a 및 도 4b는 BLT2가 발현된 세포 (CHO-BLT2 cells) 또는 BLT1이 발현된 세포 (CHO-BLT1)에서, 본 발명의 화합물 처리에 의한 세포의 주화성 억제 효과를 확인한 결과이다.4A and 4B show the results of confirming the chemotaxis inhibitory effect of cells treated with the compound of the present invention in cells expressing BLT2 (CHO-BLT2 cells) or cells expressing BLT1 (CHO-BLT1).
도 5a 내지 도 5d는 BLT2가 발현된 세포 (CHO-BLT2 cells)에서, 본 발명의 화합물 처리에 의한 세포의 주화성 억제 효과 및 IC50 (50% 억제 농도)를 확인한 결과이다.5A to 5D show results of confirming chemotaxis inhibitory effect and IC 50 (50% inhibitory concentration) of cells by treatment with a compound of the present invention in cells expressing BLT2 (CHO-BLT2 cells).
도 6a 내지 도 6c는 BLT2가 발현된 세포 (CHO-BLT2 cells) 또는 BLT1이 발현된 세포 (CHO-BLT1)에서, 본 발명의 화합물 처리에 의한 세포의 주화성 억제 효과를 확인한 결과이다.6A to 6C show the results of confirming the chemotaxis inhibitory effect of cells treated with the compound of the present invention in cells expressing BLT2 (CHO-BLT2 cells) or cells expressing BLT1 (CHO-BLT1).
도 7a 내지 도 7c는 BLT2가 발현된 세포(CHO-BLT2 cells)에서, 본 발명의 화합물 처리에 의한 LTB4와 BLT2 결합 저해 효과를 확인한 결과이다. 7A to 7C show the results of confirming the effect of inhibiting the binding of LTB4 and BLT2 by the compound treatment of the present invention in BLT2-expressing cells (CHO-BLT2 cells).
도 8a는 만성 폐쇄성 폐질환 동물모델에서, 본 발명의 화합물 처리에 의한 TNF-α 생성 억제 효과를 확인한 결과이다.Figure 8a is a result confirming the inhibitory effect of TNF-α production by the compound treatment of the present invention in an animal model of chronic obstructive pulmonary disease.
도 8b는 만성 폐쇄성 폐질환 동물모델에서, 본 발명의 화합물 처리에 의한 IL-6 생성 억제 효과를 확인한 결과이다.8b is a result confirming the inhibitory effect of IL-6 production by the compound treatment of the present invention in an animal model of chronic obstructive pulmonary disease.
도 8c는 만성 폐쇄성 폐질환 동물모델에서, 본 발명의 화합물 처리에 의한 ROS 생성 억제 효과를 확인한 결과이다.Figure 8c is a result confirming the inhibitory effect of ROS production by the compound treatment of the present invention in an animal model of chronic obstructive pulmonary disease.
도 9는 담배연기 및 지질다당류로 유발된 만성 폐쇄성 폐질환 동물 모델에서, 본 발명의 화합물 LMT-886 및 LMT-1013 처리에 의한 염증세포의 침윤 정도를 확인한 결과이다.Figure 9 is a result of confirming the degree of infiltration of inflammatory cells by treatment of LMT-886 and LMT-1013 compounds of the present invention in animal models of chronic obstructive pulmonary disease induced by tobacco smoke and lipopolysaccharide.
도 10은 담배연기 및 지질다당류로 유발된 만성 폐쇄성 폐질환 동물 모델에서, 본 발명의 화합물 LMT-886 및 LMT-1013 처리에 의한 NE를 측정한 결과이다.10 is a result of measuring the NE by treatment with compounds LMT-886 and LMT-1013 of the present invention in animal models of chronic obstructive pulmonary disease induced by tobacco smoke and lipopolysaccharide.
도 11은 담배연기 및 지질다당류로 유발된 만성 폐쇄성 폐질환 동물 모델에서, 본 발명의 화합물 LMT-886 및 LMT-1013 처리에 의한 ROS를 측정한 결과이다.11 is a result of measuring the ROS by treatment with compounds LMT-886 and LMT-1013 of the present invention in animal models of chronic obstructive pulmonary disease induced by tobacco smoke and lipopolysaccharide.
도 12는 담배연기 및 지질다당류로 유발된 만성 폐쇄성 폐질환 동물 모델에서, 본 발명의 화합물 LMT-886 및 LMT-1013 처리에 의한 TNF-α를 측정한 결과이다.12 is a result of measuring the TNF-α by treatment with compounds LMT-886 and LMT-1013 of the present invention in animal models of chronic obstructive pulmonary disease induced by tobacco smoke and lipopolysaccharide.
도 13은 담배연기 및 지질다당류로 유발된 만성 폐쇄성 폐질환 동물 모델에서, 본 발명의 화합물 LMT-886 및 LMT-1013 처리에 의한 IL-6를 측정한 결과이다.FIG. 13 shows the results of measuring IL-6 by treatment with the compounds LMT-886 and LMT-1013 of the present invention in an animal model of chronic obstructive pulmonary disease induced by tobacco smoke and lipopolysaccharide.
도 14는 담배연기 및 지질다당류로 유발된 만성 폐쇄성 폐질환 동물 모델의 폐 조직을 H&E 염색하여 확인한 결과이다.Figure 14 shows the results confirmed by H & E staining lung tissue animal models of chronic obstructive pulmonary disease induced by tobacco smoke and lipopolysaccharide.
본 발명자들은, 실시예에서 제조한 화합물을 처리한 경우, BLT2 발현 세포의 성장을 현저히 억제시킬 수 있다는 점에 기반하여 상기 화합물의 BLT2 의존적인 주화성 저해, 및 만성 폐쇄성 폐질환 치료 효과 등을 구체적으로 확인하고, 이에 기초하여 본 발명을 완성하였다.The present inventors, based on the fact that the treatment of the compound prepared in Example can significantly inhibit the growth of BLT2 expressing cells, specific effects of BLT2-dependent chemotaxis and the effect of treating chronic obstructive pulmonary disease, etc. It confirmed with and based on this, this invention was completed.
이하 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.
본 발명은 하기 화학식 1로 표시되는 화합물, 이의 이성질체 또는 이의 약학적 허용가능한 염을 유효성분으로 포함하는, 만성 폐쇄성 폐질환(COPD; chronic obstructive pulmonary disease) 예방 또는 치료용 약학적 조성물을 제공한다.The present invention provides a pharmaceutical composition for preventing or treating chronic obstructive pulmonary disease (COPD), comprising a compound represented by the following formula (1), an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
[화학식 1][Formula 1]
Figure PCTKR2018000957-appb-I000001
Figure PCTKR2018000957-appb-I000001
상기 화학식 1에서,In Chemical Formula 1,
R1은 C1~C10의 알킬이고,R 1 is C 1 -C 10 is alkyl,
R2는
Figure PCTKR2018000957-appb-I000002
,
Figure PCTKR2018000957-appb-I000003
,
Figure PCTKR2018000957-appb-I000004
,
Figure PCTKR2018000957-appb-I000005
, 또는
Figure PCTKR2018000957-appb-I000006
이며, R 2 is
Figure PCTKR2018000957-appb-I000002
,
Figure PCTKR2018000957-appb-I000003
,
Figure PCTKR2018000957-appb-I000004
,
Figure PCTKR2018000957-appb-I000005
, or
Figure PCTKR2018000957-appb-I000006
Is,
Ra는
Figure PCTKR2018000957-appb-I000007
,
Figure PCTKR2018000957-appb-I000008
,
Figure PCTKR2018000957-appb-I000009
,
Figure PCTKR2018000957-appb-I000010
,
Figure PCTKR2018000957-appb-I000011
,
Figure PCTKR2018000957-appb-I000012
,
Figure PCTKR2018000957-appb-I000013
,
Figure PCTKR2018000957-appb-I000014
,
Figure PCTKR2018000957-appb-I000015
,
Figure PCTKR2018000957-appb-I000016
,
Figure PCTKR2018000957-appb-I000017
,
Figure PCTKR2018000957-appb-I000018
,
Figure PCTKR2018000957-appb-I000019
,
Figure PCTKR2018000957-appb-I000020
,
Figure PCTKR2018000957-appb-I000021
,
Figure PCTKR2018000957-appb-I000022
,
Figure PCTKR2018000957-appb-I000023
,
Figure PCTKR2018000957-appb-I000024
,
Figure PCTKR2018000957-appb-I000025
,
Figure PCTKR2018000957-appb-I000026
,
Figure PCTKR2018000957-appb-I000027
,
Figure PCTKR2018000957-appb-I000028
, 또는 하이드록시이고,R a is
Figure PCTKR2018000957-appb-I000007
,
Figure PCTKR2018000957-appb-I000008
,
Figure PCTKR2018000957-appb-I000009
,
Figure PCTKR2018000957-appb-I000010
,
Figure PCTKR2018000957-appb-I000011
,
Figure PCTKR2018000957-appb-I000012
,
Figure PCTKR2018000957-appb-I000013
,
Figure PCTKR2018000957-appb-I000014
,
Figure PCTKR2018000957-appb-I000015
,
Figure PCTKR2018000957-appb-I000016
,
Figure PCTKR2018000957-appb-I000017
,
Figure PCTKR2018000957-appb-I000018
,
Figure PCTKR2018000957-appb-I000019
,
Figure PCTKR2018000957-appb-I000020
,
Figure PCTKR2018000957-appb-I000021
,
Figure PCTKR2018000957-appb-I000022
,
Figure PCTKR2018000957-appb-I000023
,
Figure PCTKR2018000957-appb-I000024
,
Figure PCTKR2018000957-appb-I000025
,
Figure PCTKR2018000957-appb-I000026
,
Figure PCTKR2018000957-appb-I000027
,
Figure PCTKR2018000957-appb-I000028
, Or hydroxy,
Rb는
Figure PCTKR2018000957-appb-I000029
,
Figure PCTKR2018000957-appb-I000030
,
Figure PCTKR2018000957-appb-I000031
, 또는
Figure PCTKR2018000957-appb-I000032
이고,R b is
Figure PCTKR2018000957-appb-I000029
,
Figure PCTKR2018000957-appb-I000030
,
Figure PCTKR2018000957-appb-I000031
, or
Figure PCTKR2018000957-appb-I000032
ego,
RC는
Figure PCTKR2018000957-appb-I000033
,
Figure PCTKR2018000957-appb-I000034
, 또는
Figure PCTKR2018000957-appb-I000035
이고,R C is
Figure PCTKR2018000957-appb-I000033
,
Figure PCTKR2018000957-appb-I000034
, or
Figure PCTKR2018000957-appb-I000035
ego,
Rd는 수소 또는
Figure PCTKR2018000957-appb-I000036
이고,R d is hydrogen or
Figure PCTKR2018000957-appb-I000036
ego,
Re는
Figure PCTKR2018000957-appb-I000037
또는
Figure PCTKR2018000957-appb-I000038
이고,R e is
Figure PCTKR2018000957-appb-I000037
or
Figure PCTKR2018000957-appb-I000038
ego,
R3는 수소 또는 플루오르이다.R 3 is hydrogen or fluorine.
본 발명에 따른 상기 화학식 1로 표시되는 화합물의 바람직한 예는 하기와 같다:Preferred examples of the compound represented by Formula 1 according to the present invention are as follows:
tert-부틸 4-(4-(3-(N-페닐펜탄아미도)프로프-1-이닐)벤조일)피페라진-1-카복실레이트; N-페닐-N-(3-(4-(피페라진-1-카보닐)페닐)프로프-2-이닐)펜탄아마이드; N-(3-(4-(4-메틸피페라진-1-카보닐)페닐)프로프-2-이닐)-N-페닐펜탄아마이드; N-(3-(4-(4-에틸피페라진-1-카보닐)페닐)프로프-2-이닐)-N-페닐펜탄아마이드; N-(3-(4-(4-아이소프로필피페라진-1-카보닐)페닐)프로프-2-이닐)-N-페닐펜탄아마이드; N-(3-(4-(4-(2-하이드록시에틸)피페라진-1-카보닐)페닐)프로프-2-이닐)-N-페닐펜탄아마이드; N-(3-(4-(4-(사이클로프로필메틸)피페라진-1-카보닐)페닐)프로프-2-이닐)-N-페닐펜탄아마이드; N-(3-(4-(4-사이클로헥실피페라진-1-카보닐)페닐)프로프-2-이닐)-N-페닐펜탄아마이드; N-(3-(4-(4-(사이클로헥실메틸)피페라진-1-카보닐)페닐)프로프-2-이닐)-N-페닐펜탄아마이드; N-(3-(4-(4-아이소부틸피페라진-1-카보닐)페닐)프로프-2-이닐)-N-페닐펜탄아마이드; N-페닐-N-(3-(4-(4-(프로프-2-이닐)피페라진-1-카보닐)페닐)프로프-2-이닐)펜탄아마이드; N-(3-(4-(4-시아노피페라진-1-카보닐)페닐)프로프-2-이닐)-N-페닐펜탄아마이드; tert-부틸 4-(4-(3-(N-(3-플루오로페닐)펜탄아미도)프로프-1-이닐)벤조일)피페라진-1-카복실레이트; N-(3-플루오로페닐)-N-(3-(4-(피페라진-1-카보닐)페닐)프로프-2-이닐)펜탄아마이드; N-(3-플루오로페닐)-N-(3-(4-(4-아이소프로필피페라진-1-카보닐)페닐)프로프-2-이닐)펜탄아마이드; tert-부틸 4-(4-(3-(N-(4-플루오로페닐)펜탄아미도)프로프-1-이닐)벤조일)피페라진-1-카복실레이트; N-(4-플루오로페닐)-N-(3-(4-(피페라진-1-카보닐)페닐)프로프-2-이닐)펜탄아마이드; N-(4-플루오로페닐)-N-(3-(4-(4-아이소프로필피페라진-1-카보닐)페닐)프로프-2-이닐)펜탄아마이드; N-(3-(4-(몰폴린-4-카보닐)페닐)프로프-2-이닐)-N-페닐펜탄아마이드; N-페닐-N-(3-(4-(피페리딘-1-카보닐)페닐)프로프-2-이닐)펜탄아마이드; N,N-다이에틸-4-(3-(N-페닐펜탄아미도)프로프-1-이닐)벤즈아마이드; N-페닐-N-(3-(3-(피페라진-1-카보닐)페닐)프로프-2-이닐)펜탄아마이드; N-(3-(3-(4-메틸피페라진-1-카보닐)페닐)프로프-2-이닐)-N-페닐펜탄아마이드; N-(3-(3-(4-아이소프로필피페라진-1-카보닐)페닐)프로프-2-이닐)-N-페닐펜탄아마이드; tert-부틸-4-(3-(3-(N-(4-플루오로페닐)펜탄아미도)프로프-1-이닐)벤조일)피페라진-1-카복실레이트; N-(4-플루오로페닐)-N-(3-(3-(피페라진-1-카보닐)페닐)프로프-2-이닐)펜탄아마이드; N-(4-플루오로페닐)-N-(3-(3-(4-아이소프로필피페라진-1-카보닐)페닐)프로프-2-이닐)펜탄아마이드; N-(3-(4-하이드록시페닐)프로프-2-이닐)-N-페닐펜탄아마이드; 2-(4-(3-(N-페닐펜탄아미도)프로프-1-이닐)페녹시)아세트산; tert-부틸 4-(5-(3-((N-페닐펜탄아미도)프로프-1-인-1-일)피콜리노일)피페라진-1-카복실레이트; N-페닐-N-(3-(6-(피페라진-1-카보닐)피리딘-3-일)프로프-2-인-1-일)펜탄아마이드; N-(3-(6-(4-아이소프로필피페라진-1-카보닐)피리딘-3-일)프로프-2-인-1-일)-N-페닐펜탄아마이드; N,N-다이에틸-4-(3-(N-(3-플루오로페닐)펜탄아미도)프로프-1-인-1-일)벤즈아마이드; N,N-다이에틸-4-(3-(N-(4-플루오로페닐)펜탄아미도)프로프-1-인-1-일)벤즈아마이드; N-(3-(4-(N,N-다이에틸설파모일)페닐)프로프-2-이닐)-N-페닐펜탄아마이드; N-(3-(4-(N-아이소프로필설파모일)페닐)프로프-2-이닐)-N-페닐펜탄아마이드; tert-부틸 4-(3-(N-페닐펜탄아미도)프로프-1-인-1-일)벤조에이트; 4-(3-(N-페닐펜탄아미도)프로-1-핀-1-일)벤조익산; N-에틸-4-(3-(N-페닐펜탄아미도)프로프-1-인-1-일)벤즈아마이드; N-(2-(다이메틸아미노)에틸)-4-(3-(N-페닐펜탄아미도)프로프-1-인-1-일)벤즈아마이드; 에틸 2-(4-(3-(N-페닐펜탄아미도)프로프-1-인-1-일)벤즈아미도)아세테이트; 2-(4-(3-(N-페닐펜탄아미도)프로프-1-인-1-일)벤즈아미도)아세틱산; 메틸 2-(4-(3-(N-페닐펜탄아미도)프로프-1-인-1-일)벤즈아미도)프로파노에이트; 2-(4-(3-(N-페닐펜탄아미도)프로프-1-인-1-일)벤즈아미도)프로피오닉산; 2-(4-(3-(N-(3-플루오로페닐)펜탄아미도)프로프-1-이닐)페녹시)아세트산; 및 2-(4-(3-(N-(4-플루오로페닐)펜탄아미도)프로프-1-이닐)페녹시)아세트산. tert -butyl 4- (4- (3- ( N -phenylpentaneamido) prop-1-ynyl) benzoyl) piperazin-1-carboxylate; N -phenyl- N- (3- (4- (piperazin-1-carbonyl) phenyl) prop-2-ynyl) pentaneamide; N- (3- (4- (4-methylpiperazin-1-carbonyl) phenyl) prop-2-ynyl) -N -phenylpentanamide; N- (3- (4- (4-ethylpiperazin-1-carbonyl) phenyl) prop-2-ynyl) -N -phenylpentanamide; N- (3- (4- (4-isopropylpiperazin-1-carbonyl) phenyl) prop-2-ynyl) -N -phenylpentaneamide; N- (3- (4- (4- (2-hydroxyethyl) piperazin-1-carbonyl) phenyl) prop-2-ynyl) -N -phenylpentaneamide; N- (3- (4- (4- (cyclopropylmethyl) piperazin-1-carbonyl) phenyl) prop-2-ynyl) -N -phenylpentaneamide; N- (3- (4- (4-cyclohexylpiperazine-1-carbonyl) phenyl) prop-2-ynyl) -N -phenylpentaneamide; N- (3- (4- (4- (cyclohexylmethyl) piperazin-1-carbonyl) phenyl) prop-2-ynyl) -N -phenylpentanamide; N- (3- (4- (4-isobutylpiperazin-1-carbonyl) phenyl) prop-2-ynyl) -N -phenylpentaneamide; N -phenyl- N- (3- (4- (4- (prop-2-ynyl) piperazin-1-carbonyl) phenyl) prop-2-ynyl) pentaneamide; N- (3- (4- (4-cyanopiperazin-1-carbonyl) phenyl) prop-2-ynyl) -N -phenylpentanamide; tert -butyl 4- (4- (3- ( N- (3-fluorophenyl) pentaneamido) prop-1-ynyl) benzoyl) piperazine-1-carboxylate; N - (3-fluorophenyl) - N - (3- (4- ( piperazine-1-carbonyl) phenyl) prop-2-ynyl) pentane amide; N - (3-fluorophenyl) - N - (3- (4- (4- isopropyl-piperazine-1-carbonyl) phenyl) prop-2-ynyl) pentane amide; tert -butyl 4- (4- (3- ( N- (4-fluorophenyl) pentaneamido) prop-1-ynyl) benzoyl) piperazine-1-carboxylate; N - (4-fluorophenyl) - N - (3- (4- ( piperazine-1-carbonyl) phenyl) prop-2-ynyl) pentane amide; N - (4-fluorophenyl) - N - (3- (4- (4-isopropyl-piperazine-1-carbonyl) phenyl) prop-2-ynyl) pentane amide; N- (3- (4- (morpholin-4-carbonyl) phenyl) prop-2-ynyl) -N -phenylpentanamide; N -phenyl- N- (3- (4- (piperidine-1-carbonyl) phenyl) prop-2-ynyl) pentaneamide; N , N -diethyl-4- (3- ( N -phenylpentaneamido) prop-1-ynyl) benzamide; N -phenyl- N- (3- (3- (piperazin-1-carbonyl) phenyl) prop-2-ynyl) pentaneamide; N- (3- (3- (4-methylpiperazin-1-carbonyl) phenyl) prop-2-ynyl) -N -phenylpentanamide; N- (3- (3- (4-isopropylpiperazin-1-carbonyl) phenyl) prop-2-ynyl) -N -phenylpentaneamide; tert -butyl-4- (3- (3- ( N- (4-fluorophenyl) pentaneamido) prop-1-ynyl) benzoyl) piperazine-1-carboxylate; N - (4-fluorophenyl) - N - (3- (3- ( piperazine-1-carbonyl) phenyl) prop-2-ynyl) pentane amide; N - (4- fluorophenyl) - N - (3- (3- (4- isopropyl-piperazine-1-carbonyl) phenyl) prop-2-ynyl) pentane amide; N- (3- (4-hydroxyphenyl) prop-2-ynyl) -N -phenylpentanamide; 2- (4- (3- ( N -phenylpentaneamido) prop-1-ynyl) phenoxy) acetic acid; tert -butyl 4- (5- (3-(( N -phenylpentaneamido) prop-1-yn-1-yl) picolinoyl) piperazin-1-carboxylate; N -phenyl- N- ( 3- (6- (piperazin-1-carbonyl) pyridin-3-yl) prop-2-yn-1-yl) pentaneamide; N- (3- (6- (4-isopropylpiperazin- 1-carbonyl) pyridin-3-yl) prop-2-yn-1-yl) -N -phenylpentanamide; N, N -diethyl-4- (3- ( N- (3-fluorophenyl ) Pentaneamido) prop-1-yn-1-yl) benzamide; N, N -diethyl-4- (3- ( N- (4-fluorophenyl) pentaneamido) prop-1- In-1-yl) benzamide; N- (3- (4- ( N, N -diethylsulfamoyl) phenyl) prop-2-ynyl) -N -phenylpentanamide; N- (3- (4 -( N -isopropylsulfamoyl) phenyl) prop-2-ynyl) -N -phenylpentaneamide; tert -butyl 4- (3- ( N -phenylpentaneamido) prop-1-yn-1- Yl) benzoate; 4- (3- ( N -phenylpentaneamido) prop-1-pin-1-yl) benzoic acid; N -ethyl-4- (3- ( N -phenylpentaneamido) prop -1-yn-1-yl) benzamide; N -(2- (dimethylamino) ethyl) -4- (3- ( N -phenylpentaneamido) prop-1-yn-1-yl) benzamide; ethyl 2- (4- (3- ( N -Phenylpentaneamido) prop-1-yn-1-yl) benzamido) acetate; 2- (4- (3- ( N -phenylpentaneamido) prop-1-yn-1-yl) Benzamido) acetic acid; methyl 2- (4- (3- ( N -phenylpentaneamido) prop-1-yn-1-yl) benzamido) propanoate; 2- (4- (3 -( N -phenylpentaneamido) prop-1-yn-1-yl) benzamido) propionic acid; 2- (4- (3- ( N- (3-fluorophenyl) pentaneamido) Prop-1-ynyl) phenoxy) acetic acid and 2- (4- (3- ( N- (4-fluorophenyl) pentaneamido) prop-1-ynyl) phenoxy) acetic acid.
또한, 본 발명은 하기 화학식 2로 표시되는 화합물, 이의 이성질체 또는 이의 약학적 허용가능한 염을 유효성분으로 포함하는, 만성 폐쇄성 폐질환(COPD; chronic obstructive pulmonary disease) 예방 또는 치료용 약학적 조성물을 제공한다.The present invention also provides a pharmaceutical composition for preventing or treating chronic obstructive pulmonary disease (COPD) comprising a compound represented by the following formula (2), an isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient. do.
[화학식 2][Formula 2]
Figure PCTKR2018000957-appb-I000039
Figure PCTKR2018000957-appb-I000039
상기 화학식 2에서,In Chemical Formula 2,
R1은 C1~C10의 알킬,
Figure PCTKR2018000957-appb-I000040
, 또는
Figure PCTKR2018000957-appb-I000041
이고,R 1 is C 1 -C 10 alkyl,
Figure PCTKR2018000957-appb-I000040
, or
Figure PCTKR2018000957-appb-I000041
ego,
R2는 수소,
Figure PCTKR2018000957-appb-I000042
, 또는
Figure PCTKR2018000957-appb-I000043
이고,R 2 is hydrogen,
Figure PCTKR2018000957-appb-I000042
, or
Figure PCTKR2018000957-appb-I000043
ego,
R3는 수소,
Figure PCTKR2018000957-appb-I000044
, 또는
Figure PCTKR2018000957-appb-I000045
이고,R 3 is hydrogen,
Figure PCTKR2018000957-appb-I000044
, or
Figure PCTKR2018000957-appb-I000045
ego,
R4는 수소,
Figure PCTKR2018000957-appb-I000046
, 또는
Figure PCTKR2018000957-appb-I000047
이고,R 4 is hydrogen,
Figure PCTKR2018000957-appb-I000046
, or
Figure PCTKR2018000957-appb-I000047
ego,
여기서 Ra는 수소, C1~C10의 알킬, C1~C5의 카르복실,
Figure PCTKR2018000957-appb-I000048
Where R a is hydrogen, C 1 -C 10 alkyl, C 1 -C 5 carboxyl,
Figure PCTKR2018000957-appb-I000048
R5, R6, 및 R7은 각각 독립적으로 수소, 할로겐, 니트로, 메틸, 트리플루오로메틸 또는 메톡시이며,R 5 , R 6 , and R 7 are each independently hydrogen, halogen, nitro, methyl, trifluoromethyl or methoxy,
이 때, R1이 C1~C10의 알킬이고, Ra가 수소 또는 C1~C10의 알킬인 경우; 및 R2, R3, 및 R4가 모두 동시에 수소인 경우;는 제외한다.Wherein R 1 is C 1 -C 10 alkyl and R a is hydrogen or C 1 -C 10 alkyl; And when R 2 , R 3 , and R 4 are all hydrogen at the same time.
본 발명에 따른 상기 화학식 2로 표시되는 화합물의 바람직한 예는 하기와 같다:Preferred examples of the compound represented by Formula 2 according to the present invention are as follows:
N-((3'-(4-메틸페닐설폰아미도)바이페닐-4-일)메틸)-N-페닐펜탄아마이드; N-(4'-((N-페닐펜탄아미도)메틸)바이페닐-3-일)-4-(트리플루오로메틸)벤즈아마이드; N-(3-플루오로페닐)-N-((3'-(4-메틸페닐설폰아미도)바이페닐-4-일)메틸)펜탄아마이드; N-(4'-((N-3-플루오로페닐)펜탄아미도)메틸)바이페닐-3-일)-4-(트리플루오로메틸)벤즈아마이드; 1-(3-플루오로페닐)-1-((4'-메톡시바이페닐-4-일)메틸)-3-(3-(트리플루오로메틸)페닐)유레아; N-(3-플루오로페닐)-N-((4'-메톡시바이페닐-4-일)메틸)-1-(4-메톡시페닐설폰일)메탄아마이드; 1-(3-플루오로페닐)-1-((4'-하이드록시바이페닐-4-일)메틸)-3-(3-(트리플루오로메틸)페닐)유레아; 2-(4'-((1-(3-플루오로페닐)-3-(3-(트리플루오로메틸)페닐)유레이도)메틸)바이페닐-4-일옥시)아세트산; 4-(4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)부탄산; 2-(4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)-2-메틸프로판산; (E)-3-(4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아크릴산; 3-(4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)프로판산; N-(3-플루오로페닐)-N-((4'-(2-(4-메틸피페라진-1-일)-2-옥소에톡시)바이페닐-4-일)메틸)펜탄아마이드; 프로프-2-인일 2-(4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세테이트; N-(3-플루오로페닐)-N-((4'-(프로프-2-이닐옥시)바이페닐-4-일)메틸)펜탄아마이드; N-((2'-(1H-테트라졸-5-일)바이페닐-4-일)메틸)-N-페닐펜탄아마이드; 2-(4'-((N-페닐펜탄아미도)메틸)바이페닐-4-일옥시)아세트산; 2-(4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세트산; 2-(4'-((N-(3-클로로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세트산; 2-(4'-((N-(3-브로모페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세트산; 2-(4'-((N-(3-(트리플루오로메틸)페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세트산; 2-(4'-((N-m-톨릴펜탄아미도)메틸)바이페닐-4-일옥시)아세트산; N-((4'-하이드록시바이페닐-4-일)메틸)-N-(3-니트로페닐)펜탄아마이드; 2-(4'-((N-(3-니트로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세트산; 2-(4'-((N-(3-아이오도페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세트산; 2-((4'-((N-(3-플루오로페닐)아세트아미도)메틸)-[1,1'-바이페닐]-4-일)옥시)아세트산; N-((4'-(4-아이소프로필피페라진-1-카보닐)바이페닐-4-일)메틸)-N-페닐펜탄아마이드; N-(4-플루오로페닐)-N-((4'-(4-아이소프로필피페라진-1-카보닐)바이페닐-4-일)메틸)펜탄아마이드; N-((3'-(4-아이소프로필피페라진-1-카보닐)바이페닐-4-일)메틸)-N-페닐펜탄아마이드; 및 N-(4-플루오로페닐)-N-((3'-(4-아이소프로필피페라진-1-카보닐)바이페닐-4-일)메틸)펜탄아마이드. N -((3 '-(4-methylphenylsulfonamido) biphenyl-4-yl) methyl) -N -phenylpentanamide; N- (4 '-(( N -phenylpentaneamido) methyl) biphenyl-3-yl) -4- (trifluoromethyl) benzamide; N- (3-fluorophenyl) -N -((3 '-(4-methylphenylsulfonamido) biphenyl-4-yl) methyl) pentaneamide; N- (4 '-(( N- 3-fluorophenyl) pentaneamido) methyl) biphenyl-3-yl) -4- (trifluoromethyl) benzamide; 1- (3-fluorophenyl) -1-((4'-methoxybiphenyl-4-yl) methyl) -3- (3- (trifluoromethyl) phenyl) urea; N- (3-fluorophenyl) -N -((4'-methoxybiphenyl-4-yl) methyl) -1- (4-methoxyphenylsulfonyl) methaneamide; 1- (3-fluorophenyl) -1-((4'-hydroxybiphenyl-4-yl) methyl) -3- (3- (trifluoromethyl) phenyl) urea; 2- (4 '-((1- (3-fluorophenyl) -3- (3- (trifluoromethyl) phenyl) ureido) methyl) biphenyl-4-yloxy) acetic acid; 4- (4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) butanoic acid; 2- (4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) -2-methylpropanoic acid; ( E ) -3- (4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acrylic acid; 3- (4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) propanoic acid; N- (3-fluorophenyl) -N -((4 '-(2- (4-methylpiperazin-1-yl) -2-oxoethoxy) biphenyl-4-yl) methyl) pentaneamide; Prop-2-ynyl 2- (4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetate; N- (3-fluorophenyl) -N -((4 '-(prop-2-ynyloxy) biphenyl-4-yl) methyl) pentaneamide; N -((2 '-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl) -N -phenylpentanamide; 2- (4 '-(( N -phenylpentaneamido) methyl) biphenyl-4-yloxy) acetic acid; 2- (4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetic acid; 2- (4 '-(( N- (3-chlorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetic acid; 2- (4 '-(( N- (3-bromophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetic acid; 2- (4 '-(( N- (3- (trifluoromethyl) phenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetic acid; 2- (4 '-(( Nm -tolylpentaneamido) methyl) biphenyl-4-yloxy) acetic acid; N - ((4'- hydroxy-biphenyl-4-yl) methyl) - N - (3- nitrophenyl) pentane amide; 2- (4 '-(( N- (3-nitrophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetic acid; 2- (4 '-(( N- (3-iodophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetic acid; 2-((4 '-(( N- (3-fluorophenyl) acetamido) methyl)-[1,1'-biphenyl] -4-yl) oxy) acetic acid; N -((4 '-(4-isopropylpiperazin-1-carbonyl) biphenyl-4-yl) methyl) -N -phenylpentaneamide; N- (4-fluorophenyl) -N -((4 '-(4-isopropylpiperazin-1-carbonyl) biphenyl-4-yl) methyl) pentaneamide; N -((3 '-(4-isopropylpiperazin-1-carbonyl) biphenyl-4-yl) methyl) -N -phenylpentaneamide; And N- (4-fluorophenyl) -N -((3 '-(4-isopropylpiperazin-1-carbonyl) biphenyl-4-yl) methyl) pentaneamide.
본 발명에서 사용되는 "약학적으로 허용되는" 이라는 용어는 과도한 독성, 자극, 알러지 반응 또는 기타 문제점 또는 합병증 없이 이득/위험 비가 합리적이어서 대상체 (예: 인간)의 조직과 접촉하여 사용하기에 적합하며 건전한 의학적 판단의 범주 이내인 화합물 또는 조성물을 의미한다.As used herein, the term "pharmaceutically acceptable" is suitable for use in contact with the tissues of a subject (eg, a human being) because the benefit / risk ratio is reasonable without excessive toxicity, irritation, allergic reactions or other problems or complications. A compound or composition is within the scope of sound medical judgment.
본 발명에서 사용되는 용어 "염"은 약학적으로 허용 가능한 유리산(free acid)에 의해 형성된 산 부가염이 유용하다. 산 부가염은 염산, 질산, 인산, 황산, 브롬화수소산, 요드화수소산, 아질산 또는 아인산과 같은 무기산류와 지방족 모노 및 디카르복실레이트, 페닐-치환된 알카노에이트, 하이드록시 알카노에이트 및 알칸디오에이트, 방향족 산류, 지방족 및 방향족 설폰산류와 같은 무독성 유기산으로부터 얻는다. 이러한 약학적으로 무독한 염류로는 설페이트, 피로설페이트, 바이설페이트, 설파이트, 바이설파이트, 니트레이트, 포스페이트, 모노하이드로겐 포스페이트, 디하이드로겐 포스페이트, 메타포스페이트, 피로포스페이트 클로라이드, 브로마이드, 아이오다이드, 플루오라이드, 아세테이트, 프로피오네이트, 데카노에이트, 카프릴레이트, 아크릴레이트, 포메이트, 이소부티레이트, 카프레이트, 헵타노에이트, 프로피올레이트, 옥살레이트, 말로네이트, 석시네이트, 수베레이트, 세바케이트, 푸마레이트, 말리에이트, 부틴-1,4-디오에이트, 헥산-1,6-디오에이트, 벤조에이트, 클로로벤조에이트, 메틸벤조에이트, 디니트로 벤조에이트, 하이드록시벤조에이트, 메톡시벤조에이트, 프탈레이트, 테레프탈레이트, 벤젠설포네이트, 톨루엔설포네이트, 클로로벤젠설포네이트, 크실렌설포네이트, 페닐아세테이트, 페닐프로피오네이트, 페닐부티레이트, 시트레이트, 락테이트, β-하이드록시부티레이트, 글리콜레이트, 말레이트, 타트레이트, 메탄설포네이트, 프로판설포네이트, 나프탈렌-1-설포네이트, 나프탈렌-2-설포네이트 또는 만델레이트를 포함한다.As used herein, the term "salt" is useful for acid addition salts formed with pharmaceutically acceptable free acids. Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid and aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. Obtained from non-toxic organic acids such as dioates, aromatic acids, aliphatic and aromatic sulfonic acids. Such pharmaceutically nontoxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, and iodide. Id, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suverate , Sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate, meth Oxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesul Nate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1- Sulfonates, naphthalene-2-sulfonates or mandelate.
본 발명에 따른 산 부가염은 통상의 방법, 예를 들면, 화학식 1 또는 화학식 2로 표시되는 화합물을 과량의 산 수용액 중에 용해시키고, 이 염을 수혼화성 유기 용매, 예를 들면 메탄올, 에탄올, 아세톤 또는 아세토니트릴을 사용하여 침전시켜서 제조할 수 있다. 또한 이 혼합물에서 용매나 과량의 산을 증발시킨 후 건조시키거나 또는 석출된 염을 흡입 여과시켜 제조할 수도 있다.The acid addition salt according to the present invention is dissolved in a conventional method, for example, the compound represented by the formula (1) or (2) in an excess of aqueous acid solution, and the salt is water-miscible organic solvent such as methanol, ethanol, acetone Or by precipitation with acetonitrile. It may also be prepared by evaporating the solvent or excess acid from the mixture and then drying or by suction filtration of the precipitated salt.
또한, 염기를 사용하여 약학적으로 허용 가능한 금속염을 만들 수도 있다. 알칼리 금속 또는 알칼리 토금속 염은 예를 들면, 화합물을 과량의 알칼리 금속 수산화물 또는 알칼리 토금속 수산화물 용액 중에 용해하고, 비용해 화합물 염을 여과하고, 여액을 증발, 건조시켜 얻는다. 이때, 금속염으로는 나트륨, 칼륨 또는 칼슘염을 제조하는 것이 제약상 적합하다. 이에 대응하는 은염은 알칼리 금속 또는 알칼리 토금속 염을 적당한 음염 (예, 질산은)과 반응시켜 얻는다.Bases can also be used to make pharmaceutically acceptable metal salts. Alkali metal or alkaline earth metal salts are obtained, for example, by dissolving the compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare sodium, potassium or calcium salt as the metal salt. The corresponding silver salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable negative salt (eg silver nitrate).
본 발명의 일실시예에서는 BLT2 억제 활성을 나타내는 화합물을 제조하여 (실시예 1 참조), 상기 화합물 처리에 의한 BLT2 발현 세포의 성장 억제를 확인하였다 (실험예 2 참조). 또한, BLT2 발현 세포의 주화성을 억제시킬 수 있음을 확인하였으며 (실험예 3 참조), 본 발명의 화합물을 이용하여 LTB4와 BLT2 결합 저해효과를 확인하고 (실험예 4 참조), 만성 폐쇄성 폐질환이 유도된 마우스에서, 기관지 폐포세척액 내 TNF-α, IL-6 및 ROS 생성 억제 효과를 구체적으로 확인하였는바 (실험예 5 참조) 만성 폐쇄성 폐질환의 약학적 조성물로 매우 유용하게 사용될 수 있음을 확인하였다. 아울러, 본 발명의 다른 실시예에서는 담배연기 및 지질다당류로 유발된 만성 폐쇄성 폐질환 동물 모델을 제조하여 BLT2 억제 활성을 나타내는 화합물 LMT-886 및 LMT-1013의 효능을 확인하였다(실험예 6 참조).In one embodiment of the present invention, a compound showing BLT2 inhibitory activity was prepared (see Example 1), and the growth inhibition of BLT2 expressing cells by the compound treatment was confirmed (see Experimental Example 2). In addition, it was confirmed that the chemotaxis of the BLT2 expressing cells can be inhibited (see Experimental Example 3), using the compound of the present invention confirmed the inhibitory effect of LTB4 and BLT2 binding (see Experimental Example 4), chronic obstructive pulmonary disease In this induced mouse, we specifically confirmed the inhibitory effect of TNF-α, IL-6 and ROS production in bronchoalveolar lavage fluid (see Experimental Example 5), which can be very useful as a pharmaceutical composition for chronic obstructive pulmonary disease. Confirmed. In addition, in another embodiment of the present invention, the animal models of chronic obstructive pulmonary disease induced by tobacco smoke and lipopolysaccharide were prepared to confirm the efficacy of the compounds LMT-886 and LMT-1013 exhibiting BLT2 inhibitory activity (see Experimental Example 6). .
보다 구체적으로, 본 발명자들은 본 발명의 만성 폐쇄성 폐질환 유도 마우스에 대한 기관지 폐포세척액 내 염증성 사이토카인으로써 염증성 신호전달 체계를 활성화시켜주는 TNF-α 및 IL-6의 생성 감소 효과를 확인하기 위하여, 정상대조군, 음성대조군, 본 발명의 화합물 및 비교 약물 (ROF; Roflumilast PDE4 inhibitor)을 투여한 실험군의 기관지 폐포세척액 내 TNF-α2 및 IL-6의 생성 변화를 측정하였다. 이 때, 본 발명의 종양괴사인자( TNF-α; tumor necrosis factor)는 대식세포 등에서 생산되는 사이토키닌(cytokinin)의 일종이며, 본 발명의 인터루킨-6(interleukin 6)는 B세포의 항체생산세포로의 최종 분화를 유도하는 B세포자극인자2(BSF-2)로서, 분리한 분자량이 210,000인 당단백질. T림프구, B림프구, 대식세포, 섬유아세포 등 여러 세포에서 생산되는 사이토카인이다. 또한 본 발명의 활성산소종(ROS; Reactive oxygen species)은 산소를 포함하는 화학적 반응 분자들로서, 산소의 정상적인 신진 대사의 자연 부산물로 형성되며 세포 신호전달과 항상성에 중요한 역할을 한다. 그러나, 환경 스트레스를 받는 동안 ROS 수준이 크게 증가할 수 있으며, 이것은 세포 구조에 상당한 손상을 초래할 수 있다.More specifically, the inventors of the present invention to determine the effect of reducing the production of TNF-α and IL-6 to activate the inflammatory signaling system as an inflammatory cytokine in bronchoalveolar lavage fluid for chronic obstructive pulmonary disease-induced mice of the present invention, Changes in the production of TNF-α2 and IL-6 in the bronchoalveolar lavage fluid of the experimental group to which the normal control group, the negative control group, the compound of the present invention and the comparative drug (ROF; Roflumilast PDE4 inhibitor) were administered were measured. At this time, the tumor necrosis factor (TNF-α) of the present invention is a kind of cytokinin produced by macrophages and the like, and interleukin-6 of the present invention produces B-cell antibody. B-cell stimulating factor 2 (BSF-2), which induces final differentiation into cells, wherein the glycoprotein has an isolated molecular weight of 210,000. It is a cytokine produced by several cells such as T lymphocytes, B lymphocytes, macrophages and fibroblasts. In addition, the reactive oxygen species (ROS) of the present invention are oxygen-containing chemical reaction molecules, which are formed as natural by-products of normal metabolism of oxygen and play an important role in cellular signaling and homeostasis. However, during environmental stress, ROS levels can increase significantly, which can lead to significant damage to cellular structure.
따라서, 본 발명의 화합물은 염증 매개체의 억제를 통해 효과적으로 폐조직 내 염증 반응을 유의적으로 억제하므로 만성 폐쇄성 폐질환의 예방 및 치료용 약학적 조성물의 유효성분으로써 유용하게 이용할 수 있다Therefore, the compound of the present invention effectively inhibits the inflammatory response in the lung tissue through the inhibition of the inflammatory mediators, and thus can be usefully used as an active ingredient in the pharmaceutical composition for the prevention and treatment of chronic obstructive pulmonary disease.
본 발명에서 사용되는 용어, "예방"이란 본 발명에 따른 약학적 조성물의 투여에 의해 만성 폐쇄성 폐질환을 억제시키거나 발병을 지연시키는 모든 행위를 의미한다.As used herein, the term "prevention" means any action that inhibits or delays the development of chronic obstructive pulmonary disease by administration of a pharmaceutical composition according to the present invention.
본 발명에서 사용되는 용어, "치료"란 본 발명에 따른 약학적 조성물의 투여에 의해 만성 폐쇄성 폐질환에 대한 증세가 호전되거나 이롭게 변경되는 모든 행위를 의미한다.As used herein, the term "treatment" means any action that improves or advantageously changes the symptoms for chronic obstructive pulmonary disease by administration of the pharmaceutical composition according to the present invention.
본 발명에서, 만성 폐쇄성 폐질환(COPD; chronic obstructive pulmonary disease)은 흡연 등의 유해한 입자나 공업용 가스의 흡입에 의해 폐에 비정상적인 염증 반응이 일어나면서 이로 인해 점차 기류 제한이 진행되어 폐 기능이 저하되고 호흡곤란을 유발하게 되는 호흡기 질환으로, 보다 구체적으로 담배 연기와 같이 기도를 자극하는 물질이 기도와 기관지를 반복적으로 자극하면, 기관지 내의 이물질을 제거하기 위하여 분비되는 기관지 점액의 분비가 증가함으로 기관지의 부분적 또는 전체적 폐쇄를 일으킨다. 기관지가 폐쇄되면 폐포는 확장되고 손상되어 산소와 이산화탄소의 교환능력이 손상 받게 되며, 폐쇄된 폐포는 세균이 쉽게 감염되는데, 만성 폐쇄성 폐질환 환자에게 세균이 감염되면 가스교환의 심각한 장애로 동맥혈 산소압이 급격히 감소하는 상황이 발생하여, 호흡부전에 의하여 동맥혈 이산화탄소압이 상승하면 이산화탄소 혼수가 발생할 수도 있다. 만성 폐쇄성 폐질환의 한 종류로서 폐기종, 만성 기관지염 등이 이에 속할 수 있으나, 이로써 제한되는 것은 아니다.In the present invention, chronic obstructive pulmonary disease (COPD) is an abnormal inflammatory reaction occurs in the lungs by inhalation of harmful particles such as smoking or industrial gases, thereby gradually limiting airflow and thus lowering lung function. A respiratory disorder that causes respiratory distress. More specifically, if a substance that stimulates the airways, such as cigarette smoke, repeatedly stimulates the airways and bronchus, the secretion of bronchial mucus secreted to remove foreign substances in the bronchus increases. Causes partial or complete closure. When the bronchus is closed, the alveoli expand and become damaged, and the ability to exchange oxygen and carbon dioxide is impaired. The closed alveoli are easily infected with bacteria. When bacteria are infected by patients with chronic obstructive pulmonary disease, arterial oxygen pressure is a serious disorder of gas exchange. This rapidly decreasing situation may occur, and carbon dioxide coma may occur when the arterial blood carbon dioxide pressure increases due to respiratory failure. One type of chronic obstructive pulmonary disease may include, but is not limited to, emphysema, chronic bronchitis, and the like.
또한, 본 발명의 만성 폐쇄성 폐질환은 BLT2 (Leukotriene B4 receptor 2)의 과발현에 기인한 질병일 수 있다. 보다 구체적으로, 류코트리엔(Leukotriene)은 기관지 수축을 일으키는 면역매개물질로서, BLT2 (Leukotriene B4 receptor 2)의 과발현은 만성 폐쇄성 폐질환을 일으킬 수 있다.In addition, the chronic obstructive pulmonary disease of the present invention may be a disease due to overexpression of Leukotriene B4 receptor 2 (BLT2). More specifically, leukotriene is an immune mediator that causes bronchial contraction, and overexpression of Leukotriene B4 receptor 2 (BLT2) may cause chronic obstructive pulmonary disease.
본 명세서에서 예시한 상기 질환 외에도, 당업계에 알려져 있는 BLT2-연관된 만성 폐쇄성 폐질환은 모두 본 발명의 화학식 1 또는 화학식 2의 구조를 갖는 화합물로 예방 또는 치료할 수 있는 만성 폐쇄성 폐질환에 포함되는 것으로 본다.In addition to the diseases exemplified herein, all of the BLT2-associated chronic obstructive pulmonary diseases known in the art are to be included in the chronic obstructive pulmonary disease which can be prevented or treated with a compound having the structure of Formula 1 or Formula 2 of the present invention. see.
본 발명에서, BLT2 Leukotriene B4 receptor 2)는 GPCR(G protein-coupled receptor) 군 중 하나로 LTB4 (Leukotriene B4; LTB4)에 대해 낮은 친화력을 갖는 수용체로서, 본 발명의 조성물은 BLT2에 의한 세포 성장을 억제함으로써, 만성 폐쇄성 폐질환을 예방 또는 치료할 수 있다. 보다 구체적으로 BLT2 활성으로 유도된 ROS의 생성을 저해하여 LTB4-유도된 주화성을 저해할 수 있다.In the present invention, BLT2 Leukotriene B4 receptor 2) is one of the group of G protein-coupled receptors (GPCR), which has a low affinity for LTB 4 ( Leukotriene B4; LTB 4 ), and the composition of the present invention is a cell growth by BLT2. By suppressing this, chronic obstructive pulmonary disease can be prevented or treated. More specifically, the inhibition of the production of ROS induced by BLT2 activity may inhibit LTB 4 -induced chemotaxis.
본 발명에서 사용되는 용어, "저해"는 유전자의 전사, mRNA 프로세싱, 번역, 전좌 및 성숙 중 임의의 단계를 저해하거나, 단백질과 단백질간의 결합, 단백질의 활성화 또는 이를 통한 신호전달의 저해를 의미한다. As used herein, the term "inhibition" means inhibiting any step of transcription, mRNA processing, translation, translocation, and maturation of a gene, or inhibition of protein-to-protein binding, activation of a protein, or signaling through it. .
본 발명의 약학적 조성물은 유효성분 이외에 약제학적으로 허용되는 담체를 포함할 수 있다. 이때, 약제학적으로 허용되는 담체는 제제 시에 통상적으로 이용되는 것으로서, 락토스, 덱스트로스, 수크로스, 솔비톨, 만니톨, 전분, 아카시아고무, 인산 칼슘, 알기네이트, 젤라틴, 규산 칼슘, 미세 결정성셀룰로스, 폴리비닐피로리돈, 셀룰로스, 물, 시럽, 메틸 셀룰로스, 메틸히드록시벤조에이트, 프로필 히드록시벤조에이트, 활석, 스테아르산 마그네슘 및 미네랄 오일등을 포함하나, 이에 한정되는 것은 아니다. 또한, 상기 성분들 이외에 윤활제, 습윤제, 감미제, 향미제, 유화제, 현탁제, 보존제 등을 추가로 포함할 수 있다.The pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier in addition to the active ingredient. At this time, the pharmaceutically acceptable carrier is commonly used in the formulation, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose , Polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate and mineral oil, and the like. In addition to the above components, it may further include a lubricant, a humectant, a sweetener, a flavoring agent, an emulsifier, a suspending agent, a preservative, and the like.
본 발명의 약학적 조성물은 목적하는 방법에 따라 경구 투여하거나 비경구투여(예를 들어, 정맥 내, 피하, 복강 내 또는 국소에 적용)할 수 있으며, 투여량은 환자의 상태 및 체중, 질병의 정도, 약물형태, 투여경로 및 시간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다.The pharmaceutical compositions of the present invention can be administered orally or parenterally (eg, applied intravenously, subcutaneously, intraperitoneally or topically) according to the desired method, and the dosage is determined by the condition and weight of the patient, Depending on the extent, drug form, route of administration, and time, it may be appropriately selected by those skilled in the art.
본 발명의 약학적 조성물은 약학적으로 유효한 양으로 투여한다. 본 발명에 있어서 "약학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 유효용량 수준은 환자의 질환의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출비율, 치료기간, 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 얄려진 요소에 따라 결정될 수 있다. 본 발명에 다른 약학적 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고 종래의 치료제와는 순차적 또는 동시에 투여될 수 있으며, 단일 또는 다중 투여될 수 있다. 상기한 요소들을 모두 고려하여 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 이는 당업자에 의해 용이하게 결정될 수 있다.The pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount. As used herein, the term “pharmaceutically effective amount” means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level refers to the type of disease, the severity, the activity of the drug, It may be determined according to the sensitivity to the drug, the time of administration, the route of administration and the rate of release, the duration of treatment, factors including the drug used concurrently and other factors well known in the medical field. The pharmaceutical compositions according to the present invention may be administered as individual therapeutic agents or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be single or multiple administrations. Taking all of the above factors into consideration, it is important to administer an amount that can obtain the maximum effect in a minimum amount without side effects, which can be easily determined by those skilled in the art.
구체적으로 본 발명의 약학적 조성물의 유효량은 환자의 연령, 성별, 상태, 체중, 체내에 활성 성분의 흡수도, 불활성율 및 배설속도, 질병종류, 병용되는 약물에 따라 달라질 수 있으며, 일반적으로는 체중 1kg 당 0.001 내지 150mg, 바람직하게는 0.01 내지 100mg을 매일 또는 격일 투여하거나, 1일 1 내지 3회로 나누어 투여할 수 있다. 그러나 투여 경로, 비만의 중증도, 성별, 체중, 연령 등에 따라서 증감될 수 있으므로 상기 투여량이 어떠한 방법으로도 본 발명의 범위를 한정하는 것은 아니다.Specifically, the effective amount of the pharmaceutical composition of the present invention may vary depending on the age, sex, condition, weight of the patient, the absorption of the active ingredient in the body, the inactivation rate and excretion rate, the type of disease, the drug used in general 0.001 to 150 mg, preferably 0.01 to 100 mg per 1 kg of body weight may be administered daily or every other day, or divided into 1 to 3 times a day. However, the dosage may be increased or decreased depending on the route of administration, the severity of obesity, sex, weight, age, etc., and the above dosage does not limit the scope of the present invention in any way.
또한, 본 발명은 상기 약학적 조성물을 개체에 투여하는 단계를 포함하는 만성 폐쇄성 폐질환의 치료방법을 제공한다. 본 발명에서 "개체"란 질병의 치료를 필요로 하는 대상을 의미하고, 보다 구체적으로는, 인간 또는 비-인간인 영장류, 생쥐(mouse), 개, 고양이, 말 및 소 등의 포유류를 의미한다.The present invention also provides a method of treating chronic obstructive pulmonary disease comprising administering the pharmaceutical composition to a subject. As used herein, "individual" means a subject in need of treatment for a disease, and more specifically, a mammal, such as a primate, mouse, dog, cat, horse and cow, which is human or non-human. .
이하, 본 발명의 이해를 돕기 위하여 바람직한 실시예를 제시한다. 그러나 하기의 실시예는 본 발명을 보다 쉽게 이해하기 위하여 제공되는 것일 뿐, 하기 실시예에 의해 본 발명의 내용이 한정되는 것은 아니다.Hereinafter, preferred examples are provided to aid in understanding the present invention. However, the following examples are merely provided to more easily understand the present invention, and the contents of the present invention are not limited by the following examples.
[[ 실시예Example ]]
실시예Example 1.  One. BLT2BLT2 저해 활성을 갖는 화합물의 합성 Synthesis of Compounds with Inhibitory Activity
본 발명에 따른 약학적 조성물의 유효성분으로 사용되는 비-한정적인 화합물의 예는 하기의 화합물, 이의 이성질체 및 이의 약학적으로 허용 가능한 염을 포함한다. 공지된 방법의 반응물 및/또는 출발물질을 적절히 변경하여, 본 발명에 따른 하기 화합물들을 합성하였으며 수율 및 1H NMR 측정 결과는 하기에 기재하였다.Examples of non-limiting compounds to be used as active ingredients of the pharmaceutical composition according to the present invention include the following compounds, isomers thereof and pharmaceutically acceptable salts thereof. By appropriately modifying the reactants and / or starting materials of known methods, the following compounds according to the invention were synthesized and the yield and 1 H NMR measurement results are described below.
1-1. 1-1. terttert -부틸 4-(4-(3-(-Butyl 4- (4- (3- ( NN -- 페닐펜탄아미도Phenylpentaneamido )) 프로프Prof -1--One- 이닐Inil )) 벤조일Benzoyl )피페라진-1-카복실레이트 (Piperazine-1-carboxylate ( terttert -butyl 4-(4-(3-(-butyl 4- (4- (3- ( NN -- phenylpentanamidophenylpentanamido )prop-1-ynyl)benzoyl)piperazine-1-carboxylate) () prop-1-ynyl) benzoyl) piperazine-1-carboxylate) ( LMTLMT -693)-693)
73% 수율; 1H-NMR (CDCl3, 500 MHz) δ 7.40-7.20 (9H, m), 4.65 (2H, s), 3.62-3.32 (8H, br), 2.02-1.97 (2H, t), 1.52-1.48 (2H, m), 1.40 (9H, s), 1.19-1.12 (2H, m), 0.76-0.72 (3H, t).73% yield; 1 H-NMR (CDCl 3 , 500 MHz) δ 7.40-7.20 (9H, m), 4.65 (2H, s), 3.62-3.32 (8H, br), 2.02-1.97 (2H, t), 1.52-1.48 ( 2H, m), 1.40 (9H, s), 1.19-1.12 (2H, m), 0.76-0.72 (3H, t).
1-2. 1-2. NN -페닐--Phenyl- NN -(3-(4-(피페라진-1--(3- (4- (piperazin-1- 카보닐Carbonyl )페닐)) Phenyl) 프로프Prof -2--2- 이닐Inil )) 펜탄아마이드Pentaneamide ( ( NN -phenyl--phenyl- NN -(3-(4-(piperazine-1-carbonyl)phenyl)prop-2-ynyl)pentanamide) (LMT-694)-(3- (4- (piperazine-1-carbonyl) phenyl) prop-2-ynyl) pentanamide) (LMT-694)
60% 수율; 1H-NMR (CDCl3, 500 MHz) δ 7.48-7.30 (9H, m), 4.73 (2H, s), 3.73-3.39 (4H, br), 2.97-2.86 (4H, br), 2.09-2.06 (2H, t), 1.60-1.54 (2H, m), 1.25-1.19 (2H, m), 0.83-0.80 (3H, t).60% yield; 1 H-NMR (CDCl 3 , 500 MHz) δ 7.48-7.30 (9H, m), 4.73 (2H, s), 3.73-3.39 (4H, br), 2.97-2.86 (4H, br), 2.09-2.06 ( 2H, t), 1.60-1.54 (2H, m), 1.25-1.19 (2H, m), 0.83-0.80 (3H, t).
1-3. 1-3. NN -(3-(4-(4--(3- (4- (4- 메틸피페라진Methylpiperazine -1--One- 카보닐Carbonyl )페닐)) Phenyl) 프로프Prof -2--2- 이닐Inil )-)- NN -- 페닐펜탄아마이드Phenylpentaneamide ( ( NN -(3-(4-(4--(3- (4- (4- methylpiperazinemethylpiperazine -1-carbonyl)phenyl)prop-2--1-carbonyl) phenyl) prop-2- ynylynyl )-)- NN -phenylpentanamide) (-phenylpentanamide) ( LMTLMT -692)-692)
20% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.40-7.21 (9H, m), 4.65 (2H, s), 3.71-3.34 (4H, br), 2.41-2.25 (4H, br), 2.25 (3H, s), 2.02-1.99 (2H, t), 1.54-1.46 (2H, m), 1.18-1.12 (2H, m), 0.76-0.71 (3H, t).20% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.40-7.21 (9H, m), 4.65 (2H, s), 3.71-3.34 (4H, br), 2.41-2.25 (4H, br), 2.25 (3H, s), 2.02-1.99 (2H, t), 1.54-1.46 (2H, m), 1.18-1.12 (2H, m), 0.76-0.71 (3H, t).
1-4. 1-4. NN -(3-(4-(4--(3- (4- (4- 에틸피페라진Ethyl piperazine -1--One- 카보닐Carbonyl )페닐)) Phenyl) 프로프Prof -2--2- 이닐Inil )-)- NN -- 페닐펜탄아마이드Phenylpentaneamide ( ( NN -(3-(4-(4--(3- (4- (4- EthylpiperazineEthylpiperazine -1-carbonyl)phenyl)prop-2--1-carbonyl) phenyl) prop-2- ynylynyl )-)- NN -phenylpentanamide) (-phenylpentanamide) ( LMTLMT -695)-695)
68% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.40-7.20 (9H, m), 4.65 (2H,s), 3.73-3.35 (4H,br), 2.44-2.31 (6H,m), 2.03-1.99 (2H,t), 1.54-1.46 (2H,m), 1.20-1.13 (2H,m), 1.05-1.01 (3H,t), 0.78-0.73 (3H,t).68% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.40-7.20 (9H, m), 4.65 (2H, s), 3.73-3.35 (4H, br), 2.44-2.31 (6H, m), 2.03-1.99 ( 2H, t), 1.54-1.46 (2H, m), 1.20-1.13 (2H, m), 1.05-1.01 (3H, t), 0.78-0.73 (3H, t).
1-5. 1-5. NN -(3-(4-(4--(3- (4- (4- 아이소프로필피페라진Isopropyl piperazine -1--One- 카보닐Carbonyl )페닐)) Phenyl) 프로프Prof -2--2- 이닐Inil )-)- NN -- 페닐펜탄아마이드Phenylpentaneamide ( ( NN -(3-(4-(4--(3- (4- (4- isopropylpiperazineisopropylpiperazine -1-carbonyl)phenyl)prop-2-ynyl)--1-carbonyl) phenyl) prop-2-ynyl)- NN -phenylpentanamide) (-phenylpentanamide) ( LMTLMT -696)-696)
57% 수율; 1H-NMR (CDCl3, 500 MHz) δ 7.47-7.30 (9H, m), 4.73 (2H, s), 3.78-3.40 (4H, br), 2.75-2.72 (1H, m), 2.59-2.44 (4H, br), 2.09-2.06 (2H, t), 1.59-1.56 (2H, m), 1.25-1.20 (2H, m), 1.06-1.04 (6H, d), 0.83-0.80 (3H, t).57% yield; 1 H-NMR (CDCl 3 , 500 MHz) δ 7.47-7.30 (9H, m), 4.73 (2H, s), 3.78-3.40 (4H, br), 2.75-2.72 (1H, m), 2.59-2.44 ( 4H, br), 2.09-2.06 (2H, t), 1.59-1.56 (2H, m), 1.25-1.20 (2H, m), 1.06-1.04 (6H, d), 0.83-0.80 (3H, t).
1-6. 1-6. NN -(3-(4-(4-(2-하이드록시에틸)피페라진-1--(3- (4- (4- (2-hydroxyethyl) piperazin-1- 카보닐Carbonyl )페닐)) Phenyl) 프로프Prof -2--2- 이닐Inil )-)- NN -페닐펜탄아마이드 (-Phenylpentaneamide ( NN -(3-(4-(4-(2-hydroxyethyl)-(3- (4- (4- (2-hydroxyethyl) piperazinepiperazine -1-carbonyl)phenyl)prop-2-ynyl)--1-carbonyl) phenyl) prop-2-ynyl)- NN -phenylpentanamide) (-phenylpentanamide) ( LMTLMT -827)-827)
84% 수율; 1H-NMR (CDCl3, 500MHz) δ 7.48-7.30 (9H, m), 4.73 (2H, s), 3.79 (2H, br), 3.66-3.64 (2H, t), 3.43 (2H, br), 2.60-2.46 (7H, br), 2.10-2.07 (2H, t), 1.59-1.56 (2H, m), 1.25-1.22 (2H, m), 0.83-0.80 (3H, t).84% yield; 1 H-NMR (CDCl 3 , 500 MHz) δ 7.48-7.30 (9H, m), 4.73 (2H, s), 3.79 (2H, br), 3.66-3.64 (2H, t), 3.43 (2H, br), 2.60-2.46 (7H, br), 2.10-2.07 (2H, t), 1.59-1.56 (2H, m), 1.25-1.22 (2H, m), 0.83-0.80 (3H, t).
1-7. 1-7. NN -(3-(4-(4-(-(3- (4- (4- ( 사이클로프로필메틸Cyclopropylmethyl )피페라진-1-Piperazine-1- 카보닐Carbonyl )페닐)) Phenyl) 프로프Prof -2--2- 이닐Inil )-)- NN -페닐펜탄아마이드 (-Phenylpentaneamide ( NN -(3-(4-(4-(-(3- (4- (4- ( cyclopropylmethylcyclopropylmethyl )) piperazinepiperazine -1-carbonyl)phenyl)prop-2-ynyl)--1-carbonyl) phenyl) prop-2-ynyl)- NN -phenylpentanamide) (-phenylpentanamide) ( LMTLMT -828)-828)
28% 수율; 1H-NMR (CDCl3, 500 MHz) δ 7.48-7.28 (9H, m), 4.73 (2H, s), 3.82-3.45 (4H, br), 2.63-2.49 (4H, br), 2.32-2.31 (2H, d), 2.09-2.06 (2H, t), 1.60-1.56 (2H, m), 1.25-1.20 (3H, m), 0.83-0.80 (3H, t), 0.55-0.53 (2H, m), 0.12-0.11 (2H, m).28% yield; 1 H-NMR (CDCl 3 , 500 MHz) δ 7.48-7.28 (9H, m), 4.73 (2H, s), 3.82-3.45 (4H, br), 2.63-2.49 (4H, br), 2.32-2.31 ( 2H, d), 2.09-2.06 (2H, t), 1.60-1.56 (2H, m), 1.25-1.20 (3H, m), 0.83-0.80 (3H, t), 0.55-0.53 (2H, m), 0.12-0.11 (2H, m).
1-8. 1-8. NN -(3-(4-(4--(3- (4- (4- 사이클로헥실피페라진Cyclohexylpiperazine -1--One- 카보닐Carbonyl )페닐)) Phenyl) 프로프Prof -2--2- 이닐Inil )-)- NN -- 페닐펜탄아마이드Phenylpentaneamide ( ( NN -(3-(4-(4--(3- (4- (4- cyclohexylpiperazinecyclohexylpiperazine -1-carbonyl)phenyl)prop-2-ynyl)--1-carbonyl) phenyl) prop-2-ynyl)- NN -phenylpentanamide) (-phenylpentanamide) ( LMTLMT -830)-830)
33% 수율; 1H-NMR (CDCl3, 500 MHz) δ 7.48-7.31 (9H, m), 4.73 (2H, s), 3.77-3.39 (4H, br), 2.63-2.49 (4H, br), 2.31-2.28 (1H, m), 2.09-2.06 (2H, m), 1.91-1.79 (4H, m), 1.65-1.54 (3H, m), 1.28-1.16 (6H, m), 1.13-1.08 (1H, m), 0.83-0.80 (3H, t).33% yield; 1 H-NMR (CDCl 3 , 500 MHz) δ 7.48-7.31 (9H, m), 4.73 (2H, s), 3.77-3.39 (4H, br), 2.63-2.49 (4H, br), 2.31-2.28 ( 1H, m), 2.09-2.06 (2H, m), 1.91-1.79 (4H, m), 1.65-1.54 (3H, m), 1.28-1.16 (6H, m), 1.13-1.08 (1H, m), 0.83-0.80 (3H, t).
1-9. 1-9. NN -(3-(4-(4-(-(3- (4- (4- ( 사이클로헥실메틸Cyclohexylmethyl )피페라진-1-Piperazine-1- 카보닐Carbonyl )페닐)) Phenyl) 프로프Prof -2--2- 이닐Inil )-)- NN -페닐펜탄아마이드 (-Phenylpentaneamide ( NN -(3-(4-(4-(-(3- (4- (4- ( cyclohexylmethylcyclohexylmethyl )) piperazinepiperazine -1-carbonyl)phenyl)prop-2-ynyl)--1-carbonyl) phenyl) prop-2-ynyl)- NN -phenylpentanamide) (-phenylpentanamide) ( LMTLMT -831)-831)
56% 수율; 1H-NMR (CDCl3, 500 MHz) δ 7.48-7.28 (9H, m), 4.73 (2H, s), 3.76-3.38 (4H, br), 2.45-2.31 (4H, br), 2.15-2.13 (2H, m), 2.09-2.06 (2H, m), 1.77-1.66 (5H, m), 1.59-1.56 (2H, m), 1.47-1.45 (1H, m), 1.25-1.17 (5H, m), 0.90-0.80 (5H, t).56% yield; 1 H-NMR (CDCl 3 , 500 MHz) δ 7.48-7.28 (9H, m), 4.73 (2H, s), 3.76-3.38 (4H, br), 2.45-2.31 (4H, br), 2.15-2.13 ( 2H, m), 2.09-2.06 (2H, m), 1.77-1.66 (5H, m), 1.59-1.56 (2H, m), 1.47-1.45 (1H, m), 1.25-1.17 (5H, m), 0.90-0.80 (5H, t).
1-10. 1-10. NN -(3-(4-(4--(3- (4- (4- 아이소부틸피페라진Isobutyl Piperazine -1--One- 카보닐Carbonyl )페닐)) Phenyl) 프로프Prof -2--2- 이닐Inil )-)- NN -- 페닐펜탄아마이드Phenylpentaneamide ( ( NN -(3-(4-(4--(3- (4- (4- isobutylpiperazineisobutylpiperazine -1-carbonyl)phenyl)prop-2--1-carbonyl) phenyl) prop-2- ynylynyl )-)- NN -phenylpentanamide) (-phenylpentanamide) ( LMTLMT -832)-832)
60% 수율; 1H-NMR (CDCl3, 500 MHz) δ 7.47-7.28 (9H, m), 4.73 (2H, s), 3.76-3.39 (4H, br), 2.46-2.32 (4H, br), 2.11-2.07 (4H, m), 1.79-1.76 (1H, m), 1.59-1.56 (2H, m), 1.25-1.20 (2H, m), 0.91-0.89 (6H, d), 0.83-0.80 (3H, t).60% yield; 1 H-NMR (CDCl 3 , 500 MHz) δ 7.47-7.28 (9H, m), 4.73 (2H, s), 3.76-3.39 (4H, br), 2.46-2.32 (4H, br), 2.11-2.07 ( 4H, m), 1.79-1.76 (1H, m), 1.59-1.56 (2H, m), 1.25-1.20 (2H, m), 0.91-0.89 (6H, d), 0.83-0.80 (3H, t).
1-11. 1-11. NN -페닐--Phenyl- NN -(3-(4-(4-(-(3- (4- (4- ( 프로프Prof -2--2- 이닐Inil )피페라진-1-Piperazine-1- 카보닐Carbonyl )페닐)) Phenyl) 프로프Prof -2-이닐)펜탄아마이드 (-2-ynyl) pentaneamide ( NN -phenyl--phenyl- NN -(3-(4-(4-(prop-2--(3- (4- (4- (prop-2- ynylynyl )) piperazinepiperazine -1-carbonyl)phenyl)prop-2-ynyl)pentanamide) (-1-carbonyl) phenyl) prop-2-ynyl) pentanamide) ( LMTLMT -833)-833)
51% 수율; 1H-NMR (CDCl3, 500 MHz) δ 7.48-7.28 (9H, m), 4.73 (2H, s), 3.82-3.44 (4H, br), 3.36 (2H, s), 2.65-2.51 (4H, br), 2.30 (1H, s), 2.10-2.07 (2H, m), 1.60-1.54 (2H, m), 1.26-1.19 (2H, m), 0.83-0.80 (3H, t).51% yield; 1 H-NMR (CDCl 3 , 500 MHz) δ 7.48-7.28 (9H, m), 4.73 (2H, s), 3.82-3.44 (4H, br), 3.36 (2H, s), 2.65-2.51 (4H, br), 2.30 (1H, s), 2.10-2.07 (2H, m), 1.60-1.54 (2H, m), 1.26-1.19 (2H, m), 0.83-0.80 (3H, t).
1-12. 1-12. NN -(3-(4-(4--(3- (4- (4- 시아노피페라진Cyanopiperazine -1--One- 카보닐Carbonyl )페닐)) Phenyl) 프로프Prof -2--2- 이닐Inil )-)- NN -- 페닐펜탄아마이드Phenylpentaneamide ( ( NN -(3-(4-(4--(3- (4- (4- cyanopiperazinecyanopiperazine -1-carbonyl)phenyl)prop-2--1-carbonyl) phenyl) prop-2- ynylynyl )-)- NN -phenylpentanamide) (-phenylpentanamide) ( LMTLMT -829)-829)
21% 수율; 1H-NMR (CDCl3, 500 MHz) δ 7.48-7.30 (9H, m), 4.73 (2H, s), 3.81-3.26 (8H, br), 2.09-2.06 (2H, t), 1.60-1.54 (2H, m), 1.25-1.19 (2H, m), 0.83-0.80 (3H, t).21% yield; 1 H-NMR (CDCl 3 , 500 MHz) δ 7.48-7.30 (9H, m), 4.73 (2H, s), 3.81-3.26 (8H, br), 2.09-2.06 (2H, t), 1.60-1.54 ( 2H, m), 1.25-1.19 (2H, m), 0.83-0.80 (3H, t).
1-13. 1-13. terttert -- 부틸 4-(4-(3-(Butyl 4- (4- (3- ( NN -(3--(3- 플루오로페닐Fluorophenyl )) 펜탄아미도Pentanamido )) 프로프Prof -1--One- 이닐Inil )) 벤조일Benzoyl )피페라진-1-카복실레이트 (Piperazine-1-carboxylate ( terttert -butyl 4-(4-(3-(-butyl 4- (4- (3- ( NN -(3-fluorophenyl)pentanamido)prop-1-ynyl)benzoyl)piperazine-1-carboxylate) (-(3-fluorophenyl) pentanamido) prop-1-ynyl) benzoyl) piperazine-1-carboxylate) ( LMTLMT -884)-884)
73% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.44-7.32 (5H, m), 7.12-7.06 (3H, m), 4.72 (2H, s), 3.73-3.38 (8H, br), 2.10-2.07 (2H, t), 1.59-1.57 (2H, m), 1.47 (9H, s), 1.23-1.20 (2H, m), 0.83-0.80 (3H, t).73% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.44-7.32 (5H, m), 7.12-7.06 (3H, m), 4.72 (2H, s), 3.73-3.38 (8H, br), 2.10-2.07 ( 2H, t), 1.59-1.57 (2H, m), 1.47 (9H, s), 1.23-1.20 (2H, m), 0.83-0.80 (3H, t).
1-14. 1-14. NN -(3--(3- 플루오로페닐Fluorophenyl )-)- NN -(3-(4-(피페라진-1--(3- (4- (piperazin-1- 카보닐Carbonyl )페닐)) Phenyl) 프로프Prof -2--2- 이닐Inil )펜탄아마이드 (Pentaneamide ( NN -(3--(3- fluorophenylfluorophenyl )-)- NN -(3-(4-(-(3- (4- ( piperazinepiperazine -1-carbonyl)phenyl)prop-2-ynyl)pentanamide) (-1-carbonyl) phenyl) prop-2-ynyl) pentanamide) ( LMTLMT -885)-885)
58% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.45-7.32 (5H, m), 7.15-7.07 (3H, m), 4.72 (2H, s), 3.75-3.37 (4H, br), 2.94-2.80 (4H, br), 2.10-2.07 (2H, t), 1.89 (1H, br), 1.60-1.57 (2H, m), 1.25-1.24 (2H, m), 0.84-0.82 (3H, t).58% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.45-7.32 (5H, m), 7.15-7.07 (3H, m), 4.72 (2H, s), 3.75-3.37 (4H, br), 2.94-2.80 ( 4H, br), 2.10-2.07 (2H, t), 1.89 (1H, br), 1.60-1.57 (2H, m), 1.25-1.24 (2H, m), 0.84-0.82 (3H, t).
1-15. 1-15. NN -(3--(3- 플루오로페닐Fluorophenyl )-)- NN -(3-(4-(4--(3- (4- (4- 아이소프로필피페라진Isopropyl piperazine -1--One- 카보닐Carbonyl )페닐)프로프-2-이닐)펜탄아마이드 () Phenyl) prop-2-ynyl) pentaneamide ( NN -(3--(3- fluorophenylfluorophenyl )-)- NN -(3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)prop-2-ynyl)pentanamide) (-(3- (4- (4-isopropylpiperazine-1-carbonyl) phenyl) prop-2-ynyl) pentanamide) ( LMTLMT -886)-886)
40% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.44-7.32 (5H, m), 7.15-7.06 (3H, m), 4.72 (2H, s), 3.78-3.41 (4H, br), 2.75-2.72 (1H, m), 2.59-2.45 (4H, br), 2.11-2.09 (2H, t), 1.60-1.57 (2H, m), 1.25-1.22 (2H, m), 1.06-1.05 (6H, d), 0.85-0.82 (3H, t).40% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.44-7.32 (5H, m), 7.15-7.06 (3H, m), 4.72 (2H, s), 3.78-3.41 (4H, br), 2.75-2.72 ( 1H, m), 2.59-2.45 (4H, br), 2.11-2.09 (2H, t), 1.60-1.57 (2H, m), 1.25-1.22 (2H, m), 1.06-1.05 (6H, d), 0.85-0.82 (3H, t).
1-16. 1-16. terttert -부틸 4-(4-(3-(-Butyl 4- (4- (3- ( NN -(4--(4- 플루오로페닐Fluorophenyl )) 펜탄아미도Pentanamido )) 프로프Prof -1--One- 이닐Inil )) 벤조일Benzoyl )피페라진-1-카복실레이트(Piperazine-1-carboxylate ( terttert -butyl 4-(4-(3-(-butyl 4- (4- (3- ( NN -(4-fluorophenyl)pentanamido)prop-1-ynyl)benzoyl)piperazine-1-carboxylate) (-(4-fluorophenyl) pentanamido) prop-1-ynyl) benzoyl) piperazine-1-carboxylate) ( LMTLMT -839)-839)
73% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.39-7.29 (6H, m), 7.17-7.14 (2H, m), 4.71 (2H, s), 3.73-3.38 (8H, br), 2.07-2.04 (2H, t), 1.60-1.54 (2H, m), 1.47 (9H, s), 1.25-1.19 (2H, m), 0.84-0.81 (3H, t).73% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.39-7.29 (6H, m), 7.17-7.14 (2H, m), 4.71 (2H, s), 3.73-3.38 (8H, br), 2.07-2.04 ( 2H, t), 1.60-1.54 (2H, m), 1.47 (9H, s), 1.25-1.19 (2H, m), 0.84-0.81 (3H, t).
1-17. 1-17. NN -(4--(4- 플루오로페닐Fluorophenyl )-)- NN -(3-(4-(피페라진-1--(3- (4- (piperazin-1- 카보닐Carbonyl )페닐)) Phenyl) 프로프Prof -2--2- 이닐Inil )펜탄아마이드 (Pentaneamide ( NN -(4--(4- fluorophenylfluorophenyl )-)- NN -(3-(4-(-(3- (4- ( piperazinepiperazine -1-carbonyl)phenyl)prop-2-ynyl)pentanamide) (-1-carbonyl) phenyl) prop-2-ynyl) pentanamide) ( LMTLMT -840)-840)
58% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.38-7.30 (6H, m), 7.17-7.15 (2H, m), 4.71 (2H, s), 3.77-3.40 (4H, br), 2.96-2.79 (5H, br), 2.06-2.03 (2H, t), 1.57-1.54 (2H, m), 1.25-1.22 (2H, m), 0.84-0.82 (3H, t).58% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.38-7.30 (6H, m), 7.17-7.15 (2H, m), 4.71 (2H, s), 3.77-3.40 (4H, br), 2.96-2.79 ( 5H, br), 2.06-2.03 (2H, t), 1.57-1.54 (2H, m), 1.25-1.22 (2H, m), 0.84-0.82 (3H, t).
1-18. 1-18. NN -(4--(4- 플루오로페닐Fluorophenyl )-)- NN -(3-(4-(4--(3- (4- (4- 아이소프로필피페라진Isopropyl piperazine -1--One- 카보닐Carbonyl )페닐)프로프-2-이닐)펜탄아마이드 () Phenyl) prop-2-ynyl) pentaneamide ( NN -(4--(4- fluorophenylfluorophenyl )-)- NN -(3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)prop-2-ynyl)pentanamide) (-(3- (4- (4-isopropylpiperazine-1-carbonyl) phenyl) prop-2-ynyl) pentanamide) ( LMTLMT -841)-841)
40% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.37-7.28 (6H, m), 7.17-7.13 (2H, m), 4.71 (2H, s), 3.78-3.40 (4H, br), 2.75-2.72 (1H, m), 2.59-2.45 (4H, br), 2.07-2.04 (2H, t), 1.58-1.55 (2H, m), 1.25-1.21 (2H, m), 1.06-1.04 (6H, d), 0.84-0.81 (3H, t).40% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.37-7.28 (6H, m), 7.17-7.13 (2H, m), 4.71 (2H, s), 3.78-3.40 (4H, br), 2.75-2.72 ( 1H, m), 2.59-2.45 (4H, br), 2.07-2.04 (2H, t), 1.58-1.55 (2H, m), 1.25-1.21 (2H, m), 1.06-1.04 (6H, d), 0.84-0.81 (3H, t).
1-19. 1-19. NN -(3-(4-(-(3- (4- ( 몰폴린Morpholine -4--4- 카보닐Carbonyl )페닐)) Phenyl) 프로프Prof -2--2- 이닐Inil )-)- NN -- 페닐펜탄아마이드Phenylpentaneamide ( ( NN -(3-(4-(morpholine-4-carbonyl)phenyl)prop-2-ynyl)--(3- (4- (morpholine-4-carbonyl) phenyl) prop-2-ynyl)- NN -phenylpentanamide) (LMT-682)-phenylpentanamide) (LMT-682)
수율 90%; 1H-NMR (CDCl3, 400 MHz) δ 7.48-7.28 (m, 9H), 4.73 (s, 2H), 3.74-3.66 (br, 6 H), 3.43 (br, 2H), 2.08 (m, 2H), 1.57 (m, 2H), 1.22 (m, 2H), 0.81 (t, 3H).Yield 90%; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.48-7.28 (m, 9H), 4.73 (s, 2H), 3.74-3.66 (br, 6H), 3.43 (br, 2H), 2.08 (m, 2H ), 1.57 (m, 2H), 1.22 (m, 2H), 0.81 (t, 3H).
1-20. 1-20. NN -페닐--Phenyl- NN -(3-(4-(피페리딘-1--(3- (4- (piperidine-1- 카보닐Carbonyl )페닐)) Phenyl) 프로프Prof -2--2- 이닐Inil )) 펜탄아마이드Pentaneamide ( ( NN -phenyl--phenyl- NN -(3-(4-(piperidine-1-carbonyl)phenyl)prop-2-ynyl)pentanamide) (LMT-683)-(3- (4- (piperidine-1-carbonyl) phenyl) prop-2-ynyl) pentanamide) (LMT-683)
15% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.40-7.13 (9H, m), 4.65 (2H, s, CH2), 3.62-3.24 (4H, br), 2.02-1.99 (2H,t), 1.60 (4H, br), 1.52-1.46 (2H, m), 1.44 (2H, br), 1.20-1.08 (2H, m), 0.78-0.73 (3H, t).15% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.40-7.13 (9H, m), 4.65 (2H, s, CH 2 ), 3.62-3.24 (4H, br), 2.02-1.99 (2H, t), 1.60 (4H, br), 1.52-1.46 (2H, m), 1.44 (2H, br), 1.20-1.08 (2H, m), 0.78-0.73 (3H, t).
1-21. 1-21. NN ,, NN -- 다이에틸Diethyl -4-(3-(-4- (3- ( NN -- 페닐펜탄아미도Phenylpentaneamido )) 프로프Prof -1--One- 이닐Inil )) 벤즈아마이드Benzamide ( ( NN ,, NN -diethyl-4-(3-(-diethyl-4- (3- ( NN -phenylpentanamido)prop-1-ynyl)benzamide) (-phenylpentanamido) prop-1-ynyl) benzamide) ( LMTLMT -883)-883)
39% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.48-7.30 (9H, m), 4.73 (2H, s), 3.53-3.23 (4H, br), 2.10-2.07 (2H, t), 1.59-1.57 (2H, m), 1.23-1.10 (8H, m), 0.83-0.80 (3H, t).39% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.48-7.30 (9H, m), 4.73 (2H, s), 3.53-3.23 (4H, br), 2.10-2.07 (2H, t), 1.59-1.57 ( 2H, m), 1.23-1.10 (8H, m), 0.83-0.80 (3H, t).
1-22. 1-22. NN -페닐--Phenyl- NN -(3-(3-(피페라진-1--(3- (3- (piperazin-1- 카보닐Carbonyl )페닐)) Phenyl) 프로프Prof -2--2- 이닐Inil )) 펜탄아마이드Pentaneamide ( ( NN -phenyl--phenyl- NN -(3-(3-(piperazine-1-carbonyl)phenyl)prop-2-ynyl)pentanamide) (LMT-837)-(3- (3- (piperazine-1-carbonyl) phenyl) prop-2-ynyl) pentanamide) (LMT-837)
58% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.45-7.26 (9H, m), 4.69 (2H, s), 3.75-3.36 (4H, br), 2.94-2.80 (4H, br), 2.59 (1H, br), 2.07-2.04 (2H, t), 1.56-1.53 (2H, m), 1.22-1.18 (2H, m), 0.80-0.77 (3H, t).58% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.45-7.26 (9H, m), 4.69 (2H, s), 3.75-3.36 (4H, br), 2.94-2.80 (4H, br), 2.59 (1H, br), 2.07-2.04 (2H, t), 1.56-1.53 (2H, m), 1.22-1.18 (2H, m), 0.80-0.77 (3H, t).
1-23. 1-23. NN -(3-(3-(4-메틸피페라진-1-카보닐)페닐)프로프-2-이닐)--(3- (3- (4-methylpiperazin-1-carbonyl) phenyl) prop-2-ynyl)- NN -페닐펜탄아마이드(-Phenylpentaneamide ( NN -(3-(3-(4-methylpiperazine-1-carbonyl)phenyl)prop-2-ynyl)--(3- (3- (4-methylpiperazine-1-carbonyl) phenyl) prop-2-ynyl)- NN -phenylpentanamide) (-phenylpentanamide) ( LMTLMT -838)-838)
46% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.46-7.29 (9H, m), 4.70 (2H, s), 3.79-3.39 (4H, br), 2.48-2.32 (7H, br), 2.08-2.05 (2H, t), 1.57-1.54 (2H, m), 1.23-1.19 (2H, m), 0.81-0.78 (3H, t).46% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.46-7.29 (9H, m), 4.70 (2H, s), 3.79-3.39 (4H, br), 2.48-2.32 (7H, br), 2.08-2.05 ( 2H, t), 1.57-1.54 (2H, m), 1.23-1.19 (2H, m), 0.81-0.78 (3H, t).
1-24. 1-24. NN -(3-(3-(4--(3- (3- (4- 아이소프로필피페라진Isopropyl piperazine -1--One- 카보닐Carbonyl )페닐)) Phenyl) 프로프Prof -2--2- 이닐Inil )-)- NN -- 페닐펜탄아마이드Phenylpentaneamide ( ( NN -(3-(3-(4--(3- (3- (4- isopropylpiperazineisopropylpiperazine -1-carbonyl)phenyl)prop-2-ynyl)--1-carbonyl) phenyl) prop-2-ynyl)- NN -phenylpentanamide) (-phenylpentanamide) ( LMTLMT -842)-842)
40% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.47-7.29 (9H, m), 4.71 (2H, s), 3.79-3.40 (4H, br), 2.78-2.75 (1H, m), 2.60-2.46 (4H, br), 2.09-2.06 (2H, t), 1.58-1.55 (2H, m), 1.24-1.20 (2H, m), 1.07-1.05 (6H, d), 0.82-0.79 (3H, t).40% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.47-7.29 (9H, m), 4.71 (2H, s), 3.79-3.40 (4H, br), 2.78-2.75 (1H, m), 2.60-2.46 ( 4H, br), 2.09-2.06 (2H, t), 1.58-1.55 (2H, m), 1.24-1.20 (2H, m), 1.07-1.05 (6H, d), 0.82-0.79 (3H, t).
1-25. 1-25. terttert -부틸-4-(3-(3-(-Butyl-4- (3- (3- ( NN -(4--(4- 플루오로페닐Fluorophenyl )) 펜탄아미도Pentanamido )) 프로프Prof -1--One- 이닐Inil )) 벤조일Benzoyl )피페라진-1-카복실레이트 (Piperazine-1-carboxylate ( terttert -butyl 4-(3-(3-(-butyl 4- (3- (3- ( NN -(4-fluorophenyl)pentanamido)prop-1-ynyl)benzoyl)piperazine-1-carboxylate) (-(4-fluorophenyl) pentanamido) prop-1-ynyl) benzoyl) piperazine-1-carboxylate) ( LMTLMT -887)-887)
85% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.33-7.20 (6H, m), 7.09-7.06 (2H, m), 4.62 (2H, s), 3.66-3.31 (8H, br), 2.00-1.97 (2H, t), 1.52-1.49 (2H, m), 1.47 (9H, s), 1.18-1.13 (2H, m), 0.76-0.73 (3H, t).85% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.33-7.20 (6H, m), 7.09-7.06 (2H, m), 4.62 (2H, s), 3.66-3.31 (8H, br), 2.00-1.97 ( 2H, t), 1.52-1.49 (2H, m), 1.47 (9H, s), 1.18-1.13 (2H, m), 0.76-0.73 (3H, t).
1-26. 1-26. NN -(4--(4- 플루오로페닐Fluorophenyl )-)- NN -(3-(3-(피페라진-1--(3- (3- (piperazin-1- 카보닐Carbonyl )페닐)) Phenyl) 프로프Prof -2--2- 이닐Inil )펜탄아마이드 (Pentaneamide ( NN -(4--(4- fluorophenylfluorophenyl )-)- NN -(3-(3-(-(3- (3- ( piperazinepiperazine -1-carbonyl)phenyl)prop-2-ynyl)pentanamide) (-1-carbonyl) phenyl) prop-2-ynyl) pentanamide) ( LMTLMT -888)-888)
58% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.39-7.29 (6H, m), 7.17-7.14 (2H, m), 4.70 (2H, s), 3.77-3.39 (4H, br), 2.98-2.85 (4H, br), 2.08-2.05 (2H, t), 1.60-1.54 (2H, m), 1.25-1.19 (2H, m), 0.84-0.81 (3H, t).58% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.39-7.29 (6H, m), 7.17-7.14 (2H, m), 4.70 (2H, s), 3.77-3.39 (4H, br), 2.98-2.85 ( 4H, br), 2.08-2.05 (2H, t), 1.60-1.54 (2H, m), 1.25-1.19 (2H, m), 0.84-0.81 (3H, t).
1-27. 1-27. NN -(4--(4- 플루오로페닐Fluorophenyl )-)- NN -(3-(3-(4--(3- (3- (4- 아이소프로필피페라진Isopropyl piperazine -1--One- 카보닐Carbonyl )페닐)프로프-2-이닐)펜탄아마이드 () Phenyl) prop-2-ynyl) pentaneamide ( NN -(4--(4- fluorophenylfluorophenyl )-)- NN -(3-(3-(4-isopropylpiperazine-1-carbonyl)phenyl)prop-2-ynyl)pentanamide) (-(3- (3- (4-isopropylpiperazine-1-carbonyl) phenyl) prop-2-ynyl) pentanamide) ( LMTLMT -889)-889)
40% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.37-7.29 (6H, m), 7.16-7.13 (2H, m), 4.70 (2H, s), 3.79-3.39 (4H, br), 2.75-2.73 (1H, m), 2.59-2.45 (4H, br), 2.07-2.04 (2H, t), 1.58-1.55 (2H, m), 1.25-1.21 (2H, m), 1.06-1.05 (6H, d), 0.84-0.81 (3H, t).40% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.37-7.29 (6H, m), 7.16-7.13 (2H, m), 4.70 (2H, s), 3.79-3.39 (4H, br), 2.75-2.73 ( 1H, m), 2.59-2.45 (4H, br), 2.07-2.04 (2H, t), 1.58-1.55 (2H, m), 1.25-1.21 (2H, m), 1.06-1.05 (6H, d), 0.84-0.81 (3H, t).
1-28. 1-28. NN -(3-(4--(3- (4- 하이드록시페닐Hydroxyphenyl )) 프로프Prof -2--2- 이닐Inil )-)- NN -- 페닐펜탄아마이드Phenylpentaneamide ( ( NN -(3-(4-hydroxyphenyl)prop-2-ynyl)--(3- (4-hydroxyphenyl) prop-2-ynyl)- NN -phenylpentanamide) (-phenylpentanamide) ( LMTLMT -890)-890)
75% 수율; 1H-NMR (CDCl3, 400 MHz) δ 8.15 (1H, br), 7.47-6.83 (9H, m), 4.66 (2H, s), 2.13-2.10 (2H, t), 1.60-1.54 (2H, m), 1.22-1.17 (2H, m), 0.80-0.77 (3H, t).75% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 8.15 (1H, br), 7.47-6.83 (9H, m), 4.66 (2H, s), 2.13-2.10 (2H, t), 1.60-1.54 (2H, m), 1.22-1.17 (2H, m), 0.80-0.77 (3H, t).
1-29. 2-(4-(3-(1-29. 2- (4- (3- ( NN -- 페닐펜탄아미도Phenylpentaneamido )) 프로프Prof -1--One- 이닐Inil )) 페녹시Phenoxy )아세트산 (2-(4-(3-(Acetic acid (2- (4- (3- ( NN -phenylpentanamido)prop-1-ynyl)phenoxy)acetic acid) (-phenylpentanamido) prop-1-ynyl) phenoxy) acetic acid) ( LMTLMT -891)-891)
50% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.47-6.78 (9H, m), 4.68 (2H, s), 4.58 (2H, s), 2.11-2.08 (2H, t), 1.58-1.53 (2H, m), 1.23-1.18 (2H, m), 0.81-0.78 (3H, t).50% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.47-6.78 (9H, m), 4.68 (2H, s), 4.58 (2H, s), 2.11-2.08 (2H, t), 1.58-1.53 (2H, m), 1.23-1.18 (2H, m), 0.81-0.78 (3H, t).
1-30. 1-30. terttert -부틸 4-(5-(3-((-Butyl 4- (5- (3-(( NN -- 페닐펜탄아미도Phenylpentaneamido )) 프로프Prof -1-인-1-일)-1-yn-1-yl) 피콜리노일Picolinoyl )피페라진-1-카복실레이트 (Piperazine-1-carboxylate ( terttert -butyl 4-(5-(3-(-butyl 4- (5- (3- ( NN -- phenylpentanamidophenylpentanamido )prop-1-prop-1- ynyn -1-yl)picolinoyl)piperazine-1-carboxylate) (-1-yl) picolinoyl) piperazine-1-carboxylate) ( LMTLMT -834)-834)
35% 수율; 1H-NMR (CDCl3, 400 MHz) δ 8.43 (s, 1H), 7.64 (dd, 1H),7.54 (dd, 1H), 7.36 (dd, 3H), 7.18 (m, 2H), 4.68 (s, 2H), 3.69 (br, 2H), 3.53-3.38 (br, 6H), 2.01 (m, 2H), 1.52 (m, 2H), 1.39 (s, 9H), 1.18 (m, 2H), 0.73 (t, 3H).35% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 8.43 (s, 1H), 7.64 (dd, 1H), 7.54 (dd, 1H), 7.36 (dd, 3H), 7.18 (m, 2H), 4.68 (s , 2H), 3.69 (br, 2H), 3.53-3.38 (br, 6H), 2.01 (m, 2H), 1.52 (m, 2H), 1.39 (s, 9H), 1.18 (m, 2H), 0.73 ( t, 3H).
1-31. 1-31. NN -페닐--Phenyl- NN -(3-(6-(피페라진-1--(3- (6- (piperazin-1- 카보닐Carbonyl )피리딘-3-일)Pyridin-3-yl) 프로프Prof -2-인-1-일)-2-yn-1-yl) 펜탄아마이드Pentaneamide ( ( NN -phenyl--phenyl- NN -(3-(6-(-(3- (6- ( piperazinepiperazine -1-carbonyl)-1-carbonyl) pyridinpyridin -3--3- ylyl )prop-2-prop-2- ynyn -1-yl)pentanamide) (-1-yl) pentanamide) ( LMTLMT -835)-835)
64% 수율; 1H-NMR (CDCl3, 400MHz) δ 8.43 (s, 1H), 7.66 (dd, 1H), 7.49 (dd, 1H), 7.36 (dd, 3H), 7.21 (m, 2H), 4.67 (s, 2H), 3.70 (br, 2H), 3.48 (br, 2H), 2.90 (br, 2H), 2.81 (br, 2H), 2.01 (m, 2H), 1.49 (m, 2H), 1.17 (m, 2H), 0.73 (t, 3H).64% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 8.43 (s, 1H), 7.66 (dd, 1H), 7.49 (dd, 1H), 7.36 (dd, 3H), 7.21 (m, 2H), 4.67 (s, 2H), 3.70 (br, 2H), 3.48 (br, 2H), 2.90 (br, 2H), 2.81 (br, 2H), 2.01 (m, 2H), 1.49 (m, 2H), 1.17 (m, 2H ), 0.73 (t, 3 H).
1-32. 1-32. NN -(3-(6-(4--(3- (6- (4- 아이소프로필피페라진Isopropyl piperazine -1--One- 카보닐Carbonyl )피리딘-3-일)Pyridin-3-yl) 프로프Prof -2-인-1-일)--2-yn-1-yl)- NN -페닐펜탄아마이드 (-Phenylpentaneamide ( NN -(3-(6-(4--(3- (6- (4- isopropylpiperazineisopropylpiperazine -1-carbonyl)-1-carbonyl) pyridinpyridin -3-yl)prop-2-yn-1-yl)--3-yl) prop-2-yn-1-yl)- NN -phenylpentanamide) (-phenylpentanamide) ( LMTLMT -836)-836)
51% 수율; 1H-NMR (CDCl3, 400MHz) δ 8.44 (s, 1H), 7.65 (dd, 1H), 7.51 (dd, 1H), 7.39 (dd, 3H), 7.22 (m, 2H), 4.68 (s, 2H), 3.74 (br, 2H), 3.52 (br, 2H), 2.67 (m, 1H), 2.55 (br, 2H), 2.41 (br, 2H), 2.02 (m, 2H), 1.50 (m, 2H), 1.15 (m, 2H), 0.98 (d, 6H), 0.74 (t,3H).51% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 8.44 (s, 1H), 7.65 (dd, 1H), 7.51 (dd, 1H), 7.39 (dd, 3H), 7.22 (m, 2H), 4.68 (s, 2H), 3.74 (br, 2H), 3.52 (br, 2H), 2.67 (m, 1H), 2.55 (br, 2H), 2.41 (br, 2H), 2.02 (m, 2H), 1.50 (m, 2H ), 1.15 (m, 2H), 0.98 (d, 6H), 0.74 (t, 3H).
1-33. 1-33. N,NN, N -- 다이에틸Diethyl -4-(3-(-4- (3- ( NN -(3--(3- 플루오로페닐Fluorophenyl )) 펜탄아미도Pentanamido )) 프로프Prof -1-인-1-일)벤즈아마이드 (-1-yn-1-yl) benzamide ( N,NN, N -diethyl-4-(3-(-diethyl-4- (3- ( NN -(3--(3- fluorophenylfluorophenyl )) pentanamidopentanamido )prop-1-prop-1- ynyn -1-yl)benzamide) (-1-yl) benzamide) ( LMTLMT -926)-926)
70% 수율; 1H-NMR (CDCl3, 500 MHz) δ 7.43 (1H, t, J = 7.5 Hz and 15.0 Hz, aromatic), 7.33 (4H, m, aromatic), 7.09 (3H, m, aromatic), 4.71 (2H, s, CH2), 3.53 (2H, s, CH2), 3.23 (2H, s, CH2), 2.10 (2H, m, CH2), 1.59 (2H, m, CH2), 1.24 (2H, m, CH2), 1.10 (6H, m, (CH3)2), 0.83 (3H, t, J = 7.5 Hz and 15.0 Hz, CH3).70% yield; 1 H-NMR (CDCl 3 , 500 MHz) δ 7.43 (1H, t, J = 7.5 Hz and 15.0 Hz, aromatic), 7.33 (4H, m, aromatic), 7.09 (3H, m, aromatic), 4.71 (2H , s, CH 2 ), 3.53 (2H, s, CH 2 ), 3.23 (2H, s, CH 2 ), 2.10 (2H, m, CH 2 ), 1.59 (2H, m, CH 2 ), 1.24 (2H , m, CH 2 ), 1.10 (6H, m, (CH 3 ) 2 ), 0.83 (3H, t, J = 7.5 Hz and 15.0 Hz, CH 3 ).
1-34. 1-34. N,NN, N -다이에틸-4-(3-(-Diethyl-4- (3- ( NN -(4-플루오로페닐)펜탄아미도)프로프-1-인-1-일)벤즈아마이드(-(4-fluorophenyl) pentaneamido) prop-1-yn-1-yl) benzamide ( N,NN, N -diethyl-4-(3-(-diethyl-4- (3- ( NN -(4-fluorophenyl)pentanamido)prop-1-yn-1-yl)benzamide) (-(4-fluorophenyl) pentanamido) prop-1-yn-1-yl) benzamide) ( LMTLMT -927)-927)
70% 수율; 1H-NMR (CDCl3, 500 MHz) δ 7.31 (2H, d, J = 3.5 Hz, aromatic), 7.29 (4H, d, J = 3.0 Hz, aromatic), 7.15 (2H, t, J = 8.5 Hz and 17.0 Hz, aromatic), 4.71 (2H, s, CH2), 3.53 (2H, s, CH2), 3.23 (2H, s, CH2), 2.06 (2H, t, J = 7.5 Hz and 15.0 Hz, CH2), 1.57 (2H, m, CH2), 1.22 (2H, m, CH2), 1.10 (6H, s, (CH3)2), 0.82 (3H, t, J = 7.5 Hz and 15.0 Hz, CH3).70% yield; 1 H-NMR (CDCl 3 , 500 MHz) δ 7.31 (2H, d, J = 3.5 Hz, aromatic), 7.29 (4H, d, J = 3.0 Hz, aromatic), 7.15 (2H, t, J = 8.5 Hz and 17.0 Hz, aromatic), 4.71 (2H, s, CH 2 ), 3.53 (2H, s, CH 2 ), 3.23 (2H, s, CH 2 ), 2.06 (2H, t, J = 7.5 Hz and 15.0 Hz , CH 2 ), 1.57 (2H, m, CH 2 ), 1.22 (2H, m, CH 2 ), 1.10 (6H, s, (CH 3 ) 2 ), 0.82 (3H, t, J = 7.5 Hz and 15.0 Hz, CH 3 ).
1-35. 1-35. NN -(3-(4-(-(3- (4- ( N,NN, N -- 다이에틸설파모일Diethylsulfamoyl )페닐)) Phenyl) 프로프Prof -2--2- 이닐Inil )-)- NN -- 페닐펜탄아마이드Phenylpentaneamide ( ( NN -(3-(4-(-(3- (4- ( N,NN, N -- diethylsulfamoyldiethylsulfamoyl )phenyl)prop-2-) phenyl) prop-2- ynylynyl )-)- NN -- phenylpentanamidephenylpentanamide ) (LMT-946)(LMT-946)
70% 수율; 1H-NMR (CDCl3, 500 MHz) δ 7.74 (2H, d, J = 8.0 Hz), 7.51 (4H, m), 7.43 (3H, m), 4.73 (2H, s), 3.21 (4H, s), 2.11 (2H, t), 1.52 (2H, m), 1.21 (2H, m), 0.10 (6H, t), 0.80 (3H, t).70% yield; 1 H-NMR (CDCl 3 , 500 MHz) δ 7.74 (2H, d, J = 8.0 Hz), 7.51 (4H, m), 7.43 (3H, m), 4.73 (2H, s), 3.21 (4H, s ), 2.11 (2H, t), 1.52 (2H, m), 1.21 (2H, m), 0.10 (6H, t), 0.80 (3H, t).
1-36. 1-36. NN -(3-(4-(-(3- (4- ( NN -- 아이소프로필설파모일Isopropyl sulfamoyl )페닐)) Phenyl) 프로프Prof -2--2- 이닐Inil )-)- NN -- 페닐펜탄아마이드Phenylpentaneamide ( ( NN -(3-(4-(-(3- (4- ( NN -- isopropylsulfamoylisopropylsulfamoyl )phenyl)prop-2-) phenyl) prop-2- ynylynyl )-)- NN -phenylpentanamide) (-phenylpentanamide) ( LMTLMT -947)-947)
49.5 % 수율; 1H-NMR (CDCl3, 500 MHz) δ 7.78 (2H, d, J = 8.5 Hz), 7.51-7.37 (7H, m), 4.72 (2H, s), 3.33 (1H, m), 2.10 (2H, t), 1.51 (2H, m), 1.19 (2H, m), 0.99 (6H, d, J = 6.5 Hz), 0.78 (3H, t)49.5% yield; 1 H-NMR (CDCl 3 , 500 MHz) δ 7.78 (2H, d, J = 8.5 Hz), 7.51-7.37 (7H, m), 4.72 (2H, s), 3.33 (1H, m), 2.10 (2H , t), 1.51 (2H, m), 1.19 (2H, m), 0.99 (6H, d, J = 6.5 Hz), 0.78 (3H, t)
1-37. 1-37. terttert -부틸 4--Butyl 4- (3-((3- ( NN -페닐펜탄아미도)프로프Phenylpentane amido) prop -1-인-1-일)-1-yn-1-yl) 벤조에이트Benzoate (( terttert -butyl 4-(3-(-butyl 4- (3- ( NN -- phenylpentanamidophenylpentanamido )prop-1-prop-1- ynyn -1--One- ylyl )benzoate) () benzoate) ( LMTLMT -1012)-1012)
78.3% 수율; 1H-NMR (CDCl3, 500 MHz) δ 7.88 (2H, d, J = 8.0 Hz, aromatic), 7.45 (2H, m, aromatic), 7.39 (1H, d, J = 7.0 Hz, aromatic), 7.35 (2H, d, J = 8.0 Hz, aromatic), 7.30 (2H, d, J = 5.0 Hz, aromatic), 4.72 (2H, s, CH2), 2.07 (2H, t, J = 7.5 Hz and 15 Hz, CH2), 1.56 (2H, m, CH2), 1.51 (9H, s, (CH3)3), 1.22 (2H, m, CH2), 0.80 (3H, t, 7.5 Hz and 15 Hz7.5 Hz and 15 Hz, CH3).78.3% yield; 1 H-NMR (CDCl 3 , 500 MHz) δ 7.88 (2H, d, J = 8.0 Hz, aromatic), 7.45 (2H, m, aromatic), 7.39 (1H, d, J = 7.0 Hz, aromatic), 7.35 (2H, d, J = 8.0 Hz, aromatic), 7.30 (2H, d, J = 5.0 Hz, aromatic), 4.72 (2H, s, CH 2 ), 2.07 (2H, t, J = 7.5 Hz and 15 Hz , CH 2 ), 1.56 (2H, m, CH 2 ), 1.51 (9H, s, (CH 3 ) 3 ), 1.22 (2H, m, CH 2 ), 0.80 (3H, t, 7.5 Hz and 15 Hz 7. 5 Hz and 15 Hz, CH 3 ).
1-38. 4-1-38. 4- (3-((3- ( NN -페닐펜탄아미도)프로-1-핀-1-일)벤조익산-Phenylpentaneamido) prop-1-pin-1-yl) benzoic acid (4-(3-((4- (3- ( NN -phenylpentanamido)prop-1-yn-1-yl)benzoic acid) (-phenylpentanamido) prop-1-yn-1-yl) benzoic acid) ( LMTLMT -1013)-1013)
95% 수율; 1H-NMR (MeOD, 500 MHz): δ 7.95 (2H, d, J = 8.5 Hz, aromatic), 7.51 (2H, m, aromatic), 7.45 (1H, m, aromatic), 7.44 (2H, d, J = 8.5 Hz, aromatic), 7.39 (2H, d, J = 8.0 Hz, aromatic), 4.73 (2H, s, CH2), 2.11 (2H, t, CH3), 1.21 (2H, m, CH2), 0.83 (3H, t, CH3).95% yield; 1 H-NMR (MeOD, 500 MHz): δ 7.95 (2H, d, J = 8.5 Hz, aromatic), 7.51 (2H, m, aromatic), 7.45 (1H, m, aromatic), 7.44 (2H, d, J = 8.5 Hz, aromatic), 7.39 (2H, d, J = 8.0 Hz, aromatic), 4.73 (2H, s, CH 2 ), 2.11 (2H, t, CH 3 ), 1.21 (2H, m, CH 2 ), 0.83 (3H, t, CH 3 ).
1-39. 1-39. NN -에틸-4-(3-(-Ethyl-4- (3- ( NN -- 페닐펜탄아미도Phenylpentaneamido )) 프로프Prof -1-인-1-일)-1-yn-1-yl) 벤즈아마이드Benzamide ( ( NN -ethyl-4-(3-(-ethyl-4- (3- ( NN -phenylpentanamido)prop-1-yn-1-yl)benzamide) (-phenylpentanamido) prop-1-yn-1-yl) benzamide) ( LMTLMT -1017)-1017)
66% 수율; 1H-NMR (CDCl3, 500 MHz) δ 7.69 (2H, d, J = 8.5 Hz, aromatic), 7.39 (7H, m, aromatic), 4.72 (2H, s, CH2), 3.49 (2H, t, J = 6.0 Hz and 13.0 Hz, CH2), 2.08 (2H, t, J = 7.5 Hz and 15.0 Hz, CH2), 1.57 (2H, m, CH2), 1.23 (2H, m, CH2), 0.81 (3H, t, J = 7.5 Hz and 14.5 Hz, CH3).66% yield; 1 H-NMR (CDCl 3 , 500 MHz) δ 7.69 (2H, d, J = 8.5 Hz, aromatic), 7.39 (7H, m, aromatic), 4.72 (2H, s, CH 2 ), 3.49 (2H, t , J = 6.0 Hz and 13.0 Hz, CH 2 ), 2.08 (2H, t, J = 7.5 Hz and 15.0 Hz, CH 2 ), 1.57 (2H, m, CH 2 ), 1.23 (2H, m, CH 2 ) , 0.81 (3H, t, J = 7.5 Hz and 14.5 Hz, CH 3 ).
1-40. 1-40. NN -(2-(-(2-( 다이메틸아미노Dimethylamino )에틸)-4-(3-() Ethyl) -4- (3- ( NN -- 페닐펜탄아미도Phenylpentaneamido )) 프로프Prof -1-인-1-일)벤즈아마이드 (-1-yn-1-yl) benzamide ( NN -(2-(-(2-( dimethylaminodimethylamino )ethyl)-4-(3-() ethyl) -4- (3- ( NN -- phenylpentanamidophenylpentanamido )prop-1-yn-1-yl)benzamide) () prop-1-yn-1-yl) benzamide) ( LMTLMT -1016)-1016)
74% 수율; 1H-NMR (CDCl3, 500 MHz) δ 7.71 (2H, d, J = 8.0 Hz, aromatic), 7.38 (7H, m, aromatic), 4.70 (2H, s, CH2), 3.48 (2H, m, CH2), 2.50 (2H, t, J = 6.0 Hz and 11.5 Hz, CH2), 2.24 (6H, s, (CH3)2), 2.05 (2H, t, J = 7.5 Hz and 15.0 Hz, CH2), 1.54 (2H, m, CH2), 1.20 (2H, m, CH2), 0.78 (3H, t, J = 7.0 Hz and 14.0 Hz, CH3).74% yield; 1 H-NMR (CDCl 3 , 500 MHz) δ 7.71 (2H, d, J = 8.0 Hz, aromatic), 7.38 (7H, m, aromatic), 4.70 (2H, s, CH 2 ), 3.48 (2H, m , CH 2 ), 2.50 (2H, t, J = 6.0 Hz and 11.5 Hz, CH 2 ), 2.24 (6H, s, (CH 3 ) 2 ), 2.05 (2H, t, J = 7.5 Hz and 15.0 Hz, CH 2 ), 1.54 (2H, m, CH 2 ), 1.20 (2H, m, CH 2 ), 0.78 (3H, t, J = 7.0 Hz and 14.0 Hz, CH 3 ).
1-41. 에틸 2-(4-(3-(1-41. Ethyl 2- (4- (3- ( NN -- 페닐펜탄아미도Phenylpentaneamido )) 프로프Prof -1-인-1-일)-1-yn-1-yl) 벤즈아미도Benzamido )아세테이트(ethyl 2-(4-(3-(Acetate (ethyl 2- (4- (3- ( NN -- phenylpentanamidophenylpentanamido )prop-1-prop-1- ynyn -1--One- ylyl )) benzamidobenzamido )acetate) (LMT-1014)) acetate) (LMT-1014)
54% 수율; 1H-NMR (CDCl3, 500 MHz) δ 7.74 (2H, d, J = 8.0 Hz, aromatic), 7.37 (7H, m, aromatic), 4.22 (4H, m, (CH2)2), 2.07 (2H, t, J = 7.5 Hz and 15.0 Hz, CH2), 1.56 (2H, m, CH2), 1.30 (5H, m, CH3, CH2), 1.22 (2H, m, CH2), 0.80 (3H, t, J = 7.5 Hz and 14.5 Hz, CH3).54% yield; 1 H-NMR (CDCl 3 , 500 MHz) δ 7.74 (2H, d, J = 8.0 Hz, aromatic), 7.37 (7H, m, aromatic), 4.22 (4H, m, (CH 2 ) 2 ), 2.07 ( 2H, t, J = 7.5 Hz and 15.0 Hz, CH 2 ), 1.56 (2H, m, CH 2 ), 1.30 (5H, m, CH 3 , CH 2 ), 1.22 (2H, m, CH 2 ), 0.80 (3H, t, J = 7.5 Hz and 14.5 Hz, CH 3 ).
1-42. 2-(4-(3-(1-42. 2- (4- (3- ( NN -- 페닐펜탄아미도Phenylpentaneamido )) 프로프Prof -1-인-1-일)-1-yn-1-yl) 벤즈아미도Benzamido )) 아세틱산Acetic acid (2-(4-(3-( (2- (4- (3- ( NN -phenylpentanamido)prop-1-yn-1-yl)benzamido)acetic acid) (-phenylpentanamido) prop-1-yn-1-yl) benzamido) acetic acid) ( LMTLMT -1015)-1015)
53% 수율; 1H-NMR (CDCl3 , 500 MHz) δ 7.71 (2H, d, J = 8.5 Hz, aromatic), 7.40 (7H, m, aromatic), 4.71 (2H, s, CH2), 4.23 (2H, d, J = 5.0 Hz, CH2), 2.10 (2H, t, J = 7.5 Hz and 15.5 Hz, CH2), 1.56 (2H, m, CH2), 1.22 (2H, m, CH2), 0.80 (3H, t, J = 7.0 Hz and 14.5 Hz, CH3).53% yield; 1 H-NMR (CDCl 3 , 500 MHz) δ 7.71 (2H, d, J = 8.5 Hz, aromatic), 7.40 (7H, m, aromatic), 4.71 (2H, s, CH 2 ), 4.23 (2H, d , J = 5.0 Hz, CH 2 ), 2.10 (2H, t, J = 7.5 Hz and 15.5 Hz, CH 2 ), 1.56 (2H, m, CH 2 ), 1.22 (2H, m, CH 2 ), 0.80 ( 3H, t, J = 7.0 Hz and 14.5 Hz, CH 3 ).
1-43. 1-43. 메틸methyl 2-(4-(3-( 2- (4- (3- ( NN -- 페닐펜탄아미도Phenylpentaneamido )) 프로프Prof -1-인-1-일)-1-yn-1-yl) 벤즈아미도Benzamido )) 프로파노에이트Propanoate (methyl 2-(4-(3-( (methyl 2- (4- (3- ( NN -- phenylpentanamidophenylpentanamido )prop-1-prop-1- ynyn -1-yl)benzamido)propanoate) (-1-yl) benzamido) propanoate) ( LMTLMT -1018)-1018)
42% 수율; 1H-NMR (CDCl3 , 500 MHz) δ 7.72 (2H, d, J = 8.5 Hz, aromatic), 7.37 (7H, m, aromatic), 4.76 (1H, t, J = 7.5 Hz and 14.5 Hz CH), 4.71 (2H, s, CH2), 3.76 (3H, s, CH3), 2.06 (2H, t, J = 7.5 Hz and 15.5 Hz, CH2), 1.53 (2H, m, CH2), 1.50 (3H, d, J = 7.5 Hz, CH3), 1.20 (2H, m, CH2), 0.79 (3H, t, J = 7.5 Hz and 15.0 Hz, CH3).42% yield; 1 H-NMR (CDCl 3 , 500 MHz) δ 7.72 (2H, d, J = 8.5 Hz, aromatic), 7.37 (7H, m, aromatic), 4.76 (1H, t, J = 7.5 Hz and 14.5 Hz CH) , 4.71 (2H, s, CH 2 ), 3.76 (3H, s, CH 3 ), 2.06 (2H, t, J = 7.5 Hz and 15.5 Hz, CH 2 ), 1.53 (2H, m, CH 2 ), 1.50 (3H, d, J = 7.5 Hz, CH 3 ), 1.20 (2H, m, CH 2 ), 0.79 (3H, t, J = 7.5 Hz and 15.0 Hz, CH 3 ).
1-44. 2-1-44. 2- (4-(3-((4- (3- ( NN -페닐펜탄아미도)프로프Phenylpentane amido) prop -1-인-1-일)-1-yn-1-yl) 벤즈아미도Benzamido )) 프로피오닉산Propionic acid (2-(4-(3-((2- (4- (3- ( NN -phenylpentanamido)prop-1-yn-1-yl)benzamido)propanoic acid) (LMT-1019)-phenylpentanamido) prop-1-yn-1-yl) benzamido) propanoic acid) (LMT-1019)
55% 수율; 1H-NMR (CDCl3, 500 MHz) δ 7.71 (2H, d, J = 8.0 Hz, aromatic), 7.40 (7H, m, aromatic), 4.76 (1H, t, J = 7.5 Hz and 14.5 Hz, CH), 4.72 (2H, s, CH2), 2.10 (2H, t, J = 7.5 Hz and 15.5 Hz, CH2), 1.57 (5H, m, CH3, CH2), 1.22 (2H, m, CH2), 0.80 (3H, t, J = 7.5 Hz and 15.0 Hz, CH3).55% yield; 1 H-NMR (CDCl 3 , 500 MHz) δ 7.71 (2H, d, J = 8.0 Hz, aromatic), 7.40 (7H, m, aromatic), 4.76 (1H, t, J = 7.5 Hz and 14.5 Hz, CH ), 4.72 (2H, s, CH 2 ), 2.10 (2H, t, J = 7.5 Hz and 15.5 Hz, CH 2 ), 1.57 (5H, m, CH 3 , CH 2 ), 1.22 (2H, m, CH 2 ), 0.80 (3H, t, J = 7.5 Hz and 15.0 Hz, CH 3 ).
1-45. 2-(4-(3-(1-45. 2- (4- (3- ( NN -(3--(3- 플루오로페닐Fluorophenyl )) 펜탄아미도Pentanamido )) 프로프Prof -1--One- 이닐Inil )) 페녹시Phenoxy )아세트산(2-(4-(3-(Acetic acid (2- (4- (3- ( NN -(3-fluorophenyl)pentanamido)prop-1-ynyl)phenoxy)acetic acid) (LMT-1009)-(3-fluorophenyl) pentanamido) prop-1-ynyl) phenoxy) acetic acid) (LMT-1009)
16% 수율; 1H-NMR (CDCl3, 500 MHz) δ 7.52 (1H, d, J = 7.0 Hz), 7.24 (5H, m), 6.88 (2H, d, J = 8.5 Hz), 4.68 (2H, s), 4.66 (2H, s), 2.14 (2H, t), 1.55 (2H, m), 1.24 (2H, m), 0.83 (3H, t).16% yield; 1 H-NMR (CDCl 3 , 500 MHz) δ 7.52 (1H, d, J = 7.0 Hz), 7.24 (5H, m), 6.88 (2H, d, J = 8.5 Hz), 4.68 (2H, s), 4.66 (2H, s), 2.14 (2H, t), 1.55 (2H, m), 1.24 (2H, m), 0.83 (3H, t).
1-46. 2-(4-(3-(1-46. 2- (4- (3- ( NN -(4--(4- 플루오로페닐Fluorophenyl )) 펜탄아미도Pentanamido )) 프로프Prof -1--One- 이닐Inil )) 페녹시Phenoxy )아세트산(2-(4-(3-(Acetic acid (2- (4- (3- ( NN -(4-fluorophenyl)pentanamido)prop-1-ynyl)phenoxy)acetic acid) (LMT-1010)-(4-fluorophenyl) pentanamido) prop-1-ynyl) phenoxy) acetic acid) (LMT-1010)
27 % 수율; 1H-NMR (CDCl3, 500 MHz) δ 7.41 (2H, m), 7.26 (4H, m), 6.88 (2H, d, J = 7.0 Hz), 4.66 (2H, s), 4.60 (2H, s), 2.10 (2H, t), 1.52 (2H, m), 1.23 (2H, m), 0.82 (3H, t).27% yield; 1 H-NMR (CDCl 3 , 500 MHz) δ 7.41 (2H, m), 7.26 (4H, m), 6.88 (2H, d, J = 7.0 Hz), 4.66 (2H, s), 4.60 (2H, s ), 2.10 (2H, t), 1.52 (2H, m), 1.23 (2H, m), 0.82 (3H, t).
1-47. 1-47. NN -((3'-(4--((3 '-(4- 메틸페닐설폰아미도Methylphenylsulfonamido )) 바이페닐Biphenyl -4-일)-4- days) 메틸methyl )-)- NN -- 페닐펜탄아마이드Phenylpentaneamide ( ( NN -((3'-(4--((3 '-(4- methylphenylsulfonamidomethylphenylsulfonamido )biphenyl-4-) biphenyl-4- ylyl )methyl)-) methyl)- NN -phenylpentanamide) (AC-1079)-phenylpentanamide) (AC-1079)
25% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.67 (2H, d, J = 8.0 Hz), 7.39-7.31 (7H, m), 7.23 (3H, d, J = 8.4 Hz), 7.01 (3H, d, J = 8.4 Hz), 6.54 (1H, s), 4.90 (2H, s), 2.38 (3H, s), 2.09 (2H, t), 1.61-1.56 (2H, m), 1.26-1.20 (2H, m), 0.82 (3H, t).25% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.67 (2H, d, J = 8.0 Hz), 7.39-7.31 (7H, m), 7.23 (3H, d, J = 8.4 Hz), 7.01 (3H, d , J = 8.4 Hz), 6.54 (1H, s), 4.90 (2H, s), 2.38 (3H, s), 2.09 (2H, t), 1.61-1.56 (2H, m), 1.26-1.20 (2H, m), 0.82 (3H, t).
1-48. 1-48. NN -(4'-((-(4'-(( NN -- 페닐펜탄아미도Phenylpentaneamido )) 메틸methyl )) 바이페닐Biphenyl -3-일)-4-(-3- days) -4- ( 트리플루오로메틸Trifluoromethyl )벤즈아마이드 (Benzamide ( NN -(4'-((-(4'-(( NN -- phenylpentanamidophenylpentanamido )methyl)biphenyl-3-) methyl) biphenyl-3- ylyl )-4-(trifluoromethyl)benzamide) (AC-1310)) -4- (trifluoromethyl) benzamide) (AC-1310)
25% 수율; 1H-NMR (CDCl3, 400 MHz) δ 8.45 (1H, s), 8.03 (2H, d, J = 8.0 Hz), 7.89 (1H, s), 7.73 (2H, d, J = 8.4 Hz), 7.67 (1H, d, J = 7.6 Hz), 7.49 (2H, d, J = 8.0 Hz), 7.44-7.38 (2H, m), 7.36-7.31 (3H, m), 7.238 (2H, d, J = 8.4 Hz), 7.00-6.98 (2H, m), 4.89 (2H, s), 2.06 (2H, t), 1.58-1.54 (2H, m), 1.23-1.169 (2H, m), 0.78 (3H, t).25% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 8.45 (1H, s), 8.03 (2H, d, J = 8.0 Hz), 7.89 (1H, s), 7.73 (2H, d, J = 8.4 Hz), 7.67 (1H, d, J = 7.6 Hz), 7.49 (2H, d, J = 8.0 Hz), 7.44-7.38 (2H, m), 7.36-7.31 (3H, m), 7.238 (2H, d, J = 8.4 Hz), 7.00-6.98 (2H, m), 4.89 (2H, s), 2.06 (2H, t), 1.58-1.54 (2H, m), 1.23-1.169 (2H, m), 0.78 (3H, t ).
1-49. 1-49. NN -(3--(3- 플루오로페닐Fluorophenyl )-)- NN -((3'-(4--((3 '-(4- 메틸페닐설폰아미도Methylphenylsulfonamido )) 바이페닐Biphenyl -4-일)-4- days) 메틸methyl )펜탄아마이드 (Pentaneamide ( NN -(3--(3- fluorophenylfluorophenyl )-)- NN -((3'-(4-methylphenylsulfonamido)biphenyl-4-yl)methyl)pentanamide) (AC-1080)-((3 '-(4-methylphenylsulfonamido) biphenyl-4-yl) methyl) pentanamide) (AC-1080)
25% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.67 (2H, d, J = 8.0 Hz), 7.39-7.31 (7H, m), 7.23 (3H, d, J = 8.4 Hz), 7.01 (3H, d, J = 8.4 Hz), 6.54 (1H, s), 4.90 (2H, s), 2.38 (3H, s), 2.09 (2H, t), 1.61-1.56 (2H, m), 1.26-1.20 (2H, m), 0.82 (3H, t).25% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.67 (2H, d, J = 8.0 Hz), 7.39-7.31 (7H, m), 7.23 (3H, d, J = 8.4 Hz), 7.01 (3H, d , J = 8.4 Hz), 6.54 (1H, s), 4.90 (2H, s), 2.38 (3H, s), 2.09 (2H, t), 1.61-1.56 (2H, m), 1.26-1.20 (2H, m), 0.82 (3H, t).
1-50. 1-50. NN -(4'-((-(4'-(( NN -3--3- 플루오로페닐Fluorophenyl )) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -3-일)-4-(-3- days) -4- ( 트리플루오로메틸Trifluoromethyl )벤즈아마이드 (Benzamide ( NN -(4'-((-(4'-(( NN -(3-fluorophenyl)pentanamido)methyl)biphenyl-3-yl)-4-(trifluoromethyl)benzamide) (AC-1311)-(3-fluorophenyl) pentanamido) methyl) biphenyl-3-yl) -4- (trifluoromethyl) benzamide) (AC-1311)
25% 수율; 1H-NMR (CDCl3, 400 MHz) δ 8.20 (1H, br, s), 8.03 (2H, d, J = 8.4 Hz), 7.89 (1H, m), 7.76 (2H. d. J = 8.0 Hz), 7.65 (1H, d, J = 8.0 Hz), 7.51 (2H, d, J = 8.0 Hz), 7.46-738 (2H, m), 7.34-7.28 (1H, m), 7.25 (2H, d, J = 8.4 Hz), 7.06-7.02 (1H, m), 6.81-6.74 (2H, m), 4.90 (2H, s), 2.08 (2H. t), 1.64-1.55 (2H, m), 1.33-1.19 (2H, m), 0.84 (3H,t).25% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 8.20 (1H, br, s), 8.03 (2H, d, J = 8.4 Hz), 7.89 (1H, m), 7.76 (2H.d. J = 8.0 Hz ), 7.65 (1H, d, J = 8.0 Hz), 7.51 (2H, d, J = 8.0 Hz), 7.46-738 (2H, m), 7.34-7.28 (1H, m), 7.25 (2H, d, J = 8.4 Hz), 7.06-7.02 (1H, m), 6.81-6.74 (2H, m), 4.90 (2H, s), 2.08 (2H.t), 1.64-1.55 (2H, m), 1.33-1.19 (2H, m), 0.84 (3H, t).
1-51. 1-(3-1-51. 1- (3- 플루오로페닐Fluorophenyl )-1-((4'-) -1-((4'- 메톡시바이페닐Methoxybiphenyl -4-일)-4- days) 메틸methyl )-3-(3-() -3- (3- ( 트리플루오로메틸Trifluoromethyl )페닐)유레아 (1-(3-) Phenyl) urea (1- (3- fluorophenylfluorophenyl )-1-((4'-) -1-((4'- methoxybiphenylmethoxybiphenyl -4-yl)methyl)-3-(3-(trifluoromethyl)phenyl)urea) (AC-1317)-4-yl) methyl) -3- (3- (trifluoromethyl) phenyl) urea) (AC-1317)
23.4% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.61 (1H, s), 7.53-7.48 (5H, m), 7.45-7.35 (2H, m), 7.32-7.29 (3H, m), 7.14-7.09 (1H, m), 7.02 (1H, d, J = 8.4 Hz), 6.96 (3H, d, J = 8.8 Hz), 6.32 (1H, s, br), 4.96 (2H, s), 3.85 (3H, s).23.4% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.61 (1H, s), 7.53-7.48 (5H, m), 7.45-7.35 (2H, m), 7.32-7.29 (3H, m), 7.14-7.09 ( 1H, m), 7.02 (1H, d, J = 8.4 Hz), 6.96 (3H, d, J = 8.8 Hz), 6.32 (1H, s, br), 4.96 (2H, s), 3.85 (3H, s ).
1-52. 1-52. NN -(3--(3- 플루오로페닐Fluorophenyl )-)- NN -((4'--((4'- 메톡시바이페닐Methoxybiphenyl -4-일)-4- days) 메틸methyl )-1-(4-) -1- (4- 메톡시페닐설폰일Methoxyphenylsulfonyl )메탄아마이드 (Methaneamide ( NN -(3--(3- fluorophenylfluorophenyl )-)- NN -((4'--((4'- methoxybiphenylmethoxybiphenyl -4-yl)methyl)-1-(4-methoxyphenylsulfonyl)methanamide) (AC-1312)-4-yl) methyl) -1- (4-methoxyphenylsulfonyl) methanamide) (AC-1312)
61% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.62-7.59 (2H, m), 7.48-7.45 (2H, m), 7.43 (2H, d, J = 8.0 Hz), 7.26 (2H, d, J = 0.8 Hz), 7.21-7.15 (1H, m), 6.99-6.89 (5H, m), 6.85-6.83 (1H, m), 6.79-6.76 (1H, m), 4.72 (2H, s), 3.91 (3H, s), 3.83 (3H, s).61% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.62-7.59 (2H, m), 7.48-7.45 (2H, m), 7.43 (2H, d, J = 8.0 Hz), 7.26 (2H, d, J = 0.8 Hz), 7.21-7.15 (1H, m), 6.99-6.89 (5H, m), 6.85-6.83 (1H, m), 6.79-6.76 (1H, m), 4.72 (2H, s), 3.91 (3H , s), 3.83 (3H, s).
1-53. 1-(3-1-53. 1- (3- 플루오로페닐Fluorophenyl )-1-((4'-) -1-((4'- 하이드록시바이페닐Hydroxybiphenyl -4-일)-4- days) 메틸methyl )-3-(3-() -3- (3- ( 트리플루오로메틸Trifluoromethyl )페닐)유레아 (1-(3-) Phenyl) urea (1- (3- fluorophenylfluorophenyl )-1-((4'-) -1-((4'- hydroxybiphenylhydroxybiphenyl -4-yl)methyl)-3-(3-(trifluoromethyl)phenyl)urea) (AC-1318)-4-yl) methyl) -3- (3- (trifluoromethyl) phenyl) urea) (AC-1318)
55% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.60 (1H, s), 7.53 (1H, d, J = 7.4 Hz), 7.48-7.45 (4H, m), 7.43-7.35 (2H, m), 7.31 (3H, d, J = 8.0 Hz), 7.14-7.09 (1H, m), 7.02 (1H, d, J = 8.0 Hz), 6.98-6.95 (1H, m), 6.91-6.88 (2H, m), 6.33 (1H, s), 4.96 (2H, s), 4.85 (1H, s).55% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.60 (1H, s), 7.53 (1H, d, J = 7.4 Hz), 7.48-7.45 (4H, m), 7.43-7.35 (2H, m), 7.31 (3H, d, J = 8.0 Hz), 7.14-7.09 (1H, m), 7.02 (1H, d, J = 8.0 Hz), 6.98-6.95 (1H, m), 6.91-6.88 (2H, m), 6.33 (1 H, s), 4.96 (2 H, s), 4.85 (1 H, s).
1-54. 2-(4'-((1-(3-1-54. 2- (4 '-((1- (3- 플루오로페닐Fluorophenyl )-3-(3-() -3- (3- ( 트리플루오로메틸Trifluoromethyl )페닐)) Phenyl) 유레이도Eureido )메틸)바이페닐-4-일옥시)아세트산 (2-(4'-((1-(3-) Methyl) biphenyl-4-yloxy) acetic acid (2- (4 '-((1- (3- fluorophenylfluorophenyl )-3-(3-(trifluoromethyl)phenyl)ureido)methyl)biphenyl-4-yloxy)acetic acid) (AC-1320)) -3- (3- (trifluoromethyl) phenyl) ureido) methyl) biphenyl-4-yloxy) acetic acid) (AC-1320)
96% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.61 (1H, s), 7.52-7.47 (5H, m), 7.45-7.35 (2H, m), 7.32-7.26 (3H, m), 7.09-7.15 (1H, m), 7.02-7.00 (1H, d, J = 8.4 Hz), 6.98-6.96 (3H, d, J = 8.4 Hz), 6.32 (1H, s), 4.96 (2H, s), 4.66 (2H, s), 4.31-4.26 (2H, q), 1.26 (3H, t).96% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.61 (1H, s), 7.52-7.47 (5H, m), 7.45-7.35 (2H, m), 7.32-7.26 (3H, m), 7.09-7.15 ( 1H, m), 7.02-7.00 (1H, d, J = 8.4 Hz), 6.98-6.96 (3H, d, J = 8.4 Hz), 6.32 (1H, s), 4.96 (2H, s), 4.66 (2H , s), 4.31-4.26 (2H, q), 1.26 (3H, t).
1-55. 4-(4'-((1-55. 4- (4 '-(( NN -(3--(3- 플루오로페닐Fluorophenyl )) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -4--4- 일옥시Iloxy )부탄산 (4-(4'-((Butanoic acid (4- (4 '-(( NN -(3--(3- fluorophenylfluorophenyl )) pentanamidopentanamido )methyl)biphenyl-4-) methyl) biphenyl-4- yloxyyloxy )) butanoicbutanoic acid) (AC-1322) acid) (AC-1322)
100% 수율; 1H-NMR (DMSO-d6, 400 MHz) δ 12.2 (1H, br, s), 7.58-7.53 (4H, m), 7.43-7.41 (1H, m), 7.23 (2H, d, J = 8.0 Hz), 7.20-7.17 (2H, m), 7.05 (1H, d, J = 8.4 Hz), 7.00 (2H, d, J = 8.8 Hz), 4.91 (2H, s), 4.02 (2H, t), 2.51 (2H, t), 2.40 (2H, t), 1.98-1.94 (2H, m), 1.52-1.48(2H, m), 1.24-1.18 (2H, m), 0.79 (3H, t).100% yield; 1 H-NMR (DMSO-d 6 , 400 MHz) δ 12.2 (1H, br, s), 7.58-7.53 (4H, m), 7.43-7.41 (1H, m), 7.23 (2H, d, J = 8.0 Hz), 7.20-7.17 (2H, m), 7.05 (1H, d, J = 8.4 Hz), 7.00 (2H, d, J = 8.8 Hz), 4.91 (2H, s), 4.02 (2H, t), 2.51 (2H, t), 2.40 (2H, t), 1.98-1.94 (2H, m), 1.52-1.48 (2H, m), 1.24-1.18 (2H, m), 0.79 (3H, t).
1-56. 2-(4'-((1-56. 2- (4 '-(( NN -(3--(3- 플루오로페닐Fluorophenyl )) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -4--4- 일옥시Iloxy )-2-)-2- 메틸프로판산Methylpropanoic acid (2-(4'-(( (2- (4 '-(( NN -(3--(3- fluorophenylfluorophenyl )) pentanamidopentanamido )methyl)biphenyl-4-) methyl) biphenyl-4- yloxyyloxy )-2-methylpropanoic acid) (AC-1321)) -2-methylpropanoic acid) (AC-1321)
100% 수율; 1H-NMR (DMSO-d6, 400 MHz) δ 7.54-7.51 (4H, m), 7.40-7.39 (1H, m), 7.21 (2H, d, J = 8.0 Hz), 7.16 (2H, d, J = 10.0 Hz), 7.02 (1H, d, J = 7.6 Hz), 6.87 (2H, d, J = 9.2 Hz), 4.88 (2H, s), 2.49 (2H, t), 1.52 (6H, s), 1.49-1.45 (2H, m), 1.22-1.15 (2H, m), 0.77 (3H, t).100% yield; 1 H-NMR (DMSO-d 6 , 400 MHz) δ 7.54-7.51 (4H, m), 7.40-7.39 (1H, m), 7.21 (2H, d, J = 8.0 Hz), 7.16 (2H, d, J = 10.0 Hz), 7.02 (1H, d, J = 7.6 Hz), 6.87 (2H, d, J = 9.2 Hz), 4.88 (2H, s), 2.49 (2H, t), 1.52 (6H, s) , 1.49-1.45 (2H, m), 1.22-1.15 (2H, m), 0.77 (3H, t).
1-57. (1-57. ( EE )-3-(4'-(() -3- (4 '-(( NN -(3--(3- 플루오로페닐Fluorophenyl )) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -4--4- 일옥시Iloxy )아크릴산 ((Acrylic Acid (( EE )-3-(4'-(() -3- (4 '-(( NN -(3--(3- fluorophenylfluorophenyl )) pentanamidopentanamido )methyl)biphenyl-4-yloxy)acrylic acid) (AC-1323)) methyl) biphenyl-4-yloxy) acrylic acid) (AC-1323)
29% 수율; 1H-NMR (DMSO-d6, 400 MHz) δ 12.1 (1H, s, br), 7.80 (1H, d, J = 12.0 Hz), 7.68 (2H, d, J = 8.4 Hz), 7.58 (2H, d, J = 8.0 Hz), 7.41-7.26 (1H, m), 7.24-7.19 (4H, m), 7.18-7.16 (2H, m), 7.04 (1H, d, J = 8.0 Hz), 5.52 (1H, d, J = 11.2 Hz), 4.90 (2H, s), 2.49 (2H, t), 1.50-1.44 (2H, m), 1.21-1.14 (2H, m), 0.77 (3H,t).29% yield; 1 H-NMR (DMSO-d 6 , 400 MHz) δ 12.1 (1H, s, br), 7.80 (1H, d, J = 12.0 Hz), 7.68 (2H, d, J = 8.4 Hz), 7.58 (2H , d, J = 8.0 Hz), 7.41-7.26 (1H, m), 7.24-7.19 (4H, m), 7.18-7.16 (2H, m), 7.04 (1H, d, J = 8.0 Hz), 5.52 ( 1H, d, J = 11.2 Hz), 4.90 (2H, s), 2.49 (2H, t), 1.50-1.44 (2H, m), 1.21-1.14 (2H, m), 0.77 (3H, t).
1-58. 3-(4'-((1-58. 3- (4 '-(( NN -(3--(3- 플루오로페닐Fluorophenyl )) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -4--4- 일옥시Iloxy )프로판산 (3-(4'-((Propanoic acid (3- (4 '-(( NN -(3--(3- fluorophenylfluorophenyl )) pentanamidopentanamido )methyl)biphenyl-4-) methyl) biphenyl-4- yloxyyloxy )) propanoicpropanoic acid) (AC-1324) acid) (AC-1324)
45% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.57-7.51 (4H, m), 7.43-7.38 (1H, m), 7.21 (2H, d, J = 8.0 Hz), 7.16 (2H, d, J = 10.0 Hz), 7.03 (2H, d, J = 8.0 Hz), 6.98 (2H, d, J = 8.4 Hz), 4.88 (2H, s), 4.18 (2H, t), 2.68 (2H, t), 2.12 (2H, t), 1.51-1.44 (2H, m), 1.24-1.15 (2H, m), 0.77 (3H,t).45% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.57-7.51 (4H, m), 7.43-7.38 (1H, m), 7.21 (2H, d, J = 8.0 Hz), 7.16 (2H, d, J = 10.0 Hz), 7.03 (2H, d, J = 8.0 Hz), 6.98 (2H, d, J = 8.4 Hz), 4.88 (2H, s), 4.18 (2H, t), 2.68 (2H, t), 2.12 (2H, t), 1.51-1.44 (2H, m), 1.24-1.15 (2H, m), 0.77 (3H, t).
1-59. 1-59. NN -(3--(3- 플루오로페닐Fluorophenyl )-)- NN -((4'-(2-(4--((4 '-(2- (4- 메틸피페라진Methylpiperazine -1-일)-2--1-yl) -2- 옥소에톡시Oxoethoxy )바이페닐-4-일)메틸)펜탄아마이드 () Biphenyl-4-yl) methyl) pentaneamide ( NN -(3--(3- fluorophenylfluorophenyl )-)- NN -((4'-(2-(4-methylpiperazin-1-yl)-2-oxoethoxy)biphenyl-4-yl)methyl)pentanamide) (AC-1309)-((4 '-(2- (4-methylpiperazin-1-yl) -2-oxoethoxy) biphenyl-4-yl) methyl) pentanamide) (AC-1309)
65% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.52-7.51 (2H, m), 7.458 (2H, d, J = 8.0 Hz), 7.33-7.27 (1H, m), 7.24 (2H, d, J = 8.4 Hz), 7.05-6.99 (3H, m), 6.88-6.75 (2H, m), 4.89 (2H, s), 4.68 (2H, s), 3.67-3.60 (4H, m), 2.43-2.38 (4H, m), 2.30 (3H, s), 2.10 (2H, t), 1.64-1.57 (2H, m), 1.30-1.22 (2H, m), 0.83 (3H, t).65% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.52-7.51 (2H, m), 7.458 (2H, d, J = 8.0 Hz), 7.33-7.27 (1H, m), 7.24 (2H, d, J = 8.4 Hz), 7.05-6.99 (3H, m), 6.88-6.75 (2H, m), 4.89 (2H, s), 4.68 (2H, s), 3.67-3.60 (4H, m), 2.43-2.38 (4H , m), 2.30 (3H, s), 2.10 (2H, t), 1.64-1.57 (2H, m), 1.30-1.22 (2H, m), 0.83 (3H, t).
1-60. 1-60. 프로프Prof -2-인일 2-(4'-((2-person 2- (4 '-(( NN -(3--(3- 플루오로페닐Fluorophenyl )) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -4-일옥시)아세테이트 (Prop-2-4-yloxy) acetate (Prop-2- ynylynyl 2-(4'-(( 2- (4 '-(( NN -(3-fluorophenyl)pentanamido)methyl)biphenyl-4-yloxy)acetate) (AC-1390)-(3-fluorophenyl) pentanamido) methyl) biphenyl-4-yloxy) acetate) (AC-1390)
61.3% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.51 (2H, d, J = 8.4 Hz), 7.45 (2H, d, J = 8.0 Hz), 7.33-7.28 (1H, m), 7.21 (2H, d, J = 8.0 Hz), 7.05-7.01 (1H, m), 6.97 (2H, d, J = 8.4 Hz), 6.82-6.75 (2H, m), 4.89 (2H, s), 4.83 (2H, d, J = 1.6 Hz), 4.72 (2H, s), 2.53 (1H, s), 2.09 (2H, t), 1.64-1.58 (2H, m), 1.27-1.20 (2H, m), 0.831 (3H, t).61.3% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.51 (2H, d, J = 8.4 Hz), 7.45 (2H, d, J = 8.0 Hz), 7.33-7.28 (1H, m), 7.21 (2H, d , J = 8.0 Hz), 7.05-7.01 (1H, m), 6.97 (2H, d, J = 8.4 Hz), 6.82-6.75 (2H, m), 4.89 (2H, s), 4.83 (2H, d, J = 1.6 Hz), 4.72 (2H, s), 2.53 (1H, s), 2.09 (2H, t), 1.64-1.58 (2H, m), 1.27-1.20 (2H, m), 0.831 (3H, t ).
1-61. 1-61. NN -(3--(3- 플루오로페닐Fluorophenyl )-)- NN -((4'-(-((4'-( 프로프Prof -2--2- 이닐옥시Iniloxy )) 바이페닐Biphenyl -4-일)-4- days) 메틸methyl )펜탄아마이드 (Pentaneamide ( NN -(3--(3- fluorophenylfluorophenyl )-)- NN -((4'-(prop-2--((4 '-(prop-2- ynyloxyynyloxy )biphenyl-4-yl)methyl)pentanamide) (AC-1389)) biphenyl-4-yl) methyl) pentanamide) (AC-1389)
58.2% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.54-7.50 (2H, m), 7.46 (2H, d, J = 8.4 Hz), 7.33-7.28 (1H, m), 7.23 (2H, d, J = 8.4 Hz), 7.06-7.03 (3H, m), 6.82-6.75 (2H, m), 4.89 (2H, s), 4.73 (2H, d, J = 2.0 Hz), 2.54 (1H. t), 2.09 (2H, t), 1.64-1.57 (2H, m), 1.29-1.20 (2H, m), 0.83 (3H, m).58.2% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.54-7.50 (2H, m), 7.46 (2H, d, J = 8.4 Hz), 7.33-7.28 (1H, m), 7.23 (2H, d, J = 8.4 Hz), 7.06-7.03 (3H, m), 6.82-6.75 (2H, m), 4.89 (2H, s), 4.73 (2H, d, J = 2.0 Hz), 2.54 (1H.t), 2.09 ( 2H, t), 1.64-1.57 (2H, m), 1.29-1.20 (2H, m), 0.83 (3H, m).
1-62. 1-62. NN -((2'-(1H--((2 '-(1H- 테트라졸Tetrazole -5-일)-5 days) 바이페닐Biphenyl -4-일)-4- days) 메틸methyl )-)- NN -- 페닐펜탄아마이드Phenylpentaneamide ( ( NN -((2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl)--((2 '-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl)- NN -phenylpentanamide) (AC-952)-phenylpentanamide) (AC-952)
92% 수율; 1H-NMR (MeOD, 500 MHz) δ 8.16 (1H, d, J = 6.0 Hz), 7.60-7.52 (2H, m), 7.43-7.39 (3H, m), 7.34 (1H, t), 7.25 (2H, t), 7.15 (2H, d, J = 6.4 Hz), 7.03 (2H, d, J = 6.0 Hz), 4.90 (2H, s), 2.09 (2H, t), 1.57-1.50 (2H, m), 1.22-1.18 (2H, m), 0.79 (3H, t).92% yield; 1 H-NMR (MeOD, 500 MHz) δ 8.16 (1H, d, J = 6.0 Hz), 7.60-7.52 (2H, m), 7.43-7.39 (3H, m), 7.34 (1H, t), 7.25 ( 2H, t), 7.15 (2H, d, J = 6.4 Hz), 7.03 (2H, d, J = 6.0 Hz), 4.90 (2H, s), 2.09 (2H, t), 1.57-1.50 (2H, m ), 1.22-1.18 (2H, m), 0.79 (3H, t).
1-63. 2-(4'-((1-63. 2- (4 '-(( NN -- 페닐펜탄아미도Phenylpentaneamido )) 메틸methyl )) 바이페닐Biphenyl -4--4- 일옥시Iloxy )아세트산 (2-(4'-((Acetic acid (2- (4 '-(( NN -phenylpentanamido)methyl)biphenyl-4-yloxy)acetic acid) (AC-1073)-phenylpentanamido) methyl) biphenyl-4-yloxy) acetic acid) (AC-1073)
85% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.49 (2H, d, J = 8.0 Hz), 7.41 (2H, d, J = 8.0 Hz), 7.34-7.32 (3H, m), 7.22 (2H, d, J = 8.0 Hz), 7.01-6.95 (4H, m), 4.91 (2H, s), 4.97 (2H, s), 2.10 (2H, t), 1.65-1.55 (2H, m), 1.26-1.17 (2H, m), 0.80 (3H, t).85% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.49 (2H, d, J = 8.0 Hz), 7.41 (2H, d, J = 8.0 Hz), 7.34-7.32 (3H, m), 7.22 (2H, d , J = 8.0 Hz), 7.01-6.95 (4H, m), 4.91 (2H, s), 4.97 (2H, s), 2.10 (2H, t), 1.65-1.55 (2H, m), 1.26-1.17 ( 2H, m), 0.80 (3H, t).
1-64. 2-(4'-((1-64. 2- (4 '-(( NN -(3--(3- 플루오로페닐Fluorophenyl )) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -4--4- 일옥시Iloxy )아세트산 (2-(4'-((Acetic acid (2- (4 '-(( NN -(3--(3- fluorophenylfluorophenyl )) pentanamidopentanamido )methyl)biphenyl-4-) methyl) biphenyl-4- yloxyyloxy )acetic acid) (AC-1074)acetic acid) (AC-1074)
80% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.49-7.46 (4H, t), 7.39-7.37 (1H, m), 7.18-7.14 (4H, m), 7.01 (1H, d, J = 8.0 Hz), 6.88 (2H, d, J = 8.4 Hz), 4.86 (2H, s), 4.38 (2H, s), 2.09 (2H, m), 1.47-1.44 (2H, m), 1.19-1.13 (2H, m), 0.75 (3H, t).80% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.49-7.46 (4H, t), 7.39-7.37 (1H, m), 7.18-7.14 (4H, m), 7.01 (1H, d, J = 8.0 Hz) , 6.88 (2H, d, J = 8.4 Hz), 4.86 (2H, s), 4.38 (2H, s), 2.09 (2H, m), 1.47-1.44 (2H, m), 1.19-1.13 (2H, m ), 0.75 (3H, t).
1-65. 2-(4'-((1-65. 2- (4 '-(( NN -(3--(3- 클로로페닐Chlorophenyl )) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -4--4- 일옥시Iloxy )아세트산 (2-(4'-((Acetic acid (2- (4 '-(( NN -(3--(3- chlorophenylchlorophenyl )) pentanamidopentanamido )methyl)biphenyl-4-) methyl) biphenyl-4- yloxyyloxy )acetic acid) (AC-1630)acetic acid) (AC-1630)
98% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.40-7.37 (m, 3H), 7.23 (d, J = 8.4 Hz, 2H), 7.16 (s, 1H), 6.97 (d, J = 8.0 Hz, 2H), 4.89 (s, 2H), 4.70 (s, 2H), 2.11 (t, 2H), 1.52-1.45 (m, 2H), 1.23-1.16 (m, 2H), 0.78 (d, J = 7.6 Hz, 3H).98% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.40-7.37 (m, 3H), 7.23 (d, J = 8.4 Hz, 2H), 7.16 (s, 1H), 6.97 (d, J = 8.0 Hz, 2H ), 4.89 (s, 2H), 4.70 (s, 2H), 2.11 (t, 2H), 1.52-1.45 (m, 2H), 1.23-1.16 (m, 2H), 0.78 (d, J = 7.6 Hz, 3H).
1-66. 2-(4'-((1-66. 2- (4 '-(( NN -(3--(3- 브로모페닐Bromophenyl )) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -4--4- 일옥시Iloxy )아세트산 (2-(4'-((Acetic acid (2- (4 '-(( NN -(3--(3- bromophenylbromophenyl )) pentanamidopentanamido )methyl)biphenyl-4-) methyl) biphenyl-4- yloxyyloxy )acetic acid) (AC-1633)acetic acid) (AC-1633)
87% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.51 (d, J = 8.8 Hz, 2H), 7.44 (d, J = 8.8 Hz, 3H), 7.23-7.18 (m, 4H), 6.98 (d, J = 8.0 Hz, 2H), 6.92 (d, J = 8.0 Hz, 1H), 4.88 (s, 2H), 4.71 (s, 2H), 2.09 (t, 2H), 1.63-1.57 (m, 2H), 1.25-1.21 (m, 2H), 0.83 (t, J= 7.2 Hz, 3H).87% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.51 (d, J = 8.8 Hz, 2H), 7.44 (d, J = 8.8 Hz, 3H), 7.23-7.18 (m, 4H), 6.98 (d, J = 8.0 Hz, 2H), 6.92 (d, J = 8.0 Hz, 1H), 4.88 (s, 2H), 4.71 (s, 2H), 2.09 (t, 2H), 1.63-1.57 (m, 2H), 1.25 -1.21 (m, 2H), 0.83 (t, J = 7.2 Hz, 3H).
1-67. 2-(4'-((1-67. 2- (4 '-(( NN -(3-(-(3- ( 트리플루오로메틸Trifluoromethyl )페닐)) Phenyl) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -4--4- 일옥시Iloxy )아세트산 (2-(4'-((Acetic acid (2- (4 '-(( NN -(3-(trifluoromethyl)phenyl)pentanamido)methyl)biphenyl-4-yloxy)acetic acid) (AC-1636)-(3- (trifluoromethyl) phenyl) pentanamido) methyl) biphenyl-4-yloxy) acetic acid) (AC-1636)
69% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.59 (d, J = 7.2 Hz, 1H), 7.52-7.43 (m, 5H), 7.28 (s, 1H), 7.21 (d, J = 7.6 Hz, 3H), 6.99 (d, J = 8.8 Hz, 2H), 4.93 (s, 2H), 4.77 (s, 2H), 2.08 (t, 2H), 1.62-1.54 (m, 2H), 1.23-1.19 (m, 2H), 0.82 (t, J = 7.0 Hz, 3H).69% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.59 (d, J = 7.2 Hz, 1H), 7.52-7.43 (m, 5H), 7.28 (s, 1H), 7.21 (d, J = 7.6 Hz, 3H ), 6.99 (d, J = 8.8 Hz, 2H), 4.93 (s, 2H), 4.77 (s, 2H), 2.08 (t, 2H), 1.62-1.54 (m, 2H), 1.23-1.19 (m, 2H), 0.82 (t, J = 7.0 Hz, 3H).
1-68. 2-(4'-((1-68. 2- (4 '-(( N-m-N-m- 톨릴펜탄아미도Tolylpentaneamido )) 메틸methyl )) 바이페닐Biphenyl -4--4- 일옥시Iloxy )아세트산 (2-(4'-((Acetic acid (2- (4 '-(( N-m-N-m- tolylpentanamido)methyl)biphenyl-4-yloxy)acetic acid) (AC-1639)tolylpentanamido) methyl) biphenyl-4-yloxy) acetic acid) (AC-1639)
62% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.50 (d, J = 8.8 Hz, 2H), 7.42 (s, 2H), 7.23 (t, J = 7.4 Hz, 3H), 7.11 (d, J = 7.2 Hz, 1H), 6.98 (d, J = 8.4 Hz, 2H), 6.83 (s, 1H), 6.78 (d, J = 7.6 Hz, 1H), 5.00 (s, 2H), 4.767 (s, 2H), 2.35 (s, 3H), 2.10 (t, J = 7.6 Hz, 2H), 1.64-1.53 (m, 2H), 1.26-1.25 (m, 2H), 0.81 (t, J = 6.0 Hz, 3H).62% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.50 (d, J = 8.8 Hz, 2H), 7.42 (s, 2H), 7.23 (t, J = 7.4 Hz, 3H), 7.11 (d, J = 7.2 Hz, 1H), 6.98 (d, J = 8.4 Hz, 2H), 6.83 (s, 1H), 6.78 (d, J = 7.6 Hz, 1H), 5.00 (s, 2H), 4.767 (s, 2H), 2.35 (s, 3H), 2.10 (t, J = 7.6 Hz, 2H), 1.64-1.53 (m, 2H), 1.26-1.25 (m, 2H), 0.81 (t, J = 6.0 Hz, 3H).
1-69. 1-69. NN -((4'--((4'- 하이드록시바이페닐Hydroxybiphenyl -4-일)-4- days) 메틸methyl )-)- NN -(3--(3- 니트로페닐Nitrophenyl )) 펜탄아마이드Pentaneamide ( ( NN -((4'-hydroxybiphenyl-4-yl)methyl)--((4'-hydroxybiphenyl-4-yl) methyl)- NN -(3-nitrophenyl)pentanamide) (AC-1641)-(3-nitrophenyl) pentanamide) (AC-1641)
30% 수율; 1H NMR (CDCl3, 400 MHz) δ 8.18 (d, J = 8.8 Hz, 1H), 7.95 (s, 1H), 7.52 (t, J = 8.2 Hz, 1H), 7.44 (d, J = 8.0 Hz, 4H), 7.33 (s, 1H), 7.21 (d, J = 8.0 Hz, 2H), 6.97 (d, J = 8.0 Hz, 2H), 4.95 (s, 2H), 4.89 (s, 1H), 2.09 (t, 2H), 1.66-1.54 (m, 2H), 1.27-1.22 (m, 2H), 0.86 (t, J = 9.2 Hz, 3H).30% yield; 1 H NMR (CDCl 3 , 400 MHz) δ 8.18 (d, J = 8.8 Hz, 1H), 7.95 (s, 1H), 7.52 (t, J = 8.2 Hz, 1H), 7.44 (d, J = 8.0 Hz , 4H), 7.33 (s, 1H), 7.21 (d, J = 8.0 Hz, 2H), 6.97 (d, J = 8.0 Hz, 2H), 4.95 (s, 2H), 4.89 (s, 1H), 2.09 (t, 2H), 1.66-1.54 (m, 2H), 1.27-1.22 (m, 2H), 0.86 (t, J = 9.2 Hz, 3H).
1-70. 2-(4'-((1-70. 2- (4 '-(( NN -(3--(3- 니트로페닐Nitrophenyl )) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -4--4- 일옥시Iloxy )아세트산 (2-(4'-((Acetic acid (2- (4 '-(( NN -(3--(3- nitrophenylnitrophenyl )) pentanamidopentanamido )methyl)biphenyl-4-) methyl) biphenyl-4- yloxyyloxy )acetic acid) (AC-1642)acetic acid) (AC-1642)
49% 수율; 1H-NMR (CDCl3, 400 MHz) δ 8.15 (d, J = 7.2 Hz, 1H), 8.10 (s, 1H), 7.69-7.63 (m, 2H), 7.55 (t, J = 8.2 Hz, 4H), 7.25 (d, J = 8.0 Hz, 2H), 6.97 (d, J = 8.4 Hz, 2H), 4.97 (s, 2H), 4.70 (s, 2H), 2.15 (t, 2H), 1.53-1.46 (m, 2H), 1.24-1.17 (m, 2H), 0.78 (t, J = 7.2 Hz, 3H).49% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 8.15 (d, J = 7.2 Hz, 1H), 8.10 (s, 1H), 7.69-7.63 (m, 2H), 7.55 (t, J = 8.2 Hz, 4H ), 7.25 (d, J = 8.0 Hz, 2H), 6.97 (d, J = 8.4 Hz, 2H), 4.97 (s, 2H), 4.70 (s, 2H), 2.15 (t, 2H), 1.53-1.46 (m, 2H), 1.24-1.17 (m, 2H), 0.78 (t, J = 7.2 Hz, 3H).
1-71. 2-(4'-((1-71. 2- (4 '-(( NN -(3--(3- 아이오도페닐Iodophenyl )) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -4--4- 일옥시Iloxy )아세트산 (2-(4'-((Acetic acid (2- (4 '-(( NN -(3--(3- iodophenyliodophenyl )) pentanamidopentanamido )methyl)biphenyl-4-) methyl) biphenyl-4- yloxyyloxy )acetic acid) (AC-1645)acetic acid) (AC-1645)
94% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.65 (d, J = 7.6 Hz, 1H), 7.51 (d, J = 8.8 Hz, 2H), 7.43 (t, J = 8.8 Hz, 3H), 7.21 (d, J = 8.0 Hz, 2H), 7.06 (t, J = 7.8 Hz, 1H), 6.98 (d, J = 8.4 Hz, 2H), 6.94 (d, J = 8.0 Hz, 1H), 4.87 (s, 2H), 4.71 (s, 2H), 2.1 (t, 2H), 1.63-1.55 (m, 2H), 1.26-1.19 (m, 2H), 0.83 (t, J = 7.2 Hz, 3H).94% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.65 (d, J = 7.6 Hz, 1H), 7.51 (d, J = 8.8 Hz, 2H), 7.43 (t, J = 8.8 Hz, 3H), 7.21 ( d, J = 8.0 Hz, 2H), 7.06 (t, J = 7.8 Hz, 1H), 6.98 (d, J = 8.4 Hz, 2H), 6.94 (d, J = 8.0 Hz, 1H), 4.87 (s, 2H), 4.71 (s, 2H), 2.1 (t, 2H), 1.63-1.55 (m, 2H), 1.26-1.19 (m, 2H), 0.83 (t, J = 7.2 Hz, 3H).
1-72. 2-((4'-((1-72. 2-((4 '-(( NN -(3--(3- 플루오로페닐Fluorophenyl )) 아세트아미도Acetamido )) 메틸methyl )-[1,1'-)-[1,1'- 바이페닐Biphenyl ]-4-일)옥시)아세트산 (2-((4'-((] -4-yl) oxy) acetic acid (2-((4 '-(( NN -(3--(3- fluorophenylfluorophenyl )) acetamidoacetamido )methyl)-[1,1'-biphenyl]-4-yl)oxy)acetic acid) (AC-1648)) methyl)-[1,1'-biphenyl] -4-yl) oxy) acetic acid) (AC-1648)
67% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.54 (d, J = 8.0 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H), 7.39 (q, J = 7.3 Hz, 1H), 7.24 (d, J = 8.0 Hz, 2H), 7.11 (t, J = 9.2 Hz, 1H), 7.00 (d, J = 8.4 Hz, 2H), 6.96 (d, J = 7.6 Hz, 2H), 4.93 (s, 2H), 4.69 (s, 2H), 1.93 (s, 3H)67% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.54 (d, J = 8.0 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H), 7.39 (q, J = 7.3 Hz, 1H), 7.24 ( d, J = 8.0 Hz, 2H), 7.11 (t, J = 9.2 Hz, 1H), 7.00 (d, J = 8.4 Hz, 2H), 6.96 (d, J = 7.6 Hz, 2H), 4.93 (s, 2H), 4.69 (s, 2H), 1.93 (s, 3H)
1-73. 1-73. NN -((4'-(4--((4 '-(4- 아이소프로필피페라진Isopropyl piperazine -1--One- 카보닐Carbonyl )) 바이페닐Biphenyl -4-일)-4- days) 메틸methyl )-)- NN -- 페닐펜탄아마이드Phenylpentaneamide ( ( NN -((4'-(4--((4 '-(4- isopropylpiperazineisopropylpiperazine -1-carbonyl)biphenyl-4-yl)methyl)--1-carbonyl) biphenyl-4-yl) methyl)- NN -phenylpentanamide) (AC-1649)-phenylpentanamide) (AC-1649)
50% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.60 (d, J = 8.0 Hz, 2H), 7.49 (m, J = 4.8 Hz, 4H), 7.36 (d, J = 6.4 Hz, 3H), 7.29 (d, J = 8.4 Hz, 2H), 7.02 (d, J = 6.8 Hz, 2H), 4.92 (s, 2H), 3.65 (d, 4H), 2.74 (m, 1H), 2.55 (d, 4H), 2.09 (t, J = 7.6 Hz, 2H), 1.60 (m, 2H), 1.22 (m, 2H), 1.06 (d, J = 6.8 Hz, 6H), 0.82 (t, J = 7.4 Hz, 3H).50% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.60 (d, J = 8.0 Hz, 2H), 7.49 (m, J = 4.8 Hz, 4H), 7.36 (d, J = 6.4 Hz, 3H), 7.29 ( d, J = 8.4 Hz, 2H), 7.02 (d, J = 6.8 Hz, 2H), 4.92 (s, 2H), 3.65 (d, 4H), 2.74 (m, 1H), 2.55 (d, 4H), 2.09 (t, J = 7.6 Hz, 2H), 1.60 (m, 2H), 1.22 (m, 2H), 1.06 (d, J = 6.8 Hz, 6H), 0.82 (t, J = 7.4 Hz, 3H).
1-74. 1-74. NN -(4--(4- 플루오로페닐Fluorophenyl )-)- NN -((4'-(4--((4 '-(4- 아이소프로필피페라진Isopropyl piperazine -1--One- 카보닐Carbonyl )) 바이페닐Biphenyl -4-일)메틸)펜탄아마이드 (-4-yl) methyl) pentaneamide ( NN -(4--(4- fluorophenylfluorophenyl )-)- NN -((4'-(4--((4 '-(4- isopropylpiperazineisopropylpiperazine -1-carbonyl)biphenyl-4-yl)methyl)pentanamide) (AC-1650)-1-carbonyl) biphenyl-4-yl) methyl) pentanamide) (AC-1650)
41% 수율; 1H-NMR (CDCl3 ,400 MHz) δ 7.60 (d, J = 8.4 Hz, 2H), 7.49 (m, J = 6.0 Hz, 4H), 7.27 (d, J = 8.0 Hz, 2H), 7.00 (m, J = 6.7 Hz, 4H), 4.89 (s, 2H), 3.67 (d, 4H), 2.77 (m, 1H), 2.57 (d, 4H), 2.07 (t, J = 7.2 Hz, 2H), 1.59 (m, 2H), 1.23 (m, 2H), 1.07 (d, J = 6.0 Hz, 6H), 0.83 (t, J = 7.4 Hz, 3H).41% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.60 (d, J = 8.4 Hz, 2H), 7.49 (m, J = 6.0 Hz, 4H), 7.27 (d, J = 8.0 Hz, 2H), 7.00 ( m, J = 6.7 Hz, 4H), 4.89 (s, 2H), 3.67 (d, 4H), 2.77 (m, 1H), 2.57 (d, 4H), 2.07 (t, J = 7.2 Hz, 2H), 1.59 (m, 2H), 1.23 (m, 2H), 1.07 (d, J = 6.0 Hz, 6H), 0.83 (t, J = 7.4 Hz, 3H).
1-75. 1-75. NN -((3'-(4--((3 '-(4- 아이소프로필피페라진Isopropyl piperazine -1--One- 카보닐Carbonyl )) 바이페닐Biphenyl -4-일)-4- days) 메틸methyl )-)- NN -- 페닐펜탄아마이드Phenylpentaneamide ( ( N-N- ((3'-(4-((3 '-(4- isopropylpiperazineisopropylpiperazine -1-carbonyl)biphenyl-4-yl)methyl)--1-carbonyl) biphenyl-4-yl) methyl)- NN -phenylpentanamide) (AC-1651)-phenylpentanamide) (AC-1651)
70% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.61 (d, J = 6.8 Hz, 2H), 7.49 (d, J = 7.6 Hz, 2H), 7.45 (d, 1H), 7.354 (m, 4H), 7.28 (s, 2H), 7.01 (d, J = 7.2 Hz, 2H,), 4.92 (s, 2H), 3.64 (d, 4H), 2.72 (m, 1H), 2.53 (d, 4H), 2.09 (t, J = 7.4 Hz, 2H), 1.59 (m, 2H), 1.23 (m, 2H), 1.05 (d, J = 6.8 Hz, 6H), 0.82 (t, J = 7.2 Hz, 3H).70% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.61 (d, J = 6.8 Hz, 2H), 7.49 (d, J = 7.6 Hz, 2H), 7.45 (d, 1H), 7.354 (m, 4H), 7.28 (s, 2H), 7.01 (d, J = 7.2 Hz, 2H,), 4.92 (s, 2H), 3.64 (d, 4H), 2.72 (m, 1H), 2.53 (d, 4H), 2.09 ( t, J = 7.4 Hz, 2H), 1.59 (m, 2H), 1.23 (m, 2H), 1.05 (d, J = 6.8 Hz, 6H), 0.82 (t, J = 7.2 Hz, 3H).
1-76. 1-76. NN -(4--(4- 플루오로페닐Fluorophenyl )-)- NN -((3'-(4--((3 '-(4- 아이소프로필피페라진Isopropyl piperazine -1--One- 카보닐Carbonyl )) 바이페닐Biphenyl -4-일)메틸)펜탄아마이드 (-4-yl) methyl) pentaneamide ( N-N- (4-(4- fluorophenylfluorophenyl )-)- NN -((3'-(4--((3 '-(4- isopropylpiperazineisopropylpiperazine -1-carbonyl)biphenyl-4-yl)methyl)pentanamide) (AC-1652)-1-carbonyl) biphenyl-4-yl) methyl) pentanamide) (AC-1652)
70% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.61 (q, 2H), 7.47 (m, J = 6.0 Hz, 3H), 7.34 (d, J = 7.2 Hz, 1H), 7.26 (d, J = 7.6 Hz, 2H), 7.03 (m, 2H), 6.96 (m, 2H), 4.88 (s, 2H), 3.65 (d, 4H), 2.74 (m, 1H), 2.54 (d, 4H), 2.06 (t, J = 7.6 Hz, 2H), 1.58 (m, 2H), 1.25 (m, 2H), 1.06 (d, J = 6.8 Hz, 6H), 0.83 (t, J = 7.4 Hz, 3H).70% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.61 (q, 2H), 7.47 (m, J = 6.0 Hz, 3H), 7.34 (d, J = 7.2 Hz, 1H), 7.26 (d, J = 7.6 Hz, 2H), 7.03 (m, 2H), 6.96 (m, 2H), 4.88 (s, 2H), 3.65 (d, 4H), 2.74 (m, 1H), 2.54 (d, 4H), 2.06 (t , J = 7.6 Hz, 2H), 1.58 (m, 2H), 1.25 (m, 2H), 1.06 (d, J = 6.8 Hz, 6H), 0.83 (t, J = 7.4 Hz, 3H).
1-77. 4'-((1-77. 4'-(( NN -(2--(2- 플루오로페닐Fluorophenyl )) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -4--4- 카복실산Carboxylic acid (4'-(( (4'-(( NN -(2-fluorophenyl)pentanamido)methyl)biphenyl-4-carboxylic acid) (AC-1071)-(2-fluorophenyl) pentanamido) methyl) biphenyl-4-carboxylic acid) (AC-1071)
94 % 수율; 1H-NMR (CDCl3, 400 MHz) δ 8.16 (2H, d, J = 8.4 Hz), 7.67 (2H, d, J = 8.4 Hz), 7.54 (2H, d, J = 7.6 Hz), 7.31 (2H, d, J = 8.4 Hz), 7.18-7.08 (3H, m), 7.00-6.96 (1H, t), 5.28 (1H, d, J = 14.4 Hz), 4.56 (1H, d, J = 14.4 Hz), 2.09 (2H, t), 1.63-1.59 (2H, m), 1.27-1.22 (2H, m), 0.83 (3H, t).94% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 8.16 (2H, d, J = 8.4 Hz), 7.67 (2H, d, J = 8.4 Hz), 7.54 (2H, d, J = 7.6 Hz), 7.31 ( 2H, d, J = 8.4 Hz), 7.18-7.08 (3H, m), 7.00-6.96 (1H, t), 5.28 (1H, d, J = 14.4 Hz), 4.56 (1H, d, J = 14.4 Hz ), 2.09 (2H, t), 1.63-1.59 (2H, m), 1.27-1.22 (2H, m), 0.83 (3H, t).
1-78. 4'-((1-78. 4'-(( NN -(4--(4- 플루오로페닐Fluorophenyl )) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -4--4- 카복실산Carboxylic acid (4'-(( (4'-(( NN -(4-fluorophenyl)pentanamido)methyl)biphenyl-4-carboxylic acid) (AC-1072)-(4-fluorophenyl) pentanamido) methyl) biphenyl-4-carboxylic acid) (AC-1072)
90% 수율; 1H-NMR (CDCl3, 400 MHz) δ 8.17 (2H, d, J = 8.4 Hz), 7.68 (2H, d, J = 8 Hz), 7.56 (2H, d, J = 8.0 Hz), 7.30 (2H, d, J = 7.6 Hz), 7.04-6.98 (4H, m), 4.91 (2H, s), 2.07 (2H, t), 1.62-1.58 (2H, m), 1.25-1.23 (2H, m), 0.83 (3H, t).90% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 8.17 (2H, d, J = 8.4 Hz), 7.68 (2H, d, J = 8 Hz), 7.56 (2H, d, J = 8.0 Hz), 7.30 ( 2H, d, J = 7.6 Hz), 7.04-6.98 (4H, m), 4.91 (2H, s), 2.07 (2H, t), 1.62-1.58 (2H, m), 1.25-1.23 (2H, m) , 0.83 (3H, t).
1-79. 4'-((1-79. 4'-(( NN -(2--(2- 메톡시페닐Methoxyphenyl )) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -3--3- 카복실산Carboxylic acid (4'-(( (4'-(( NN -(2-methoxyphenyl)pentanamido)methyl)biphenyl-3-carboxylic acid) (AC-1076)-(2-methoxyphenyl) pentanamido) methyl) biphenyl-3-carboxylic acid) (AC-1076)
90% 수율; 1H-NMR (CDCl3, 400 MHz) δ 8.13 (1H, s), 7.90-7.86 (2H, m), 7.62-7.54 (3H, m), 7.26 (2H, d, J = 7.6 Hz), 7.06 (2H, d, J = 8.8 Hz), 6.89 (2H, d, J = 8.8 Hz), 4.83 (2H, s), 3.70 (3H, s), 2.05-2.01 (2H, m), 1.46-1.41 (2H, m), 0.75 (3H, t).90% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 8.13 (1H, s), 7.90-7.86 (2H, m), 7.62-7.54 (3H, m), 7.26 (2H, d, J = 7.6 Hz), 7.06 (2H, d, J = 8.8 Hz), 6.89 (2H, d, J = 8.8 Hz), 4.83 (2H, s), 3.70 (3H, s), 2.05-2.01 (2H, m), 1.46-1.41 ( 2H, m), 0.75 (3H, t).
1-80. 4'-((1-80. 4'-(( NN -(3--(3- 메톡시페닐Methoxyphenyl )) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -3--3- 카복실산Carboxylic acid (4'-(( (4'-(( NN -(3-methoxyphenyl)pentanamido)methyl)biphenyl-3-carboxylic acid) (AC-1077)-(3-methoxyphenyl) pentanamido) methyl) biphenyl-3-carboxylic acid) (AC-1077)
92% 수율; 1H-NMR (CDCl3, 400 MHz) δ 8.24 (1H, s), 7.89 (1H, d, J = 7.2 Hz), 7.84 (1H, d, J = 7.2 Hz), 7.59-7.52 (3H, m), 7.29 (2H, d, J = 7.6 Hz), 7.00-6.60 (4H, m), 4.89 (2H, s), 3.78 (3H. s), 2.13 (2H, t), 1.62-1.52 (2H, m), 1.19-1.16 (2H, m), 0.83 (3H, t).92% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 8.24 (1H, s), 7.89 (1H, d, J = 7.2 Hz), 7.84 (1H, d, J = 7.2 Hz), 7.59-7.52 (3H, m ), 7.29 (2H, d, J = 7.6 Hz), 7.00-6.60 (4H, m), 4.89 (2H, s), 3.78 (3H.s), 2.13 (2H, t), 1.62-1.52 (2H, m), 1.19-1.16 (2H, m), 0.83 (3H, t).
1-81. 4'-((1-81. 4'-(( NN -(4--(4- 메톡시페닐Methoxyphenyl )) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -3--3- 카복실산Carboxylic acid (4'-(( (4'-(( NN -(4-methoxyphenyl)pentanamido)methyl)biphenyl-3-carboxylic acid) (AC-1078)-(4-methoxyphenyl) pentanamido) methyl) biphenyl-3-carboxylic acid) (AC-1078)
92% 수율; 1H-NMR (CDCl3, 400 MHz) δ 8.32 (1H, s), 8.07 (1H, d, J = 7.6 Hz), 7.82 (1H, d, J = 8.0 Hz), 7.55-7.53 (3H, m), 7.30 (2H, d, J = 7.6 Hz) 6.92-6.83 (4H, m), 4.90 (2H, s), 3.81 (3H, s), 2.09 (2H, t), 1.59-1.56 (2H, m), 1.25-1.20 (2H, m), 0.83 (3H, t).92% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 8.32 (1H, s), 8.07 (1H, d, J = 7.6 Hz), 7.82 (1H, d, J = 8.0 Hz), 7.55-7.53 (3H, m ), 7.30 (2H, d, J = 7.6 Hz) 6.92-6.83 (4H, m), 4.90 (2H, s), 3.81 (3H, s), 2.09 (2H, t), 1.59-1.56 (2H, m ), 1.25-1.20 (2H, m), 0.83 (3H, t).
1-82. 1-82. NN -((2'-(4--((2 '-(4- 메틸피페라진Methylpiperazine -1--One- 카보닐Carbonyl )) 바이페닐Biphenyl -4-일)-4- days) 메틸methyl )-)- NN -- 페닐펜탄아마이드Phenylpentaneamide ( ( NN -((2'-(4--((2 '-(4- methylpiperazinemethylpiperazine -1-carbonyl)biphenyl-4--1-carbonyl) biphenyl-4- ylyl )methyl)-) methyl)- NN -phenylpentanamide) (AC-888)-phenylpentanamide) (AC-888)
93% 수율; 1H-NMR (DMSO-d6, 500 MHz) δ 7.71 (m, 1H), 7.61 (m, 3H), 7.51 (m, 1H), 7.39 (m, 2H), 7.34 (m, 2H), 7.27 (m, 2H), 7.19 (m, 2H), 4.90 (s, 2H), 3.6 (d, 4H), 2.36 (d, 4H), 2.19 (s, 3H), 2.07 (m, 2H), 1.48 (m, 2H), 1.18 (m, 2H), 0.76 (t, 3H).93% yield; 1 H-NMR (DMSO-d 6 , 500 MHz) δ 7.71 (m, 1H), 7.61 (m, 3H), 7.51 (m, 1H), 7.39 (m, 2H), 7.34 (m, 2H), 7.27 (m, 2H), 7.19 (m, 2H), 4.90 (s, 2H), 3.6 (d, 4H), 2.36 (d, 4H), 2.19 (s, 3H), 2.07 (m, 2H), 1.48 ( m, 2H), 1.18 (m, 2H), 0.76 (t, 3H).
1-83. 1-83. NN -((3'-(4-메틸피페라진-1-카보닐)바이페닐-4-일)메틸)--((3 '-(4-methylpiperazin-1-carbonyl) biphenyl-4-yl) methyl)- NN -페닐펜탄아마이드(-Phenylpentaneamide ( NN -((3'-(4-methylpiperazine-1-carbonyl)biphenyl-4-yl)methyl)--((3 '-(4-methylpiperazine-1-carbonyl) biphenyl-4-yl) methyl)- NN -phenylpentanamide) (AC-889)-phenylpentanamide) (AC-889)
93% 수율; 1H-NMR (DMSO-d6, 500 MHz) δ 7.71 (m, 1H), 7.61 (m, 3H), 7.51 (m, 1H), 7.42 (m, 2H), 7.30 (m, 2H), 7.25 (m, 2H), 7.19 (m, 2H), 4.90 (s, 2H), 3.16 (d, 4H), 2.38 (d, 4H), 2.18 (s, 3H), 2.07 (m, 2H) 1.48 (m, 2H), 1.18 (m, 2H), 0.76 (t, 3H).93% yield; 1 H-NMR (DMSO-d 6 , 500 MHz) δ 7.71 (m, 1H), 7.61 (m, 3H), 7.51 (m, 1H), 7.42 (m, 2H), 7.30 (m, 2H), 7.25 (m, 2H), 7.19 (m, 2H), 4.90 (s, 2H), 3.16 (d, 4H), 2.38 (d, 4H), 2.18 (s, 3H), 2.07 (m, 2H) 1.48 (m , 2H), 1.18 (m, 2H), 0.76 (t, 3H).
1-84. 4'-((1-84. 4'-(( NN -(3--(3- 플루오로페닐Fluorophenyl )) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -2--2- 카복실산Carboxylic acid (4'-(((4'-(( NN -(3-fluorophenyl)pentanamido)methyl)biphenyl-2-carboxylic acid) (AC-891)-(3-fluorophenyl) pentanamido) methyl) biphenyl-2-carboxylic acid) (AC-891)
94% 수율; 1H-NMR (DMSO-d6, 500 MHz) δ 12.8 (s, br, 1H), 7.7 (m, 1H), 7.55 (m, 1H), 7.45 (m, 2H), 7.35 (m, 2H), 7.25 (m, 2H), 7.20 (m, 3H), 7.05 (m, 1H), 4.93 (s, 2H), 2.14 (m, 2H), 1.49 (m, 2H), 1.20 (m, 2H), 0.78 (t, 3H).94% yield; 1 H-NMR (DMSO-d 6 , 500 MHz) δ 12.8 (s, br, 1H), 7.7 (m, 1H), 7.55 (m, 1H), 7.45 (m, 2H), 7.35 (m, 2H) , 7.25 (m, 2H), 7.20 (m, 3H), 7.05 (m, 1H), 4.93 (s, 2H), 2.14 (m, 2H), 1.49 (m, 2H), 1.20 (m, 2H), 0.78 (t, 3 H).
1-85. 4'-((1-85. 4'-(( NN -(3--(3- 플루오로페닐Fluorophenyl )) 펜탄아미도Pentanamido )) 메틸methyl )) 바이페닐Biphenyl -4--4- 카복실산Carboxylic acid (4'-(( (4'-(( NN -(3-fluorophenyl)pentanamido)methyl)biphenyl-4-carboxylic acid) (AC-893)-(3-fluorophenyl) pentanamido) methyl) biphenyl-4-carboxylic acid) (AC-893)
94% 수율; 1H-NMR (DMSO-d6, 500 MHz) δ 13.1 (s, br, 1H), 8.12 (d, 1H), 7.85 (d, 2H), 7.66 (d, 2H), 7.56 (m, 2H), 7.20 (m, 2H), 7.20 (m, 2H,) 7.05 (m, 1H), 4.91 (s, 2H), 2.08 (m, 2H), 1.48 (m, 2H), 1.18 (m, 2H), 0.76 (t, 3H).94% yield; 1 H-NMR (DMSO-d 6 , 500 MHz) δ 13.1 (s, br, 1H), 8.12 (d, 1H), 7.85 (d, 2H), 7.66 (d, 2H), 7.56 (m, 2H) , 7.20 (m, 2H), 7.20 (m, 2H,) 7.05 (m, 1H), 4.91 (s, 2H), 2.08 (m, 2H), 1.48 (m, 2H), 1.18 (m, 2H), 0.76 (t, 3 H).
1-86. 1-86. NN -(3--(3- 플루오로페닐Fluorophenyl )-)- NN -((4'-(-((4'-( 몰폴린Morpholine -4--4- 카보닐Carbonyl )-[1,1'-)-[1,1'- 바이페닐Biphenyl -4-일)메틸)펜탄아마이드 (-4-yl) methyl) pentaneamide ( N-N- (3-(3- fluorophenylfluorophenyl )-)- NN -((4'-(-((4'-( morpholinemorpholine -4-carbonyl)-[1,1'-biphenyl]-4-yl)methyl)pentanamide) (AC-950)-4-carbonyl)-[1,1'-biphenyl] -4-yl) methyl) pentanamide) (AC-950)
93% 수율; 1H-NMR (DMSO-d6, 500 MHz) δ 7.95 (m, 1H), 7.70 (d, 2H), 7.62 (d, 2H), 7.44 (d, 2H), 7.36 m, 2H), 7.27 (m, 2H), 7.19 (d, 2H), 4.90 (s, 2H), 3.01 (d, 4H), 2.5 (s, 3H), 2.36 (d, 4H), 2.07 (m, 2H), 1.48 (m, 2H), 1.18 (m, 2H), 0.76 (t, 3H).93% yield; 1 H-NMR (DMSO-d 6 , 500 MHz) δ 7.95 (m, 1H), 7.70 (d, 2H), 7.62 (d, 2H), 7.44 (d, 2H), 7.36 m, 2H), 7.27 ( m, 2H), 7.19 (d, 2H), 4.90 (s, 2H), 3.01 (d, 4H), 2.5 (s, 3H), 2.36 (d, 4H), 2.07 (m, 2H), 1.48 (m , 2H), 1.18 (m, 2H), 0.76 (t, 3H).
1-87. 1-87. NN -(3--(3- 플루오로페닐Fluorophenyl )-)- NN -((4'-(4--((4 '-(4- 메틸피페라진Methylpiperazine -1--One- 카보닐Carbonyl )) 바이페닐Biphenyl -4-일)메틸)펜탄아마이드 (-4-yl) methyl) pentaneamide ( NN -(3--(3- fluorophenylfluorophenyl )-)- NN -((4'-(4--((4 '-(4- methylpiperazinemethylpiperazine -1-carbonyl)biphenyl-4-yl)methyl)pentanamide) (AC-951)-1-carbonyl) biphenyl-4-yl) methyl) pentanamide) (AC-951)
93% 수율; 1H-NMR (DMSO-d6, 500 MHz) δ 7.95 (1H, m), 7.70 (2H, d), 7.62 (2H, d), 7.44 (2H, d), 7.36 (2H, m), 7.27 (2H, m), 7.19 (2H, d), 4.90 (2H, s), 3.01 (4H, d), 2.5 (3H, s), 2.36 (4H, d), 2.07 (2H, m), 1.48 (2H, m), 1.18 (2H, m), 0.76 (3H, t).93% yield; 1 H-NMR (DMSO-d 6 , 500 MHz) δ 7.95 (1H, m), 7.70 (2H, d), 7.62 (2H, d), 7.44 (2H, d), 7.36 (2H, m), 7.27 (2H, m), 7.19 (2H, d), 4.90 (2H, s), 3.01 (4H, d), 2.5 (3H, s), 2.36 (4H, d), 2.07 (2H, m), 1.48 ( 2H, m), 1.18 (2H, m), 0.76 (3H, t).
1-88. 1-88. NN -((4'--((4'- 메톡시바이페닐Methoxybiphenyl -4-일)-4- days) 메틸methyl )-)- NN -- 페닐펜탄아마이드Phenylpentaneamide ( ( NN -((4'-methoxybiphenyl-4-yl)methyl)--((4'-methoxybiphenyl-4-yl) methyl)- NN -phenylpentanamide) (AC-1067)-phenylpentanamide) (AC-1067)
100% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.51 (2H, d, J = 8.4 Hz), 7.45 (2H, d, J = 8.0 Hz), 7.34-7.30 (3H, m), 7.24 (2H, d, J = 8.0 Hz), 7.01 (2H, d, J = 7.2 Hz), 6.96 (2H, d, J = 8.8 Hz), 4.90 (2H, s), 3.85 (3H, s), 2.08 (2H, t), 1.63-1.57 (2H, m), 1.26-1.20 (2H, m), 0.83 (3H, t).100% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.51 (2H, d, J = 8.4 Hz), 7.45 (2H, d, J = 8.0 Hz), 7.34-7.30 (3H, m), 7.24 (2H, d , J = 8.0 Hz), 7.01 (2H, d, J = 7.2 Hz), 6.96 (2H, d, J = 8.8 Hz), 4.90 (2H, s), 3.85 (3H, s), 2.08 (2H, t ), 1.63-1.57 (2H, m), 1.26-1.20 (2H, m), 0.83 (3H, t).
1-89. 1-89. NN -((4'--((4'- 하이드록시바이페닐Hydroxybiphenyl -4-일)-4- days) 메틸methyl )-)- NN -- 페닐펜탄아마이드Phenylpentaneamide ( ( NN -((4'-hydroxybiphenyl-4-yl)methyl)--((4'-hydroxybiphenyl-4-yl) methyl)- NN -phenylpentanamide) (AC-1069)-phenylpentanamide) (AC-1069)
80% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.44-7.37 (4H, m), 7.35-7.31 (3H, m), 7.26 (2H, d, J = 8.4 Hz), 7.03 (2H, d, J = 6.8 Hz), 6.88 (2H, d, J = 8.4 Hz), 5.37 (1H, br, s), 4.91 (2H, s), 2.10 (2H, t), 1.63-1.57 (2H, m), 1.25-1.20 (2H, m), 0.83 (3H, t).80% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.44-7.37 (4H, m), 7.35-7.31 (3H, m), 7.26 (2H, d, J = 8.4 Hz), 7.03 (2H, d, J = 6.8 Hz), 6.88 (2H, d, J = 8.4 Hz), 5.37 (1H, br, s), 4.91 (2H, s), 2.10 (2H, t), 1.63-1.57 (2H, m), 1.25- 1.20 (2H, m), 0.83 (3H, t).
1-90. 1-90. NN -(3--(3- 플루오로페닐Fluorophenyl )-)- NN -((4'--((4'- 메톡시바이페닐Methoxybiphenyl -4-일)-4- days) 메틸methyl )) 펜탄아마이드Pentaneamide ( ( NN -(3-fluorophenyl)--(3-fluorophenyl)- NN -((4'-methoxybiphenyl-4-yl)methyl)pentanamide) (AC-1068)-((4'-methoxybiphenyl-4-yl) methyl) pentanamide) (AC-1068)
100% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.52-7.45 (4H, m), 7.31-7.30 (1H, m), 7.23 (2H, d, J = 8.4 Hz), 7.03-7.03 (1H, m), 6.97 (2H, d, J = 8.8 Hz), 6.82-6.80 (2H, m), 4.89 (2H, s), 3.85 (3H, s), 2.10 (2H, t), 1.62-1.57 (2H, m), 1.27-1.22 (2H, m), 0.83 (3H, t).100% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.52-7.45 (4H, m), 7.31-7.30 (1H, m), 7.23 (2H, d, J = 8.4 Hz), 7.03-7.03 (1H, m) , 6.97 (2H, d, J = 8.8 Hz), 6.82-6.80 (2H, m), 4.89 (2H, s), 3.85 (3H, s), 2.10 (2H, t), 1.62-1.57 (2H, m ), 1.27-1.22 (2H, m), 0.83 (3H, t).
1-91. 1-91. NN -(3--(3- 플루오로페닐Fluorophenyl )-)- NN -((4'--((4'- 하이드록시바이페닐Hydroxybiphenyl -4-일)-4- days) 메틸methyl )) 펜탄아마이드Pentaneamide ( ( NN -(3--(3- fluorophenylfluorophenyl )-)- NN -((4'--((4'- hydroxybiphenylhydroxybiphenyl -4--4- ylyl )methyl)methyl) pentanamidepentanamide ) (AC-1070)(AC-1070)
85% 수율; 1H-NMR (CDCl3 , 400 MHz) δ 7.44-7.42 (4H, m), 7.35-7.29 (1H, m), 7.22 (2H, d, J = 8.0 Hz), 7.06-7.02 (1H, m), 6.88 (2H, d, J = 8.0 Hz), 6.85-6.78 (2H, m), 5.60 (1H, br, s), 4.90 (2H, s), 2.12 (2H, t), 1.65-1.57 (2H, m), 1.30-1.20 (2H, m), 0.83 (3H, t).85% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.44-7.42 (4H, m), 7.35-7.29 (1H, m), 7.22 (2H, d, J = 8.0 Hz), 7.06-7.02 (1H, m) , 6.88 (2H, d, J = 8.0 Hz), 6.85-6.78 (2H, m), 5.60 (1H, br, s), 4.90 (2H, s), 2.12 (2H, t), 1.65-1.57 (2H , m), 1.30-1.20 (2H, m), 0.83 (3H, t).
1-92. 1-92. NN -(3--(3- 클로로페닐Chlorophenyl )-)- NN -((4'--((4'- 메톡시바이페닐Methoxybiphenyl -4-일)-4- days) 메틸methyl )) 펜탄아마이드Pentaneamide ( ( NN -(3-chlorophenyl)--(3-chlorophenyl)- NN -((4'-methoxybiphenyl-4-yl)methyl)pentanamide) (AC-1628)-((4'-methoxybiphenyl-4-yl) methyl) pentanamide) (AC-1628)
85% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.52-7.49 (m, 2H), 7.46 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H) 7.22 (d, J = 8.4 Hz, 2H), 7.06 (s, 1H), 6.98-6.94 (m, 2H), 6.88 (d, J = 7.6 Hz, 1H), 4.88 (s, 2H), 3.84 (s, 3H), 2.08 (t, J = 7.0 Hz, 2H), 1.65-1.56 (m, 2H), 1.29-1.20 (m, 2H), 0.83 (t, J = 7.2 Hz, 3H).85% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.52-7.49 (m, 2H), 7.46 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H) 7.22 (d, J = 8.4 Hz, 2H), 7.06 (s, 1H), 6.98-6.94 (m, 2H), 6.88 (d, J = 7.6 Hz, 1H), 4.88 (s, 2H), 3.84 (s, 3H), 2.08 ( t, J = 7.0 Hz, 2H), 1.65-1.56 (m, 2H), 1.29-1.20 (m, 2H), 0.83 (t, J = 7.2 Hz, 3H).
1-93. 1-93. NN -(3--(3- 클로로페닐Chlorophenyl )-)- NN -((4'--((4'- 하이드록시바이페닐Hydroxybiphenyl -4-일)-4- days) 메틸methyl )) 펜탄아마이드Pentaneamide ( ( NN -(3-chlorophenyl)--(3-chlorophenyl)- NN -((4'-hydroxybiphenyl-4-yl)methyl)pentanamide) (AC-1629)-((4'-hydroxybiphenyl-4-yl) methyl) pentanamide) (AC-1629)
88% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.43 (d, J = 8.4 Hz, 4H), 7.32-7.25 (m, 2H), 7.21 (d, J = 8.0 Hz, 2H), 7.08 (s, 1H), 6.91-6.85 (m, 3H), 5.49 (s, 1H), 4.88 (s, 2H), 2.10 (t, J = 7.2 Hz, 2H), 1.64-1.57 (m, 2H), 1.27-1.22 (m, 2H), 0.83 (t, J = 7.2 Hz, 3H).88% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.43 (d, J = 8.4 Hz, 4H), 7.32-7.25 (m, 2H), 7.21 (d, J = 8.0 Hz, 2H), 7.08 (s, 1H ), 6.91-6.85 (m, 3H), 5.49 (s, 1H), 4.88 (s, 2H), 2.10 (t, J = 7.2 Hz, 2H), 1.64-1.57 (m, 2H), 1.27-1.22 ( m, 2H), 0.83 (t, J = 7.2 Hz, 3H).
1-94. 1-94. NN -(3--(3- 브로모페닐Bromophenyl )-)- NN -((4'--((4'- 메톡시바이페닐Methoxybiphenyl -4-일)-4- days) 메틸methyl )) 펜탄아마이드Pentaneamide ( ( NN -(3-bromophenyl)--(3-bromophenyl)- NN -((4'-methoxybiphenyl-4-yl)methyl)pentanamide) (AC-1631)-((4'-methoxybiphenyl-4-yl) methyl) pentanamide) (AC-1631)
73% 수율; 1H-NMR (CDCl3, 400MHz) δ 7.51 (d, J = 8.8 Hz, 2H), 7.46 (d, J = 8.4 Hz, 3H), 7.23-7.18 (m, 4H), 6.96 (d, J = 8.8 Hz, 2H), 6.91 (d, J = 7.6 Hz, 1H), 4.88 (s, 2H), 3.84 (s, 3H), 2.08 (t, J = 7.2 Hz, 2H), 1.61 -1.55 (m, 2H), 1.27-1.21 (m, 2H), 0.83 (t, J = 7.2 Hz, 3H).73% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.51 (d, J = 8.8 Hz, 2H), 7.46 (d, J = 8.4 Hz, 3H), 7.23-7.18 (m, 4H), 6.96 (d, J = 8.8 Hz, 2H), 6.91 (d, J = 7.6 Hz, 1H), 4.88 (s, 2H), 3.84 (s, 3H), 2.08 (t, J = 7.2 Hz, 2H), 1.61 -1.55 (m, 2H), 1.27-1.21 (m, 2H), 0.83 (t, J = 7.2 Hz, 3H).
1-95. 1-95. N-N- (3-(3- 브로모페닐Bromophenyl )-)- N-N- ((4'-((4'- 하이드록시바이페닐Hydroxybiphenyl -4-일)-4- days) 메틸methyl )) 펜탄아마이드Pentaneamide ( ( NN -(3-bromophenyl)--(3-bromophenyl)- NN -((4'-hydroxybiphenyl-4-yl)methyl)pentanamide) (AC-1632)-((4'-hydroxybiphenyl-4-yl) methyl) pentanamide) (AC-1632)
89% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.47-7.42 (m, 5H), 7.24-7.19 (m, 4H), 6.94 (d, J = 7.6 Hz, 1H), 6.87 (d, J = 8.0 Hz, 2H), 5.49 (s, 1H), 4.88 (s, 2H), 2.10 (t, J = 7.2 Hz, 2H), 1.64-1.58 (m, 2H), 1.29-1.20 (m, 2H), 0.83 (t, J = 7.2 Hz, 3H).89% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.47-7.42 (m, 5H), 7.24-7.19 (m, 4H), 6.94 (d, J = 7.6 Hz, 1H), 6.87 (d, J = 8.0 Hz , 2H), 5.49 (s, 1H), 4.88 (s, 2H), 2.10 (t, J = 7.2 Hz, 2H), 1.64-1.58 (m, 2H), 1.29-1.20 (m, 2H), 0.83 ( t, J = 7.2 Hz, 3H).
1-96. 1-96. NN -((4'-메톡시바이페닐-4-일)메틸)--((4'-methoxybiphenyl-4-yl) methyl)- NN -(3-(트리플루오로메틸)페닐)펜탄아마이드(-(3- (trifluoromethyl) phenyl) pentaneamide ( NN -((4'-methoxybiphenyl-4-yl)methyl)--((4'-methoxybiphenyl-4-yl) methyl)- NN -(3-(trifluoromethyl)phenyl)pentanamide) (AC-1634)-(3- (trifluoromethyl) phenyl) pentanamide) (AC-1634)
75% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.58 (d, J = 7.6 Hz, 1H), 7.5 (dd, J = 3.0, 11.8 Hz, 2H), 7.46 (d, J = 7.6 Hz, 3H), 7.28 (s, 1H), 7.21 (d , J = 8.0 Hz, 2H), 7.17 (d, J = 7.2 Hz, 1H), 6.97 (dd, J = 3.0, 11.8 Hz, 2H), 4.91 (s, 2H), 3.84 (s, 3H), 2.05 (s, 2H), 1.64-1.56 (m, 2H), 1.28-1.19 (m, 2H), 0.82 (t, J = 7.6 Hz, 3H).75% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.58 (d, J = 7.6 Hz, 1H), 7.5 (dd, J = 3.0, 11.8 Hz, 2H), 7.46 (d, J = 7.6 Hz, 3H), 7.28 (s, 1H), 7.21 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 7.2 Hz, 1H), 6.97 (dd, J = 3.0, 11.8 Hz, 2H), 4.91 (s, 2H ), 3.84 (s, 3H), 2.05 (s, 2H), 1.64-1.56 (m, 2H), 1.28-1.19 (m, 2H), 0.82 (t, J = 7.6 Hz, 3H).
1-97. 1-97. NN -((4'--((4'- 하이드록시바이페닐Hydroxybiphenyl -4-일)-4- days) 메틸methyl )-)- N-N- (3-((3- ( 트리플루오로메틸Trifluoromethyl )페닐)펜탄아마이드 ((Phenyl) pentaneamide ( NN -((4'--((4'- hydroxybiphenylhydroxybiphenyl -4--4- ylyl )methyl)-) methyl)- NN -(3-(trifluoromethyl)phenyl)pentanamide) (AC-1635)-(3- (trifluoromethyl) phenyl) pentanamide) (AC-1635)
96% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.59 (d, J = 7.6 Hz, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.44 (d, J = 8.4 Hz, 4H), 7.29 (s, 1H), 7.21 (q, 3H), 6.89 (d, J = 11.6 Hz, 2H), 5.14 (s, 1H), 4.91 (s, 2H), 2.06 (t, 2H), 1.64-1.58 (m, 2H), 1.28-1.2 (m, 2H), 0.82 (t, J = 7.4 Hz, 3H).96% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.59 (d, J = 7.6 Hz, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.44 (d, J = 8.4 Hz, 4H), 7.29 ( s, 1H), 7.21 (q, 3H), 6.89 (d, J = 11.6 Hz, 2H), 5.14 (s, 1H), 4.91 (s, 2H), 2.06 (t, 2H), 1.64-1.58 (m , 2H), 1.28-1.2 (m, 2H), 0.82 (t, J = 7.4 Hz, 3H).
1-98. 1-98. N-N- ((4'-((4'- 메톡시바이페닐Methoxybiphenyl -4-일)-4- days) 메틸methyl )-)- N-m-N-m- 톨릴펜탄아마이드Tolylpentaneamide ( ( NN -((4'-methoxybiphenyl-4-yl)methyl)--((4'-methoxybiphenyl-4-yl) methyl)- N-mN-m -tolylpentanamide) (AC-1637)-tolylpentanamide) (AC-1637)
90% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.51 (d, J = 7.6 Hz, 2H), 7.45 (d, J = 7.6 Hz, 2H), 7.21 (t, J = 10.0 Hz, 3H), 7.11 (d, J = 7.2 Hz, 1H), 6.97 (d, J = 7.6 Hz, 2H), 6.84 (s, 1H), 6.78 (d, J = 8.0 Hz, 1H), 4.88 (s, 2H), 3.848 (s, 3H), 2.31 (s, 3H), 2.08 (t, J = 7.4 Hz, 2H), 1.63-1.55 (m, 2H), 1.26-1.20 (m, 2H), 0.82 (t, J = 7.4 Hz, 3H).90% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.51 (d, J = 7.6 Hz, 2H), 7.45 (d, J = 7.6 Hz, 2H), 7.21 (t, J = 10.0 Hz, 3H), 7.11 ( d, J = 7.2 Hz, 1H), 6.97 (d, J = 7.6 Hz, 2H), 6.84 (s, 1H), 6.78 (d, J = 8.0 Hz, 1H), 4.88 (s, 2H), 3.848 ( s, 3H), 2.31 (s, 3H), 2.08 (t, J = 7.4 Hz, 2H), 1.63-1.55 (m, 2H), 1.26-1.20 (m, 2H), 0.82 (t, J = 7.4 Hz , 3H).
1-99. 1-99. NN -((4'--((4'- 하이드록시바이페닐Hydroxybiphenyl -4-일)-4- days) 메틸methyl )-)- NN -- mm -- 톨릴펜탄아마이드Tolylpentaneamide ( ( NN -((4'-hydroxybiphenyl-4-yl)methyl)-((4'-hydroxybiphenyl-4-yl) methyl) -N-m--N-m- tolylpentanamide) (AC-1638)tolylpentanamide) (AC-1638)
83% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.41-7.36 (m, 4H), 7.25-7.21 (m, 3H), 7.13 (d, J = 7.6 Hz, 1H), 6.97 (s, br, 1H), 6.89 (s, 1H), 6.85 (d, J = 6.8 Hz, 3H), 4.89 (s, 2H), 2.33 (s, 3H), 2.14 (t, J = 7.6 Hz, 2H), 1.64-1.56 (m, 2H), 1.28-1.18 (m, 2H), 0.81 (t, J = 7.2 Hz, 3H).83% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.41-7.36 (m, 4H), 7.25-7.21 (m, 3H), 7.13 (d, J = 7.6 Hz, 1H), 6.97 (s, br, 1H) , 6.89 (s, 1H), 6.85 (d, J = 6.8 Hz, 3H), 4.89 (s, 2H), 2.33 (s, 3H), 2.14 (t, J = 7.6 Hz, 2H), 1.64-1.56 ( m, 2H), 1.28-1.18 (m, 2H), 0.81 (t, J = 7.2 Hz, 3H).
1-100. 1-100. NN -(3--(3- 아이오도페닐Iodophenyl )-)- NN -((4'--((4'- 메톡시바이페닐Methoxybiphenyl -4-일)-4- days) 메틸methyl )) 펜탄아마이드Pentaneamide ( ( NN -(3-iodophenyl)--(3-iodophenyl)- NN -((4'-methoxybiphenyl-4-yl)methyl)pentanamide) (AC-1643)-((4'-methoxybiphenyl-4-yl) methyl) pentanamide) (AC-1643)
80% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.64 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 8.8 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 7.41 (s, 1H), 7.21 (d, J = 8.0 Hz, 2H), 7.06 (t, J = 8.0 Hz, 1H), 6.96 (d, J = 8.8 Hz, 3H), 4.87 (s, 2H), 3.84 (s, 3H), 2.07 (t, J = 7.0 Hz, 2H), 1.63-4.57 (m, 2H), 1.29-1.2(m, 2H), 0.83 (t, J = 7.4 Hz, 3H).80% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.64 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 8.8 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 7.41 ( s, 1H), 7.21 (d, J = 8.0 Hz, 2H), 7.06 (t, J = 8.0 Hz, 1H), 6.96 (d, J = 8.8 Hz, 3H), 4.87 (s, 2H), 3.84 ( s, 3H), 2.07 (t, J = 7.0 Hz, 2H), 1.63-4.57 (m, 2H), 1.29-1.2 (m, 2H), 0.83 (t, J = 7.4 Hz, 3H).
1-101. 1-101. NN -((4'--((4'- 하이드록시바이페닐Hydroxybiphenyl -4-일)-4- days) 메틸methyl )-)- NN -(3--(3- 아이오도페닐Iodophenyl )) 펜탄아마이드Pentaneamide ( ( NN -((4'--((4'- hydroxybiphenylhydroxybiphenyl -4--4- ylyl )methyl)-) methyl)- NN -(3--(3- iodophenyliodophenyl )) pentanamidepentanamide ) (AC-1644)(AC-1644)
90% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.65 (d, J = 8.0 Hz, 1H), 7.46-7.43 (m, 5H), 7.21 (d, J = 7.6 Hz, 2H), 7.06 (t, J = 8.0 Hz, 1H), 6.95 (d, J = 8.8 Hz, 1H), 6.86 (d, J = 8.4 Hz, 2H), 5.08 (s, 1H), 4.871 (s, 2H), 2.07 (t, 2H), 1.63-1.59 (m, 2H), 1.29-1.21 (m, 2H), 0.86 (t, 3H).90% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.65 (d, J = 8.0 Hz, 1H), 7.46-7.43 (m, 5H), 7.21 (d, J = 7.6 Hz, 2H), 7.06 (t, J = 8.0 Hz, 1H), 6.95 (d, J = 8.8 Hz, 1H), 6.86 (d, J = 8.4 Hz, 2H), 5.08 (s, 1H), 4.871 (s, 2H), 2.07 (t, 2H ), 1.63-1.59 (m, 2H), 1.29-1.21 (m, 2H), 0.86 (t, 3H).
1-102. 1-102. NN -(3--(3- 플루오로페닐Fluorophenyl )-)- NN -((4'--((4'- 메톡시바이페닐Methoxybiphenyl -4-일)-4- days) 메틸methyl )) 아세트아마이드Acetamide ( ( NN -(3--(3- fluorophenylfluorophenyl )-)- N-N- ((4'-((4'- methoxybiphenylmethoxybiphenyl -4--4- ylyl )methyl)methyl) acetamideacetamide ) (AC-1646)(AC-1646)
81% 수율; 1H-NMR (CDCl3, 400 MHz) δ 7.51 (d, J = 8.8 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 7.31 (q, J = 7.6 Hz, 1H), 7.25 (d, J = 8.4 Hz, 2H), 7.03 (t, J = 7.6 Hz, 1H), 6.97 (d, J = 8.8 Hz, 2H), 6.81 (dd, J = 8.4, 20.0 Hz, 2H), 4.90 (s, 2H), 3.85 (s, 3H), 1.93 (s, 3H).81% yield; 1 H-NMR (CDCl 3 , 400 MHz) δ 7.51 (d, J = 8.8 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 7.31 (q, J = 7.6 Hz, 1H), 7.25 ( d, J = 8.4 Hz, 2H), 7.03 (t, J = 7.6 Hz, 1H), 6.97 (d, J = 8.8 Hz, 2H), 6.81 (dd, J = 8.4, 20.0 Hz, 2H), 4.90 ( s, 2H), 3.85 (s, 3H), 1.93 (s, 3H).
1-103. 1-103. NN -(3--(3- 플루오로페닐Fluorophenyl )-)- NN -((4'--((4'- 하이드록시Hydroxy -[1,1'--[1,1'- 바이페닐Biphenyl ]-4-일)] -4-day) 메틸methyl )아세트아마이드 (Acetamide ( NN -(3--(3- fluorophenylfluorophenyl )-)- N-N- ((4'-((4'- hydroxyhydroxy -[1,1'-biphenyl]-4-yl)methyl)acetamide) (AC-1647)-(1,1'-biphenyl] -4-yl) methyl) acetamide) (AC-1647)
69% 수율; 1H NMR (CDCl3, 400 MHz) δ 7.45 (d, J = 8.8 Hz, 4H), 7.32 (q, J = 7.3 Hz, 1H), 7.24 (d, J = 8.0 Hz, 2H), 7.04 (t, J = 8.2 Hz, 1H), 6.89 (d, J = 7.2 Hz, 2H), 6.84 (d, J = 7.2 Hz, 1H), 6.79 (d, J = 8.8 Hz, 1H), 5.013 (s, 1H), 4.90 (s, 2H), 1.93 (s, 3H).69% yield; 1 H NMR (CDCl 3 , 400 MHz) δ 7.45 (d, J = 8.8 Hz, 4H), 7.32 (q, J = 7.3 Hz, 1H), 7.24 (d, J = 8.0 Hz, 2H), 7.04 (t , J = 8.2 Hz, 1H), 6.89 (d, J = 7.2 Hz, 2H), 6.84 (d, J = 7.2 Hz, 1H), 6.79 (d, J = 8.8 Hz, 1H), 5.013 (s, 1H ), 4.90 (s, 2H), 1.93 (s, 3H).
[[ 실험예Experimental Example ]]
실험예Experimental Example 1.  One. BLT2가BLT2 is 발현된 세포 또는  Expressed cells or BLT2가BLT2 is 발현되지 않은 세포의 준비 Preparation of Unexpressed Cells
본 실험을 위하여, BLT2가 발현되지 않은 세포 및 BLT2가 발현된 세포 (CHO-BLT2 cells)를 하기와 같은 방법으로 준비하였다. For this experiment, cells without BLT2 expression and cells with BLT2 expression (CHO-BLT2 cells) were prepared in the following manner.
CHO 세포는 한국세포주은행 (KCLB, 10061)으로부터 얻었으며, 이를 10%의 FBS (fetal bovine serum; Life technologies, Inc.), 페니실린 (50 units/㎖) 및 antibiotic antimycotic solution (Life technologies, Inc.)이 포함된 RPMI 1640 medium (Invitrogen) 에서 37 ℃, 5% CO2 조건에서 배양하였다. 상기 세포를 3일간 각각 Trypsin-EDTA를 사용하여 나누어 (splitting) 성장 단계로 유지시켰으며, PBS (phosphate-buffered saline; 137 mM NaCl, 2.7 mM KCl, 10 mM Na2HPO4, 2m MKH2PO4)로 세척하고, 이 후 새로운 배지에 첨가하여 BLT2가 발현되지 않은 세포를 준비하였다. CHO cells were obtained from the Korea Cell Line Bank (KCLB, 10061), which contained 10% FBS (fetal bovine serum; Life technologies, Inc.), penicillin (50 units / ml), and antibiotic antimycotic solution (Life technologies, Inc.). It was incubated at 37 ℃, 5% CO 2 conditions in RPMI 1640 medium (Invitrogen) containing the. The cells were maintained in the growth phase by splitting with Trypsin-EDTA for 3 days, respectively, with PBS (phosphate-buffered saline; 137 mM NaCl, 2.7 mM KCl, 10 mM Na 2 HPO 4 , 2m MKH 2 PO 4 ) And then added to fresh medium to prepare cells without BLT2 expression.
또한, 안정된 CHO/BLT2 클론 (stable CHO/BLT2 clones)의 제조를 위해, CHO-K1 세포를 HA-tagged human BLT2를 코딩하는 pcDNA3-long form BLT2로 형질전환하고, 0.4 ㎎/㎖의 G418 (Invitrogen, Carlsbad, CA, USA)로 선별하였다. BLT2 발현을 스크리닝하기 위해, 상기 선별된 클론을 인간-특이적 BLT2 프라이머를 사용하는 RT-PCR로 분석하였고, 대표적인 클론을 BLT2가 발현된 세포(CHO-BLT2)로 실험에 사용하였다.In addition, for the preparation of stable CHO / BLT2 clones, CHO-K1 cells were transformed with pcDNA3-long form BLT2 encoding HA-tagged human BLT2, and 0.4 mg / ml of G418 (Invitrogen). , Carlsbad, CA, USA). To screen for BLT2 expression, the selected clones were analyzed by RT-PCR using human-specific BLT2 primers, and representative clones were used in the experiments with cells expressing BLT2 (CHO-BLT2).
실험예Experimental Example 2.  2. BLT2가BLT2 is 발현된  Manifested 세포에 대한 성장 억제효과Growth inhibitory effect on cells 확인  Confirm
상기 실시예에서 제조한 화합물의 처리에 따른 세포 생존율을 3-(4,5-디메틸티아졸-2-일)-2,5-디페닐테트라졸륨 브로마이드 (MTT) 방법으로 측정하였다.Cell viability according to the treatment of the compound prepared in the above Example was measured by the 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide (MTT) method.
보다 구체적으로, 상기 실험예 1에서 준비한 1 × 104 개의 BLT2가 발현되지 않은 세포 (CHO-pcDNA 3.1 cells) 및 BLT2가 발현된 세포 (CHO-BLT2 cells)를 96 ㎜ 배양 접시 (culture dish)에 분주하고 24시간 동안 세포를 배양시켰다. 이 후, 배양액을 제거하고 무혈청 RPMI 배지를 첨가하였으며. 2시간 후, 상기 실시예에서 준비한 화합물 10 μM, 대조군인 DMSO (화합물 용매) 10 μM, 양성 대조군인 LY255283 ((1-[5-ethyl-2-hydroxy-4-[[6-methyl-6-(1H-tetrazol-5-yl)heptyl]oxy] phenyl]-ethanone) (Cayman) 10 μM을 각각의 세포에 1시간 동안 전처리하였다. 이 후, LTB4 (300nM)를 처리한 후 24시간 동안 배양하였다. 20μL의 MTT 용액 (5 ㎎/㎖, Sigma-Aldrich)을 각 웰에 가하고 습한 CO2 인큐베이터에서 37 ℃, 4 시간 동안 배양한 후, 상층액을 제거하고, 200 ㎕의 DMSO를 각 웰에 가해 불용성 보라색 포마잔 결정을 용해시켰다. 550 ㎚에서의 흡광도를 마이크로플레이트 리더(Molecular Devices, Sunnyvale, CA)를 이용하여 측정하였으며, 모든 측정은 3회 반복 수행하였다.More specifically, 1 × 10 4 prepared in Experimental Example 1 Cells without BLT2 expression (CHO-pcDNA 3.1 cells) and cells with BLT2 expression (CHO-BLT2 cells) were dispensed into a 96 mm culture dish and cultured for 24 hours. Thereafter, the culture was removed and serum-free RPMI medium was added. After 2 hours, 10 μM of the compound prepared in the above example, 10 μM of DMSO (compound solvent) as a control, LY255283 ((1- [5-ethyl-2-hydroxy-4-[[6-methyl-6-) as a positive control 10 μM of (1H-tetrazol-5-yl) heptyl] oxy] phenyl] -ethanone (Cayman) was pretreated in each cell for 1 hour, after which LTB 4 (300nM) was treated and incubated for 24 hours. 20 μL of MTT solution (5 mg / ml, Sigma-Aldrich) was added to each well and incubated for 4 hours at 37 ° C. in a humid CO 2 incubator, then the supernatant was removed and 200 μl of DMSO was added to each well to insoluble. The purple formazan crystals were dissolved. Absorbance at 550 nm was measured using a microplate reader (Molecular Devices, Sunnyvale, Calif.) And all measurements were repeated three times.
그 결과, 도 1a 내지 도 1e에 나타낸 바와 같이, BLT2가 발현된 세포(CHO-BLT2 cells)에 BLT2의 리간드인 LTB4 (300nM)를 처리한 경우 (DMSO+), 에탄올을 처리한 경우 (DMSO-)와 비교하여, 세포 성장이 20%에서 35%까지 증가하였고, BLT2가 발현된 세포 (CHO-BLT2)에서, 양성 대조군인 LY255283을 전 처리한 경우, 대조군인 DMSO를 처리한 경우와 비교하여 약 90%의 세포 성장을 나타냈으며, 상기 실시예의 화합물 처리에 따른 세포 성장 억제 효과를 확인하였다. 구체적으로, 본 발명의 화합물 (LMT-692, LMT-694, LMT-696, LMT-1013)을 10μM 전 처리한 경우, 대조군인 DMSO와 비교하여 각각 88.0%, 16.7%, 56.6%, 96.3%의 세포 성장을 나타내었는바, 성장 억제 효과를 확인하였다. 이와 마찬가지로 LMT-837 (65%), LMT-841 (60%), LMT-842 (70%), LMT-883 (99%), LMT-886 (99%), LMT-1016 (99%), LMT-1018 (71.6%), LMT-1019 (99%)의 화합물에서도 성장 억제효과를 확인하였다.As a result, as shown in FIGS. 1A to 1E, LTB 4 which is a ligand of BLT2 to BLT2-expressing cells (CHO-BLT2 cells) (300 nM) treated (DMSO +) and ethanol treated (DMSO-) cell growth increased from 20% to 35%, and in BLT2 expressed cells (CHO-BLT2), positive control Phosphorus LY255283 pre-treated, showed about 90% cell growth compared to the control group treated with DMSO, confirming the effect of inhibiting cell growth according to the compound treatment of the Example. Specifically, when the compound of the present invention (LMT-692, LMT-694, LMT-696, LMT-1013) 10μM pretreatment, compared to the control group DMSO of 88.0%, 16.7%, 56.6%, 96.3% respectively Cell growth was shown, confirming the growth inhibitory effect. Similarly, LMT-837 (65%), LMT-841 (60%), LMT-842 (70%), LMT-883 (99%), LMT-886 (99%), LMT-1016 (99%), LMT-1018 (71.6%), LMT-1019 (99%) also confirmed the growth inhibitory effect.
또한, 도 2a 내지 도 2d에 나타낸 바와 같이, BLT2가 발현된 세포(CHO-BLT2 cells)에 BLT2의 리간드인 LTB4 (300nM)를 처리한 경우 (DMSO+), 에탄올을 처리한 경우 (DMSO-)와 비교하여, 세포 성장이 20%에서 35%까지 증가하였고, BLT2가 발현된 세포 (CHO-BLT2)에서, 양성 대조군인 LY255283을 전 처리한 경우, 대조군인 DMSO를 처리한 경우와 비교하여 약 90%의 세포 성장을 나타냈으며, 상기 실시예의 화합물 처리에 따른 세포 성장 억제 효과를 확인하였다. 구체적으로, 본 발명의 화합물 AC-1632 (78.7%), AC-1635 (71.6%), AC-1646 (72.1%) 및 AC-1650 (82.2%)의 화합물에서 성장 억제효과를 확인하였다.In addition, as shown in Figures 2a to 2d, LTB 4 which is a ligand of BLT2 to BLT2-expressing cells (CHO-BLT2 cells) (300 nM) treated (DMSO +) and ethanol treated (DMSO-) cell growth increased from 20% to 35%, and in BLT2 expressed cells (CHO-BLT2), positive control Phosphorus LY255283 pre-treated, showed about 90% cell growth compared to the control group treated with DMSO, confirming the effect of inhibiting cell growth according to the compound treatment of the Example. Specifically, the growth inhibitory effect of the compounds of the present invention AC-1632 (78.7%), AC-1635 (71.6%), AC-1646 (72.1%) and AC-1650 (82.2%) was confirmed.
상기 실험결과는, 본 발명의 화합물 (LMT-692, LMT-696, LMT-837, LMT-841, LMT-842, LMT-883, LMT-886, LMT-1013, LMT-1016, LMT-1018, LMT-1019, AC-1632, AC-1635, AC-1646 및 AC-1650)은 BLT2로 유도된 세포 증식을 매우 우수한 효율로 억제할 수 있으며, 상기 화합물은 BLT2 관련 만성 폐쇄성 폐질환의 치료제로 활용 가능한 약학적 성분 (BLT2-blocking pharmacological molecules)으로 이용될 수 있음을 의미한다.The experimental results, the compounds of the present invention (LMT-692, LMT-696, LMT-837, LMT-841, LMT-842, LMT-883, LMT-886, LMT-1013, LMT-1016, LMT-1018, LMT-1019, AC-1632, AC-1635, AC-1646 and AC-1650) can inhibit BLT2-induced cell proliferation with excellent efficiency, and the compound is used as a therapeutic agent for BLT2-related chronic obstructive pulmonary disease. It can be used as a possible pharmaceutical ingredient (BLT2-blocking pharmacological molecules).
실험예Experimental Example 3.  3. LTBLTB 44 로in 유도된  Induced BLT2BLT2 의존적인 주화성 저해효과 확인 Identify dependent chemotaxis inhibitory effect
주화성 (Chemotactic motility)은 6.5-㎜ 직경의 폴리카보네이트 필터 (8-μm 의 공극 크기, Corning Costar)를 구비한 Transwell 챔버를 이용하여 분석하였다. 구체적으로, 필터의 아래쪽 표면을 37 ℃에서 1시간 동안 무혈청 RPMI 1640 배지 중의 10 ㎍/㎖ 파이브로넥틴으로 코팅하였다. 다양한 양의 LTB4를 포함한 RPMI 1640 배지와 함께 건조, 코팅된 필터를 Transwell 챔버의 아래쪽 웰에 두고, 무혈청 RPMI 1640 배지에 BLT1 및 BLT2를 안정적으로 발현하는 CHO 세포를 최종적으로 2 × 104 cells/100 ㎕로 윗쪽 웰에 로딩하여 실험하였다.Chemotactic motility was analyzed using a Transwell chamber equipped with a 6.5-mm diameter polycarbonate filter (8-μm pore size, Corning Costar). Specifically, the bottom surface of the filter was coated with 10 μg / ml fibronectin in serum free RPMI 1640 medium at 37 ° C. for 1 hour. A dry, coated filter with RPMI 1640 medium containing varying amounts of LTB 4 is placed in the bottom well of the Transwell chamber and finally 2 × 10 4 cells of CHO cells stably expressing BLT1 and BLT2 in serum-free RPMI 1640 medium. Experiments were performed by loading the upper wells with / 100 μl.
저해제들의 효과를 평가할 때 세포들은 분주 전 30분 동안 각각의 저해제로 전처리하였다. 37 ℃, 5% CO2에서 3시간 동안 배양한 후, 필터들을 메탄올로 3분 동안 고정시키고, 헤마톡실린 및 에오신으로 10분 동안 염색하였다. 본 실험에서, 세포는 BLT2가 발현된 세포(CHO-BLT2 cells) 및 BLT1이 발현된 세포(CHO-BLT1)를 이용하였으며, 양성대조군으로 각각 LY255283 및 U75302를, 비교대조군으로 BLT2의 리간드인 LTB4 , (300 nM), BLT1의 리간드인 LTB4 (10nM), LPA (lysophosphatidic acid; 100nM)를 이용하였다. 주화성은 광학현미경 하에서 (배율, × 200), 필터의 아래쪽 측면 상의 세포를 계수함으로써 정량하였다. 각 분석에서 6개의 필드를 계수하였고, 각각의 샘플은 2회씩 분석하였으며, 상기 분석은 3회씩 반복 수행하였다.When evaluating the effects of the inhibitors, the cells were pretreated with each inhibitor for 30 minutes before dispensing. After 3 hours of incubation at 37 ° C., 5% CO 2 , the filters were fixed with methanol for 3 minutes and stained with hematoxylin and eosin for 10 minutes. In this experiment, the cells used BLT2-expressing cells (CHO-BLT2 cells) and BLT1-expressing cells (CHO-BLT1), LY255283 and U75302 as the positive control, respectively, and LTB 4 , the ligand of BLT2 as the control. , (300 nM), LTB 4 , the ligand of BLT1 (10nM) and LPA (lysophosphatidic acid; 100nM) were used. Chemotaxis was quantified by counting cells on the lower side of the filter under an optical microscope (magnification, x 200). Six fields were counted in each assay, each sample analyzed twice, and the assay was repeated three times.
그 결과, 도 3a, 도 3b 및 하기 표 1에 나타낸 바와 같이, BLT2를 발현하는 세포(CHO-BLT2 cells)에서, 본 발명의 화합물 (LMT-692, LMT-696)의 농도가 증가함에 따라 (10-4, 10-3, 10-2, 10-1, 1, 10 및 102), 무 혈청 조건 하에서 CHO-BLT2 세포의 주화성이 억제됨을 확인하였으며, LMT-692 및 LMT-696의 화합물의 IC50 (50% 억제 농도)는 각각 7.566 μM 및 2.003 μM 이었다.As a result, as shown in Figures 3a, 3b and Table 1 below, in the BLT2 expressing cells (CHO-BLT2 cells), as the concentration of the compounds of the present invention (LMT-692, LMT-696) increases ( 10 -4 , 10 -3 , 10 -2 , 10 -1 , 1, 10 and 10 2 ), it was confirmed that chemotaxis of CHO-BLT2 cells under serum-free conditions, compounds of LMT-692 and LMT-696 IC 50 (50% inhibitory concentration) was 7.566 μM and 2.003 μM, respectively.
Figure PCTKR2018000957-appb-T000001
Figure PCTKR2018000957-appb-T000001
또한, 하기 표 2에 나타낸 바와 같이, BLT2를 발현하는 세포(CHO-BLT2 cells)에서, 본 발명의 화합물 LMT-1013의 농도가 증가함에 따라, 무 혈청 조건 하에서 CHO-BLT2 세포의 주화성이 억제됨을 확인하였으며, LMT-1013 화합물의 IC50 (50% 억제 농도)는 62.35 nM 이었다. 마찬가지로 BLT1을 발현하는 세포(CHO-BLT1 cells)에서, 본 발명의 화합물 LMT-1013의 농도가 증가함에 따라, 무 혈청 조건 하에서 CHO-BLT2 세포의 주화성이 억제됨을 확인하였으며, LMT-1013 화합물의 IC50 (50% 억제 농도)는 10 μM 이상이였다.In addition, as shown in Table 2 below, in the cells expressing BLT2 (CHO-BLT2 cells), as the concentration of the compound LMT-1013 of the present invention increases, chemotaxis of CHO-BLT2 cells is suppressed under serum-free conditions. The IC 50 (50% inhibitory concentration) of the LMT-1013 compound was 62.35 nM. Likewise, in the cells expressing BLT1 (CHO-BLT1 cells), as the concentration of the compound LMT-1013 of the present invention was increased, it was confirmed that chemotaxis of CHO-BLT2 cells was suppressed under serum-free conditions. IC 50 (50% inhibitory concentration) was at least 10 μΜ.
Figure PCTKR2018000957-appb-T000002
Figure PCTKR2018000957-appb-T000002
또한, 도 4a 및 도 4b에 나타낸 바와 같이, BLT2가 발현된 세포 (CHO-BLT2 cells)에 BLT2의 리간드인 LTB4 (300nM)를 처리한 경우 (DMSO+), 에탄올을 처리한 경우 (DMSO-)와 비교하여, 세포 주화성이 2.4배 증가 되었으며, 양성대조군으로 사용된 LY255283를 전처리 (10μM)한 경우, 리간드인 LTB4를 처리한 경우와 비교하여 대비 90%의 주화성을 나타냄을 확인하였다. 이와 마찬가지로 BLT1이 발현된 세포 (CHO-BLT1)에서, 리간드인 LTB4 (10nM)를 처리한 경우 (DMSO+), 에탄올을 처리한 경우 (DMSO-)와 비교하여, 세포 주화성이 2.2배 증가되었으며, 양성대조군으로 사용된 U75302를 전처리 (10μM)한 경우, 리간드인 LTB4를 처리한 경우와 비교하여 90%의 주화성을 나타냄을 확인하였다. 다만, 본 발명의 화합물 (LMT-692, LMT-694, LMT-696)의 경우, BLT2가 발현된 세포에 10 μM 전처리한 경우, 리간드인 LTB4 처리 (DMSO+)에 비해 주화성이 각각 66%, 90%, 70.3% 억제됨을 확인한 반면, BLT1가 발현된 세포(CHO-BLT1)에서는 리간드인 LTB4 처리 (DMSO+)에 비해 주화성이 억제되지 않음을 확인하였다.In addition, as shown in FIGS. 4A and 4B, LTB 4 which is a ligand of BLT2 to BLT2-expressing cells (CHO-BLT2 cells) When (300nM) treated (DMSO +) and ethanol treated (DMSO-), cell chemotaxis was 2.4-fold increased, and LY255283 used as a positive control pretreated (10μM), the ligand LTB Compared to the case of 4 treated, it was confirmed that the coinability of 90%. Similarly, in the cells expressing BLT1 (CHO-BLT1), the ligand LTB 4 (10 nM) treated (DMSO +), ethanol treated compared to (DMSO-), the cell chemotaxis increased 2.2 times, the pretreatment (10 μM) of U75302 used as a positive control, the ligand LTB It was confirmed that 90% of chemotaxis was shown in comparison with the case where 4 was treated. However, in the case of the compound of the present invention (LMT-692, LMT-694, LMT-696), when the BLT2 expressed cells 10 μM pretreatment, LTB 4 is a ligand Compared with treatment (DMSO +), chemotaxis was 66%, 90%, and 70.3% inhibited, whereas LTB 4 , a ligand, was expressed in BLT1-expressing cells (CHO-BLT1). It was confirmed that chemotaxis was not suppressed compared to treatment (DMSO +).
또한, 도 5a 내지 도 5d 및 하기 표 3에 나타낸 바와 같이, BLT2를 발현하는 세포(CHO-BLT2 cells)에서, 본 발명의 화합물 (AC-1074)의 농도가 증가함에 따라 (10-4, 10-3, 10-2, 10-1, 1, 10 및 102), 무 혈청 조건 하에서 CHO-BLT2 세포의 주화성이 억제됨을 확인하였으며, AC-1074의 화합물의 IC50 (50% 억제 농도)는 6.024 μM 이었다.In addition, as shown in FIGS. 5A to 5D and Table 3 below, in the cells expressing BLT2 (CHO-BLT2 cells), as the concentration of the compound of the present invention (AC-1074) increases (10 −4 , 10) -3 , 10 -2 , 10 -1 , 1, 10 and 10 2 ), it was confirmed that chemotaxis of CHO-BLT2 cells under serum-free conditions, IC 50 (50% inhibitory concentration) of the compound of AC-1074 Was 6.024 μΜ.
Figure PCTKR2018000957-appb-T000003
Figure PCTKR2018000957-appb-T000003
또한, 도 6a에 나타낸 바와 같이, BLT2가 발현된 세포(CHO-BLT2 cells)에 BLT2의 리간드인 LTB4 (300nM)를 처리한 경우 (DMSO+), 에탄올을 처리한 경우 (DMSO-)와 비교하여, 세포 주화성이 2.9배 증가되었고, 양성대조군으로 사용된 LY255283를 10 μM 전처리한 경우, 리간드인 LTB4를 처리한 경우와 비교하여 90% 의 주화성을 나타내었으며, 본 발명의 화합물 (AC-1074)을 BLT2가 발현된 세포에 10 μM 전처리한 경우, 리간드인 LTB4를 처리한 경우 (DMSO+)와 비교하여 주화성이 53% 억제됨을 확인하였다.In addition, as shown in Figure 6a, LTB 4 which is a ligand of BLT2 in BLT2-expressing cells (CHO-BLT2 cells) (300 nM) treated (DMSO +) and ethanol treated (DMSO-), compared to 2.9-fold increase in cell chemotaxis, 10 μM pretreated LY255283 used as a positive control, the ligand LTB 4 To It showed 90% chemotaxis compared to the treatment, and when the compound of the present invention (AC-1074) was pretreated with 10 μM of cells expressing BLT2, the ligand was treated with LTB 4 (DMSO +). It was confirmed that 53% inhibition of chemotaxis.
또한, 도 6b에 나타낸 바와 같이, BLT1이 발현된 세포(CHO-BLT1 cells)에 BLT1의 리간드인 LTB4 (10nM)를 처리한 경우 (DMSO+), 에탄올을 처리한 경우 (DMSO-)와 비교하여, 세포 주화성이 2.8배 증가되었고, 본 발명의 화합물 (AC-1074)을 BLT2가 발현된 세포에 10 μM 전처리한 경우, 리간드인 LTB4를 처리한 경우 (DMSO+)와 비교하여 주화성의 변화가 없음을 확인하였다.In addition, as shown in FIG. 6B, LTB 4 which is a ligand of BLT1 in BLT1-expressing cells (CHO-BLT1 cells) When treated with (10 nM) (DMSO +), compared with (DMSO-) with ethanol, the cell chemotaxis was increased by 2.8-fold, and the compound (AC-1074) of the present invention was added to cells expressing BLT2 10. In case of pretreatment with M, it was confirmed that there was no change in chemotaxis compared to (DMSO +) when the ligand LTB 4 was treated.
또한, 도 6c에 나타낸 바와 같이, BLT2가 발현된 세포(CHO-BLT2 cells)에 LPA (lysophosphatidic acid) (100nM)를 처리한 경우 (DMSO+), 에탄올을 처리한 경우 (DMSO-)와 비교하여, 세포 주화성이 3.4배 증가되었고, 본 발명의 화합물 (AC-1074)을 BLT2가 발현된 세포에 10 μM 전처리한 경우, 리간드인 LPA를 처리한 경우 (DMSO+)와 비교하여 주화성의 변화가 없음을 확인하였다.In addition, as shown in FIG. 6C, when BLT2-expressing cells (CHO-BLT2 cells) were treated with LPA (lysophosphatidic acid) (100nM) (DMSO +), and ethanol-treated (DMSO-), Cell chemotaxis was increased 3.4-fold, and when the compound of the present invention (AC-1074) was pretreated with 10 μM of BLT2-expressing cells, there was no change in chemotaxis compared to the ligand-treated LPA (DMSO +). It was confirmed.
상기 결과로부터, BLT2가 안정하게 발현되고 있는 세포 (CHO-BLT2)에서, 주화성 활성은 LTB4 자극에 인해 증가되며, 본 발명의 화합물 (LMT-692, LMT-696, LMT-1013, 및 AC-1074)은 이러한 주화성을 현저히 저해시킬 수 있는바, LTB4에 의해 유도된 BLT2-의존적 주화성을 저해시키기 위한 약학적 성분으로 이용될 수 있음을 의미한다.From the above results, chemotactic activity was LTB 4 in cells stably expressing BLT2 (CHO-BLT2). Increased due to stimulation, the compounds of the present invention (LMT-692, LMT-696, LMT-1013, and AC-1074) can significantly inhibit this chemotaxis, as the BLT2-dependent strain induced by LTB 4 It can be used as a pharmaceutical component to inhibit Mars.
실험예Experimental Example 4.  4. LTBLTB 44 와Wow BLT2BLT2 결합 저해효과 확인 Confirmation of binding inhibitory effect
LTB4와 BLT2 결합 (ligand binding affinity) 저해는 동위원소 트리튬(H3) 표기표 LTB4([3H]LTB4, ARC)(specific activity 160.0 Ci/mmol)를 사용하여 분석하였다. 실험방법은 CHO-BLT2 세포 2 × 106 개를 100 ㎜ 배양접시에 깔고 48 시간 동안 배양한 후 다음 과정을 진행한다. 수확한 세포를 균질기(homogenizer)로 1분씩 총 5회 사용하여 세포막의 단백질들을 분리한다. 그 후 4 ℃에서 45,000 RPM으로 40 분간 원심분리를 진행하여 세포막의 단백질만 수확하고 이를 40 ㎍/45 ㎕ 농도로 정량하였다. 동일하게 정량된 BLT2가 포함된 세포막 단백질에 각각 동일한 양의 [3H]LTB4 (5 nM)를 처리하고 농도별(10-9, 10-8, 10-7, 10-6 및 10-5 M)로 화합물을 처리하였을 때, 트리튬이 표기된 LTB4와 BLT2의 결합 억제정도를 Hidex 300sL 액체섬광계수기를 사용하여 측정하였다.LTB 4 and BLT2 binding (ligand binding affinity) inhibition was analyzed using the isotope tritium (H3) label LTB 4 ([3H] LTB 4, ARC) (specific activity 160.0 Ci / mmol). Experimental method is to put 2 × 10 6 CHO-BLT2 cells in a 100 mm culture dish and incubate for 48 hours before proceeding. The harvested cells are used five times for one minute in a homogenizer to separate the proteins of the cell membrane. Thereafter, centrifugation was performed for 40 minutes at 45,000 RPM at 4 ° C. to harvest only protein of the cell membrane and quantify it at a concentration of 40 μg / 45 μl. Cell membrane proteins containing equally quantified BLT2 were treated with the same amount of [3H] LTB 4 (5 nM), respectively, and at different concentrations (10 -9 , 10 -8 , 10 -7 , 10 -6 and 10 -5 M). ), The degree of inhibition of the binding of tritium-labeled LTB 4 and BLT2 was measured using a Hidex 300sL liquid scintillation counter.
그 결과, 도 7a 및 도 7b에 나타낸 바와 같이, BLT2를 발현하는 세포(CHO-BLT2 cells)에서, 본 발명의 화합물 (LMT-696 및 LMT-1013)의 농도가 증가함에 따라 (10-9, 10-8, 10-7, 10-6 및 10-5) LTB4와 BLT2의 결합이 억제됨을 확인하였으며, LMT-696 및 LMT-1013의 화합물의 IC50 (50% 결합 억제 농도)는 각각 5.6 nM 및 30.74 nM이었다.As a result, as shown in FIGS. 7A and 7B, in the BHO expressing cells (CHO-BLT2 cells), as the concentration of the compounds of the present invention (LMT-696 and LMT-1013) increased (10 -9 , 10 -8 , 10 -7 , 10 -6 and 10 -5 ) showed that the binding of LTB 4 to BLT2 was inhibited, and the IC 50 (50% binding inhibition concentration) of the compounds of LMT-696 and LMT-1013 was 5.6, respectively. nM and 30.74 nM.
또한, 도 7c에 나타낸 바와 같이, BLT2를 발현하는 세포(CHO-BLT2 cells)에서, 본 발명의 화합물 (AC-1074)의 농도가 증가함에 따라 (10-9, 10-8, 10-7, 10-6 및 10-5) LTB4와 BLT2의 결합이 억제됨을 확인하였으며, AC-1074 화합물의 IC50 (50% 결합 억제 농도)는 140.35 nM 이었다.In addition, as shown in Figure 7c, in the BLT2 expressing cells (CHO-BLT2 cells), as the concentration of the compound (AC-1074) of the present invention increases (10 -9 , 10 -8 , 10 -7 , 10 -6 and 10 -5 ) the binding of LTB 4 and BLT2 was inhibited, the IC 50 (50% binding inhibition concentration) of the AC-1074 compound was 140.35 nM.
실험예Experimental Example 5.  5. BLT2BLT2 억제를 통한 만성 폐쇄성 폐질환 치료 효과 확인 Inhibition of chronic obstructive pulmonary disease
5-1. 만성 폐쇄성 폐질환(5-1. Chronic obstructive pulmonary disease ( COPDCOPD ; chronic obstructive pulmonary disease)을 유발한 동물 모델의 제조; Preparation of animal models causing chronic obstructive pulmonary disease
담배연기로 유발된 만성 폐쇄성 폐질환(COPD) 동물모델 실험은 한국생명공학연구원(KRIBB)에서 수행되었다. 보다 구체적으로, 실험 마우스에 담배 추출물로 유발되는 만성 폐쇄성 폐질환을 일으키기 위해 하기와 같이 표준담배 추출물(Cigarette smoking, CS)을 제조하였다. ISO 3402 규정에 의거하여 표준담배 CM7(Coresta Monitering Cigarette 7, Heinr Borgwaldt, Germany) 60개피의 담배연기 응축물 포집을 온도 22±2 ℃ 및 상대습도 60±5 %로 유지되는 흡연실에서 실시하였으며, ISO 3308 규정에 의거하여 자동흡연장치(Automatic smoking machine, RM20, Heinr Borgwaldt, ISO 3308 규격품)를 이용하여 흡연부피 35.0±0.3 ㎖, 흡연주기 60±0.5 초, 흡연시간 2.00±0.02 초로 궐련담배를 연소시켰고, 꽁초길이는 팁페이퍼(tip paper)길이 + 3 ㎜ (겉포장지(overwrap) + 3 ㎜)로 하였으며, 92 ㎜의 캠프릿지 필터(cambridge filter, ISO3308 규격품)로 담배연기 응축물을 포집하였다. 담배연기 응축물이 포집 된 캠프릿지 필터를 시가렛 홀더(cigaratte holder)에서 분리하여 각각 100 ㎖ 삼각플라스크에 넣고 추출용매 아이소프로파놀을 50 ㎖씩 가하여 잘 흔든 다음, 실온에서 8 시간 이상 방치하여 추출하였다. 추출 후에 여과한 후, 감압여과 농축기로 농축하였으며 3 개의 삼각플라스크에 들어있는 농축액을 신티레이션 바이알(scintillation vial)에 모으고 질소 가스를 이용하여 완전 농축하였다.Toxic smoke-induced chronic obstructive pulmonary disease (COPD) animal model experiments were conducted by the Korea Institute of Bioscience and Biotechnology (KRIBB). More specifically, standard tobacco extract (Cigarette smoking, CS) was prepared as follows to cause chronic obstructive pulmonary disease caused by tobacco extract in experimental mice. In accordance with ISO 3402, 60 cigarette smoke condensate collections were carried out in a smoking room maintained at a temperature of 22 ± 2 ° C and a relative humidity of 60 ± 5%, according to the ISO 3402 standard, Coresta Monitering Cigarette 7, Heinr Borgwaldt, Germany. Cigarette cigarettes were burned using an automatic smoking machine (Automatic smoking machine, RM20, Heinr Borgwaldt, ISO 3308 standard) with a smoking volume of 35.0 ± 0.3 ml, a smoking cycle of 60 ± 0.5 seconds and a smoking time of 2.00 ± 0.02 seconds. The length of the butts was set to tip paper length + 3 mm (overwrap + 3 mm), and the smoke smoke condensate was collected by a 92 mm cambridge filter (ISO 3308 standard product). The filter cartridge, which collected the smoke smoke condensate, was separated from the cigaratte holder and placed in a 100 ml Erlenmeyer flask, and then shaken well by adding 50 ml of extraction solvent isopropanol, followed by extraction at room temperature for at least 8 hours. . After extraction, the resultant was filtered, concentrated with a vacuum filter concentrator, and the concentrates contained in three Erlenmeyer flasks were collected in scintillation vials and completely concentrated with nitrogen gas.
오리엔트바이오사(한국)에서 공급받은 수컷 8주령의 마우스(BALB/c, specific pathogen-free, SPF, 18~20 g)에 실험 당일까지 고형사료(항생제 무첨가, 삼양사료 Co.)와 물을 충분히 공급하였고, 온도 22±2 ℃, 습도 55±15 % 및 12 시간의 명암사이클(light-dark cycle)의 환경에서 1 주간 적응시킨 후 실험에 사용하였다. 8 주령 BALB/c 마우스를 7 % 클로랄 하이드레이트(chloral hydrate)로 마취한 후 움직임이 없을 때 생쥐의 앞니를 고무밴드로 고정시킨 후, 리포다당체(lipopolysaccharide, LPS) 100 ㎍/㎖에 표준담배 추출물(Cigarette smoking, CS) 4 ㎎/㎖을 1:1로 섞은 것(LPS+CS)을 주 1회 3 주간 마우스 코와 입에 각각 50 ㎕씩, 합 100 ㎕를 기관 내 주사(intratrachea) 흡입시켜 만성 폐쇄성 폐질환 마우스 모델을 만들었다.Male 8-week-old mice (BALB / c, SPF, 18-20 g) supplied by Orient Biotech Co., Ltd. (Korea) were thoroughly fed with solid feed (no antibiotics, Samyang Feed Co.) and water until the day of the experiment. It was supplied and used for experiments after 1 week of adaptation in a temperature of 22 ± 2 ° C., a humidity of 55 ± 15% and a light-dark cycle of 12 hours. After 8-week-old BALB / c mice were anesthetized with 7% chloral hydrate, the mouse's incisors were fixed with rubber bands when there was no movement, and then standard tobacco extract was added to 100 μg / ml of lipopolysaccharide (LPS). (Cigarette smoking, CS) A mixture of 4 mg / ml 1: 1 (LPS + CS) was inhaled by intratracheal injection with 100 μl of intranasal injection of 50 μl each in the nose and mouth of mice for 3 weeks. A chronic obstructive pulmonary disease mouse model was created.
5-2. 만성 폐쇄성 폐질환(5-2. Chronic obstructive pulmonary disease ( COPDCOPD ) 동물 모델에서의 기관지 폐포세척액 내 In Bronchoalveolar Lavage Fluid in Animal Models TNFTNF -α 생성 억제 효과 확인-α production inhibitory effect
담배연기로 유발된 만성 폐쇄성 폐질환 동물모델에서 약물의 효과를 확인하기 위한 중요 인자로서, 주로 폐포세척액(BALF)에서의 TNF-α, IL-6, 또는 ROS 등의 생성을 확인한다. 따라서 본 발명의 화합물의 만성 폐쇄성 폐질환 치료 효과를 확인하기 위해 하기와 같이 실험을 하였다. 본 발명의 화합물 AC-1013을 10 ㎎/㎏ 또는 20 ㎎/㎏을 농도 별로 상기 실험예 5-1에 기재된 LPS+CS를 마우스의 기관 내 주사하기 1 시간 전에 경구투여하였다. 본 실험에서는 아무런 처리를 하지 않은 정상대조군과, LPS+CS를 처리한 음성대조군, LPS+CS를 처리하기 1 시간 전 비교약물인 ROF(Roflumilast PDE4 inhibitor)를 10 ㎎/㎏의 농도로 경구투여한 실험군, 본 발명의 화합물 AC-1013을 10 ㎎/㎏ 경구투여한 실험군 및 화합물 AC-1013을 20 ㎎/㎏ 경구투여한 실험군으로 나누었다. 마우스에서 분리한 기관지 폐포세척액에서 TNF-α, ROS 및 IL-6의 생성 수준을 측정하였다. TNF-α의 항체(antibody)를 코팅(coating) 완충용액(291195, R&D System)에 희석하여 마이크로플레이트(microplate)에 코팅한 후 4 ℃에서 하루동안 방치(overnight)하고 각 웰(well)을 3 회 워싱(washing) 완충용액으로 세척한 후 10 배 희석한 혈청을 100 ㎕씩 분주하였다. 또한, 1 시간 동안 실온에서 방치한 후 2회 워싱 완충용액으로 세척한 다음 아비딘-에이치알피 결합 항체(Avidin-HRP conjugeted antibody, DY998, R&D System)를 100 ㎕ 처리하고 1 시간 동안 실온에서 방치한 후 다시 세척하였다. 그 후에, TMB(5,5'-tetramethylbenzidine) 기질을 100 ㎕씩 분주하고 암소에서 30 분간 방치한 후 50 ㎕의 스탑(stop) 용액을 처리하고 ELISA leader(Emax, Molecular Devices)로 450nm에서 흡광도를 측정하였다.As an important factor for confirming the effect of drugs in animal models of chronic obstructive pulmonary disease caused by tobacco smoke, the production of TNF-α, IL-6, or ROS in alveolar lavage fluid (BALF) is mainly confirmed. Therefore, the following experiment was conducted to confirm the effect of the treatment of chronic obstructive pulmonary disease of the compound of the present invention. 10 mg / kg or 20 mg / kg of compound AC-1013 of the present invention was administered orally 1 hour prior to intratracheal injection of LPS + CS described in Experimental Example 5-1 in mice. In this experiment, normal control group without any treatment, negative control group treated with LPS + CS, and ROF (Roflumilast PDE4 inhibitor), a comparative drug, were administered orally at a concentration of 10 mg / kg 1 hour before LPS + CS treatment. The experimental group, the experimental group administered orally with 10 mg / kg of compound AC-1013 of the present invention, and the experimental group administered orally with 20 mg / kg of compound AC-1013. Production levels of TNF-α, ROS, and IL-6 were measured in bronchoalveolar lavage fluid isolated from mice. The TNF-α antibody was diluted in a coating buffer solution (291195, R & D System), coated on a microplate, and then left overnight at 4 ° C for 3 wells. After washing with the washing buffer (washing), 100 μl of serum diluted 10-fold was dispensed. In addition, it was left at room temperature for 1 hour, washed twice with washing buffer, and then treated with 100 [mu] l of avidin-HRP conjugeted antibody (DY998, R & D System) and left at room temperature for 1 hour. Washed again. Subsequently, 100 μl of TMB (5,5'-tetramethylbenzidine) substrate was aliquoted, left in the dark for 30 minutes, treated with 50 μl stop solution and absorbed at 450 nm with ELISA leader (Emax, Molecular Devices). Measured.
그 결과, 도 8a에 나타낸 바와 같이, COPD가 유도된 음성대조군은 기관지 폐포세척액 내 TNF-α의 생성이 정상대조군에 비해 현저하게 증가하였으며, 본 발명의 화합물 AC-1013을 투여한 실험군은 음성대조군에 비해 TNF-α의 생성이 억제되는 것을 확인하였다.As a result, as shown in Figure 8a, the COPD-induced negative control group significantly increased the production of TNF-α in bronchoalveolar lavage fluid compared to the normal control group, the experimental group administered the compound of the present invention AC-1013 negative control group It was confirmed that the production of TNF-α is inhibited as compared with that of.
5-3. 만성 폐쇄성 폐질환(5-3. Chronic obstructive pulmonary disease ( COPDCOPD ) 동물 모델에서의 기관지 폐포세척액 내 IL-6 생성 억제 효과 확인) Inhibition of IL-6 Production in Bronchoalveolar Lavage Fluid in Animal Models
본 발명의 화합물 AC-1013이 만성 폐쇄성 폐질환 마우스 모델에서 기관지 폐포세척액 내 IL-6 생성 변화에 미치는 영향을 알아보기 위해 상기 실험예 5-2에 기재된 방법과 동일한 방법으로 실험하였다.In order to investigate the effect of the compound AC-1013 of the present invention on the change of IL-6 production in bronchoalveolar lavage fluid in the chronic obstructive pulmonary disease mouse model, it was tested in the same manner as described in Experimental Example 5-2.
그 결과, 도 8b에 나타낸 바와 같이, COPD가 유도된 음성대조군은 기관지 폐포세척액 내 IL-6의 생성이 정상대조군에 비해 현저하게 증가하였으며, 본 발명의 화합물 AC-1013을 투여한 실험군은 음성대조군에 비해 IL-6의 생성이 억제되는 것을 확인하였다.As a result, as shown in Figure 8b, the COPD-induced negative control group significantly increased the production of IL-6 in bronchoalveolar lavage fluid compared with the normal control group, the experimental group administered the compound of the present invention AC-1013 negative control group It was confirmed that the production of IL-6 is inhibited compared with that of.
5-4. 만성 폐쇄성 폐질환(5-4. Chronic obstructive pulmonary disease ( COPDCOPD ) 동물 모델에서의 기관지 폐포세척액 내 In Bronchoalveolar Lavage Fluid in Animal Models ROSROS 생성 억제 효과 확인 Confirmation of generation suppression effect
본 발명의 화합물 AC-1013 투여에 의한 반응성 산소 생성량(ROS; Reactive oxygen species)을 측정하기 위하여, 상기 실험예 5-2에 기재된 각 개체의 일부 기관지 폐포 세척액을 PBS로 세척한 뒤, 10 μM 2,7-디클로로플루오레세인 디아세테이트(2,7-dichlorofluorescein diacetate) (35845, Sigma, , St. Louis, MO)를 첨가하여 10 분간 상온 암실에서 방치한 후, spectroflurometer로 측정하였다(Ex = 480 ㎚, Em = 522 ㎚).In order to measure the amount of reactive oxygen species (ROS; Reactive oxygen species) by administration of the compound of the present invention AC-1013, some bronchial alveolar lavage fluid of each individual described in Experimental Example 5-2 was washed with PBS, and then 10 μM 2 2,7-dichlorofluorescein diacetate (35845, Sigma,, St. Louis, Mo.) was added thereto, and left in a dark room at room temperature for 10 minutes, followed by measurement with a spectroflurometer (Ex = 480 nm). , Em = 522 nm).
그 결과, 도 8c에 나타낸 바와 같이, 본 발명의 화합물 AC-1013 투여에 의해, 활성 산소 발생량은 COPD가 유도된 음성대조군 및 비교 약물(ROF) 처리군보다 감소한 것을 확인하여, 뛰어난 활성 산소 발생량 억제 효과를 확인하였다.As a result, as shown in FIG. 8C, by the administration of the compound AC-1013 of the present invention, it was confirmed that the amount of active oxygen generation was reduced compared to the negative control group and the comparative drug (ROF) -induced COPD-induced suppression of superior active oxygen generation. The effect was confirmed.
실험예Experimental Example 6. 화합물  6. Compound LMTLMT -886 및 -886 and LMTLMT -1013의 -1013 COPDCOPD 치료 효과 확인 Confirm treatment effect
6-1. 담배연기 및 6-1. Cigarette smoke and 지질다당류로As a lipopolysaccharide 유발된 만성 폐쇄성 폐질환 동물모델의 제조 Preparation of Induced Chronic Obstructive Pulmonary Disease Animal Model
담배연기(Cigarette smoke ,CS) 및 지질다당류(lipopolysaccharide, LPS)로 유발된 만성 폐쇄성 폐질환(COPD) 동물 모델에서 약물의 효과를 확인하기 위하여, 본 발명의 화합물 LMT-886 및 LMT-1013은 한국파비스제약에서 파우더 형태로 제공받아 적절한 용매에 녹여서 사용하였고, 6주령 수컷 C57BL/6N 마우스는 ㈜코아텍(한국)으로부터 공급받아 실험에 사용하였다.In order to examine the effects of drugs in animal models of chronic obstructive pulmonary disease (COPD) induced by Cigarette smoke (CS) and lipopolysaccharide (LPS), the compounds LMT-886 and LMT-1013 of the present invention It was used in the form of powder from Parvis Pharmaceuticals, dissolved in an appropriate solvent, and 6-week-old male C57BL / 6N mice were supplied from KOTEC (Korea) and used for experiments.
상기 마우스는 1일 1시간씩 총 8개비의 담배연기에 노출시켰으며, LPS는 5μg/50μl/mouse로 비강 내 투여(intranasal administration)하였다. 본 발명의 화합물(LMT-886 및 LMT-1013)은 담배연기에 노출되기 1시간 전에 경구투여 하였다. The mice were exposed to a total of 8 cigarette smokes for 1 hour per day, and LPS was intranasally administered at 5 μg / 50 μl / mouse. Compounds of the invention (LMT-886 and LMT-1013) were administered orally 1 hour before exposure to tobacco smoke.
6-2. 염증세포침윤 확인6-2. Inflammatory cell infiltration
담배연기는 폐조직 내 강력한 자극물질로 작용하여, 염증성 신호전달체계를 활성화시켜 폐 염증을 더욱 악화시키는 특징을 가지므로, 염증을 억제하는 것은 만성 폐쇄성 폐질환 개선 효과의 지표로 삼을 수 있기 때문에 염증성 세포 (Neutrophils, Macrophages 등)의 침윤을 확인하였다. 이에 상기 실시예 6-1에 기재된 COPD 마우스의 기관지 폐포세척액 내 염증세포의 수를 확인하기 위하여, 기관지 삽입술을 이용해 마우스의 폐에 saline (PBS: phosphate buffered saline) 700ul (total volume 1.4 ml)을 총 두 번 삽입하여 폐포세척액을 수득한 다음, 원심분리(14,000 rpm, 4℃, 5min)하여 세포가 분리된 1.5ml tube에 PBS 1ml를 넣어 Tapping한 후, 각 샘플당 100 μl를 취득해 cytospin(한일과학, 한국)을 이용하여 1000rpm에서 5분간 회전시켜 슬라이드에 부착시켰다. 그 후, Diff-Quik staining kit를 이용하여 세포의 핵과 세포질을 염색하여 염증세포를 구분하고 현미경으로 검정하여 세포수를 계산하였다. Tobacco smoke acts as a powerful stimulant in the lung tissue and activates the inflammatory signaling system, which further exacerbates pulmonary inflammation. Therefore, suppressing inflammation can be used as an index for improving chronic obstructive pulmonary disease. Infiltration of inflammatory cells (Neutrophils, Macrophages, etc.) was confirmed. Therefore, in order to confirm the number of inflammatory cells in the bronchial alveolar lavage fluid of the COPD mouse described in Example 6-1, 700ul (total volume 1.4 ml) of saline (PBS: phosphate buffered saline) was added to the lungs of the mouse using bronchial implantation. After inserting twice to obtain alveolar lavage fluid, centrifugation (14,000 rpm, 4 ° C, 5 min) was carried out by tapping 1 ml of PBS into a 1.5 ml tube from which cells were separated, and then 100 μl of each sample was obtained for cytospin (Hanil). Science, Korea) was attached to the slide by rotating for 5 minutes at 1000rpm. Thereafter, the nucleus and cytoplasm of the cells were stained using a Diff-Quik staining kit to distinguish inflammatory cells, and the number of cells was calculated by microscopic examination.
그 결과, 도 9에 나타낸 바와 같이, 본 발명의 화합물 LMT-886 및 LMT-1013은 COPD마우스의 염증세포(호중구)의 침윤을 유의적으로 감소시켰다. As a result, as shown in Figure 9, the compounds of the present invention LMT-886 and LMT-1013 significantly reduced the infiltration of inflammatory cells (neutrophils) of COPD mice.
6-3. NE 및 6-3. NE and ROSROS 측정 Measure
폐기종을 유발하는 독성물질에는 neutrophil elastase (NE)와 reactive oxygen species (ROS)가 있는데, Dichlorofluorescin diacetate (DCFDA)은 세포막을 통과할 수 있는 oxidation-sensitive probe로서 세포 내 상기 ROS와 반응하여 세포막을 통과 할 수 없는 형광 물질인 DCF로 전환된다. Toxic agents that cause emphysema include neutrophil elastase (NE) and reactive oxygen species (ROS). Dichlorofluorescin diacetate (DCFDA) is an oxidation-sensitive probe that can cross cell membranes and reacts with the ROS in the cell It is converted to DCF, which is an unknown fluorescent substance.
이에 본 발명의 화합물 LMT-886 및 LMT-1013 투여에 의한 NE 및 ROS를 측정하기 위하여, 상기 실시예 6-1에 기재된 COPD 마우스의 폐에 saline (PBS: phosphate buffered saline) 700ul (total volume 1.4 ml)을 두 번 넣었다 뺀 다음 취득한 폐포세척액은 14,000 rpm, 4℃, 5min 조건에서 상층액과 세포를 분리였다. Therefore, in order to measure NE and ROS by administration of the compounds LMT-886 and LMT-1013 of the present invention, 700ul of saline (PBS: phosphate buffered saline) in the lungs of COPD mice described in Example 6-1 (total volume 1.4 ml) The alveolar lavage fluid was separated and supernatant was separated from the supernatant at 14,000 rpm, 4 ° C, and 5 min.
상기 분리된 세포가 담겨 있는 1.5ml tube에는 PBS를 1ml 넣어 Tapping후 샘플 당 100ul를 채취한 다음 DCFDA를 사용하여 ROS를 측정(the fluorescence intensity 485 nm 530 nm)하고, Elastase substrate VIII(CALBIOCHEMCFDA)를 사용해, Colorimetric 기법(405nm에서 흡광도 측정)을 통하여 NE를 측정하였다. In a 1.5ml tube containing the separated cells, 1ml of PBS was added and 100ul of sample was collected after tapping, and then ROS was measured using DCFDA (the fluorescence intensity 485 nm 530 nm), and Elastase substrate VIII (CALBIOCHEMCFDA) was used. NE was measured using Colorimetric technique (absorbance measurement at 405 nm).
그 결과, 도 10 및 도 11에 나타낸 바와 같이, NE(도 10 참조)와 ROS(도 11 참조)는 COPD마우스의 기관지 폐포세척액 내에서 현저히 증가하였으나, 본 발명의 화합물 LMT-886 및 LMT-1013의 경구 투여에 따라 독성물질의 생성이 유의적으로 감소하는 것을 확인하였다.As a result, as shown in FIGS. 10 and 11, NE (see FIG. 10) and ROS (see FIG. 11) were significantly increased in bronchoalveolar lavage fluid of COPD mice, but the compounds LMT-886 and LMT-1013 of the present invention. It was confirmed that the oral administration of significantly reduced production of toxic substances.
6-4. 6-4. TNFTNF -α 및 IL-6 측정-α and IL-6 measurements
본 발명의 화합물 LMT-886 및 LMT-1013 투여에 의한 염증성 사이토카인 TNF-α 및 IL-6의 변화를 측정하기 위하여, 상기 실시예 6-1에 기재된 COPD 마우스의 폐에 saline (PBS: phosphate buffered saline) 700ul (total volume 1.4 ml)을 두 번 넣었다 뺀 다음 취득한 폐포세척액은 14,000 rpm, 4℃, 5min 조건에서 상층액과 세포를 분리하였다. 상기 상층액의 TNF-α 및 IL-6의 레벨을 측정하기 위하여 ELISA kit(BD Bioscience, San Diego, CA)을 사용하였으며, 각 제조회사의 프로토콜에 따라 실시하였다. 구체적으로는 TNF-α혹은 IL-6 항체가 부착된 96 웰 플레이트에 상등액을 분주하여 2시간동안 부착시킨 후, 세척액으로 세척하고, detection 항체를 HRP와 함께 1시간동안 부착시킨 다음, 다시 세척하였다. 그리고 TMB 기질을 이용하여 발색반응을 한 후, 황산용액으로 반응을 중지시킨 다음, SPARKTM 10 M multimode microplate reader (Tecan system inc., CA, USA)를 사용하여 450 nm에서 흡광도를 측정하였다. In order to measure changes in the inflammatory cytokines TNF-α and IL-6 by administration of the compounds LMT-886 and LMT-1013, saline (PBS: phosphate buffered) in the lungs of COPD mice described in Example 6-1 After saline) 700ul (total volume 1.4 ml) was added and removed twice, supernatant and cells were separated at 14,000 rpm, 4 ° C, and 5min. ELISA kit (BD Bioscience, San Diego, Calif.) Was used to measure the levels of TNF-α and IL-6 in the supernatant, and was performed according to the protocol of each manufacturer. Specifically, the supernatant was dispensed on a 96 well plate to which TNF-α or IL-6 antibody was attached and attached for 2 hours, followed by washing with a washing solution, and the detection antibody was attached with HRP for 1 hour and then washed again. . After the color reaction was performed using a TMB substrate, the reaction was stopped with sulfuric acid solution, and the absorbance was measured at 450 nm using a SPARK ™ 10 M multimode microplate reader (Tecan system inc., CA, USA).
그 결과, 도 12 및 도 13에 나타낸 바와 같이, TNF-α(도 12 참조)와 IL-6(도 13 참조)는 COPD 마우스 기관지 폐포세척액에서 현저히 증가하였으나, 본 발명의 화합물 LMT-886 및 LMT-1013의 경구투여는 상기 TNF-α 및 IL-6과 같은 사이토카인의 생성을 현저히 감소시키는 것을 확인하였다.As a result, as shown in FIGS. 12 and 13, TNF-α (see FIG. 12) and IL-6 (see FIG. 13) were significantly increased in COPD mouse bronchial alveolar lavage fluid, but the compounds LMT-886 and LMT of the present invention. Oral administration of -1013 was found to significantly reduce the production of cytokines such as TNF-α and IL-6.
6-5. H&E 염색6-5. H & E Dyeing
조직병리검사를 위해 폐를 떼어내어 즉시 10% formaldehyde 용액에 고정한 후 세절하여 흐르는 물에 8 시간 수세한 다음, epoxy에 포매하고, 이것을 microtome으로 절편을 만들었다. 표준방법에 의하여 폐조직 내 염증을 관찰하기 위하여 H&E(Hematoxylin and eosin)으로 염색을 실시하였으며, Histomount용액(invitrogen, USA)으로 고정시킨 후, 광학현미경을 이용하여 폐조직의 병리학적 변화를 검경하였다.For histopathology, the lungs were removed, immediately fixed in 10% formaldehyde solution, rinsed and washed with running water for 8 hours, embedded in epoxy, and sections were made of microtome. In order to observe inflammation in lung tissue by standard method, staining was performed with hematoxylin and eosin (H & E), and then fixed with Histomount solution (invitrogen, USA), and pathological changes of lung tissue were examined using an optical microscope. .
그 결과, 도 14에 나타낸 바와 같이, COPD군에서는 세기관지 주변에 염증세포의 침윤이 현저히 증가되는 반면, 본 발명의 화합물 LMT-886 및 LMT-1013 처리군(10 or 20 mg/kg)에서는 염증 세포의 침윤이 감소하는 것으로 나타났다. As a result, as shown in FIG. 14, infiltration of inflammatory cells around the bronchioles was significantly increased in the COPD group, whereas the inflammatory cells in the compound LMT-886 and LMT-1013 treated groups (10 or 20 mg / kg) of the present invention. The infiltration of appeared to decrease.
상기로부터, 본 발명의 화합물 LMT-886 및 LMT-1013은 담배연기 및 지질다당류로 유발된 만성 폐쇄성 폐질환 동물 모델에서 폐의 염증을 개선하는 효능을 보이며, 저하된 폐 기능을 회복시킬 수 있을 것으로 판단된다.From the above, the compounds LMT-886 and LMT-1013 of the present invention is shown to improve the inflammation of the lungs in animal models of chronic obstructive pulmonary disease caused by tobacco smoke and lipopolysaccharide, and may be able to restore the reduced lung function. Judging.
전술한 본 발명의 설명은 예시를 위한 것이며, 본 발명이 속하는 기술분야의 통상의 지식을 가진 자는 본 발명의 기술적 사상이나 필수적인 특징을 변경하지 않고서 다른 구체적인 형태로 쉽게 변형이 가능하다는 것을 이해할 수 있을 것이다. 그러므로 이상에서 기술한 실시예들은 모든 면에서 예시적인 것이며 한정적이 아닌 것으로 이해해야만 한다.The foregoing description of the present invention is intended for illustration, and it will be understood by those skilled in the art that the present invention may be easily modified in other specific forms without changing the technical spirit or essential features of the present invention. will be. Therefore, it should be understood that the embodiments described above are exemplary in all respects and not restrictive.
본 발명의 BTL2 억제 활성을 나타내는 화합물은 우수한 주화성 억제 효과 및 만성 폐쇄성 폐질환 치료 효과를 나타내는바, 이에, 본 발명의 화합물은 만성 폐쇄성 폐질환(COPD; chronic obstructive pulmonary disease)을 예방 또는 치료하기 위한 약학적 조성물의 유효성분으로 유용하게 사용될 수 있을 것으로 기대된다.Compounds exhibiting BTL2 inhibitory activity of the present invention exhibits an excellent chemotactic inhibitory effect and a treatment effect for chronic obstructive pulmonary disease, whereby the compounds of the present invention are for preventing or treating chronic obstructive pulmonary disease (COPD). It is expected that it may be usefully used as an active ingredient of a pharmaceutical composition.

Claims (9)

  1. 하기 화학식 1로 표시되는 화합물, 이의 이성질체 또는 이의 약학적 허용가능한 염을 유효성분으로 포함하는, 만성 폐쇄성 폐질환(COPD; chronic obstructive pulmonary disease) 예방 또는 치료용 약학적 조성물.A pharmaceutical composition for preventing or treating chronic obstructive pulmonary disease (COPD) comprising a compound represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
    [화학식 1][Formula 1]
    Figure PCTKR2018000957-appb-I000049
    Figure PCTKR2018000957-appb-I000049
    상기 화학식 1에서,In Chemical Formula 1,
    R1은 C1~C10의 알킬이고,R 1 is C 1 -C 10 is alkyl,
    R2는
    Figure PCTKR2018000957-appb-I000050
    ,
    Figure PCTKR2018000957-appb-I000051
    ,
    Figure PCTKR2018000957-appb-I000052
    ,
    Figure PCTKR2018000957-appb-I000053
    , 또는
    Figure PCTKR2018000957-appb-I000054
    이며,     R 2 is
    Figure PCTKR2018000957-appb-I000050
    ,
    Figure PCTKR2018000957-appb-I000051
    ,
    Figure PCTKR2018000957-appb-I000052
    ,
    Figure PCTKR2018000957-appb-I000053
    , or
    Figure PCTKR2018000957-appb-I000054
    Is,
    Ra는
    Figure PCTKR2018000957-appb-I000055
    ,
    Figure PCTKR2018000957-appb-I000056
    ,
    Figure PCTKR2018000957-appb-I000057
    ,
    Figure PCTKR2018000957-appb-I000058
    ,
    Figure PCTKR2018000957-appb-I000059
    ,
    Figure PCTKR2018000957-appb-I000060
    ,
    Figure PCTKR2018000957-appb-I000061
    ,
    Figure PCTKR2018000957-appb-I000062
    ,
    Figure PCTKR2018000957-appb-I000063
    ,
    Figure PCTKR2018000957-appb-I000064
    ,
    Figure PCTKR2018000957-appb-I000065
    ,
    Figure PCTKR2018000957-appb-I000066
    ,
    Figure PCTKR2018000957-appb-I000067
    ,
    Figure PCTKR2018000957-appb-I000068
    ,
    Figure PCTKR2018000957-appb-I000069
    ,
    Figure PCTKR2018000957-appb-I000070
    ,
    Figure PCTKR2018000957-appb-I000071
    ,
    Figure PCTKR2018000957-appb-I000072
    ,
    Figure PCTKR2018000957-appb-I000073
    ,
    Figure PCTKR2018000957-appb-I000074
    ,
    Figure PCTKR2018000957-appb-I000075
    ,
    Figure PCTKR2018000957-appb-I000076
    , 또는 하이드록시이고,    R a is
    Figure PCTKR2018000957-appb-I000055
    ,
    Figure PCTKR2018000957-appb-I000056
    ,
    Figure PCTKR2018000957-appb-I000057
    ,
    Figure PCTKR2018000957-appb-I000058
    ,
    Figure PCTKR2018000957-appb-I000059
    ,
    Figure PCTKR2018000957-appb-I000060
    ,
    Figure PCTKR2018000957-appb-I000061
    ,
    Figure PCTKR2018000957-appb-I000062
    ,
    Figure PCTKR2018000957-appb-I000063
    ,
    Figure PCTKR2018000957-appb-I000064
    ,
    Figure PCTKR2018000957-appb-I000065
    ,
    Figure PCTKR2018000957-appb-I000066
    ,
    Figure PCTKR2018000957-appb-I000067
    ,
    Figure PCTKR2018000957-appb-I000068
    ,
    Figure PCTKR2018000957-appb-I000069
    ,
    Figure PCTKR2018000957-appb-I000070
    ,
    Figure PCTKR2018000957-appb-I000071
    ,
    Figure PCTKR2018000957-appb-I000072
    ,
    Figure PCTKR2018000957-appb-I000073
    ,
    Figure PCTKR2018000957-appb-I000074
    ,
    Figure PCTKR2018000957-appb-I000075
    ,
    Figure PCTKR2018000957-appb-I000076
    , Or hydroxy,
    Rb는
    Figure PCTKR2018000957-appb-I000077
    ,
    Figure PCTKR2018000957-appb-I000078
    ,
    Figure PCTKR2018000957-appb-I000079
    , 또는
    Figure PCTKR2018000957-appb-I000080
    이고,    R b is
    Figure PCTKR2018000957-appb-I000077
    ,
    Figure PCTKR2018000957-appb-I000078
    ,
    Figure PCTKR2018000957-appb-I000079
    , or
    Figure PCTKR2018000957-appb-I000080
    ego,
    RC는
    Figure PCTKR2018000957-appb-I000081
    ,
    Figure PCTKR2018000957-appb-I000082
    , 또는
    Figure PCTKR2018000957-appb-I000083
    이고,    R C is
    Figure PCTKR2018000957-appb-I000081
    ,
    Figure PCTKR2018000957-appb-I000082
    , or
    Figure PCTKR2018000957-appb-I000083
    ego,
    Rd는 수소 또는
    Figure PCTKR2018000957-appb-I000084
    이고,    R d is hydrogen or
    Figure PCTKR2018000957-appb-I000084
    ego,
    Re는
    Figure PCTKR2018000957-appb-I000085
    또는
    Figure PCTKR2018000957-appb-I000086
    이고,    R e is
    Figure PCTKR2018000957-appb-I000085
    or
    Figure PCTKR2018000957-appb-I000086
    ego,
    R3는 수소 또는 플루오르이다.R 3 is hydrogen or fluorine.
  2. 제 1항에 있어서,The method of claim 1,
    상기 화학식 1로 표시되는 화합물은 하기 화합물들로 이루어진 군으로부터 선택되는 어느 하나인 것을 특징으로 하는, 만성 폐쇄성 폐질환 예방 또는 치료용 약학적 조성물:Compound represented by the formula (1) is any one selected from the group consisting of the following, chronic obstructive pulmonary disease preventing or treating pharmaceutical composition:
    tert-부틸 4-(4-(3-(N-페닐펜탄아미도)프로프-1-이닐)벤조일)피페라진-1-카복실레이트; N-페닐-N-(3-(4-(피페라진-1-카보닐)페닐)프로프-2-이닐)펜탄아마이드; N-(3-(4-(4-메틸피페라진-1-카보닐)페닐)프로프-2-이닐)-N-페닐펜탄아마이드; N-(3-(4-(4-에틸피페라진-1-카보닐)페닐)프로프-2-이닐)-N-페닐펜탄아마이드; N-(3-(4-(4-아이소프로필피페라진-1-카보닐)페닐)프로프-2-이닐)-N-페닐펜탄아마이드; N-(3-(4-(4-(2-하이드록시에틸)피페라진-1-카보닐)페닐)프로프-2-이닐)-N-페닐펜탄아마이드; N-(3-(4-(4-(사이클로프로필메틸)피페라진-1-카보닐)페닐)프로프-2-이닐)-N-페닐펜탄아마이드; N-(3-(4-(4-사이클로헥실피페라진-1-카보닐)페닐)프로프-2-이닐)-N-페닐펜탄아마이드; N-(3-(4-(4-(사이클로헥실메틸)피페라진-1-카보닐)페닐)프로프-2-이닐)-N-페닐펜탄아마이드; N-(3-(4-(4-아이소부틸피페라진-1-카보닐)페닐)프로프-2-이닐)-N-페닐펜탄아마이드; N-페닐-N-(3-(4-(4-(프로프-2-이닐)피페라진-1-카보닐)페닐)프로프-2-이닐)펜탄아마이드; N-(3-(4-(4-시아노피페라진-1-카보닐)페닐)프로프-2-이닐)-N-페닐펜탄아마이드; tert-부틸 4-(4-(3-(N-(3-플루오로페닐)펜탄아미도)프로프-1-이닐)벤조일)피페라진-1-카복실레이트; N-(3-플루오로페닐)-N-(3-(4-(피페라진-1-카보닐)페닐)프로프-2-이닐)펜탄아마이드; N-(3-플루오로페닐)-N-(3-(4-(4-아이소프로필피페라진-1-카보닐)페닐)프로프-2-이닐)펜탄아마이드; tert-부틸 4-(4-(3-(N-(4-플루오로페닐)펜탄아미도)프로프-1-이닐)벤조일)피페라진-1-카복실레이트; N-(4-플루오로페닐)-N-(3-(4-(피페라진-1-카보닐)페닐)프로프-2-이닐)펜탄아마이드; N-(4-플루오로페닐)-N-(3-(4-(4-아이소프로필피페라진-1-카보닐)페닐)프로프-2-이닐)펜탄아마이드; N-(3-(4-(몰폴린-4-카보닐)페닐)프로프-2-이닐)-N-페닐펜탄아마이드; N-페닐-N-(3-(4-(피페리딘-1-카보닐)페닐)프로프-2-이닐)펜탄아마이드; N,N-다이에틸-4-(3-(N-페닐펜탄아미도)프로프-1-이닐)벤즈아마이드; N-페닐-N-(3-(3-(피페라진-1-카보닐)페닐)프로프-2-이닐)펜탄아마이드; N-(3-(3-(4-메틸피페라진-1-카보닐)페닐)프로프-2-이닐)-N-페닐펜탄아마이드; N-(3-(3-(4-아이소프로필피페라진-1-카보닐)페닐)프로프-2-이닐)-N-페닐펜탄아마이드; tert-부틸-4-(3-(3-(N-(4-플루오로페닐)펜탄아미도)프로프-1-이닐)벤조일)피페라진-1-카복실레이트; N-(4-플루오로페닐)-N-(3-(3-(피페라진-1-카보닐)페닐)프로프-2-이닐)펜탄아마이드; N-(4-플루오로페닐)-N-(3-(3-(4-아이소프로필피페라진-1-카보닐)페닐)프로프-2-이닐)펜탄아마이드; N-(3-(4-하이드록시페닐)프로프-2-이닐)-N-페닐펜탄아마이드; 2-(4-(3-(N-페닐펜탄아미도)프로프-1-이닐)페녹시)아세트산; tert-부틸 4-(5-(3-((N-페닐펜탄아미도)프로프-1-인-1-일)피콜리노일)피페라진-1-카복실레이트; N-페닐-N-(3-(6-(피페라진-1-카보닐)피리딘-3-일)프로프-2-인-1-일)펜탄아마이드; N-(3-(6-(4-아이소프로필피페라진-1-카보닐)피리딘-3-일)프로프-2-인-1-일)-N-페닐펜탄아마이드; N,N-다이에틸-4-(3-(N-(3-플루오로페닐)펜탄아미도)프로프-1-인-1-일)벤즈아마이드; N,N-다이에틸-4-(3-(N-(4-플루오로페닐)펜탄아미도)프로프-1-인-1-일)벤즈아마이드; N-(3-(4-(N,N-다이에틸설파모일)페닐)프로프-2-이닐)-N-페닐펜탄아마이드; N-(3-(4-(N-아이소프로필설파모일)페닐)프로프-2-이닐)-N-페닐펜탄아마이드; tert-부틸 4-(3-(N-페닐펜탄아미도)프로프-1-인-1-일)벤조에이트; 4-(3-(N-페닐펜탄아미도)프로-1-핀-1-일)벤조익산; N-에틸-4-(3-(N-페닐펜탄아미도)프로프-1-인-1-일)벤즈아마이드; N-(2-(다이메틸아미노)에틸)-4-(3-(N-페닐펜탄아미도)프로프-1-인-1-일)벤즈아마이드; 에틸 2-(4-(3-(N-페닐펜탄아미도)프로프-1-인-1-일)벤즈아미도)아세테이트; 2-(4-(3-(N-페닐펜탄아미도)프로프-1-인-1-일)벤즈아미도)아세틱산; 메틸 2-(4-(3-(N-페닐펜탄아미도)프로프-1-인-1-일)벤즈아미도)프로파노에이트; 2-(4-(3-(N-페닐펜탄아미도)프로프-1-인-1-일)벤즈아미도)프로피오닉산; 2-(4-(3-(N-(3-플루오로페닐)펜탄아미도)프로프-1-이닐)페녹시)아세트산; 및 2-(4-(3-(N-(4-플루오로페닐)펜탄아미도)프로프-1-이닐)페녹시)아세트산. tert -butyl 4- (4- (3- ( N -phenylpentaneamido) prop-1-ynyl) benzoyl) piperazin-1-carboxylate; N -phenyl- N- (3- (4- (piperazin-1-carbonyl) phenyl) prop-2-ynyl) pentaneamide; N- (3- (4- (4-methylpiperazin-1-carbonyl) phenyl) prop-2-ynyl) -N -phenylpentanamide; N- (3- (4- (4-ethylpiperazin-1-carbonyl) phenyl) prop-2-ynyl) -N -phenylpentanamide; N- (3- (4- (4-isopropylpiperazin-1-carbonyl) phenyl) prop-2-ynyl) -N -phenylpentaneamide; N- (3- (4- (4- (2-hydroxyethyl) piperazin-1-carbonyl) phenyl) prop-2-ynyl) -N -phenylpentaneamide; N- (3- (4- (4- (cyclopropylmethyl) piperazin-1-carbonyl) phenyl) prop-2-ynyl) -N -phenylpentaneamide; N- (3- (4- (4-cyclohexylpiperazine-1-carbonyl) phenyl) prop-2-ynyl) -N -phenylpentaneamide; N- (3- (4- (4- (cyclohexylmethyl) piperazin-1-carbonyl) phenyl) prop-2-ynyl) -N -phenylpentanamide; N- (3- (4- (4-isobutylpiperazin-1-carbonyl) phenyl) prop-2-ynyl) -N -phenylpentaneamide; N -phenyl- N- (3- (4- (4- (prop-2-ynyl) piperazin-1-carbonyl) phenyl) prop-2-ynyl) pentaneamide; N- (3- (4- (4-cyanopiperazin-1-carbonyl) phenyl) prop-2-ynyl) -N -phenylpentanamide; tert -butyl 4- (4- (3- ( N- (3-fluorophenyl) pentaneamido) prop-1-ynyl) benzoyl) piperazine-1-carboxylate; N - (3-fluorophenyl) - N - (3- (4- ( piperazine-1-carbonyl) phenyl) prop-2-ynyl) pentane amide; N - (3-fluorophenyl) - N - (3- (4- (4- isopropyl-piperazine-1-carbonyl) phenyl) prop-2-ynyl) pentane amide; tert -butyl 4- (4- (3- ( N- (4-fluorophenyl) pentaneamido) prop-1-ynyl) benzoyl) piperazine-1-carboxylate; N - (4-fluorophenyl) - N - (3- (4- ( piperazine-1-carbonyl) phenyl) prop-2-ynyl) pentane amide; N - (4-fluorophenyl) - N - (3- (4- (4-isopropyl-piperazine-1-carbonyl) phenyl) prop-2-ynyl) pentane amide; N- (3- (4- (morpholin-4-carbonyl) phenyl) prop-2-ynyl) -N -phenylpentanamide; N -phenyl- N- (3- (4- (piperidine-1-carbonyl) phenyl) prop-2-ynyl) pentaneamide; N , N -diethyl-4- (3- ( N -phenylpentaneamido) prop-1-ynyl) benzamide; N -phenyl- N- (3- (3- (piperazin-1-carbonyl) phenyl) prop-2-ynyl) pentaneamide; N- (3- (3- (4-methylpiperazin-1-carbonyl) phenyl) prop-2-ynyl) -N -phenylpentanamide; N- (3- (3- (4-isopropylpiperazin-1-carbonyl) phenyl) prop-2-ynyl) -N -phenylpentaneamide; tert -butyl-4- (3- (3- ( N- (4-fluorophenyl) pentaneamido) prop-1-ynyl) benzoyl) piperazine-1-carboxylate; N - (4-fluorophenyl) - N - (3- (3- ( piperazine-1-carbonyl) phenyl) prop-2-ynyl) pentane amide; N - (4- fluorophenyl) - N - (3- (3- (4- isopropyl-piperazine-1-carbonyl) phenyl) prop-2-ynyl) pentane amide; N- (3- (4-hydroxyphenyl) prop-2-ynyl) -N -phenylpentanamide; 2- (4- (3- ( N -phenylpentaneamido) prop-1-ynyl) phenoxy) acetic acid; tert -butyl 4- (5- (3-(( N -phenylpentaneamido) prop-1-yn-1-yl) picolinoyl) piperazin-1-carboxylate; N -phenyl- N- ( 3- (6- (piperazin-1-carbonyl) pyridin-3-yl) prop-2-yn-1-yl) pentaneamide; N- (3- (6- (4-isopropylpiperazin- 1-carbonyl) pyridin-3-yl) prop-2-yn-1-yl) -N -phenylpentanamide; N, N -diethyl-4- (3- ( N- (3-fluorophenyl ) Pentaneamido) prop-1-yn-1-yl) benzamide; N, N -diethyl-4- (3- ( N- (4-fluorophenyl) pentaneamido) prop-1- In-1-yl) benzamide; N- (3- (4- ( N, N -diethylsulfamoyl) phenyl) prop-2-ynyl) -N -phenylpentanamide; N- (3- (4 -( N -isopropylsulfamoyl) phenyl) prop-2-ynyl) -N -phenylpentaneamide; tert -butyl 4- (3- ( N -phenylpentaneamido) prop-1-yn-1- Yl) benzoate; 4- (3- ( N -phenylpentaneamido) prop-1-pin-1-yl) benzoic acid; N -ethyl-4- (3- ( N -phenylpentaneamido) prop -1-yn-1-yl) benzamide; N -(2- (dimethylamino) ethyl) -4- (3- ( N -phenylpentaneamido) prop-1-yn-1-yl) benzamide; ethyl 2- (4- (3- ( N -Phenylpentaneamido) prop-1-yn-1-yl) benzamido) acetate; 2- (4- (3- ( N -phenylpentaneamido) prop-1-yn-1-yl) Benzamido) acetic acid; methyl 2- (4- (3- ( N -phenylpentaneamido) prop-1-yn-1-yl) benzamido) propanoate; 2- (4- (3 -( N -phenylpentaneamido) prop-1-yn-1-yl) benzamido) propionic acid; 2- (4- (3- ( N- (3-fluorophenyl) pentaneamido) Prop-1-ynyl) phenoxy) acetic acid and 2- (4- (3- ( N- (4-fluorophenyl) pentaneamido) prop-1-ynyl) phenoxy) acetic acid.
  3. 하기 화학식 2로 표시되는 화합물, 이의 이성질체 또는 이의 약학적 허용가능한 염을 유효성분으로 포함하는, 만성 폐쇄성 폐질환(COPD; chronic obstructive pulmonary disease) 예방 또는 치료용 약학적 조성물을 제공한다.It provides a pharmaceutical composition for the prevention or treatment of chronic obstructive pulmonary disease (COPD) comprising a compound represented by the formula (2), an isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
    [화학식 2][Formula 2]
    Figure PCTKR2018000957-appb-I000087
    Figure PCTKR2018000957-appb-I000087
    상기 화학식 2에서,In Chemical Formula 2,
    R1은 C1~C10의 알킬,
    Figure PCTKR2018000957-appb-I000088
    , 또는
    Figure PCTKR2018000957-appb-I000089
    이고,    R 1 is C 1 -C 10 alkyl,
    Figure PCTKR2018000957-appb-I000088
    , or
    Figure PCTKR2018000957-appb-I000089
    ego,
    R2는 수소,
    Figure PCTKR2018000957-appb-I000090
    , 또는
    Figure PCTKR2018000957-appb-I000091
    이고,    R 2 is hydrogen,
    Figure PCTKR2018000957-appb-I000090
    , or
    Figure PCTKR2018000957-appb-I000091
    ego,
    R3는 수소,
    Figure PCTKR2018000957-appb-I000092
    , 또는
    Figure PCTKR2018000957-appb-I000093
    이고,    R 3 is hydrogen,
    Figure PCTKR2018000957-appb-I000092
    , or
    Figure PCTKR2018000957-appb-I000093
    ego,
    R4는 수소,
    Figure PCTKR2018000957-appb-I000094
    , 또는
    Figure PCTKR2018000957-appb-I000095
    이고,    R 4 is hydrogen,
    Figure PCTKR2018000957-appb-I000094
    , or
    Figure PCTKR2018000957-appb-I000095
    ego,
    여기서 Ra는 수소, C1~C10의 알킬, C1~C5의 카르복실,
    Figure PCTKR2018000957-appb-I000096
    Where R a is hydrogen, C 1 -C 10 alkyl, C 1 -C 5 carboxyl,
    Figure PCTKR2018000957-appb-I000096
    R5, R6, 및 R7은 각각 독립적으로 수소, 할로겐, 니트로, 메틸, 트리플루오로메틸 또는 메톡시이며,R 5 , R 6 , and R 7 are each independently hydrogen, halogen, nitro, methyl, trifluoromethyl or methoxy,
    이 때, R1이 C1~C10의 알킬이고, Ra가 수소 또는 C1~C10의 알킬인 경우; 및 R2, R3, 및 R4가 모두 동시에 수소인 경우;는 제외한다.Wherein R 1 is C 1 -C 10 alkyl and R a is hydrogen or C 1 -C 10 alkyl; And when R 2 , R 3 , and R 4 are all hydrogen at the same time.
  4. 제 3항에 있어서,The method of claim 3, wherein
    상기 화학식 2로 표시되는 화합물은 하기 화합물들로 이루어진 군으로부터 선택되는 어느 하나인 것을 특징으로 하는, 만성 폐쇄성 폐질환 예방 또는 치료용 약학적 조성물:Compound represented by the formula (2) is any one selected from the group consisting of the following compounds, chronic obstructive pulmonary disease preventing or treating pharmaceutical composition:
    N-((3'-(4-메틸페닐설폰아미도)바이페닐-4-일)메틸)-N-페닐펜탄아마이드; N-(4'-((N-페닐펜탄아미도)메틸)바이페닐-3-일)-4-(트리플루오로메틸)벤즈아마이드; N-(3-플루오로페닐)-N-((3'-(4-메틸페닐설폰아미도)바이페닐-4-일)메틸)펜탄아마이드; N-(4'-((N-3-플루오로페닐)펜탄아미도)메틸)바이페닐-3-일)-4-(트리플루오로메틸)벤즈아마이드; 1-(3-플루오로페닐)-1-((4'-메톡시바이페닐-4-일)메틸)-3-(3-(트리플루오로메틸)페닐)유레아; N-(3-플루오로페닐)-N-((4'-메톡시바이페닐-4-일)메틸)-1-(4-메톡시페닐설폰일)메탄아마이드; 1-(3-플루오로페닐)-1-((4'-하이드록시바이페닐-4-일)메틸)-3-(3-(트리플루오로메틸)페닐)유레아; 2-(4'-((1-(3-플루오로페닐)-3-(3-(트리플루오로메틸)페닐)유레이도)메틸)바이페닐-4-일옥시)아세트산; 4-(4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)부탄산; 2-(4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)-2-메틸프로판산; (E)-3-(4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아크릴산; 3-(4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)프로판산; N-(3-플루오로페닐)-N-((4'-(2-(4-메틸피페라진-1-일)-2-옥소에톡시)바이페닐-4-일)메틸)펜탄아마이드; 프로프-2-인일 2-(4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세테이트; N-(3-플루오로페닐)-N-((4'-(프로프-2-이닐옥시)바이페닐-4-일)메틸)펜탄아마이드; N-((2'-(1H-테트라졸-5-일)바이페닐-4-일)메틸)-N-페닐펜탄아마이드; 2-(4'-((N-페닐펜탄아미도)메틸)바이페닐-4-일옥시)아세트산; 2-(4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세트산; 2-(4'-((N-(3-클로로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세트산; 2-(4'-((N-(3-브로모페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세트산; 2-(4'-((N-(3-(트리플루오로메틸)페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세트산; 2-(4'-((N-m-톨릴펜탄아미도)메틸)바이페닐-4-일옥시)아세트산; N-((4'-하이드록시바이페닐-4-일)메틸)-N-(3-니트로페닐)펜탄아마이드; 2-(4'-((N-(3-니트로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세트산; 2-(4'-((N-(3-아이오도페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세트산; 2-((4'-((N-(3-플루오로페닐)아세트아미도)메틸)-[1,1'-바이페닐]-4-일)옥시)아세트산; N-((4'-(4-아이소프로필피페라진-1-카보닐)바이페닐-4-일)메틸)-N-페닐펜탄아마이드; N-(4-플루오로페닐)-N-((4'-(4-아이소프로필피페라진-1-카보닐)바이페닐-4-일)메틸)펜탄아마이드; N-((3'-(4-아이소프로필피페라진-1-카보닐)바이페닐-4-일)메틸)-N-페닐펜탄아마이드; 및 N-(4-플루오로페닐)-N-((3'-(4-아이소프로필피페라진-1-카보닐)바이페닐-4-일)메틸)펜탄아마이드. N -((3 '-(4-methylphenylsulfonamido) biphenyl-4-yl) methyl) -N -phenylpentanamide; N- (4 '-(( N -phenylpentaneamido) methyl) biphenyl-3-yl) -4- (trifluoromethyl) benzamide; N- (3-fluorophenyl) -N -((3 '-(4-methylphenylsulfonamido) biphenyl-4-yl) methyl) pentaneamide; N- (4 '-(( N- 3-fluorophenyl) pentaneamido) methyl) biphenyl-3-yl) -4- (trifluoromethyl) benzamide; 1- (3-fluorophenyl) -1-((4'-methoxybiphenyl-4-yl) methyl) -3- (3- (trifluoromethyl) phenyl) urea; N- (3-fluorophenyl) -N -((4'-methoxybiphenyl-4-yl) methyl) -1- (4-methoxyphenylsulfonyl) methaneamide; 1- (3-fluorophenyl) -1-((4'-hydroxybiphenyl-4-yl) methyl) -3- (3- (trifluoromethyl) phenyl) urea; 2- (4 '-((1- (3-fluorophenyl) -3- (3- (trifluoromethyl) phenyl) ureido) methyl) biphenyl-4-yloxy) acetic acid; 4- (4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) butanoic acid; 2- (4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) -2-methylpropanoic acid; ( E ) -3- (4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acrylic acid; 3- (4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) propanoic acid; N- (3-fluorophenyl) -N -((4 '-(2- (4-methylpiperazin-1-yl) -2-oxoethoxy) biphenyl-4-yl) methyl) pentaneamide; Prop-2-ynyl 2- (4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetate; N- (3-fluorophenyl) -N -((4 '-(prop-2-ynyloxy) biphenyl-4-yl) methyl) pentaneamide; N -((2 '-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl) -N -phenylpentanamide; 2- (4 '-(( N -phenylpentaneamido) methyl) biphenyl-4-yloxy) acetic acid; 2- (4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetic acid; 2- (4 '-(( N- (3-chlorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetic acid; 2- (4 '-(( N- (3-bromophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetic acid; 2- (4 '-(( N- (3- (trifluoromethyl) phenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetic acid; 2- (4 '-(( Nm -tolylpentaneamido) methyl) biphenyl-4-yloxy) acetic acid; N - ((4'- hydroxy-biphenyl-4-yl) methyl) - N - (3- nitrophenyl) pentane amide; 2- (4 '-(( N- (3-nitrophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetic acid; 2- (4 '-(( N- (3-iodophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetic acid; 2-((4 '-(( N- (3-fluorophenyl) acetamido) methyl)-[1,1'-biphenyl] -4-yl) oxy) acetic acid; N -((4 '-(4-isopropylpiperazin-1-carbonyl) biphenyl-4-yl) methyl) -N -phenylpentaneamide; N- (4-fluorophenyl) -N -((4 '-(4-isopropylpiperazin-1-carbonyl) biphenyl-4-yl) methyl) pentaneamide; N -((3 '-(4-isopropylpiperazin-1-carbonyl) biphenyl-4-yl) methyl) -N -phenylpentaneamide; And N- (4-fluorophenyl) -N -((3 '-(4-isopropylpiperazin-1-carbonyl) biphenyl-4-yl) methyl) pentaneamide.
  5. 제 1항 내지 제 4항 중 어느 한 항에 있어서,The method according to any one of claims 1 to 4,
    상기 조성물은 BLT2 (Leukotriene B4 receptor 2) 활성을 저해시키는 것을 특징으로 하는, 만성 폐쇄성 폐질환 예방 또는 치료용 약학적 조성물.The composition is characterized in that to inhibit the Leukkotriene B4 receptor 2 (BLT2) activity, pharmaceutical composition for preventing or treating chronic obstructive pulmonary disease.
  6. 하기 화학식 1로 표시되는 화합물, 이의 이성질체 또는 이의 약학적 허용가능한 염을 개체에 투여하는 단계를 포함하는, 만성 폐쇄성 폐질환 예방 또는 치료 방법.A method of preventing or treating chronic obstructive pulmonary disease, comprising administering to a subject a compound represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof.
    [화학식 1][Formula 1]
    Figure PCTKR2018000957-appb-I000097
    Figure PCTKR2018000957-appb-I000097
    상기 화학식 1에서,In Chemical Formula 1,
    R1은 C1~C10의 알킬이고,R 1 is C 1 -C 10 is alkyl,
    R2는
    Figure PCTKR2018000957-appb-I000098
    ,
    Figure PCTKR2018000957-appb-I000099
    ,
    Figure PCTKR2018000957-appb-I000100
    ,
    Figure PCTKR2018000957-appb-I000101
    , 또는
    Figure PCTKR2018000957-appb-I000102
    이며,     R 2 is
    Figure PCTKR2018000957-appb-I000098
    ,
    Figure PCTKR2018000957-appb-I000099
    ,
    Figure PCTKR2018000957-appb-I000100
    ,
    Figure PCTKR2018000957-appb-I000101
    , or
    Figure PCTKR2018000957-appb-I000102
    Is,
    Ra는
    Figure PCTKR2018000957-appb-I000103
    ,
    Figure PCTKR2018000957-appb-I000104
    ,
    Figure PCTKR2018000957-appb-I000105
    ,
    Figure PCTKR2018000957-appb-I000106
    ,
    Figure PCTKR2018000957-appb-I000107
    ,
    Figure PCTKR2018000957-appb-I000108
    ,
    Figure PCTKR2018000957-appb-I000109
    ,
    Figure PCTKR2018000957-appb-I000110
    ,
    Figure PCTKR2018000957-appb-I000111
    ,
    Figure PCTKR2018000957-appb-I000112
    ,
    Figure PCTKR2018000957-appb-I000113
    ,
    Figure PCTKR2018000957-appb-I000114
    ,
    Figure PCTKR2018000957-appb-I000115
    ,
    Figure PCTKR2018000957-appb-I000116
    ,
    Figure PCTKR2018000957-appb-I000117
    ,
    Figure PCTKR2018000957-appb-I000118
    ,
    Figure PCTKR2018000957-appb-I000119
    ,
    Figure PCTKR2018000957-appb-I000120
    ,
    Figure PCTKR2018000957-appb-I000121
    ,
    Figure PCTKR2018000957-appb-I000122
    ,
    Figure PCTKR2018000957-appb-I000123
    ,
    Figure PCTKR2018000957-appb-I000124
    , 또는 하이드록시이고,    R a is
    Figure PCTKR2018000957-appb-I000103
    ,
    Figure PCTKR2018000957-appb-I000104
    ,
    Figure PCTKR2018000957-appb-I000105
    ,
    Figure PCTKR2018000957-appb-I000106
    ,
    Figure PCTKR2018000957-appb-I000107
    ,
    Figure PCTKR2018000957-appb-I000108
    ,
    Figure PCTKR2018000957-appb-I000109
    ,
    Figure PCTKR2018000957-appb-I000110
    ,
    Figure PCTKR2018000957-appb-I000111
    ,
    Figure PCTKR2018000957-appb-I000112
    ,
    Figure PCTKR2018000957-appb-I000113
    ,
    Figure PCTKR2018000957-appb-I000114
    ,
    Figure PCTKR2018000957-appb-I000115
    ,
    Figure PCTKR2018000957-appb-I000116
    ,
    Figure PCTKR2018000957-appb-I000117
    ,
    Figure PCTKR2018000957-appb-I000118
    ,
    Figure PCTKR2018000957-appb-I000119
    ,
    Figure PCTKR2018000957-appb-I000120
    ,
    Figure PCTKR2018000957-appb-I000121
    ,
    Figure PCTKR2018000957-appb-I000122
    ,
    Figure PCTKR2018000957-appb-I000123
    ,
    Figure PCTKR2018000957-appb-I000124
    , Or hydroxy,
    Rb는
    Figure PCTKR2018000957-appb-I000125
    ,
    Figure PCTKR2018000957-appb-I000126
    ,
    Figure PCTKR2018000957-appb-I000127
    , 또는
    Figure PCTKR2018000957-appb-I000128
    이고,    R b is
    Figure PCTKR2018000957-appb-I000125
    ,
    Figure PCTKR2018000957-appb-I000126
    ,
    Figure PCTKR2018000957-appb-I000127
    , or
    Figure PCTKR2018000957-appb-I000128
    ego,
    RC는
    Figure PCTKR2018000957-appb-I000129
    ,
    Figure PCTKR2018000957-appb-I000130
    , 또는
    Figure PCTKR2018000957-appb-I000131
    이고,    R C is
    Figure PCTKR2018000957-appb-I000129
    ,
    Figure PCTKR2018000957-appb-I000130
    , or
    Figure PCTKR2018000957-appb-I000131
    ego,
    Rd는 수소 또는
    Figure PCTKR2018000957-appb-I000132
    이고,    R d is hydrogen or
    Figure PCTKR2018000957-appb-I000132
    ego,
    Re는
    Figure PCTKR2018000957-appb-I000133
    또는
    Figure PCTKR2018000957-appb-I000134
    이고,    R e is
    Figure PCTKR2018000957-appb-I000133
    or
    Figure PCTKR2018000957-appb-I000134
    ego,
    R3는 수소 또는 플루오르이다.R 3 is hydrogen or fluorine.
  7. 하기 화학식 1로 표시되는 화합물, 이의 이성질체 또는 이의 약학적 허용가능한 염의 만성 폐쇄성 폐질환 예방 또는 치료 용도.Use for the prevention or treatment of chronic obstructive pulmonary disease of a compound represented by the following formula (1), an isomer thereof or a pharmaceutically acceptable salt thereof.
    [화학식 1][Formula 1]
    Figure PCTKR2018000957-appb-I000135
    Figure PCTKR2018000957-appb-I000135
    상기 화학식 1에서,In Chemical Formula 1,
    R1은 C1~C10의 알킬이고,R 1 is C 1 -C 10 is alkyl,
    R2는
    Figure PCTKR2018000957-appb-I000136
    ,
    Figure PCTKR2018000957-appb-I000137
    ,
    Figure PCTKR2018000957-appb-I000138
    ,
    Figure PCTKR2018000957-appb-I000139
    , 또는
    Figure PCTKR2018000957-appb-I000140
    이며,     R 2 is
    Figure PCTKR2018000957-appb-I000136
    ,
    Figure PCTKR2018000957-appb-I000137
    ,
    Figure PCTKR2018000957-appb-I000138
    ,
    Figure PCTKR2018000957-appb-I000139
    , or
    Figure PCTKR2018000957-appb-I000140
    Is,
    Ra는
    Figure PCTKR2018000957-appb-I000141
    ,
    Figure PCTKR2018000957-appb-I000142
    ,
    Figure PCTKR2018000957-appb-I000143
    ,
    Figure PCTKR2018000957-appb-I000144
    ,
    Figure PCTKR2018000957-appb-I000145
    ,
    Figure PCTKR2018000957-appb-I000146
    ,
    Figure PCTKR2018000957-appb-I000147
    ,
    Figure PCTKR2018000957-appb-I000148
    ,
    Figure PCTKR2018000957-appb-I000149
    ,
    Figure PCTKR2018000957-appb-I000150
    ,
    Figure PCTKR2018000957-appb-I000151
    ,
    Figure PCTKR2018000957-appb-I000152
    ,
    Figure PCTKR2018000957-appb-I000153
    ,
    Figure PCTKR2018000957-appb-I000154
    ,
    Figure PCTKR2018000957-appb-I000155
    ,
    Figure PCTKR2018000957-appb-I000156
    ,
    Figure PCTKR2018000957-appb-I000157
    ,
    Figure PCTKR2018000957-appb-I000158
    ,
    Figure PCTKR2018000957-appb-I000159
    ,
    Figure PCTKR2018000957-appb-I000160
    ,
    Figure PCTKR2018000957-appb-I000161
    ,
    Figure PCTKR2018000957-appb-I000162
    , 또는 하이드록시이고,    R a is
    Figure PCTKR2018000957-appb-I000141
    ,
    Figure PCTKR2018000957-appb-I000142
    ,
    Figure PCTKR2018000957-appb-I000143
    ,
    Figure PCTKR2018000957-appb-I000144
    ,
    Figure PCTKR2018000957-appb-I000145
    ,
    Figure PCTKR2018000957-appb-I000146
    ,
    Figure PCTKR2018000957-appb-I000147
    ,
    Figure PCTKR2018000957-appb-I000148
    ,
    Figure PCTKR2018000957-appb-I000149
    ,
    Figure PCTKR2018000957-appb-I000150
    ,
    Figure PCTKR2018000957-appb-I000151
    ,
    Figure PCTKR2018000957-appb-I000152
    ,
    Figure PCTKR2018000957-appb-I000153
    ,
    Figure PCTKR2018000957-appb-I000154
    ,
    Figure PCTKR2018000957-appb-I000155
    ,
    Figure PCTKR2018000957-appb-I000156
    ,
    Figure PCTKR2018000957-appb-I000157
    ,
    Figure PCTKR2018000957-appb-I000158
    ,
    Figure PCTKR2018000957-appb-I000159
    ,
    Figure PCTKR2018000957-appb-I000160
    ,
    Figure PCTKR2018000957-appb-I000161
    ,
    Figure PCTKR2018000957-appb-I000162
    , Or hydroxy,
    Rb는
    Figure PCTKR2018000957-appb-I000163
    ,
    Figure PCTKR2018000957-appb-I000164
    ,
    Figure PCTKR2018000957-appb-I000165
    , 또는
    Figure PCTKR2018000957-appb-I000166
    이고,    R b is
    Figure PCTKR2018000957-appb-I000163
    ,
    Figure PCTKR2018000957-appb-I000164
    ,
    Figure PCTKR2018000957-appb-I000165
    , or
    Figure PCTKR2018000957-appb-I000166
    ego,
    RC는
    Figure PCTKR2018000957-appb-I000167
    ,
    Figure PCTKR2018000957-appb-I000168
    , 또는
    Figure PCTKR2018000957-appb-I000169
    이고,    R C is
    Figure PCTKR2018000957-appb-I000167
    ,
    Figure PCTKR2018000957-appb-I000168
    , or
    Figure PCTKR2018000957-appb-I000169
    ego,
    Rd는 수소 또는
    Figure PCTKR2018000957-appb-I000170
    이고,    R d is hydrogen or
    Figure PCTKR2018000957-appb-I000170
    ego,
    Re는
    Figure PCTKR2018000957-appb-I000171
    또는
    Figure PCTKR2018000957-appb-I000172
    이고,    R e is
    Figure PCTKR2018000957-appb-I000171
    or
    Figure PCTKR2018000957-appb-I000172
    ego,
    R3는 수소 또는 플루오르이다.R 3 is hydrogen or fluorine.
  8. 하기 화학식 2로 표시되는 화합물, 이의 이성질체 또는 이의 약학적 허용가능한 염을 개체에 투여하는 단계를 포함하는, 만성 폐쇄성 폐질환 예방 또는 치료 방법.A method of preventing or treating chronic obstructive pulmonary disease, comprising administering to a subject a compound represented by Formula 2, an isomer thereof, or a pharmaceutically acceptable salt thereof.
    [화학식 2][Formula 2]
    [화학식 2][Formula 2]
    Figure PCTKR2018000957-appb-I000173
    Figure PCTKR2018000957-appb-I000173
    상기 화학식 2에서,In Chemical Formula 2,
    R1은 C1~C10의 알킬,
    Figure PCTKR2018000957-appb-I000174
    , 또는
    Figure PCTKR2018000957-appb-I000175
    이고,    R 1 is C 1 -C 10 alkyl,
    Figure PCTKR2018000957-appb-I000174
    , or
    Figure PCTKR2018000957-appb-I000175
    ego,
    R2는 수소,
    Figure PCTKR2018000957-appb-I000176
    , 또는
    Figure PCTKR2018000957-appb-I000177
    이고,    R 2 is hydrogen,
    Figure PCTKR2018000957-appb-I000176
    , or
    Figure PCTKR2018000957-appb-I000177
    ego,
    R3는 수소,
    Figure PCTKR2018000957-appb-I000178
    , 또는
    Figure PCTKR2018000957-appb-I000179
    이고,    R 3 is hydrogen,
    Figure PCTKR2018000957-appb-I000178
    , or
    Figure PCTKR2018000957-appb-I000179
    ego,
    R4는 수소,
    Figure PCTKR2018000957-appb-I000180
    , 또는
    Figure PCTKR2018000957-appb-I000181
    이고,    R 4 is hydrogen,
    Figure PCTKR2018000957-appb-I000180
    , or
    Figure PCTKR2018000957-appb-I000181
    ego,
    여기서 Ra는 수소, C1~C10의 알킬, C1~C5의 카르복실,
    Figure PCTKR2018000957-appb-I000182
    Where R a is hydrogen, C 1 -C 10 alkyl, C 1 -C 5 carboxyl,
    Figure PCTKR2018000957-appb-I000182
    R5, R6, 및 R7은 각각 독립적으로 수소, 할로겐, 니트로, 메틸, 트리플루오로메틸 또는 메톡시이며,R 5 , R 6 , and R 7 are each independently hydrogen, halogen, nitro, methyl, trifluoromethyl or methoxy,
    이 때, R1이 C1~C10의 알킬이고, Ra가 수소 또는 C1~C10의 알킬인 경우; 및 R2, R3, 및 R4가 모두 동시에 수소인 경우;는 제외한다.Wherein R 1 is C 1 -C 10 alkyl and R a is hydrogen or C 1 -C 10 alkyl; And when R 2 , R 3 , and R 4 are all hydrogen at the same time.
  9. 하기 화학식 2로 표시되는 화합물, 이의 이성질체 또는 이의 약학적 허용가능한 염의 만성 폐쇄성 폐질환 예방 또는 치료 용도.Use for the prevention or treatment of chronic obstructive pulmonary disease of the compound represented by the following formula (2), isomers thereof or pharmaceutically acceptable salts thereof.
    [화학식 2][Formula 2]
    Figure PCTKR2018000957-appb-I000183
    Figure PCTKR2018000957-appb-I000183
    상기 화학식 2에서,In Chemical Formula 2,
    R1은 C1~C10의 알킬,
    Figure PCTKR2018000957-appb-I000184
    , 또는
    Figure PCTKR2018000957-appb-I000185
    이고,    R 1 is C 1 -C 10 alkyl,
    Figure PCTKR2018000957-appb-I000184
    , or
    Figure PCTKR2018000957-appb-I000185
    ego,
    R2는 수소,
    Figure PCTKR2018000957-appb-I000186
    , 또는
    Figure PCTKR2018000957-appb-I000187
    이고,    R 2 is hydrogen,
    Figure PCTKR2018000957-appb-I000186
    , or
    Figure PCTKR2018000957-appb-I000187
    ego,
    R3는 수소,
    Figure PCTKR2018000957-appb-I000188
    , 또는
    Figure PCTKR2018000957-appb-I000189
    이고,    R 3 is hydrogen,
    Figure PCTKR2018000957-appb-I000188
    , or
    Figure PCTKR2018000957-appb-I000189
    ego,
    R4는 수소,
    Figure PCTKR2018000957-appb-I000190
    , 또는
    Figure PCTKR2018000957-appb-I000191
    이고,    R 4 is hydrogen,
    Figure PCTKR2018000957-appb-I000190
    , or
    Figure PCTKR2018000957-appb-I000191
    ego,
    여기서 Ra는 수소, C1~C10의 알킬, C1~C5의 카르복실,
    Figure PCTKR2018000957-appb-I000192
    Where R a is hydrogen, C 1 -C 10 alkyl, C 1 -C 5 carboxyl,
    Figure PCTKR2018000957-appb-I000192
    R5, R6, 및 R7은 각각 독립적으로 수소, 할로겐, 니트로, 메틸, 트리플루오로메틸 또는 메톡시이며,R 5 , R 6 , and R 7 are each independently hydrogen, halogen, nitro, methyl, trifluoromethyl or methoxy,
    이 때, R1이 C1~C10의 알킬이고, Ra가 수소 또는 C1~C10의 알킬인 경우; 및 R2, R3, 및 R4가 모두 동시에 수소인 경우;는 제외한다.Wherein R 1 is C 1 -C 10 alkyl and R a is hydrogen or C 1 -C 10 alkyl; And when R 2 , R 3 , and R 4 are all hydrogen at the same time.
PCT/KR2018/000957 2017-01-23 2018-01-22 Pharmaceutical composition comprising compound having blt inhibiting activity as effective ingredient for preventing or treating chronic obstructive pulmonary disease WO2018135918A1 (en)

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KR20030068547A (en) * 2000-10-27 2003-08-21 오르토-맥네일 파마슈티칼, 인코퍼레이티드 Novel amidoalkyl-piperidine and amidoalkyl-piperazine derivatives useful for the treatment of nervous system disorders
WO2008073929A1 (en) * 2006-12-11 2008-06-19 Wyeth Ion channel modulators
US20110136877A1 (en) * 2008-01-07 2011-06-09 Ligand Pharmaceuticals Inc. 2-phenyl phenoxyacetic acids useful for treating inflammatory disorders
KR20130017073A (en) * 2011-08-05 2013-02-19 동국대학교 산학협력단 New biphenyl derivative or pharmaceutically acceptable salt thereof, and pharmaceutical composition for treating or preventing inflammatory diseases or autoimmune diseases containing the same as an active ingredient
CN104045552A (en) * 2013-03-13 2014-09-17 上海先声药物研究有限公司 Medicinal compound as neuroprotective agent
KR20170012151A (en) * 2015-07-24 2017-02-02 동국대학교 산학협력단 Novel compound having BLT-inhibitory activity and composition for preventing or treating inflammatory diseases comprising the same as an active ingredient

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20030068547A (en) * 2000-10-27 2003-08-21 오르토-맥네일 파마슈티칼, 인코퍼레이티드 Novel amidoalkyl-piperidine and amidoalkyl-piperazine derivatives useful for the treatment of nervous system disorders
WO2008073929A1 (en) * 2006-12-11 2008-06-19 Wyeth Ion channel modulators
US20110136877A1 (en) * 2008-01-07 2011-06-09 Ligand Pharmaceuticals Inc. 2-phenyl phenoxyacetic acids useful for treating inflammatory disorders
KR20130017073A (en) * 2011-08-05 2013-02-19 동국대학교 산학협력단 New biphenyl derivative or pharmaceutically acceptable salt thereof, and pharmaceutical composition for treating or preventing inflammatory diseases or autoimmune diseases containing the same as an active ingredient
CN104045552A (en) * 2013-03-13 2014-09-17 上海先声药物研究有限公司 Medicinal compound as neuroprotective agent
KR20170012151A (en) * 2015-07-24 2017-02-02 동국대학교 산학협력단 Novel compound having BLT-inhibitory activity and composition for preventing or treating inflammatory diseases comprising the same as an active ingredient

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