WO2017018751A1 - Blt 저해 활성을 갖는 신규 화합물 및 이를 유효성분으로 포함하는 염증성 질환 예방 또는 치료용 조성물 - Google Patents
Blt 저해 활성을 갖는 신규 화합물 및 이를 유효성분으로 포함하는 염증성 질환 예방 또는 치료용 조성물 Download PDFInfo
- Publication number
- WO2017018751A1 WO2017018751A1 PCT/KR2016/008070 KR2016008070W WO2017018751A1 WO 2017018751 A1 WO2017018751 A1 WO 2017018751A1 KR 2016008070 W KR2016008070 W KR 2016008070W WO 2017018751 A1 WO2017018751 A1 WO 2017018751A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- methyl
- biphenyl
- fluorophenyl
- equiv
- yloxy
- Prior art date
Links
Images
Classifications
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
-
- 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
- A61K31/4965—Non-condensed pyrazines
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/02—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
- C07C233/04—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C233/07—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
- C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
Definitions
- the present invention relates to a novel compound and its use, and more particularly, to a novel compound exhibiting inhibitory activity of Leukotriene B4 receptor 2 (BLT2) and a pharmaceutical composition for preventing or treating inflammatory diseases comprising the same as an active ingredient.
- BLT2 Leukotriene B4 receptor 2
- Inflammatory reactions are one of the body's immune systems that are activated through various mechanisms of action to protect against physical or chemical agents, bacterial infections, and immunological stimuli. However, if such an inflammatory response persists, it promotes mucosal damage, thereby causing inflammatory diseases such as rheumatoid arthritis, arteriosclerosis, gastritis, and asthma due to redness, fever, swelling, pain, and dysfunction. have. These inflammatory reactions are classified into acute and chronic inflammations over time, and acute inflammations can cause symptoms such as erythema, fever, pain, and edema, while inflammatory reactions last several days to several weeks. Is a prolonged inflammatory state, sometimes over several years to decades, and is accompanied by histological changes such as invasion of monocytes, proliferation of fibroblasts and capillaries, fibrosis due to increased connective tissue, and tissue destruction. .
- pro-inflammatory cytokines pro-inflammatory cytokines
- interferon-gamma INF- ⁇
- tumor necrosis factor- ⁇ TNF- ⁇
- interleukin-1 interleukin-1, IL-1
- interleukin during inflammatory processes in the body INF- ⁇
- cytokines such as -6 (interleukin-6, IL-6), nitric oxide (NO) and prostaglandin E2 (PGE2)
- cytokines such as -6 (interleukin-6, IL-6), nitric oxide (NO) and prostaglandin E2 (PGE2) are well known as major inflammatory agents.
- 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 substance that induces more effective termination of inflammation, in order to solve the conventional problems as described above, has produced a novel compound showing a BLT2 inhibitory activity, including the compound It was the first to develop an inflammatory disease treatment.
- the present invention has been made to solve the above problems, the present inventors have confirmed the therapeutic effect of the inflammatory disease of the novel compound showing the BLT2 inhibitory activity and completed the present invention based on this.
- Another object of the present invention is to provide a pharmaceutical composition for preventing or treating inflammatory diseases, comprising the novel compound or a pharmaceutically acceptable salt thereof as an active ingredient.
- the present invention provides a novel compound or a pharmaceutically acceptable salt thereof exhibiting BLT2 inhibitory activity.
- the compound is N -((3 '-(4-methylphenylsulfonamido) biphenyl-4-yl) methyl) -N -phenylpentaneamide; 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- (
- the present invention provides a pharmaceutical composition for preventing or treating an inflammatory disease, comprising the novel compound or a pharmaceutically acceptable salt thereof as an active ingredient.
- the inflammatory disease may be selected from the group consisting of asthma, atherosclerosis, cancer, itching of the skin, rheumatoid arthritis and inflammatory bowel disease.
- the composition may inhibit Leukotriene B4 receptor 2 (BLT2) activity.
- BLT2 Leukotriene B4 receptor 2
- It provides a method of treating an inflammatory disease comprising administering the pharmaceutical composition to a subject.
- the present invention provides a therapeutic use of an inflammatory disease of a composition comprising the novel compound or a pharmaceutically acceptable salt thereof.
- the present invention relates to a novel compound that exhibits Leukotriene B4 receptor 2 (BLT2) inhibitory activity and a pharmaceutical composition for preventing or treating an inflammatory disease comprising the same.
- BLT2 Leukotriene B4 receptor 2
- the present inventors have identified a novel compound that exhibits BTL2 inhibitory activity in order to solve in vivo instability and difficulty in mass production, which are problems of conventional inflammatory disease treatment substances, and has excellent cancer cell death enhancement and metastasis suppression effect and chemotaxis inhibition of the compound.
- the effects and anti-asthma effects have been confirmed experimentally, it is expected to be useful as a pharmaceutical composition for treating inflammatory diseases.
- 1A to 1D show the results of confirming the growth inhibitory effect of the compound of the present invention in cells expressing BLT2 (CHO-BLT2).
- Figure 2a to 2c is a result of confirming whether cancer cell death enhanced by the treatment of the compound of the present invention and the anti-cancer drug cisplatin complex in ovarian cancer cells (SKOV-3 cells) showing anticancer drug resistance.
- 3A to 3D show results of confirming chemotaxis inhibitory effect and IC50 (50% inhibitory concentration) of cells by treatment with a compound 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).
- Figure 7 is a result of confirming the effect of reducing airway hypersensitivity by the compound treatment of the present invention in mice with severe asthma induced.
- the present inventors based on the fact that the treatment of the novel compound prepared in the example can significantly inhibit the growth of BLT2 expressing cells, enhance the cancer cell death of the compound, inhibit cancer cell metastasis, inhibit BLT2-dependent chemotaxis, and The anti-asthma effect and the like have been specifically confirmed, and the present invention has been completed based on this.
- the present invention provides a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
- 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 butyl and R 2 is When R 3 , R 4 , R 5 , R 6 , and R 7 are hydrogen;
- R 1 is butyl
- R 3 is When R 2 , R 4 , R 5 , R 6 , and R 7 are hydrogen
- R 1 is butyl
- R 4 is , R 2 , R 3 , R 5 , R 6 , and R 7 are hydrogen
- R 1 is butyl
- R 4 is , R 2 , R 3 , R 5 , R 6 , and R 7 are hydrogen
- R 1 is butyl
- R 4 is When R 6 is fluorine, R 2 , R 3 , R 5 , and R 7 are hydrogen;
- R 1 is pentyl
- R 4 is When R 6 is fluorine
- R 2 , R 3 , R 5 , and R 7 are hydrogen
- R 1 is pentyl
- R 4 is , Except that R 6 is fluorine, R 2 , R 3 , R 5 , and R 7 are hydrogen.
- Preferred examples of the compound represented by Formula 1 according to the present invention are as follows:
- the term "pharmaceutically acceptable” is suitable for use in contact with the tissue 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 salts according to the present invention can be dissolved in conventional methods, for example, by dissolving a compound represented by the formula (1) in an excess of an aqueous solution of an acid, which salt is a water miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. It can be prepared by precipitation using. 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 novel compound exhibiting BLT2 inhibitory activity was prepared a novel compound exhibiting BLT2 inhibitory activity (see Examples 1 to 57), and confirmed the growth inhibition of BLT2 expressing cells by the novel compound treatment (see Experimental Example 2).
- cancer cell death may be enhanced by complex treatment with cisplatin, an anticancer agent, and that chemotaxis of BLT2 expressing cells may be inhibited (see Experimental Examples 3 to 4), and LTB4 and BLT2 binding inhibition using the compound of the present invention.
- the effect was confirmed (see Experimental Example 5), and in asthma-induced mice, the effect of reducing airway hypersensitivity and the inhibition of IL-4 production was specifically identified (see Experimental Example 6). Confirmed that it can.
- the present invention provides a pharmaceutical composition for preventing or treating an inflammatory disease, comprising the compound or a pharmaceutically acceptable salt thereof as an active ingredient.
- prevention means any action that inhibits or delays the development of an inflammatory disease by administration of a pharmaceutical composition according to the present invention.
- treatment means any action that improves or advantageously alters the symptoms of an inflammatory disease by administration of a pharmaceutical composition according to the present invention.
- the inflammatory disease is due to overexpression of Leukotriene B4 receptor 2 (BLT2), and may be at least one selected from asthma, atherosclerosis, cancer, skin itch, rheumatoid arthritis and inflammatory bowel disease, but is limited thereto. It is not.
- BLT2 Leukotriene B4 receptor 2
- all BLT2-associated inflammatory diseases known in the art are considered to be included in inflammatory diseases that can be prevented or treated with a compound having the structure of Formula 1 of the present invention.
- the cancer may be any cancer caused by overexpression of BLT2 or the oncogene Ras.
- the cancer may be selected from the group consisting of bladder cancer, prostate cancer, pancreatic cancer, breast cancer, brain tumor, skin cancer, and liver cancer, but is not limited thereto.
- 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 By inhibiting the inflammatory 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.
- 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 administered as single or multiple doses. 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 kg of body weight may be administered daily or every other day, or divided into 1 to 3 times a day.
- the dose may be increased or decreased depending on the route of administration, the severity of obesity, sex, weight, age, etc., the above dosage does not limit the scope of the present invention by any method.
- the present invention also provides a method of treating an inflammatory 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. .
- reaction mixture was filtered and extracted with ethyl acetate (EA), dried with anhydrous MgSO 4 , evaporated to concentration, and then purified by Medium Pressure Liquid Chromatography (MPLC) to obtain 3'-nitrobiphenyl.
- EA ethyl acetate
- MgSO 4 Medium Pressure Liquid Chromatography
- Step 2 N -((3'- Nitrobiphenyl -4- days) methyl Aniline ( N -((3'- nitrobiphenyl -4- yl Manufacture of methyl) aniline)
- 3'-nitrobiphenyl-4-carbaldehyde (1.0 equiv) and aniline (Aniline) (3.0 equiv) obtained in step 1 were dissolved in methanol, and then stirred at room temperature for 4 hours. The reaction until imine was formed was observed by thin layer chromatography (TLC). After imine was formed, 1M NaCNBH 3 (1.0 equiv) and 0.5M ZnCl 2 were added to the solution. (1.0 equiv) mixed methanol solution was added and stirred overnight at room temperature.
- Step 3 N -((3'- Nitrobiphenyl -4- days) methyl )- N - Phenylpentaneamide ( N -((3'- nitrobiphenyl -4-yl) methyl)- N -phenylpentanamide)
- N -((3'-nitrobiphenyl-4-yl) methyl) aniline obtained in step 2 was dissolved in dichloromethane (DCM), triethanolamine (TEA) was added, and then on ice Cooled. Valeroyl chloride (3.0 equiv) was added to the mixed solution, followed by stirring at room temperature for 4 hours. After the reaction was completed, RBF was added, and the organic solvent layer was washed with brine and separated. Thereafter, the organic solvent layer was collected, water was removed with anhydrous magnesium sulfate (MgSO 4 ), filtered, and then concentrated by evaporation.
- DCM dichloromethane
- TAA triethanolamine
- Valeroyl chloride (3.0 equiv) was added to the mixed solution, followed by stirring at room temperature for 4 hours. After the reaction was completed, RBF was added, and the organic solvent layer was washed with brine and separated. Thereafter, the organic solvent layer was collected, water was removed with anhydrous magnesium s
- Step 4 N -((3'- Aminobiphenyl -4- days) methyl )- N - Phenylpentaneamide ( N -((3'- aminobiphenyl -4-yl) methyl)- N -phenylpentanamide)
- N -((3'-nitrobiphenyl-4-yl) methyl) -N-phenylpentanamide (1.0 equiv) obtained in step 3 above was mixed well with RBF, and methanol was added thereto. After cooling the RBF, 10% Pd / C (20 wt%) was added and the mixed solution was stirred overnight at room temperature, H 2 feed conditions. After the reaction was completed, the resultant was filtered through a pad of silica, and then concentrated by evaporation.
- the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give N-((3'-aminobiphenyl-4-yl) methyl) -N-phenylpentaneamide (N-((3'-aminobiphenyl-4-yl) methyl) -N-phenylpentanamide) was obtained (92% yield).
- MPLC Medium Pressure Liquid Chromatography
- Step 5 N -((3 '-(4- Methylphenylsulfonamido ) Biphenyl -4- days) methyl )- N - Phenylpentaneamide ( N -((3 '-(4-methylphenylsulfonamido) biphenyl-4-yl) methyl)- N -phenylpentanamide)
- N -((3'-aminobiphenyl-4-yl) methyl) -N -phenylpentaneamide (1.0 equiv) and Triethylamine (2.0 equiv) obtained in step 4 were added to a dichloromethane (DCM) solution. After thawing, it was cooled on ice. Thereafter, 4-methoxybenzene sulfonyl chloride (1.5 equiv) was added, followed by stirring overnight at room temperature. After the reaction was completed, DCM was concentrated by evaporation.
- DCM dichloromethane
- the concentrate was purified by column chromatography to give the final product, N -((3 '-(4-methylphenylsulfonamido) biphenyl-4-yl) methyl) -N -phenylpentanamide ( N -((3'- (4-methylphenylsulfonamido) biphenyl-4-yl) methyl) -N- phenylpentanamide) was obtained (25% yield).
- Step 1 (3- Fluoro -((3'- Nitrobiphenyl -4- days) methyl Aniline (3- fluoro - N -((3'- nitrobiphenyl Preparation of -4-yl) methyl) aniline)
- Step 2 ( N -(3- Fluorophenyl )- N -((3'- Nitrobiphenyl -4- days) methyl ) Pentaneamide ( N -(3-fluorophenyl)- N Preparation of-((3'-nitrobiphenyl-4-yl) methyl) pentanamide)
- step 1 (3-fluoro-((3'-nitrobiphenyl-4-yl) methyl) aniline obtained in step 1 was dissolved in dichloromethane (DCM) and triethanolamine (TEA) was added thereto. After the reaction was completed, valeroyl chloride (3.0 equiv) was added, followed by stirring at room temperature for 4 hours, after completion of the reaction, RBF was added thereto, and the organic solvent layer was added thereto. After washing with brine and separating, the organic solvent layers were combined, the water was removed with anhydrous magnesium sulfate (MgSO 4 ), filtered and evaporated to concentrate the concentrated solution by Medium Pressure Liquid Chromatography (MPLC).
- MgSO 4 anhydrous magnesium sulfate
- Step 3 N -((3'- Aminobiphenyl -4- days) methyl )- N -(3- Fluorophenyl ) Pentaneamide ( N -((3'-aminobiphenyl-4-yl) methyl)- N Preparation of-(3-fluorophenyl) pentanamide)
- N- (3-fluorophenyl) -N -((3'-nitrobiphenyl-4-yl) methyl) pentaneamide (1.0 equiv) obtained in step 2 was mixed well with RBF, and methanol After cooling the RBF, 10% Pd / C (20wt%) was added and the mixed solution was stirred overnight at room temperature, H 2 feed conditions, after completion of the reaction, filtered through a pad of silica ., and then concentrated by evaporation the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) N - ((3'- amino-biphenyl-4-yl) methyl) - N - pentane amide (3-fluorophenyl) (N - ((3'-aminobiphenyl-4 -yl) methyl) - N - (3-fluorophenyl) pentanamide a) was obtained (89% yield).
- MPLC Medium Pressure Liquid Chromatography
- Step 4 N -(3- Fluorophenyl )- N -((3 '-(4- Methylphenylsulfonamido ) Biphenyl -4- days) methyl ) Pentaneamide ( N -(3-fluorophenyl)- N Preparation of-((3 '-(4-methylphenylsulfonamido) biphenyl-4-yl) methyl) pentanamide)
- the concentrate was purified by column chromatography to obtain the final product, N- (3-fluorophenyl) -N -((3 '-(4-methylphenylsulfonamido) biphenyl-4-yl) methyl) pentaneamide ( N -(3-fluorophenyl) -N -((3 '-(4-methylphenylsulfonamido) biphenyl-4-yl) methyl) pentanamide) was obtained (25% yield).
- N obtained in Step 3 in Example 3 - ((3'-amino-biphenyl-4-yl) methyl) - N - pentane amide, methyl -p- toluic acid trifluoroacetate (3-fluorophenyl) ( Trifluromethyl-p-toluic acid (1.2 equiv), EDC (1.2 equiv), HOBt (1.2 equiv), and N , N -diisopropylethylamine (DIPEA) (1.2 equiv) in dichloromethane, DCM After dissolving in solution, it was stirred overnight at room temperature. After the reaction was completed, water was added.
- DIPEA N -diisopropylethylamine
- step 2 3 - Fluoro - N -((4'- Methoxybiphenyl -4- days) methyl Aniline (3- fluoro - N -((4'- methoxybiphenyl Preparation of -4-yl) methyl) aniline)
- step 1 4-methoxybiphenyl-4-carbaldehyde (1.0 equiv) and 3-fluoroaniline (3-fluroaniline) (3.0 equiv) obtained in step 1 were dissolved in methanol, and then stirred at room temperature for 4 hours. . The reaction until imine was formed was observed by thin layer chromatography (TLC). After imine was formed, 1M NaCNBH 3 (1.0 equiv) and 0.5M ZnCl 2 were added to the solution. (1.0 equiv) mixed methanol solution was added and stirred overnight at room temperature.
- TLC thin layer chromatography
- step 3 1 -(3- Fluorophenyl ) -1-((4'- Methoxybiphenyl -4- days) methyl ) -3- (3- ( Trifluoromethyl ) Phenyl) Urea (1- (3- fluorophenyl ) -1-((4'- methoxybiphenyl -4- yl ) methyl) -3- (3- ( trifluoromethyl Preparation of) phenyl) urea)
- 3-fluoro- N -((4-methoxybiphenyl-4-yl) methyl) aniline obtained in step 2 was dissolved in tetrahydrofuran (THF) solution, and then trifluoromethylphenyl isocyanate (trifluromethylphenyl isocyanate) (1.0 equiv) was added, the mixed solution was stirred overnight, and after completion of the reaction, silica was added to adsorb RBF and the crude product, which was purified by Medium Pressure Liquid Chromatography (MPLC).
- MPLC Medium Pressure Liquid Chromatography
- the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give the final product N- (3-fluorophenyl) -N -((4'-methoxybiphenyl-4-yl) methyl) -1- (4- Methoxyphenylsulfonyl) methaneamide ( N- (3-fluorophenyl) -N -((4'-methoxybiphenyl-4-yl) methyl) -1- (4-methoxyphenylsulfonyl) methanamide) was obtained (61% yield). .
- MPLC Medium Pressure Liquid Chromatography
- Example 7 1- (3- Fluorophenyl ) -1-((4'- Hydroxybiphenyl -4- days) methyl ) -3- (3- ( Trifluoromethyl ) Phenyl) urea (1- (3- fluorophenyl ) -1-((4'- hydroxybiphenyl -4- yl Preparation of) methyl) -3- (3- (trifluoromethyl) phenyl) urea) (AC-1318)
- Step 1 ethyl-2- (4 '-((1- (3- Fluorophenyl ) -3- (3- ( Trifluoromethyl ) Phenyl) Eureido ) methyl ) Biphenyl 4-yloxy) acetate (Ethyl-2- (4 '-((1- (3- fluorophenyl ) -3- (3- (trifluoromethyl) phenyl) ureido) methyl) biphenyl-4-yloxy) acetate)
- the organic solvent layer was washed with brine, dried with anhydrous magnesium sulfate (MgSO 4 ), and the organic solvent layer was concentrated by evaporation.
- the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give ethyl-2- (4 '-((1- (3-fluorophenyl) -3- (3- (trifluoromethyl) phenyl) ureido) methyl ) Biphenyl-4-yloxy) acetate (Ethyl-2- (4 '-((1- (3-fluorophenyl) -3- (3- (trifluoromethyl) phenyl) ureido) methyl) biphenyl-4-yloxy) acetate ) (96% yield).
- step 2 2 -(4 '-((1- (3- Fluorophenyl ) -3- (3- ( Trifluoromethyl ) Phenyl) Eureido ) methyl ) Biphenyl -4- Iloxy Acetic acid (2- (4 '-((1- (3- fluorophenyl ) -3- (3- ( trifluoromethyl ) phenyl) ureido ) methyl) biphenyl-4-yloxy) acetic acid)
- Step 1 N -(3- Fluorophenyl )- N -((4'- Methoxybiphenyl -4- days) methyl ) Pentaneamide ( N -(3-fluorophenyl)- N Preparation of-((4'-methoxybiphenyl-4-yl) methyl) pentanamide)
- the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give N- (3-fluorophenyl) -N -((4'-methoxybiphenyl-4-yl) methyl) pentaneamide ( N- (3-fluorophenyl ) -N -((4'-methoxybiphenyl-4-yl) methyl) pentanamide) was obtained (100% yield).
- MPLC Medium Pressure Liquid Chromatography
- Step 2 N -(3- Fluorophenyl )- N -((4'- Hydroxybiphenyl -4- days) methyl ) Pentaneamide ( N -(3-fluorophenyl)- N Preparation of-((4'-hydroxybiphenyl-4-yl) methyl) pentanamide)
- N- (3-fluorophenyl) -N -((4'-methoxybiphenyl-4-yl) methyl) pentaneamide (1.0 equiv) obtained in step 1 was diluted with dichloromethane (DCM). After melting in, cooled on ice. At 0 ° C., BBr 3 was slowly added and the mixed solution was stirred at room temperature for 3 hours. The reaction was observed by thin layer chromatography (TLC). After the reaction was completed, ice was added to RBF, and extracted with DCM. Separating the organic solvent layer. Water was removed with anhydrous magnesium sulfate (MgSO 4 ), and the organic solvent layer was filtered and then concentrated by evaporation.
- DCM dichloromethane
- the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give N- (3-fluorophenyl) -N -((4'-hydroxybiphenyl-4-yl) methyl) pentaneamide ( N- (3-fluorophenyl ) -N -((4'-hydroxybiphenyl-4-yl) methyl) pentanamide) was obtained (85% yield).
- MPLC Medium Pressure Liquid Chromatography
- Step 3 ethyl 4- (4 '-(( N -(3- Fluorophenyl ) Pentanamido ) methyl ) Biphenyl -4- Iloxy ) Butanoate (Ethyl 4- (4 '-(( N Preparation of-(3-fluorophenyl) pentanamido) methyl) biphenyl-4-yloxy) butanoate)
- N- (3-fluorophenyl) -N -((4'-hydroxybiphenyl-4-yl) methyl) pentaneamide (1.0 equiv) and K 2 CO 3 (3.0 equiv) obtained in step 2 were prepared. It was dissolved in N , N -dimethylformamide (DMF) solution and then cooled on ice. Ethyl 4-chlorobutanoate (3.0 equiv) was added and the mixed solution was stirred overnight at room temperature, N 2 feed conditions. After the reaction, water was added, and the aqueous layer was extracted with ethyl acetate (EA).
- EA ethyl acetate
- the organic solvent layer was washed with brine, dried with anhydrous magnesium sulfate (MgSO 4 ), and the organic solvent layer was concentrated by evaporation.
- the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give ethyl 4- (4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) butanoate (Ethyl 4- (4 '-(( N- (3-fluorophenyl) pentanamido) methyl) biphenyl-4-yloxy) butanoate) was obtained (92% yield).
- step 4 4 -(4'-(( N -(3- Fluorophenyl ) Pentanamido ) methyl ) Biphenyl -4- Iloxy Butanoic acid (4- (4 '-(( N Preparation of-(3-fluorophenyl) pentanamido) methyl) biphenyl-4-yloxy) butanoic acid)
- Ethyl 4- (4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) butanoate obtained in step 3 (Ethyl 4- (4'-( ( N- (3-fluorophenyl) pentanamido) methyl) biphenyl-4-yloxy) butanoate) was mixed well with tetrahydrofuran (THF) solution, LiOH solution was added and stirred for 4 hours. After the reaction was completed, the mixed solution was concentrated, 2N HCl was added until acidic, and extracted with ethyl acetate (EA).
- THF tetrahydrofuran
- step 3 of Example 9 using ethyl 2-chloro-2-methylpropanoate (3.0 equiv) instead of ethyl 4-chlorobutanoate (Ethyl 4-chlorobutanoate) Ethyl 4- (4 '-(( N- (3-fluorophenyl) pentanamido) methyl) biphenyl-4-yloxy) butanoate (Ethyl 4- (4'-(( N- (3-fluorophenyl) pentanamido) methyl) biphenyl -4-yloxy) butanoate) was obtained (yield 92%), and the final product 2- (4 '-(( N- (3-fluorophenyl) pentaneamido) in the same manner as in step 4 of Example 9 Methyl) biphenyl-4-yloxy) -2-methylpropanoic acid 2- (4 '-(( N- (3-fluorophenyl) pentanamido)
- step 3 of Example 9 using methyl (2E) -3-chloroacrylate (3.0 equiv) instead of ethyl 4-chlorobutanoate (E) -methyl 3- (4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acrylate ((E) -methyl 3- (4'- (( N- (3-fluorophenyl) pentanamido) methyl) biphenyl-4-yloxy) acrylate) was prepared (yield 100%), and the final product (E) -3- ( 4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acrylic acid ((E) -3- (4'-(( N- (3-fluorophenyl) pentanamido ) methyl) biphenyl-4-yloxy) acrylic acid) was obtained (29% yield).
- step 3 of Example 9 using methyl 3-chloroacetate (3.0 equiv) instead of ethyl 4-chlorobutanoate, methyl 3- (4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) propanoate (Methyl 3- (4 '-(( N- (3-fluorophenyl) pentanamido) methyl) biphenyl-4 -yloxy) propanoate) (yield 26.2%), and the final product 3- (4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) in the same manner as in step 4 of Example 9
- Biphenyl-4-yloxy) propanoic acid (3- (4 '-(( N- (3-fluorophenyl) pentanamido) methyl) biphenyl-4-yloxy) propanoic acid) was obtained (45% yield).
- Step 1 methyl 2- (4 '-(( N -(3- Fluorophenyl ) Pentanamido ) methyl ) Biphenyl -4- Iloxy Acetate (Methyl 2- (4 '-(( N Preparation of-(3-fluorophenyl) pentanamido) methyl) biphenyl-4-yloxy) acetate)
- N- (3-fluorophenyl) -N -((4'-hydroxybiphenyl-4-yl) methyl) pentaneamide and K 2 CO 3 (3.0 equiv) obtained in step 2 of Example 9 were prepared. It was dissolved in N , N -dimethylformamide (DMF) solution and then cooled on ice. Methyl bromoacetate (3.0 equiv) was added and the mixed solution was stirred overnight at room temperature, N 2 feed conditions. After the reaction was completed, water was added, and the aqueous layer was extracted with ethyl acetate (EA).
- EA ethyl acetate
- the organic solvent layer was washed with brine, dried with anhydrous magnesium sulfate (MgSO 4 ), and the organic solvent layer was concentrated by evaporation.
- the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to prepare methyl 2- (4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetate (Methyl 2- (4 '-(( N- (3-fluorophenyl) pentanamido) methyl) biphenyl-4-yloxy) acetate) was obtained.
- step 2 2 -(4'-(( N -(3- Fluorophenyl ) Pentanamido ) methyl ) Biphenyl -4- Iloxy Acetic acid (2- (4 '-(( N Preparation of-(3-fluorophenyl) pentanamido) methyl) biphenyl-4-yloxy) acetic acid)
- Methyl 2- (4 ′-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetate obtained in step 1 above was added to a tetrahydrofuran (THF) solution. After mixing well, LiOH solution was added and stirred for 4 hours. After the reaction was completed, the mixed solution was concentrated, 2N HCl was added until acidic, and extracted with ethyl acetate (EA).
- THF tetrahydrofuran
- Step 3 N -(3- Fluorophenyl ) -N -((4 '-(2- (4- Methylpiperazine -1-yl) -2- Oxoethoxy ) Biphenyl -4- days) methyl Pentaneamide ( N -(3- fluorophenyl )- N -((4 '-(2- (4- methylpiperazin -One- yl )-2- oxoethoxy ) biphenyl-4-yl) methyl) pentanamide)
- N- (3-fluorophenyl)- The concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to yield N- (3-fluorophenyl)-, the final product.
- MPLC Medium Pressure Liquid Chromatography
- the organic solvent layer was washed with brine, dried with anhydrous magnesium sulfate (MgSO 4 ), and the organic solvent layer was concentrated by evaporation.
- the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give the final product, Prop-2-ynyl 2- (4 '-(( N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4- Iloxy) acetate (Prop-2-ynyl 2- (4 '-(( N- (3-fluorophenyl) pentanamido) methyl) biphenyl-4-yloxy) acetate) was obtained (61.3% yield).
- N- (3-fluorophenyl) -N -((4'-hydroxybiphenyl-4-yl) methyl) pentaneamide and K 2 CO 3 (3.0 equiv) obtained in step 2 of Example 9 were prepared. It was dissolved in N , N -dimethylformamide (DMF) solution and then cooled on ice. After adding methyl propiolate (3.0 equiv), the mixed solution was stirred overnight at room temperature, N 2 feed conditions. After the reaction was completed, water was added, and the aqueous layer was extracted with ethyl acetate (EA).
- EA ethyl acetate
- the organic solvent layer was washed with brine, dried with anhydrous magnesium sulfate (MgSO 4 ), and the organic solvent layer was concentrated by evaporation.
- the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give N- (3-fluorophenyl) -N -((4 '-(prop-2-ynyloxy) biphenyl-4-yl) methyl as the final product.
- MPLC Medium Pressure Liquid Chromatography
- Step 1 methyl 4 '-((2- Fluorophenylamino ) methyl ) Biphenyl -2- Carboxylate Preparation of (Methyl 4 '-((2-fluorophenylamino) methyl) biphenyl-2-carboxylate)
- Methyl 4'-formylbiphenyl-4-carboxylate (1.0 equiv) and 2-fluoroaniline (3.0 equiv) were dissolved in methanol, and then at room temperature. Stirred for 4 h. The reaction until imine was formed was observed by thin layer chromatography (TLC). After imine was formed, 1M NaCNBH 3 (1.0 equiv) and 0.5M ZnCl 2 were added to the solution. (1.0 equiv) mixed methanol solution was added and stirred overnight at room temperature.
- Step 2 methyl 4'-(( N -(2- Fluorophenyl ) Pentanamido ) methyl ) Biphenyl -4- Carboxylate (Methyl 4 '-(( N -(1-fluorophenyl) pentanamido) methyl) biphenyl-4-carboxylate)
- Methyl 4 '-((2-fluorophenylamino) methyl) biphenyl-4-carboxylate obtained in step 1 was dissolved in dichloromethane (DCM) and triethanolamine (TEA) was added thereto. , Cooled on ice. Valeroyl chloride (3.0 equiv) was added to the mixed solution, followed by stirring at room temperature for 4 hours. After the reaction was completed, RBF was added, and the organic solvent layer was washed with brine and separated. Thereafter, the organic solvent layer was collected, water was removed with anhydrous magnesium sulfate (MgSO 4 ), filtered, and then concentrated by evaporation.
- DCM dichloromethane
- TAA triethanolamine
- the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to obtain methyl 4 '-(( N- (2-fluorophenyl) pentaneamido) methyl) biphenyl-4-carboxylate (Methyl 4'-(( N- (1-fluorophenyl) pentanamido) methyl) biphenyl-4-carboxylate) was obtained (95% yield).
- MPLC Medium Pressure Liquid Chromatography
- step 3 4 '-(( N -(2- Fluorophenyl ) Pentanamido ) methyl ) Biphenyl -4- Carboxylic acid (4'-(( N Preparation of-(2-fluorophenyl) pentanamido) methyl) biphenyl-4-carboxylic acid)
- step 2 4 '-(( N- (2-fluorophenyl) pentaneamido) methyl) biphenyl-4-carboxylate (1.0 equiv) obtained in step 2 was mixed well with tetrahydrofuran (THF) , LiOH solution was added and stirred for 4 hours. After the reaction was completed, the mixed solution was concentrated, 2N HCl was added until acidic, and extracted with ethyl acetate (EA).
- THF tetrahydrofuran
- EA ethyl acetate
- Methyl 4'-formylbiphenyl-3-carboxylate instead of methyl 4'-formylbiphenyl-4-carboxylate, 2-methoxyaniline instead of 2-fluoroaniline (2 4 '-((2-methoxyphenylamino) methyl) biphenyl-3-carboxylate (Methyl 4'-((2-Methoxyphenylamino) methyl) in the same manner as in Step 1 of Example 16 using -Methoxyaniline ) biphenyl-3-carboxylate) and methyl 4 '-(( N- (2-methoxyphenyl) pentaneamido) methyl) biphenyl-3- in the same manner as in steps 2 and 3 of Example 16 Carboxylate (Methyl 4 '-(( N- (2-Methoxyphenyl) pentanamido) methyl) biphenyl-3-carboxylate) was prepared, resulting in 4'-(( N- (2-
- Methyl 4'-formylbiphenyl-3-carboxylate instead of methyl 4'-formylbiphenyl-4-carboxylate, 3-methoxyaniline instead of 2-fluoroaniline (3 4 '-((3-methoxyphenylamino) methyl) biphenyl-3-carboxylate (Methyl 4'-((3-Methoxyphenylamino) methyl) in the same manner as in Step 1 of Example 16 using -Methoxyaniline ) biphenyl-3-carboxylate) and methyl 4 '-(( N- (3-methoxyphenyl) pentaneamido) methyl) biphenyl-3- in the same manner as in steps 2 and 3 of Example 16.
- Carboxylate (Methyl 4 '-(( N- (3-Methoxyphenyl) pentanamido) methyl) biphenyl-3-carboxylate) was prepared, resulting in 4'-(( N- (3-methoxyphenyl) pentaneamido) Methyl) biphenyl-3-carboxylic acid (4 '-(( N- (3-methoxyphenyl) pentanamido) methyl) biphenyl-3-carboxylic acid) was obtained (92% yield).
- Example 20 4 '-(( N -(4- Methoxyphenyl ) Pentanamido ) methyl ) Biphenyl -3- Carboxylic acid (4'-(( N Preparation of-(4-methoxyphenyl) pentanamido) methyl) biphenyl-3-carboxylic acid) (AC-1078)
- Methyl 4'-formylbiphenyl-3-carboxylate instead of methyl 4'-formylbiphenyl-4-carboxylate, 4-methoxyaniline instead of 2-fluoroaniline (4 4 '-((4-methoxyphenylamino) methyl) biphenyl-3-carboxylate (Methyl 4'-((4-Methoxyphenylamino) methyl) in the same manner as in Step 1 of Example 16 using -Methoxyaniline ) biphenyl-3-carboxylate) and methyl 4 '-(( N- (4-methoxyphenyl) pentaneamido) methyl) biphenyl-3- in the same manner as in Step 2 and Step 3 of Example 16 A carboxylate (Methyl 4 '-(( N- (4-Methoxyphenyl) pentanamido) methyl) biphenyl-3-carboxylate) was prepared, resulting in 4'-(( N
- Methyl 3-bromobenzoate (1.0 equiv) and 4-formylphenylboronic acid (1.1 equiv) are mixed well with RBF, followed by 1,4 dioxane (1,4 dioxane).
- H 2 O (5: 1) was dissolved in a mixed solution.
- Pd (dppf) Cl 2 .DCM (0.05 equiv) was added to the mixed solution to degassing for 20 minutes, and Na 2 CO 3 was added to degassing again for 20 minutes. Once again degassed for 15 minutes, it was heated to reflux for 4 hours.
- Step 2 methyl 4'-(( Phenylamino ) methyl ) Biphenyl -3- Carboxylate (methyl 4 '-( Preparation of (phenylamino) methyl) biphenyl-2-carboxylate)
- Methyl 4′-formylbiphenyl-3-carboxylate (1.0 equiv) and aniline (aniline) (3.0 equiv) obtained in step 1 were dissolved in methanol, and then stirred at room temperature for 4 hours. The reaction until imine was formed was observed by thin layer chromatography (TLC). After imine was formed, 1M NaCNBH 3 (1.0 equiv) and 0.5M ZnCl 2 were added to the solution. (1.0 equiv) mixed methanol solution was added and stirred overnight at room temperature.
- Step 3 methyl 4 '-((N- Phenylpentaneamido ) methyl ) Biphenyl -3- Carboxylate Preparation of (methyl 4 '-((N-phenylpentanamido) methyl) biphenyl-3-carboxylate)
- step 2 4 '-((phenylamino) methyl) biphenyl-3-carboxylate obtained in step 2 was dissolved in dichloromethane (DCM), triethanolamine (TEA) was added, and then cooled on ice. Valeroyl chloride (2.0 equiv) was added to the mixed solution, followed by stirring at room temperature for 4 hours. After the reaction was completed, RBF was added, and the organic solvent layer was washed with brine and separated. Thereafter, the organic solvent layer was collected, water was removed with anhydrous magnesium sulfate (MgSO 4 ), filtered, and then concentrated by evaporation.
- DCM dichloromethane
- TAA triethanolamine
- Valeroyl chloride 2.0 equiv
- step 4 4 '-((N- Phenylpentaneamido ) methyl ) Biphenyl -3- Carboxylic acid Preparation of (4 '-((N-phenylpentanamido) methyl) biphenyl-3-carboxylic acid)
- Methyl 4 ′-((N-phenylpentaneamido) methyl) biphenyl-3-carboxylate (1.0 equiv) obtained in step 3 was mixed well with tetrahydrofuran (THF), and then LiOH solution was added thereto. , Was stirred for 4 hours. After the reaction was completed, the mixed solution was concentrated, 2N HCl was added until acidic, and extracted with ethyl acetate (EA).
- EA ethyl acetate
- Step 5 N-((3 '-(4-methoxypiperazin-1-carbonyl) biphenyl-4-yl) methyl) -N-phenylpentanamide (N-((3'-(4-methylpiperazine -1-carbonyl) biphenyl-4-yl) methyl) -N-phenylpentanamide)
- the concentrate was purified by column chromatography to obtain N-((3 '-(4-methoxypiperazin-1-carbonyl) biphenyl-4-yl) methyl) -N-phenylpentanamide (N- ((3 '-(4-methylpiperazine-1-carbonyl) biphenyl-4-yl) methyl) -N-phenylpentanamide) was obtained (93% yield).
- Example 23 4 '-(( N -(3- Fluorophenyl ) Pentanamido ) methyl ) Biphenyl -2- Carboxylic acid (4'-(( N Preparation of-(3-fluorophenyl) pentanamido) methyl) biphenyl-2-carboxylic acid) (AC-891)
- Methyl 3-bromobenzoate (1.0 equiv) and 4-formylphenylboronic acid (1.1 equiv) are mixed well with RBF, followed by 1,4 dioxane (1,4 dioxane).
- H 2 O (5: 1) was dissolved in a mixed solution.
- Pd (dppf) Cl 2 .DCM (0.05 equiv) was added to the mixed solution to degassing for 20 minutes, and Na 2 CO 3 was added to degassing again for 20 minutes. Once again degassed for 15 minutes, it was heated to reflux for 4 hours.
- step 2 4 '-((3- Fluorophenylamino ) methyl ) Biphenyl -2- Carboxylate (4 '-( Preparation of (3-fluorophenylamino) methyl) biphenyl-2-carboxylate)
- Methyl 4'-formylbiphenyl-2-carboxylate (1.0 equiv) and 3-fluoroaniline (3-fluoroaniline) (3.0 equiv) obtained in step 1 were dissolved in methanol, and then stirred at room temperature for 4 hours. It was. The reaction until imine was formed was observed by thin layer chromatography (TLC). After imine was formed, 1M NaCNBH 3 (1.0 equiv) and 0.5M ZnCl 2 were added to the solution. (1.0 equiv) mixed methanol solution was added and stirred overnight at room temperature.
- Step 3 Methyl 4 '- (( N- (3- fluorophenyl) pentane amido) methyl) biphenyl-2-carboxylate (Methyl 4' - ((N- (3-fluorophenyl) pentanamido) methyl) biphenyl -2-carboxylate)
- step 2 4 '-((3-fluorophenylamino) methyl) biphenyl-2-carboxylate obtained in step 2 was dissolved in dichloromethane (DCM), triethanolamine (TEA) was added, and then ice Cooled in. Valeroyl chloride (2.0 equiv) was added to the mixed solution, followed by stirring at room temperature for 4 hours. After the reaction was completed, RBF was added, and the organic solvent layer was washed with brine and separated. Thereafter, the organic solvent layer was collected, water was removed with anhydrous magnesium sulfate (MgSO 4 ), filtered, and then concentrated by evaporation.
- DCM dichloromethane
- TAA triethanolamine
- Valeroyl chloride 2.0 equiv
- the concentrate was purified by column chromatography to prepare methyl 4 '-((N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-2-carboxylate (Methyl 4'-((N- (3- fluorophenyl) pentanamido) methyl) biphenyl-2-carboxylate) was obtained (92% yield).
- step 4 4 '-((N- (3- Fluorophenyl ) Pentanamido ) methyl ) Biphenyl -2- Carboxylic acid Preparation of (4 '-((N- (3-fluorophenyl) pentanamido) methyl) biphenyl-2-carboxylic acid)
- Methyl 4 ′-((N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-2-carboxylate (1.0 equiv) obtained in step 3 was mixed well with tetrahydrofuran (THF). Then LiOH solution was added and stirred for 4 hours. After the reaction was completed, the mixed solution was concentrated, 2N HCl was added until acidic, and extracted with ethyl acetate (EA).
- EA ethyl acetate
- Example 24 4 '-(( N -(3- Fluorophenyl ) Pentanamido ) methyl ) Biphenyl -4- Carboxylic acid (4'-(( N Preparation of-(3-fluorophenyl) pentanamido) methyl) biphenyl-4-carboxylic acid) (AC-893)
- Methyl 3-bromobenzoate (1.0 equiv) and 4-formylphenylboronic acid (1.1 equiv) are mixed well with RBF, followed by 1,4 dioxane (1,4 dioxane).
- H 2 O (5: 1) was dissolved in a mixed solution.
- Pd (dppf) Cl 2 .DCM (0.05 equiv) was added to the mixed solution to degassing for 20 minutes, and Na 2 CO 3 was added to degassing again for 20 minutes. Once again degassed for 15 minutes, it was heated to reflux for 4 hours.
- Step 2 methyl 4 '-((3- Fluoroamino ) methyl ) Biphenyl -4- Carboxylate (Methyl 4 '-( Preparation of (3-fluorophenylamino) methyl) biphenyl-4-carboxylate)
- Methyl 4'-formylbiphenyl-4-carboxylate (1.0 equiv) and 3-fluoroaniline (3-fluoroaniline) (3.0 equiv) obtained in step 1 were dissolved in methanol, and then stirred at room temperature for 4 hours. It was. The reaction until imine was formed was observed by thin layer chromatography (TLC). After imine was formed, 1M NaCNBH 3 (1.0 equiv) and 0.5M ZnCl 2 were added to the solution. (1.0 equiv) mixed methanol solution was added and stirred overnight at room temperature.
- Step 3 methyl 4 '-((N- (3- Fluorophenyl ) Pentanamido ) methyl ) Biphenyl -4- Carbosylate Preparation of (Methyl 4 '-((N- (3-fluorophenyl) pentanamido) methyl) biphenyl-4-carboxylate)
- Methyl 4 '-((3-fluoroamino) methyl) biphenyl-4-carboxylate obtained in step 2 was dissolved in dichloromethane (DCM), triethanolamine (TEA) was added, and then ice Cooled at. Valeroyl chloride (2.0 equiv) was added to the mixed solution, followed by stirring at room temperature for 4 hours. After the reaction was completed, RBF was added, and the organic solvent layer was washed with brine and separated. Thereafter, the organic solvent layer was collected, water was removed with anhydrous magnesium sulfate (MgSO 4 ), filtered, and then concentrated by evaporation.
- DCM dichloromethane
- TAA triethanolamine
- Valeroyl chloride 2.0 equiv
- step 4 4 '-((N- (3- Fluorophenyl ) Pentanamido ) methyl ) Biphenyl -4- Carboxylic acid Preparation of (4 '-((N- (3-fluorophenyl) pentanamido) methyl) biphenyl-4-carboxylic acid)
- Methyl 4 ′-((N- (3-fluorophenyl) pentaneamido) methyl) biphenyl-4-carbosylate (1.0 equiv) obtained in step 3 above was added to tetrahydrofuran (THF). After mixing, LiOH solution was added and stirred for 4 hours. After the reaction was completed, the mixed solution was concentrated, 2N HCl was added until acidic, and extracted with ethyl acetate (EA).
- EA ethyl acetate
- Example 25 N -(3- Fluorophenyl )- N -((4'-( Morpholine -4- Carbonyl )-[1,1'- Biphenyl -4- days) methyl ) Pentaneamide ( N- (3-fluorophenyl)- N Preparation of-((4 '-(morpholine-4-carbonyl)-[1,1'-biphenyl] -4-yl) methyl) pentanamide) (AC-950)
- the concentrate was purified by column chromatography to give the final product N- (3-fluorophenyl) -N-((4 '-(morpholine-4-carbonyl)-[1,1'-biphenyl-4- Il) methyl) pentaneamide (N- (3-fluorophenyl) -N-((4 '-(morpholine-4-carbonyl)-[1,1'-biphenyl] -4-yl) methyl) pentanamide) was obtained. (93% yield).
- Example 26 N -(3- Fluorophenyl )- N -((4 '-(4- Methylpiperazine -One- Carbonyl ) Biphenyl -4- days) methyl ) Pentaneamide ( N -(3- fluorophenyl )- N -((4 '-(4- methylpiperazine -1-carbonyl) biphenyl-4- yl methyl) pentanamide Preparation of (AC-951)
- step 1 4 '-(( N -(3- Fluorophenyl ) Pentanamido ) methyl ) Biphenyl -4- Carboxylic acid (4'-(( N Preparation of-(3-fluorophenyl) pentanamido) methyl) biphenyl-4-carboxylic acid)
- Phenyl) pentaneamido) methyl) biphenyl-4-carboxylate (Methyl 4 '-(( N- (3-Methoxyphenyl) pentanamido) methyl) biphenyl-4-carboxylate) was prepared and 4'-(( N- ( 3-methoxyphenyl) pentaneamido) methyl) biphenyl-4-carboxylic acid (4 '-(( N- (3-methoxyphenyl) pentanamido) methyl) biphenyl-4-carboxylic acid) was obtained (94% yield). .
- Step 2 N -(3- Fluorophenyl )- N -((4 '-(4- Methylpiperazine -One- Carbonyl ) Biphenyl -4- days) methyl ) Pentaneamide ( N -(3-fluorophenyl)- N Preparation of-((4 '-(4-methylpiperazine-1-carbonyl) biphenyl-4-yl) methyl) pentanamide)
- the concentrate was purified by column chromatography to give the final product N- (3-fluorophenyl) -N -((4 '-(4-methylpiperazin-1-carbonyl) biphenyl-4-yl) methyl) Pentaneamide (N- (3-fluorophenyl) -N -((4 '-(4-methylpiperazine-1-carbonyl) biphenyl-4-yl) methyl) pentanamide) was obtained (93% yield).
- Example 27 N -((2 '-(1H- Tetrazole -5 days) Biphenyl -4- days) methyl )- N - Phenylpentaneamide ( N -((2 '-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl)- N -phenylpentanamide) (AC-952)
- step 1 4 '-(( Phenylamino ) methyl ) Biphenyl -2- Carbon Nitrile (4'-(( phenylamino ) methyl) biphenyl-2-carbonitrile)
- the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give 4 '-((phenylamino) methyl) biphenyl-2-carbonitrile (4'-((phenylamino) methyl) biphenyl-2-carbonitrile) ( 86% yield).
- MPLC Medium Pressure Liquid Chromatography
- Step 2 N -((2'- Cyanophenyl -4- days) methyl )- N - Phenylpentaneamide (N-((2'- cyanobiphenyl -4- yl Preparation of Methyl) -N-phenylpentanamide)
- step 1 4 '-((phenylamino) methyl) biphenyl-2-carbonitrile obtained in step 1 was dissolved in dichloromethane (DCM), triethanolamine (TEA) was added, and then cooled on ice. .
- Valeroyl chloride (3.0 equiv) was added to the mixed solution, followed by stirring at room temperature for 4 hours. After the reaction was completed, RBF was added, and the organic solvent layer was washed with brine and separated. Thereafter, the organic solvent layer was collected, water was removed with anhydrous magnesium sulfate (MgSO 4 ), filtered, and then concentrated by evaporation.
- MgSO 4 anhydrous magnesium sulfate
- the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give N -((2'-cyanophenyl-4-yl) methyl) -N -phenylpentanamide (N-((2'-cyanobiphenyl-4-yl) methyl) -N-phenylpentanamide) was obtained (92%).
- MPLC Medium Pressure Liquid Chromatography
- Step 3 N -((2 '-(1H- Tetrazole -5 days) Biphenyl -4- days) methyl )- N - Phenylpentaneamide ( N -((2 '-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl)- N -phenylpentanamide)
- the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give N -((2 '-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl) -N -phenylpentanamide ( N -((2 '-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl) -N- phenylpentanamide) was obtained (92% yield).
- MPLC Medium Pressure Liquid Chromatography
- Step 2 N -((4'- Methoxybiphenyl -4- days) methyl Aniline ( N -((4'- methoxybiphenyl -4- yl Manufacture of methyl) aniline)
- Step 3 N -((4'- Methoxybiphenyl -4- days) methyl )- N - Phenylpentaneamide ( N -((4'- methoxybiphenyl -4-yl) methyl)- N -phenylpentanamide)
- N -((4'-methoxybiphenyl-4-yl) methyl) aniline obtained in step 2 was dissolved in dichloromethane (DCM), triethanolamine (TEA) was added, and then on ice Cooled. Valeroyl chloride (3.0 equiv) was added to the mixed solution, followed by stirring at room temperature for 4 hours. After the reaction was completed, RBF was added, and the organic solvent layer was washed with brine and separated. Thereafter, the organic solvent layer was collected, water was removed with anhydrous magnesium sulfate (MgSO 4 ), filtered, and then concentrated by evaporation.
- DCM dichloromethane
- TAA triethanolamine
- Valeroyl chloride (3.0 equiv) was added to the mixed solution, followed by stirring at room temperature for 4 hours. After the reaction was completed, RBF was added, and the organic solvent layer was washed with brine and separated. Thereafter, the organic solvent layer was collected, water was removed with anhydrous magnesium
- the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give the final product, N -((4'-methoxybiphenyl-4-yl) methyl) -N -phenylpentaneamide ( N -((4'-methoxybiphenyl- 4-yl) methyl) -N- phenylpentanamide) was obtained (100% yield).
- MPLC Medium Pressure Liquid Chromatography
- N -((4'-methoxybiphenyl-4-yl) methyl) -N -phenylpentaneamide (1.0 equiv) obtained in Example 28 was dissolved in a dichloromethane (DCM) solution, and then iced. Cooled at. At 0 ° C., BBr 3 was slowly added and the mixed solution was stirred at room temperature for 3 hours. The reaction was observed by thin layer chromatography (TLC). After the reaction was completed, ice was added to RBF, and extracted with DCM. Separating the organic solvent layer. Water was removed with anhydrous magnesium sulfate (MgSO 4 ), and the organic solvent layer was filtered and then concentrated by evaporation.
- DCM dichloromethane
- the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give N -((4'-hydroxybiphenyl-4-yl) methyl) -N -phenylpentanamide ( N -((4'-hydroxybiphenyl-) as a final product. 4-yl) methyl) -N- phenylpentanamide) was obtained (80% yield).
- MPLC Medium Pressure Liquid Chromatography
- Step 1 ethyl (2- (4 '-(( N - Phenylpentaneamido ) methyl ) Biphenyl -4- Iloxy Acetate (Ethyl (2- (4 '-(( N -phenylpentanamido) methyl) biphenyl-4-yloxy) acetate)
- N -((4'-hydroxybiphenyl-4-yl) methyl) -N -phenylpentaneamide (1.0 equiv) and K 2 CO 3 (3.0 equiv) obtained in Example 29 were replaced with N , N -di Dissolved in methylformamide (DMF) solution and cooled on ice.
- Ethylbromoacetate (3.0 equiv) was added and the mixed solution was stirred overnight at room temperature, N 2 feed conditions. After the reaction was completed, water was added, and the aqueous layer was extracted with ethyl acetate (EA).
- the organic solvent layer was washed with brine, dried with anhydrous magnesium sulfate (MgSO 4 ), and the organic solvent layer was concentrated by evaporation.
- the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give ethyl (2- (4 '-(( N -phenylpentaneamido) methyl) biphenyl-4-yloxy) acetate (Ethyl (2- (4'- (( N- phenylpentanamido) methyl) biphenyl-4-yloxy) acetate was obtained.
- MPLC Medium Pressure Liquid Chromatography
- step 2 2 -(4'-(( N - Phenylpentaneamido ) methyl ) Biphenyl -4- Iloxy Acetic acid (2- (4 '-(( N -phenylpentanamido) methyl) biphenyl-4-yloxy) acetic acid)
- Ethyl (2- (4 '-(( N -phenylpentaneamido) methyl) biphenyl-4-yloxy) acetate (1.0 equiv) obtained in step 1 was mixed well with tetrahydrofuran (THF). Then, LiOH solution was added and stirred for 4 hours After completion of the reaction, the mixed solution was concentrated and 2N HCl was added until acidic and extracted with ethyl acetate (EA) in vacuo.
- EA ethyl acetate
- Example 32 N -(3- Fluorophenyl )- N -((4'- Hydroxybiphenyl -4- days) methyl ) Pentaneamide ( N -(3-fluorophenyl)- N Preparation of-((4'-hydroxybiphenyl-4-yl) methyl) pentanamide) (AC-1070)
- N- (3-fluorophenyl) -N -((4'-methoxybiphenyl-4-yl) methyl) pentaneamide (1.0 equiv) obtained in Example 31 was converted to dichloromethane (DCM). After dissolving in solution, it was cooled in ice. At 0 ° C., BBr 3 was slowly added and the mixed solution was stirred at room temperature for 3 hours. The reaction was observed by thin layer chromatography (TLC). After the reaction was completed, ice was added to RBF, and extracted with DCM. Separating the organic solvent layer. Water was removed with anhydrous magnesium sulfate (MgSO 4 ), and the organic solvent layer was filtered and then concentrated by evaporation.
- DCM dichloromethane
- the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give N- (3-fluorophenyl) -N -((4'-hydroxybiphenyl-4-yl) methyl) pentaneamide ( N- ( 3-fluorophenyl) -N -((4'-hydroxybiphenyl-4-yl) methyl) pentanamide) was obtained (85% yield).
- MPLC Medium Pressure Liquid Chromatography
- 1-bromo-4-methoxybenzene (1.0 equiv) and 4-formylphenylboronic acid (1.1 equiv) are mixed well with RBF, and then 1,4 Dioxane (1,4 dioxane): dissolved in H 2 O (10: 1) mixed solution.
- Pd (dppf) Cl 2 .DCM (0.05 equiv) was added to the mixed solution to degassing for 20 minutes, and Na 2 CO 3 was added to degassing again for 20 minutes. Once again degassed for 15 minutes, it was heated to reflux for 4 hours.
- step 2 3 - Chloro -N- ((4'-methoxyphenyl-4-yl) methyl) aniline (3- chloro -N-((4'- methoxybiphenyl Preparation of -4-yl) methyl) aniline)
- Step 3 N- (3- Chlorophenyl ) -N- ((4'-methoxybiphenyl-4-yl) methyl) pentaneamide (N- (3- chlorophenyl ) -N-((4'-methoxybiphenyl-4-yl) methyl) pentanamide)
- the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give the final compound, N- (3-chlorophenyl) -N-((4'-methoxybiphenyl-4-yl) methyl) pentaneamide (N- (3 -chlorophenyl) -N-((4'-methoxybiphenyl-4-yl) methyl) pentanamide) was obtained (85% yield).
- MPLC Medium Pressure Liquid Chromatography
- N- (3-chlorophenyl) -N-((4'-methoxybiphenyl-4-yl) methyl) pentaneamide (1.0 equiv) obtained in Example 34 was diluted with dichloromethane (DCM). After melting in, cooled on ice. At 0 ° C., BBr 3 was slowly added and the mixed solution was stirred at room temperature for 3 hours. The reaction was observed by thin layer chromatography (TLC). After the reaction was completed, ice was added to RBF, and extracted with DCM. Separating the organic solvent layer. Water was removed with anhydrous magnesium sulfate (MgSO 4 ), and the organic solvent layer was filtered and then concentrated by evaporation.
- DCM dichloromethane
- the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give N- (3-chlorophenyl) -N-((4'-hydroxybiphenyl-4-yl) methyl) pentaneamide (N- (3) as a final product.
- MPLC Medium Pressure Liquid Chromatography
- Step 1 ethyl 2- (4 ′-((N- (3- Chlorophenyl ) Pentanamido ) methyl ) Biphenyl -4- Iloxy Preparation of Acetate (ethyl 2- (4 '-((N- (3-chlorophenyl) pentanamido) methyl) biphenyl-4-yloxy) acetate)
- N- (3-chlorophenyl) -N-((4'-hydroxybiphenyl-4-yl) methyl) pentaneamide (1.0 equiv) and K 2 CO 3 (3.0 equiv) obtained in Example 35 were prepared. It was dissolved in N , N -dimethylformamide (DMF) solution and then cooled on ice. After adding ethylchloroacetate (3.0 equiv), the mixed solution was stirred overnight at room temperature, N 2 supply conditions. After the reaction was completed, water was added, and the aqueous layer was extracted with ethyl acetate (EA).
- EA ethyl acetate
- the organic solvent layer was washed with brine, dried with anhydrous magnesium sulfate (MgSO 4 ), and the organic solvent layer was concentrated by evaporation.
- the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to obtain ethyl 2- (4 '-((N- (3-chlorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetate (ethyl 2- ( 4 '-((N- (3-chlorophenyl) pentanamido) methyl) biphenyl-4-yloxy) acetate) was obtained (75% yield).
- MPLC Medium Pressure Liquid Chromatography
- step 2 2 -(4 '-((N- (3- Chlorophenyl ) Pentanamido ) methyl ) Biphenyl -4- Iloxy Preparation of acetic acid (2- (4 '-((N- (3-chlorophenyl) pentanamido) methyl) biphenyl-4-yloxy) acetic acid)
- Ethyl 2- (4 '-((N- (3-chlorophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetate (1.0 equiv) obtained in step 1 was added with tetrahydrofuran (THF). After mixing well), LiOH solution was added and stirred for 4 hours. After the reaction was completed, the mixed solution was concentrated, 2N HCl was added until acidic, and extracted with ethyl acetate (EA).
- 1-bromo-4-methoxybenzene (1.0 equiv) and 4-formylphenylboronic acid (1.1 equiv) are mixed well with RBF, and then 1,4 Dioxane (1,4 dioxane): dissolved in H 2 O (10: 1) mixed solution.
- Pd (dppf) Cl 2 .DCM (0.05 equiv) was added to the mixed solution to degassing for 20 minutes, and Na 2 CO 3 was added to degassing again for 20 minutes. Once again degassed for 15 minutes, it was heated to reflux for 4 hours.
- step 2 3 - Bromo -N- ((4'-methoxyphenyl-4-yl) methyl) aniline (3- chloro -N-((4'- methoxybiphenyl Preparation of -4-yl) methyl) aniline)
- Step 3 N- (3- Bromophenyl ) -N- ((4'-methoxybiphenyl-4-yl) methyl) pentaneamide (N- (3- bromophenyl ) -N-((4'-methoxybiphenyl-4-yl) methyl) pentanamide)
- step 2 3-bromo-N-((4'-methoxyphenyl-4-yl) methyl) aniline obtained in step 2 was dissolved in dichloromethane (DCM) and triethanolamine (TEA) was added thereto. Then cooled on ice. Valeroyl chloride (2.0 equiv) was added to the mixed solution, followed by stirring at room temperature for 4 hours. After the reaction was completed, RBF was added, and the organic solvent layer was washed with brine and separated. Thereafter, the organic solvent layer was collected, water was removed with anhydrous magnesium sulfate (MgSO 4 ), filtered, and then concentrated by evaporation.
- DCM dichloromethane
- TAA triethanolamine
- the concentrated solution was purified by Medium Pressure Liquid Chromatography (MPLC) to obtain a final compound, N- (3-bromophenyl) -N-((4'-methoxybiphenyl-4-yl) methyl) pentaneamide (N- ( 3-bromophenyl) -N-((4'-methoxybiphenyl-4-yl) methyl) pentanamide) was obtained (73% yield).
- MPLC Medium Pressure Liquid Chromatography
- N- (3-bromophenyl) -N-((4'-methoxybiphenyl-4-yl) methyl) pentaneamide (1.0 equiv) obtained in Example 37 was converted to dichloromethane (DCM). After dissolving in solution, it was cooled in ice. At 0 ° C., BBr 3 was slowly added and the mixed solution was stirred at room temperature for 3 hours. The reaction was observed by thin layer chromatography (TLC). After the reaction was completed, ice was added to RBF, and extracted with DCM. Separating the organic solvent layer. Water was removed with anhydrous magnesium sulfate (MgSO 4 ), and the organic solvent layer was filtered and then concentrated by evaporation.
- DCM dichloromethane
- the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to yield N- (3-bromophenyl) -N-((4'-hydroxybiphenyl-4-yl) methyl) pentaneamide (N- ( 3-bromophenyl) -N-((4'-hydroxybiphenyl-4-yl) methyl) pentanamide) was obtained (89% yield).
- MPLC Medium Pressure Liquid Chromatography
- Step 1 ethyl 2- (4 ′-((N- (3- Bromophenyl ) Pentanamido ) methyl ) Biphenyl -4- Iloxy Preparation of Acetate (ethyl 2- (4 '-((N- (3-bromophenyl) pentanamido) methyl) biphenyl-4-yloxy) acetate)
- the organic solvent layer was washed with brine, dried with anhydrous magnesium sulfate (MgSO 4 ), and the organic solvent layer was concentrated by evaporation.
- the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give ethyl 2- (4 '-((N- (3-bromophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetate (ethyl 2- (4 '-((N- (3-bromophenyl) pentanamido) methyl) biphenyl-4-yloxy) acetate) was obtained (85% yield).
- MPLC Medium Pressure Liquid Chromatography
- step 2 2 -(4 '-((N- (3- Bromophenyl ) Pentanamido ) methyl ) Biphenyl -4- Iloxy Preparation of acetic acid (2- (4 '-((N- (3-bromophenyl) pentanamido) methyl) biphenyl-4-yloxy) acetic acid)
- Ethyl 2- (4 '-((N- (3-bromophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetate (1.0 equiv) obtained in step 1 was converted to tetrahydrofuran, THF) was mixed well, then LiOH solution was added and stirred for 4 hours. After the reaction was completed, the mixed solution was concentrated, 2N HCl was added until acidic, and extracted with ethyl acetate (EA).
- Example 40 N -((4'- Methoxybiphenyl -4- days) methyl )- N - (3- ( Trifluoromethyl ) Phenyl) Pentaneamide ( N -((4'-methoxybiphenyl-4-yl) methyl)- N Preparation of-(3- (trifluoromethyl) phenyl) pentanamide) (AC-1634)
- 1-bromo-4-methoxybenzene (1.0 equiv) and 4-formylphenylboronic acid (1.1 equiv) are mixed well with RBF, and then 1,4 Dioxane (1,4 dioxane): dissolved in H 2 O (10: 1) mixed solution.
- Pd (dppf) Cl 2 .DCM (0.05 equiv) was added to the mixed solution to degassing for 20 minutes, and Na 2 CO 3 was added to degassing again for 20 minutes. Once again degassed for 15 minutes, it was heated to reflux for 4 hours.
- Step 2 N-((4'- Methoxybiphenyl -4- days) methyl ) -3- (Trifluoromethyl) aniline (N- ( Preparation of (4'-methoxybiphenyl-4-yl) methyl) -3- (trifluoromethyl) aniline)
- Step 3 N-((4'- Methoxybiphenyl -4- days) methyl ) -N- (3- ( Trifluoromethyl ) Phenyl) Pentaneamide
- N-((4'-methoxybiphenyl-4-yl) methyl) -3- (trifluoromethyl) aniline obtained in step 2 was dissolved in dichloromethane (DCM) and triethanolamine , TEA) was added and then cooled on ice.
- Valeroyl chloride 2.0 equiv was added to the mixed solution, followed by stirring at room temperature for 4 hours. After the reaction was completed, RBF was added, and the organic solvent layer was washed with brine and separated. Thereafter, the organic solvent layer was collected, water was removed with anhydrous magnesium sulfate (MgSO 4 ), filtered, and then concentrated by evaporation.
- the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give N-((4'-methoxybiphenyl-4-yl) methyl) -N- (3- (trifluoromethyl) phenyl) pentaneamide as a final compound.
- MPLC Medium Pressure Liquid Chromatography
- N-((4'-methoxybiphenyl-4-yl) methyl) -N- (3- (trifluoromethyl) phenyl) pentaneamide (1.0 equiv) obtained in Example 40 was converted to dichloromethane ( dichloromethane, DCM) solution, and then cooled on ice. At 0 ° C., BBr 3 was slowly added and the mixed solution was stirred at room temperature for 3 hours. The reaction was observed by thin layer chromatography (TLC). After the reaction was completed, ice was added to RBF, and extracted with DCM. Separating the organic solvent layer. Water was removed with anhydrous magnesium sulfate (MgSO 4 ), and the organic solvent layer was filtered and then concentrated by evaporation.
- dichloromethane dichloromethane, DCM
- TLC thin layer chromatography
- the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give N-((4'-hydroxybiphenyl-4-yl) methyl) -N- (3- (trifluoromethyl) phenyl) pentaneamide as a final product.
- MPLC Medium Pressure Liquid Chromatography
- Step 1 ethyl 2- (4 ′-((N- (3- ( Trifluoro ) Phenyl) Pentanamido ) methyl ) Biphenyl -4- Iloxy Preparation of Acetate (ethyl 2- (4 '-((N- (3- (trifluoromethyl) phenyl) pentanamido) methyl) biphenyl-4-yloxy) acetate)
- EA ethyl acetate
- the organic solvent layer was washed with brine, dried with anhydrous magnesium sulfate (MgSO 4 ), and the organic solvent layer was concentrated by evaporation.
- the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give 2- (4 '-((N- (3- (trifluoro) phenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetate (ethyl 2- (4 '-((N- (3- (trifluoromethyl) phenyl) pentanamido) methyl) biphenyl-4-yloxy) acetate) was obtained (100% yield).
- MPLC Medium Pressure Liquid Chromatography
- step 2 2 -(4 '-((N- (3- ( Trifluoromethyl ) Phenyl) Pentanamido ) methyl ) Biphenyl -4- Iloxy Preparation of acetic acid (2- (4 '-((N- (3- (trifluoromethyl) phenyl) pentanamido) methyl) biphenyl-4-yloxy) acetic acid)
- 1-bromo-4-methoxybenzene (1.0 equiv) and 4-formylphenylboronic acid (1.1 equiv) are mixed well with RBF, and then 1,4 Dioxane (1,4 dioxane): dissolved in H 2 O (10: 1) mixed solution.
- Pd (dppf) Cl 2 .DCM (0.05 equiv) was added to the mixed solution to degassing for 20 minutes, and Na 2 CO 3 was added to degassing again for 20 minutes. Once again degassed for 15 minutes, it was heated to reflux for 4 hours.
- Step 2 N-((4'- Methoxybiphenyl -4- days) methyl ) -3- (Trifluoromethyl) aniline (N- ( Preparation of (4'-methoxybiphenyl-4-yl) methyl) -3- (trifluoromethyl) aniline)
- Step 3 N-((4'- Methoxybiphenyl -4- days) methyl ) -N-m- Tolylpentaneamide (N-((4'- methoxybiphenyl Preparation of -4-yl) methyl) -N-m-tolylpentanamide)
- N-((4'-methoxybiphenyl-4-yl) methyl) -3- (trifluoromethyl) aniline obtained in step 2 was dissolved in dichloromethane (DCM) and triethanolamine , TEA) was added and then cooled on ice.
- Valeroyl chloride 2.0 equiv was added to the mixed solution, followed by stirring at room temperature for 4 hours. After the reaction was completed, RBF was added, and the organic solvent layer was washed with brine and separated. Thereafter, the organic solvent layer was collected, water was removed with anhydrous magnesium sulfate (MgSO 4 ), filtered, and then concentrated by evaporation.
- the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to obtain the final compound, N-((4'-methoxybiphenyl-4-yl) methyl) -Nm-tolylpentaneamide (N-((4'-methoxybiphenyl- 4-yl) methyl) -Nm-tolylpentanamide) was obtained (90% yield).
- MPLC Medium Pressure Liquid Chromatography
- N-((4'-methoxybiphenyl-4-yl) methyl) -Nm-tolylpentanamide (1.0 equiv) obtained in Example 43 was dissolved in a dichloromethane (DCM) solution, and then iced. Cooled at. At 0 ° C., BBr 3 was slowly added and the mixed solution was stirred at room temperature for 3 hours. The reaction was observed by thin layer chromatography (TLC). After the reaction was completed, ice was added to RBF, and extracted with DCM. Separating the organic solvent layer. Water was removed with anhydrous magnesium sulfate (MgSO 4 ), and the organic solvent layer was filtered and then concentrated by evaporation.
- DCM dichloromethane
- the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give N-((4'-hydroxyphenyl-4-yl) methyl) -Nm-tolylpentaneamide (N-((4'-hydroxybiphenyl-4) as a final product.
- MPLC Medium Pressure Liquid Chromatography
- Step 1 ethyl 2- (4 '-((N-m- Tolylpentaneamido ) methyl ) Biphenyl -4- Iloxy Preparation of Acetate (ethyl 2- (4 '-((N-m-tolylpentanamido) methyl) biphenyl-4-yloxy) acetate)
- N-((4'-hydroxyphenyl-4-yl) methyl) -Nm-tolylpentaneamide (1.0 equiv) and K 2 CO 3 (3.0 equiv) obtained in Example 44 were replaced with N , N -dimethyl. It was dissolved in formamide (DMF) solution and then cooled on ice. After adding ethylchloroacetate (3.0 equiv), the mixed solution was stirred overnight at room temperature, N 2 supply conditions. After the reaction was completed, water was added, and the aqueous layer was extracted with ethyl acetate (EA).
- EA ethyl acetate
- the organic solvent layer was washed with brine, dried with anhydrous magnesium sulfate (MgSO 4 ), and the organic solvent layer was concentrated by evaporation.
- the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to obtain ethyl 2- (4 '-((Nm-tolylpentaneamido) methyl) biphenyl-4-yloxy) acetate (ethyl 2- (4'-(( Nm-tolylpentanamido) methyl) biphenyl-4-yloxy) acetate) was obtained (100% yield).
- MPLC Medium Pressure Liquid Chromatography
- step 2 2 -(4 '-((N-m- Tolylpentaneamido ) methyl ) Biphenyl -4- Iloxy Preparation of acetic acid (2- (4 '-((N-m-tolylpentanamido) methyl) biphenyl-4-yloxy) acetic acid)
- Ethyl 2- (4 '-((Nm-tolylpentaneamido) methyl) biphenyl-4-yloxy) acetate (1.0 equiv) obtained in step 1 was mixed well with tetrahydrofuran (THF). , LiOH solution was added and stirred for 4 hours. After the reaction was completed, the mixed solution was concentrated, 2N HCl was added until acidic, and extracted with ethyl acetate (EA).
- 1-bromo-4-methoxybenzene (1.0 equiv) and 4-formylphenylboronic acid (1.1 equiv) are mixed well with RBF, and then 1,4 Dioxane (1,4 dioxane): dissolved in H 2 O (10: 1) mixed solution.
- Pd (dppf) Cl 2 .DCM (0.05 equiv) was added to the mixed solution to degassing for 20 minutes, and Na 2 CO 3 was added to degassing again for 20 minutes. Once again degassed for 15 minutes, it was heated to reflux for 4 hours.
- Step 2 N-((4'- Methoxybiphenyl -4- days) methyl ) -3- Nitroaniline (N- ( (4'- methoxybiphenyl Preparation of -4-yl) methyl) -3-nitroaniline)
- Step 3 N-((4'- Methoxybiphenyl -4- days) methyl ) -N- (3-nitrophenyl) pentaneamide
- Step 3 N-((4'- Methoxybiphenyl -4- days) methyl ) -N- (3-nitrophenyl) pentaneamide
- N-((4'-methoxybiphenyl-4-yl) methyl) -3-nitroaniline obtained in step 2 was dissolved in dichloromethane (DCM) and triethanolamine (TEA) was added thereto. Then cooled on ice. Valeroyl chloride (2.0 equiv) was added to the mixed solution, followed by stirring at room temperature for 4 hours. After the reaction was completed, RBF was added, and the organic solvent layer was washed with brine and separated. Thereafter, the organic solvent layer was collected, water was removed with anhydrous magnesium sulfate (MgSO 4 ), filtered, and then concentrated by evaporation.
- DCM dichloromethane
- TAA triethanolamine
- the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give N-((4'-methoxybiphenyl-4-yl) methyl) -N- (3-nitrophenyl) pentaneamide (N-((4 '). -methoxybiphenyl-4-yl) methyl) -N- (3-nitrophenyl) pentanamide) was obtained (91% yield).
- MPLC Medium Pressure Liquid Chromatography
- Step 4 N-((4'- Hydroxyphenyl -4- days) methyl ) -N- (3- Nitrophenyl ) Pentaneamide Preparation of (N-((4'-hydroxybiphenyl-4-yl) methyl) -N- (3-nitrophenyl) pentanamide)
- N-((4'-methoxybiphenyl-4-yl) methyl) -N- (3-nitrophenyl) pentaneamide (1.0 equiv) obtained in step 3 was added to a dichloromethane (DCM) solution. After thawing, it was cooled on ice. At 0 ° C., BBr 3 was slowly added and the mixed solution was stirred at room temperature for 3 hours. The reaction was observed by thin layer chromatography (TLC). After the reaction was completed, ice was added to RBF, and extracted with DCM. Separating the organic solvent layer. Water was removed with anhydrous magnesium sulfate (MgSO 4 ), and the organic solvent layer was filtered and then concentrated by evaporation.
- DCM dichloromethane
- the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to yield N-((4'-hydroxyphenyl-4-yl) methyl) -N- (3-nitrophenyl) pentaneamide (N-((4 '-hydroxybiphenyl-4-yl) methyl) -N- (3-nitrophenyl) pentanamide) was obtained (30% yield).
- MPLC Medium Pressure Liquid Chromatography
- Step 1 ethyl 2- (4 ′-((N- (3- Nitrophenyl ) Pentanamido ) methyl ) Biphenyl -4- Iloxy Preparation of Acetate (ethyl 2- (4 '-((N- (3-nitrophenyl) pentanamido) methyl) biphenyl-4-yloxy) acetate)
- N-((4'-hydroxyphenyl-4-yl) methyl) -N- (3-nitrophenyl) pentanamide (1.0 equiv) and K 2 CO 3 (3.0 equiv) obtained in Example 46 were added to N. , Dissolved in N -dimethylformamide (DMF) solution and cooled on ice. After adding ethylchloroacetate (3.0 equiv), the mixed solution was stirred overnight at room temperature, N 2 supply conditions. After the reaction was completed, water was added, and the aqueous layer was extracted with ethyl acetate (EA).
- EA ethyl acetate
- the organic solvent layer was washed with brine, dried with anhydrous magnesium sulfate (MgSO 4 ), and the organic solvent layer was concentrated by evaporation.
- the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give ethyl 2- (4 '-((N- (3-nitrophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetate (ethyl 2- ( 4 '-((N- (3-nitrophenyl) pentanamido) methyl) biphenyl-4-yloxy) acetate) was obtained (91% yield).
- MPLC Medium Pressure Liquid Chromatography
- step 2 2 -(4 '-((N- (3- Nitrophenyl ) Pentanamido ) methyl ) Biphenyl -4- Iloxy Preparation of acetic acid (2- (4 '-((N- (3-nitrophenyl) pentanamido) methyl) biphenyl-4-yloxy) acetic acid)
- Ethyl 2- (4 ′-((N- (3-nitrophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetate (1.0 equiv) obtained in step 1 was added to tetrahydrofuran (THF). After mixing well), LiOH solution was added and stirred for 4 hours. After the reaction was completed, the mixed solution was concentrated, 2N HCl was added until acidic, and extracted with ethyl acetate (EA).
- Example 48 N -(3- Iodophenyl )- N -((4'- Methoxybiphenyl -4- days) methyl ) Pentaneamide ( N -(3-iodophenyl)- N Preparation of-((4'-methoxybiphenyl-4-yl) methyl) pentanamide) (AC-1643)
- 1-bromo-4-methoxybenzene (1.0 equiv) and 4-formylphenylboronic acid (1.1 equiv) are mixed well with RBF, and then 1,4 Dioxane (1,4 dioxane): dissolved in H 2 O (10: 1) mixed solution.
- Pd (dppf) Cl 2 .DCM (0.05 equiv) was added to the mixed solution to degassing for 20 minutes, and Na 2 CO 3 was added to degassing again for 20 minutes. Once again degassed for 15 minutes, it was heated to reflux for 4 hours.
- step 2 3 - Iodo -N-((4'- Methoxybiphenyl -4- days) methyl Aniline (3- iodo -N-((4'- methoxybiphenyl Preparation of -4-yl) methyl) aniline)
- step 1 4'-methoxybiphenyl-4-carbaldehyde (1.0 equiv) and 3-iodoaniline (2.0 equiv) obtained in step 1 were dissolved in methanol, and then stirred at room temperature for 4 hours. It was. The reaction until imine was formed was observed by thin layer chromatography (TLC). After imine was formed, 1M NaCNBH 3 (1.0 equiv) and 0.5M ZnCl 2 were added to the solution. (1.0 equiv) mixed methanol solution was added and stirred overnight at room temperature.
- TLC thin layer chromatography
- Step 3 N- (3- Iodophenyl ) -N-((4'- Methoxybiphenyl -4- days) methyl ) Pentaneamide (N- (3- iodophenyl ) -N-((4'-methoxybiphenyl-4-yl) methyl) pentanamide)
- step 2 3-iodo-N-((4'-methoxybiphenyl-4-yl) methyl) aniline obtained in step 2 was dissolved in dichloromethane (DCM) and triethanolamine (TEA) After addition, it was cooled on ice. Valeroyl chloride (2.0 equiv) was added to the mixed solution, followed by stirring at room temperature for 4 hours. After the reaction was completed, RBF was added, and the organic solvent layer was washed with brine and separated. Thereafter, the organic solvent layer was collected, water was removed with anhydrous magnesium sulfate (MgSO 4 ), filtered, and then concentrated by evaporation.
- DCM dichloromethane
- TOA triethanolamine
- the concentrated solution was purified by Medium Pressure Liquid Chromatography (MPLC), and the final compound, N- (3-iodophenyl) -N-((4'-methoxybiphenyl-4-yl) methyl) pentaneamide (N- (3-iodophenyl) -N-((4'-methoxybiphenyl-4-yl) methyl) pentanamide) was obtained (80% yield).
- MPLC Medium Pressure Liquid Chromatography
- N- (3-iodophenyl) -N-((4'-methoxybiphenyl-4-yl) methyl) pentaneamide (1.0 equiv) obtained in Example 48 was converted to dichloromethane (DCM). After dissolving in solution, it was cooled in ice. At 0 ° C., BBr 3 was slowly added and the mixed solution was stirred at room temperature for 3 hours. The reaction was observed by thin layer chromatography (TLC). After the reaction was completed, ice was added to RBF, and extracted with DCM. Separating the organic solvent layer. Water was removed with anhydrous magnesium sulfate (MgSO 4 ), and the organic solvent layer was filtered and then concentrated by evaporation.
- DCM dichloromethane
- the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to yield N-((4'-hydroxybiphenyl-4-yl) methyl) -N- (3-iodophenyl) pentaneamide (N- ( (4'-hydroxybiphenyl-4-yl) methyl) -N- (3-iodophenyl) pentanamide) was obtained (90% yield).
- MPLC Medium Pressure Liquid Chromatography
- Example 50 2- (4 '-(( N -(3- Iodophenyl ) Pentanamido ) methyl ) Biphenyl -4- Iloxy Acetic acid (2- (4 '-(( N Preparation of-(3-iodophenyl) pentanamido) methyl) biphenyl-4-yloxy) acetic acid) (AC-1645)
- Step 1 ethyl 2- (4 ′-((N- (3- Iodophenyl ) Pentanamido ) methyl ) Biphenyl -4- Iloxy Preparation of Acetate (ethyl 2- (4 '-((N- (3-iodophenyl) pentanamido) methyl) biphenyl-4-yloxy) acetate)
- the organic solvent layer was washed with brine, dried with anhydrous magnesium sulfate (MgSO 4 ), and the organic solvent layer was concentrated by evaporation.
- the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give ethyl 2- (4 '-((N- (3-iodophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetate (ethyl 2- (4 '-((N- (3-iodophenyl) pentanamido) methyl) biphenyl-4-yloxy) acetate) was obtained (89% yield).
- MPLC Medium Pressure Liquid Chromatography
- step 2 2 -(4 '-((N- (3- Iodophenyl ) Pentanamido ) methyl ) Biphenyl -4- Iloxy Preparation of acetic acid (2- (4 '-((N- (3-iodophenyl) pentanamido) methyl) biphenyl-4-yloxy) acetic acid)
- Ethyl 2- (4 '-((N- (3-iodophenyl) pentaneamido) methyl) biphenyl-4-yloxy) acetate (1.0 equiv) obtained in step 1 was converted to tetrahydrofuran, THF) was mixed well, then LiOH solution was added and stirred for 4 hours. After the reaction was completed, the mixed solution was concentrated, 2N HCl was added until acidic, and extracted with ethyl acetate (EA).
- 1-bromo-4-methoxybenzene (1.0 equiv) and 4-formylphenylboronic acid (1.1 equiv) are mixed well with RBF, and then 1,4 Dioxane (1,4 dioxane): dissolved in H 2 O (10: 1) mixed solution.
- Pd (dppf) Cl 2 .DCM (0.05 equiv) was added to the mixed solution to degassing for 20 minutes, and Na 2 CO 3 was added to degassing again for 20 minutes. Once again degassed for 15 minutes, it was heated to reflux for 4 hours.
- step 2 3 - Fluoro -N-((4'- Methoxybiphenyl -4- days) methyl Aniline (3- fluoro -N-((4'- methoxybiphenyl Preparation of -4-yl) methyl) aniline)
- Step 3 N- (3- Fluorophenyl ) -N-((4'- Methoxybiphenyl -4- days) methyl ) Pentaneamide Preparation of (N- (3-fluorophenyl) -N-((4'-methoxybiphenyl-4-yl) methyl) pentanamide)
- step 2 3-fluoro-N-((4'-methoxybiphenyl-4-yl) methyl) aniline obtained in step 2 was dissolved in dichloromethane (DCM) and triethanolamine (TEA) After addition, it was cooled on ice. Valeroyl chloride (2.0 equiv) was added to the mixed solution, followed by stirring at room temperature for 4 hours. After the reaction was completed, RBF was added, and the organic solvent layer was washed with brine and separated. Thereafter, the organic solvent layer was collected, water was removed with anhydrous magnesium sulfate (MgSO 4 ), filtered, and then concentrated by evaporation.
- DCM dichloromethane
- TOA triethanolamine
- the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to obtain N- (3-fluorophenyl) -N-((4'-methoxybiphenyl-4-yl) methyl) pentaneamide (N- (3-fluorophenyl) -N-((4'-methoxybiphenyl-4-yl) methyl) pentanamide) was obtained (81% yield).
- MPLC Medium Pressure Liquid Chromatography
- N-((4'-hydroxybiphenyl-4-yl) methyl) -N- (3-iodophenyl) pentaneamide (1.0 equiv) obtained in Example 51 was converted to dichloromethane (DCM). After dissolving in solution, it was cooled in ice. At 0 ° C., BBr 3 was slowly added and the mixed solution was stirred at room temperature for 3 hours. The reaction was observed by thin layer chromatography (TLC). After the reaction was completed, ice was added to RBF, and extracted with DCM. Separating the organic solvent layer. Water was removed with anhydrous magnesium sulfate (MgSO 4 ), and the organic solvent layer was filtered and then concentrated by evaporation.
- DCM dichloromethane
- the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give N- (3-fluorophenyl) -N-((4'-hydroxy- [1,1'-biphenyl] -4-yl) as a final product.
- MPLC Medium Pressure Liquid Chromatography
- Example 53 2-((4 '-(( N -(3- Fluorophenyl ) Acetamido ) methyl )-[1,1'- Biphenyl ] -4-day) Oxy Acetic acid (2-((4 '-(( N -(3-fluorophenyl) acetamido) methyl)-[1,1'-biphenyl] -4-yl) oxy) acetic acid) (AC- 1648 of Produce
- Step 1 ethyl 2- (4 ′-((N- (3- Fluorophenyl ) Acetoamido ) methyl ) Biphenyl -4- Iloxy Preparation of Acetate (ethyl 2- (4 '-((N- (3-fluorophenyl) acetamido) methyl) biphenyl-4-yloxy) acetate)
- EA ethyl acetate
- the organic solvent layer was washed with brine, dried with anhydrous magnesium sulfate (MgSO 4 ), and the organic solvent layer was concentrated by evaporation.
- the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give ethyl 2- (4 '-((N- (3-fluorophenyl) acetoamido) methyl) biphenyl-4-yloxy) acetate (ethyl 2- (4 '-((N- (3-fluorophenyl) acetamido) methyl) biphenyl-4-yloxy) acetate) was obtained (91% yield).
- MPLC Medium Pressure Liquid Chromatography
- step 2 2 -((4 '-((N- (3- Fluorophenyl ) Acetamido ) methyl )-[1,1'- Biphenyl ] -4-day) Oxy Preparation of acetic acid (2-((4 '-((N- (3-fluorophenyl) acetamido) methyl)-[1,1'-biphenyl] -4-yl) oxy) acetic acid)
- Ethyl 2- (4 '-((N- (3-fluorophenyl) acetoamido) methyl) biphenyl-4-yloxy) acetate (1.0 equiv) obtained in step 1 was converted to tetrahydrofuran, THF) was mixed well, then LiOH solution was added and stirred for 4 hours. After the reaction was completed, the mixed solution was concentrated, 2N HCl was added until acidic, and extracted with ethyl acetate (EA).
- Example 54 N -((4 '-(4- Isopropyl piperazine -One- Carbonyl ) Biphenyl -4- days) methyl )- N - Phenylpentaneamide ( N -((4 '-(4-isopropylpiperazine-1-carbonyl) biphenyl-4-yl) methyl)- N -phenylpentanamide) (AC-1649)
- reaction mixture was filtered and extracted with ethyl acetate (EA), dried with anhydrous MgSO 4 , evaporated to concentration, and then purified by Medium Pressure Liquid Chromatography (MPLC) to obtain methyl 4'-formylbiphenyl.
- EA ethyl acetate
- MgSO 4 Medium Pressure Liquid Chromatography
- Step 2 methyl 4'-(( Phenylamino ) methyl ) Biphenyl -4- Carboxylate Preparation of (methyl 4 '-((phenylamino) methyl) biphenyl-4-carboxylate)
- Methyl 4′-formylbiphenyl-4-carboxylate (1.0 equiv) and aniline (aniline) (3.0 equiv) obtained in step 1 were dissolved in methanol, and then stirred at room temperature for 4 hours. The reaction until imine was formed was observed by thin layer chromatography (TLC). After imine was formed, 1M NaCNBH 3 (1.0 equiv) and 0.5M ZnCl 2 were added to the solution. (1.0 equiv) mixed methanol solution was added and stirred overnight at room temperature.
- Step 3 methyl 4 '-((N- Phenylpentaneamido ) methyl ) Biphenyl -4- Carboxylate (methyl 4 '-( Preparation of (N-phenylpentanamido) methyl) biphenyl-4-carboxylate)
- Methyl 4 '-((phenylamino) methyl) biphenyl-4-carboxylate obtained in step 2 was dissolved in dichloromethane (DCM), triethanolamine (TEA) was added, and then cooled on ice. .
- Valeroyl chloride 2.0 equiv was added to the mixed solution, followed by stirring at room temperature for 4 hours. After the reaction was completed, RBF was added, and the organic solvent layer was washed with brine and separated. Thereafter, the organic solvent layer was collected, water was removed with anhydrous magnesium sulfate (MgSO 4 ), filtered, and then concentrated by evaporation.
- the concentrated solution was purified by Medium Pressure Liquid Chromatography (MPLC), and methyl 4 '-((N-phenylpentaneamido) methyl) biphenyl-4-carboxylate (methyl 4'-((N-phenylpentanamido) methyl) biphenyl -4-carboxylate) was obtained (57% yield).
- MPLC Medium Pressure Liquid Chromatography
- step 4 4 '-((N- Phenylpentaneamido ) methyl ) Biphenyl -4- Carboxylic acid Preparation of (4 '-((N-phenylpentanamido) methyl) biphenyl-4-carboxylic acid)
- Methyl 4 ′-((N-phenylpentaneamido) methyl) biphenyl-4-carboxylate (1.0 equiv) obtained in step 3 was mixed well with tetrahydrofuran (THF), and then LiOH solution was added thereto. , Was stirred for 4 hours. After the reaction was completed, the mixed solution was concentrated, 2N HCl was added until acidic, and extracted with ethyl acetate (EA).
- EA ethyl acetate
- step 5 4 '-((N- Phenylpentaneamido ) methyl ) Biphenyl -4- Carboxylic acid Preparation of (4 '-((N-phenylpentanamido) methyl) biphenyl-4-carboxylic acid)
- the concentrate was purified by column chromatography to obtain 4 '-((N-phenylpentaneamido) methyl) biphenyl-4-carboxylic acid (4'-((N-phenylpentanamido) methyl) biphenyl-4-carboxylic acid ) was obtained (50% yield).
- Example 55 N -(4-fluorophenyl)- N -((4 '-(4-isopropylpiperazin-1-carbonyl) biphenyl-4-yl) methyl) pentaneamide ( N -(4-fluorophenyl)- N Preparation of-((4 '-(4-isopropylpiperazine-1-carbonyl) biphenyl-4-yl) methyl) pentanamide) (AC-1650)
- Step 1 methyl 4'- Formylbiphenyl -4- Carboxylate (methyl 4'- formylbiphenyl -4- carboxylate Manufacture of
- reaction mixture was filtered and extracted with ethyl acetate (EA), dried with anhydrous MgSO 4 , evaporated to concentration, and then purified by Medium Pressure Liquid Chromatography (MPLC) to obtain methyl 4'-formylbiphenyl.
- EA ethyl acetate
- MgSO 4 Medium Pressure Liquid Chromatography
- Step 2 methyl 4 '-((4- Fluorophenylamino ) methyl ) Biphenyl -4- Carboxylate Preparation of (methyl 4 '-((4-fluorophenylamino) methyl) biphenyl-4-carboxylate)
- Step 3 methyl 4 '-((N- (4- Fluorophenyl Pentaamido) methyl ) Biphenyl -4- Carboxylate (methyl 4 '-((N- Preparation of (4-fluorophenyl) pentanamido) methyl) biphenyl-4-carboxylate)
- step 2 4 '-((4-fluorophenylamino) methyl) biphenyl-4-carboxylate obtained in step 2 was dissolved in dichloromethane (DCM), triethanolamine (TEA) was added, and then ice Cooled in. Valeroyl chloride (2.0 equiv) was added to the mixed solution, followed by stirring at room temperature for 12 hours. After the reaction was completed, RBF was added, and the organic solvent layer was washed with brine and separated. Thereafter, the organic solvent layer was collected, water was removed with anhydrous magnesium sulfate (MgSO 4 ), filtered, and then concentrated by evaporation.
- DCM dichloromethane
- TAA triethanolamine
- Valeroyl chloride 2.0 equiv
- the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give methyl 4 '-((N- (4-fluorophenyl) pentamido) methyl) biphenyl-4-carboxylate (methyl 4'-((N- (4-fluorophenyl) pentanamido) methyl) biphenyl-4-carboxylate) was obtained (85% yield).
- MPLC Medium Pressure Liquid Chromatography
- step 4 4 '-((N- (4- Fluorophenyl Pentaamido) methyl ) Biphenyl -4- Carboxylic acid Preparation of (4 '-((N- (4-fluorophenyl) pentanamido) methyl) biphenyl-4-carboxylic acid)
- Methyl 4 ′-((N- (4-fluorophenyl) pentamido) methyl) biphenyl-4-carboxylate (1.0 equiv) obtained in step 3 was mixed well with tetrahydrofuran (THF). Then LiOH solution was added and stirred for 4 hours. After the reaction was completed, the mixed solution was concentrated, 2N HCl was added until acidic, and extracted with ethyl acetate (EA).
- EA ethyl acetate
- Step 5 N -(4-fluorofluorophenyl) -N-((4 '-(4-isopropylliprazin-1-carbonyl) biphenyl-4-yl) methyl) pentaneamide ( N Preparation of-(4-fluorophenyl) -N-((4 '-(4-isopropylpiperazine-1-carbonyl) biphenyl-4-yl) methyl) pentanamide)
- Example 56 N -((3 '-(4- Isopropyl piperazine -One- Carbonyl ) Biphenyl -4- days) methyl )- N - Phenylpentaneamide ( N- ((3 '-(4-isopropylpiperazine-1-carbonyl) biphenyl-4-yl) methyl)- N Preparation of -phenylpentanamide) (AC-1651)
- Methyl 2-bromobenzoate (1.0 equiv) and 4-formylphenylboronic acid (1.1 equiv) are mixed well with RBF, followed by 1,4 dioxane (1,4 dioxane).
- H 2 O (10: 1) was dissolved in a mixed solution.
- Pd (dppf) Cl 2 .DCM (0.05 equiv) was added to the mixed solution to degassing for 20 minutes, and Na 2 CO 3 was added to degassing again for 20 minutes. Once again degassed for 15 minutes, it was heated to reflux for 4 hours.
- reaction mixture was filtered and extracted with ethyl acetate (EA), dried with anhydrous MgSO 4 , evaporated to concentration, and then purified by Medium Pressure Liquid Chromatography (MPLC) to obtain methyl 4'-formylbiphenyl.
- EA ethyl acetate
- MgSO 4 Medium Pressure Liquid Chromatography
- Step 2 methyl 4'-(( Phenylamino ) methyl ) Biphenyl -3- Carboxylate Preparation of (methyl 4 '-((phenylamino) methyl) biphenyl-4-carboxylate)
- Methyl 4′-formylbiphenyl-3-carboxylate (1.0 equiv) and aniline (aniline) (3.0 equiv) obtained in step 1 were dissolved in methanol, and then stirred at room temperature for 4 hours. The reaction until imine was formed was observed by thin layer chromatography (TLC). After imine was formed, 1M NaCNBH 3 (1.0 equiv) and 0.5M ZnCl 2 were added to the solution. (1.0 equiv) mixed methanol solution was added and stirred overnight at room temperature.
- Step 3 methyl 4 '-((N- Phenylpentaneamido ) methyl ) Biphenyl -3- Carboxylate Preparation of (methyl 4 '-((N-phenylpentanamido) methyl) biphenyl-3-carboxylate)
- Methyl 4 '-((phenylamino) methyl) biphenyl-3-carboxylate obtained in step 2 was dissolved in dichloromethane (DCM), triethanolamine (TEA) was added, and then cooled on ice. .
- Valeroyl chloride 2.0 equiv was added to the mixed solution, followed by stirring at room temperature for 4 hours. After the reaction was completed, RBF was added, and the organic solvent layer was washed with brine and separated. Thereafter, the organic solvent layer was collected, water was removed with anhydrous magnesium sulfate (MgSO 4 ), filtered, and then concentrated by evaporation.
- MgSO 4 anhydrous magnesium sulfate
- the concentrated solution was purified by Medium Pressure Liquid Chromatography (MPLC), and methyl 4 '-((N-phenylpentaneamido) methyl) biphenyl-3-carboxylate (methyl 4'-((N-phenylpentanamido) methyl) biphenyl -3-carboxylate) was obtained (96% yield).
- MPLC Medium Pressure Liquid Chromatography
- step 4 4 '-((N- Phenylpentaneamido ) methyl ) Biphenyl -3- Carboxylic acid Preparation of (4 '-((N-phenylpentanamido) methyl) biphenyl-3-carboxylic acid)
- Methyl 4 ′-((N-phenylpentaneamido) methyl) biphenyl-3-carboxylate (1.0 equiv) obtained in step 3 was mixed well with tetrahydrofuran (THF), and then LiOH solution was added thereto. , Was stirred for 4 hours. After the reaction was completed, the mixed solution was concentrated, 2N HCl was added until acidic, and extracted with ethyl acetate (EA).
- EA ethyl acetate
- Step 5 N-((3 '-(4- Isopropyl piperazine -One- Carbonyl ) Biphenyl -4- days) methyl ) -N- Phenylpentaneamide
- the concentrate was purified by column chromatography to obtain N-((3 '-(4-isopropylpiperazin-1-carbonyl) biphenyl-4-yl) methyl) -N-phenylpentaneamide (N- ((3 '-(4-isopropylpiperazine-1-carbonyl) biphenyl-4-yl) methyl) -N-phenylpentanamide) was obtained (70% yield).
- Methyl 2-bromobenzoate (1.0 equiv) and 4-formylphenylboronic acid (1.1 equiv) are mixed well with RBF, followed by 1,4 dioxane (1,4 dioxane).
- H 2 O (10: 1) was dissolved in a mixed solution.
- Pd (dppf) Cl 2 .DCM (0.05 equiv) was added to the mixed solution to degassing for 20 minutes, and Na 2 CO 3 was added to degassing again for 20 minutes. Once again degassed for 15 minutes, it was heated to reflux for 4 hours.
- reaction mixture was filtered and extracted with ethyl acetate (EA), dried with anhydrous MgSO 4 , evaporated to concentration, and then purified by Medium Pressure Liquid Chromatography (MPLC) to obtain methyl 4'-formylbiphenyl.
- EA ethyl acetate
- MgSO 4 Medium Pressure Liquid Chromatography
- Step 2 methyl 4 '-((4- Fluorophenylamino ) methyl ) Biphenyl -3- Carboxylate Preparation of (methyl 4 '-((4-fluorophenylamino) methyl) biphenyl-3-carboxylate)
- Methyl 4'-formylbiphenyl-3-carboxylate (1.0 equiv) and 4-fluoroaniline (4-fluoroaniline) (3.0 equiv) obtained in step 1 were dissolved in methanol, and then stirred at room temperature for 4 hours. It was. The reaction until imine was formed was observed by thin layer chromatography (TLC). After imine was formed, 1M NaCNBH 3 (1.0 equiv) and 0.5M ZnCl 2 were added to the solution. (1.0 equiv) mixed methanol solution was added and stirred overnight at room temperature.
- Step 3 methyl 4 '-((N- (4- Fluorophenyl ) Pentanamido ) methyl ) Biphenyl -3- Carboxylate (methyl 4 '-((N- Preparation of (4-fluorophenyl) pentanamido) methyl) biphenyl-3-carboxylate)
- Methyl 4 '-((4-fluorophenylamino) methyl) biphenyl-3-carboxylate obtained in step 2 was dissolved in dichloromethane (DCM) and triethanolamine (TEA) was added thereto. Cooled on ice. Valeroyl chloride (2.0 equiv) was added to the mixed solution, followed by stirring at room temperature for 4 hours. After the reaction was completed, RBF was added, and the organic solvent layer was washed with brine and separated. Thereafter, the organic solvent layer was collected, water was removed with anhydrous magnesium sulfate (MgSO 4 ), filtered, and then concentrated by evaporation.
- DCM dichloromethane
- TAA triethanolamine
- the concentrate was purified by Medium Pressure Liquid Chromatography (MPLC) to give methyl 4 '-((N- (4-fluorophenyl) pentaneamido) methyl) biphenyl-3-carboxylate (methyl 4'-((N -(4-fluorophenyl) pentanamido) methyl) biphenyl-3-carboxylate) was obtained (96% yield).
- MPLC Medium Pressure Liquid Chromatography
- step 4 4 '-((N- (4- Fluorophenyl ) Pentanamido ) methyl ) Biphenyl -3- Carboxylic acid Preparation of (4 '-((N- (4-fluorophenyl) pentanamido) methyl) biphenyl-3-carboxylic acid)
- Methyl 4 ′-((N- (4-fluorophenyl) pentaneamido) methyl) biphenyl-3-carboxylate (1.0 equiv) obtained in step 3 was mixed well with tetrahydrofuran (THF). Then LiOH solution was added and stirred for 4 hours. After the reaction was completed, the mixed solution was concentrated, 2N HCl was added until acidic, and extracted with ethyl acetate (EA).
- EA ethyl acetate
- Step 5 N- (4- fluorophenyl ) -N-((3 '-(4- isopropylpiperazine -1-carbonyl) biphenyl-4-yl) methyl) pentanamide (N- (4- fluorophenyl ) -N-((3 '-(4- isopropylpiperazine -1-carbonyl) biphenyl-4-yl) methyl) pentanamide)
- the concentrate was purified by column chromatography to obtain the final product, methyl 4 '-((4-fluorophenylamino) methyl) biphenyl-3-carboxylate N- (4-fluorophenyl) -N-((3'-( 4-isopropylpiperazine-1-carbonyl) biphenyl-4-yl) methyl) pentanamide (N- (4-fluorophenyl) -N-((3 '-(4-isopropylpiperazine-1-carbonyl) biphenyl-4-yl) methyl) pentanamide) was obtained (70% yield).
- 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, in PBS (phosphate-buffered saline; 137 mM NaCl, 2.7 mM KCl, 10 mM Na 2 HPO 4 , 2mMKH 2 PO 4 ) Washed and then added to fresh medium to prepare cells free of 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. 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 the cell proliferation induced by BLT2 with very good efficiency, the compound is anti-cancer, anti-asthma Or BLT2-blocking pharmacological molecules, which can be used as therapeutic agents for the inhibition of other forms of BLT2-related inflammatory diseases.
- the inventors have experimentally confirmed that the expression of BLT2 increases proportionally with the degree of anticancer drug resistance, and the anticancer drug resistance is significantly reduced by BLT2 inhibition. Therefore, in the ovarian cancer cells (SKOV-3 cells) exhibiting anticancer drug resistance, when the compound of the present invention in combination with the anticancer drug cisplatin, to determine whether cancer cell death is induced despite the anticancer drug resistance.
- Cancer cell death was measured using 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide (MTT) method. More specifically, 1 ⁇ 10 5 showing anticancer drug resistance Ovarian cancer cells (SKOV-3 cells) were dispensed onto a 12-well culture dish and incubated for 24 hours. 10 ⁇ M of the compound prepared in the above example, 10 ⁇ M of the control DMSO (solvent of the compound) and 10 ⁇ M of the positive control LY255283 were each pretreated in 0.5% serum RPMI medium for 30 minutes. Subsequently, cisplatin, an anticancer agent, was treated with 50 ⁇ M and then cultured for 24 hours.
- MTT 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide
- the compounds of the present invention can reduce the cancer drug resistance to induce cancer cell death by cisplatin, an anticancer drug with excellent efficiency, anticancer effect It can be used as a pharmaceutical ingredient for enhancement.
- 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 into the upper wells at / 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 positive controls, respectively, and LTB 4 , a ligand of BLT2 as a comparative control.
- LTB 4 which is a ligand of BLT2 to BLT2-expressing cells (CHO-BLT2 cells) (300 nM) treated (DMSO +), ethanol treated compared to (DMSO-), the cell chemotaxis was increased 2.9-fold, and 10 ⁇ M pretreatment of 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 to 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.
- BLT2-expressing cells CHO-BLT2 cells
- LPA lysophosphatidic acid
- DMSO + ethanol treated
- DMSO- ethanol treated
- chemotactic activity is LTB 4 in cells stably expressing BLT2 (CHO-BLT2).
- the compound of the present invention AC-1074
- the compound of the present invention can significantly inhibit this chemotaxis, can be used as a pharmaceutical component for inhibiting BLT2-dependent chemotaxis induced by LTB 4 Means.
- LTB 4 and BLT2 binding (ligand binding affinity) inhibition was analyzed by isotope tritium (H3) using the 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 proteins of the cell membrane and quantitate them at a concentration of 40 ⁇ g / 45 ⁇ L.
- mast cells play an important role.
- mast cells are activated to release various cytokines (interlukin-4 and interlukin-13).
- the cytokine causes phenomena such as influx of inflammatory cells, mucus production, and airway contraction.
- the present inventors received female BALB / c mice that were 7 weeks old (18-20 g) from Orient (Seoungnam, Korea) and used them in the experiments to induce asthma.
- Airway hypersensitivity was measured 24 days after initial sensitization, and mice were dissected on day 25 to observe the asthma phenotype of inflammatory cytokine IL-4 expression and the influx of inflammatory cells (neutrophils).
- airway hypersensitivity measurement was performed after the administration of metacholine (up to 6.25 mg / ml to 50 mg / ml depending on conditions), which is an airway constrictor. Airway constrictor administration was sprayed through the inlet of the chamber for 3 minutes using an ultrasonic nebulizer. Airway hypersensitivity was analyzed using enhanced pause as an indicator of asthma.
- asthma-induced mice OVA / DMSO
- AC-1074 the compound of the present invention
- the compound of the present invention (AC-1074) can suppress airway hyperresponsiveness in the asthma animal model and the compound (AC-1074) can alleviate the symptoms of asthma by inhibiting the production of inflammatory cytokine IL-4, anti It can be used as a pharmaceutical ingredient with an asthma effect.
- the present invention relates to a novel compound that exhibits Leukotriene B4 receptor 2 (BLT2) inhibitory activity and a pharmaceutical composition for preventing or treating an inflammatory disease comprising the same.
- BLT2 Leukotriene B4 receptor 2
- the present inventors have identified a novel compound that exhibits BTL2 inhibitory activity in order to solve in vivo instability and difficulty in mass production, which are problems of conventional inflammatory disease treatment substances, and has excellent cancer cell death enhancement and metastasis suppression effect and chemotaxis inhibition of the compound.
- the effects and anti-asthma effects have been confirmed experimentally, it is expected to be useful as a pharmaceutical composition for treating inflammatory diseases.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
Claims (7)
- 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염:[화학식 1]상기 화학식 1에서,여기서 Ra는 수소, C1~C10의 알킬, C1~C5의 카르복실,R5, R6, 및 R7은 각각 독립적으로 수소, 할로겐, 니트로, 메틸, 트리플루오로메틸 또는 메톡시이며,
- 제 1항에 있어서,상기 화학식 1로 표시되는 화합물은 하기 화합물들로 이루어진 군으로부터 선택되는 것을 특징으로 하는, 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염: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;4'-((N-(2-플루오로페닐)펜탄아미도)메틸)바이페닐-4-카복실산;4'-((N-(4-플루오로페닐)펜탄아미도)메틸)바이페닐-4-카복실산;4'-((N-(2-메톡시페닐)펜탄아미도)메틸)바이페닐-3-카복실산;4'-((N-(3-메톡시페닐)펜탄아미도)메틸)바이페닐-3-카복실산;4'-((N-(4-메톡시페닐)펜탄아미도)메틸)바이페닐-3-카복실산;N-((2'-(4-메톡시피페라진-1-카보닐)바이페닐-4-일)메틸)-N-페닐펜탄아마이드;N-((3'-(4-메틸피페라진-1-카보닐)바이페닐-4-일)메틸)-N-페닐펜탄아마이드;4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-2-카복실산;4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-4-카복실산;N-(3-플루오로페닐)-N-((4'-(몰폴린-4-카보닐)-[1,1'-바이페닐-4-일)메틸)펜탄아마이드;N-(3-플루오로페닐)-N-((4'-(4-메틸피페라진-1-카보닐)바이페닐-4-일)메틸)펜탄아마이드;N-((2'-(1H-테트라졸-5-일)바이페닐-4-일)메틸)-N-페닐펜탄아마이드;N-((4'-메톡시바이페닐-4-일)메틸)-N-페닐펜탄아마이드;N-((4'-하이드록시바이페닐-4-일)메틸)-N-페닐펜탄아마이드;2-(4'-((N-페닐펜탄아미도)메틸)바이페닐-4-일옥시)아세트산;N-(3-플루오로페닐)-N-((4'-메톡시바이페닐-4-일)메틸)펜탄아마이드;N-(3-플루오로페닐)-N-((4'-하이드록시바이페닐-4-일)메틸)펜탄아마이드;2-(4'-((N-(3-플루오로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세트산;N-(3-클로로페닐)-N-((4'-메톡시바이페닐-4-일)메틸)펜탄아마이드;N-(3-클로로페닐)-N-((4'-하이드록시바이페닐-4-일)메틸)펜탄아마이드;2-(4'-((N-(3-클로로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세트산;N-(3-브로모페닐)-N-((4'-메톡시바이페닐-4-일)메틸)펜탄아마이드;N-((4'-(하이드록시바이페닐-4-일)메틸)-N-(3-(트리플루오로메틸)페닐)펜탄아마이드;2-(4'-((N-(3-브로모페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세트산;N-((4'-메톡시바이페닐-4-일)메틸)-N-(3-(트리플루오로메틸)페닐)펜탄아마이드;N-((4'-하이드록시바이페닐-4-일)메틸)-N-(3-니트로페닐)펜탄아마이드;2-(4'-((N-(3-(트리플루오로메틸)페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세트산;N-((4'메톡시바이페닐-4-일)메틸)-N-m-톨릴펜탄아마이드;N-((4'-하이드록시페닐-4-일)메틸)-N-m-톨릴펜탄아마이드;2-(4'-((N-m-톨릴펜탄아미도)메틸)바이페닐-4-일옥시)아세트산;N-((4'-하이드록시페닐-4-일)메틸)-N-(3-니트로페닐)펜탄아마이드;2-(4'-((N-(3-니트로페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세트산;N-(3-아이오도페닐)-N-((4'-메톡시바이페닐-4-일)메틸)펜탄아마이드;N-((4'-하이드록시바이페닐-4-일)메틸)-N-(3-아이오도페닐)펜탄아마이드;2-(4'-((N-(3-아이오도페닐)펜탄아미도)메틸)바이페닐-4-일옥시)아세트산;N-(3-플루오로페닐)-N-((4'-하이드록시바이페닐-4-일)메틸)아세트아마이드;N-(3-플루오로페닐)-N-((4'-하이드록시-[1,1'-바이페닐]-4-일)메틸)아세트아마이드;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)-[1,1'-바이페닐]-4-일)메틸)펜탄아마이드;N-((3'-(4-아이소프로필피페라진-1-카보닐)바이페닐-4-일)메틸)-N-페닐펜탄아마이드; 및N-(4-플루오로페닐)-N-((3'-(4-아이소프로필피페라진-1-카보닐)바이페닐-4-일)메틸)펜탄아마이드.
- 제 1항 또는 제 2항의 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는, 염증성 질환 예방 또는 치료용 약학적 조성물.
- 제 3항에 있어서,상기 염증성 질환은 천식, 죽상경화증, 암, 피부가려움증, 류마티스 관절염 및 염증성 장 질환으로 이루어진 군으로부터 선택되는 것을 특징으로 하는, 조성물.
- 제 3항에 있어서,상기 조성물은 BLT2 (Leukotriene B4 receptor 2) 활성을 저해시키는 것을 특징으로 하는, 조성물.
- 제 1항 또는 제 2항의 화합물 또는 이의 약학적으로 허용가능한 염을 개체에 투여하는 단계를 포함하는, 염증성 질환의 예방 또는 치료 방법.
- 제 1항 또는 제 2항의 화합물 또는 이의 약학적으로 허용가능한 염의 염증성 질환의 예방 또는 치료 용도.
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201680055552.XA CN108349875B (zh) | 2015-07-24 | 2016-07-23 | 具有blt抑制活性的化合物和包含其作为活性成分的用于预防或治疗炎症性疾病的组合物 |
EP16830784.1A EP3327001B1 (en) | 2015-07-24 | 2016-07-23 | Novel compound having blt inhibitory activity and composition, for preventing or treating inflammatory diseases, comprising same as active ingredient |
US15/745,348 US10494333B2 (en) | 2015-07-24 | 2016-07-23 | Compound having BLT inhibitory activity and composition, for preventing or treating inflammatory diseases, comprising same as active ingredient |
JP2018503552A JP6814794B2 (ja) | 2015-07-24 | 2016-07-23 | Blt阻害活性を有する新規化合物およびこれを有効成分として含む炎症性疾患の予防または治療用組成物 |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR10-2015-0105097 | 2015-07-24 | ||
KR20150105097 | 2015-07-24 | ||
KR10-2016-0093760 | 2016-07-22 | ||
KR1020160093760A KR101796390B1 (ko) | 2015-07-24 | 2016-07-22 | Blt 저해 활성을 갖는 신규 화합물 및 이를 유효성분으로 포함하는 염증성 질환 예방 또는 치료용 조성물 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2017018751A1 true WO2017018751A1 (ko) | 2017-02-02 |
Family
ID=57884727
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/KR2016/008070 WO2017018751A1 (ko) | 2015-07-24 | 2016-07-23 | Blt 저해 활성을 갖는 신규 화합물 및 이를 유효성분으로 포함하는 염증성 질환 예방 또는 치료용 조성물 |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2017018751A1 (ko) |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2018170173A1 (en) * | 2017-03-15 | 2018-09-20 | Metacrine, Inc. | Farnesoid x receptor agonists and uses thereof |
WO2018170182A1 (en) * | 2017-03-15 | 2018-09-20 | Metacrine, Inc. | Farnesoid x receptor agonists and uses thereof |
WO2018170167A1 (en) * | 2017-03-15 | 2018-09-20 | Metacrine, Inc. | Farnesoid x receptor agonists and uses thereof |
WO2018170165A1 (en) * | 2017-03-15 | 2018-09-20 | Metacrine, Inc. | Farnesoid x receptor agonists and uses thereof |
WO2018170166A1 (en) * | 2017-03-15 | 2018-09-20 | Metacrine, Inc. | Farnesoid x receptor agonists and uses thereof |
US11084817B2 (en) | 2018-09-18 | 2021-08-10 | Metacrine, Inc. | Farnesoid X receptor agonists and uses thereof |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006083477A2 (en) * | 2005-01-07 | 2006-08-10 | Synta Pharmaceuticals Corp. | Compounds for inflammation and immune-related uses |
US20080132574A1 (en) * | 2004-04-26 | 2008-06-05 | Shinji Nakade | Novel Blt2-Mediated Disease, Blt2 Binding Agent And the Compound |
WO2008073929A1 (en) * | 2006-12-11 | 2008-06-19 | Wyeth | Ion channel modulators |
KR20090125837A (ko) * | 2007-03-23 | 2009-12-07 | 고려대학교 산학협력단 | 천식 치료를 위한 류코트리엔 b4 수용체 blt2의 저해제의 용도 |
KR20130017073A (ko) * | 2011-08-05 | 2013-02-19 | 동국대학교 산학협력단 | 신규한 바이페닐 유도체 또는 이의 약학적으로 허용가능한 염, 및 이를 유효성분으로 포함하는 염증성 질환 또는 자가면역질환의 예방 또는 치료용 약학적 조성물 |
-
2016
- 2016-07-23 WO PCT/KR2016/008070 patent/WO2017018751A1/ko active Application Filing
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20080132574A1 (en) * | 2004-04-26 | 2008-06-05 | Shinji Nakade | Novel Blt2-Mediated Disease, Blt2 Binding Agent And the Compound |
WO2006083477A2 (en) * | 2005-01-07 | 2006-08-10 | Synta Pharmaceuticals Corp. | Compounds for inflammation and immune-related uses |
WO2008073929A1 (en) * | 2006-12-11 | 2008-06-19 | Wyeth | Ion channel modulators |
KR20090125837A (ko) * | 2007-03-23 | 2009-12-07 | 고려대학교 산학협력단 | 천식 치료를 위한 류코트리엔 b4 수용체 blt2의 저해제의 용도 |
KR20130017073A (ko) * | 2011-08-05 | 2013-02-19 | 동국대학교 산학협력단 | 신규한 바이페닐 유도체 또는 이의 약학적으로 허용가능한 염, 및 이를 유효성분으로 포함하는 염증성 질환 또는 자가면역질환의 예방 또는 치료용 약학적 조성물 |
Cited By (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10927082B2 (en) | 2017-03-15 | 2021-02-23 | Metacrine, Inc. | Farnesoid X receptor agonists and uses thereof |
CN110637015A (zh) * | 2017-03-15 | 2019-12-31 | 梅塔科林公司 | 法尼醇x受体激动剂及其用途 |
WO2018170167A1 (en) * | 2017-03-15 | 2018-09-20 | Metacrine, Inc. | Farnesoid x receptor agonists and uses thereof |
WO2018170165A1 (en) * | 2017-03-15 | 2018-09-20 | Metacrine, Inc. | Farnesoid x receptor agonists and uses thereof |
WO2018170173A1 (en) * | 2017-03-15 | 2018-09-20 | Metacrine, Inc. | Farnesoid x receptor agonists and uses thereof |
KR20190121399A (ko) * | 2017-03-15 | 2019-10-25 | 메타크린, 인크. | 파네소이드 x 수용체 효능제 및 이의 용도 |
WO2018170182A1 (en) * | 2017-03-15 | 2018-09-20 | Metacrine, Inc. | Farnesoid x receptor agonists and uses thereof |
CN110637011A (zh) * | 2017-03-15 | 2019-12-31 | 梅塔科林公司 | 法尼醇x受体激动剂及其用途 |
WO2018170166A1 (en) * | 2017-03-15 | 2018-09-20 | Metacrine, Inc. | Farnesoid x receptor agonists and uses thereof |
US10961198B2 (en) | 2017-03-15 | 2021-03-30 | Metacrine, Inc. | Farnesoid X receptor agonists and uses thereof |
CN110637011B (zh) * | 2017-03-15 | 2024-05-14 | 奥加诺沃公司 | 法尼醇x受体激动剂及其用途 |
US11236071B1 (en) | 2017-03-15 | 2022-02-01 | Metacrine, Inc. | Farnesoid X receptor agonists and uses thereof |
CN110637015B (zh) * | 2017-03-15 | 2024-04-02 | 奥加诺沃公司 | 法尼醇x受体激动剂及其用途 |
KR102588982B1 (ko) | 2017-03-15 | 2023-10-12 | 오가노보, 인크. | 파네소이드 x 수용체 효능제 및 이의 용도 |
US11773094B2 (en) | 2018-09-18 | 2023-10-03 | Organovo, Inc. | Farnesoid X receptor agonists and uses thereof |
US11084817B2 (en) | 2018-09-18 | 2021-08-10 | Metacrine, Inc. | Farnesoid X receptor agonists and uses thereof |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2017018751A1 (ko) | Blt 저해 활성을 갖는 신규 화합물 및 이를 유효성분으로 포함하는 염증성 질환 예방 또는 치료용 조성물 | |
WO2011083999A2 (ko) | 바이구아나이드 유도체, 이의 제조방법 및 이를 유효성분으로 함유하는 약학 조성물 | |
WO2016032120A1 (ko) | 신규한 아미노-페닐-설포닐-아세테이트 유도체 및 이의 용도 | |
WO2021060890A1 (ko) | 헤테로아릴아미도피리딘올 유도체 및 이를 유효성분으로 포함하는 자가면역질환의 예방 또는 치료용 약학적 조성물. | |
WO2016080810A2 (ko) | 바이구아나이드 화합물 및 이의 용도 | |
CN101522637A (zh) | 可用于治疗香草素受体1相关病症的苯并咪唑衍生物 | |
WO2012161518A2 (ko) | RORα의 활성자로서의 신규한 thiourea 유도체 및 이를 함유하는 약학적 조성물 | |
WO2020262996A1 (ko) | 신규한 아미노알칸산에 바이페닐기를 도입한 유도체 화합물 및 이를 포함하는 항진균성 약학적 조성물 | |
WO2014069963A1 (en) | Thioaryl derivatives as gpr120 agonists | |
AU2019381113A1 (en) | Novel compound as protein kinase inhibitor, and pharmaceutical composition comprising thereof | |
WO2013019091A2 (en) | A COMPOUND FOR INHIBITING 11β-HYDROXY STEROID DEHYDROGENASE 1, AND A PHARMACEUTICAL COMPOSITION COMPRISING THE SAME | |
WO2014119947A1 (en) | Biaryl- or heterocyclic biaryl-substituted cyclohexene derivative compounds as cetp inhibitors | |
EP3060549A1 (en) | Novel antifungal oxodihydropyridinecarbohydrazide derivative | |
WO2017131425A1 (ko) | Jnk 저해 활성을 갖는 신규한 이미다졸 유도체 및 이의 용도 | |
WO2012148140A2 (ko) | 혈관 신생 억제 및 항산화 효과를 가지는 이미다졸계 알칼로이드 유도체 및 이의 제조방법 | |
WO2021096314A1 (ko) | 신규한 벤즈이미다졸 유도체 및 이의 용도 | |
WO2022103149A1 (ko) | 신규한 카바졸 유도체 및 이를 유효성분으로 포함하는 암의 예방 또는 치료용 약학적 조성물 | |
WO2022050749A1 (ko) | 디아실글리세롤 아실트랜스퍼라제 2 억제제로서 유용한 신규 바이아릴 유도체 및 이의 용도 | |
WO2021034087A1 (ko) | 신규한 암전이 억제 활성을 갖는 화합물, 이의 제조방법 및 상기 화합물을 포함하는 암 전이 및 침윤 억제, 또는 대장암 치료용 약학적 조성물 | |
WO2017123038A1 (ko) | 피리딘올 유도체 또는 이의 약제학적 허용 가능한 염 및 이를 유효성분으로 함유하는 약학 조성물 | |
WO2017135786A1 (ko) | 신규 아미드 화합물 및 이의 용도 | |
WO2019093699A1 (ko) | 셀레노사마필린 a와 그 유도체, 이의 제조방법 및 이를 유효성분으로 포함하는 암 예방 및 치료용 조성물 | |
WO2017018750A1 (ko) | Blt 저해 활성을 갖는 신규 화합물 및 이를 유효성분으로 포함하는 염증성 질환 예방 또는 치료용 조성물 | |
WO2023090908A1 (ko) | 신규 플라보노이드 유도체 및 이를 유효성분으로 포함하는 대사성 질환의 예방 또는 치료용 약학 조성물 | |
WO2022139564A1 (ko) | 신규한 아미노알칸산에 바이페닐기를 도입한 유도체 화합물 및 이를 포함하는 항염증용 조성물 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 16830784 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: 2018503552 Country of ref document: JP Kind code of ref document: A |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2016830784 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 15745348 Country of ref document: US |