WO2018164549A1 - Novel compound having malate dehydrogenase inhibitory activity and pharmaceutical composition for preventing or treating cancer comprising same as active ingredient - Google Patents
Novel compound having malate dehydrogenase inhibitory activity and pharmaceutical composition for preventing or treating cancer comprising same as active ingredient Download PDFInfo
- Publication number
- WO2018164549A1 WO2018164549A1 PCT/KR2018/002861 KR2018002861W WO2018164549A1 WO 2018164549 A1 WO2018164549 A1 WO 2018164549A1 KR 2018002861 W KR2018002861 W KR 2018002861W WO 2018164549 A1 WO2018164549 A1 WO 2018164549A1
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- WIPO (PCT)
- Prior art keywords
- methyl
- phenoxy
- benzoate
- trimethylpentan
- acetamido
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 172
- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 69
- 201000011510 cancer Diseases 0.000 title claims abstract description 55
- 230000002401 inhibitory effect Effects 0.000 title claims abstract description 36
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 26
- 102000013460 Malate Dehydrogenase Human genes 0.000 title claims abstract description 17
- 108010026217 Malate Dehydrogenase Proteins 0.000 title claims abstract description 17
- 239000004480 active ingredient Substances 0.000 title claims abstract description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 224
- -1 hydroxy, methoxy, 2-propynyl Chemical group 0.000 claims description 143
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 70
- 238000000034 method Methods 0.000 claims description 63
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 40
- 150000003839 salts Chemical class 0.000 claims description 29
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 24
- 239000000203 mixture Substances 0.000 claims description 22
- 229910052757 nitrogen Inorganic materials 0.000 claims description 16
- 230000000694 effects Effects 0.000 claims description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
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- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims description 12
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 12
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 claims description 10
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 10
- CRZVLUCELMROJU-UHFFFAOYSA-N 1-[4-[[4-(trifluoromethyl)phenyl]methyl]piperazin-1-yl]-2-[4-(2,4,4-trimethylpentan-2-yl)phenoxy]ethanone Chemical compound FC(C1=CC=C(CN2CCN(CC2)C(COC2=CC=C(C=C2)C(C)(CC(C)(C)C)C)=O)C=C1)(F)F CRZVLUCELMROJU-UHFFFAOYSA-N 0.000 claims description 9
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- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 8
- LPLIRUZJZGGXSY-MDZDMXLPSA-N methyl 3-[[(e)-3-[4-(1-adamantyl)phenoxy]prop-2-enoyl]amino]benzoate Chemical compound COC(=O)C1=CC=CC(NC(=O)\C=C\OC=2C=CC(=CC=2)C23CC4CC(CC(C4)C2)C3)=C1 LPLIRUZJZGGXSY-MDZDMXLPSA-N 0.000 claims description 8
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- 125000000217 alkyl group Chemical group 0.000 claims description 7
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 7
- RUZLIIJDZBWWSA-INIZCTEOSA-N methyl 2-[[(1s)-1-(7-methyl-2-morpholin-4-yl-4-oxopyrido[1,2-a]pyrimidin-9-yl)ethyl]amino]benzoate Chemical group COC(=O)C1=CC=CC=C1N[C@@H](C)C1=CC(C)=CN2C(=O)C=C(N3CCOCC3)N=C12 RUZLIIJDZBWWSA-INIZCTEOSA-N 0.000 claims description 7
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
- C07C235/38—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
Definitions
- the present invention relates to a novel compound having inhibitory activity of MDH1 (malate dehydrogenases 1) or MDH2 (malate dehydrogenases 2) and a pharmaceutical composition for preventing or treating cancer comprising the same as an active ingredient.
- the malic acid-asphalic acid shuttle is a mechanism that plays an important role in delivering NADH to the mitochondria in the cytoplasm generated during glycolysis.
- the malic acid-asphalic acid shuttle is made by malic dehydrogenases (MDHs) and glutamate oxaloacetate transaminases (GOTs) present in the cytoplasm and mitochondria.
- Aminooxyacetic acid an inhibitor of the maleic acid-asphalic acid shuttle, inhibits the proliferation of breast cancer cells by preventing glucose from becoming a product of the tricarboxylic acid cycle.
- GOT2 Mitochondrial GOT2
- MDH1 and MDH2 isozymes produced by different MDH genes are present in the cytoplasm and mitochondrial matrix.
- MDH1 and MDH2 reversibly serve to convert malate and oxaloacetate (OAA) using the NAD / NADH cofactor system.
- OAA oxaloacetate
- MDH1 in the cytoplasm oxidizes NADH to NAD + by reducing oxalic acid to malic acid.
- malic acid-asphalic acid shuttle malic acid is transported into the mitochondria and oxidized back to oxalic acid by mitochondrial MDH2 to produce NADH.
- the generated NADH generates ATP through an electron transport system.
- MDH2 involved in the TCA cycle is involved in ATP production through respiration.
- the present inventors while continuing to research to develop a more effective cancer treatment material, in order to solve the conventional problems as described above, the substrate binding site and active site structure of MDH1 and MDH2 is very similar to that of MDH1 and MDH2
- a compound was prepared that simultaneously inhibits the activities of MDH1 and MDH2, and a cancer therapeutic agent containing the compound was first devised to complete the present invention.
- the present invention has been made to solve the above problems, the present inventors have confirmed the cancer preventive or therapeutic effect of the compound that inhibits the activity of MDH1 and / or MDH2 to complete the present invention based on this.
- Another object of the present invention is to provide a pharmaceutical composition for preventing or treating cancer, which comprises as an active ingredient a compound, an isomer thereof, or a pharmaceutically acceptable salt thereof, which exhibits MDH1 and / or MDH2 inhibitory activity.
- the present invention provides a compound represented by the following formula (1), an isomer thereof or a pharmaceutically acceptable salt thereof.
- X is methylene group, ethane group, ethylene group, n -propylene group or isopropylene;
- R 1 is a nitro group, trifluoromethyl group, C 1 -C 20 alkyl or C 1 -C 20 cycloalkyl
- R 2 is , , , , , , ,
- R 2 is when,
- R 3 is methyl or 2-propynyl
- R 4 is methyl, hydrogen, hydroxy, methoxy, 2-propynyl, , , , , or ego;
- R 2 is when,
- R 5 is , or ego
- R 2 is when,
- R 6 is methyl or hydroxy
- R 2 is when,
- R 7 may be C or N.
- R 1 may be substituted with adamantyl, tert -butyl, pentyl, cyclopentyl, cyclohexyl, or 2,4,4-trimethylpentin-2-yl.
- R 1 is adamantyl
- X is methylene group, ethane group, ethylene group, n -propylene group or isopropylene
- R 2 is ego
- R 4 is methyl, hydrogen, hydroxy, , , or And
- R 3 may be methyl.
- the compound may be a compound represented by the following formula (2).
- R 1 is adamantyl or tert -butyl
- R 2 is , or ego
- R 2 is when,
- R 3 is methyl or 2-propynyl
- R 4 is methyl, hydrogen or hydroxy
- R 2 is when,
- R 6 is methyl or hydroxy
- R 2 is when,
- R 7 may be C or N.
- the compound may be a compound represented by the following formula (3).
- R 1 is a nitro group, trifluoromethyl group, adamantyl, tert -butyl, pentyl, cyclopentyl, cyclohexyl, or 2,4,4-trimethylpentin-2-yl;
- R 2 is , , , , , or ego
- R 2 is when,
- R 3 is methyl or 2-propynyl
- R 4 is methyl, hydrogen, hydroxy, methoxy, 2-propynyl, , , , , or Can be.
- the compound may be any one or more selected from the group consisting of:
- the present invention provides a pharmaceutical composition for preventing or treating cancer comprising the compound represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
- the composition may inhibit the activity of malate dehydrogenases 1 (MDH1) and / or malate dehydrogenases 2 (MDH2).
- MDH1 malate dehydrogenases 1
- MDH2 malate dehydrogenases 2
- the composition may simultaneously inhibit the activity of MDH1 (malate dehydrogenases 1) and MDH2 (malate dehydrogenases 2).
- the present invention provides a method for preventing or treating cancer, comprising administering the pharmaceutical composition to a subject.
- the present invention provides a cancer prevention or treatment of the composition comprising the compound, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
- the present invention relates to a compound exhibiting inhibitory activity of MDH1 (malate dehydrogenases 1) and / or MDH2 (malate dehydrogenases 2) and a pharmaceutical composition for preventing or treating cancer, comprising the same as an active ingredient.
- MDH1 malate dehydrogenases 1
- MDH2 malate dehydrogenases 2
- a pharmaceutical composition for preventing or treating cancer comprising the same as an active ingredient.
- the present inventors have experimentally confirmed the mitochondrial respiratory inhibitory effect and excellent cancer cell growth inhibitory effect in cancer cells of the compound showing MDH1 and / or MDH2 inhibitory activity, the compound of the present invention is useful as a pharmaceutical composition for treating cancer It is expected to be used.
- 1 is a schematic diagram illustrating the synthesis of 55 compounds of the present invention (compounds 3-1 to 3-34, compounds 6-1 to 6-10 and compounds 9-1 to 9-11).
- Figure 2 shows the overexpressed recombinant MDH2 protein isolated and purified in the present invention.
- Figure 3 is the result of measuring the enzyme kinetics (enzyme kinetics) of MDH1 and MDH2 according to the change of NADH concentration of the compound of the present invention.
- OCR oxygen consumption rate
- Figures 7a and 7b is a result of confirming that the tumor size or volume after administration of the compound of the present invention.
- Figure 7c is a result confirming that the weight of the tumor after administration of the compound of the present invention.
- the present inventors when treated with the compound prepared in Example, exhibits the inhibitory activity of MDH1 / 2 expression, HIF-1 ⁇ expression inhibitory activity, mitochondrial respiratory inhibitory effect in cancer cells and excellent cancer cell growth
- the inhibitory effect etc. were confirmed specifically, and this invention was completed based on this.
- the present invention provides a compound represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof.
- X is methylene group, ethane group, ethylene group, n -propylene group or isopropylene;
- R 1 is a nitro group, trifluoromethyl group, C 1 -C 20 alkyl or C 1 -C 20 cycloalkyl
- R 2 is , , , , , , ,
- R 2 is when,
- R 3 is methyl or 2-propynyl
- R 4 is methyl, hydrogen, hydroxy, methoxy, 2-propynyl, , , , , or Can be.
- R 2 is when,
- R 5 is , or Can be.
- R 2 is when,
- R 6 may be methyl or hydroxy.
- R 2 is when,
- R 7 may be C or N.
- R 1 is adamantyl, tert -butyl, pentyl, cyclopentyl, cyclohexyl, or 2,4,4-trimethylpentin-2-yl.
- R 1 is adamantyl
- X is methylene group, ethane group, ethylene group, n -propylene group or isopropylene
- R 2 is ego
- R 4 is methyl, hydrogen, hydroxy, , , or And
- R 3 may be methyl.
- the compound may be a compound represented by the following formula (2).
- R 1 is adamantyl or tert -butyl
- R 2 is , or ego
- R 2 is when,
- R 3 is methyl or 2-propynyl
- R 4 is methyl, hydrogen or hydroxy
- R 2 is when,
- R 6 is methyl or hydroxy
- R 2 is when,
- R 7 is C or N.
- the compound may be a compound represented by the following formula (3).
- R 1 is a nitro group, trifluoromethyl group, adamantyl, tert -butyl, pentyl, cyclopentyl, cyclohexyl, or 2,4,4-trimethylpentin-2-yl;
- R 2 is , , , , , or ego
- R 2 is when,
- R 3 is methyl or 2-propynyl
- R 4 is methyl, hydrogen, hydroxy, methoxy, 2-propynyl, , , , , or Can be.
- C 1 -C 20 alkyl refers to a monovalent alkyl group having 1 to 20 carbon atoms.
- the term is exemplified by functional groups such as methyl, ethyl, n -propyl, i -propyl, n -butyl, i -butyl, tert -butyl, n -hexyl and the like.
- C 1 -C 20 cycloalkyl refers to a saturated hydrocarbon ring compound having a single ring (eg cyclohexyl) or multiple condensed ring (eg norbornyl), cyclopentyl, Cyclohexyl, norbornyl, adamantane and the like.
- methylene group used in the present invention means a bond in the form of-(CH 2 )-, and means a form when one carbon is bonded to X in the general formula (1) of the present invention.
- N is 1 or 2.
- ethane group used in the present invention means a bond in the form of-(C 2 H 4 )-, and refers to a form when two carbons are bonded to X in Formula 1 of the present invention.
- ethylene group used in the present invention means a bond in the form of-(C 2 H 2 )-, and means the form when two carbons are bonded to X in the general formula (1) of the present invention.
- n -propylene group used in the present invention means a bond in the form of-(C 3 H 6 )-, and in the formula (1) of the present invention means a form when three carbons are bonded to the X in a straight chain form. do.
- isopropylene group refers to a bond in the form of-(C 3 H 6 )-, wherein in the formula (1) of the present invention, when X is combined with three carbons in a crushed or branched form, it means.
- 2-propynyl refers to -CH 2 C ⁇ CH, and means a linear hydrocarbon group of three carbon atoms, including unsaturated carbon bonded to the triple bond at the end.
- Substituents comprising alkyl and other alkyl moieties described in the present invention include both straight and pulverized forms.
- 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 tissues of a subject (eg, a human being) because the benefit / risk ratio is reasonable without excessive toxicity, irritation, allergic reactions or other problems or complications.
- a compound or composition is within the scope of sound medical judgment.
- Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid and aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. Obtained from non-toxic organic acids such as dioates, aromatic acids, aliphatic and aromatic sulfonic acids.
- Such pharmaceutically nontoxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, and iodide.
- the acid addition salt according to the present invention is dissolved in a conventional method, for example, the compound represented by Formula 1 of the present invention in an excess of an aqueous acid solution, and the salt is mixed with a water miscible organic solvent such as methanol, ethanol, It can be prepared by precipitation with acetone or acetonitrile. It may also be prepared by evaporating the solvent or excess acid from the mixture and then drying or by suction filtration of the precipitated salt.
- a water miscible organic solvent such as methanol, ethanol
- 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).
- the present invention provides a pharmaceutical composition for preventing or treating cancer, comprising the compound represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. .
- composition of the present invention includes a pharmaceutical and nutraceutical composition.
- prevention means any action that inhibits cancer or delays the onset by administration of a pharmaceutical composition according to the invention.
- treatment means any action that improves or beneficially alters the symptoms of cancer by administration of a pharmaceutical composition according to the present invention.
- Cancer a disease to be prevented and treated by the composition of the present invention, is classified into a disease in which normal tissue cells proliferate unlimitedly for any cause and continue to develop rapidly regardless of the living phenomenon of the living body or the surrounding tissue state.
- Cancer includes, but is not limited to, dysplasia, hyperplasia, solid tumors, and hematopoietic stem cell cancer, and includes various cancer types known in the art.
- Other cancers may include, but are not limited to, cancers of the following organs or organs: brain, heart, lung, stomach, large intestine, genitourinary tract, liver, bone, nervous system, gynecology, blood, skin, breast and adrenal gland. It doesn't work.
- cancer cells include glioma (Schwannoma, glioblastoma, astrocytoma), neuroblastoma, pheochromocytoma, adrenal ganglia, meningioma, adrenal cortex, medulloblastoma, rhabdomyosarcoma, kidney cancer, various types of cancer Vascular cancer, osteoblastic osteocarcinoma, prostate cancer, ovarian cancer, uterine myoma, salivary gland cancer, choroid plexus cancer, breast cancer, pancreatic cancer, colon cancer, colon cancer and megakaryocyte leukemia; And sarcomas, such as malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, moles dysplastic nevi, lipoma, hemangioma, cutaneous fibroma, keloid, fibrosarcoma or angiosarcoma, and melanoma Includes skin cancer, including.
- MDH1 or MDH2 of the present invention are isoenzymes produced by different MDH genes, where MDH is present in the cytoplasm and mitochondrial matrix. More specifically, MDH1 and MDH2 reversibly serve to convert malate and oxaloacetate (OAA) using a NAD / NADH cofactor system. MDH1 in the cytoplasm oxidizes NADH to NAD + by reducing oxalic acid to malic acid. In the malic acid-asphalic acid shuttle, malic acid is transported into the mitochondria and oxidized back to oxalic acid by mitochondrial MDH2 to produce NADH. The generated NADH generates ATP through an electron transport system. In addition, MDH2 involved in the TCA cycle is involved in ATP production through respiration.
- OOA oxaloacetate
- composition of the present invention can inhibit the activity of MDH1 (malate dehydrogenases 1) and / or MDH2 (malate dehydrogenases 2), and in particular can inhibit the activity of MDH1 and MDH2 simultaneously.
- 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 inhibitory activity of MDH1 and MDH2 by the compound treatment synthesized according to the preparation method of the present invention was confirmed (see Experimental Example 1).
- MDH inhibition mechanism was confirmed using the compound of the present invention (see Experimental Example 2)
- HIF-1 ⁇ inhibitory activity was confirmed using the compound of the present invention (see Experimental Example 3)
- mitochondria in cancer cells The respiratory inhibitory effect was confirmed (see Experimental Example 4), and cancer cell transplantation mouse model was used to specifically confirm the effect of reducing tumor weight and size (see Experimental Example 5) as a pharmaceutical composition for cancer prevention or treatment. It was confirmed that it can be used very usefully.
- the compound represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof according to the present invention may be usefully used as a pharmaceutical composition for preventing, ameliorating or treating cancer including the same as an active ingredient.
- the pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier in addition to the active ingredient.
- the pharmaceutically acceptable carrier is commonly used in the formulation, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose , Polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate and mineral oil, and the like.
- it may further include a lubricant, a humectant, a sweetener, a flavoring agent, an emulsifier, a suspending agent, a preservative, and the like.
- compositions of the present invention can be administered orally or parenterally (eg, applied intravenously, subcutaneously, intraperitoneally or topically) according to the desired method, and the dosage is determined by the condition and weight of the patient, Depending on the extent, drug form, route of administration, and time, it may be appropriately selected by those skilled in the art.
- the pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount.
- pharmaceutically effective amount means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level refers to the type of disease, the severity, the activity of the drug, It may be determined according to the sensitivity to the drug, the time of administration, the route of administration and the rate of release, the duration of treatment, factors including the drug used concurrently and other factors well known in the medical field.
- the pharmaceutical compositions according to the present invention may be administered as individual therapeutic agents or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be single or multiple administrations. Taking all of the above factors into consideration, it is important to administer an amount that can obtain the maximum effect in a minimum amount without side effects, which can be easily determined by those skilled in the art.
- the effective amount of the pharmaceutical composition of the present invention may vary depending on the age, sex, condition, weight of the patient, the absorption of the active ingredient in the body, the inactivation rate and excretion rate, the type of disease, the drug used in general 0.001 to 150 mg, preferably 0.01 to 100 mg per 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 for preventing, controlling or treating cancer 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. .
- examples of the non-limiting compound used as an active ingredient of the pharmaceutical composition include the following compounds, isomers thereof and pharmaceutically acceptable salts thereof.
- the reactants and / or starting materials of known methods were appropriately modified to synthesize the following compounds according to the present invention.
- Reagents and conditions a) (i) K 2 CO 3 , methyl-4-bromobutanoate or methyl-2-bromo-2-methylpropanoate (Methyl 2-bromo-2 -methylpropanoate), DMF; (ii) LiOH, THF / H 2 O; b) EDC.HCl, HOBT, DIPEA, DMF, NH 2 -R 2 ; c) PPh 3 , Methylpropiolate, Toluene; d, g) LiOH, THF / H 2 O; e) EDC.HCl, HOBT, DIPEA, DMF, NH 2 -R 2 or HATU, DIPEA, DMF, NH 2 -R 2 ; f) Pd / C, H 2 , MeOH; h) EDC.HCl, HOBT, DIPEA, DMF, NH 2 -R 2 or HATU, DIPEA, DMF /
- the concentrate was purified by silica gel column chromatography to afford methyl 3- (2- (4- (2,4,4-trimethylpentane-2-yl) phenoxy) acetamido) benzoate (white solid, 0.10 g, 64.1% yield).
- the concentrate was purified by silica gel column chromatography to afford methyl 4-hydroxy-3- (2- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) acetamido) benzoate (White solid, 1.00 g, 64.1% yield).
- the concentrate was purified by silica gel column chromatography to obtain N- (4- (trifluoromethyl) phenyl) -2- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) acetamide. Obtained (white solid, 0.11 g, 71.5% yield).
- the concentrate was purified by silica gel column chromatography to obtain N- (4- (4-methylpiperazin-1-yl) phenyl) -2- (4- (2,4,4-trimethylpentane-2-yl) phenoxy Acetamide was obtained (white solid, 0.12 g, 72.7% yield).
- the concentrate was purified by silica gel column chromatography to obtain 1- (4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) -2- (4- (2,4,4-trimethylpentane- 2-yl) phenoxy) ethanone was obtained (white solid, 0.15 g, 81.0% yield).
- the concentrate was purified by silica gel column chromatography to obtain 1- (4- (prop-2-ynyl) piperazin-1-yl) -2- (4- (2,4,4-trimethylpentane-2-yl Phenoxy) ethanone was obtained (white solid, 0.11 g, 78.5% yield).
- the concentrate was purified by silica gel column chromatography to obtain N- (3-hydroxy-adamantane-1-yl) -2- (4- (2,4,4-trimethylpentane-2-yl) phenoxy) Acetamide was obtained (white solid, 0.12 g, 76.9% yield).
- Methyl 3- (2- (4-adamantan-1-yl-phenoxy) acetamido) -4-hydroxybenzoate (1.0 equiv), anhydrous potassium carbonate (3.0 equiv) and ethyl chloroacetate (2.0 equiv) are mixed in DMF and at room temperature After stirring overnight, the mixture was concentrated under reduced pressure, and the obtained residue was diluted with EtOAc and washed with sodium bicarbonate, water and brine. The organic layers were combined, dried over anhydrous magnesium sulfate (anhydrous MgSO 4 ), and then concentrated under reduced pressure.
- the concentrate was purified by silica gel column chromatography to methyl 3- (2- (4-adamantane-1-yl-phenoxy) acetamido) -4- (2- (pyrrolidin-1-yl) Oxy) benzoate was obtained (white solid, 0.09 g, 75.0% yield).
- the concentrate was purified by silica gel column chromatography to afford methyl 3- (2- (4-adamantane-1-yl-phenoxy) acetamido) -4- (3-morpholinopropoxy) benzoate. (White solid, 0.09 g, 69.7% yield).
- the concentrate was purified by silica gel column chromatography to afford methyl 4-methoxy-3- (2- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) acetamido) benzoate (White solid, 0.08 g, 77.6% yield).
- the methoxyethane (2.0 equiv) was mixed with DMF, stirred at room temperature overnight, concentrated under reduced pressure, and the obtained residue was diluted with EtOAc, washed with sodium bicarbonate, water and brine. After collection of the organic layer was removed, the dried over anhydrous magnesium sulfate (anhydrous MgSO 4), and concentrated under reduced pressure.
- the concentrate was purified by silica gel column chromatography to give methyl 3- (2- (4-adamantane-1-yl-phenoxy) -2-methylpropaneamido) benzoate (white solid, 0.12 g, 84.5% yield).
- the concentrate was purified by silica gel column chromatography to afford methyl 3- (2-methyl-2- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) propaneamido) benzoate. (White solid, 0.11 g, 75.8% yield).
- the concentrate was purified by silica gel column chromatography to prepare methyl-4-hydroxy-3- (2-methyl-2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) Obtained benzoate (white solid, 0.03 g, 83.2% yield).
- the concentrate was purified by silica gel column chromatography to afford methyl 4-hydroxy-3- (4- (4- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) butanamido) benzoate (White solid, 0.10 g, 66.2% yield).
- the concentrate was purified by silica gel column chromatography ( E ) -3H- [1,2,3] triazolo [4,5-b] pyridin-3-yl 3- (4- (2,4,4-trimethyl Pentan-2-yl) phenoxy) acrylate was obtained (white solid, 0.05 g, 44.6% yield).
- the concentrate was purified by silica gel column chromatography to afford methyl 3- (3- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) propaneamido) benzoate (white solid, 0.13 g, 88.4% yield).
- the concentrate was purified by silica gel column chromatography to afford methyl 4-hydroxy-3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) benzoate. (White solid, 0.01 g, 75.0% yield).
- the concentrate was purified by silica gel column chromatography to afford methyl 2-methyl-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) benzoate ( Yellow solid, 0.05 g, 61.0% yield).
- the concentrate was purified by silica gel column chromatography to give isopropyl 3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) benzoate (clear liquid, 0.06 g, 26.5% yield).
- the concentrate was purified by silica gel column chromatography to give methyl 5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) nicotinate (white solid, 0.06 g, 40.3% yield).
- the concentrate was purified by silica gel column chromatography to obtain N- (3- (morpholine-4-carbonyl) phenyl) -3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propane Amide was obtained (white solid, 0.08 g, 53.0% yield).
- the concentrate was purified by silica gel column chromatography to give ethyl 2- (3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) benzamido) acetate (White solid, 0.14 g, 64.4% yield).
- an MDH2 recombinant protein was prepared.
- the MDH2 gene was purchased from the Korea Human Genetics Bank (Korean Human GeneBank, KUGI, NM_005918), and amplified by PCR and cloned into the pET28a vector (Merck, Germany). Thereafter, the plasmid vector was introduced into E. coli Rosetta 2 (DE3), followed by IPTG treatment to overexpress MDH2 recombinant protein.
- the overexpressed recombinant MDH2 protein was purified by Ni-NTA affinity chromatography, TEV enzyme cleavage, and size-exclusion chromatography.
- the inhibitory activity of the compounds against MDH1 and MDH2 recombinant proteins produced in Experimental Examples 1-1, 1-2, 1-3 and 1-4 were measured. More specifically, 0.25 nM MDH1 recombinant protein (Biovision) or MDH2 recombinant protein was prepared using 200 ⁇ M oxaloacetate, nicotinamide adenine dinucleotide (NADH), the compound prepared in Example 1, and MDH assay buffer (100 mM potassium phosphate, pH 7.4) for 30 minutes. Thereafter, the change in NADH concentration in the solution by oxidation of NADH (NAD + ) by MDH1 or MDH2 enzyme was measured at absorbance 340 nm.
- NADH nicotinamide adenine dinucleotide
- HIF-1 ⁇ hyperoxia-inducible factor-1 ⁇
- HIF-1 ⁇ hypoxia-inducible factor-1 ⁇
- FBS fetal calf serum
- the cells were incubated for 24 hours in a cell incubator. Cells were incubated for 6 hours at 1% oxygen, 94% nitrogen and 5% carbon dioxide conditions to induce accumulation of HIF-1 ⁇ protein by hypoxia.
- the change in oxygen consumption rate was measured. More specifically, the oxygen consumption rate (OCR) of the mitochondria was measured using an XF24 extracellular flux analyzer (Seaholes). After HCT-116 cells (1 ⁇ 10 5 cells) were incubated for 24 hours in a measuring plate (XF24 cell cultureplate), the culture medium was exchanged with XF measuring medium and incubated for 1 hour in a cell incubator without carbon dioxide.
- OCR oxygen consumption rate
- the oxygen consumption rate of mitochondria was measured three times in non-drug cells, three times after administration of the ATP synthesis inhibitor oligomycin (1 ⁇ M), and three times after administration of the chemical decoupling agent carbonyl cyanide p -trifluoromethoxyphenylhydrazone (0.5 ⁇ M). Oxygen consumption was measured three times after administration of rotenone (1 ⁇ M) and antimycin A (1 ⁇ M).
- HCT-116 cells (1 ⁇ 10 5 cells) were treated with compound 9-2 and hypoxic specific sensitive fluorescent probe MAR (Gray, 0.5 ⁇ M), and then incubated for 6 hours in a cell incubator under hypoxic conditions. Thereafter, changes in intracellular fluorescence intensity due to hypoxia were measured and quantified by a real-time cell observation analysis system (Incusite, Essen).
- compound 9-2 was orally administered once daily at a concentration of 20 mg / kg, and 3, 5, 7, 10, 12, 14, 17, 19, 21, and 24 days Body weight and tumor size of the nude mouse were measured using Equation 1 below. Mice were sacrificed 24 days after Compound 9-2 administration to determine the weight and size of the extracted tumor.
- the cell proliferation inhibitory activity of the compound 9-2 prepared according to the above Example was confirmed.
- the cell lines used in the experiment were lung cancer cell lines A549 and H1703, colorectal cancer cell lines HCT116 and HT29, liver cancer (liver).
- cancer cell lines Hep3B and HepG2 gastric or stomach cancer cell lines NUGC-3 and AGS, kidney and renal cancer cell lines 786-O and Caki-1, breast cancer cell lines MCF-7 and MDA -MB-231, prostate cancer cell line PC3, pancreatic cancer cell line MIA-PaCa-2, cervical cancer cell line HeLa, normal cell WI-38 and CCD-32Lu cell lines.
- the cell line was suspended in DMEM medium containing 5% fetal bovine serum (FBS), and then transferred to a 96 well plate (3 ⁇ 10 3 cells / well) for 24 hours in a 37 ° C. cell incubator maintaining 5% carbon dioxide. It was.
- Compound 9-2 was treated at various concentrations, incubated for 72 hours, and the cells were fixed with an aqueous 10% formalin solution, followed by staining with 0.5% methylene blue solution. Thereafter, the concentration change of methylene blue extracted with an aqueous 0.5% hydrochloric acid solution was measured at an absorbance of 600 nm.
- Compound 9-2 inhibited the proliferation of various cancer cell lines that are normal cell lines, and showed a particularly strong inhibitory effect in A549, HCT116, HepG2 cells. Compound 9-2 was found to have no effect on the proliferation of normal cell lines in a concentration range that inhibits cancer cell proliferation.
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Abstract
The present invention relates to a compound exhibiting inhibitory activity of at least one of malate dehydrogenases 1 (MDH1) and malate dehydrogenases 2 (MDH2), and a pharmaceutical composition for preventing or treating cancer comprising the same as an active ingredient. The inventors of the present invention have experimentally confirmed that the compound exhibiting the MDH1 and/or MDH2 inhibitory activity has an inhibitory effect on mitochondrial respiration in cancer cells, an excellent inhibitory effect on cancer cell growth, etc.. Thus, the compound of the present invention is expected to be effectively used as a pharmaceutical composition for treating cancer.
Description
본 발명은 MDH1 (malate dehydrogenases 1) 또는 MDH2 (malate dehydrogenases 2)의 저해 활성을 갖는 신규 화합물 및 이를 유효성분으로 포함하는 암 예방 또는 치료용 약학적 조성물에 관한 것이다.The present invention relates to a novel compound having inhibitory activity of MDH1 (malate dehydrogenases 1) or MDH2 (malate dehydrogenases 2) and a pharmaceutical composition for preventing or treating cancer comprising the same as an active ingredient.
본 출원은 2017년 3월 9일에 출원된 한국특허출원 제10-2017-0029916호 및 2018년 3월 8일에 출원된 한국특허출원 제10-2018-0027397호에 기초한 우선권을 주장하며, 해당 출원의 명세서 및 도면에 개시된 모든 내용은 본 출원에 원용된다. This application claims the priority based on Korean Patent Application No. 10-2017-0029916, filed March 9, 2017 and Korean Patent Application No. 10-2018-0027397, filed March 8, 2018, All content disclosed in the specification and drawings of an application is incorporated in this application.
암세포는 정상세포와 비교하여 호기성 해당작용 (aerobic glycolysis), 지방산 합성 (fatty acid synthesis)의 증가, 빠른 글루타민 (glutamine) 대사 등 대사 측면에서의 다양한 변화가 나타난다. 특히, 해당작용의 활성화는 ATP 생성, 생체 물질의 생합성 및 산화-환원 조절 등의 변화를 야기시킨다. 말릭산-아스팔산 셔틀 은 해당작용시 발생한 세포질 내 NADH를 미토콘드리아로 전달하는 중요한 역할을 하는 기작이다. 말릭산-아스팔산 셔틀은 세포질과 미토콘드리아에 존재하는 말릭산 탈수소효소 (MDHs; malate dehydrogenases) 및 글루탐산 옥살로아세테이트 아민전이효소 (GOTs; glutamate oxaloacetate transaminases)에 의해 이루어진다. 말릭산-아스팔산 셔틀의 저해제인 아미노옥시아세트 산 (AOA; Aminooxyacetic acid)은 당(glucose)이 TCA 회로 (tricarboxylic acid cycle)의 산물이 되는 것을 방지함으로써, 유방암 세포의 증식을 억제한다. 또한, 췌장암에서 미토콘드리아에서 존재하는 GOT2 (Mitochondrial GOT2)의 아세틸화가 말릭산-아스팔산을 통해 NADH의 이동을 촉진하고 암세포의 증식에 필요한 ATP 생성에 관여한다는 사실이 보고되었다.Compared to normal cells, cancer cells exhibit various changes in metabolism such as aerobic glycolysis, increased fatty acid synthesis, and rapid glutamine metabolism. In particular, activation of glycolysis causes changes in ATP production, biosynthesis of biomaterials, and redox regulation. The malic acid-asphalic acid shuttle is a mechanism that plays an important role in delivering NADH to the mitochondria in the cytoplasm generated during glycolysis. The malic acid-asphalic acid shuttle is made by malic dehydrogenases (MDHs) and glutamate oxaloacetate transaminases (GOTs) present in the cytoplasm and mitochondria. Aminooxyacetic acid (AOA), an inhibitor of the maleic acid-asphalic acid shuttle, inhibits the proliferation of breast cancer cells by preventing glucose from becoming a product of the tricarboxylic acid cycle. In addition, it has been reported that acetylation of GOT2 (Mitochondrial GOT2) present in mitochondria in pancreatic cancer promotes the migration of NADH through malic acid-asphalic acid and is involved in the production of ATP necessary for the proliferation of cancer cells.
한편 서로 다른 MDH 유전자에 의해 생성되는 MDH1 및 MDH2 이소자임 (isoenzymes)은 세포질과 미토콘드리아 매트릭스에 존재한다. MDH1 및 MDH2는 가역적으로 NAD/NADH 보조인자 (cofactor) 시스템을 사용하여 말릭산 (malate)과 옥살산 (oxaloacetate, OAA)을 전환시키는 역할을 한다. 세포질에 있는 MDH1은 옥살산을 말릭산으로 환원시켜 NADH를 NAD+로 산화시킨다. 말릭산-아스팔산 셔틀에서 말릭산은 미토콘드리아의 안으로 이동되고 mitochondrial MDH2에 의해 옥살산으로 다시 산화되고 NADH를 생성한다. 생성된 NADH는 전자전달계를 통해 ATP를 생성한다. 이 외에도, TCA cycle에 관련된 MDH2는 호흡을 통해 ATP 생성에 관여한다.Meanwhile, MDH1 and MDH2 isozymes produced by different MDH genes are present in the cytoplasm and mitochondrial matrix. MDH1 and MDH2 reversibly serve to convert malate and oxaloacetate (OAA) using the NAD / NADH cofactor system. MDH1 in the cytoplasm oxidizes NADH to NAD + by reducing oxalic acid to malic acid. In the malic acid-asphalic acid shuttle, malic acid is transported into the mitochondria and oxidized back to oxalic acid by mitochondrial MDH2 to produce NADH. The generated NADH generates ATP through an electron transport system. In addition, MDH2 involved in the TCA cycle is involved in ATP production through respiration.
최근 MDH1 및 MDH2의 암 관련성이 보고되고 있으며, 글루타민 의존형 췌장암 (PDAC; Glutamine-dependent pancreatic ductaladenocarcinoma)세포에서 글루타민 대사를 리프로그래밍 (glutamine metabolism reprogramming)하여, 세포 내 환원 상태 (redox state)를 유지하기 위해 MDH1을 필요로 한다는 사실이 보고되었다. MDH1를 녹다운 (knockdown)한 결과, PDAC 세포가 사멸하였으며, 또한, 지방산 합성을 억제함으로써 ERBB2 (Erb-B2 receptor tyrosine kinase 2)-positive BT474 유방암 세포의 증식을 억제함을 관찰하였다. 또한, MDH2가 많이 발현되는 전립선 암세포는 항암제 저항성을 나타내고 재발없는 생존 (relapse-free survival)기간이짧은 것으로 보고되고 있는데, 이러한 전립선암 세포주에서 MDH2를 녹다운 하면, 암세포주의 대사의 비효율 유도함으로써 세포의 증식과 도세탁셀 (docetaxel)에 대한 감수성이 증가됨을 확인하였다. 현재 암을 치료하고자 하는 시도가 다양하게 진행되고 있으나 (한국공개특허 10-2010-0126924), 내성 등의 부작용을 가진다는 문제점이 있고, MDH1 및 MDH2의 암관련성에 대한 연구가 보고되고 있으나, 항암제로서 MDH1 및 MDH2 저해제를 개발하려는 시도는 이루어지지 않고 있다.Recently, cancer-related associations of MDH1 and MDH2 have been reported, and glutamine metabolism reprogramming in glutamine-dependent pancreatic ductaladenocarcinoma (PDAC) cells is used to maintain intracellular redox state. It has been reported that it requires MDH1. As a result of knocking down MDH1, it was observed that PDAC cells were killed and also inhibited proliferation of ERBB2 (Erb-B2 receptor tyrosine kinase 2) -positive BT474 breast cancer cells by inhibiting fatty acid synthesis. In addition, prostate cancer cells expressing MDH2 are reported to be anti-cancer drug resistant and have a short relapse-free survival period. When knocking down MDH2 in these prostate cancer cell lines, induction of metabolism of cancer cell lines leads to inefficiency of the cells. It was confirmed that the proliferation and sensitivity to docetaxel (docetaxel) is increased. At present, various attempts have been made to treat cancer (Korean Patent Laid-Open Publication No. 10-2010-0126924), but there is a problem of having side effects such as resistance, and studies on cancer-related effects of MDH1 and MDH2 have been reported, but anticancer drugs Attempts to develop MDH1 and MDH2 inhibitors have not been made.
이에, 본 발명자들은 상기와 같은 종래의 문제점을 해결하기 위하여, 보다 효과적인 암 치료 물질을 개발하기 위한 연구를 계속하던 중, MDH1 및 MDH2의 기질 결합 부위 및 활성부위 구조는 매우 유사하여 MDH1 및 MDH2의 활성을 동시에 억제하는 MDH1/2 dualinhibitor를개발할 수 있을 것으로 예측하고, MDH1 및 MDH2의 활성을 동시에 억제하는 화합물을 제조하였으며, 상기 화합물을 포함하는 암 치료제를 최초로 고안하여, 본 발명을 완성하였다.Accordingly, the present inventors while continuing to research to develop a more effective cancer treatment material, in order to solve the conventional problems as described above, the substrate binding site and active site structure of MDH1 and MDH2 is very similar to that of MDH1 and MDH2 In anticipation of the possibility of developing MDH1 / 2 dualinhibitors that simultaneously inhibit activity, a compound was prepared that simultaneously inhibits the activities of MDH1 and MDH2, and a cancer therapeutic agent containing the compound was first devised to complete the present invention.
본 발명은 상기와 같은 문제점을 해결하기 위해 안출된 것으로서, 본 발명자들은 MDH1 및/또는 MDH2의 활성을 억제하는 화합물의 암 예방 또는 치료 효과를 확인하고 이에 기초하여 본 발명을 완성하게 되었다.The present invention has been made to solve the above problems, the present inventors have confirmed the cancer preventive or therapeutic effect of the compound that inhibits the activity of MDH1 and / or MDH2 to complete the present invention based on this.
이에, 본 발명의 목적은 MDH1 및/또는 MDH2 억제 활성을 나타내는 화합물, 이의 이성질체 또는 이의 약학적으로 허용 가능한 염을 제공하는 것이다.It is therefore an object of the present invention to provide compounds, isomers thereof or pharmaceutically acceptable salts thereof which exhibit MDH1 and / or MDH2 inhibitory activity.
또한, 본 발명의 다른 목적은 MDH1 및/또는 MDH2 억제 활성을 나타내는 화합물, 이의 이성질체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는, 암 예방 또는 치료용 약학적 조성물을 제공하는 것이다.Another object of the present invention is to provide a pharmaceutical composition for preventing or treating cancer, which comprises as an active ingredient a compound, an isomer thereof, or a pharmaceutically acceptable salt thereof, which exhibits MDH1 and / or MDH2 inhibitory activity.
그러나 본 발명이 이루고자 하는 기술적 과제는 이상에서 언급한 과제에 제한되지 않으며, 언급되지 않은 또 다른 과제들은 아래의 기재로부터 당업자에게 명확하게 이해될 수 있을 것이다.However, the technical problem to be achieved by the present invention is not limited to the above-mentioned problem, another task that is not mentioned will be clearly understood by those skilled in the art from the following description.
상기와 같은 본 발명의 목적을 달성하기 위하여, 본 발명은 하기 화학식 1로 표시되는 화합물, 이의 이성질체 또는 이의 약학적 허용가능한 염을 제공을 제공한다.In order to achieve the object of the present invention as described above, the present invention provides a compound represented by the following formula (1), an isomer thereof or a pharmaceutically acceptable salt thereof.
[화학식 1][Formula 1]
이 때, 상기 화학식 1에 있어서,At this time, in the formula (1),
X는 메틸렌기, 에테인기, 에틸렌기, n-프로필렌기 또는 아이소프로필렌이고;X is methylene group, ethane group, ethylene group, n -propylene group or isopropylene;
R1은 니트로기, 트리플루오로메틸기, C1-C20 알킬 또는 C1-C20 사이클로알킬이고; 및R 1 is a nitro group, trifluoromethyl group, C 1 -C 20 alkyl or C 1 -C 20 cycloalkyl; And
상기 R3는 메틸 또는 2-프로핀일이고; 및R 3 is methyl or 2-propynyl; And
상기 R4는 메틸, 수소, 하이드록시, 메톡시, 2-프로핀일, , , , , , 또는 이고; R 4 is methyl, hydrogen, hydroxy, methoxy, 2-propynyl, , , , , , or ego;
상기 R6는 메틸 또는 하이드록시이고; 및R 6 is methyl or hydroxy; And
상기 R7는 C 또는 N일 수 있다. R 7 may be C or N.
본 발명의 일 구현예로서, 상기 R1은 아다만틸, tert-부틸, 펜틸, 사이클로펜틸, 사이클로헥실, 또는 2,4,4-트리메틸펜테인-2-일으로 치환될 수 있다.In one embodiment of the present invention, R 1 may be substituted with adamantyl, tert -butyl, pentyl, cyclopentyl, cyclohexyl, or 2,4,4-trimethylpentin-2-yl.
또한, 본 발명의 일 구현예로서, 상기 R1은 아다만틸이고;In addition, in one embodiment of the present invention, R 1 is adamantyl;
X는 메틸렌기, 에테인기, 에틸렌기, n-프로필렌기 또는 아이소프로필렌이고; 및 X is methylene group, ethane group, ethylene group, n -propylene group or isopropylene; And
상기 R3는 메틸일 수 있다. R 3 may be methyl.
또한, 본 발명의 일 구현예로서, 본 화합물은 하기 화학식 2로 표시되는 화합물일 수 있다. In addition, as an embodiment of the present invention, the compound may be a compound represented by the following formula (2).
[화학식 2][Formula 2]
이 때, 상기 화학식 2에 있어서,At this time, in the formula (2),
상기 R1은 아다만틸 또는 tert-부틸이고; 및 R 1 is adamantyl or tert -butyl; And
상기 R3는 메틸 또는 2-프로핀일이고; R 3 is methyl or 2-propynyl;
상기 R4는 메틸, 수소 또는 하이드록시이고; R 4 is methyl, hydrogen or hydroxy;
상기 R6는 메틸 또는 하이드록시이고; 및R 6 is methyl or hydroxy; And
상기 R7는 C 또는 N일 수 있다. R 7 may be C or N.
또한, 본 발명의 일 구현예로서, 본 화합물은 하기 화학식 3으로 표시되는 화합물일 수 있다. In addition, as an embodiment of the present invention, the compound may be a compound represented by the following formula (3).
[화학식 3][Formula 3]
이 때, 화학식 3에 있어서,At this time, in the formula (3),
상기 R1은 니트로기, 트리플루오로메틸기, 아다만틸, tert-부틸, 펜틸, 사이클로펜틸, 사이클로헥실, 또는 2,4,4-트리메틸펜테인-2-일이고;R 1 is a nitro group, trifluoromethyl group, adamantyl, tert -butyl, pentyl, cyclopentyl, cyclohexyl, or 2,4,4-trimethylpentin-2-yl;
상기 R3는 메틸 또는 2-프로핀일이고; 및R 3 is methyl or 2-propynyl; And
상기 R4는 메틸, 수소, 하이드록시, 메톡시, 2-프로핀일, , , , , , 또는 일 수 있다. R 4 is methyl, hydrogen, hydroxy, methoxy, 2-propynyl, , , , , , or Can be.
본 발명의 다른 구현예로서, 상기 화합물은 다음으로 이루어진 군에서 선택된 어느 하나 이상일 수 있다.In another embodiment of the present invention, the compound may be any one or more selected from the group consisting of:
(1) 메틸 3-(2-(4-니트로페녹시)아세트아미도)벤조네이트(Methyl 3-(2-(4-nitrophenoxy)acetamido)benzoate);(1) Methyl 3- (2- (4-nitrophenoxy) acetamido) benzoate (Methyl 3- (2- (4-nitrophenoxy) acetamido) benzoate);
(2) 메틸 3-(2-(4-트리플루오로메틸)페녹시)아세트아미도)벤조에이트(Methyl 3-(2-(4-(trifluoromethyl)phenoxy)acetamido)benzoate);(2) methyl 3- (2- (4-trifluoromethyl) phenoxy) acetamido) benzoate (Methyl 3- (2- (4- (trifluoromethyl) phenoxy) acetamido) benzoate);
(3) 메틸 3-(2-(4-tert-부틸페녹시)아세트아미도)벤조에이트 (Methyl 3-(2-(4-tert-butylphenoxy)acetamido)benzoate) ;(3) methyl 3- (2- (4-tert-butylphenoxy) acetamido) benzoate (Methyl 3- (2- (4-tert-butylphenoxy) acetamido) benzoate);
(4) 메틸 3-(2-(p-톨리록시)아세트아미도)벤조에이트(Methyl 3-(2-(p-tolyloxy)acetamido)benzoate);(4) Methyl 3- (2- (p-tolyloxy) acetamido) benzoate (Methyl 3- (2- (p-tolyloxy) acetamido) benzoate);
(5) 메틸 3-(2-(4-에틸페녹시)아세트아미도)벤조에이트 (Methyl 3-(2-(4-ethylphenoxy)acetamido)benzoate) ;(5) methyl 3- (2- (4-ethylphenoxy) acetamido) benzoate (Methyl 3- (2- (4-ethylphenoxy) acetamido) benzoate);
(6) 메틸 3-(2-(4-프로필페녹시)아세트아미도)벤조에이트 (Methyl 3-(2-(4-propylphenoxy)acetamido)benzoate);(6) methyl 3- (2- (4-propylphenoxy) acetamido) benzoate (Methyl 3- (2- (4-propylphenoxy) acetamido) benzoate);
(7) 메틸 3-(2-(4-부틸 페녹시)아세트아미도)벤조에이트;(7) methyl 3- (2- (4-butyl phenoxy) acetamido) benzoate;
(8) 메틸 3-(2-(4-펜틸페녹시)아세트아미도)벤조에이트 (Methyl 3-(2-(4-pentylphenoxy)acetamido)benzoate) ;(8) methyl 3- (2- (4-pentylphenoxy) acetamido) benzoate (Methyl 3- (2- (4-pentylphenoxy) acetamido) benzoate);
(9) 메틸 3-(2-(4-사이클로펜틸페녹시)아세트아미도)벤조에이트 (Methyl 3-(2-(4-cyclopentylphenoxy)acetamido)benzoate) ;(9) methyl 3- (2- (4-cyclopentylphenoxy) acetamido) benzoate (Methyl 3- (2- (4-cyclopentylphenoxy) acetamido) benzoate);
(10) 메틸 3-(2-(4-사이클로헥실페녹시)아세트아미도)벤조에이트 (Methyl 3-(2-(4-cyclohexylphenoxy)acetamido)benzoate);(10) methyl 3- (2- (4-cyclohexylphenoxy) acetamido) benzoate (Methyl 3- (2- (4-cyclohexylphenoxy) acetamido) benzoate);
(11) 메틸 3-(2-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)아세트아미도)벤조에이트 (Methyl 3-(2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acetamido)benzoate);(11) Methyl 3- (2- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) acetamido) benzoate (Methyl 3- (2- (4- (2,4) , 4-trimethylpentan-2-yl) phenoxy) acetamido) benzoate);
(12) 메틸 4-하이드록시-3-(2-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)아세트아미도)벤조에이트 (Methyl 4-hydroxy-3-(2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acetamido)benzoate); (12) Methyl 4-hydroxy-3- (2- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) acetamido) benzoate (Methyl 4-hydroxy-3- ( 2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamido) benzoate);
(13) N-(4-(트리플루오로메틸)페닐)-2-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)아세트아마이드 (N-(4-(trifluoromethyl)phenyl)-2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acetamide) ;(13) N- (4- (trifluoromethyl) phenyl) -2- (4- (2,4,4-trimethylpentin-2-yl) phenoxy) acetamide (N- (4- (trifluoromethyl ) phenyl) -2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamide);
(14) N-(4-(4-메틸피페라진-1-일)페닐)-2-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)아세트아마이드 (N-(4-(4-methylpiperazin-1-yl)phenyl)-2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acetamide);(14) N- (4- (4-methylpiperazin-1-yl) phenyl) -2- (4- (2,4,4-trimethylpentin-2-yl) phenoxy) acetamide (N- (4- (4-methylpiperazin-1-yl) phenyl) -2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamide);
(15) 1-(4-(4-(트리플루오로메틸)벤질)피페라진-1-일)-2-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)에탄온 (1-(4-(4-(trifluoromethyl)benzyl)piperazin-1-yl)-2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)ethanone) ;(15) 1- (4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) -2- (4- (2,4,4-trimethylpentane-2-yl) phenoxy) Ethanone (1- (4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) -2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) ethanone);
(16) 1-(4-(프로프-2-인일)피페라진-1-일)-2-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)에탄온 (1-(4-(prop-2-ynyl)piperazin-1-yl)-2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)ethanone);(16) 1- (4- (prop-2-ynyl) piperazin-1-yl) -2- (4- (2,4,4-trimethylpentane-2-yl) phenoxy) ethanone ( 1- (4- (prop-2-ynyl) piperazin-1-yl) -2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) ethanone);
(17) 프로프-2-인일 4-하이드록시-3-(2-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)아세트아미도)벤조에이트 (Prop-2-ynyl 4-hydroxy-3-(2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acetamido)benzoate);(17) Prop-2-ynyl 4-hydroxy-3- (2- (4- (2,4,4-trimethylpentane-2-yl) phenoxy) acetamido) benzoate (Prop-2 -ynyl 4-hydroxy-3- (2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamido) benzoate);
(18) N-(3-하이드록시-아다만테인-1-일)-2-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)아세트아마이드 (N-(3-hydroxy-adamantan-1-yl)-2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acetamide) ;(18) N- (3-hydroxy-adamantane-1-yl) -2- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) acetamide (N- (3 -hydroxy-adamantan-1-yl) -2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamide);
(19) 메틸 3-(2-(4-아다만테인-1-일-페녹시)아세트아미도)벤조에이트 (Methyl 3-(2-(4-adamantan-1-yl-phenoxy)acetamido)benzoate) ;(19) Methyl 3- (2- (4-adamantane-1-yl-phenoxy) acetamido) benzoate (Methyl 3- (2- (4-adamantan-1-yl-phenoxy) acetamido) benzoate );
(20) 메틸 3-(2-(4-아다만테인-1-일-페녹시)아세트아미도 4-하이드록시벤조에이트(Methyl 3-(2-(4-adamantan-1-yl-phenoxy)acetamido)-4-hydroxybenzoate);(20) Methyl 3- (2- (4-adamantane-1-yl-phenoxy) acetamido 4-hydroxybenzoate (Methyl 3- (2- (4-adamantan-1-yl-phenoxy) acetamido) -4-hydroxybenzoate);
(21) 메틸 3-(2-(4-아다만테인-1-일-페녹시)아세트아미도)-4-(2-에톡시-2-옥소에톡시)벤조에이트(Methyl 3-(2-(4-adamantan-1-yl-phenoxy)acetamido)-4-(2-ethoxy-2-oxoethoxy)benzoate) ;(21) Methyl 3- (2- (4-adamantane-1-yl-phenoxy) acetamido) -4- (2-ethoxy-2-oxoethoxy) benzoate (Methyl 3- (2 -(4-adamantan-1-yl-phenoxy) acetamido) -4- (2-ethoxy-2-oxoethoxy) benzoate);
(22) 메틸 3-(2-(4-아다만테인-1-일-페녹시)아세트아미도)-4-(2-(피롤리딘-1-일)에톡시)벤조에이트 (Methyl 3-(2-(4-adamantan-1-yl-phenoxy)acetamido)-4-(2-(pyrrolidin-1-yl)ethoxy)benzoate);(22) Methyl 3- (2- (4-adamantane-1-yl-phenoxy) acetamido) -4- (2- (pyrrolidin-1-yl) ethoxy) benzoate (Methyl 3 -(2- (4-adamantan-1-yl-phenoxy) acetamido) -4- (2- (pyrrolidin-1-yl) ethoxy) benzoate);
(23) 메틸 3-(2-(4-아다만테인-1-일-페녹시)아세트아미도)-4-(3-모르폴리노프로폭시)벤조에이트 (Methyl 3-(2-(4-adamantan-1-yl-phenoxy)acetamido)-4-(3-morpholinopropoxy)benzoate);(23) Methyl 3- (2- (4-adamantane-1-yl-phenoxy) acetamido) -4- (3-morpholinopropoxy) benzoate (Methyl 3- (2- (4 -adamantan-1-yl-phenoxy) acetamido) -4- (3-morpholinopropoxy) benzoate);
(24) 메틸 4-메톡시-3-(2-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)아세트아미도)벤조에이트 (Methyl 4-methoxy-3-(2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acetamido)benzoate); (24) Methyl 4-methoxy-3- (2- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) acetamido) benzoate (Methyl 4-methoxy-3- ( 2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamido) benzoate);
(25) 메틸 4-(2-메톡시에톡시)-3-(2-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)아세트아미도)벤조에이트 (Methyl 4-(2-methoxyethoxy)-3-(2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acetamido)benzoate); (25) Methyl 4- (2-methoxyethoxy) -3- (2- (4- (2,4,4-trimethylpentane-2-yl) phenoxy) acetamido) benzoate (Methyl 4 -(2-methoxyethoxy) -3- (2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamido) benzoate);
(26) 메틸 4-(2-모르폴리노에톡시)-3-(2-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)아세트아미도)벤조에이트 (Methyl 4-(2-morpholinoethoxy)-3-(2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acetamido)benzoate);(26) Methyl 4- (2-morpholinoethoxy) -3- (2- (4- (2,4,4-trimethylpentane-2-yl) phenoxy) acetamido) benzoate (Methyl 4- (2-morpholinoethoxy) -3- (2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamido) benzoate);
(27) 메틸 4-(프로프-2-인일옥시)-3-(2-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)아세트아미도)벤조에이트 (Methyl 4-(prop-2-ynyloxy)-3-(2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acetamido)benzoate) ;(27) Methyl 4- (prop-2-ynyloxy) -3- (2- (4- (2,4,4-trimethylpentane-2-yl) phenoxy) acetamido) benzoate (Methyl 4- (prop-2-ynyloxy) -3- (2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamido) benzoate);
(28) 메틸 4-(4-메톡시벤질옥시)-3-(2-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)아세트아미도)벤조에이트 (Methyl 4-(4-methoxybenzyloxy)-3-(2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acetamido)benzoate) ;(28) Methyl 4- (4-methoxybenzyloxy) -3- (2- (4- (2,4,4-trimethylpentane-2-yl) phenoxy) acetamido) benzoate (Methyl 4 -(4-methoxybenzyloxy) -3- (2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamido) benzoate);
(29) 메틸 3-(2-(4-아다만테인-1-일-페녹시)-2-메틸프로판아미도)벤조에이트 (Methyl 3-(2-(4-adamantan-1-yl-phenoxy)-2-methylpropanamido)benzoate) ;(29) Methyl 3- (2- (4-adamantane-1-yl-phenoxy) -2-methylpropaneamido) benzoate (Methyl 3- (2- (4-adamantan-1-yl-phenoxy ) -2-methylpropanamido) benzoate);
(30) 메틸 3-(2-메틸-2-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)프로판아미도)벤조에이트 (Methyl 3-(2-methyl-2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)propanamido)benzoate) ;(30) Methyl 3- (2-methyl-2- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) propaneamido) benzoate (Methyl 3- (2-methyl-2 -(4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamido) benzoate);
(31) 메틸- 4-하이드록시-3-(2-메틸-2-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)프로판아미도)벤조에이트(Methyl 4-hydroxy-3-(2-methyl-2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)propanamido)benzoate) ;(31) Methyl-4-hydroxy-3- (2-methyl-2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) benzoate (Methyl 4-hydroxy -3- (2-methyl-2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamido) benzoate);
(32) 메틸 3-[4-(4-아다만테인-1-일-페녹시)부탄아미도]벤조에이트 (Methyl 3-[4-(4-adamantan-1-yl-phenoxy)butanamido]benzoate) ;(32) Methyl 3- [4- (4-adamantane-1-yl-phenoxy) butanamido] benzoate (Methyl 3- [4- (4-adamantan-1-yl-phenoxy) butanamido] benzoate );
(33) 메틸 3-(4-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)부탄아미도)벤조에이트 (Methyl 3-(4-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)butanamido)benzoate) ;(33) Methyl 3- (4- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) butanamido) benzoate (Methyl 3- (4- (4- (2,4) , 4-trimethylpentan-2-yl) phenoxy) butanamido) benzoate);
(34) 메틸 4-하이드록시-3-(4-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)부탄아미도)벤조에이트 (Methyl 4-hydroxy-3-(4-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)butanamido)benzoate); (34) Methyl 4-hydroxy-3- (4- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) butanamido) benzoate (Methyl 4-hydroxy-3- ( 4- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) butanamido) benzoate);
(35) (E)-3-[3-(4-아다만테인-1-일-페녹시)-아크릴오일아미노]-벤조익 산 메틸 에스테르((E)-3-[3-(4-Adamantan-1-yl-phenoxy)-acryloylamino]-benzoic acid methyl ester);(35) (E) -3- [3- (4-adamantane-1-yl-phenoxy) -acryloylamino] -benzoic acid methyl ester ((E) -3- [3- (4- Adamantan-1-yl-phenoxy) -acryloylamino] -benzoic acid methyl ester);
(36) (E)-3-{3-[4-(2,4,4-트리메틸펜탄-2-일)페녹시]아크릴아미도}벤조익 산 메틸 에스테르((E)-3-{3-[4-(2,4,4-Trimethylpentan-2-yl)phenoxy]acrylamido}benzoic acid methyl ester) ;(36) (E) -3- {3- [4- (2,4,4-trimethylpentan-2-yl) phenoxy] acrylamido} benzoic acid methyl ester ((E) -3- {3 -[4- (2,4,4-Trimethylpentan-2-yl) phenoxy] acrylamido} benzoic acid methyl ester);
(37) (E)-메틸4-메틸-3-(3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)아크릴아미도)벤조에이트((E)-methyl 4-methyl-3-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acrylamido)benzoate) ;(37) (E) -methyl4-methyl-3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate ((E) -methyl 4 -methyl-3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate);
(38) (E)-메틸2-메틸-5-(3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)아크릴아미도)벤조에이트((E)-methyl 2-methyl-5-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acrylamido)benzoate) ;(38) (E) -methyl2-methyl-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate ((E) -methyl 2 -methyl-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate);
(39) (E)-메틸2-하이드록시-5-(3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)아크릴아미도)벤조에이트((E)-methyl 2-hydroxy-5-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acrylamido)benzoate) ;(39) (E) -methyl2-hydroxy-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate ((E) -methyl 2-hydroxy-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate);
(40) (E)-이소프로필 3-(3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)아크릴아미도)벤조에이트((E)-isopropyl 3-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acrylamido)benzoate);(40) (E) -isopropyl 3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate ((E) -isopropyl 3- (3 -(4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate);
(41) (E)-메틸 2,4-다이메틸-5-(3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)아크릴아미도)벤조에이트((E)-methyl 2,4-dimethyl-5-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acrylamido)benzoate); (41) (E) -methyl 2,4-dimethyl-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate ((E) -methyl 2,4-dimethyl-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate);
(42) (E)-3H-[1,2,3]트리아졸로[4,5-b]피리딘-3-일 3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)아크릴레이트((E)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl 3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acrylate) ;(42) (E) -3H- [1,2,3] triazolo [4,5-b] pyridin-3-yl 3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy Acrylate ((E) -3H- [1,2,3] triazolo [4,5-b] pyridin-3-yl 3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy ) acrylate);
(43) (E)-1H-벤조[d][1,2,3]트리아졸-1-일 3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)아크릴레이트((E)-1H-benzo[d][1,2,3]triazol-1-yl 3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acrylate) ;(43) (E) -1H-benzo [d] [1,2,3] triazol-1-yl 3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylate ((E) -1H-benzo [d] [1,2,3] triazol-1-yl 3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylate);
(44) (E)-메틸 4-하이드록시-3-(3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)아크릴아미도)벤조에이트((E)-methyl 4-hydroxy-3-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acrylamido)benzoate);(44) (E) -methyl 4-hydroxy-3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate ((E) -methyl 4-hydroxy-3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate);
(45) 메틸 3-[3-(4-아다만테인-1-일-페녹시)프로판아미도]벤조에이트 (Methyl 3-(3-(4-(adamantan-1-yl)phenoxy)propanamido)benzoate);(45) Methyl 3- [3- (4-adamantane-1-yl-phenoxy) propanamido] benzoate (Methyl 3- (3- (4- (adamantan-1-yl) phenoxy) propanamido) benzoate);
(46) 메틸 3-(3-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)프로판아미도)벤조에이트 (Methyl 3-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)propanamido)benzoate) ;(46) Methyl 3- (3- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) propaneamido) benzoate (Methyl 3- (3- (4- (2,4) , 4-trimethylpentan-2-yl) phenoxy) propanamido) benzoate);
(47) 메틸 4-하이드록시-3-(3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)프로판아미도)벤조에이트(Methyl 4-hydroxy-3-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)propanamido)benzoate) ;(47) Methyl 4-hydroxy-3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) benzoate (Methyl 4-hydroxy-3- (3 -(4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamido) benzoate);
(48)메틸 4-메틸-3-(3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)프로판아미도)벤조에이트(Methyl 4-methyl-3-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)propanamido)benzoate) ;(48) methyl 4-methyl-3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) benzoate (Methyl 4-methyl-3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamido) benzoate);
(49) 메틸 2-메틸-5-(3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)프로판아미도)벤조에이트(Methyl 2-methyl-5-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)propanamido)benzoate) ;(49) Methyl 2-methyl-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) benzoate (Methyl 2-methyl-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamido) benzoate);
(50)메틸 2-하이드록시-5-(3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)프로판아미도)벤조에이트(Methyl 2-hydroxy-5-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)propanamido)benzoate) ;(50) Methyl 2-hydroxy-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) benzoate (Methyl 2-hydroxy-5- (3 -(4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamido) benzoate);
(51) 이소프로필 3-(3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)프로판아미도)벤조에이트(Isopropyl 3-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)propanamido)benzoate);(51) Isopropyl 3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) benzoate (Isopropyl 3- (3- (4- (2,4 , 4-trimethylpentan-2-yl) phenoxy) propanamido) benzoate);
(52) 메틸 5-(3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)프로판아미도)니코티네이트; (Methyl 5-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)propanamido)nicotinate) (52) methyl 5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) nicotinate; (Methyl 5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamido) nicotinate)
(53) N-(3-(모르폴린-4-카보닐)페닐)-3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)프로판아마이드(N-(3-(Morpholine-4-carbonyl)phenyl)-3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)propanamide) ;(53) N- (3- (morpholin-4-carbonyl) phenyl) -3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamide (N- (3- (Morpholine-4-carbonyl) phenyl) -3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamide);
(54) 에틸 2-(3-(3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)프로판아미도)벤즈아미도)아세테이트(Ethyl 2-(3-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)propanamido)benzamido)acetate) ; 또는(54) ethyl 2- (3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) benzamido) acetate (Ethyl 2- (3- (3 -(4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamido) benzamido) acetate); or
(55) (S)-메틸 3-메틸-2-(3-(3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)프로판아미도)벤즈아미도)부타노에이트((S)-methyl 3-methyl-2-(3-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)propanamido)benzamido)butanoate).(55) (S) -methyl 3-methyl-2- (3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) benzamido) butano Ate ((S) -methyl 3-methyl-2- (3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamido) benzamido) butanoate).
본 발명은 상기 화학식 1로 표시되는 화합물, 이들의 이성질체 또는 이들의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 암 예방 또는 치료용 약학적 조성물을 제공한다.The present invention provides a pharmaceutical composition for preventing or treating cancer comprising the compound represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명의 일 구현예로서, 상기 조성물은 MDH1 (malate dehydrogenases 1) 및/또는 MDH2 (malate dehydrogenases 2)의 활성을 저해시킬 수 있다.In one embodiment of the present invention, the composition may inhibit the activity of malate dehydrogenases 1 (MDH1) and / or malate dehydrogenases 2 (MDH2).
본 발명의 일 구현예로서, 상기 조성물은 MDH1 (malate dehydrogenases 1) 및 MDH2 (malate dehydrogenases 2)의 활성을 동시에 저해시킬 수 있다.In one embodiment of the invention, the composition may simultaneously inhibit the activity of MDH1 (malate dehydrogenases 1) and MDH2 (malate dehydrogenases 2).
본 발명은 상기 약학적 조성물을 개체에 투여하는 단계를 포함하는 암 예방 또는 치료방법을 제공한다.The present invention provides a method for preventing or treating cancer, comprising administering the pharmaceutical composition to a subject.
본 발명은 상기 화합물, 이의 이성질체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 조성물의 암 예방 또는 치료용도를 제공한다.The present invention provides a cancer prevention or treatment of the composition comprising the compound, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명은 MDH1 (malate dehydrogenases 1) 및/또는 MDH2 (malate dehydrogenases 2)의 억제 활성을 나타내는 화합물 및 이를 유효성분으로 포함하는, 암 예방 또는 치료용 약학적 조성물에 관한 것이다. 본 발명자들은 MDH1 및/또는 MDH2 억제 활성을 나타내는 화합물의 암세포 내 미토콘드리아 호흡 억제 효과 및 우수한 암세포 성장 억제 효과 등을 실험적으로 확인하였는바, 본 발명의 화합물은 암을 치료하기 위한 약학적 조성물로 유용하게 사용될 수 있을 것으로 기대된다.The present invention relates to a compound exhibiting inhibitory activity of MDH1 (malate dehydrogenases 1) and / or MDH2 (malate dehydrogenases 2) and a pharmaceutical composition for preventing or treating cancer, comprising the same as an active ingredient. The present inventors have experimentally confirmed the mitochondrial respiratory inhibitory effect and excellent cancer cell growth inhibitory effect in cancer cells of the compound showing MDH1 and / or MDH2 inhibitory activity, the compound of the present invention is useful as a pharmaceutical composition for treating cancer It is expected to be used.
도 1은 본 발명의 화합물 55종(화합물 3-1 내지 3-34, 화합물 6-1 내지 6-10 및 화합물 9-1 내지 9-11)의 합성 과정을 도식화한 것이다. 1 is a schematic diagram illustrating the synthesis of 55 compounds of the present invention (compounds 3-1 to 3-34, compounds 6-1 to 6-10 and compounds 9-1 to 9-11).
도 2는 본 발명에서 분리 및 정제한 과발현된 재조합 MDH2 단백질을 나타낸 것이다.Figure 2 shows the overexpressed recombinant MDH2 protein isolated and purified in the present invention.
도 3은 본 발명의 화합물의 NADH 농도 변화에 따른 MDH1 및 MDH2의 효소반응속도 (enzyme kinetics)를 측정한 결과이다.Figure 3 is the result of measuring the enzyme kinetics (enzyme kinetics) of MDH1 and MDH2 according to the change of NADH concentration of the compound of the present invention.
도 4는 본 발명의 화합물의 HIF-1α 억제 활성을 면역블롯분석 (immunoblot analysis)을 이용하여 확인한 결과이다.4 is a result of confirming the HIF-1α inhibitory activity of the compounds of the present invention using immunoblot analysis (immunoblot analysis).
도 5는 본 발명의 화합물의 암세포 내 미토콘드리아의 산소 소비율 (OCR)을 측정한 결과이다.5 is a result of measuring the oxygen consumption rate (OCR) of mitochondria in cancer cells of the compound of the present invention.
도 6은 본 발명의 화합물의 미토콘드리아의 산소 소비율 억제에 의한 세포 내 산소 농도 증가를 산소 감응 형광 프로브를 이용하여 확인한 결과이다.6 is a result of confirming the increase in the oxygen concentration in the cell by inhibiting the oxygen consumption rate of the mitochondria of the compound of the present invention using an oxygen-sensitive fluorescent probe.
도 7a 및 도 7b는 본 발명의 화합물을 투여한 후 종양의 크기 또는 부피가 감소한 것을 확인한 결과이다.Figures 7a and 7b is a result of confirming that the tumor size or volume after administration of the compound of the present invention.
도 7c는 본 발명의 화합물을 투여한 후 종양의 무게가 감소한 것을 확인한 결과이다.Figure 7c is a result confirming that the weight of the tumor after administration of the compound of the present invention.
본 발명자들은, 실시예에서 제조한 화합물을 처리한 경우, MDH1/2 발현 억제 활성을 나타낸다는 점에 기반하여 본 발명의 화합물의 HIF-1α 발현 억제 활성, 암세포 내 미토콘드리아 호흡 억제 효과 및 우수한 암세포 성장 억제 효과 등을 구체적으로 확인하고, 이에 기초하여 본 발명을 완성하였다.The present inventors, when treated with the compound prepared in Example, exhibits the inhibitory activity of MDH1 / 2 expression, HIF-1α expression inhibitory activity, mitochondrial respiratory inhibitory effect in cancer cells and excellent cancer cell growth The inhibitory effect etc. were confirmed specifically, and this invention was completed based on this.
이하 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.
본 발명은 하기 화학식 1로 표시되는 화합물, 이의 이성질체 또는 이의 약학적 허용가능한 염을 제공한다.The present invention provides a compound represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof.
[화학식 1][Formula 1]
이 때, 상기 화학식 1에 있어서,At this time, in the formula (1),
X는 메틸렌기, 에테인기, 에틸렌기, n-프로필렌기 또는 아이소프로필렌이고;X is methylene group, ethane group, ethylene group, n -propylene group or isopropylene;
R1은 니트로기, 트리플루오로메틸기, C1-C20 알킬 또는 C1-C20 사이클로알킬이고; 및R 1 is a nitro group, trifluoromethyl group, C 1 -C 20 alkyl or C 1 -C 20 cycloalkyl; And
상기 R3는 메틸 또는 2-프로핀일이고; 및R 3 is methyl or 2-propynyl; And
상기 R4는 메틸, 수소, 하이드록시, 메톡시, 2-프로핀일, , , , , , 또는 일 수 있다. R 4 is methyl, hydrogen, hydroxy, methoxy, 2-propynyl, , , , , , or Can be.
상기 R6는 메틸 또는 하이드록시일 수 있다. R 6 may be methyl or hydroxy.
상기 R7는 C 또는 N일 수 있다. R 7 may be C or N.
더욱 바람직하게는, 상기 화학식 1에 있어서, 상기 R1은 아다만틸, tert-부틸, 펜틸, 사이클로펜틸, 사이클로헥실, 또는 2,4,4-트리메틸펜테인-2-일이다.More preferably, in Formula 1, R 1 is adamantyl, tert -butyl, pentyl, cyclopentyl, cyclohexyl, or 2,4,4-trimethylpentin-2-yl.
더욱 바람직하게는, 상기 화학식 1에 있어서, 상기 R1은 아다만틸이고;More preferably, in Chemical Formula 1, R 1 is adamantyl;
X는 메틸렌기, 에테인기, 에틸렌기, n-프로필렌기 또는 아이소프로필렌이고; 및 X is methylene group, ethane group, ethylene group, n -propylene group or isopropylene; And
상기 R3는 메틸일 수 있다. R 3 may be methyl.
더욱 바람직하게는, 본 화합물은 하기 화학식 2로 표시되는 화합물일 수 있다.More preferably, the compound may be a compound represented by the following formula (2).
[화학식 2][Formula 2]
이 때, 상기 화학식 2에 있어서,At this time, in the formula (2),
상기 R1은 아다만틸 또는 tert-부틸이고; 및 R 1 is adamantyl or tert -butyl; And
상기 R3는 메틸 또는 2-프로핀일이고; R 3 is methyl or 2-propynyl;
상기 R4는 메틸, 수소 또는 하이드록시이고; R 4 is methyl, hydrogen or hydroxy;
상기 R6는 메틸 또는 하이드록시이고; 및R 6 is methyl or hydroxy; And
상기 R7는 C 또는 N이다.R 7 is C or N.
더욱 바람직하게는, 본 화합물은 하기 화학식 3으로 표시되는 화합물일 수 있다. More preferably, the compound may be a compound represented by the following formula (3).
[화학식 3][Formula 3]
이 때, 화학식 3에 있어서,At this time, in the formula (3),
상기 R1은 니트로기, 트리플루오로메틸기, 아다만틸, tert-부틸, 펜틸, 사이클로펜틸, 사이클로헥실, 또는 2,4,4-트리메틸펜테인-2-일이고;R 1 is a nitro group, trifluoromethyl group, adamantyl, tert -butyl, pentyl, cyclopentyl, cyclohexyl, or 2,4,4-trimethylpentin-2-yl;
상기 R3는 메틸 또는 2-프로핀일이고; 및R 3 is methyl or 2-propynyl; And
상기 R4는 메틸, 수소, 하이드록시, 메톡시, 2-프로핀일, , , , , , 또는 일 수 있다. R 4 is methyl, hydrogen, hydroxy, methoxy, 2-propynyl, , , , , , or Can be.
다음은 본 발명에 따른 화합물들을 제조하는 여러 가지 치환기의 정의를 설명한다.The following describes the definition of the various substituents for preparing the compounds according to the invention.
본 발명에서 사용된 용어 "C1-C20 알킬"은 탄소원자수 1 내지 20의 1가 알킬기를 의미한다. 이 용어는 메틸, 에틸, n-프로필, i-프로필, n-부틸, i-부틸, tert-부틸, n-헥실 등과 같은 기능기를 예로 들 수 있다.The term "C 1 -C 20 alkyl" as used herein refers to a monovalent alkyl group having 1 to 20 carbon atoms. The term is exemplified by functional groups such as methyl, ethyl, n -propyl, i -propyl, n -butyl, i -butyl, tert -butyl, n -hexyl and the like.
본 발명에서 사용된 용어 "C1-C20 사이클로알킬"은 단일 고리(예를 들면 시이클로헥실) 또는 다중 축합 고리(예를 들면 노보닐)을 갖는 포화 탄화수소고리화합물을 의미하며, 사이클로펜틸, 사이클로헥실, 노보닐, 아다만테인 등을 포함한다.As used herein, the term “C 1 -C 20 cycloalkyl” refers to a saturated hydrocarbon ring compound having a single ring (eg cyclohexyl) or multiple condensed ring (eg norbornyl), cyclopentyl, Cyclohexyl, norbornyl, adamantane and the like.
본 발명에서 사용된 용어 "메틸렌기"는 -(CH2)- 형태의 결합을 의미하며, 본 발명의 화학식 1에서 상기 X에 탄소 1개가 결합 될 때의 형태를 의미한다. 상기 n은 1 또는 2이다. The term "methylene group" used in the present invention means a bond in the form of-(CH 2 )-, and means a form when one carbon is bonded to X in the general formula (1) of the present invention. N is 1 or 2.
본 발명에서 사용된 용어 "에테인기"는 -(C2H4)- 형태의 결합을 의미하며, 본 발명의 화학식 1에서 상기 X에 탄소 2개가 결합 될 때의 형태를 의미한다. The term "ethane group" used in the present invention means a bond in the form of-(C 2 H 4 )-, and refers to a form when two carbons are bonded to X in Formula 1 of the present invention.
본 발명에서 사용된 용어 "에틸렌기"는 -(C2H2)- 형태의 결합을 의미하며, 본 발명의 화학식 1에서 상기 X에 탄소 2개가 결합 될 때의 형태를 의미한다.The term "ethylene group" used in the present invention means a bond in the form of-(C 2 H 2 )-, and means the form when two carbons are bonded to X in the general formula (1) of the present invention.
본 발명에서 사용된 용어 "n-프로필렌기"는 -(C3H6)- 형태의 결합을 의미하며, 본 발명의 화학식 1에서 상기 X에 탄소 3개가 직쇄 형태로 결합될 때의 형태를 의미한다.The term " n -propylene group" used in the present invention means a bond in the form of-(C 3 H 6 )-, and in the formula (1) of the present invention means a form when three carbons are bonded to the X in a straight chain form. do.
본 발명에서 사용된 용어 "아이소프로필렌기"는 -(C3H6)- 형태의 결합을 의미하며, 본 발명의 화학식 1에서 상기 X에 탄소 3개가 분쇄 또는 측쇄 형태로 결합될 때의 형태를 의미한다.As used herein, the term "isopropylene group" refers to a bond in the form of-(C 3 H 6 )-, wherein in the formula (1) of the present invention, when X is combined with three carbons in a crushed or branched form, it means.
본 발명에서 사용된 용어 "2-프로핀일"은 -CH2C≡CH를 의미하며, 말단에 삼중결합으로 결합된 불포화 탄소를 포함하는, 3개의 탄소원자의 선형 탄화수소기를 의미한다.As used herein, the term "2-propynyl" refers to -CH 2 C≡CH, and means a linear hydrocarbon group of three carbon atoms, including unsaturated carbon bonded to the triple bond at the end.
본 발명에 기재된 알킬 및 그 외 알킬부분을 포함하는 치환체는 직쇄 또는 분쇄 형태를 모두 포함한다.Substituents comprising alkyl and other alkyl moieties described in the present invention include both straight and pulverized forms.
본 발명에 따른 상기 화학식 1로 표시되는 화합물의 바람직한 예는 하기와 같다:Preferred examples of the compound represented by Formula 1 according to the present invention are as follows:
(1) 메틸 3-(2-(4-니트로페녹시)아세트아미도)벤조네이트(Methyl 3-(2-(4-nitrophenoxy)acetamido)benzoate);(1) Methyl 3- (2- (4-nitrophenoxy) acetamido) benzoate (Methyl 3- (2- (4-nitrophenoxy) acetamido) benzoate);
(2) 메틸 3-(2-(4-트리플루오로메틸)페녹시)아세트아미도)벤조에이트(Methyl 3-(2-(4-(trifluoromethyl)phenoxy)acetamido)benzoate);(2) methyl 3- (2- (4-trifluoromethyl) phenoxy) acetamido) benzoate (Methyl 3- (2- (4- (trifluoromethyl) phenoxy) acetamido) benzoate);
(3) 메틸 3-(2-(4-tert-부틸페녹시)아세트아미도)벤조에이트 (Methyl 3-(2-(4-tert-butylphenoxy)acetamido)benzoate) ;(3) methyl 3- (2- (4-tert-butylphenoxy) acetamido) benzoate (Methyl 3- (2- (4-tert-butylphenoxy) acetamido) benzoate);
(4) 메틸 3-(2-(p-톨리록시)아세트아미도)벤조에이트(Methyl 3-(2-(p-tolyloxy)acetamido)benzoate);(4) Methyl 3- (2- (p-tolyloxy) acetamido) benzoate (Methyl 3- (2- (p-tolyloxy) acetamido) benzoate);
(5) 메틸 3-(2-(4-에틸페녹시)아세트아미도)벤조에이트 (Methyl 3-(2-(4-ethylphenoxy)acetamido)benzoate) ;(5) methyl 3- (2- (4-ethylphenoxy) acetamido) benzoate (Methyl 3- (2- (4-ethylphenoxy) acetamido) benzoate);
(6) 메틸 3-(2-(4-프로필페녹시)아세트아미도)벤조에이트 (Methyl 3-(2-(4-propylphenoxy)acetamido)benzoate);(6) methyl 3- (2- (4-propylphenoxy) acetamido) benzoate (Methyl 3- (2- (4-propylphenoxy) acetamido) benzoate);
(7) 메틸 3-(2-(4-부틸 페녹시)아세트아미도)벤조에이트;(7) methyl 3- (2- (4-butyl phenoxy) acetamido) benzoate;
(8) 메틸 3-(2-(4-펜틸페녹시)아세트아미도)벤조에이트 (Methyl 3-(2-(4-pentylphenoxy)acetamido)benzoate) ;(8) methyl 3- (2- (4-pentylphenoxy) acetamido) benzoate (Methyl 3- (2- (4-pentylphenoxy) acetamido) benzoate);
(9) 메틸 3-(2-(4-사이클로펜틸페녹시)아세트아미도)벤조에이트 (Methyl 3-(2-(4-cyclopentylphenoxy)acetamido)benzoate) ;(9) methyl 3- (2- (4-cyclopentylphenoxy) acetamido) benzoate (Methyl 3- (2- (4-cyclopentylphenoxy) acetamido) benzoate);
(10) 메틸 3-(2-(4-사이클로헥실페녹시)아세트아미도)벤조에이트 (Methyl 3-(2-(4-cyclohexylphenoxy)acetamido)benzoate);(10) methyl 3- (2- (4-cyclohexylphenoxy) acetamido) benzoate (Methyl 3- (2- (4-cyclohexylphenoxy) acetamido) benzoate);
(11) 메틸 3-(2-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)아세트아미도)벤조에이트 (Methyl 3-(2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acetamido)benzoate);(11) Methyl 3- (2- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) acetamido) benzoate (Methyl 3- (2- (4- (2,4) , 4-trimethylpentan-2-yl) phenoxy) acetamido) benzoate);
(12) 메틸 4-하이드록시-3-(2-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)아세트아미도)벤조에이트 (Methyl 4-hydroxy-3-(2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acetamido)benzoate); (12) Methyl 4-hydroxy-3- (2- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) acetamido) benzoate (Methyl 4-hydroxy-3- ( 2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamido) benzoate);
(13) N-(4-(트리플루오로메틸)페닐)-2-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)아세트아마이드 (N-(4-(trifluoromethyl)phenyl)-2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acetamide) ;(13) N- (4- (trifluoromethyl) phenyl) -2- (4- (2,4,4-trimethylpentin-2-yl) phenoxy) acetamide (N- (4- (trifluoromethyl ) phenyl) -2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamide);
(14) N-(4-(4-메틸피페라진-1-일)페닐)-2-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)아세트아마이드 (N-(4-(4-methylpiperazin-1-yl)phenyl)-2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acetamide);(14) N- (4- (4-methylpiperazin-1-yl) phenyl) -2- (4- (2,4,4-trimethylpentin-2-yl) phenoxy) acetamide (N- (4- (4-methylpiperazin-1-yl) phenyl) -2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamide);
(15) 1-(4-(4-(트리플루오로메틸)벤질)피페라진-1-일)-2-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)에탄온 (1-(4-(4-(trifluoromethyl)benzyl)piperazin-1-yl)-2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)ethanone) ;(15) 1- (4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) -2- (4- (2,4,4-trimethylpentane-2-yl) phenoxy) Ethanone (1- (4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) -2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) ethanone);
(16) 1-(4-(프로프-2-인일)피페라진-1-일)-2-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)에탄온 (1-(4-(prop-2-ynyl)piperazin-1-yl)-2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)ethanone);(16) 1- (4- (prop-2-ynyl) piperazin-1-yl) -2- (4- (2,4,4-trimethylpentane-2-yl) phenoxy) ethanone ( 1- (4- (prop-2-ynyl) piperazin-1-yl) -2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) ethanone);
(17) 프로프-2-인일 4-하이드록시-3-(2-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)아세트아미도)벤조에이트 (Prop-2-ynyl 4-hydroxy-3-(2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acetamido)benzoate);(17) Prop-2-ynyl 4-hydroxy-3- (2- (4- (2,4,4-trimethylpentane-2-yl) phenoxy) acetamido) benzoate (Prop-2 -ynyl 4-hydroxy-3- (2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamido) benzoate);
(18) N-(3-하이드록시-아다만테인-1-일)-2-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)아세트아마이드 (N-(3-hydroxy-adamantan-1-yl)-2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acetamide) ;(18) N- (3-hydroxy-adamantane-1-yl) -2- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) acetamide (N- (3 -hydroxy-adamantan-1-yl) -2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamide);
(19) 메틸 3-(2-(4-아다만테인-1-일-페녹시)아세트아미도)벤조에이트 (Methyl 3-(2-(4-adamantan-1-yl-phenoxy)acetamido)benzoate) ;(19) Methyl 3- (2- (4-adamantane-1-yl-phenoxy) acetamido) benzoate (Methyl 3- (2- (4-adamantan-1-yl-phenoxy) acetamido) benzoate );
(20) 메틸 3-(2-(4-아다만테인-1-일-페녹시)아세트아미도 4-하이드록시벤조에이트(Methyl 3-(2-(4-adamantan-1-yl-phenoxy)acetamido)-4-hydroxybenzoate);(20) Methyl 3- (2- (4-adamantane-1-yl-phenoxy) acetamido 4-hydroxybenzoate (Methyl 3- (2- (4-adamantan-1-yl-phenoxy) acetamido) -4-hydroxybenzoate);
(21) 메틸 3-(2-(4-아다만테인-1-일-페녹시)아세트아미도)-4-(2-에톡시-2-옥소에톡시)벤조에이트(Methyl 3-(2-(4-adamantan-1-yl-phenoxy)acetamido)-4-(2-ethoxy-2-oxoethoxy)benzoate) ;(21) Methyl 3- (2- (4-adamantane-1-yl-phenoxy) acetamido) -4- (2-ethoxy-2-oxoethoxy) benzoate (Methyl 3- (2 -(4-adamantan-1-yl-phenoxy) acetamido) -4- (2-ethoxy-2-oxoethoxy) benzoate);
(22) 메틸 3-(2-(4-아다만테인-1-일-페녹시)아세트아미도)-4-(2-(피롤리딘-1-일)에톡시)벤조에이트 (Methyl 3-(2-(4-adamantan-1-yl-phenoxy)acetamido)-4-(2-(pyrrolidin-1-yl)ethoxy)benzoate);(22) Methyl 3- (2- (4-adamantane-1-yl-phenoxy) acetamido) -4- (2- (pyrrolidin-1-yl) ethoxy) benzoate (Methyl 3 -(2- (4-adamantan-1-yl-phenoxy) acetamido) -4- (2- (pyrrolidin-1-yl) ethoxy) benzoate);
(23) 메틸 3-(2-(4-아다만테인-1-일-페녹시)아세트아미도)-4-(3-모르폴리노프로폭시)벤조에이트 (Methyl 3-(2-(4-adamantan-1-yl-phenoxy)acetamido)-4-(3-morpholinopropoxy)benzoate);(23) Methyl 3- (2- (4-adamantane-1-yl-phenoxy) acetamido) -4- (3-morpholinopropoxy) benzoate (Methyl 3- (2- (4 -adamantan-1-yl-phenoxy) acetamido) -4- (3-morpholinopropoxy) benzoate);
(24) 메틸 4-메톡시-3-(2-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)아세트아미도)벤조에이트 (Methyl 4-methoxy-3-(2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acetamido)benzoate); (24) Methyl 4-methoxy-3- (2- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) acetamido) benzoate (Methyl 4-methoxy-3- ( 2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamido) benzoate);
(25) 메틸 4-(2-메톡시에톡시)-3-(2-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)아세트아미도)벤조에이트 (Methyl 4-(2-methoxyethoxy)-3-(2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acetamido)benzoate); (25) Methyl 4- (2-methoxyethoxy) -3- (2- (4- (2,4,4-trimethylpentane-2-yl) phenoxy) acetamido) benzoate (Methyl 4 -(2-methoxyethoxy) -3- (2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamido) benzoate);
(26) 메틸 4-(2-모르폴리노에톡시)-3-(2-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)아세트아미도)벤조에이트 (Methyl 4-(2-morpholinoethoxy)-3-(2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acetamido)benzoate);(26) Methyl 4- (2-morpholinoethoxy) -3- (2- (4- (2,4,4-trimethylpentane-2-yl) phenoxy) acetamido) benzoate (Methyl 4- (2-morpholinoethoxy) -3- (2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamido) benzoate);
(27) 메틸 4-(프로프-2-인일옥시)-3-(2-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)아세트아미도)벤조에이트 (Methyl 4-(prop-2-ynyloxy)-3-(2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acetamido)benzoate) ;(27) Methyl 4- (prop-2-ynyloxy) -3- (2- (4- (2,4,4-trimethylpentane-2-yl) phenoxy) acetamido) benzoate (Methyl 4- (prop-2-ynyloxy) -3- (2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamido) benzoate);
(28) 메틸 4-(4-메톡시벤질옥시)-3-(2-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)아세트아미도)벤조에이트 (Methyl 4-(4-methoxybenzyloxy)-3-(2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acetamido)benzoate) ;(28) Methyl 4- (4-methoxybenzyloxy) -3- (2- (4- (2,4,4-trimethylpentane-2-yl) phenoxy) acetamido) benzoate (Methyl 4 -(4-methoxybenzyloxy) -3- (2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamido) benzoate);
(29) 메틸 3-(2-(4-아다만테인-1-일-페녹시)-2-메틸프로판아미도)벤조에이트 (Methyl 3-(2-(4-adamantan-1-yl-phenoxy)-2-methylpropanamido)benzoate) ;(29) Methyl 3- (2- (4-adamantane-1-yl-phenoxy) -2-methylpropaneamido) benzoate (Methyl 3- (2- (4-adamantan-1-yl-phenoxy ) -2-methylpropanamido) benzoate);
(30) 메틸 3-(2-메틸-2-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)프로판아미도)벤조에이트 (Methyl 3-(2-methyl-2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)propanamido)benzoate) ;(30) Methyl 3- (2-methyl-2- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) propaneamido) benzoate (Methyl 3- (2-methyl-2 -(4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamido) benzoate);
(31) 메틸- 4-하이드록시-3-(2-메틸-2-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)프로판아미도)벤조에이트(Methyl 4-hydroxy-3-(2-methyl-2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)propanamido)benzoate) ;(31) Methyl-4-hydroxy-3- (2-methyl-2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) benzoate (Methyl 4-hydroxy -3- (2-methyl-2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamido) benzoate);
(32) 메틸 3-[4-(4-아다만테인-1-일-페녹시)부탄아미도]벤조에이트 (Methyl 3-[4-(4-adamantan-1-yl-phenoxy)butanamido]benzoate) ;(32) Methyl 3- [4- (4-adamantane-1-yl-phenoxy) butanamido] benzoate (Methyl 3- [4- (4-adamantan-1-yl-phenoxy) butanamido] benzoate );
(33) 메틸 3-(4-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)부탄아미도)벤조에이트 (Methyl 3-(4-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)butanamido)benzoate) ;(33) Methyl 3- (4- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) butanamido) benzoate (Methyl 3- (4- (4- (2,4) , 4-trimethylpentan-2-yl) phenoxy) butanamido) benzoate);
(34) 메틸 4-하이드록시-3-(4-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)부탄아미도)벤조에이트 (Methyl 4-hydroxy-3-(4-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)butanamido)benzoate); (34) Methyl 4-hydroxy-3- (4- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) butanamido) benzoate (Methyl 4-hydroxy-3- ( 4- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) butanamido) benzoate);
(35) (E)-3-[3-(4-아다만테인-1-일-페녹시)-아크릴오일아미노]-벤조익 산 메틸 에스테르((E)-3-[3-(4-Adamantan-1-yl-phenoxy)-acryloylamino]-benzoic acid methyl ester);(35) (E) -3- [3- (4-adamantane-1-yl-phenoxy) -acryloylamino] -benzoic acid methyl ester ((E) -3- [3- (4- Adamantan-1-yl-phenoxy) -acryloylamino] -benzoic acid methyl ester);
(36) (E)-3-{3-[4-(2,4,4-트리메틸펜탄-2-일)페녹시]아크릴아미도}벤조익 산 메틸 에스테르((E)-3-{3-[4-(2,4,4-Trimethylpentan-2-yl)phenoxy]acrylamido}benzoic acid methyl ester) ;(36) (E) -3- {3- [4- (2,4,4-trimethylpentan-2-yl) phenoxy] acrylamido} benzoic acid methyl ester ((E) -3- {3 -[4- (2,4,4-Trimethylpentan-2-yl) phenoxy] acrylamido} benzoic acid methyl ester);
(37) (E)-메틸4-메틸-3-(3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)아크릴아미도)벤조에이트((E)-methyl 4-methyl-3-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acrylamido)benzoate) ;(37) (E) -methyl4-methyl-3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate ((E) -methyl 4 -methyl-3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate);
(38) (E)-메틸2-메틸-5-(3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)아크릴아미도)벤조에이트((E)-methyl 2-methyl-5-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acrylamido)benzoate) ;(38) (E) -methyl2-methyl-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate ((E) -methyl 2 -methyl-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate);
(39) (E)-메틸2-하이드록시-5-(3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)아크릴아미도)벤조에이트((E)-methyl 2-hydroxy-5-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acrylamido)benzoate) ;(39) (E) -methyl2-hydroxy-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate ((E) -methyl 2-hydroxy-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate);
(40) (E)-이소프로필 3-(3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)아크릴아미도)벤조에이트((E)-isopropyl 3-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acrylamido)benzoate);(40) (E) -isopropyl 3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate ((E) -isopropyl 3- (3 -(4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate);
(41) (E)-메틸 2,4-다이메틸-5-(3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)아크릴아미도)벤조에이트((E)-methyl 2,4-dimethyl-5-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acrylamido)benzoate); (41) (E) -methyl 2,4-dimethyl-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate ((E) -methyl 2,4-dimethyl-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate);
(42) (E)-3H-[1,2,3]트리아졸로[4,5-b]피리딘-3-일 3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)아크릴레이트((E)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl 3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acrylate) ;(42) (E) -3H- [1,2,3] triazolo [4,5-b] pyridin-3-yl 3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy Acrylate ((E) -3H- [1,2,3] triazolo [4,5-b] pyridin-3-yl 3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy ) acrylate);
(43) (E)-1H-벤조[d][1,2,3]트리아졸-1-일 3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)아크릴레이트((E)-1H-benzo[d][1,2,3]triazol-1-yl 3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acrylate) ;(43) (E) -1H-benzo [d] [1,2,3] triazol-1-yl 3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylate ((E) -1H-benzo [d] [1,2,3] triazol-1-yl 3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylate);
(44) (E)-메틸 4-하이드록시-3-(3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)아크릴아미도)벤조에이트((E)-methyl 4-hydroxy-3-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acrylamido)benzoate);(44) (E) -methyl 4-hydroxy-3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate ((E) -methyl 4-hydroxy-3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate);
(45) 메틸 3-[3-(4-아다만테인-1-일-페녹시)프로판아미도]벤조에이트 (Methyl 3-(3-(4-(adamantan-1-yl)phenoxy)propanamido)benzoate);(45) Methyl 3- [3- (4-adamantane-1-yl-phenoxy) propanamido] benzoate (Methyl 3- (3- (4- (adamantan-1-yl) phenoxy) propanamido) benzoate);
(46) 메틸 3-(3-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)프로판아미도)벤조에이트 (Methyl 3-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)propanamido)benzoate) ;(46) Methyl 3- (3- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) propaneamido) benzoate (Methyl 3- (3- (4- (2,4) , 4-trimethylpentan-2-yl) phenoxy) propanamido) benzoate);
(47) 메틸 4-하이드록시-3-(3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)프로판아미도)벤조에이트(Methyl 4-hydroxy-3-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)propanamido)benzoate) ;(47) Methyl 4-hydroxy-3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) benzoate (Methyl 4-hydroxy-3- (3 -(4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamido) benzoate);
(48)메틸 4-메틸-3-(3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)프로판아미도)벤조에이트(Methyl 4-methyl-3-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)propanamido)benzoate) ;(48) methyl 4-methyl-3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) benzoate (Methyl 4-methyl-3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamido) benzoate);
(49) 메틸 2-메틸-5-(3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)프로판아미도)벤조에이트(Methyl 2-methyl-5-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)propanamido)benzoate) ;(49) Methyl 2-methyl-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) benzoate (Methyl 2-methyl-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamido) benzoate);
(50)메틸 2-하이드록시-5-(3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)프로판아미도)벤조에이트(Methyl 2-hydroxy-5-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)propanamido)benzoate) ;(50) Methyl 2-hydroxy-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) benzoate (Methyl 2-hydroxy-5- (3 -(4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamido) benzoate);
(51) 이소프로필 3-(3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)프로판아미도)벤조에이트(Isopropyl 3-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)propanamido)benzoate);(51) Isopropyl 3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) benzoate (Isopropyl 3- (3- (4- (2,4 , 4-trimethylpentan-2-yl) phenoxy) propanamido) benzoate);
(52) 메틸 5-(3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)프로판아미도)니코티네이트; (Methyl 5-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)propanamido)nicotinate) (52) methyl 5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) nicotinate; (Methyl 5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamido) nicotinate)
(53) N-(3-(모르폴린-4-카보닐)페닐)-3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)프로판아마이드(N-(3-(Morpholine-4-carbonyl)phenyl)-3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)propanamide) ;(53) N- (3- (morpholin-4-carbonyl) phenyl) -3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamide (N- (3- (Morpholine-4-carbonyl) phenyl) -3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamide);
(54) 에틸 2-(3-(3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)프로판아미도)벤즈아미도)아세테이트(Ethyl 2-(3-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)propanamido)benzamido)acetate) ; 또는(54) ethyl 2- (3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) benzamido) acetate (Ethyl 2- (3- (3 -(4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamido) benzamido) acetate); or
(55) (S)-메틸 3-메틸-2-(3-(3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)프로판아미도)벤즈아미도)부타노에이트((S)-methyl 3-methyl-2-(3-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)propanamido)benzamido)butanoate).(55) (S) -methyl 3-methyl-2- (3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) benzamido) butano Ate ((S) -methyl 3-methyl-2- (3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamido) benzamido) butanoate).
본 발명에서 사용되는 "약학적으로 허용되는" 이라는 용어는 과도한 독성, 자극, 알러지 반응 또는 기타 문제점 또는 합병증 없이 이득/위험 비가 합리적이어서 대상체 (예: 인간)의 조직과 접촉하여 사용하기에 적합하며 건전한 의학적 판단의 범주 이내인 화합물 또는 조성물을 의미한다.As used herein, the term "pharmaceutically acceptable" is suitable for use in contact with the tissues of a subject (eg, a human being) because the benefit / risk ratio is reasonable without excessive toxicity, irritation, allergic reactions or other problems or complications. A compound or composition is within the scope of sound medical judgment.
본 발명에서 사용되는 용어 "염"은 약학적으로 허용 가능한 유리산(free acid)에 의해 형성된 산 부가염이 유용하다. 산 부가염은 염산, 질산, 인산, 황산, 브롬화수소산, 요드화수소산, 아질산 또는 아인산과 같은 무기산류와 지방족 모노 및 디카르복실레이트, 페닐-치환된 알카노에이트, 하이드록시 알카노에이트 및 알칸디오에이트, 방향족 산류, 지방족 및 방향족 설폰산류와 같은 무독성 유기산으로부터 얻는다. 이러한 약학적으로 무독한 염류로는 설페이트, 피로설페이트, 바이설페이트, 설파이트, 바이설파이트, 니트레이트, 포스페이트, 모노하이드로겐 포스페이트, 디하이드로겐 포스페이트, 메타포스페이트, 피로포스페이트 클로라이드, 브로마이드, 아이오다이드, 플루오라이드, 아세테이트, 프로피오네이트, 데카노에이트, 카프릴레이트, 아크릴레이트, 포메이트, 이소부티레이트, 카프레이트, 헵타노에이트, 프로피올레이트, 옥살레이트, 말로네이트, 석시네이트, 수베레이트, 세바케이트, 푸마레이트, 말리에이트, 부틴-1,4-디오에이트, 헥산-1,6-디오에이트, 벤조에이트, 클로로벤조에이트, 메틸벤조에이트, 디니트로 벤조에이트, 하이드록시벤조에이트, 메톡시벤조에이트, 프탈레이트, 테레프탈레이트, 벤젠설포네이트, 톨루엔설포네이트, 클로로벤젠설포네이트, 크실렌설포네이트, 페닐아세테이트, 페닐프로피오네이트, 페닐부티레이트, 시트레이트, 락테이트, β-하이드록시부티레이트, 글리콜레이트, 말레이트, 타트레이트, 메탄설포네이트, 프로판설포네이트, 나프탈렌-1-설포네이트, 나프탈렌-2-설포네이트 또는 만델레이트를 포함한다.As used herein, the term "salt" is useful for acid addition salts formed with pharmaceutically acceptable free acids. Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid and aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. Obtained from non-toxic organic acids such as dioates, aromatic acids, aliphatic and aromatic sulfonic acids. Such pharmaceutically nontoxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, and iodide. Id, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suverate , Sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate, meth Oxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesul Nate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1- Sulfonates, naphthalene-2-sulfonates or mandelate.
본 발명에 따른 산 부가염은 통상의 방법, 예를 들면, 본 발명의 상기 화학식 1로 표시되는 화합물을 과량의 산 수용액 중에 용해시키고, 이 염을 수혼화성 유기 용매, 예를 들면 메탄올, 에탄올, 아세톤 또는 아세토니트릴을 사용하여 침전시켜서 제조할 수 있다. 또한 이 혼합물에서 용매나 과량의 산을 증발시킨 후 건조시키거나 또는 석출된 염을 흡입 여과시켜 제조할 수도 있다.The acid addition salt according to the present invention is dissolved in a conventional method, for example, the compound represented by Formula 1 of the present invention in an excess of an aqueous acid solution, and the salt is mixed with a water miscible organic solvent such as methanol, ethanol, It can be prepared by precipitation with acetone or acetonitrile. It may also be prepared by evaporating the solvent or excess acid from the mixture and then drying or by suction filtration of the precipitated salt.
또한, 염기를 사용하여 약학적으로 허용 가능한 금속염을 만들 수도 있다. 알칼리 금속 또는 알칼리 토금속 염은 예를 들면, 화합물을 과량의 알칼리 금속 수산화물 또는 알칼리 토금속 수산화물 용액 중에 용해하고, 비용해 화합물 염을 여과하고, 여액을 증발, 건조시켜 얻는다. 이때, 금속염으로는 나트륨, 칼륨 또는 칼슘염을 제조하는 것이 제약상 적합하다. 이에 대응하는 은염은 알칼리 금속 또는 알칼리 토금속 염을 적당한 음염 (예, 질산은)과 반응시켜 얻는다.Bases can also be used to make pharmaceutically acceptable metal salts. Alkali metal or alkaline earth metal salts are obtained, for example, by dissolving the compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare sodium, potassium or calcium salt as the metal salt. The corresponding silver salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable negative salt (eg silver nitrate).
본 발명의 일실시예에서는 본 발명의 화학식 1에 따른 화합물을 제조하여 NMR 또는 Mass 스펙트럼으로 구조를 분석 및 확인하였다.(실시예 1 참조). In one embodiment of the present invention to prepare a compound according to the formula (1) of the present invention was analyzed and confirmed the structure by NMR or Mass spectrum (see Example 1).
또한, 본 발명의 다른 양태로서, 본 발명은 상기 화학식 1로 표시되는 화합물, 이들의 이성질체 또는 이들의 약학적으로 허용 가능한 염을 유효성분으로 포함하는, 암 예방 또는 치료용 약학적 조성물을 제공한다.In another aspect of the present invention, the present invention provides a pharmaceutical composition for preventing or treating cancer, comprising the compound represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. .
또한 본 발명의 조성물은 약학적 및 건강기능식품 조성물을 포함한다.In addition, the composition of the present invention includes a pharmaceutical and nutraceutical composition.
본 발명에서 사용되는 용어, "예방"이란 본 발명에 따른 약학적 조성물의 투여에 의해 암을 억제시키거나 발병을 지연시키는 모든 행위를 의미한다.As used herein, the term "prevention" means any action that inhibits cancer or delays the onset by administration of a pharmaceutical composition according to the invention.
본 발명에서 사용되는 용어, "치료"란 본 발명에 따른 약학적 조성물의 투여에 의해 암에 대한 증세가 호전되거나 이롭게 변경되는 모든 행위를 의미한다.As used herein, the term "treatment" means any action that improves or beneficially alters the symptoms of cancer by administration of a pharmaceutical composition according to the present invention.
본 발명의 조성물에 의한 예방, 치료 대상 질병인 "암"은 정상인 조직세포가 어떤 원인으로 무제한 증식하여 그 생체의 생활현상이나 주위의 조직상태 등에 관계없이 급속한 발육을 계속하는 질환으로 구분되며, "암"은 이형성, 과다형성, 고형 종양 및 조혈모세포 암을 포함하며, 이로 한정되지는 않으며, 당해 분야에 공지되어 있는 다양한 암 유형을 포함한다. 또 다른 암으로는 다음의 장기 또는 기관: 뇌, 심장, 폐, 위장, 대장, 비뇨생식관, 간, 뼈, 신경계, 부인과, 혈액, 피부, 유방 및 부신의 암을 포함할 수 있으나, 이로 한정되지는 않는다. 또 다른 유형의 암세포로는 신경교종 (신경초종(Schwannoma), 교모소포종, 성상세포종), 신경모세포종, 갈색세포종, 부신경절종, 뇌수막종, 부신피질암, 수모세포종, 횡문근육종, 신장암, 다양한 유형의 혈관암, 골모세포성 골암 (osteoblastic osteocarcinoma), 전립선암, 난소암, 자궁 근종, 침샘암, 맥락총암, 유방암, 췌장암, 결장암, 대장암 및 거대핵세포성 백혈병; 및, 악성 흑색종, 기저세포암, 편평세포암, 카포시 육종 (Karposi's sarcoma), 이형성 모반 (moles dysplastic nevi), 지방종, 혈관종, 피부섬유종, 켈로이드, 섬유육종 또는 혈관육종과 같은 육종, 및 흑색종을 포함한 피부암이 포함된다."Cancer", a disease to be prevented and treated by the composition of the present invention, is classified into a disease in which normal tissue cells proliferate unlimitedly for any cause and continue to develop rapidly regardless of the living phenomenon of the living body or the surrounding tissue state. Cancer "includes, but is not limited to, dysplasia, hyperplasia, solid tumors, and hematopoietic stem cell cancer, and includes various cancer types known in the art. Other cancers may include, but are not limited to, cancers of the following organs or organs: brain, heart, lung, stomach, large intestine, genitourinary tract, liver, bone, nervous system, gynecology, blood, skin, breast and adrenal gland. It doesn't work. Other types of cancer cells include glioma (Schwannoma, glioblastoma, astrocytoma), neuroblastoma, pheochromocytoma, adrenal ganglia, meningioma, adrenal cortex, medulloblastoma, rhabdomyosarcoma, kidney cancer, various types of cancer Vascular cancer, osteoblastic osteocarcinoma, prostate cancer, ovarian cancer, uterine myoma, salivary gland cancer, choroid plexus cancer, breast cancer, pancreatic cancer, colon cancer, colon cancer and megakaryocyte leukemia; And sarcomas, such as malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, moles dysplastic nevi, lipoma, hemangioma, cutaneous fibroma, keloid, fibrosarcoma or angiosarcoma, and melanoma Includes skin cancer, including.
또한, 본 발명의 암은 MDH1 및/또는 MDH2의 과발현에 기인한 질병일 수 있다. 보다 구체적으로, 본 발명의 MDH1 또는 MDH2는 서로 다른 MDH 유전자에 의해 생성되는 이소자임 (isoenzymes)으로서, MDH는 세포질과 미토콘드리아 매트릭스에 존재한다. 보다 구체적으로, MDH1 및 MDH2는 가역적으로 NAD/NADH 보조인자 (cofactor) 시스템을 사용하여 말릭산 (malate)과 옥살산 (oxaloacetate, OAA)을 전환시키는 역할을 한다. 세포질에 있는 MDH1은 옥살산을 말릭산으로 환원시켜 NADH를 NAD+로 산화시킨다. 말릭산-아스팔산 셔틀에서 말릭산은 미토콘드리아의 안으로 이동되고 mitochondrial MDH2에 의해 옥살산으로 다시 산화되고 NADH를 생성한다. 생성된 NADH는 전자전달계를 통해 ATP를 생성한다. 이 외에도, TCA cycle에 관련된 MDH2는 호흡을 통해 ATP 생성에 관여한다.In addition, the cancer of the present invention may be a disease due to overexpression of MDH1 and / or MDH2. More specifically, MDH1 or MDH2 of the present invention are isoenzymes produced by different MDH genes, where MDH is present in the cytoplasm and mitochondrial matrix. More specifically, MDH1 and MDH2 reversibly serve to convert malate and oxaloacetate (OAA) using a NAD / NADH cofactor system. MDH1 in the cytoplasm oxidizes NADH to NAD + by reducing oxalic acid to malic acid. In the malic acid-asphalic acid shuttle, malic acid is transported into the mitochondria and oxidized back to oxalic acid by mitochondrial MDH2 to produce NADH. The generated NADH generates ATP through an electron transport system. In addition, MDH2 involved in the TCA cycle is involved in ATP production through respiration.
따라서, 본 발명의 조성물은 MDH1 (malate dehydrogenases 1) 및/또는 MDH2 (malate dehydrogenases 2)의 활성을 저해할 수 있으며, 특히 MDH1 및 MDH2의 활성을 동시에 저해할 수 있다. Therefore, the composition of the present invention can inhibit the activity of MDH1 (malate dehydrogenases 1) and / or MDH2 (malate dehydrogenases 2), and in particular can inhibit the activity of MDH1 and MDH2 simultaneously.
본 발명에서 사용되는 용어, "저해"는 유전자의 전사, mRNA 프로세싱, 번역, 전좌 및 성숙 중 임의의 단계를 저해하거나, 단백질과 단백질간의 결합, 단백질의 활성화 또는 이를 통한 신호전달의 저해를 의미한다. As used herein, the term "inhibition" means inhibiting any step of transcription, mRNA processing, translation, translocation, and maturation of a gene, or inhibition of protein-to-protein binding, activation of a protein, or signaling through it. .
본 발명의 일 실시예에서는 본 발명의 제조방법에 따라 합성된 화합물 처리에 의한 MDH1 및 MDH2 억제 활성을 확인하였다 (실험예 1 참조). 또한, 본 발명의 화합물을 이용하여 MDH 억제 기전을 확인하였으며 (실험예 2 참조), 본 발명의 화합물을 이용하여 HIF-1α 억제 활성 효과를 확인하고 (실험예 3 참조), 암세포 내에서의 미토콘드리아 호흡 억제 효과를 확인하였으며 (실험예 4 참조), 암세포 이식 마우스 모델을 활용하여, 종양의 무게 및 크기가 감소한 효과를 구체적으로 확인하였는바 (실험예 5 참조) 암 예방 또는 치료의 약학적 조성물로 매우 유용하게 사용될 수 있음을 확인하였다.In one embodiment of the present invention, the inhibitory activity of MDH1 and MDH2 by the compound treatment synthesized according to the preparation method of the present invention was confirmed (see Experimental Example 1). In addition, MDH inhibition mechanism was confirmed using the compound of the present invention (see Experimental Example 2), HIF-1α inhibitory activity was confirmed using the compound of the present invention (see Experimental Example 3), and mitochondria in cancer cells. The respiratory inhibitory effect was confirmed (see Experimental Example 4), and cancer cell transplantation mouse model was used to specifically confirm the effect of reducing tumor weight and size (see Experimental Example 5) as a pharmaceutical composition for cancer prevention or treatment. It was confirmed that it can be used very usefully.
따라서 본 발명에 따른 상기 화학식 1로 표시되는 화합물, 이의 이성질체 또는 이의 약학적으로 허용 가능한 염은 이를 유효성분으로 포함하는 암의 예방, 개선 또는 치료용 약학적 조성물로 유용하게 사용될 수 있다.Therefore, the compound represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof according to the present invention may be usefully used as a pharmaceutical composition for preventing, ameliorating or treating cancer including the same as an active ingredient.
본 발명의 약학적 조성물은 유효성분 이외에 약제학적으로 허용되는 담체를 포함할 수 있다. 이때, 약제학적으로 허용되는 담체는 제제 시에 통상적으로 이용되는 것으로서, 락토스, 덱스트로스, 수크로스, 솔비톨, 만니톨, 전분, 아카시아고무, 인산 칼슘, 알기네이트, 젤라틴, 규산 칼슘, 미세 결정성셀룰로스, 폴리비닐피로리돈, 셀룰로스, 물, 시럽, 메틸 셀룰로스, 메틸히드록시벤조에이트, 프로필 히드록시벤조에이트, 활석, 스테아르산 마그네슘 및 미네랄 오일등을 포함하나, 이에 한정되는 것은 아니다. 또한, 상기 성분들 이외에 윤활제, 습윤제, 감미제, 향미제, 유화제, 현탁제, 보존제 등을 추가로 포함할 수 있다.The pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier in addition to the active ingredient. At this time, the pharmaceutically acceptable carrier is commonly used in the formulation, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose , Polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate and mineral oil, and the like. In addition to the above components, it may further include a lubricant, a humectant, a sweetener, a flavoring agent, an emulsifier, a suspending agent, a preservative, and the like.
본 발명의 약학적 조성물은 목적하는 방법에 따라 경구 투여하거나 비경구투여(예를 들어, 정맥 내, 피하, 복강 내 또는 국소에 적용)할 수 있으며, 투여량은 환자의 상태 및 체중, 질병의 정도, 약물형태, 투여경로 및 시간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다.The pharmaceutical compositions of the present invention can be administered orally or parenterally (eg, applied intravenously, subcutaneously, intraperitoneally or topically) according to the desired method, and the dosage is determined by the condition and weight of the patient, Depending on the extent, drug form, route of administration, and time, it may be appropriately selected by those skilled in the art.
본 발명의 약학적 조성물은 약학적으로 유효한 양으로 투여한다. 본 발명에 있어서 "약학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 유효용량 수준은 환자의 질환의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출비율, 치료기간, 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 얄려진 요소에 따라 결정될 수 있다. 본 발명에 다른 약학적 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고 종래의 치료제와는 순차적 또는 동시에 투여될 수 있으며, 단일 또는 다중 투여될 수 있다. 상기한 요소들을 모두 고려하여 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 이는 당업자에 의해 용이하게 결정될 수 있다.The pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount. As used herein, the term “pharmaceutically effective amount” means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level refers to the type of disease, the severity, the activity of the drug, It may be determined according to the sensitivity to the drug, the time of administration, the route of administration and the rate of release, the duration of treatment, factors including the drug used concurrently and other factors well known in the medical field. The pharmaceutical compositions according to the present invention may be administered as individual therapeutic agents or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be single or multiple administrations. Taking all of the above factors into consideration, it is important to administer an amount that can obtain the maximum effect in a minimum amount without side effects, which can be easily determined by those skilled in the art.
구체적으로 본 발명의 약학적 조성물의 유효량은 환자의 연령, 성별, 상태, 체중, 체내에 활성 성분의 흡수도, 불활성율 및 배설속도, 질병종류, 병용되는 약물에 따라 달라질 수 있으며, 일반적으로는 체중 1 ㎏ 당 0.001 내지 150 ㎎, 바람직하게는 0.01 내지 100 ㎎을 매일 또는 격일 투여하거나, 1일 1 내지 3회로 나누어 투여할 수 있다. 그러나 투여 경로, 비만의 중증도, 성별, 체중, 연령 등에 따라서 증감 될 수 있으므로 상기 투여량이 어떠한 방법으로도 본 발명의 범위를 한정하는 것은 아니다.Specifically, the effective amount of the pharmaceutical composition of the present invention may vary depending on the age, sex, condition, weight of the patient, the absorption of the active ingredient in the body, the inactivation rate and excretion rate, the type of disease, the drug used in general 0.001 to 150 mg, preferably 0.01 to 100 mg per kg of body weight may be administered daily or every other day, or divided into 1 to 3 times a day. However, since 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.
또한, 본 발명은 상기 약학적 조성물을 개체에 투여하는 단계를 포함하는 암의 예방, 조절 또는 치료방법을 제공한다. 본 발명에서 "개체"란 질병의 치료를 필요로 하는 대상을 의미하고, 보다 구체적으로는, 인간 또는 비-인간인 영장류, 생쥐(mouse), 개, 고양이, 말 및 소 등의 포유류를 의미한다.The present invention also provides a method for preventing, controlling or treating cancer comprising administering the pharmaceutical composition to a subject. As used herein, "individual" means a subject in need of treatment for a disease, and more specifically, a mammal, such as a primate, mouse, dog, cat, horse and cow, which is human or non-human. .
이하, 본 발명의 이해를 돕기 위하여 바람직한 실시예를 제시한다. 그러나 하기의 실시예는 본 발명을 보다 쉽게 이해하기 위하여 제공되는 것일 뿐, 하기 실시예에 의해 본 발명의 내용이 한정되는 것은 아니다.Hereinafter, preferred examples are provided to aid in understanding the present invention. However, the following examples are merely provided to more easily understand the present invention, and the contents of the present invention are not limited by the following examples.
[실시예]EXAMPLE
실시예Example
1. One.
MDH1MDH1
및 And
MDH2MDH2
저해 활성을 갖는 화합물의 합성 Synthesis of Compounds with Inhibitory Activity
본 발명에 따른 MDH 억제제로서, 약학적 조성물의 유효성분으로 사용되는 비-한정적인 화합물의 예는 하기의 화합물, 이의 이성질체 및 이의 약학적으로 허용 가능한 염을 포함한다. 공지된 방법의 반응물 및/또는 출발물질을 적절히 변경하여, 본 발명에 따른 하기 화합물들을 합성하였다. As the MDH inhibitor according to the present invention, examples of the non-limiting compound used as an active ingredient of the pharmaceutical composition include the following compounds, isomers thereof and pharmaceutically acceptable salts thereof. The reactants and / or starting materials of known methods were appropriately modified to synthesize the following compounds according to the present invention.
먼저, 본 발명에 따른 하기 화합물들의 합성 공정은 도 1에 기재된 바와 같고, 각 공정에 사용된 시약 및 조건은 하기에 기재하였다. First, the synthesis process of the following compounds according to the present invention is as described in Figure 1, the reagents and conditions used in each process is described below.
시약 및 조건: a)(i) K2CO3, 메틸-4-브로모부타노에이트(methyl 4-bromobutanoate) 또는 메틸-2-브로모-2-메틸프로파노에이트(Methyl 2-bromo-2-methylpropanoate), DMF; (ii) LiOH, THF/H2O; b)EDC·HCl, HOBT, DIPEA, DMF, NH2-R2; c)PPh3, Methylpropiolate, Toluene; d,g)LiOH, THF/H2O; e)EDC·HCl, HOBT, DIPEA, DMF, NH2-R2 또는 HATU, DIPEA, DMF, NH2-R2; f)Pd/C, H2, MeOH; h)EDC·HCl, HOBT, DIPEA, DMF, NH2-R2 또는 HATU, DIPEA, DMF/THF, NH2-R2 또는 i)CDI, THF; ii)NH2-R2, imidazole, THF.Reagents and conditions: a) (i) K 2 CO 3 , methyl-4-bromobutanoate or methyl-2-bromo-2-methylpropanoate (Methyl 2-bromo-2 -methylpropanoate), DMF; (ii) LiOH, THF / H 2 O; b) EDC.HCl, HOBT, DIPEA, DMF, NH 2 -R 2 ; c) PPh 3 , Methylpropiolate, Toluene; d, g) LiOH, THF / H 2 O; e) EDC.HCl, HOBT, DIPEA, DMF, NH 2 -R 2 or HATU, DIPEA, DMF, NH 2 -R 2 ; f) Pd / C, H 2 , MeOH; h) EDC.HCl, HOBT, DIPEA, DMF, NH 2 -R 2 or HATU, DIPEA, DMF / THF, NH 2 -R 2 or i) CDI, THF; ii) NH 2 -R 2 , imidazole, THF.
또한, 본 발명에 따른 MDH 억제제로서 수득한 화합물의 구체적인 합성 과정 및 이들의 수율 및 NMR 측정 결과는 하기에 기재하였다. In addition, specific synthetic procedures of the compounds obtained as MDH inhibitors according to the present invention and their yields and NMR measurement results are described below.
1-1. 화합물 3-1 내지 화합물 3-34의 합성1-1. Synthesis of Compound 3-1 to Compound 3-34
하기 화합물 3-1 내지 화합물 3-34는 도 1에 기재된 바와 같이 화합물 1을 출발물질로 하여 화합물 2를 중간체로 거쳐 합성하였다. Compounds 3-1 to 3-34 were synthesized through Compound 2 as an intermediate as Compound 1 as a starting material, as shown in FIG.
먼저, 화합물 2의 합성 공정은 다음과 같다. First, the synthesis process of compound 2 is as follows.
화합물 2의 합성 공정: 화합물 1 (1.0 equiv), 무수 포타슘 카보네이트(anhydrous potassium carbonate) (2.0 equiv) 및 메틸-4-브로모부타노에이트(methyl 4-bromobutanoate) 또는 메틸 알파-브로모이소부틸레이트(methyl α-bromoisobutyrate) (2.0 equiv)의 혼합물을 DMF 내에서 상온 조건 하 밤새 교반하였다. 반응 혼합물을 EtOAc 로 희석하고, 계속해서 수용성 소듐 바이카보네이트, 브라인 및 물로 세척하였다. 유기층을 모아 무수 황산마그네슘 (anhydrous MgSO4)으로 수분을 제거하였다. 용매를 여과하고 감압 조건 하에서 증발시켜 실리카 젤 컬럼 크로마토그래피로 정제한 조 건조물이 에스테르 화합물이 되도록 하였다. THF/H2O (1:1) 내 에스테르 화합물 현탁액 (1.0 equiv)을 리튬 하이드록사이드 모노하이드레이트(lithium hydroxide monohydrate) (3.0 equiv) 에 추가하고 상온에서 밤새 교반하였다. 반응 혼합물을 10% HCl로 중성화하고, EtOAc로 희석하고 그리고 연속하여 수용성 소듐 바이카보네에트, 브라인 및 물로 세척하였다. 유기층을 모아 무수 황산마그네슘 (anhydrous MgSO4)으로 수분을 제거하였다. 용매를 여과하고 감압 조건 하에서 증발시켜 실리카 젤 컬럼 크로마토그래피로 정제한 조 건조물을 수득하였다. Synthesis process of compound 2: compound 1 (1.0 equiv), anhydrous potassium carbonate (2.0 equiv) and methyl 4-bromobutanoate or methyl alpha-bromoisobutyrate A mixture of (methyl α-bromoisobutyrate) (2.0 equiv) was stirred overnight at room temperature in DMF. The reaction mixture was diluted with EtOAc and then washed with aqueous sodium bicarbonate, brine and water. The organic layer was collected and water was removed with anhydrous magnesium sulfate (anhydrous MgSO 4 ). The solvent was filtered and evaporated under reduced pressure so that the crude dry matter purified by silica gel column chromatography became an ester compound. An ester compound suspension (1.0 equiv) in THF / H 2 O (1: 1) was added to lithium hydroxide monohydrate (3.0 equiv) and stirred overnight at room temperature. The reaction mixture was neutralized with 10% HCl, diluted with EtOAc and subsequently washed with water soluble sodium bicarbonatenet, brine and water. The organic layer was collected and water was removed with anhydrous magnesium sulfate (anhydrous MgSO 4 ). The solvent was filtered and evaporated under reduced pressure to give a crude dried product which was purified by silica gel column chromatography.
화합물 3-1. : 메틸 3-(2-(4-니트로페녹시)아세트아미도)벤조네이트(Methyl 3-(2-(4-nitrophenoxy)acetamido)benzoate)Compound 3-1. : Methyl 3- (2- (4-nitrophenoxy) acetamido) benzoate (Methyl 3- (2- (4-nitrophenoxy) acetamido) benzoate)
2-(4-nitrophenoxy)acetic acid (1.0 equiv), 및 methyl 3-aminobenzoate (1.0 equiv)를 DMF (dimethylformamide) 에 혼합하고 이를 EDC·HCl (N-(3-dimethylaminopropyl)-N`-ethylcarbonate hydrochloride) (1.2 equiv), HOBT (1-hydroxybenzotriazole) (1.2 equiv) 및 DIPEA (N,N-diisopropylethylamine) (2.5 equiv)에 첨가하였다. 반응 혼합물을 상온에서 밤새 교반한 후, 감압하여 농축한 뒤, 얻어진 잔사를 EtOAc로 희석하고, 물 및 brine으로 세척하였다. 유기층을 모아 무수 황산마그네슘 (anhydrous MgSO4)으로 수분을 제거한 후, 감압하에 농축하였다. 상기 농축액을 실리카겔 컬럼 크로마토그래피로 정제하여 메틸 3-(2-(4-니트로페녹시)아세트아미도)벤조네이트를 수득하였다 (흰색 고체, 0.21 g, 64.2 % 수율).2- (4-nitrophenoxy) acetic acid (1.0 equiv), and methyl 3-aminobenzoate (1.0 equiv) were mixed with DMF (dimethylformamide) and EDCHCl ( N- (3-dimethylaminopropyl) -N `-ethylcarbonate hydrochloride) (1.2 equiv), HOBT (1-hydroxybenzotriazole) (1.2 equiv) and DIPEA ( N, N- diisopropylethylamine) (2.5 equiv). The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the residue obtained was diluted with EtOAc and washed with water and brine. The organic layers were combined, dried over anhydrous magnesium sulfate (anhydrous MgSO 4 ), and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to give methyl 3- (2- (4-nitrophenoxy) acetamido) benzoate (white solid, 0.21 g, 64.2% yield).
1H-NMR (400 MHz, DMSO) δ 10.5 (brs, 1H), 8.33 (t, J = 1.8 Hz, 1H), 8.25 (d, J = 9.4 Hz, 2H), 7.89 (m, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.50 (t, J = 8.0 Hz, 1H), 7.23 (d, J = 9.0 Hz, 2H), 4.95 (s, 2H), 3.86 (s, 3H); 13C-NMR (100 MHz, DMSO)δ 166.4, 163.5, 141.7, 139.1, 130.6, 129.7, 126.3, 124.8, 124.5, 120.5, 115.7, 67.6, 52.7; HRMS [M+H] calcd [C16H15N2O6]: 329.0852, Found: 329.0676; Purity97.3%(as determined by RP-HPLC, method A,tR = 14.62 min). 1 H-NMR (400 MHz, DMSO) δ 10.5 (brs, 1H), 8.33 (t, J = 1.8 Hz, 1H), 8.25 (d, J = 9.4 Hz, 2H), 7.89 (m, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.50 (t, J = 8.0 Hz, 1H), 7.23 (d, J = 9.0 Hz, 2H), 4.95 (s, 2H), 3.86 (s, 3H); 13 C-NMR (100 MHz, DMSO) δ 166.4, 163.5, 141.7, 139.1, 130.6, 129.7, 126.3, 124.8, 124.5, 120.5, 115.7, 67.6, 52.7; HRMS [M + H] calcd [ C 16 H 15 N 2 O 6]: 329.0852, Found: 329.0676; Purity 97.3% (as determined by RP-HPLC, method A, tR = 14.62 min).
화합물 3-2. : 메틸 3-(2-(4-트리플루오로메틸)페녹시)아세트아미도)벤조에이트(Methyl 3-(2-(4-(trifluoromethyl)phenoxy)acetamido)benzoate)Compound 3-2. : Methyl 3- (2- (4-trifluoromethyl) phenoxy) acetamido) benzoate (Methyl 3- (2- (4- (trifluoromethyl) phenoxy) acetamido) benzoate)
2-(4-(trifluoromethyl)phenoxy)acetic acid (1.0 equiv), 및 methyl 3-aminobenzoate (1.0 equiv)를 DMF에 혼합하고 이를 EDC·HCl (1.2 equiv), HOBT (1.2 equiv) 및 DIPEA (2.5 equiv)에 첨가하였다. 반응 혼합물을 상온에서 밤새 교반한 후, 감압하여 농축한 뒤, 얻어진 잔사를 EtOAc로 희석하고, 물 및 brine으로 세척하였다. 유기층을 모아 무수 황산마그네슘 (anhydrous MgSO4)으로 수분을 제거한 후, 감압하에 농축하였다. 상기 농축액을 실리카겔 컬럼 크로마토그래피로 정제하여 메틸 3-(2-(4-트리플루오로메틸)페녹시)아세트아미도)벤조에이트를 수득하였다 (흰색 고체, 0.01g, 40.8 % 수율).2- (4- (trifluoromethyl) phenoxy) acetic acid (1.0 equiv), and methyl 3-aminobenzoate (1.0 equiv) were mixed in DMF and EDCHCl (1.2 equiv), HOBT (1.2 equiv) and DIPEA (2.5 equiv) )). The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the residue obtained was diluted with EtOAc and washed with water and brine. The organic layers were combined, dried over anhydrous magnesium sulfate (anhydrous MgSO 4 ), and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to afford methyl 3- (2- (4-trifluoromethyl) phenoxy) acetamido) benzoate (white solid, 0.01 g, 40.8% yield).
1H-NMR (400 MHz, CDCl3)δ 8.32 (s, 1H), 8.07 (s, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.85 (d, J = 7.2 Hz, 1H), 7.64 (d, J = 8.4 Hz, 2H), 7.46 (t, J = 7.8 Hz, 1H), 7.09 (d, J = 8.4 Hz, 2H), 4.68 (s, 2H), 3.93 (s, 3H), 1.62 (s, 2H); 13C-NMR (100 MHz, CDCl3)δ 166.5, 159.1, 136.8, 131.0, 129.4, 127.5, 127.4, 127.4, 126.1, 124.6, 120.9, 114.9, 67.4, 52.3; HRMS [M+H] calcd [C17H15F3NO4]: 354.0875, found: 354.0929; Purity99.99%(as determined by RP-HPLC, method A, tR = 17.70 min). 1 H-NMR (400 MHz, CDCl 3 ) δ 8.32 (s, 1H), 8.07 (s, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.85 (d, J = 7.2 Hz, 1H), 7.64 (d, J = 8.4 Hz, 2H), 7.46 (t, J = 7.8 Hz, 1H), 7.09 (d, J = 8.4 Hz, 2H), 4.68 (s, 2H), 3.93 (s, 3H), 1.62 (s, 2 H); 13 C-NMR (100 MHz, CDCl 3 ) δ 166.5, 159.1, 136.8, 131.0, 129.4, 127.5, 127.4, 127.4, 126.1, 124.6, 120.9, 114.9, 67.4, 52.3; HRMS [M + H] calcd [C 17 H 15 F 3 NO 4 ]: 354.0875, found: 354.0929; Purity 99.9% (as determined by RP-HPLC, method A, tR = 17.70 min).
화합물 3-3. : 메틸 3-(2-(4-Compound 3-3. : Methyl 3- (2- (4-
terttert
-부틸페녹시)아세트아미도)벤조에이트 (Methyl 3-(2-(4--Butylphenoxy) acetamido) benzoate (Methyl 3- (2- (4-
terttert
-butylphenoxy)acetamido)benzoate) -butylphenoxy) acetamido) benzoate)
2-(4-tert-butylphenoxy)acetic acid (1.0 equiv) 및 methyl 3-aminobenzoate (1.0 equiv)를 DMF에 혼합하여 이를 EDC·HCl (1.2 equiv), HOBT (1.2 equiv) 및 DIPEA (2.5 equiv)에 첨가하였다. 반응 혼합물을 상온에서 밤새 교반한 후, 감압하여 농축한 뒤, 얻어진 잔사를 EtOAc로 희석하고, 물 및 brine으로 세척하였다. 유기층을 모아 무수 황산마그네슘 (anhydrous MgSO4)으로 수분을 제거한 후, 감압하에 농축하였다. 상기 농축액을 실리카겔 컬럼 크로마토그래피로 정제하여 메틸 3-(2-(4-tert-부틸페녹시)아세트아미도)벤조에이트를 수득하였다 (흰색 고체, 0.11 g, 61.3 % 수율).The 2- (4- tert -butylphenoxy) acetic acid (1.0 equiv) and methyl 3-aminobenzoate (1.0 equiv) to a mixture of DMF in this EDC · HCl (1.2 equiv), HOBT (1.2 equiv) and DIPEA (2.5 equiv) Added. The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the residue obtained was diluted with EtOAc and washed with water and brine. The organic layers were combined, dried over anhydrous magnesium sulfate (anhydrous MgSO 4 ), and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to afford methyl 3- (2- (4- tert -butylphenoxy) acetamido) benzoate (white solid, 0.11 g, 61.3% yield).
1H-NMR (400 MHz, CDCl3)δ 8.40 (s, 1H), 8.07 (s, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.47 (t, J = 12.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 2H), 6.93 (d, J = 8.0 Hz, 2H), 4.61 (s, 2H), 3.92 (s, 3H), 1.31 (s, 9H); 13C-NMR (100 MHz, CDCl3)δ 166.7,166.6, 154.8, 145.5, 137.1, 131.1, 129.3, 126.8, 125.9, 124.5, 120.9, 114.4, 67.8, 52.3, 34.2, 31.5; HRMS [M+H] calcd [C20H24NO4]: 342.1705, Found: 342.1705; Purity100%(as determined by RP-HPLC, method A, tR = 18.66 min). 1 H-NMR (400 MHz, CDCl 3 ) δ 8.40 (s, 1H), 8.07 (s, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.47 (t, J = 12.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 2H), 6.93 (d, J = 8.0 Hz, 2H), 4.61 (s, 2H), 3.92 (s, 3H), 1.31 (s, 9 H); 13 C-NMR (100 MHz, CDCl 3 ) δ 166.7,166.6, 154.8, 145.5, 137.1, 131.1, 129.3, 126.8, 125.9, 124.5, 120.9, 114.4, 67.8, 52.3, 34.2, 31.5; HRMS [M + H] calcd [C 20 H 24 NO 4 ]: 342.1705, Found: 342.1705; Purity 100% (as determined by RP-HPLC, method A, tR = 18.66 min).
화합물 3-4. : 메틸 3-(2-(Compound 3-4. Methyl 3- (2- (
pp
-톨리록시)아세트아미도)벤조에이트(Methyl 3-(2-(-Tolyoxy) acetamido) benzoate (Methyl 3- (2- (
pp
-tolyloxy)acetamido)benzoate)-tolyloxy) acetamido) benzoate)
2-(p-tolyloxy)acetic acid (1.0 equiv) 및 methyl 3-aminobenzoate (1.0 equiv)를 DMF에 혼합하여 이를 EDC·HCl (1.2 equiv), HOBT (1.2 equiv) 및 DIPEA (2.5 equiv)에 첨가하였다. 반응 혼합물을 상온에서 밤새 교반한 후, 감압하여 농축한 뒤, 얻어진 잔사를 EtOAc로 희석하고, 물 및 brine으로 세척하였다. 유기층을 모아 무수 황산마그네슘 (anhydrous MgSO4)으로 수분을 제거한 후, 감압하에 농축하였다. 상기 농축액을 실리카겔 컬럼 크로마토그래피로 정제하여 메틸 3-(2-(p-톨리록시)아세트아미도)벤조에이트를 수득하였다 (흰색 고체, 0.10 g, 40.4 % 수율).2- ( p -tolyloxy) acetic acid (1.0 equiv) and methyl 3-aminobenzoate (1.0 equiv) were mixed in DMF and added to EDCHCl (1.2 equiv), HOBT (1.2 equiv) and DIPEA (2.5 equiv). . The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the residue obtained was diluted with EtOAc and washed with water and brine. The organic layers were combined, dried over anhydrous magnesium sulfate (anhydrous MgSO 4 ), and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to give methyl 3- (2- ( p -tolyloxy) acetamido) benzoate (white solid, 0.10 g, 40.4% yield).
1H-NMR (400 MHz, CDCl3)δ 8.51 (s, 1H), 8.09 (t, J = 8.0 Hz, 1H), 7.99 (m, 1H), 7.80 (d, J = 7.4 Hz, 1H), 7.40 (t, J = 8.0 Hz, 1H), 7.12 (d, J = 8.2 Hz, 2H), 6.87 (m, 2H), 4.56 (s, 2H), 3.89 (s, 3H), 2.29 (s, 3H); 13C-NMR (100 MHz, CDCl3)δ 166.7, 166.5, 154.9, 137.2, 131.8, 130.9, 130.3, 129.2, 125.8, 124.5, 120.9, 114.6, 67.7, 52.3, 20.5; HRMS [M+H] calcd [C17H18NO4]: 300.1158, Found: 300.1232; Purity100%(as determined by RP-HPLC, method A, tR = 16.29 min). 1 H-NMR (400 MHz, CDCl 3 ) δ 8.51 (s, 1H), 8.09 (t, J = 8.0 Hz, 1H), 7.99 (m, 1H), 7.80 (d, J = 7.4 Hz, 1H), 7.40 (t, J = 8.0 Hz, 1H), 7.12 (d, J = 8.2 Hz, 2H), 6.87 (m, 2H), 4.56 (s, 2H), 3.89 (s, 3H), 2.29 (s, 3H ); 13 C-NMR (100 MHz, CDCl 3 ) δ 166.7, 166.5, 154.9, 137.2, 131.8, 130.9, 130.3, 129.2, 125.8, 124.5, 120.9, 114.6, 67.7, 52.3, 20.5; HRMS [M + H] calcd [C 17 H 18 NO 4 ]: 300.1158, Found: 300.1232; Purity 100% (as determined by RP-HPLC, method A, tR = 16.29 min).
화합물 3-5. : 메틸 3-(2-(4-에틸페녹시)아세트아미도)벤조에이트 (Methyl 3-(2-(4-ethylphenoxy)acetamido)benzoate) Compound 3-5. Methyl 3- (2- (4-ethylphenoxy) acetamido) benzoate (Methyl 3- (2- (4-ethylphenoxy) acetamido) benzoate)
2-(4-ethylphenoxy)acetic acid (1.0 equiv) 및 methyl 3-aminobenzoate (1.0 equiv)를 DMF에 혼합하여 이를 EDC· HCl (1.2 equiv), HOBT (1.2 equiv) 및 DIPEA (2.5 equiv)에 첨가하였다. 반응 혼합물을 상온에서 밤새 교반한 후, 감압하여 농축한 뒤, 얻어진 잔사를 EtOAc로 희석하고, 물 및 brine으로 세척하였다. 유기층을 모아 무수 황산마그네슘 (anhydrous MgSO4)으로 수분을 제거한 후, 감압하에 농축하였다. 상기 농축액을 실리카겔 컬럼 크로마토그래피로 정제하여 메틸 3-(2-(4-에틸페녹시)아세트아미도)벤조에이트를 수득하였다 (흰색 고체, 0.34 g, 97.2 % 수율).2- (4-ethylphenoxy) acetic acid (1.0 equiv) and methyl 3-aminobenzoate (1.0 equiv) were mixed in DMF and added to EDC.HCl (1.2 equiv), HOBT (1.2 equiv) and DIPEA (2.5 equiv). . The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the residue obtained was diluted with EtOAc and washed with water and brine. The organic layers were combined, dried over anhydrous magnesium sulfate (anhydrous MgSO 4 ), and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to give methyl 3- (2- (4-ethylphenoxy) acetamido) benzoate (white solid, 0.34 g, 97.2% yield).
1H-NMR (400 MHz, CDCl3)δ 8.48 (brs, 1H), 8.00 (m, 1H), 7.81 (m, 1H), 7.42 (t, J = 7.8 Hz, 1H), 7.16 (d, J = 8.0 Hz, 2H), 6.91 (m, 2H), 4.59 (s, 2H), 3.90 (s, 3H), 2.61 (q, J = 7.4 Hz, 2H), 1.23 (m, 3H); 13C-NMR (100 MHz, CDCl3)δ 166.7, 166.5, 155.0, 138.3, 137.1, 13.9, 129.2, 129.1, 125.8, 124.5, 120.9, 114.7, 67.7, 52.2, 28.0, 15.8; HRMS [M+H] calcd [C18H20NO4]: 314.1314, Found: 314.1379; Purity100%(as determined by RP-HPLC, method A, tR = 18.06 min). 1 H-NMR (400 MHz, CDCl 3 ) δ 8.48 (brs, 1H), 8.00 (m, 1H), 7.81 (m, 1H), 7.42 (t, J = 7.8 Hz, 1H), 7.16 (d, J = 8.0 Hz, 2H), 6.91 (m, 2H), 4.59 (s, 2H), 3.90 (s, 3H), 2.61 (q, J = 7.4 Hz, 2H), 1.23 (m, 3H); 13 C-NMR (100 MHz, CDCl 3 ) δ 166.7, 166.5, 155.0, 138.3, 137.1, 13.9, 129.2, 129.1, 125.8, 124.5, 120.9, 114.7, 67.7, 52.2, 28.0, 15.8; HRMS [M + H] calcd [ C 18 H 20 NO 4]: 314.1314, Found: 314.1379; Purity 100% (as determined by RP-HPLC, method A, tR = 18.06 min).
화합물 3-6. : 메틸 3-(2-(4-프로필페녹시)아세트아미도)벤조에이트 (Methyl 3-(2-(4-propylphenoxy)acetamido)benzoate)Compound 3-6. Methyl 3- (2- (4-propylphenoxy) acetamido) benzoate (Methyl 3- (2- (4-propylphenoxy) acetamido) benzoate)
2-(4-propylphenoxy)acetic acid (1.0 equiv) 및 methyl 3-aminobenzoate (1.0 equiv)를 DMF 에 혼합하여 이를 EDC·HCl (1.2 equiv), HOBT (1.2 equiv) 및 DIPEA (2.5 equiv)에 첨가하였다. 반응 혼합물을 상온에서 밤새 교반한 후, 감압하여 농축한 뒤, 얻어진 잔사를 EtOAc로 희석하고, 물 및 brine으로 세척하였다. 유기층을 모아 무수 황산마그네슘 (anhydrous MgSO4)으로 수분을 제거한 후, 감압하에 농축하였다. 상기 농축액을 실리카겔 컬럼 크로마토그래피로 정제하여 메틸 3-(2-(4-프로필페녹시)아세트아미도)벤조에이트를 수득하였다 (흰색 고체, 0.31 g, 90.5 % 수율).2- (4-propylphenoxy) acetic acid (1.0 equiv) and methyl 3-aminobenzoate (1.0 equiv) were mixed with DMF and added to EDC.HCl (1.2 equiv), HOBT (1.2 equiv) and DIPEA (2.5 equiv). . The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the residue obtained was diluted with EtOAc and washed with water and brine. The organic layers were combined, dried over anhydrous magnesium sulfate (anhydrous MgSO 4 ), and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to give methyl 3- (2- (4-propylphenoxy) acetamido) benzoate (white solid, 0.31 g, 90.5% yield).
1H-NMR (400 MHz, CDCl3)δ 8.46 (brs, 1H), 8.09 (t, J = 1.8 Hz, 1H), 8.00 (dd, J = 8.2 Hz, 1H), 7.82 (dd, J = 7.8 Hz, 1H), 7.42 (t, J = 8.0 Hz, 1H), 7.14 (d, J = 8.6 Hz, 2H), 6.90 (m, 2H), 4.59 (s, 2H), 3.91 (s, 3H), 2.54 (m, 2H), 1.61 (m, 2H), 0.93 (t, J = 7.2 Hz, 3H); 13C-NMR (100 MHz, CDCl3)δ 166.7, 166.6, 155.0, 137.1, 136.8, 131.0, 129.7, 129.2, 125.8, 124.5, 120.9, 114.6, 67.7, 52.3, 37.1, 24.7, 13.7; HRMS [M+H] calcd [C19H22NO4]: 328.2471, Found: 328.1546; Purity100%(as determined by RP-HPLC, method A, tR = 19.92 min). 1 H-NMR (400 MHz, CDCl 3 ) δ 8.46 (brs, 1H), 8.09 (t, J = 1.8 Hz, 1H), 8.00 (dd, J = 8.2 Hz, 1H), 7.82 (dd, J = 7.8 Hz, 1H), 7.42 (t, J = 8.0 Hz, 1H), 7.14 (d, J = 8.6 Hz, 2H), 6.90 (m, 2H), 4.59 (s, 2H), 3.91 (s, 3H), 2.54 (m, 2H), 1.61 (m, 2H), 0.93 (t, J = 7.2 Hz, 3H); 13 C-NMR (100 MHz, CDCl 3 ) δ 166.7, 166.6, 155.0, 137.1, 136.8, 131.0, 129.7, 129.2, 125.8, 124.5, 120.9, 114.6, 67.7, 52.3, 37.1, 24.7, 13.7; HRMS [M + H] calcd [C 19 H 22 NO 4 ]: 328.2471, Found: 328.1546; Purity 100% (as determined by RP-HPLC, method A, tR = 19.92 min).
화합물 3-7. : 메틸 3-(2-(4-부틸 페녹시)아세트아미도)벤조에이트(Methyl 3-(2-(4-Butylphenoxy)acetamido)benzoate)Compound 3-7. : Methyl 3- (2- (4-butylphenoxy) acetamido) benzoate (Methyl 3- (2- (4-Butylphenoxy) acetamido) benzoate)
2-(4-butylphenoxy)acetic acid (1.0 equiv) 및 methyl 3-aminobenzoate (1.0 equiv)를 DMF 에 혼합하여 이를 EDC·HCl (1.2 equiv), HOBT (1.2 equiv) 및 DIPEA (2.5 equiv)에 첨가하였다. 반응 혼합물을 상온에서 밤새 교반한 후, 감압하여 농축한 뒤, 얻어진 잔사를 EtOAc로 희석하고, 물 및 brine으로 세척하였다. 유기층을 모아 무수 황산마그네슘 (anhydrous MgSO4)으로 수분을 제거한 후, 감압하에 농축하였다. 상기 농축액을 실리카겔 컬럼 크로마토그래피로 정제하여 메틸 3-(2-(4-부틸 페녹시)아세트아미도)벤조에이트를 수득하였다 (흰색 고체, 0.32 g, 98.4 % 수율).2- (4-butylphenoxy) acetic acid (1.0 equiv) and methyl 3-aminobenzoate (1.0 equiv) were mixed in DMF and added to EDC.HCl (1.2 equiv), HOBT (1.2 equiv) and DIPEA (2.5 equiv). . The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the residue obtained was diluted with EtOAc and washed with water and brine. The organic layers were combined, dried over anhydrous magnesium sulfate (anhydrous MgSO 4), and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to give methyl 3- (2- (4-butyl phenoxy) acetamido) benzoate (white solid, 0.32 g, 98.4% yield).
1H-NMR (400 MHz, CDCl3) δ 8.52 (brs, 1H), 8.10 (s, 1H), 7.99 (dd, J = 8.2, 1.2 Hz, 1H), 7.80 (d, J = 7.8 Hz, 1H), 7.40 (t, J = 7.8 Hz, 1H), 7.13 (d, J = 8.6 Hz, 2H), 6.89 (d, J = 8.6 Hz, 2H), 4.57 (s, 2H), 3.89 (s, 3H), 2.56 (t, J = 7.6 Hz, 2H), 1.56 (m, 2H), 1.34 (m, 2H), 0.92 (t, J = 7.4 Hz, 3H); 13C-NMR (100 MHz, CDCl3) δ 166.8, 166.5, 155.0, 137.2, 137.0, 130.9, 129.6, 129.2, 125.8, 124.5, 120.9, 114.6, 67.7, 52.2, 34.7, 33.8, 22.3, 14.0; HRMS [M + H] calcd [C20H24NO4] 342.1627, found 342.1694; Purity100%(as determined by RP-HPLC, method A, tR = 21.59 min). 1 H-NMR (400 MHz, CDCl 3 ) δ 8.52 (brs, 1H), 8.10 (s, 1H), 7.99 (dd, J = 8.2, 1.2 Hz, 1H), 7.80 (d, J = 7.8 Hz, 1H ), 7.40 (t, J = 7.8 Hz, 1H), 7.13 (d, J = 8.6 Hz, 2H), 6.89 (d, J = 8.6 Hz, 2H), 4.57 (s, 2H), 3.89 (s, 3H ), 2.56 (t, J = 7.6 Hz, 2H), 1.56 (m, 2H), 1.34 (m, 2H), 0.92 (t, J = 7.4 Hz, 3H); 13 C-NMR (100 MHz, CDCl 3 ) δ 166.8, 166.5, 155.0, 137.2, 137.0, 130.9, 129.6, 129.2, 125.8, 124.5, 120.9, 114.6, 67.7, 52.2, 34.7, 33.8, 22.3, 14.0; HRMS [M + H] calcd [ C 20 H 24 NO 4] 342.1627, found 342.1694; Purity 100% (as determined by RP-HPLC, method A, tR = 21.59 min).
화합물 3-8. : 메틸 3-(2-(4-펜틸페녹시)아세트아미도)벤조에이트 (Methyl 3-(2-(4-pentylphenoxy)acetamido)benzoate) Compound 3-8. : Methyl 3- (2- (4-pentylphenoxy) acetamido) benzoate (Methyl 3- (2- (4-pentylphenoxy) acetamido) benzoate)
2-(4-pentylphenoxy)acetic acid (1.0 equiv) 및 methyl 3-aminobenzoate (1.0 equiv)를 DMF에 혼합하여 이를 EDC·HCl (1.2 equiv), HOBT (1.2 equiv) 및 DIPEA (2.5 equiv)에 첨가하였다. 반응 혼합물을 상온에서 밤새 교반한 후, 감압하여 농축한 뒤, 얻어진 잔사를 EtOAc로 희석하고, 물 및 brine으로 세척하였다. 유기층을 모아 무수 황산마그네슘 (anhydrous MgSO4)으로 수분을 제거한 후, 감압하에 농축하였다. 상기 농축액을 실리카겔 컬럼 크로마토그래피로 정제하여 메틸 3-(2-(4-펜틸페녹시)아세트아미도)벤조에이트를 수득하였다 (노란색 고체, 0.13 g, 81.2 % 수율).2- (4-pentylphenoxy) acetic acid (1.0 equiv) and methyl 3-aminobenzoate (1.0 equiv) were mixed in DMF and added to EDCHCl (1.2 equiv), HOBT (1.2 equiv) and DIPEA (2.5 equiv). . The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the residue obtained was diluted with EtOAc and washed with water and brine. The organic layers were combined, dried over anhydrous magnesium sulfate (anhydrous MgSO 4 ), and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to give methyl 3- (2- (4-pentylphenoxy) acetamido) benzoate (yellow solid, 0.13 g, 81.2% yield).
1H-NMR (400 MHz, CDCl3)δ 8.40 (s, 1H), 8.07 (s, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.44 (t, J = 12.0 Hz, 1H), 7.15 (d, J = 8.0 Hz, 2H), 6.91 (d, J = 8.0 Hz, 2H), 4.60 (s, 2H), 3.92 (s, 3H), 2.56 (t, J = 8.0 Hz, 2H), 1.61-1.57 (m, 2H), 1.34-1.29 (m, 4H), 0.89 (t, J = 4.0 Hz, 1H); 13C-NMR (100 MHz, CDCl3)δ 166.7, 166.6, 155.0, 137.2, 137.1, 131.1, 129.7, 129.3, 125.9, 124.5, 120.9, 114.7,67.8, 52.3, 35.0, 31.4, 31.3, 22.5, 14.0; HRMS [M+H] calcd [C21H26NO4]: 356.1862, Found: 356.1862; Purity100%(as determined by RP-HPLC, method A, tR = 23.53 min). 1 H-NMR (400 MHz, CDCl 3 ) δ 8.40 (s, 1H), 8.07 (s, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.44 (t, J = 12.0 Hz , 1H), 7.15 (d, J = 8.0 Hz, 2H), 6.91 (d, J = 8.0 Hz, 2H), 4.60 (s, 2H), 3.92 (s, 3H), 2.56 (t, J = 8.0 Hz, 2H), 1.61-1.57 (m, 2H), 1.34-1.29 (m, 4H), 0.89 (t, J = 4.0 Hz, 1H); 13 C-NMR (100 MHz, CDCl 3 ) δ 166.7, 166.6, 155.0, 137.2, 137.1, 131.1, 129.7, 129.3, 125.9, 124.5, 120.9, 114.7,67.8, 52.3, 35.0, 31.4, 31.3, 22.5, 14.0; HRMS [M + H] calcd [C 21 H 26 NO 4 ]: 356.1862, Found: 356.1862; Purity 100% (as determined by RP-HPLC, method A, tR = 23.53 min).
화합물 3-9. : 메틸 3-(2-(4-사이클로펜틸페녹시)아세트아미도)벤조에이트 (Methyl 3-(2-(4-cyclopentylphenoxy)acetamido)benzoate) Compound 3-9. : Methyl 3- (2- (4-cyclopentylphenoxy) acetamido) benzoate (Methyl 3- (2- (4-cyclopentylphenoxy) acetamido) benzoate)
2-(4-cyclopentylphenoxy)acetic acid (1.0 equiv) 및 methyl 3-aminobenzoate (1.0 equiv)를 DMF에 혼합하여 이를 EDC·HCl (1.2 equiv), HOBT (1.2 equiv) 및 DIPEA (2.5 equiv)에 첨가하였다. 반응 혼합물을 상온에서 밤새 교반한 후, 감압하여 농축한 뒤, 얻어진 잔사를 EtOAc로 희석하고, 물 및 brine으로 세척하였다. 유기층을 모아 무수 황산마그네슘 (anhydrous MgSO4)으로 수분을 제거한 후, 감압하에 농축하였다. 상기 농축액을 실리카겔 컬럼 크로마토그래피로 정제하여 메틸 3-(2-(4-사이클로펜틸페녹시)아세트아미도)벤조에이트를 수득하였다 (노란색 고체, 0.10 g, 62.5 % 수율).2- (4-cyclopentylphenoxy) acetic acid (1.0 equiv) and methyl 3-aminobenzoate (1.0 equiv) were mixed in DMF and added to EDCHCl (1.2 equiv), HOBT (1.2 equiv) and DIPEA (2.5 equiv). . The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the residue obtained was diluted with EtOAc and washed with water and brine. The organic layers were combined, dried over anhydrous magnesium sulfate (anhydrous MgSO 4 ), and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to give methyl 3- (2- (4-cyclopentylphenoxy) acetamido) benzoate (yellow solid, 0.10 g, 62.5% yield).
1H-NMR (400 MHz, CDCl3)δ 8.39 (s, 1H), 8.07 (s, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.45 (t, J = 12.0 Hz, 1H), 7.22 (d, J = 8.0 Hz, 2H), 6.92 (d, J = 8.0 Hz, 2H), 4.61 (s, 2H), 3.93 (s, 3H), 2.98-2.94 (m, 1H), 2.06-2.05 (m, 2H), 1.82-1.77 (m, 2H), 1.70-1.67 (m, 2H), 1.57-1.52 (m, 4H); 13C-NMR (100 MHz, CDCl3)δ 166.7, 166.6, 155.1, 140.8, 137.1, 131.1, 129.3, 128.4, 125.9, 124.5, 120.9, 114.7, 67.9, 52.3, 45.2, 34.7, 25.4; HRMS [M+H] calcd [C21H24NO4]: 354.1705, Found: 354.1705; Purity100%(as determined by RP-HPLC, method A, tR = 22.03 min). 1 H-NMR (400 MHz, CDCl 3 ) δ 8.39 (s, 1H), 8.07 (s, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.45 (t, J = 12.0 Hz, 1H), 7.22 (d, J = 8.0 Hz, 2H), 6.92 (d, J = 8.0 Hz, 2H), 4.61 (s, 2H), 3.93 (s, 3H), 2.98-2.94 (m, 1H), 2.06-2.05 (m, 2H), 1.82-1.77 (m, 2H), 1.70-1.67 (m, 2H), 1.57-1.52 (m, 4H); 13 C-NMR (100 MHz, CDCl 3 ) δ 166.7, 166.6, 155.1, 140.8, 137.1, 131.1, 129.3, 128.4, 125.9, 124.5, 120.9, 114.7, 67.9, 52.3, 45.2, 34.7, 25.4; HRMS [M + H] calcd [C 21 H 24 NO 4 ]: 354.1705, Found: 354.1705; Purity 100% (as determined by RP-HPLC, method A, tR = 22.03 min).
화합물 3-10. : 메틸 3-(2-(4-사이클로헥실페녹시)아세트아미도)벤조에이트 (Methyl 3-(2-(4-cyclohexylphenoxy)acetamido)benzoate)Compound 3-10. : Methyl 3- (2- (4-cyclohexylphenoxy) acetamido) benzoate (Methyl 3- (2- (4-cyclohexylphenoxy) acetamido) benzoate)
2-(4-cyclohexylphenoxy)acetic acid (1.0 equiv) 및 methyl 3-aminobenzoate (1.0 equiv)를 DMF에 혼합하여 이를 EDC·HCl (1.2 equiv), HOBT (1.2 equiv) 및 DIPEA (2.5 equiv)에 첨가하였다. 반응 혼합물을 상온에서 밤새 교반한 후, 감압하여 농축한 뒤, 얻어진 잔사를 EtOAc로 희석하고, 물 및 brine으로 세척하였다. 유기층을 모아 무수 황산마그네슘 (anhydrous MgSO4)으로 수분을 제거한 후, 감압하에 농축하였다. 상기 농축액을 실리카겔 컬럼 크로마토그래피로 정제하여 메틸 3-(2-(4-사이클로펜틸페녹시)아세트아미도)벤조에이트를 수득하였다 (노란색 고체, 0.11 g, 70.5 % 수율).2- (4-cyclohexylphenoxy) acetic acid (1.0 equiv) and methyl 3-aminobenzoate (1.0 equiv) were mixed in DMF and added to EDCHCl (1.2 equiv), HOBT (1.2 equiv) and DIPEA (2.5 equiv). . The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the residue obtained was diluted with EtOAc and washed with water and brine. The organic layers were combined, dried over anhydrous magnesium sulfate (anhydrous MgSO 4 ), and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to afford methyl 3- (2- (4-cyclopentylphenoxy) acetamido) benzoate (yellow solid, 0.11 g, 70.5% yield).
1H-NMR (400 MHz, CDCl3)δ 8.39 (s, 1H), 8.07 (s, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.45 (t, J = 12.0 Hz, 1H), 7.19 (d, J = 8.0 Hz, 2H), 6.92 (d, J = 8.0 Hz, 2H), 4.60 (s, 2H), 3.92 (s, 3H), 2.50-2.46 (m, 1H), 1.84-1.76 (m, 4H), 1.73-1.58 (m, 2H), 1.44(m, 4H); 13C-NMR (100 MHz, CDCl3)δ 166.7, 166.6, 155.1, 142.4, 137.1, 131.1, 129.3, 128.1, 125.9, 124.5, 120.9, 114.7, 67.8, 52.3, 43.3, 34.6, 26.9, 26.1; HRMS [M+H] calcd [C22H26NO4]: 368.1862, Found: 368.1862; Purity100%(as determined by RP-HPLC, method A, tR = 23.62 min). 1 H-NMR (400 MHz, CDCl 3 ) δ 8.39 (s, 1H), 8.07 (s, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.45 (t, J = 12.0 Hz, 1H), 7.19 (d, J = 8.0 Hz, 2H), 6.92 (d, J = 8.0 Hz, 2H), 4.60 (s, 2H), 3.92 (s, 3H), 2.50-2.46 (m, 1H), 1.84-1.76 (m, 4H), 1.73-1.58 (m, 2H), 1.44 (m, 4H); 13 C-NMR (100 MHz, CDCl 3 ) δ 166.7, 166.6, 155.1, 142.4, 137.1, 131.1, 129.3, 128.1, 125.9, 124.5, 120.9, 114.7, 67.8, 52.3, 43.3, 34.6, 26.9, 26.1; HRMS [M + H] calcd [C 22 H 26 NO 4 ]: 368.1862, Found: 368.1862; Purity 100% (as determined by RP-HPLC, method A, tR = 23.62 min).
화합물 3-11. : 메틸 3-(2-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)아세트아미도)벤조에이트 (Methyl 3-(2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acetamido)benzoate)Compound 3-11. : Methyl 3- (2- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) acetamido) benzoate (Methyl 3- (2- (4- (2,4,4) -trimethylpentan-2-yl) phenoxy) acetamido) benzoate)
2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acetic acid (1.0 equiv) 및 methyl 3-aminobenzoate (1.0 equiv)를 DMF에 혼합하여 이를 EDC·HCl (1.2 equiv), HOBT (1.2 equiv) 및 DIPEA (2.5 equiv)에 첨가하였다. 반응 혼합물을 질소 하에 상온에서 밤새 교반한 후, 감압하여 농축한 뒤, 얻어진 잔사를 EtOAc로 희석하고, 물 및 brine으로 세척하였다. 유기층을 모아 무수 황산마그네슘 (anhydrous MgSO4)으로 수분을 제거한 후, 감압하에 농축하였다. 상기 농축액을 실리카겔 컬럼 크로마토그래피로 정제하여 메틸 3-(2-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)아세트아미도)벤조에이트를 수득하였다 (흰색 고체, 0.10 g, 64.1 % 수율).2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetic acid (1.0 equiv) and methyl 3-aminobenzoate (1.0 equiv) were mixed with DMF and mixed with EDCHCl (1.2 equiv), HOBT (1.2 equiv) and DIPEA (2.5 equiv). The reaction mixture was stirred at room temperature overnight under nitrogen, then concentrated under reduced pressure, and the obtained residue was diluted with EtOAc and washed with water and brine. The organic layers were combined, dried over anhydrous magnesium sulfate (anhydrous MgSO 4 ), and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to afford methyl 3- (2- (4- (2,4,4-trimethylpentane-2-yl) phenoxy) acetamido) benzoate (white solid, 0.10 g, 64.1% yield).
1H-NMR (400 MHz, CDCl3)δ 8.46 (s, 1H), 8.08 (s, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.44-7.32 (m, 1H), 7.33 (d, J = 8.0 Hz, 2H), 6.90 (d, J = 8.0 Hz, 2H), 4.60 (s, 2H), 3.91 (s, 3H) 1.71 (s, 2H), 1.35 (s, 6H), 0.71 (s, 9H); 13C-NMR (100 MHz, CDCl3)δ 166.7, 166.6, 154.6, 144.3, 137.1, 131.0, 129.3, 127.5, 125.8, 124.5, 120.9, 114.0, 67.6, 56.9, 52.3, 30.1, 32.3, 31.8, 31.6; HRMS [M+H] calcd [C24H32NO4]: 398.2331, Found: 398.2331; Purity100%(as determined by RP-HPLC, method A, tR = 26.11 min). 1 H-NMR (400 MHz, CDCl 3 ) δ 8.46 (s, 1H), 8.08 (s, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.44-7.32 (m, 1H), 7.33 (d, J = 8.0 Hz, 2H), 6.90 (d, J = 8.0 Hz, 2H), 4.60 (s, 2H), 3.91 (s, 3H) 1.71 (s, 2H), 1.35 (s, 6H), 0.71 (s, 9H); 13 C-NMR (100 MHz, CDCl 3 ) δ 166.7, 166.6, 154.6, 144.3, 137.1, 131.0, 129.3, 127.5, 125.8, 124.5, 120.9, 114.0, 67.6, 56.9, 52.3, 30.1, 32.3, 31.8, 31.6; HRMS [M + H] calcd [C 24 H 32 NO 4 ]: 398.2331, Found: 398.2331; Purity 100% (as determined by RP-HPLC, method A, tR = 26.11 min).
화합물 3-12. : 메틸 4-하이드록시-3-(2-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)아세트아미도)벤조에이트 (Methyl 4-hydroxy-3-(2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acetamido)benzoate) Compound 3-12. : Methyl 4-hydroxy-3- (2- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) acetamido) benzoate (Methyl 4-hydroxy-3- (2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamido) benzoate)
2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acetic acid (1.0 equiv), methyl 3-amino-4-hydroxybenzoate (1.0 equiv)를 DMF에 혼합하여 이를 EDC·HCl (1.2 equiv), HOBT (1.2 equiv) 및 DIPEA (2.5 equiv)를 첨가하였다. 반응 혼합물을 질소 하에 상온에서 밤새 교반한 후, 감압하여 농축한 뒤, 얻어진 잔사를 EtOAc로 희석하고, 물 및 brine으로 세척하였다. 유기층을 모아 무수 황산마그네슘 (anhydrous MgSO4)으로 수분을 제거한 후, 감압하에 농축하였다. 상기 농축액을 실리카겔 컬럼 크로마토그래피로 정제하여 메틸 4-하이드록시-3-(2-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)아세트아미도)벤조에이트를 수득하였다 (흰색 고체, 1.00 g, 64.1 % 수율).2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetic acid (1.0 equiv) and methyl 3-amino-4-hydroxybenzoate (1.0 equiv) were mixed with DMF and mixed with EDCHCl (1.2 equiv), HOBT (1.2 equiv) and DIPEA (2.5 equiv) were added. The reaction mixture was stirred at room temperature overnight under nitrogen, then concentrated under reduced pressure, and the obtained residue was diluted with EtOAc and washed with water and brine. The organic layers were combined, dried over anhydrous magnesium sulfate (anhydrous MgSO 4 ), and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to afford methyl 4-hydroxy-3- (2- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) acetamido) benzoate (White solid, 1.00 g, 64.1% yield).
1H-NMR (400 MHz, CDCl3)δ 9.75 (s, 1H), 8.60 (s, 1H), 7.85-7.83 (m, 1H), 7.73 (s, 1H), 7.38-7.34 (m, 2H), 7.06 (d, J = 8.0 Hz, 1H), 6.94-6.90 (m, 2H), 4.68 (s, 2H), 3.89 (s, 3H), 1.73 (s, 2H), 1.36 (s, 6H), 0.72 (s, 9H); 13C-NMR (100 MHz, CDCl3)δ 168.2, 166.7, 154.5, 147.2, 144.6, 129.2, 128.0, 127.6, 122.3, 121.3, 119.5, 114.2, 67.5, 57.0, 52.3, 38.1, 32.3, 31.8, 31.6; HRMS [M+H] calcd [C24H32NO5]: 414.2280, Found: 414.2280; Purity100%(as determined by RP-HPLC, method A, tR = 24.95 min). 1 H-NMR (400 MHz, CDCl 3 ) δ 9.75 (s, 1H), 8.60 (s, 1H), 7.85-7.83 (m, 1H), 7.73 (s, 1H), 7.38-7.34 (m, 2H) , 7.06 (d, J = 8.0 Hz, 1H), 6.94-6.90 (m, 2H), 4.68 (s, 2H), 3.89 (s, 3H), 1.73 (s, 2H), 1.36 (s, 6H), 0.72 (s, 9 H); 13 C-NMR (100 MHz, CDCl 3 ) δ 168.2, 166.7, 154.5, 147.2, 144.6, 129.2, 128.0, 127.6, 122.3, 121.3, 119.5, 114.2, 67.5, 57.0, 52.3, 38.1, 32.3, 31.8, 31.6; HRMS [M + H] calcd [C 24 H 32 NO 5 ]: 414.2280, Found: 414.2280; Purity 100% (as determined by RP-HPLC, method A, tR = 24.95 min).
화합물 3-13. : Compound 3-13. :
NN
-(4-(트리플루오로메틸)페닐)-2-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)아세트아마이드 (-(4- (trifluoromethyl) phenyl) -2- (4- (2,4,4-trimethylpentin-2-yl) phenoxy) acetamide (
NN
-(4-(trifluoromethyl)phenyl)-2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acetamide) -(4- (trifluoromethyl) phenyl) -2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamide)
2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acetic acid (1.0 equiv), 4-(trifluoromethyl)aniline (1.0 equiv)를 DMF에 혼합하여 이를 EDC·HCl (1.2 equiv), HOBT (1.2 equiv) 및 DIPEA (2.5 equiv)를 첨가하였다. 반응 혼합물을 질소 하에 상온에서 밤새 교반한 후, 감압하여 농축한 뒤, 얻어진 잔사를 EtOAc로 희석하고, 물 및 brine으로 세척하였다. 유기층을 모아 무수 황산마그네슘 (anhydrous MgSO4)으로 수분을 제거한 후, 감압하에 농축하였다. 상기 농축액을 실리카겔 컬럼 크로마토그래피로 정제하여 N-(4-(트리플루오로메틸)페닐)-2-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)아세트아마이드를 수득하였다 (흰색 고체, 0.11g, 71.5 % 수율).2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetic acid (1.0 equiv) and 4- (trifluoromethyl) aniline (1.0 equiv) were mixed with DMF and mixed with EDCHCl (1.2 equiv). , HOBT (1.2 equiv) and DIPEA (2.5 equiv) were added. The reaction mixture was stirred at room temperature overnight under nitrogen, then concentrated under reduced pressure, and the obtained residue was diluted with EtOAc and washed with water and brine. The organic layers were combined, dried over anhydrous magnesium sulfate (anhydrous MgSO 4 ), and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to obtain N- (4- (trifluoromethyl) phenyl) -2- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) acetamide. Obtained (white solid, 0.11 g, 71.5% yield).
1H-NMR (400 MHz, CDCl3)δ 8.43 (s, 1H), 7.72 (d, J = 8.8 Hz, 2H), 7.61 (d, J = 8.8 Hz, 2H), 7.35 (d, J = 6.4 Hz, 2H), 6.91 (d, J = 6.8 Hz, 2H), 4.62 (s, 2H), 1.72 (s, 2H), 1.36 (s, 6H), 0.71 (s, 9H); 13C-NMR (100 MHz, CDCl3)δ 166.8, 154.5, 144.5, 139.9, 127.6, 126.8, 126.4, 126.3, 120.0, 114.1, 67.6, 56.9, 38.1, 32.3, 31.8, 31.6; HRMS [M+H] calcd [C23H29F3NO2]: 408.2150, Found: 408.2150; Purity100%(as determined by RP-HPLC, method A, tR = 28.40 min). 1 H-NMR (400 MHz, CDCl 3 ) δ 8.43 (s, 1H), 7.72 (d, J = 8.8 Hz, 2H), 7.61 (d, J = 8.8 Hz, 2H), 7.35 (d, J = 6.4 Hz, 2H), 6.91 (d, J = 6.8 Hz, 2H), 4.62 (s, 2H), 1.72 (s, 2H), 1.36 (s, 6H), 0.71 (s, 9H); 13 C-NMR (100 MHz, CDCl 3 ) δ 166.8, 154.5, 144.5, 139.9, 127.6, 126.8, 126.4, 126.3, 120.0, 114.1, 67.6, 56.9, 38.1, 32.3, 31.8, 31.6; HRMS [M + H] calcd [C 23 H 29 F 3 NO 2 ]: 408.2150, Found: 408.2150; Purity 100% (as determined by RP-HPLC, method A, tR = 28.40 min).
화합물 3-14. : Compound 3-14. :
NN
-(4-(4-메틸피페라진-1-일)페닐)-2-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)아세트아마이드 (-(4- (4-methylpiperazin-1-yl) phenyl) -2- (4- (2,4,4-trimethylpentane-2-yl) phenoxy) acetamide (
NN
-(4-(4-methylpiperazin-1-yl)phenyl)-2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acetamide)-(4- (4-methylpiperazin-1-yl) phenyl) -2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamide)
2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acetic acid (1.0 equiv), 4-(4-methylpiperazin-1-yl)aniline (1.0 equiv)를 DMF에 혼합하여 이를 EDC·HCl (1.2 equiv), HOBT (1.2 equiv) 및 DIPEA (2.5 equiv)를 첨가하였다. 반응 혼합물을 질소 하에 상온에서 밤새 교반한 후, 감압하여 농축한 뒤, 얻어진 잔사를 EtOAc로 희석하고, 물 및 brine으로 세척하였다. 유기층을 모아 무수 황산마그네슘 (anhydrous MgSO4)으로 수분을 제거한 후, 감압하에 농축하였다. 상기 농축액을 실리카겔 컬럼 크로마토그래피로 정제하여 N-(4-(4-메틸피페라진-1-일)페닐)-2-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)아세트아마이드를 수득하였다 (흰색 고체, 0.12 g, 72.7 % 수율).2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetic acid (1.0 equiv) and 4- (4-methylpiperazin-1-yl) aniline (1.0 equiv) were mixed with DMF and EDC HCl (1.2 equiv), HOBT (1.2 equiv) and DIPEA (2.5 equiv) were added. The reaction mixture was stirred at room temperature overnight under nitrogen, then concentrated under reduced pressure, and the obtained residue was diluted with EtOAc and washed with water and brine. The organic layers were combined, dried over anhydrous magnesium sulfate (anhydrous MgSO 4 ), and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to obtain N- (4- (4-methylpiperazin-1-yl) phenyl) -2- (4- (2,4,4-trimethylpentane-2-yl) phenoxy Acetamide was obtained (white solid, 0.12 g, 72.7% yield).
1H-NMR (400 MHz, CDCl3)δ 8.17 (s, 1H), 7.45 (d, J = 9.2 Hz, 2H), 7.33 (d, J = 8.8 Hz, 2H), 6.92-6.88 (m, 4H), 4.58 (s, 2H), 3.25-3.23 (m, 4H), 2.68-2.67 (m, 4H), 2.42 (s, 3H), 1.71 (s, 2H), 1.31 (s, 6H), 0.71 (s, 9H); 13C-NMR (100 MHz, CDCl3)δ 166.2, 154.7, 148.7, 144.1, 129.2, 127.5, 121.6, 116.6, 114.0, 67.7, 57.0, 55.1, 49.4, 46.1, 38.1, 32.3, 31.8, 31.6; HRMS [M+H] calcd [C27H40N3O2]: 438.3121, Found: 438.3121; Purity100%(as determined by RP-HPLC, method A, tR = 12.56 min). 1 H-NMR (400 MHz, CDCl 3 ) δ 8.17 (s, 1H), 7.45 (d, J = 9.2 Hz, 2H), 7.33 (d, J = 8.8 Hz, 2H), 6.92-6.88 (m, 4H ), 4.58 (s, 2H), 3.25-3.23 (m, 4H), 2.68-2.67 (m, 4H), 2.42 (s, 3H), 1.71 (s, 2H), 1.31 (s, 6H), 0.71 ( s, 9H); 13 C-NMR (100 MHz, CDCl 3 ) δ 166.2, 154.7, 148.7, 144.1, 129.2, 127.5, 121.6, 116.6, 114.0, 67.7, 57.0, 55.1, 49.4, 46.1, 38.1, 32.3, 31.8, 31.6; HRMS [M + H] calcd [C 27 H 40 N 3 0 2 ]: 438.3121, Found: 438.3121; Purity 100% (as determined by RP-HPLC, method A, tR = 12.56 min).
화합물 3-15. : 1-(4-(4-(트리플루오로메틸)벤질)피페라진-1-일)-2-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)에탄온 (1-(4-(4-(trifluoromethyl)benzyl)piperazin-1-yl)-2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)ethanone) Compound 3-15. : 1- (4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) -2- (4- (2,4,4-trimethylpentane-2-yl) phenoxy) ethanone (1- (4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) -2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) ethanone)
2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acetic acid (1.0 equiv), 1-(4-(trifluoromethyl)benzyl)piperazine (1.0 equiv)를 DMF에 혼합하여 이를 EDC·HCl (1.2 equiv), HOBT (1.2 equiv) 및 DIPEA (2.5 equiv)를 첨가하였다. 반응 혼합물을 질소 하에 상온에서 밤새 교반한 후, 감압하여 농축한 뒤, 얻어진 잔사를 EtOAc로 희석하고, 물 및 brine으로 세척하였다. 유기층을 모아 무수 황산마그네슘 (anhydrous MgSO4)으로 수분을 제거한 후, 감압하에 농축하였다. 상기 농축액을 실리카겔 컬럼 크로마토그래피로 정제하여 1-(4-(4-(트리플루오로메틸)벤질)피페라진-1-일)-2-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)에탄온을 수득하였다 (흰색 고체, 0.15 g, 81.0 % 수율).2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetic acid (1.0 equiv) and 1- (4- (trifluoromethyl) benzyl) piperazine (1.0 equiv) were mixed with DMF and mixed with EDC. HCl (1.2 equiv), HOBT (1.2 equiv) and DIPEA (2.5 equiv) were added. The reaction mixture was stirred at room temperature overnight under nitrogen, then concentrated under reduced pressure, and the obtained residue was diluted with EtOAc and washed with water and brine. The organic layers were combined, dried over anhydrous magnesium sulfate (anhydrous MgSO 4 ), and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to obtain 1- (4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) -2- (4- (2,4,4-trimethylpentane- 2-yl) phenoxy) ethanone was obtained (white solid, 0.15 g, 81.0% yield).
1H-NMR (400 MHz, CDCl3)δ 7.58 (d, J = 7.6 Hz, 2H), 7.43 (d, J = 7.6 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 6.85 (d, J = 8.8 Hz, 2H), 4.66 (s, 2H), 3.63-3.59 (m, 4H), 3.56 (s, 2H), 2.40-2.39 (m, 4H), 1.70 (s, 2H), 1.38 (s, 6H), 0.71 (s, 9H); 13C-NMR (100 MHz, CDCl3) δ 166.6, 155.4, 143.2, 142.0, 129.4, 129.1, 127.2, 125.3, 125.2, 113.8, 67.9, 62.2, 57.0, 53.2, 52.7, 45.4, 42.1, 38.0, 32.3, 31.8, 31.6; HRMS [M+H] calcd [C28H38F3N2O2]: 491.2885, Found: 491.2885; Purity100%(as determined by RP-HPLC, method A, tR =14.31min). 1 H-NMR (400 MHz, CDCl 3 ) δ 7.58 (d, J = 7.6 Hz, 2H), 7.43 (d, J = 7.6 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 6.85 ( d, J = 8.8 Hz, 2H ), 4.66 (s, 2H), 3.63-3.59 (m, 4H), 3.56 (s, 2H), 2.40-2.39 (m, 4H), 1.70 (s, 2H), 1.38 (s, 6H), 0.71 (s, 9H); 13 C-NMR (100 MHz, CDCl 3 ) δ 166.6, 155.4, 143.2, 142.0, 129.4, 129.1, 127.2, 125.3, 125.2, 113.8, 67.9, 62.2, 57.0, 53.2, 52.7, 45.4, 42.1, 38.0, 32.3, 31.8, 31.6; HRMS [M + H] calcd [C 28 H 38 F 3 N 2 O 2 ]: 491.2885, Found: 491.2885; Purity 100% (as determined by RP-HPLC, method A, t R = 14.31 min).
화합물 3-16. : 1-(4-(프로프-2-인일)피페라진-1-일)-2-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)에탄온 (1-(4-(prop-2-ynyl)piperazin-1-yl)-2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)ethanone)Compound 3-16. : 1- (4- (prop-2-ynyl) piperazin-1-yl) -2- (4- (2,4,4-trimethylpentin-2-yl) phenoxy) ethanone (1- (4- (prop-2-ynyl) piperazin-1-yl) -2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) ethanone)
2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acetic acid (1.0 equiv), 1-(prop-2-ynyl)piperazine (1.0 equiv)를 DMF에 혼합하여 이를 EDC·HCl (1.2 equiv), HOBT (1.2 equiv) 및 DIPEA (2.5 equiv)를 첨가하였다. 반응 혼합물을 질소 하에 상온에서 밤새 교반한 후, 감압하여 농축한 뒤, 얻어진 잔사를 EtOAc로 희석하고, 물 및 brine으로 세척하였다. 유기층을 모아 무수 황산마그네슘 (anhydrous MgSO4)으로 수분을 제거한 후, 감압하에 농축하였다. 상기 농축액을 실리카겔 컬럼 크로마토그래피로 정제하여 1-(4-(프로프-2-인일)피페라진-1-일)-2-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)에탄온을 수득하였다 (흰색 고체, 0.11 g, 78.5 % 수율).2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetic acid (1.0 equiv) and 1- (prop-2-ynyl) piperazine (1.0 equiv) were mixed with DMF and EDCHCl (1.2 equiv), HOBT (1.2 equiv) and DIPEA (2.5 equiv) were added. The reaction mixture was stirred at room temperature overnight under nitrogen, then concentrated under reduced pressure, and the obtained residue was diluted with EtOAc and washed with water and brine. The organic layers were combined, dried over anhydrous magnesium sulfate (anhydrous MgSO 4 ), and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to obtain 1- (4- (prop-2-ynyl) piperazin-1-yl) -2- (4- (2,4,4-trimethylpentane-2-yl Phenoxy) ethanone was obtained (white solid, 0.11 g, 78.5% yield).
1H-NMR (400 MHz, CDCl3)δ 7.30 (d, J = 8.0 Hz, 2H), 6.85 (d, J = 8.0 Hz, 2H), 4.67 (s, 2H), 3.68-3.63 (m, 4H), 3.29 (t, J = 4.0 Hz, 2H), 2.56-2.51 (m, 4H), 2.25 (t, J = 4.0 Hz, 1H), 1.69 (s, 2H), 1.33 (s, 6H), 0.70 (s, 9H); 13C-NMR (100 MHz, CDCl3)δ 166.6, 155.4, 143.3, 127.2, 113.8, 78.1, 73.6, 67.9, 57.0, 51.9, 51.6, 46.8, 45.2, 41.9, 38.0, 32.3, 31.8, 31.6; HRMS [M+H] calcd [C23H35N2O2]: 371.2699, Found: 371.2699; Purity100%(as determined by RP-HPLC, method A, tR = 11.38 min). 1 H-NMR (400 MHz, CDCl 3 ) δ 7.30 (d, J = 8.0 Hz, 2H), 6.85 (d, J = 8.0 Hz, 2H), 4.67 (s, 2H), 3.68-3.63 (m, 4H ), 3.29 (t, J = 4.0 Hz, 2H), 2.56-2.51 (m, 4H), 2.25 (t, J = 4.0 Hz, 1H), 1.69 (s, 2H), 1.33 (s, 6H), 0.70 (s, 9H); 13 C-NMR (100 MHz, CDCl 3 ) δ 166.6, 155.4, 143.3, 127.2, 113.8, 78.1, 73.6, 67.9, 57.0, 51.9, 51.6, 46.8, 45.2, 41.9, 38.0, 32.3, 31.8, 31.6; HRMS [M + H] calcd [C 23 H 35 N 2 O 2 ]: 371.2699, Found: 371.2699; Purity 100% (as determined by RP-HPLC, method A, tR = 11.38 min).
화합물 3-17. : 프로프-2-인일 4-하이드록시-3-(2-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)아세트아미도)벤조에이트 (Prop-2-ynyl 4-hydroxy-3-(2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acetamido)benzoate)Compound 3-17. : Prop-2-ynyl 4-hydroxy-3- (2- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) acetamido) benzoate (Prop-2-ynyl 4-hydroxy-3- (2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamido) benzoate)
2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acetic acid (1.0 equiv), prop-2-ynyl 3-amino-4-hydroxybenzoate (1.0 equiv)를 DMF에 혼합하여 이를 EDC·HCl (1.2 equiv), HOBT (1.2 equiv) 및 DIPEA (2.5 equiv)를 첨가하였다. 반응 혼합물을 질소 하에 상온에서 밤새 교반한 후, 감압하여 농축한 뒤, 얻어진 잔사를 EtOAc로 희석하고, 물 및 brine으로 세척하였다. 유기층을 모아 무수 황산마그네슘 (anhydrous MgSO4)으로 수분을 제거한 후, 감압하에 농축하였다. 상기 농축액을 실리카겔 컬럼 크로마토그래피로 정제하여 프로프-2-인일 4-하이드록시-3-(2-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)아세트아미도)벤조에이트를 수득하였다 (흰색 고체, 0.10 g, 60.6 % 수율).2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetic acid (1.0 equiv) and prop-2-ynyl 3-amino-4-hydroxybenzoate (1.0 equiv) were mixed with DMF and EDC HCl (1.2 equiv), HOBT (1.2 equiv) and DIPEA (2.5 equiv) were added. The reaction mixture was stirred at room temperature overnight under nitrogen, then concentrated under reduced pressure, and the obtained residue was diluted with EtOAc and washed with water and brine. The organic layers were combined, dried over anhydrous magnesium sulfate (anhydrous MgSO 4 ), and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to give prop-2-ynyl 4-hydroxy-3- (2- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) acetamido ) Benzoate was obtained (white solid, 0.10 g, 60.6% yield).
1H-NMR (400 MHz, CDCl3)δ 9.84 (s, 1H), 8.63 (s, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 4.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 2H), 7.07 (d, J = 8.0 Hz, 1H), 6.92 (d, J = 8.0 Hz, 2H), 4.91 (d, J = 4.0 Hz, 2H), 4.69 (s, 2H), 2.51 (t, J = 4.0 Hz, 1H), 1.72 (s, 2H), 1.36 (s, 6H), 0.72 (s, 9H); 13C-NMR (100 MHz, CDCl3)δ 169.0, 164.9, 154.2, 153.7, 144.8, 129.6, 127.7, 124.6, 124.5, 121.6, 120.2, 114.1, 77.7, 75.1, 67.1, 56.9, 52.4, 38.1, 32.3, 31.8, 31.6; HRMS [M+H] calcd [C26H32NO5]: 438.2280, Found: 438.2280; Purity100%(as determined by RP-HPLC, method A, tR = 24.56 min). 1 H-NMR (400 MHz, CDCl 3 ) δ 9.84 (s, 1H), 8.63 (s, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 4.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 2H), 7.07 (d, J = 8.0 Hz, 1H), 6.92 (d, J = 8.0 Hz, 2H), 4.91 (d, J = 4.0 Hz, 2H), 4.69 ( s, 2H), 2.51 (t, J = 4.0 Hz, 1H), 1.72 (s, 2H), 1.36 (s, 6H), 0.72 (s, 9H); 13 C-NMR (100 MHz, CDCl 3 ) δ 169.0, 164.9, 154.2, 153.7, 144.8, 129.6, 127.7, 124.6, 124.5, 121.6, 120.2, 114.1, 77.7, 75.1, 67.1, 56.9, 52.4, 38.1, 32.3, 31.8, 31.6; HRMS [M + H] calcd [ C 26 H 32 NO 5]: 438.2280, Found: 438.2280; Purity 100% (as determined by RP-HPLC, method A, tR = 24.56 min).
화합물 3-18. : Compound 3-18. :
NN
-(3-하이드록시-아다만테인-1-일)-2-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)아세트아마이드 (-(3-hydroxy-adamantane-1-yl) -2- (4- (2,4,4-trimethylpentane-2-yl) phenoxy) acetamide (
NN
-(3-hydroxy-adamantan-1-yl)-2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acetamide) -(3-hydroxy-adamantan-1-yl) -2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamide)
2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acetic acid (1.0 equiv), 3-hydroxy-adamantan-1-yl-amine (1.0 equiv)를 DMF에 혼합하여 이를 EDC·HCl (1.2 equiv), HOBT (1.2 equiv) 및 DIPEA (2.5 equiv)를 첨가하였다. 반응 혼합물을 질소 하에 상온에서 밤새 교반한 후, 감압하여 농축한 뒤, 얻어진 잔사를 EtOAc로 희석하고, 물 및 brine으로 세척하였다. 유기층을 모아 무수 황산마그네슘 (anhydrous MgSO4)으로 수분을 제거한 후, 감압하에 농축하였다. 상기 농축액을 실리카겔 컬럼 크로마토그래피로 정제하여 N-(3-하이드록시-아다만테인-1-일)-2-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)아세트아마이드를 수득하였다 (흰색 고체, 0.12g, 76.9 % 수율).2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetic acid (1.0 equiv) and 3-hydroxy-adamantan-1-yl-amine (1.0 equiv) were mixed with DMF and mixed with EDC. HCl (1.2 equiv), HOBT (1.2 equiv) and DIPEA (2.5 equiv) were added. The reaction mixture was stirred at room temperature overnight under nitrogen, then concentrated under reduced pressure, and the obtained residue was diluted with EtOAc and washed with water and brine. The organic layers were combined, dried over anhydrous magnesium sulfate (anhydrous MgSO 4 ), and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to obtain N- (3-hydroxy-adamantane-1-yl) -2- (4- (2,4,4-trimethylpentane-2-yl) phenoxy) Acetamide was obtained (white solid, 0.12 g, 76.9% yield).
1H-NMR (400 MHz, CDCl3)δ 8.02 (s, 1H), 7.31 (d, J = 4.0 Hz, 2H), 6.81 (d, J = 12.0 Hz, 2H), 6.31 (s, 1H), 4.36 (s, 2H), 2.28 (s, 2H), 2.02 (s, 2H), 1.99 (s, 4H), 1.70 (s, 6H), 1.58 (s, 2H), 1.34 (s, 6H), 0.70 (s, 9H); 13C-NMR (100 MHz, CDCl3)δ 167.4, 154.7, 143.7, 127.4, 113.9, 69.0, 67.6, 57.0, 54.2, 48.9, 44.0, 40.2, 38.0, 34.8, 32.3, 31.7, 31.6, 30.6; HRMS [M+H] calcd [C26H40NO3]: 414.3008, Found: 414.3008; Purity100%(as determined by RP-HPLC, method A, tR = 23.33 min). 1 H-NMR (400 MHz, CDCl 3 ) δ 8.02 (s, 1H), 7.31 (d, J = 4.0 Hz, 2H), 6.81 (d, J = 12.0 Hz, 2H), 6.31 (s, 1H), 4.36 (s, 2H), 2.28 (s, 2H), 2.02 (s, 2H), 1.99 (s, 4H), 1.70 (s, 6H), 1.58 (s, 2H), 1.34 (s, 6H), 0.70 (s, 9H); 13 C-NMR (100 MHz, CDCl 3 ) δ 167.4, 154.7, 143.7, 127.4, 113.9, 69.0, 67.6, 57.0, 54.2, 48.9, 44.0, 40.2, 38.0, 34.8, 32.3, 31.7, 31.6, 30.6; HRMS [M + H] calcd [C 26 H 40 NO 3 ]: 414.3008, Found: 414.3008; Purity 100% (as determined by RP-HPLC, method A, tR = 23.33 min).
화합물 3-19. : 메틸 3-(2-(4-아다만테인-1-일-페녹시)아세트아미도)벤조에이트 (Methyl 3-(2-(4-adamantan-1-yl-phenoxy)acetamido)benzoate) Compound 3-19. : Methyl 3- (2- (4-adamantane-1-yl-phenoxy) acetamido) benzoate (Methyl 3- (2- (4-adamantan-1-yl-phenoxy) acetamido) benzoate)
(4-adamantan-1-yl-phenoxy)acetic acid (1.0 equiv) 및 methyl 3-aminobenzoate (1.0 equiv)를 DMF에 혼합하여 이를 EDC·HCl (1.2 equiv), HOBT (1.2 equiv) 및 DIPEA (2.5 equiv)를 첨가하였다. 반응 혼합물을 상온에서 밤새 교반 한 후, 감압하여 농축한 뒤, 얻어진 잔사를 EtOAc (Ethyl Acetate)로 희석하고, 물 및 brine으로 세척하였다. 유기층을 모아 무수 황산마그네슘 (anhydrous MgSO4)으로 수분을 제거한 후, 감압하에 농축하였다. 상기 농축액을 실리카겔 컬럼 크로마토그래피로 정제하여 메틸 3-(2-(4-아다만테인-1-일-페녹시)아세트아미도)벤조에이트를 수득하였다 (흰색 고체, 0.12 g, 82.2 % 수율).(4-adamantan-1-yl-phenoxy) acetic acid (1.0 equiv) and methyl 3-aminobenzoate (1.0 equiv) were mixed with DMF, which was then mixed with EDCHCl (1.2 equiv), HOBT (1.2 equiv) and DIPEA (2.5 equiv). ) Was added. The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the obtained residue was diluted with EtOAc (Ethyl Acetate) and washed with water and brine. The organic layers were combined, dried over anhydrous magnesium sulfate (anhydrous MgSO 4 ), and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to give methyl 3- (2- (4-adamantane-1-yl-phenoxy) acetamido) benzoate (white solid, 0.12 g, 82.2% yield) .
1H-NMR (400 MHz, CDCl3)δ 8.40 (s, 1H), 8.07 (s, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.43 (t, J = 8.0 Hz, 1H), 7.33 (d, J = 8.0 Hz, 2H), 6.95 (d, J = 8.0 Hz, 1H), 4.61 (s, 2H), 3.92 (s, 3H), 2.09 (brs, 3H), 1.82-1.81 (m, 6H), 1.77-1.72 (m, 6H); 13C-NMR (100 MHz, CDCl3)δ 166.7, 166.6, 154.8, 145.8, 137.1, 131.1, 129.3, 126.3, 125.9, 124.5, 120.9, 114.4, 67.8, 52.3, 43.3, 36.8, 35.7, 29.0; HRMS [M+H] calcd [C26H30NO4]: 420.2175, Found: 420.2175; Purity100%(as determined by RP-HPLC, method A, tR = 26.99 min). 1 H-NMR (400 MHz, CDCl 3 ) δ 8.40 (s, 1H), 8.07 (s, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.43 (t, J = 8.0 Hz, 1H), 7.33 (d, J = 8.0 Hz, 2H), 6.95 (d, J = 8.0 Hz, 1H), 4.61 (s, 2H), 3.92 (s, 3H), 2.09 (brs, 3 H), 1.82-1.81 (m, 6 H), 1.77-1.72 (m, 6 H); 13 C-NMR (100 MHz, CDCl 3) δ 166.7, 166.6, 154.8, 145.8, 137.1, 131.1, 129.3, 126.3, 125.9, 124.5, 120.9, 114.4, 67.8, 52.3, 43.3, 36.8, 35.7, 29.0; HRMS [M + H] calcd [C 26 H 30 NO 4 ]: 420.2175, Found: 420.2175; Purity 100% (as determined by RP-HPLC, method A, tR = 26.99 min).
화합물 3-20. : 메틸 3-(2-(4-아다만테인-1-일-페녹시)아세트아미도 4-하이드록시벤조에이트(Methyl 3-(2-(4-adamantan-1-yl-phenoxy)acetamido)-4-hydroxybenzoate)Compound 3-20. : Methyl 3- (2- (4-adamantane-1-yl-phenoxy) acetamido 4-hydroxybenzoate (Methyl 3- (2- (4-adamantan-1-yl-phenoxy) acetamido) -4-hydroxybenzoate)
2-(4-(adamantan-1-yl)phenoxy)acetic acid (1.0 equiv) 및 methyl 3-amino-4-hydroxybenzoate (1.0 equiv)를 DMF에 혼합하여 이를 EDC·HCl (1.2 equiv), HOBT (1.2 equiv) 및 DIPEA (2.5 equiv)를 첨가하였다. 반응 혼합물을 상온에서 밤새 교반 한 후, 감압하여 농축한 뒤, 얻어진 잔사를 EtOAc (Ethyl Acetate)로 희석하고, 물 및 brine으로 세척하였다. 유기층을 모아 무수 황산마그네슘 (anhydrous MgSO4)으로 수분을 제거한 후, 감압하에 농축하였다. 상기 농축액을 실리카겔 컬럼 크로마토그래피로 정제하여 메틸 3-(2-(4-아다만테인-1-일-페녹시)아세트아미도 4-하이드록시벤조에이트를 수득하였다.2- (4- (adamantan-1-yl) phenoxy) acetic acid (1.0 equiv) and methyl 3-amino-4-hydroxybenzoate (1.0 equiv) were mixed with DMF and mixed with EDCHCl (1.2 equiv), HOBT (1.2 equiv) and DIPEA (2.5 equiv) were added. The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the obtained residue was diluted with EtOAc (Ethyl Acetate) and washed with water and brine. After collection of the organic layer was removed, the dried over anhydrous magnesium sulfate (anhydrous MgSO 4), and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to afford methyl 3- (2- (4-adamantane-1-yl-phenoxy) acetamido 4-hydroxybenzoate.
1H-NMR (300 MHz, DMSO) δ 11.10 (s, 1H), 9.24 (s, 1H), 8.69 (m, 1H), 7.60-7.64 (m, 1H), 7.30 (d, J = 8.4 Hz, 2H), 6.94-6.99 (m, 3H), 4.74 (s, 2H), 3.79 (s, 3H), 2.04 (m, 3H), 1.83 (m, 6H), 1.72 (m, 6H); MS (ESI) m/z 434 (M-H)-; HRMS (ESI) m/z calcd for C26H29O5NNa [(M+Na)+] 458.1943, found: 458.1942. 1 H-NMR (300 MHz, DMSO) δ 11.10 (s, 1H), 9.24 (s, 1H), 8.69 (m, 1H), 7.60-7.64 (m, 1H), 7.30 (d, J = 8.4 Hz, 2H), 6.94-6.99 (m, 3H), 4.74 (s, 2H), 3.79 (s, 3H), 2.04 (m, 3H), 1.83 (m, 6H), 1.72 (m, 6H); MS (ESI) m / z 434 (M − H) − ; HRMS (ESI) m / z calcd for C 26 H 29 O 5 NNa [(M + Na) + ] 458.1943, found: 458.1942.
화합물 3-21. :메틸 3-(2-(4-아다만테인-1-일-페녹시)아세트아미도)-4-(2-에톡시-2-옥소에톡시)벤조에이트(Methyl 3-(2-(4-adamantan-1-yl-phenoxy)acetamido)-4-(2-ethoxy-2-oxoethoxy)benzoate) Compound 3-21. : Methyl 3- (2- (4-adamantane-1-yl-phenoxy) acetamido) -4- (2-ethoxy-2-oxoethoxy) benzoate (Methyl 3- (2- ( 4-adamantan-1-yl-phenoxy) acetamido) -4- (2-ethoxy-2-oxoethoxy) benzoate)
Methyl 3-(2-(4-adamantan-1-yl-phenoxy)acetamido)-4-hydroxybenzoate (1.0 equiv), anhydrous potassium carbonate (3.0 equiv) 및 ethyl chloroacetate (2.0 equiv)를 DMF에 혼합하고 이를 상온에서 밤새 교반한 후, 감압하여 농축한 뒤, 얻어진 잔사를 EtOAc로 희석하고, sodium bicarbonate, 물 및 brine으로 세척하였다. 유기층을 모아 무수 황산마그네슘 (anhydrous MgSO4)으로 수분을 제거한 후, 감압하에 농축하였다. 상기 농축액을 실리카겔 컬럼 크로마토그래피로 정제하여 메틸 3-(2-(4-아다만테인-1-일-페녹시)아세트아미도)-4-(2-에톡시-2-옥소에톡시)벤조에이트를 수득하였다 (흰색 고체, 0.09 g, 75.0 % 수율).Methyl 3- (2- (4-adamantan-1-yl-phenoxy) acetamido) -4-hydroxybenzoate (1.0 equiv), anhydrous potassium carbonate (3.0 equiv) and ethyl chloroacetate (2.0 equiv) are mixed in DMF and at room temperature After stirring overnight, the mixture was concentrated under reduced pressure, and the obtained residue was diluted with EtOAc and washed with sodium bicarbonate, water and brine. The organic layers were combined, dried over anhydrous magnesium sulfate (anhydrous MgSO 4 ), and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to afford methyl 3- (2- (4-adamantane-1-yl-phenoxy) acetamido) -4- (2-ethoxy-2-oxoethoxy) benzo Obtain was obtained (white solid, 0.09 g, 75.0% yield).
1H-NMR (400 MHz, CDCl3)δ 9.27 (s, 1H), 9.06 (s, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 8.0 Hz, 2H), 7.01 (d, J = 8.0 Hz, 2H), 6.84 (d, J = 8.0 Hz, 1H), 4.71 (s, 2H), 4.64 (s, 2H), 4.28 (q, J = 8.0 Hz, 2H), 3.90 (s, 3H), 2.09 (brs, 3H), 1.89-1.88 (m, 6H), 1.77-1.75 (m, 6H), 1.28 (t, J = 12.0 Hz, 3H); 13C-NMR (100 MHz, CDCl3)δ 166.7, 166.7, 155.0, 150.3, 145.4, 127.3, 126.6, 126.1, 124.4, 121.7, 114.5, 111.3, 67.8, 66.2, 61.8, 52.1, 43.3, 36.7, 35.7, 28.9, 14.2; HRMS [M+H] calcd [C30H36NO7]: 522.2492, Found: 522.2492; Purity>96.0% (as determined by RP-HPLC, method A, tR = 28.66 min). 1 H-NMR (400 MHz, CDCl 3 ) δ 9.27 (s, 1H), 9.06 (s, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 8.0 Hz, 2H), 7.01 (d, J = 8.0 Hz, 2H), 6.84 (d, J = 8.0 Hz, 1H), 4.71 (s, 2H), 4.64 (s, 2H), 4.28 (q, J = 8.0 Hz, 2H), 3.90 (s, 3H), 2.09 (brs, 3H), 1.89-1.88 (m, 6H), 1.77-1.75 (m, 6H), 1.28 (t, J = 12.0 Hz, 3H); 13 C-NMR (100 MHz, CDCl 3) δ 166.7, 166.7, 155.0, 150.3, 145.4, 127.3, 126.6, 126.1, 124.4, 121.7, 114.5, 111.3, 67.8, 66.2, 61.8, 52.1, 43.3, 36.7, 35.7, 28.9, 14.2; HRMS [M + H] calcd [C 30 H 36 NO 7 ]: 522.2492, Found: 522.2492; Purity> 96.0% (as determined by RP-HPLC, method A, tR = 28.66 min).
화합물 3-22. : 메틸 3-(2-(4-아다만테인-1-일-페녹시)아세트아미도)-4-(2-(피롤리딘-1-일)에톡시)벤조에이트 (Methyl 3-(2-(4-adamantan-1-yl-phenoxy)acetamido)-4-(2-(pyrrolidin-1-yl)ethoxy)benzoate)Compound 3-22. : Methyl 3- (2- (4-adamantane-1-yl-phenoxy) acetamido) -4- (2- (pyrrolidin-1-yl) ethoxy) benzoate (Methyl 3- ( 2- (4-adamantan-1-yl-phenoxy) acetamido) -4- (2- (pyrrolidin-1-yl) ethoxy) benzoate)
Methyl 3-(2-(4-adamantan-1-yl-phenoxy)acetamido)-4-hydroxybenzoate (1.0 equiv), anhydrous potassium carbonate (3.0 equiv) 및 1-(2-chloroethyl)pyrrolidine (2.0 equiv)를 DMF에 혼합하고 이를 상온에서 밤새 교반한 후, 감압하여 농축한 뒤, 얻어진 잔사를 EtOAc로 희석하고, sodium bicarbonate, 물 및 brine으로 세척하였다. 유기층을 모아 무수 황산마그네슘 (anhydrous MgSO4)으로 수분을 제거한 후, 감압하에 농축하였다. 상기 농축액을 실리카겔 컬럼 크로마토그래피로 정제하여 메틸 3-(2-(4-아다만테인-1-일-페녹시)아세트아미도)-4-(2-(피롤리딘-1-일)에톡시)벤조에이트를 수득하였다 (흰색 고체, 0.09 g, 75.0 % 수율).Methyl 3- (2- (4-adamantan-1-yl-phenoxy) acetamido) -4-hydroxybenzoate (1.0 equiv), anhydrous potassium carbonate (3.0 equiv) and 1- (2-chloroethyl) pyrrolidine (2.0 equiv) The mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the obtained residue was diluted with EtOAc and washed with sodium bicarbonate, water and brine. The organic layers were combined, dried over anhydrous magnesium sulfate (anhydrous MgSO 4 ), and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to methyl 3- (2- (4-adamantane-1-yl-phenoxy) acetamido) -4- (2- (pyrrolidin-1-yl) Oxy) benzoate was obtained (white solid, 0.09 g, 75.0% yield).
1H-NMR (400 MHz, CDCl3)δ 9.06 (s, 1H), 9.02 (s, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 8.0 Hz, 2H), 6.95-6.91 (m, 3H), 4.62 (s, 2H), 4.22 (t, J = 4.0 Hz, 2H), 3.89 (s, 3H), 2.92 (t, J = 4.0 Hz, 2H), 2.64-2.62 (m, 4H), 2.09 (brs, 3H), 1.89-1.88 (m, 6H), 1.77-1.72 (m, 10H); 13C-NMR (100 MHz, CDCl3)δ 114.4, 110.6, 68.3, 68.0, 54.8, 54.7, 52.0, 43.4, 36.7, 35.7, 28.9, 23.6; HRMS [M+H] calcd [C32H41N2O5]: 533.3015, Found: 533.3015; Purity100%(as determined by RP-HPLC, method A, tR = 13.39 min). 1 H-NMR (400 MHz, CDCl 3) δ 9.06 (s, 1H), 9.02 (s, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 8.0 Hz, 2H), 6.95-6.91 (m, 3H), 4.62 (s, 2H), 4.22 (t, J = 4.0 Hz, 2H), 3.89 (s, 3H), 2.92 (t, J = 4.0 Hz, 2H), 2.64-2.62 (m, 4H), 2.09 (brs, 3H), 1.89-1.88 (m, 6H), 1.77-1.72 (m, 10H); 13 C-NMR (100 MHz, CDCl 3 ) δ 114.4, 110.6, 68.3, 68.0, 54.8, 54.7, 52.0, 43.4, 36.7, 35.7, 28.9, 23.6; HRMS [M + H] calcd [C 32 H 41 N 2 O 5 ]: 533.3015, Found: 533.3015; Purity 100% (as determined by RP-HPLC, method A, tR = 13.39 min).
화합물 3-23. : 메틸 3-(2-(4-아다만테인-1-일-페녹시)아세트아미도)-4-(3-모르폴리노프로폭시)벤조에이트 (Methyl 3-(2-(4-adamantan-1-yl-phenoxy)acetamido)-4-(3-morpholinopropoxy)benzoate)Compound 3-23. : Methyl 3- (2- (4-adamantane-1-yl-phenoxy) acetamido) -4- (3-morpholinopropoxy) benzoate (Methyl 3- (2- (4-adamantan -1-yl-phenoxy) acetamido) -4- (3-morpholinopropoxy) benzoate)
Methyl 3-(2-(4-adamantan-1-yl-phenoxy)acetamido)-4-hydroxybenzoate (1.0 equiv), anhydrous potassium carbonate (3.0 equiv) 및 4-(3-chloropropyl)morpholine (2.0 equiv)를 DMF에 혼합하고 이를 상온에서 밤새 교반한 후, 감압하여 농축한 뒤, 얻어진 잔사를 EtOAc로 희석하고, sodium bicarbonate, 물 및 brine으로 세척하였다. 유기층을 모아 무수 황산마그네슘 (anhydrous MgSO4)으로 수분을 제거한 후, 감압하에 농축하였다. 상기 농축액을 실리카겔 컬럼 크로마토그래피로 정제하여 메틸 3-(2-(4-아다만테인-1-일-페녹시)아세트아미도)-4-(3-모르폴리노프로폭시)벤조에이트를 수득하였다 (흰색 고체, 0.09 g, 69.7 % 수율).Methyl 3- (2- (4-adamantan-1-yl-phenoxy) acetamido) -4-hydroxybenzoate (1.0 equiv), anhydrous potassium carbonate (3.0 equiv) and 4- (3-chloropropyl) morpholine (2.0 equiv) The mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the obtained residue was diluted with EtOAc and washed with sodium bicarbonate, water and brine. The organic layers were combined, dried over anhydrous magnesium sulfate (anhydrous MgSO 4 ), and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to afford methyl 3- (2- (4-adamantane-1-yl-phenoxy) acetamido) -4- (3-morpholinopropoxy) benzoate. (White solid, 0.09 g, 69.7% yield).
1H-NMR (400 MHz, CDCl3)δ 9.05 (s, 1H), 9.04 (s, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 8.0 Hz, 2H), 6.94-6.92 (m, 3H), 4.62 (s, 2H), 4.16 (t, J = 4.0 Hz, 2H), 3.90 (s, 3H), 3.69-3.68 (m, 4H), 2.53 (t, J = 4.0 Hz, 2H), 2.42-2.40 (m, 4H), 2.09 (brs, 3H), 2.02 (t, J = 4.0 Hz, 2H), 1.89-1.88 (m, 6H), 1.77-1.72 (m, 6H); 13C-NMR (100 MHz, CDCl3)δ 166.8, 166.3, 154.9, 151.1, 145.7, 126.7, 126.5, 126.3, 123.0, 120.9, 114.4, 110.3, 68.0, 66.9, 55.2, 53.7, 52.0, 43.4, 36.7, 35.7, 28.9; HRMS [M+H] calcd [C33H43N2O6]: 563.3121, Found: 563.3121; Purity100%(as determined by RP-HPLC, method A, tR = 13.38 min). 1 H-NMR (400 MHz, CDCl 3 ) δ 9.05 (s, 1H), 9.04 (s, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 8.0 Hz, 2H), 6.94-6.92 (m, 3H), 4.62 (s, 2H), 4.16 (t, J = 4.0 Hz, 2H), 3.90 (s, 3H), 3.69-3.68 (m, 4H), 2.53 (t, J = 4.0 Hz, 2H), 2.42-2.40 (m, 4H), 2.09 (brs, 3H), 2.02 (t, J = 4.0 Hz, 2H), 1.89-1.88 (m, 6H), 1.77-1.72 (m, 6H ); 13 C-NMR (100 MHz, CDCl 3 ) δ 166.8, 166.3, 154.9, 151.1, 145.7, 126.7, 126.5, 126.3, 123.0, 120.9, 114.4, 110.3, 68.0, 66.9, 55.2, 53.7, 52.0, 43.4, 36.7, 35.7, 28.9; HRMS [M + H] calcd [C 33 H 43 N 2 O 6 ]: 563.3121, Found: 563.3121; Purity 100% (as determined by RP-HPLC, method A, tR = 13.38 min).
화합물 3-24. : 메틸 4-메톡시-3-(2-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)아세트아미도)벤조에이트 (Methyl 4-methoxy-3-(2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acetamido)benzoate) Compound 3-24. : Methyl 4-methoxy-3- (2- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) acetamido) benzoate (Methyl 4-methoxy-3- (2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamido) benzoate)
Methyl 4-hydroxy-3-(2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acetamido)benzoate (1.0 equiv), anhydrous potassium carbonate (3.0 equiv) 및 methyl iodide (2.0 equiv)를 DMF에 혼합하고 이를 상온에서 밤새 교반한 후, 감압하여 농축한 뒤, 얻어진 잔사를 EtOAc로 희석하고, sodium bicarbonate, 물 및 brine으로 세척하였다. 유기층을 모아 무수 황산마그네슘 (anhydrous MgSO4)으로 수분을 제거한 후, 감압하에 농축하였다. 상기 농축액을 실리카겔 컬럼 크로마토그래피로 정제하여 메틸 4-메톡시-3-(2-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)아세트아미도)벤조에이트를 수득하였다 (흰색 고체, 0.08 g, 77.6 % 수율).Methyl 4-hydroxy-3- (2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamido) benzoate (1.0 equiv), anhydrous potassium carbonate (3.0 equiv) and methyl iodide (2.0 equiv) The mixture was mixed with DMF and stirred at room temperature overnight, concentrated under reduced pressure, and the obtained residue was diluted with EtOAc, washed with sodium bicarbonate, water and brine. After collection of the organic layer was removed, the dried over anhydrous magnesium sulfate (anhydrous MgSO 4), and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to afford methyl 4-methoxy-3- (2- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) acetamido) benzoate (White solid, 0.08 g, 77.6% yield).
1H-NMR (400 MHz, CDCl3)δ 9.03 (s, 1H), 8.97 (s, 1H), 7.85-7.83 (m, 1H), 7.33 (d, J = 8.0 Hz, 2H), 6.93-6.90 (m, 3H), 4.63 (s, 2H), 3.93 (s, 3H), 3.89 (s, 3H), 1.71 (s, 2H), 1.35 (s, 6H), 0.71 (s, 9H); 13C-NMR (100 MHz, CDCl3)δ 166.7, 166.5, 154.8, 151.9, 144.1, 127.5, 126.8, 126.5, 123.1, 121.1, 114.1, 109.6, 67.9, 56.9, 56.1, 52.0, 38.1, 32.3, 31.8, 31.7; HRMS [M+H] calcd [C25H34NO5]: 428.2437, Found: 428.2437; Purity100%(as determined by RP-HPLC, method A, tR = 27.91 min). 1 H-NMR (400 MHz, CDCl 3 ) δ 9.03 (s, 1H), 8.97 (s, 1H), 7.85-7.83 (m, 1H), 7.33 (d, J = 8.0 Hz, 2H), 6.93-6.90 (m, 3H), 4.63 (s, 2H), 3.93 (s, 3H), 3.89 (s, 3H), 1.71 (s, 2H), 1.35 (s, 6H), 0.71 (s, 9H); 13 C-NMR (100 MHz, CDCl 3 ) δ 166.7, 166.5, 154.8, 151.9, 144.1, 127.5, 126.8, 126.5, 123.1, 121.1, 114.1, 109.6, 67.9, 56.9, 56.1, 52.0, 38.1, 32.3, 31.8, 31.7; HRMS [M + H] calcd [C 25 H 34 NO 5 ]: 428.2437, Found: 428.2437; Purity 100% (as determined by RP-HPLC, method A, tR = 27.91 min).
화합물 3-25. : 메틸 4-(2-메톡시에톡시)-3-(2-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)아세트아미도)벤조에이트 (Methyl 4-(2-methoxyethoxy)-3-(2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acetamido)benzoate) Compound 3-25. : Methyl 4- (2-methoxyethoxy) -3- (2- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) acetamido) benzoate (Methyl 4- ( 2-methoxyethoxy) -3- (2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamido) benzoate)
Methyl 4-hydroxy-3-(2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acetamido)benzoate (1.0 equiv), anhydrous potassium carbonate (3.0 equiv) 및 1-chloro-2-methoxyethane (2.0 equiv)를 DMF 에 혼합하고 이를 상온에서 밤새 교반한 후, 감압하여 농축한 뒤, 얻어진 잔사를 EtOAc로 희석하고, sodium bicarbonate, 물 및 brine으로 세척하였다. 유기층을 모아 무수 황산마그네슘 (anhydrous MgSO4)으로 수분을 제거한 후, 감압하에 농축하였다. 상기 농축액을 실리카겔 컬럼 크로마토그래피로 정제하여 메틸 4-(2-메톡시에톡시)-3-(2-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)아세트아미도)벤조에이트를 수득하였다 (흰색 고체, 0.10 g, 87.7 % 수율).Methyl 4-hydroxy-3- (2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamido) benzoate (1.0 equiv), anhydrous potassium carbonate (3.0 equiv) and 1-chloro-2- The methoxyethane (2.0 equiv) was mixed with DMF, stirred at room temperature overnight, concentrated under reduced pressure, and the obtained residue was diluted with EtOAc, washed with sodium bicarbonate, water and brine. After collection of the organic layer was removed, the dried over anhydrous magnesium sulfate (anhydrous MgSO 4), and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to give methyl 4- (2-methoxyethoxy) -3- (2- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) acetami Benzoate was obtained (white solid, 0.10 g, 87.7% yield).
1H-NMR (400 MHz, CDCl3)δ 9.15 (s, 1H), 9.06 (s, 1H), 7.83-7.80 (m, 1H), 7.32 (d, J = 8.0 Hz, 2H), 6.94-6.90 (m, 3H), 4.62 (s, 2H), 4.23 (t, J = 4.0 Hz, 2H), 3.89 (s, 3H), 3.78 (t, J = 4.0 Hz, 2H), 3.44 (s, 3H), 1.71 (s, 2H), 1.34 (s, 6H), 0.70 (s, 9H); 13C-NMR (100 MHz, CDCl3)δ 166.7, 166.4, 154.8, 151.0, 144.0, 127.4, 126.9, 126.6, 123.4, 121.0, 114.0, 110.7, 70.7, 68.4, 67.0, 59.2, 57.0, 52.0, 38.1, 32.3, 31.8, 31.6; HRMS [M+H] calcd [C27H38NO6]: 472.2699, Found: 472.2699; Purity100%(as determined by RP-HPLC, method A, tR = 27.57 min). 1 H-NMR (400 MHz, CDCl 3 ) δ 9.15 (s, 1H), 9.06 (s, 1H), 7.83-7.80 (m, 1H), 7.32 (d, J = 8.0 Hz, 2H), 6.94-6.90 (m, 3H), 4.62 (s, 2H), 4.23 (t, J = 4.0 Hz, 2H), 3.89 (s, 3H), 3.78 (t, J = 4.0 Hz, 2H), 3.44 (s, 3H) , 1.71 (s, 2 H), 1.34 (s, 6 H), 0.70 (s, 9 H); 13 C-NMR (100 MHz, CDCl 3 ) δ 166.7, 166.4, 154.8, 151.0, 144.0, 127.4, 126.9, 126.6, 123.4, 121.0, 114.0, 110.7, 70.7, 68.4, 67.0, 59.2, 57.0, 52.0, 38.1, 32.3, 31.8, 31.6; HRMS [M + H] calcd [C 27 H 38 NO 6 ]: 472.2699, Found: 472.2699; Purity 100% (as determined by RP-HPLC, method A, tR = 27.57 min).
화합물 3-26. : 메틸 4-(2-모르폴리노에톡시)-3-(2-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)아세트아미도)벤조에이트 (Methyl 4-(2-morpholinoethoxy)-3-(2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acetamido)benzoate)Compound 3-26. : Methyl 4- (2-morpholinoethoxy) -3- (2- (4- (2,4,4-trimethylpentane-2-yl) phenoxy) acetamido) benzoate (Methyl 4- (2-morpholinoethoxy) -3- (2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamido) benzoate)
Methyl 4-hydroxy-3-(2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acetamido)benzoate (1.0 equiv), anhydrous potassium carbonate (3.0 equiv) 및 4-(2-chloroethyl)morpholine (2.0 equiv)을 DMF에 혼합하고 이를 상온에서 밤새 교반한 후, 감압하여 농축한 뒤, 얻어진 잔사를 EtOAc로 희석하고, sodium bicarbonate, 물 및 brine으로 세척하였다. 유기층을 모아 무수 황산마그네슘 (anhydrous MgSO4)으로 수분을 제거한 후, 감압하에 농축하였다. 상기 농축액을 실리카겔 컬럼 크로마토그래피로 정제하여 메틸 4-(2-모르폴리노에톡시)-3-(2-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)아세트아미도)벤조에이트를 수득하였다 (흰색 고체, 0.09 g, 70.8 % 수율).Methyl 4-hydroxy-3- (2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamido) benzoate (1.0 equiv), anhydrous potassium carbonate (3.0 equiv) and 4- (2-chloroethyl ) morpholine (2.0 equiv) was mixed with DMF, stirred at room temperature overnight, concentrated under reduced pressure, and the obtained residue was diluted with EtOAc, washed with sodium bicarbonate, water and brine. After collection of the organic layer was removed, the dried over anhydrous magnesium sulfate (anhydrous MgSO 4), and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to afford methyl 4- (2-morpholinoethoxy) -3- (2- (4- (2,4,4-trimethylpentane-2-yl) phenoxy) acetate. Amido) benzoate was obtained (white solid, 0.09 g, 70.8% yield).
1H-NMR (400 MHz, CDCl3)δ 9.06 (s, 1H), 9.04 (s, 1H), 7.84-7.81 (m, 1H), 7.32 (d, J = 8.0 Hz, 2H), 6.93-6.88 (m, 3H), 4.62 (s, 2H), 4.21 (t, J = 4.0 Hz, 2H), 3.90 (s, 3H), 3.69-3.66 (m, 4H), 2.83 (t, J = 4.0 Hz, 2H), 2.56-2.54 (m, 4H), 1.71 (s, 2H), 1.34 (s, 6H), 0.71 (s, 9H); 13C-NMR (100 MHz, CDCl3)δ 166.7, 166.4, 154.8, 151.0, 144.3, 127.5, 126.7, 123.3, 121.1, 114.1, 110.6, 68.1, 66.9, 66.8, 57.5, 56.9, 54.0, 52.1, 38.1, 32.3, 31.8, 31.6; HRMS [M+H] calcd [C30H43N2O6]: 527.3121, Found: 527.3121; Purity100%(as determined by RP-HPLC, method A, tR = 12.9 min). 1 H-NMR (400 MHz, CDCl 3 ) δ 9.06 (s, 1H), 9.04 (s, 1H), 7.84-7.81 (m, 1H), 7.32 (d, J = 8.0 Hz, 2H), 6.93-6.88 (m, 3H), 4.62 (s, 2H), 4.21 (t, J = 4.0 Hz, 2H), 3.90 (s, 3H), 3.69-3.66 (m, 4H), 2.83 (t, J = 4.0 Hz, 2H), 2.56-2.54 (m, 4H), 1.71 (s, 2H), 1.34 (s, 6H), 0.71 (s, 9H); 13 C-NMR (100 MHz, CDCl 3 ) δ 166.7, 166.4, 154.8, 151.0, 144.3, 127.5, 126.7, 123.3, 121.1, 114.1, 110.6, 68.1, 66.9, 66.8, 57.5, 56.9, 54.0, 52.1, 38.1, 32.3, 31.8, 31.6; HRMS [M + H] calcd [C 30 H 43 N 2 O 6 ]: 527.3121, Found: 527.3121; Purity 100% (as determined by RP-HPLC, method A, tR = 12.9 min).
화합물 3-27. : 메틸 4-(프로프-2-인일옥시)-3-(2-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)아세트아미도)벤조에이트 (Methyl 4-(prop-2-ynyloxy)-3-(2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acetamido)benzoate) Compound 3-27. : Methyl 4- (prop-2-ynyloxy) -3- (2- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) acetamido) benzoate (Methyl 4- (prop-2-ynyloxy) -3- (2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamido) benzoate)
Methyl 4-hydroxy-3-(2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acetamido)benzoate (1.0 equiv), anhydrous potassium carbonate (3.0 equiv) 및 propargyl bromide (2.0 equiv)를 DMF에 혼합하고 이를 상온에서 밤새 교반한 후, 감압하여 농축한 뒤, 얻어진 잔사를 EtOAc로 희석하고, sodium bicarbonate, 물 및 brine으로 세척하였다. 유기층을 모아 무수 황산마그네슘 (anhydrous MgSO4)으로 수분을 제거한 후, 감압하에 농축하였다. 상기 농축액을 실리카겔 컬럼 크로마토그래피로 정제하여 메틸 4-(프로프-2-인일옥시)-3-(2-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)아세트아미도)벤조에이트를 수득하였다 (흰색 고체, 0.10 g, 91.7 % 수율).Methyl 4-hydroxy-3- (2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamido) benzoate (1.0 equiv), anhydrous potassium carbonate (3.0 equiv) and propargyl bromide (2.0 equiv) The mixture was mixed with DMF and stirred at room temperature overnight, concentrated under reduced pressure, and the obtained residue was diluted with EtOAc, washed with sodium bicarbonate, water and brine. After collection of the organic layer was removed, the dried over anhydrous magnesium sulfate (anhydrous MgSO 4), and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to afford methyl 4- (prop-2-ynyloxy) -3- (2- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) acetate. Amido) benzoate was obtained (white solid, 0.10 g, 91.7% yield).
1H-NMR (400 MHz, CDCl3)δ 9.06 (s, 1H), 9.02 (s, 1H), 7.85-7.83 (m, 1H), 7.33 (d, J = 8.0 Hz, 2H), 7.04 (d, J = 8.0 Hz, 1H), 6.92 (d, J = 8.0 Hz, 2H), 4.81 (s, 2H), 4.63 (s, 2H), 3.90 (s, 3H), 2.60 (t, J = 4.0 Hz, 2H), 1.71 (s, 2H), 1.34 (s, 6H), 0.71 (s, 9H); 13C-NMR (100 MHz, CDCl3)δ 166.6, 166.4, 154.8, 149.8, 144.1, 127.4, 127.0, 126.5, 124.1, 121.4, 114.1, 111.1, 67.8, 57.0, 56.8, 52.1, 38.1, 32.3, 31.9, 31.8, 31.6; HRMS [M+H] calcd [C27H34NO5]: 452.2437, Found: 452.2437; Purity100%(as determined by RP-HPLC, method A, tR = 27.33 min). 1 H-NMR (400 MHz, CDCl 3 ) δ 9.06 (s, 1H), 9.02 (s, 1H), 7.85-7.83 (m, 1H), 7.33 (d, J = 8.0 Hz, 2H), 7.04 (d , J = 8.0 Hz, 1H), 6.92 (d, J = 8.0 Hz, 2H), 4.81 (s, 2H), 4.63 (s, 2H), 3.90 (s, 3H), 2.60 (t, J = 4.0 Hz , 2H), 1.71 (s, 2H), 1.34 (s, 6H), 0.71 (s, 9H); 13 C-NMR (100 MHz, CDCl 3 ) δ 166.6, 166.4, 154.8, 149.8, 144.1, 127.4, 127.0, 126.5, 124.1, 121.4, 114.1, 111.1, 67.8, 57.0, 56.8, 52.1, 38.1, 32.3, 31.9, 31.8, 31.6; HRMS [M + H] calcd [C 27 H 34 NO 5 ]: 452.2437, Found: 452.2437; Purity 100% (as determined by RP-HPLC, method A, tR = 27.33 min).
화합물 3-28. : 메틸 4-(4-메톡시벤질옥시)-3-(2-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)아세트아미도)벤조에이트 (Methyl 4-(4-methoxybenzyloxy)-3-(2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acetamido)benzoate) Compound 3-28. : Methyl 4- (4-methoxybenzyloxy) -3- (2- (4- (2,4,4-trimethylpentin-2-yl) phenoxy) acetamido) benzoate (Methyl 4- ( 4-methoxybenzyloxy) -3- (2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamido) benzoate)
Methyl 4-hydroxy-3-(2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acetamido)benzoate (1.0 equiv), anhydrous potassium carbonate (3.0 equiv) 및 p-methoxy benzyl chloride (2.0 equiv)을 DMF에 혼합하고 이를 상온에서 밤새 교반한 후, 감압하여 농축한 뒤, 얻어진 잔사를 EtOAc로 희석하고, sodium bicarbonate, 물 및 brine으로 세척하였다. 유기층을 모아 무수 황산마그네슘 (anhydrous MgSO4)으로 수분을 제거한 후, 감압하에 농축하였다. 상기 농축액을 실리카겔 컬럼 크로마토그래피로 정제하여 메틸 4-(4-메톡시벤질옥시)-3-(2-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)아세트아미도)벤조에이트를 수득하였다 (흰색 고체, 0.11 g, 85.2 % 수율).Methyl 4-hydroxy-3- (2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamido) benzoate (1.0 equiv), anhydrous potassium carbonate (3.0 equiv) and p -methoxy benzyl chloride ( 2.0 equiv) was mixed with DMF, stirred at room temperature overnight, concentrated under reduced pressure, and the obtained residue was diluted with EtOAc and washed with sodium bicarbonate, water and brine. After collection of the organic layer was removed, the dried over anhydrous magnesium sulfate (anhydrous MgSO 4), and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to give methyl 4- (4-methoxybenzyloxy) -3- (2- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) acetami Benzoate was obtained (white solid, 0.11 g, 85.2% yield).
1H-NMR (400 MHz, CDCl3)δ 9.20 (s, 1H), 9.09 (s, 1H), 7.86-7.83 (m, 1H), 7.39 (d, J = 8.0 Hz, 2H), 7.21 (d, J = 8.0 Hz, 2H), 7.03 (d, J = 8.0 Hz, 2H), 6.96 (d, J = 8.0 Hz, 2H), 6.53 (d, J = 8.0 Hz, 2H), 5.08 (s, 2H), 4.54 (s, 2H), 3.90 (s, 3H), 3.87 (s, 3H), 1.71 (s, 2H), 1.34 (s, 6H), 0.71 (s, 9H); 13C-NMR (100 MHz, CDCl3)δ 166.8, 166.2, 160.0, 154.6, 151.0, 143.9, 129.9, 129.8, 127.6, 127.2, 126.9, 126.6, 123.3, 120.6, 114.3, 113.9, 110.6, 70.9, 67.5, 57.0, 55.3, 52.0, 38.0, 32.3, 31.8, 31.6; HRMS [M+H] calcd [C32H40NO6]: 534.2856, Found: 534.2856; Purity100%(as determined by RP-HPLC, method A, tR = 30.37 min). 1 H-NMR (400 MHz, CDCl 3 ) δ 9.20 (s, 1H), 9.09 (s, 1H), 7.86-7.83 (m, 1H), 7.39 (d, J = 8.0 Hz, 2H), 7.21 (d , J = 8.0 Hz, 2H), 7.03 (d, J = 8.0 Hz, 2H), 6.96 (d, J = 8.0 Hz, 2H), 6.53 (d, J = 8.0 Hz, 2H), 5.08 (s, 2H ), 4.54 (s, 2H), 3.90 (s, 3H), 3.87 (s, 3H), 1.71 (s, 2H), 1.34 (s, 6H), 0.71 (s, 9H); 13 C-NMR (100 MHz, CDCl 3 ) δ 166.8, 166.2, 160.0, 154.6, 151.0, 143.9, 129.9, 129.8, 127.6, 127.2, 126.9, 126.6, 123.3, 120.6, 114.3, 113.9, 110.6, 70.9, 67.5, 57.0, 55.3, 52.0, 38.0, 32.3, 31.8, 31.6; HRMS [M + H] calcd [C 32 H 40 NO 6 ]: 534.2856, Found: 534.2856; Purity 100% (as determined by RP-HPLC, method A, tR = 30.37 min).
화합물 3-29. : 메틸 3-(2-(4-아다만테인-1-일-페녹시)-2-메틸프로판아미도)벤조에이트 (Methyl 3-(2-(4-adamantan-1-yl-phenoxy)-2-methylpropanamido)benzoate) Compound 3-29. : Methyl 3- (2- (4-adamantane-1-yl-phenoxy) -2-methylpropaneamido) benzoate (Methyl 3- (2- (4-adamantan-1-yl-phenoxy)- 2-methylpropanamido) benzoate)
2-(4-adamantan-1-yl-phenoxy)-2-methylpropanoic acid (1.0 equiv), methyl 3-aminobenzoate (1.0 equiv)를 DMF에 혼합하여 이를 EDC·HCl (1.2 equiv), HOBT (1.2 equiv) 및 DIPEA (2.5 equiv)를 첨가하였다. 반응 혼합물을 상온에서 밤새 교반한 후, 감압하여 농축한 뒤, 얻어진 잔사를 EtOAc로 희석하고, 물 및 brine으로 세척하였다. 유기층을 모아 무수 황산마그네슘 (anhydrous MgSO4)으로 수분을 제거한 후, 감압하에 농축하였다. 상기 농축액을 실리카겔 컬럼 크로마토그래피로 정제하여 메틸 3-(2-(4-아다만테인-1-일-페녹시)-2-메틸프로판아미도)벤조에이트를 수득하였다 (흰색 고체, 0.12 g, 84.5 % 수율).2- (4-adamantan-1-yl-phenoxy) -2-methylpropanoic acid (1.0 equiv) and methyl 3-aminobenzoate (1.0 equiv) were mixed with DMF and mixed with EDCHCl (1.2 equiv) and HOBT (1.2 equiv). And DIPEA (2.5 equiv). The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the residue obtained was diluted with EtOAc and washed with water and brine. After collection of the organic layer was removed, the dried over anhydrous magnesium sulfate (anhydrous MgSO 4), and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to give methyl 3- (2- (4-adamantane-1-yl-phenoxy) -2-methylpropaneamido) benzoate (white solid, 0.12 g, 84.5% yield).
1H-NMR (400 MHz, CDCl3)δ 8.74 (s, 1H) 8.14 (t, J =2.0 Hz, 1H), 7.95-7.92 (m, 1H), 7.82-7.79 (m, 1H), 7.43 (t, J = 8.0 Hz, 1H), 7.27 (d, J = 9.2Hz, 2H), 6.93 (d, J = 8.4 Hz, 2H), 3.91 (s, 3H), 2.09 (brs, 3H), 1.88-1.86 (m, 6H), 1.76-1.74 (m, 6H), 1.57 (s, 6H); 13C-NMR (100 MHz, CDCl3)δ 173.5, 166.7, 151.3, 147.2, 137.8, 131.0, 129.2, 125.8, 125.4, 124.1, 121.5, 120.6, 81.8, 52.2, 43.3, 36.7, 35.8, 28.9, 25.0; HRMS (EI) m/z [M+H] calcd [C28H34NO]: 4448.2488, found: 448.2488; Purity100%(as determined by RP-HPLC, method A, tR = 29.60 min). 1 H-NMR (400 MHz, CDCl 3 ) δ 8.74 (s, 1H) 8.14 (t, J = 2.0 Hz, 1H), 7.95-7.92 (m, 1H), 7.82-7.79 (m, 1H), 7.43 ( t, J = 8.0 Hz, 1H), 7.27 (d, J = 9.2 Hz, 2H), 6.93 (d, J = 8.4 Hz, 2H), 3.91 (s, 3H), 2.09 (brs, 3H), 1.88- 1.86 (m, 6H), 1.76-1.74 (m, 6H), 1.57 (s, 6H); 13 C-NMR (100 MHz, CDCl 3 ) δ 173.5, 166.7, 151.3, 147.2, 137.8, 131.0, 129.2, 125.8, 125.4, 124.1, 121.5, 120.6, 81.8, 52.2, 43.3, 36.7, 35.8, 28.9, 25.0; HRMS (EI) m / z [M + H] calcd [C 28 H 34 NO]: 4448.2488, found: 448.2488; Purity 100% (as determined by RP-HPLC, method A, tR = 29.60 min).
화합물 3-30. : 메틸 3-(2-메틸-2-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)프로판아미도)벤조에이트 (Methyl 3-(2-methyl-2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)propanamido)benzoate) Compound 3-30. : Methyl 3- (2-methyl-2- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) propaneamido) benzoate (Methyl 3- (2-methyl-2- ( 4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamido) benzoate)
2-methyl-2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)propanoic acid (1.0 equiv), methyl 3-aminobenzoate (1.0 equiv)를 DMF에 혼합하여 이를 EDC·HCl (1.2 equiv), HOBT (1.2 equiv) 및 DIPEA (2.5 equiv)를 첨가하였다. 반응 혼합물을 상온에서 밤새 교반한 후, 감압하여 농축한 뒤, 얻어진 잔사를 EtOAc로 희석하고, 물 및 brine으로 세척하였다. 유기층을 모아 무수 황산마그네슘 (anhydrous MgSO4)으로 수분을 제거한 후, 감압하에 농축하였다. 상기 농축액을 실리카겔 컬럼 크로마토그래피로 정제하여 메틸 3-(2-메틸-2-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)프로판아미도)벤조에이트를 수득하였다 (흰색 고체, 0.11 g, 75.8 % 수율).2-methyl-2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanoic acid (1.0 equiv) and methyl 3-aminobenzoate (1.0 equiv) were mixed with DMF and mixed with EDCHCl (1.2 equiv), HOBT (1.2 equiv) and DIPEA (2.5 equiv) were added. The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the residue obtained was diluted with EtOAc and washed with water and brine. After collection of the organic layer was removed, the dried over anhydrous magnesium sulfate (anhydrous MgSO 4), and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to afford methyl 3- (2-methyl-2- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) propaneamido) benzoate. (White solid, 0.11 g, 75.8% yield).
1H-NMR (400 MHz, CDCl3)δ 8.79 (s, 1H), 8.14 (t, J = 2.0 Hz, 1H), 7.96-7.93 (m, 1H), 7.82-7.80 (m, 1H), 7.43 (t, J = 8.0 Hz, 1H), 7.28 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 9.2 Hz, 2H), 3.91 (s, 3H), 1.71(s, 2H), 1.55 (s, 6H), 1.35 (s, 6H), 0.70 (s, 9H); 13C-NMR (100 MHz, CDCl3)δ 173.4, 166.6, 151.1, 145.8, 137.8, 130.9, 129.1, 127.1, 125.4, 124.1, 121.4, 120.7, 81.8, 57.1, 52.1, 38.1, 32.3, 31.7, 31.6, 24.9; HRMS (EI) m/z [M+H] calcd [C26H36NO4]: 426.2644, found: 426.2644; Purity100%(as determined by RP-HPLC, method A, tR = 28.88 min). 1 H-NMR (400 MHz, CDCl 3 ) δ 8.79 (s, 1H), 8.14 (t, J = 2.0 Hz, 1H), 7.96-7.93 (m, 1H), 7.82-7.80 (m, 1H), 7.43 (t, J = 8.0 Hz, 1H), 7.28 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 9.2 Hz, 2H), 3.91 (s, 3H), 1.71 (s, 2H), 1.55 (s, 6H), 1.35 (s, 6H), 0.70 (s, 9H); 13 C-NMR (100 MHz, CDCl 3 ) δ 173.4, 166.6, 151.1, 145.8, 137.8, 130.9, 129.1, 127.1, 125.4, 124.1, 121.4, 120.7, 81.8, 57.1, 52.1, 38.1, 32.3, 31.7, 31.6, 24.9; HRMS (EI) m / z [M + H] calcd [C 26 H 36 NO 4 ]: 426.2644, found: 426.2644; Purity 100% (as determined by RP-HPLC, method A, tR = 28.88 min).
화합물 3-31. : 메틸-4-하이드록시-3-(2-메틸-2-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)프로판아미도)벤조에이트(Methyl 4-hydroxy-3-(2-methyl-2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)propanamido)benzoate) Compound 3-31. : Methyl-4-hydroxy-3- (2-methyl-2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) benzoate (Methyl 4-hydroxy-3 -(2-methyl-2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamido) benzoate)
2-methyl-2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)propanoic acid (1.0 equiv), methyl 3-amino-4-hydroxybenzoate (1.0 equiv)를 DMF에 혼합하여 이를 EDC·HCl (1.2 equiv), HOBT (1.2 equiv) 및 DIPEA (2.5 equiv)를 첨가하였다. 반응 혼합물을 상온에서 밤새 교반한 후, 감압하여 농축한 뒤, 얻어진 잔사를 EtOAc로 희석하고, 물 및 brine으로 세척하였다. 유기층을 모아 무수 황산마그네슘 (anhydrous MgSO4)으로 수분을 제거한 후, 감압하에 농축하였다. 상기 농축액을 실리카겔 컬럼 크로마토그래피로 정제하여 메틸-4-하이드록시-3-(2-메틸-2-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)프로판아미도)벤조에이트를 수득하였다 (흰색 고체, 0.03 g, 83.2 % 수율).2-methyl-2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanoic acid (1.0 equiv) and methyl 3-amino-4-hydroxybenzoate (1.0 equiv) were mixed with DMF and EDC HCl (1.2 equiv), HOBT (1.2 equiv) and DIPEA (2.5 equiv) were added. The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the residue obtained was diluted with EtOAc and washed with water and brine. After collection of the organic layer was removed, the dried over anhydrous magnesium sulfate (anhydrous MgSO 4), and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to prepare methyl-4-hydroxy-3- (2-methyl-2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) Obtained benzoate (white solid, 0.03 g, 83.2% yield).
1H-NMR (400 MHz, CDCl3)δ 10.1 (s, 1H), 9.09 (s, 1H), 7.82 (dd, J = 8.6 Hz, 1H), 7.77 (d, J = 2.0 Hz, 1H), 7.32 (d, J = 8.6 Hz, 2H), 7.05 (d, J = 8.6 Hz, 1H), 6.93 (d, J = 8.6 Hz, 2H), 3.87 (s, 3H), 1.72 (s, 2H), 1.57 (s, 6H), 1.37 (s, 6H), 0.71 (s, 9H); 13C-NMR (100 MHz, CDCl3)δ 175.7, 166.3, 153.2, 150.5, 146.5, 128.9, 127.2, 124.9, 124.2, 122.2, 122.0, 119.7, 81.7, 57.1, 52.0, 38.2, 32.3, 31.7, 31.5, 24.9; HRMS [M+H] calcd [C26H36NO5]: 442.2515, Found: 442.2576; Purity100%(as determined by RP-HPLC, method A, tR = 16.29 min). 1 H-NMR (400 MHz, CDCl 3 ) δ 10.1 (s, 1H), 9.09 (s, 1H), 7.82 (dd, J = 8.6 Hz, 1H), 7.77 (d, J = 2.0 Hz, 1H), 7.32 (d, J = 8.6 Hz, 2H), 7.05 (d, J = 8.6 Hz, 1H), 6.93 (d, J = 8.6 Hz, 2H), 3.87 (s, 3H), 1.72 (s, 2H), 1.57 (s, 6H), 1.37 (s, 6H), 0.71 (s, 9H); 13 C-NMR (100 MHz, CDCl 3 ) δ 175.7, 166.3, 153.2, 150.5, 146.5, 128.9, 127.2, 124.9, 124.2, 122.2, 122.0, 119.7, 81.7, 57.1, 52.0, 38.2, 32.3, 31.7, 31.5, 24.9; HRMS [M + H] calcd [C 26 H 36 NO 5 ]: 442.2515, Found: 442.2576; Purity 100% (as determined by RP-HPLC, method A, tR = 16.29 min).
화합물 3-32. : 메틸 3-[4-(4-아다만테인-1-일-페녹시)부탄아미도]벤조에이트 (Methyl 3-[4-(4-adamantan-1-yl-phenoxy)butanamido]benzoate) Compound 3-32. : Methyl 3- [4- (4-adamantane-1-yl-phenoxy) butanamido] benzoate (Methyl 3- [4- (4-adamantan-1-yl-phenoxy) butanamido] benzoate)
4-(4-(adamantan-1-yl)phenoxy)butanoic acid (1.0 equiv), methyl 3-aminobenzoate (1.0 equiv)를 DMF에 혼합하여 이를 EDC·HCl (1.2 equiv), HOBT (1.2 equiv) 및 DIPEA (2.5 equiv)를 첨가하였다. 반응 혼합물을 상온에서 밤새 교반한 후, 감압하여 농축한 뒤, 얻어진 잔사를 EtOAc로 희석하고, 물 및 brine으로 세척하였다. 유기층을 모아 무수 황산마그네슘 (anhydrous MgSO4)으로 수분을 제거한 후, 감압하에 농축하였다. 상기 농축액을 실리카겔 컬럼 크로마토그래피로 정제하여 메틸 3-[4-(4-아다만테인-1-일-페녹시)부탄아미도]벤조에이트를 수득하였다 (흰색 고체, 0.11 g, 77.5 % 수율).4- (4- (adamantan-1-yl) phenoxy) butanoic acid (1.0 equiv), methyl 3-aminobenzoate (1.0 equiv) were mixed with DMF and mixed with EDCHCl (1.2 equiv), HOBT (1.2 equiv) and DIPEA (2.5 equiv) was added. The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the residue obtained was diluted with EtOAc and washed with water and brine. After collection of the organic layer was removed, the dried over anhydrous magnesium sulfate (anhydrous MgSO 4), and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to afford methyl 3- [4- (4-adamantane-1-yl-phenoxy) butanamido] benzoate (white solid, 0.11 g, 77.5% yield). .
1H-NMR (400 MHz, CDCl3)δ 8.35 (s, 1H), 7.83 (d, J = 7.6 Hz, 1H), 7.78 (d, J = 7.6 Hz, 1H), 7.4 (d, J = 8.0 Hz, 2H), 7.28 (s, 1H), 6.86 (d, J = 8.8 Hz, 2H), 4.06 (t, J = 6.0 Hz, 2H), 3.90 (s, 3H), 2.60 (t, J = 7.2 Hz, 2H), 2.18-2.24 (m, 2H), 2.08 (brs, 3H), 1.88-1.86 (m, 6H), 1.76-1.74 (m, 6H); 13C-NMR (100 MHz, CDCl3)δ 170.9, 166.7, 156.4, 144.1, 138.1, 130.9, 129.2, 125.8, 125.3, 124.2, 120.6, 114.0, 66.8, 52.2, 43.4, 36.8, 35.6, 34.2, 30.9, 29.0, 25.1; HRMS (EI) m/z [M+H] calcd [C28H33NO4]: 448.2488, found: 448.2478; Purity100%(as determined by RP-HPLC, method A, tR = 27.50 min). 1 H-NMR (400 MHz, CDCl 3 ) δ 8.35 (s, 1H), 7.83 (d, J = 7.6 Hz, 1H), 7.78 (d, J = 7.6 Hz, 1H), 7.4 (d, J = 8.0 Hz, 2H), 7.28 (s, 1H), 6.86 (d, J = 8.8 Hz, 2H), 4.06 (t, J = 6.0 Hz, 2H), 3.90 (s, 3H), 2.60 (t, J = 7.2 Hz, 2H), 2.18-2.24 (m, 2H), 2.08 (brs, 3H), 1.88-1.86 (m, 6H), 1.76-1.74 (m, 6H); 13 C-NMR (100 MHz, CDCl 3 ) δ 170.9, 166.7, 156.4, 144.1, 138.1, 130.9, 129.2, 125.8, 125.3, 124.2, 120.6, 114.0, 66.8, 52.2, 43.4, 36.8, 35.6, 34.2, 30.9, 29.0, 25.1; HRMS (EI) m / z [M + H] calcd [C 28 H 33 NO 4 ]: 448.2488, found: 448.2478; Purity 100% (as determined by RP-HPLC, method A, tR = 27.50 min).
화합물 3-33. : 메틸 3-(4-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)부탄아미도)벤조에이트 (Methyl 3-(4-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)butanamido)benzoate) Compound 3-33. : Methyl 3- (4- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) butaneamido) benzoate (Methyl 3- (4- (4- (2,4,4) -trimethylpentan-2-yl) phenoxy) butanamido) benzoate)
4-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)butanoic acid (1.0 equiv), methyl 3-aminobenzoate (1.0 equiv)를 DMF에 혼합하여 이를 EDC·HCl (1.2 equiv), HOBT (1.2 equiv) 및 DIPEA (2.5 equiv)를 첨가하였다. 반응 혼합물을 상온에서 밤새 교반한 후, 감압하여 농축한 뒤, 얻어진 잔사를 EtOAc로 희석하고, 물 및 brine으로 세척하였다. 유기층을 모아 무수 황산마그네슘 (anhydrous MgSO4)으로 수분을 제거한 후, 감압하에 농축하였다. 상기 농축액을 실리카겔 컬럼 크로마토그래피로 정제하여 메틸 3-(4-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)부탄아미도)벤조에이트를 수득하였다 (흰색 고체, 0.12 g, 82.7 % 수율).4- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) butanoic acid (1.0 equiv) and methyl 3-aminobenzoate (1.0 equiv) were mixed with DMF and mixed with EDCHCl (1.2 equiv) and HOBT (1.2 equiv) and DIPEA (2.5 equiv) were added. The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the residue obtained was diluted with EtOAc and washed with water and brine. After collection of the organic layer was removed, the dried over anhydrous magnesium sulfate (anhydrous MgSO 4), and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to give methyl 3- (4- (4- (4- (2,4,4-trimethylpentane-2-yl) phenoxy) butanamido) benzoate (white solid, 0.12 g, 82.7% yield).
1H-NMR (400 MHz, CDCl3)δ 8.05 (s, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.77 (d, J = 7.6 Hz, 1H), 7.49 (s, 1H), 7.38 (t, J = 8.0 Hz, 1H), 7.26 (d, J = 8.4 Hz, 2H), 6.82 (d, J = 8.8 Hz, 2H), 4.04 (t, J = 6.6 Hz, 4H), 3.91 (s, 3H), 2.61 (t, J = 7.2 Hz, 2H), 2.26-2.19 (m, 2H), 1.70 (s, 2H), 1.34 (s, 6H), 0.71 (s, 9H); 13C-NMR (100 MHz, CDCl3)δ 171.5, 166.9, 156.3, 142.4, 138.4, 130.6, 129.0, 127.0, 125.1, 124.5, 120.8, 113.6, 66.8, 56.9, 52.2, 37.9, 34.0, 32.7, 31.7, 31.6, 25.1; HRMS (EI) m/z [M+H] calcd [C26H36NO4]: 426.2644, found: 426.2644; Purity100%(as determined by RP-HPLC, method A, tR = 26.93 min). 1 H-NMR (400 MHz, CDCl 3 ) δ 8.05 (s, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.77 (d, J = 7.6 Hz, 1H), 7.49 (s, 1H), 7.38 (t, J = 8.0 Hz, 1H), 7.26 (d, J = 8.4 Hz, 2H), 6.82 (d, J = 8.8 Hz, 2H), 4.04 (t, J = 6.6 Hz, 4H), 3.91 ( s, 3H), 2.61 (t, J = 7.2 Hz, 2H), 2.26-2.19 (m, 2H), 1.70 (s, 2H), 1.34 (s, 6H), 0.71 (s, 9H); 13 C-NMR (100 MHz, CDCl 3 ) δ 171.5, 166.9, 156.3, 142.4, 138.4, 130.6, 129.0, 127.0, 125.1, 124.5, 120.8, 113.6, 66.8, 56.9, 52.2, 37.9, 34.0, 32.7, 31.7, 31.6, 25.1; HRMS (EI) m / z [M + H] calcd [C 26 H 36 NO 4 ]: 426.2644, found: 426.2644; Purity 100% (as determined by RP-HPLC, method A, tR = 26.93 min).
화합물 3-34. : 메틸 4-하이드록시-3-(4-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)부탄아미도)벤조에이트 (Methyl 4-hydroxy-3-(4-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)butanamido)benzoate) Compound 3-34. : Methyl 4-hydroxy-3- (4- (4- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) butanamido) benzoate (Methyl 4-hydroxy-3- (4- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) butanamido) benzoate)
4-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)butanoic acid (1.0 equiv), methyl 3-amino-4-hydroxybenzoate (1.0 equiv)를 DMF에 혼합하여 이를 EDC·HCl (1.2 equiv), HOBT (1.2 equiv) 및 DIPEA (2.5 equiv)를 첨가하였다. 반응 혼합물을 상온에서 밤새 교반한 후, 감압하여 농축한 뒤, 얻어진 잔사를 EtOAc로 희석하고, 물 및 brine으로 세척하였다. 유기층을 모아 무수 황산마그네슘 (anhydrous MgSO4)으로 수분을 제거한 후, 감압하에 농축하였다. 상기 농축액을 실리카겔 컬럼 크로마토그래피로 정제하여 메틸 4-하이드록시-3-(4-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)부탄아미도)벤조에이트를 수득하였다 (흰색 고체, 0.10 g, 66.2 % 수율).4- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) butanoic acid (1.0 equiv) and methyl 3-amino-4-hydroxybenzoate (1.0 equiv) were mixed with DMF and added to EDCHCl (1.2 equiv), HOBT (1.2 equiv) and DIPEA (2.5 equiv) were added. The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the residue obtained was diluted with EtOAc and washed with water and brine. After collection of the organic layer was removed, the dried over anhydrous magnesium sulfate (anhydrous MgSO 4), and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to afford methyl 4-hydroxy-3- (4- (4- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) butanamido) benzoate (White solid, 0.10 g, 66.2% yield).
1H-NMR (400 MHz, CDCl3)δ 8.10 (s, 1H), 7.80 (dd, J = 2.0, 6.4 Hz, 1H), 7.72 (d, J = 1.6 Hz, 1H), 7.26 (d, J =8.4 Hz, 2H), 7.01 (d, J = 8.4 Hz, 1H), 6.80 (d, J =8.8 Hz, 2H), 4.06 (t, J = 5.6 Hz, 2H), 3.86 (s, 3H), 2.72 (t, J = 7.2 Hz, 6.8 Hz, 2H), 2.24-2.21 (m, 2H), 1.69 (s, 2H), 1.33 (s, 6H), 0.70 (s, 9H); 13C-NMR (100 MHz, CDCl3)δ 173.8, 166.8, 156.1, 153.4, 142.8, 128.7, 127.1, 125.8, 124.3, 121.9, 119.6, 113.6 66.7, 56.9, 52.2, 38.0, 33.6, 32.3, 31.8, 31.6, 25.2; HRMS (EI) m/z [M+H] calcd [C26H36NO5]: 442.2593, found: 442.2593; Purity100%(as determined by RP-HPLC, method A, tR = 25.63 min). 1 H-NMR (400 MHz, CDCl 3 ) δ 8.10 (s, 1H), 7.80 (dd, J = 2.0, 6.4 Hz, 1H), 7.72 (d, J = 1.6 Hz, 1H), 7.26 (d, J = 8.4 Hz, 2H), 7.01 (d, J = 8.4 Hz, 1H), 6.80 (d, J = 8.8 Hz, 2H), 4.06 (t, J = 5.6 Hz, 2H), 3.86 (s, 3H), 2.72 (t, J = 7.2 Hz, 6.8 Hz, 2H), 2.24-2.21 (m, 2H), 1.69 (s, 2H), 1.33 (s, 6H), 0.70 (s, 9H); 13 C-NMR (100 MHz, CDCl 3 ) δ 173.8, 166.8, 156.1, 153.4, 142.8, 128.7, 127.1, 125.8, 124.3, 121.9, 119.6, 113.6 66.7, 56.9, 52.2, 38.0, 33.6, 32.3, 31.8, 31.6 , 25.2; HRMS (EI) m / z [M + H] calcd [C 26 H 36 NO 5 ]: 442.2593, found: 442.2593; Purity 100% (as determined by RP-HPLC, method A, tR = 25.63 min).
1-2. 화합물 6-1 내지 화합물 6-9의 합성1-2. Synthesis of Compound 6-1 to Compound 6-9
하기 화합물 6-1 내지 화합물 6-9는 도 1에 기재된 바와 같이 화합물 1을 출발물질로 하여 화합물 4 및 화합물 5를 중간체로 거쳐 합성하였다. Compounds 6-1 to 6-9 were synthesized through Compound 4 and Compound 5 as intermediates, using Compound 1 as a starting material as described in FIG.
먼저, 화합물 4 및 화합물 5의 합성 공정은 다음과 같다. First, the synthesis process of compound 4 and compound 5 is as follows.
화합물 4 합성 공정: 화합물 1 (1.0 equiv) 및 메틸 프로피올레이트 (2.0 equiv)의 톨루엔 내 혼합물을 -10 oC에서 Ph3P (1.0equiv)에 첨가하였다. 상기 혼합물을 115 oC까지 가열하고 2시간 동안 교반하였다. 용매를 감압 조건 하에서 제거하고 잔사는 실리카 젤 컬럼 크로마토그래피로 정제하였다. Compound 4 Synthesis Process : A mixture in toluene of compound 1 (1.0 equiv) and methyl propiolate (2.0 equiv) was added to Ph 3 P (1.0 equiiv) at −10 ° C. The mixture was heated to 115 ° C. and stirred for 2 hours. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography.
화합물 5 합성 공정: THF/H2O(1:1) 내 에스테르 화합물 4 (1.0 equiv)의 현탁액을 리튬 하이드록사이드 모노하이드레이트 (3.0 equiv)에 첨가하였고, 상온에서 밤새 교반하였다. 반응 혼합물을 10% HCl으로 중성화하였고, EtOA로 희석하였으며, 연속하여 수용성 소듐 바이카보네이트, 브라인 및 물로 세척하였다. 유기층을 모아 무수 황산마그네슘 (anhydrous MgSO4)으로 수분을 제거하였다. 용매를 여과하고 감압 조건 하에서 증발시키고 실리카 젤 컬럼 크로마토그래피로 정제하여 조 건조체를 수득하였다. Compound 5 Synthesis Process: A suspension of ester compound 4 (1.0 equiv) in THF / H 2 O (1: 1) was added to lithium hydroxide monohydrate (3.0 equiv) and stirred overnight at room temperature. The reaction mixture was neutralized with 10% HCl, diluted with EtOA and washed successively with aqueous sodium bicarbonate, brine and water. The organic layer was collected and water was removed with anhydrous magnesium sulfate (anhydrous MgSO 4 ). The solvent was filtered off, evaporated under reduced pressure and purified by silica gel column chromatography to give a crude dry matter.
화합물 6-1. : (Compound 6-1. : (
EE
)-3-[3-(4-아다만테인-1-일-페녹시)-아크릴오일아미노]-벤조익 산 메틸 에스테르(() -3- [3- (4-adamantane-1-yl-phenoxy) -acryloylamino] -benzoic acid methyl ester ((
EE
)-3-[3-(4-Adamantan-1-yl-phenoxy)-acryloylamino]-benzoic acid methyl ester)) -3- [3- (4-Adamantan-1-yl-phenoxy) -acryloylamino] -benzoic acid methyl ester)
(E)-3-(4-(adamantan-1-yl)phenoxy)acrylic acid (1.0 equiv), methyl 3-aminobenzoate (1.0 equiv)를 DMF에 혼합하여 이를 EDC·HCl (1.2 equiv), HOBT (1.2 equiv) 및 DIPEA (2.5 equiv)를 첨가하였다. 반응 혼합물을 상온에서 밤새 교반한 후, 감압하여 농축한 뒤, 얻어진 잔사를 EtOAc로 희석하고, 물 및 brine으로 세척하였다. 유기층을 모아 무수 황산마그네슘 (anhydrous MgSO4)으로 수분을 제거한 후, 감압하에 농축하였다. 상기 농축액을 실리카겔 컬럼 크로마토그래피로 정제하여 (E)-3-[3-(4-Adamantan-1-yl-phenoxy)-acryloylamino]-benzoic acid methyl ester를 수득하였다 (흰색 고체, 0.23 g, 88.5 % 수율).( E ) -3- (4- (adamantan-1-yl) phenoxy) acrylic acid (1.0 equiv) and methyl 3-aminobenzoate (1.0 equiv) were mixed with DMF and added to EDCHCl (1.2 equiv), HOBT (1.2 equiv) and DIPEA (2.5 equiv) were added. The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the residue obtained was diluted with EtOAc and washed with water and brine. After collection of the organic layer was removed, the dried over anhydrous magnesium sulfate (anhydrous MgSO 4), and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to give ( E ) -3- [3- (4-Adamantan-1-yl-phenoxy) -acryloylamino] -benzoic acid methyl ester (white solid, 0.23 g, 88.5%). yield).
1H-NMR (CDCl3, 300MHz)δ 8.06 (s, 1H), 7.89-7.95 (m, 2H), 7.77 (d, J = 7.5 Hz, 1H), 7.33-7.42 (m, 3H), 7.02 (d, J = 8.7 Hz, 2H), 5.68 (d, J = 11.7 Hz, 1H), 3.90 (s, 3H), 2.11 (m, 3H), 1.90 (m, 6H), 1.77 (m, 6H); HRMS (EI) m/z calcd for C27H29NO4 [M+H] 431.2097, found:431.2101. 1 H-NMR (CDCl 3 , 300 MHz) δ 8.06 (s, 1H), 7.89-7.95 (m, 2H), 7.77 (d, J = 7.5 Hz, 1H), 7.33-7.42 (m, 3H), 7.02 ( d, J = 8.7 Hz, 2H), 5.68 (d, J = 11.7 Hz, 1H), 3.90 (s, 3H), 2.11 (m, 3H), 1.90 (m, 6H), 1.77 (m, 6H); HRMS (EI) m / z calcd for C 27 H 29 NO 4 [M + H] 431. 2097, found: 431.2101.
화합물 6-2. :(Compound 6-2. :(
EE
)-3-3-[4-(2,4,4-트리메틸펜탄-2-일)페녹시]아크릴아미도벤조익 산 메틸 에스테르(() -3-3- [4- (2,4,4-trimethylpentan-2-yl) phenoxy] acrylamidobenzoic acid methyl ester ((
EE
)-3-3-[4-(2,4,4-Trimethylpentan-2-yl)phenoxy]acrylamidobenzoic acid methyl ester) ) -3-3- [4- (2,4,4-Trimethylpentan-2-yl) phenoxy] acrylamidobenzoic acid methyl ester)
(E)-3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acrylic acid (1.0 equiv), methyl 3-aminobenzoate (1.0 equiv)를 DMF에 혼합하여 이를 EDC·HCl (1.2 equiv), HOBT (1.2 equiv) 및 DIPEA (2.5 equiv)를 첨가하였다. 반응 혼합물을 상온에서 밤새 교반한 후, 감압하여 농축한 뒤, 얻어진 잔사를 EtOAc로 희석하고, 물 및 brine으로 세척하였다. 유기층을 모아 무수 황산마그네슘 (anhydrous MgSO4)으로 수분을 제거한 후, 감압하에 농축하였다. 상기 농축액을 실리카겔 컬럼 크로마토그래피로 정제하여 (E)-3-3-[4-(2,4,4-트리메틸펜탄-2-일)페녹시]아크릴아미도벤조익 산 메틸 에스테르를 수득하였다 (흰색 고체, 0.07 g, 62.8 % 수율).( E ) -3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylic acid (1.0 equiv) and methyl 3-aminobenzoate (1.0 equiv) were mixed with DMF to give EDCHCl (1.2 equiv), HOBT (1.2 equiv) and DIPEA (2.5 equiv) were added. The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the residue obtained was diluted with EtOAc and washed with water and brine. After collection of the organic layer was removed, the dried over anhydrous magnesium sulfate (anhydrous MgSO 4), and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to give ( E ) -3-3- [4- (2,4,4-trimethylpentan-2-yl) phenoxy] acrylamidobenzoic acid methyl ester ( White solid, 0.07 g, 62.8% yield).
1H-NMR (DMSO, 300 MHz) δ 8.05 (m, 1H), 7.89-7.93 (m, 2H), 7.78 (d, J = 7.8 Hz, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.37 (d, J = 8.4 Hz, 2H), 7.11 (s, 1H), 7.00 (d, J = 8.7 Hz, 2H), 5.66 (d, J = 11.4 Hz, 1H), 3.91 (s, 3H), 1.73 (s, 2H), 1.37 (s, 6H), 0.72 (s, 9H); HRMS (EI) m/z calcd for C25H31NO4 [M+] 409.2253, found: 409.2256. 1 H-NMR (DMSO, 300 MHz) δ 8.05 (m, 1H), 7.89-7.93 (m, 2H), 7.78 (d, J = 7.8 Hz, 1H), 7.41 (d, J = 8.4 Hz, 1H) , 7.37 (d, J = 8.4 Hz, 2H), 7.11 (s, 1H), 7.00 (d, J = 8.7 Hz, 2H), 5.66 (d, J = 11.4 Hz, 1H), 3.91 (s, 3H) , 1.73 (s, 2 H), 1.37 (s, 6 H), 0.72 (s, 9 H); HRMS (EI) m / z calcd for C 25 H 31 NO 4 [M + ] 409.2253, found: 409.2256.
화합물 6-3. : (Compound 6-3. : (
EE
)-메틸4-메틸-3-(3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)아크릴아미도)벤조에이트(() -Methyl4-methyl-3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate ((
EE
)-methyl 4-methyl-3-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acrylamido)benzoate) ) -methyl 4-methyl-3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate)
(E)-3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acrylic acid (1.0 equiv), methyl 3-amino-4-methylbenzoate (1.0 equiv)를 DMF에 혼합하여 이를 HATU (1.2 equiv) 및 DIPEA (0.7 equiv)를 첨가하였다. 반응 혼합물을 상온에서 밤새 교반한 후, 감압하여 농축한 뒤, 얻어진 잔사를 EtOAc로 희석하고, 물 및 brine으로 세척하였다. 유기층을 모아 무수 황산마그네슘 (anhydrous MgSO4)으로 수분을 제거한 후, 감압하에 농축하였다. 상기 농축액을 실리카겔 컬럼 크로마토그래피로 정제하여 (E)-메틸4-메틸-3-(3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)아크릴아미도)벤조에이트를 수득하였다 (흰색 고체, 0.04 g, 40.2 % 수율).( E ) -3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylic acid (1.0 equiv) and methyl 3-amino-4-methylbenzoate (1.0 equiv) were mixed with DMF and HATU (1.2 equiv) and DIPEA (0.7 equiv) were added. The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the residue obtained was diluted with EtOAc and washed with water and brine. After collection of the organic layer was removed, the dried over anhydrous magnesium sulfate (anhydrous MgSO 4), and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to give ( E ) -methyl4-methyl-3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate Obtained (white solid, 0.04 g, 40.2% yield).
1H-NMR (400 MHz, CDCl3)δ 7.93 (d, J = 11.6 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.37 (d, J = 8.4 Hz, 2H), 7.29 (s, 1H), 7.01 (d, J = 8.8 Hz, 2H), 6.80 (s, 1H), 5.69 (d, J = 10.8, 1H), 3.90 (s, 3H), 2.33 (s, 3H), 1.72 (s, 2H), 1.36 (s, 6H), 0.70 (s, 9H); Purity99.99%(as determined by RP-HPLC, method A, tR = 26.11 min). 1 H-NMR (400 MHz, CDCl 3 ) δ 7.93 (d, J = 11.6 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.37 (d, J = 8.4 Hz, 2H), 7.29 ( s, 1H), 7.01 (d, J = 8.8 Hz, 2H), 6.80 (s, 1H), 5.69 (d, J = 10.8, 1H), 3.90 (s, 3H), 2.33 (s, 3H), 1.72 (s, 2H), 1.36 (s, 6H), 0.70 (s, 9H); Purity 99.9% (as determined by RP-HPLC, method A, tR = 26.11 min).
화합물 6-4. (Compound 6-4. (
EE
)-메틸2-메틸-5-(3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)아크릴아미도)벤조에이트(() -Methyl2-methyl-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate ((
EE
)-methyl 2-methyl-5-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acrylamido)benzoate) ) -methyl 2-methyl-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate)
(E)-3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acrylic acid (1.0 equiv), methyl 5-amino-2-methylbenzoate (1.0 equiv)를 DMF에 혼합하여 이를 HATU (1.2 equiv) 및 DIPEA (0.7 equiv)를 첨가하였다. 반응 혼합물을 상온에서 밤새 교반한 후, 감압하여 농축한 뒤, 얻어진 잔사를 EtOAc로 희석하고, 물 및 brine으로 세척하였다. 유기층을 모아 무수 황산마그네슘 (anhydrous MgSO4)으로 수분을 제거한 후, 감압하에 농축하였다. 상기 농축액을 실리카겔 컬럼 크로마토그래피로 정제하여 (E)-메틸2-메틸-5-(3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)아크릴아미도)벤조에이트를 수득하였다 (흰색 고체, 0.04 g, 40.2 % 수율).( E ) -3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylic acid (1.0 equiv) and methyl 5-amino-2-methylbenzoate (1.0 equiv) were mixed with DMF and HATU (1.2 equiv) and DIPEA (0.7 equiv) were added. The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the residue obtained was diluted with EtOAc and washed with water and brine. After collection of the organic layer was removed, the dried over anhydrous magnesium sulfate (anhydrous MgSO 4), and concentrated under reduced pressure. The concentrated solution was purified by silica gel column chromatography ( E ) -methyl2-methyl-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate Obtained (white solid, 0.04 g, 40.2% yield).
1H-NMR (400 MHz, CDCl3):δ 8.03 (s, 1H), 7.89 (d, J = 11.6 Hz, 1H), 7.70 (d, J = 6.4 Hz, 1H), 7.53 (s, 1H), 7.34 (d, J = 8.4 Hz, 2H), 7.18 (d, J = 8.4 Hz, 1H), 6.97 (d, J = 8.4 Hz, 2H), 5.71 (d, J = 12.0 Hz, 1H), 3.84 (s, 3H), 2.54 (s, 3H), 1.71 (s, 2H), 1.35 (s, 6H), 0.70 (s, 9H); Purity99.99%(as determined by RP-HPLC, method A, tR = 27.35 min). 1 H-NMR (400 MHz, CDCl 3 ): δ 8.03 (s, 1H), 7.89 (d, J = 11.6 Hz, 1H), 7.70 (d, J = 6.4 Hz, 1H), 7.53 (s, 1H) , 7.34 (d, J = 8.4 Hz, 2H), 7.18 (d, J = 8.4 Hz, 1H), 6.97 (d, J = 8.4 Hz, 2H), 5.71 (d, J = 12.0 Hz, 1H), 3.84 (s, 3H), 2.54 (s, 3H), 1.71 (s, 2H), 1.35 (s, 6H), 0.70 (s, 9H); Purity 99.9% (as determined by RP-HPLC, method A, tR = 27.35 min).
화합물 6-5. : (Compound 6-5. : (
EE
)-메틸2-하이드록시-5-(3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)아크릴아미도)벤조에이트(() -Methyl2-hydroxy-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate ((
EE
)-methyl 2-hydroxy-5-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acrylamido)benzoate) ) -methyl 2-hydroxy-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate)
(E)-3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acrylic acid (1.0 equiv), methyl 5-amino-2-hydroxybenzoate (1.0 equiv)를 DMF에 혼합하여 이를 HATU (1.2 equiv) 및 DIPEA (0.7 equiv)를 첨가하였다. 반응 혼합물을 상온에서 밤새 교반한 후, 감압하여 농축한 뒤, 얻어진 잔사를 EtOAc로 희석하고, 물 및 brine으로 세척하였다. 유기층을 모아 무수 황산마그네슘 (anhydrous MgSO4)으로 수분을 제거한 후, 감압하에 농축하였다. 상기 농축액을 실리카겔 컬럼 크로마토그래피로 정제하여 (E)-메틸2-하이드록시-5-(3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)아크릴아미도)벤조에이트를 수득하였다 (흰색 고체, 0.03 g, 29.9 % 수율).( E ) -3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylic acid (1.0 equiv) and methyl 5-amino-2-hydroxybenzoate (1.0 equiv) were mixed with DMF and HATU (1.2 equiv) and DIPEA (0.7 equiv) were added. The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the residue obtained was diluted with EtOAc and washed with water and brine. After collection of the organic layer was removed, the dried over anhydrous magnesium sulfate (anhydrous MgSO 4), and concentrated under reduced pressure. The concentrated solution was purified by silica gel column chromatography to give ( E ) -methyl2-hydroxy-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzo Obtain was obtained (white solid, 0.03 g, 29.9% yield).
1H-NMR (400 MHz, CDCl3)δ 10.63 (s, 1H), 8.13 (s, 1H), 7.88 (d, J = 11.6 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.35-7.33 (m, 3H), 6.97 (d, J = 8.4 Hz, 2H), 6.93 (d, J = 8.8 Hz, 1H), 5.68 (d, J = 12.0 Hz, 1H), 3.90 (s, 3H), 1.71 (s, 2H), 1.35 (s, 6H), 0.70 (s, 9H); Purity99.99%(as determined by RP-HPLC, method A, tR = 26.40 min). 1 H-NMR (400 MHz, CDCl 3 ) δ 10.63 (s, 1H), 8.13 (s, 1H), 7.88 (d, J = 11.6 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.35-7.33 (m, 3H), 6.97 (d, J = 8.4 Hz, 2H), 6.93 (d, J = 8.8 Hz, 1H), 5.68 (d, J = 12.0 Hz, 1H), 3.90 (s, 3H ), 1.71 (s, 2H), 1.35 (s, 6H), 0.70 (s, 9H); Purity 99.9% (as determined by RP-HPLC, method A, tR = 26.40 min).
화합물 6-6. : (Compound 6-6. : (
EE
)-이소프로필 3-(3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)아크릴아미도)벤조에이트(() -Isopropyl 3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate ((
EE
)-isopropyl 3-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acrylamido)benzoate)) -isopropyl 3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate)
(E)-3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acrylic acid (1.0 equiv), isopropyl 3-aminobenzoate (1.0 equiv)를 DMF에 혼합하여 이를 HATU (1.2 equiv) 및 DIPEA (0.7 equiv)를 첨가하였다. 반응 혼합물을 상온에서 밤새 교반한 후, 감압하여 농축한 뒤, 얻어진 잔사를 EtOAc로 희석하고, 물 및 brine으로 세척하였다. 유기층을 모아 무수 황산마그네슘 (anhydrous MgSO4)으로 수분을 제거한 후, 감압하에 농축하였다. 상기 농축액을 실리카겔 컬럼 크로마토그래피로 정제하여 (E)-이소프로필 3-(3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)아크릴아미도)벤조에이트를 수득하였다 (흰색 고체, 0.05 g, 48.2 % 수율).( E ) -3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylic acid (1.0 equiv) and isopropyl 3-aminobenzoate (1.0 equiv) were mixed with DMF and HATU (1.2 equiv) And DIPEA (0.7 equiv). The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the residue obtained was diluted with EtOAc and washed with water and brine. After collection of the organic layer was removed, the dried over anhydrous magnesium sulfate (anhydrous MgSO 4), and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to give ( E ) -isopropyl 3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate (White solid, 0.05 g, 48.2% yield).
1H-NMR (400 MHz, CDCl3) δ 7.99 (brs, 2H), 7.92 (d, J = 11.6 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.42-7.35 (m, 3H), 7.31 (s, 1H), 7.00 (d, J = 9.2 Hz, 2H), 5.70 (d, J = 11.6 Hz, 1H), 5.28-5.21 (m, 1H), 1.72 (s, 2H), 1.37-1.35 (m, 12H), 0.70 (s, 9H); Purity99.99%(as determined by RP-HPLC, method A, tR = 28.62 min). 1 H-NMR (400 MHz, CDCl 3 ) δ 7.99 (brs, 2H), 7.92 (d, J = 11.6 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.42-7.35 (m, 3H ), 7.31 (s, 1H), 7.00 (d, J = 9.2 Hz, 2H), 5.70 (d, J = 11.6 Hz, 1H), 5.28-5.21 (m, 1H), 1.72 (s, 2H), 1.37 -1.35 (m, 12H), 0.70 (s, 9H); Purity 99.99% (as determined by RP-HPLC, method A, tR = 28.62 min).
화합물 6-7. : (Compound 6-7. : (
EE
)-메틸 2,4-다이메틸-5-(3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)아크릴아미도)벤조에이트(() -Methyl 2,4-dimethyl-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate ((
EE
)-methyl 2,4-dimethyl-5-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acrylamido)benzoate) ) -methyl 2,4-dimethyl-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate)
(E)-3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acrylic acid (1.0 equiv), methyl 5-amino-2,4-dimethylbenzoate (1.0 equiv)를 DMF에 혼합하여 이를 HATU (1.2 equiv) 및 DIPEA (0.7 equiv)를 첨가하였다. 반응 혼합물을 상온에서 밤새 교반한 후, 감압하여 농축한 뒤, 얻어진 잔사를 EtOAc로 희석하고, 물 및 brine으로 세척하였다. 유기층을 모아 무수 황산마그네슘 (anhydrous MgSO4)으로 수분을 제거한 후, 감압하에 농축하였다. 상기 농축액을 실리카겔 컬럼 크로마토그래피로 정제하여 (E)-메틸 2,4-다이메틸-5-(3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)아크릴아미도)벤조에이트를 수득하였다 (흰색 고체, 0.07 g, 57.3 % 수율).( E ) -3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylic acid (1.0 equiv) and methyl 5-amino-2,4-dimethylbenzoate (1.0 equiv) were mixed with DMF It was added HATU (1.2 equiv) and DIPEA (0.7 equiv). The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the residue obtained was diluted with EtOAc and washed with water and brine. After collection of the organic layer was removed, the dried over anhydrous magnesium sulfate (anhydrous MgSO 4), and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to give ( E ) -methyl 2,4-dimethyl-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido ) Benzoate was obtained (white solid, 0.07 g, 57.3% yield).
1H-NMR (400 MHz, CDCl3)δ 8.33 (s, 1H), 7.91 (d, J = 11.6 Hz, 1H), 7.35 (d, J = 8.8 Hz, 2H), 7.06 (s, 1H), 6.99 (d, J = 8.4, 2H), 6.91 (s, 1H), 5.70 (brs, 1H), 3.85 (s, 3H), 2.54 (s, 3H), 2.25 (s, 3H), 1.72 (s, 2H), 1.35 (s, 6H), 0.70 (s, 9H) ; Purity99.99%(as determined by RP-HPLC, method A, tR = 27.02 min). 1 H-NMR (400 MHz, CDCl 3 ) δ 8.33 (s, 1H), 7.91 (d, J = 11.6 Hz, 1H), 7.35 (d, J = 8.8 Hz, 2H), 7.06 (s, 1H), 6.99 (d, J = 8.4, 2H), 6.91 (s, 1H), 5.70 (brs, 1H), 3.85 (s, 3H), 2.54 (s, 3H), 2.25 (s, 3H), 1.72 (s, 2H), 1.35 (s, 6H), 0.70 (s, 9H); Purity 99.9% (as determined by RP-HPLC, method A, tR = 27.02 min).
화합물 6-8. : (Compound 6-8. : (
EE
)-3H-[1,2,3]트리아졸로[4,5-b]피리딘-3-일 3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)아크릴레이트 (() -3H- [1,2,3] triazolo [4,5-b] pyridin-3-yl 3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylate ( (
EE
)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl 3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acrylate) ) -3H- [1,2,3] triazolo [4,5-b] pyridin-3-yl 3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylate)
(E)-3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acrylic acid (1.0 equiv), methyl 5-aminothiophene-2-carboxylate (1.0 equiv)를 DMF에 혼합하여 이를 HATU (1.2 equiv) 및 DIPEA (0.7 equiv)를 첨가하였다. 반응 혼합물을 상온에서 밤새 교반한 후, 감압하여 농축한 뒤, 얻어진 잔사를 EtOAc로 희석하고, 물 및 brine으로 세척하였다. 유기층을 모아 무수 황산마그네슘 (anhydrous MgSO4)으로 수분을 제거한 후, 감압하에 농축하였다. 상기 농축액을 실리카겔 컬럼 크로마토그래피로 정제하여 (E)-3H-[1,2,3]트리아졸로[4,5-b]피리딘-3-일 3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)아크릴레이트를 수득하였다 (흰색 고체, 0.05 g, 44.6 % 수율).( E ) -3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylic acid (1.0 equiv) and methyl 5-aminothiophene-2-carboxylate (1.0 equiv) were mixed with DMF and HATU (1.2 equiv) and DIPEA (0.7 equiv) were added. The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the residue obtained was diluted with EtOAc and washed with water and brine. After collection of the organic layer was removed, the dried over anhydrous magnesium sulfate (anhydrous MgSO 4), and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography ( E ) -3H- [1,2,3] triazolo [4,5-b] pyridin-3-yl 3- (4- (2,4,4-trimethyl Pentan-2-yl) phenoxy) acrylate was obtained (white solid, 0.05 g, 44.6% yield).
1H-NMR (400 MHz, CDCl3)δ 8.74 (d, J = 4.4 Hz, 1H), 8.44 (d, J = 8.0 Hz, 1H), 8.18 (d, J = 12.0 Hz, 1H), 7.46-7.41 (m, 3H), 7.06 (d, J = 8.8 Hz, 2H), 5.83 (d, J = 12.0 Hz, 1H), 1.75 (s, 2H), 1.37 (s, 6H), 0.71(s, 9H). 1 H-NMR (400 MHz, CDCl 3 ) δ 8.74 (d, J = 4.4 Hz, 1H), 8.44 (d, J = 8.0 Hz, 1H), 8.18 (d, J = 12.0 Hz, 1H), 7.46- 7.41 (m, 3H), 7.06 (d, J = 8.8 Hz, 2H), 5.83 (d, J = 12.0 Hz, 1H), 1.75 (s, 2H), 1.37 (s, 6H), 0.71 (s, 9H ).
화합물 6-9. : (Compound 6-9. : (
EE
)-1H-벤조[d][1,2,3]트리아졸-1-일 3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)아크릴레이트(() -1H-benzo [d] [1,2,3] triazol-1-yl 3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylate ((
EE
)-1H-benzo[d][1,2,3]triazol-1-yl 3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acrylate) ) -1H-benzo [d] [1,2,3] triazol-1-yl 3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylate)
(E)-3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acrylic acid (1.0 equiv), methyl 2-aminoisonicotinate (1.0 equiv)를 DMF에 혼합하여 이를 HATU (1.2 equiv) 및 DIPEA (0.7 equiv)를 첨가하였다. 반응 혼합물을 상온에서 밤새 교반한 후, 감압하여 농축한 뒤, 얻어진 잔사를 EtOAc로 희석하고, 물 및 brine으로 세척하였다. 유기층을 모아 무수 황산마그네슘 (anhydrous MgSO4)으로 수분을 제거한 후, 감압하에 농축하였다. 상기 농축액을 실리카겔 컬럼 크로마토그래피로 정제하여 (E)-1H-벤조[d][1,2,3]트리아졸-1-일 3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)아크릴레이트를 수득하였다 (흰색 고체, 0.05 g, 54.0 % 수율).( E ) -3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylic acid (1.0 equiv) and methyl 2-aminoisonicotinate (1.0 equiv) were mixed with DMF and HATU (1.2 equiv) And DIPEA (0.7 equiv). The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the residue obtained was diluted with EtOAc and washed with water and brine. After collection of the organic layer was removed, the dried over anhydrous magnesium sulfate (anhydrous MgSO 4), and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to give ( E ) -1H-benzo [d] [1,2,3] triazol-1-yl 3- (4- (2,4,4-trimethylpentan-2- I) phenoxy) acrylate was obtained (white solid, 0.05 g, 54.0% yield).
1H-NMR (400 MHz, CDCl3)δ 8.25 (d, J = 13.6 Hz, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.77 (d, J = 4.0 Hz, 2H), 7.56-7.52 (m, 1H), 7.41 (d, J = 8.8 Hz, 2H), 7.09 (d, J = 8.4 Hz, 2H), 6.71 (d, J = 13.6 Hz, 1H), 1.74 (s, 2H), 1.38 (s, 6H), 0.73 (s, 9H). 1 H-NMR (400 MHz, CDCl 3 ) δ 8.25 (d, J = 13.6 Hz, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.77 (d, J = 4.0 Hz, 2H), 7.56- 7.52 (m, 1H), 7.41 (d, J = 8.8 Hz, 2H), 7.09 (d, J = 8.4 Hz, 2H), 6.71 (d, J = 13.6 Hz, 1H), 1.74 (s, 2H), 1.38 (s, 6 H), 0.73 (s, 9 H).
화합물 6-10. : (Compound 6-10. : (
EE
)-메틸 4-하이드록시-3-(3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)아크릴아미도)벤조에이트(() -Methyl 4-hydroxy-3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate ((
EE
)-methyl 4-hydroxy-3-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acrylamido)benzoate)) -methyl 4-hydroxy-3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate)
(E)-3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acrylic acid (1.0 equiv), methyl 3-amino-4-hydroxybenzoate (1.0 equiv)를 DMF에 혼합하여 이를 EDC·HCl (1.2 equiv), HOBT (1.2 equiv) 및 DIPEA (2.5 equiv)를 첨가하였다. 반응 혼합물을 질소 하에 상온에서 밤새 교반한 후, 감압하여 농축한 뒤, 얻어진 잔사를 EtOAc로 희석하고, 물 및 brine으로 세척하였다. 유기층을 모아 무수 황산마그네슘 (anhydrous MgSO4)으로 수분을 제거한 후, 감압하에 농축하였다. 상기 농축액을 실리카겔 컬럼 크로마토그래피로 정제하여 (E)-메틸 4-하이드록시-3-(3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)아크릴아미도)벤조에이를 수득하였다 (흰색 고체, 0.01g, 56.2 % 수율).( E ) -3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylic acid (1.0 equiv) and methyl 3-amino-4-hydroxybenzoate (1.0 equiv) were mixed with DMF to give EDC HCl (1.2 equiv), HOBT (1.2 equiv) and DIPEA (2.5 equiv) were added. The reaction mixture was stirred at room temperature overnight under nitrogen, then concentrated under reduced pressure, and the obtained residue was diluted with EtOAc and washed with water and brine. After collection of the organic layer was removed, the dried over anhydrous magnesium sulfate (anhydrous MgSO 4), and concentrated under reduced pressure. The concentrated solution was purified by silica gel column chromatography ( E ) -methyl 4-hydroxy-3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzo A was obtained (white solid, 0.01 g, 56.2% yield).
1H-NMR (400 MHz, CDCl3)δ 10.47 (s, 1H), 7.97 (d, J = 11.2 Hz, 1H), 7.80 (dd, J = 2.0, 9.0 Hz, 1H), 7.67 (d, J = 2.0 Hz, 1H), 7.39 (d, J = 8.8 Hz, 2H), 7.00-7.02 (m, 3H), 5.73 (d, J = 11.2 Hz, 1H), 3.88 (s, 3H), 1.74 (s, 2H), 1.37 (s, 6H), 0.72 (s, 9H); 13C-NMR (100 MHz, CDCl3)δ 167.0, 166.7, 160.2, 153.8, 153.5, 147.3, 128.8, 127.7, 125.9, 124.2, 121.8, 120.0, 117.1, 101.8, 56.9, 52.1, 38.3, 32.3, 31.7, 31.6; HRMS (EI) m/z calcd for C25H32NO5 [M+H] 426.2202, found: 426.2286; Purity99.99%(as determined by RP-HPLC, method A, tR = 26.18 min). 1 H-NMR (400 MHz, CDCl 3 ) δ 10.47 (s, 1H), 7.97 (d, J = 11.2 Hz, 1H), 7.80 (dd, J = 2.0, 9.0 Hz, 1H), 7.67 (d, J = 2.0 Hz, 1H), 7.39 (d, J = 8.8 Hz, 2H), 7.00-7.02 (m, 3H), 5.73 (d, J = 11.2 Hz, 1H), 3.88 (s, 3H), 1.74 (s , 2H), 1.37 (s, 6H), 0.72 (s, 9H); 13 C-NMR (100 MHz, CDCl 3 ) δ 167.0, 166.7, 160.2, 153.8, 153.5, 147.3, 128.8, 127.7, 125.9, 124.2, 121.8, 120.0, 117.1, 101.8, 56.9, 52.1, 38.3, 32.3, 31.7, 31.6; HRMS (EI) m / z calcd for C 25 H 32 NO 5 [M + H] 426.2202, found: 426.2286; Purity 99.9% (as determined by RP-HPLC, method A, tR = 26.18 min).
1-3. 화합물 9-1 및 화합물 9-11의 합성1-3. Synthesis of Compound 9-1 and Compound 9-11
하기 화합물 9-1 내지 화합물 9-11은 도 1에 기재된 바와 같이 화합물 1을 출발물질로 하여 화합물 8을 중간체로 거쳐 합성하였다. Compounds 9-1 to 9-11 were synthesized through Compound 8 as an intermediate as Compound 1 as a starting material, as shown in FIG. 1.
먼저, 화합물 8의 합성 공정은 다음과 같다. First, the synthesis process of compound 8 is as follows.
화합물 8의 합성 공정: 아크릴산 메틸 에스테르 화합물 4 (1.0 equiv)의 메탄올 용액을 10% Pd/C (10% w/w)로 처리하였다. 반응물을 상온에서 1 atm 수소 기압 하에서 수소 첨가하였고, 반응 혼합물을 밤새 교반하였다. 반응 완료 후에, 혼합물을 Celite pad를 통해 여과하고 농축하였다. 결과물을 실리카젤 컬럼 크로마토그래피를 통해 정제하였다. 메틸 에스테르 화합물 7의 THF/H2O(1:1) 현탁액을 리튬 하이드록시 모노하이드레이트 (4.0equiv)에 첨가하였고, 상온에서 밤새 교반하였다. 반응 혼합물을 10% HCl으로 중성화하고, EtOA로 희석하고, 연속하여 수용성 소듐 바이카보네이트, 브라인 및 물로 세척하였다. 유기층을 모아 무수 황산마그네슘으로 건조하였다. 용매를 여과하고 감압 하에서 증발시키고 실리카 젤 컬럼 크로마토그래피를 이용해 정제하여 조 건조체를 수득하였다. Synthesis Process of Compound 8: A methanol solution of acrylic acid methyl ester compound 4 (1.0 equiv) was treated with 10% Pd / C (10% w / w). The reaction was hydrogenated at 1 atm hydrogen atmosphere at room temperature and the reaction mixture was stirred overnight. After completion of the reaction, the mixture was filtered through Celite pad and concentrated. The result was purified via silica gel column chromatography. A THF / H 2 O (1: 1) suspension of methyl ester compound 7 was added to lithium hydroxy monohydrate (4.0equiv) and stirred at room temperature overnight. The reaction mixture was neutralized with 10% HCl, diluted with EtOA and subsequently washed with water soluble sodium bicarbonate, brine and water. The organic layer was collected and dried over anhydrous magnesium sulfate. The solvent was filtered off, evaporated under reduced pressure and purified using silica gel column chromatography to give a crude dry matter.
화합물 9-1. :메틸 3-[3-(4-아다만테인-1-일-페녹시)프로판아미도]벤조에이트 (Methyl 3-(3-(4-(adamantan-1-yl)phenoxy)propanamido)benzoate)Compound 9-1. Methyl 3- (3- (4- (adamantan-1-yl) phenoxy) propanamido) benzoate): Methyl 3- [3- (4-adamantane-1-yl-phenoxy) propanamido] benzoate
3-(4-adamantan-1-yl-phenoxy)-propanoic acid (1.0 equiv) 및 methyl 3-aminobenzoate (1.0 equiv)를 DMF에 혼합하여 이를 EDC·HCl (1.2 equiv), HOBT (1.2 equiv) 및 DIPEA (2.5 equiv)에 첨가하였다. 반응 혼합물을 상온에서 밤새 교반한 후, 감압하여 농축한 뒤, 얻어진 잔사를 EtOAc로 희석하고, 물 및 brine으로 세척하였다. 유기층을 모아 무수 황산마그네슘 (anhydrous MgSO4)으로 수분을 제거한 후, 감압하에 농축하였다. 상기 농축액을 실리카겔 컬럼 크로마토그래피로 정제하여 메틸 3-[3-(4-아다만테인-1-일-페녹시)프로판아미도]벤조에이트를 수득하였다 (흰색 고체, 0.12 g, 83.3 % 수율).3- (4-adamantan-1-yl-phenoxy) -propanoic acid (1.0 equiv) and methyl 3-aminobenzoate (1.0 equiv) were mixed with DMF and mixed with EDCHCl (1.2 equiv), HOBT (1.2 equiv) and DIPEA. (2.5 equiv). The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the residue obtained was diluted with EtOAc and washed with water and brine. After collection of the organic layer was removed, the dried over anhydrous magnesium sulfate (anhydrous MgSO 4), and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to give methyl 3- [3- (4-adamantane-1-yl-phenoxy) propanamido] benzoate (white solid, 0.12 g, 83.3% yield) .
1H-NMR (400 MHz, CDCl3)δ 8.29 (s, 1H), 7.79-7.82 (m, 2H), 7.54 (d, J = 7.6 Hz, 1H), 7.48 (d, J = 8.0 Hz, 2H), 6.91 (d, J = 8.8 Hz, 2H), 4.32 (t, J = 6.0 Hz, 2H), 3.89 (s, 3H), 2.65 (t, J = 7.2 Hz, 2H), 2.02 (brs, 3H), 1.99-1.97 (m, 6H), 1.77-1.71 (m, 6H); 13C-NMR (100 MHz, CDCl3)δ 169.2, 166.7, 155.7, 144.9, 138.0, 130.9, 129.1, 126.1, 125.4, 124.4, 120.8, 114.2, 64.2, 52.2, 43.4, 36.8, 35.6, 29.6, 28.8; HRMS (EI) m/z [M+H] calcd [C27H31NO4]: 433.2253, found: 433.2257; Purity100%(as determined by RP-HPLC, method A, tR = 26.80 min). 1 H-NMR (400 MHz, CDCl 3 ) δ 8.29 (s, 1H), 7.79-7.82 (m, 2H), 7.54 (d, J = 7.6 Hz, 1H), 7.48 (d, J = 8.0 Hz, 2H ), 6.91 (d, J = 8.8 Hz, 2H), 4.32 (t, J = 6.0 Hz, 2H), 3.89 (s, 3H), 2.65 (t, J = 7.2 Hz, 2H), 2.02 (brs, 3H ), 1.99-1.97 (m, 6H), 1.77-1.71 (m, 6H); 13 C-NMR (100 MHz, CDCl 3 ) δ 169.2, 166.7, 155.7, 144.9, 138.0, 130.9, 129.1, 126.1, 125.4, 124.4, 120.8, 114.2, 64.2, 52.2, 43.4, 36.8, 35.6, 29.6, 28.8; HRMS (EI) m / z [M + H] calcd [C 27 H 31 NO 4 ]: 433.2253. Found: 433.2257; Purity 100% (as determined by RP-HPLC, method A, tR = 26.80 min).
화합물 9-2. : 메틸 3-(3-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)프로판아미도)벤조에이트 (Methyl 3-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)propanamido)benzoate) Compound 9-2. : Methyl 3- (3- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) propaneamido) benzoate (Methyl 3- (3- (4- (2,4,4) -trimethylpentan-2-yl) phenoxy) propanamido) benzoate)
3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)propanoic acid (1.0 equiv) 및 methyl 3-aminobenzoate (1.0 equiv)를 DMF에 혼합하여 이를 EDC·HCl (1.2 equiv), HOBT (1.2 equiv) 및 DIPEA (2.5 equiv)에 첨가하였다. 반응 혼합물을 상온에서 밤새 교반한 후, 감압하여 농축한 뒤, 얻어진 잔사를 EtOAc로 희석하고, 물 및 brine으로 세척하였다. 유기층을 모아 무수 황산마그네슘 (anhydrous MgSO4)으로 수분을 제거한 후, 감압하에 농축하였다. 상기 농축액을 실리카겔 컬럼 크로마토그래피로 정제하여 메틸 3-(3-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)프로판아미도)벤조에이트를 수득하였다 (흰색 고체, 0.13 g, 88.4 % 수율).3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanoic acid (1.0 equiv) and methyl 3-aminobenzoate (1.0 equiv) were mixed with DMF and mixed with EDCHCl (1.2 equiv), HOBT (1.2 equiv) and DIPEA (2.5 equiv). The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the residue obtained was diluted with EtOAc and washed with water and brine. After collection of the organic layer was removed, the dried over anhydrous magnesium sulfate (anhydrous MgSO 4), and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to afford methyl 3- (3- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) propaneamido) benzoate (white solid, 0.13 g, 88.4% yield).
1H-NMR (400 MHz, CDCl3)δ 8.18 (s, 1H), 8.07 (t, J = 1.6 Hz, 1H), 7.88-7.86 (m, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.38 (t, J = 8.0 Hz, 1H), 7.29 (d, J = 8.8 Hz, 2H), 6.86 (d, J = 9.2 Hz, 2H), 4.32 (t, J = 4.0 Hz, 2H), 3.89 (s, 3H), 2.85 (t, J = 4.0 Hz, 2H), 1.70 (s, 2H), 1.34 (s, 6H), 0.71 (s, 9H); 13C-NMR (100 MHz, CDCl3)δ 169.2, 166.7, 155.6, 143.4, 138.0, 130.9, 129.2, 127.3, 125.4, 124.4, 120.8, 113.8, 64.1, 56.9, 52.2, 38.0, 37.8, 32.3, 31.8, 31.6, 29.7; HRMS (EI) m/z [M+H] calcd [C25H34NO4]: 412.2488, found 412.2488; Purity100%(as determined by RP-HPLC, method A, tR = 26.00 min). 1 H-NMR (400 MHz, CDCl 3 ) δ 8.18 (s, 1H), 8.07 (t, J = 1.6 Hz, 1H), 7.88-7.86 (m, 1H), 7.77 (d, J = 8.0 Hz, 1H ), 7.38 (t, J = 8.0 Hz, 1H), 7.29 (d, J = 8.8 Hz, 2H), 6.86 (d, J = 9.2 Hz, 2H), 4.32 (t, J = 4.0 Hz, 2H), 3.89 (s, 3H), 2.85 (t, J = 4.0 Hz, 2H), 1.70 (s, 2H), 1.34 (s, 6H), 0.71 (s, 9H); 13 C-NMR (100 MHz, CDCl 3 ) δ 169.2, 166.7, 155.6, 143.4, 138.0, 130.9, 129.2, 127.3, 125.4, 124.4, 120.8, 113.8, 64.1, 56.9, 52.2, 38.0, 37.8, 32.3, 31.8, 31.6, 29.7; HRMS (EI) m / z [M + H] calcd [C 25 H 34 NO 4 ]: 412.2488, found 412.2488; Purity 100% (as determined by RP-HPLC, method A, tR = 26.00 min).
화합물 9-3. : 메틸 4-하이드록시-3-(3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)프로판아미도)벤조에이트(Methyl 4-hydroxy-3-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)propanamido)benzoate) Compound 9-3. : Methyl 4-hydroxy-3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) benzoate (Methyl 4-hydroxy-3- (3- ( 4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamido) benzoate)
3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)propanoic acid (1.0 equiv) 및 methyl 3-amino-4-hydroxybenzoate (1.0 equiv)를 DMF에 혼합하여 이를 EDC·HCl (1.2 equiv), HOBT (1.2 equiv) 및 DIPEA (2.5 equiv)에 첨가하였다. 반응 혼합물을 상온에서 밤새 교반한 후, 감압하여 농축한 뒤, 얻어진 잔사를 EtOAc로 희석하고, 물 및 brine으로 세척하였다. 유기층을 모아 무수 황산마그네슘 (anhydrous MgSO4)으로 수분을 제거한 후, 감압하에 농축하였다. 상기 농축액을 실리카겔 컬럼 크로마토그래피로 정제하여 메틸 4-하이드록시-3-(3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)프로판아미도)벤조에이트를 수득하였다 (흰색 고체, 0.01 g, 75.0 % 수율).3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanoic acid (1.0 equiv) and methyl 3-amino-4-hydroxybenzoate (1.0 equiv) were mixed with DMF to give EDCHCl (1.2 equiv), HOBT (1.2 equiv) and DIPEA (2.5 equiv). The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the residue obtained was diluted with EtOAc and washed with water and brine. After collection of the organic layer was removed, the dried over anhydrous magnesium sulfate (anhydrous MgSO 4), and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to afford methyl 4-hydroxy-3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) benzoate. (White solid, 0.01 g, 75.0% yield).
1H-NMR (400MHz, CDCl3)δ 9.74 (s, 1H), 8.36 (s, 1H), 7.81(dd, J = 2.0 Hz, 1H),7.67 (d, J = 2.0 Hz, 1H), 7.32 (d, J = 8.8 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 6.89 (d, J = 8.4 Hz, 2H), 4.35 (t, J = 5.4 Hz, 2H), 3.88 (s, 3H), 2.94 (t, J = 5.6 Hz, 2H), 1.71 (s, 2H), 1.34 (s, 6H), 0.71 (s, 9H); 13CNMR (100 MHz, CDCl3)δ 171.7, 166.4, 155.3, 153.2, 143.7, 128.9, 127.3, 125.5, 124.2, 122.1, 119.7, 113.9, 63.8, 56.9, 52.1, 38.0, 36.8, 32.3, 31.7, 31.6; HRMS (EI) m/z calcd for C25H34NO5 [M+H] 428.2359, found: 428.2431; Purity99.99%(as determined by RP-HPLC, method A, tR = 24.09 min). 1 H-NMR (400 MHz, CDCl 3 ) δ 9.74 (s, 1H), 8.36 (s, 1H), 7.81 (dd, J = 2.0 Hz, 1H), 7.07 (d, J = 2.0 Hz, 1H), 7.32 (d, J = 8.8 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 6.89 (d, J = 8.4 Hz, 2H), 4.35 (t, J = 5.4 Hz, 2H), 3.88 (s , 3H), 2.94 (t, J = 5.6 Hz, 2H), 1.71 (s, 2H), 1.34 (s, 6H), 0.71 (s, 9H); 13 CNMR (100 MHz, CDCl 3 ) δ 171.7, 166.4, 155.3, 153.2, 143.7, 128.9, 127.3, 125.5, 124.2, 122.1, 119.7, 113.9, 63.8, 56.9, 52.1, 38.0, 36.8, 32.3, 31.7, 31.6; HRMS (EI) m / z calcd for C 25 H 34 NO 5 [M + H] 428.2359, found: 428.2431; Purity 99.9% (as determined by RP-HPLC, method A, tR = 24.09 min).
화합물 9-4. : Compound 9-4. :
메틸methyl
4- 4-
메틸methyl
-3-(3-(4-(2,4,4--3- (3- (4- (2,4,4-
트리메틸펜탄Trimethylpentane
-2-일)-2 days)
페녹시Phenoxy
))
프로Pro
판아미도)벤조에이트(Methyl 4-methyl-3-(3-(4-(2,4,4-Panamido) benzoate (Methyl 4-methyl-3- (3- (4- (2,4,4-
trimethylpentantrimethylpentan
-2-yl)phenoxy)propanamido)benzoate) -2-yl) phenoxy) propanamido) benzoate)
3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)propanoic acid (1.0 equiv) 및 methyl 3-amino-4-methylbenzoate (1.2 equiv)를 THF에 혼합하여 이를 HATU (1.5 equiv) 및 DIPEA (1.5 equiv)에 첨가하였다. 반응 혼합물을 상온에서 밤새 교반한 후, 감압하여 농축한 뒤, 얻어진 잔사를 EtOAc로 희석하고, 물 및 brine으로 세척하였다. 유기층을 모아 무수 황산마그네슘 (anhydrous MgSO4)으로 수분을 제거한 후, 감압하에 농축하였다. 상기 농축액을 실리카겔 컬럼 크로마토그래피로 정제하여 메틸 4-메틸-3-(3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)프로판아미도)벤조에이트를 수득하였다 (흰색 고체, 0.02 g, 28.2 % 수율).3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanoic acid (1.0 equiv) and methyl 3-amino-4-methylbenzoate (1.2 equiv) were mixed with THF and HATU (1.5 equiv) And DIPEA (1.5 equiv). The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the residue obtained was diluted with EtOAc and washed with water and brine. After collection of the organic layer was removed, the dried over anhydrous magnesium sulfate (anhydrous MgSO 4), and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to afford methyl 4-methyl-3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) benzoate ( White solid, 0.02 g, 28.2% yield).
1H-NMR (500 MHz, CDCl3)δ 8.55 (s, 1H), 7.98 (s, 1H), 7.75-7.77 (m, 1H), 7.31 (d, J = 9.0 Hz, 2H), 7.24 (d, J = 8.5 Hz, 1H), 6.88 (d, J = 9.0 Hz, 2H), 4.35 (t, J = 5.5 Hz, 2H), 3.90 (s, 3H), 2.92 (t, J = 5.5 Hz, 2H), 2.28 (s, 3H), 1.72 (s, 2H), 1.36 (s, 6H), 0.72 (s, 9H); 13C-NMR (125 MHz, CDCl3)δ 169.4, 166.8, 155.5, 143.4, 135.9, 134.3, 130.5, 128.8, 127.4, 126.2, 123.9, 113.6, 64.1, 57.0, 52.1, 38.0, 37.7, 32.3, 31.8, 31.7, 18.2. 1 H-NMR (500 MHz, CDCl 3 ) δ 8.55 (s, 1H), 7.98 (s, 1H), 7.75-7.77 (m, 1H), 7.31 (d, J = 9.0 Hz, 2H), 7.24 (d , J = 8.5 Hz, 1H), 6.88 (d, J = 9.0 Hz, 2H), 4.35 (t, J = 5.5 Hz, 2H), 3.90 (s, 3H), 2.92 (t, J = 5.5 Hz, 2H ), 2.28 (s, 3H), 1.72 (s, 2H), 1.36 (s, 6H), 0.72 (s, 9H); 13 C-NMR (125 MHz, CDCl 3 ) δ 169.4, 166.8, 155.5, 143.4, 135.9, 134.3, 130.5, 128.8, 127.4, 126.2, 123.9, 113.6, 64.1, 57.0, 52.1, 38.0, 37.7, 32.3, 31.8, 31.7, 18.2.
화합물 9-5. : 메틸 2-메틸-5-(3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)프로판아미도)벤조에이트(Methyl 2-methyl-5-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)propanamido)benzoate) Compound 9-5. : Methyl 2-methyl-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) benzoate (Methyl 2-methyl-5- (3- (4 -(2,4,4-trimethylpentan-2-yl) phenoxy) propanamido) benzoate)
3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)propanoic acid (1.0 equiv) 및 methyl 5-amino-2-methylbenzoate (1.2 equiv)를 DMF에 혼합하여 이를 HATU (1.5 equiv) 및 DIPEA (1.5 equiv)에 첨가하였다. 반응 혼합물을 상온에서 밤새 교반한 후, 감압하여 농축한 뒤, 얻어진 잔사를 EtOAc로 희석하고, 물 및 brine으로 세척하였다. 유기층을 모아 무수 황산마그네슘 (anhydrous MgSO4)으로 수분을 제거한 후, 감압하에 농축하였다. 상기 농축액을 실리카겔 컬럼 크로마토그래피로 정제하여 메틸 2-메틸-5-(3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)프로판아미도)벤조에이트 를 수득하였다 (노랑색 고체, 0.05 g, 61.0 % 수율).3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanoic acid (1.0 equiv) and methyl 5-amino-2-methylbenzoate (1.2 equiv) were mixed with DMF and HATU (1.5 equiv) And DIPEA (1.5 equiv). The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the residue obtained was diluted with EtOAc and washed with water and brine. After collection of the organic layer was removed, the dried over anhydrous magnesium sulfate (anhydrous MgSO 4), and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to afford methyl 2-methyl-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) benzoate ( Yellow solid, 0.05 g, 61.0% yield).
1H-NMR (500 MHz, CDCl3)δ 8.06 (s, 1H), 8.01 (d, J = 2.0 Hz, 1H), 7.65 - 7.67 (m, 1H), 7.30 (d, J = 8.5 Hz, 2H), 7.19 (d, J = 8.5 Hz, 1H), 6.87 (d, J = 9.0 Hz, 2H), 4.32 (t, J = 6.0 Hz, 2H), 3.87 (s, 3H), 2.84 (t, J = 5.0 Hz, 2H), 2.55 (s, 3H), 1.72 (s, 2H), 1.35 (s, 6H), 0.72 (s, 9H); 13C-NMR (125 MHz, CDCl3)δ 169.2, 167.6, 155.7, 143.3, 136.1, 135.6, 132.3, 129.8, 127.3, 123.7, 121.9, 113.8, 64.1, 56.9, 52.0, 38.0, 37.7, 32.3, 31.8, 31.7, 21.2. 1 H-NMR (500 MHz, CDCl 3 ) δ 8.06 (s, 1H), 8.01 (d, J = 2.0 Hz, 1H), 7.65-7.67 (m, 1H), 7.30 (d, J = 8.5 Hz, 2H ), 7.19 (d, J = 8.5 Hz, 1H), 6.87 (d, J = 9.0 Hz, 2H), 4.32 (t, J = 6.0 Hz, 2H), 3.87 (s, 3H), 2.84 (t, J = 5.0 Hz, 2H), 2.55 (s, 3H), 1.72 (s, 2H), 1.35 (s, 6H), 0.72 (s, 9H); 13 C-NMR (125 MHz, CDCl 3 ) δ 169.2, 167.6, 155.7, 143.3, 136.1, 135.6, 132.3, 129.8, 127.3, 123.7, 121.9, 113.8, 64.1, 56.9, 52.0, 38.0, 37.7, 32.3, 31.8, 31.7, 21.2.
화합물 9-6. : 메틸 2-하이드록시-5-(3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)프로판아미도)벤조에이트( Methyl 2-hydroxy-5-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)propanamido)benzoate) Compound 9-6. : Methyl 2-hydroxy-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) benzoate (Methyl 2-hydroxy-5- (3- ( 4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamido) benzoate)
THF 내 CDI (1,1-Carbonyldiimidazole) (1.0 equiv)의 용액을 일부 첨가하고, 상온에서 45분 동안 교반하였다. 다른 플라스크에서, 이미다졸(1.1 equiv)을 THF 내에 메틸 5-아미노-2-하이드록시벤조에이트 (0.9 equiv)의 용액에 첨가하였다. 산/CDI 혼합물을 아닐린-이미다졸 용액에 첨가하였고, 아르곤 하에서 밤새 교반하였다. 용매를 진공 하에서 증발시키고 결과물을 실리카 젤 컬럼 크로마토그래피로 정제하였다 (흰색 고체, 0.08 g, 33.4 % 수율).Some solution of CDI (1,1-Carbonyldiimidazole) (1.0 equiv) in THF was added and stirred at room temperature for 45 minutes. In another flask, imidazole (1.1 equiv) was added to a solution of methyl 5-amino-2-hydroxybenzoate (0.9 equiv) in THF. The acid / CDI mixture was added to the aniline-imidazole solution and stirred overnight under argon. The solvent was evaporated under vacuum and the result was purified by silica gel column chromatography (white solid, 0.08 g, 33.4% yield).
1H-NMR (500 MHz, CDCl3)δ 10.64 (s,1H), 8.10 (d, J = 3.0 Hz, 1H,), 7.89 (brs, 1H), 7.47 (dd, J = 3.0, 8.5 Hz, 1H), 7.31 (d, J = 9.0 Hz, 2H), 6.94 (d, J = 9.0 Hz, 1H), 6.87 (d, J = 9.0 Hz, 2H), 4.33 (t, J = 6.0 Hz, 2H), 3.93 (s, 3H), 2.83 (t, J = 6.0 Hz, 2H), 1.72 (s, 2H), 1.35 (s, 6H), 0.72 (s, 9H); 13C-NMR (125 MHz, CDCl3)δ 170.2, 169.1, 158.5, 155.6, 143.3, 129.4, 128.7, 127.3, 121.6, 117.9, 113.8, 112.1, 64.1, 56.9, 52.4, 38.0, 37.5, 32.3, 31.8, 31.7. 1 H-NMR (500 MHz, CDCl 3 ) δ 10.64 (s, 1H), 8.10 (d, J = 3.0 Hz, 1H,), 7.89 (brs, 1H), 7.47 (dd, J = 3.0, 8.5 Hz, 1H), 7.31 (d, J = 9.0 Hz, 2H), 6.94 (d, J = 9.0 Hz, 1H), 6.87 (d, J = 9.0 Hz, 2H), 4.33 (t, J = 6.0 Hz, 2H) , 3.93 (s, 3H), 2.83 (t, J = 6.0 Hz, 2H), 1.72 (s, 2H), 1.35 (s, 6H), 0.72 (s, 9H); 13 C-NMR (125 MHz, CDCl 3 ) δ 170.2, 169.1, 158.5, 155.6, 143.3, 129.4, 128.7, 127.3, 121.6, 117.9, 113.8, 112.1, 64.1, 56.9, 52.4, 38.0, 37.5, 32.3, 31.8, 31.7.
화합물 9-7. : 이소프로필 3-(3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)프로판아미도)벤조에이트(Isopropyl 3-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)propanamido)benzoate)Compound 9-7. : Isopropyl 3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) benzoate (Isopropyl 3- (3- (4- (2,4,4) -trimethylpentan-2-yl) phenoxy) propanamido) benzoate)
3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)propanoic acid (1.0 equiv) 및 isopropyl 3-aminobenzoate (1.2 equiv)를 DMF에 혼합하여 이를 HATU (1.5 equiv) 및 DIPEA (1.5 equiv)에 첨가하였다. 반응 혼합물을 상온에서 밤새 교반한 후, 감압하여 농축한 뒤, 얻어진 잔사를 EtOAc로 희석하고, 물 및 brine으로 세척하였다. 유기층을 모아 무수 황산마그네슘 (anhydrous MgSO4)으로 수분을 제거한 후, 감압하에 농축하였다. 상기 농축액을 실리카겔 컬럼 크로마토그래피로 정제하여 이소프로필 3-(3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)프로판아미도)벤조에이트를 수득하였다 (투명한 액체, 0.06 g, 26.5 % 수율).3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanoic acid (1.0 equiv) and isopropyl 3-aminobenzoate (1.2 equiv) were mixed with DMF to form HATU (1.5 equiv) and DIPEA (1.5 equiv). The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the residue obtained was diluted with EtOAc and washed with water and brine. After collection of the organic layer was removed, the dried over anhydrous magnesium sulfate (anhydrous MgSO 4), and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to give isopropyl 3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) benzoate (clear liquid, 0.06 g, 26.5% yield).
1H-NMR (500 MHz, CDCl3)δ 7.99 (brs, 2H), 7.93 (d, J = 7.0 Hz, 1H), 7.79 (d, J = 7.0 Hz, 1H), 7.41 (t, J = 8.0 Hz, 1H), 7.32 (d, J = 9.0 Hz, 2H), 6.89 (d, J = 8.0 Hz, 2H), 5.25 (m, 1H), 4.35 (t, J = 6.0 Hz, 2H), 2.87 (t, J = 6.0 Hz, 2H), 1.72 (s, 2H), 1.38 (d, J = 6.5 Hz, 6H), 1.36 (s, 6H), 0.72 (s, 9H); 13C-NMR (125 MHz, CDCl3)δ 169.2, 165.7, 155.6, 143.4, 137.9, 131.6, 129.1, 127.3, 125.3, 124.3, 120.6, 113.8, 68.6, 64.1, 56.9, 38.0, 37.8, 32.3, 31.8, 31.7, 21.9. 1 H-NMR (500 MHz, CDCl 3 ) δ 7.99 (brs, 2H), 7.93 (d, J = 7.0 Hz, 1H), 7.79 (d, J = 7.0 Hz, 1H), 7.41 (t, J = 8.0 Hz, 1H), 7.32 (d, J = 9.0 Hz, 2H), 6.89 (d, J = 8.0 Hz, 2H), 5.25 (m, 1H), 4.35 (t, J = 6.0 Hz, 2H), 2.87 ( t, J = 6.0 Hz, 2H), 1.72 (s, 2H), 1.38 (d, J = 6.5 Hz, 6H), 1.36 (s, 6H), 0.72 (s, 9H); 13 C-NMR (125 MHz, CDCl 3 ) δ 169.2, 165.7, 155.6, 143.4, 137.9, 131.6, 129.1, 127.3, 125.3, 124.3, 120.6, 113.8, 68.6, 64.1, 56.9, 38.0, 37.8, 32.3, 31.8, 31.7, 21.9.
화합물 9-8. : 메틸 5-(3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)프로판아미도)니코티네이트 (Methyl 5-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)propanamido)nicotinate) Compound 9-8. : Methyl 5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) nicotinate (Methyl 5- (3- (4- (2,4,4) -trimethylpentan-2-yl) phenoxy) propanamido) nicotinate)
3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)propanoic acid (1.0 equiv) 및 methyl 5-aminonicotinate (1.2 equiv)를 THF에 혼합하여 이를 EDC·HCl (1.5 equiv), HOBT (1.5 equiv) 및 DIPEA (1.5 equiv)에 첨가하였다. 반응 혼합물을 상온에서 밤새 교반한 후, 감압하여 농축한 뒤, 얻어진 잔사를 EtOAc로 희석하고, 물 및 brine으로 세척하였다. 유기층을 모아 무수 황산마그네슘 (anhydrous MgSO4)으로 수분을 제거한 후, 감압하에 농축하였다. 상기 농축액을 실리카겔 컬럼 크로마토그래피로 정제하여 메틸 5-(3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)프로판아미도)니코티네이트를 수득하였다 (흰색 고체, 0.06 g, 40.3 % 수율).3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanoic acid (1.0 equiv) and methyl 5-aminonicotinate (1.2 equiv) were mixed with THF and EDCHCl (1.5 equiv), HOBT (1.5 equiv) and DIPEA (1.5 equiv). The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the residue obtained was diluted with EtOAc and washed with water and brine. After collection of the organic layer was removed, the dried over anhydrous magnesium sulfate (anhydrous MgSO 4), and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to give methyl 5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) nicotinate (white solid, 0.06 g, 40.3% yield).
1H-NMR (500 MHz, CDCl3)δ 8.97 (d, J = 1.5 Hz, 1H), 8.84 (d, J = 2.5 Hz, 1H), 8.64 (t, J = 2.0 Hz, 1H), 8.27 (s, 1H), 7.32 (d, J = 9.0 Hz, 2H), 6.88 (d, J = 8.5 Hz, 2H), 4.35 (t, J = 5.0 Hz, 2H), 3.95 (s, 3H), 2.91 (t, J = 5.5 Hz, 2H), 2.72 (s, 2H), 1.35 (s, 6H), 0.72 (s, 9H); 13C-NMR (125 MHz, CDCl3)δ 169.7, 165.5, 155.4, 146.3, 144.8, 143.7, 127.7, 127.4, 113.8, 63.9, 56.9, 52.6, 38.0, 37.6, 32.3, 31.8, 31.7. 1 H-NMR (500 MHz, CDCl 3 ) δ 8.97 (d, J = 1.5 Hz, 1H), 8.84 (d, J = 2.5 Hz, 1H), 8.64 (t, J = 2.0 Hz, 1H), 8.27 ( s, 1H), 7.32 (d, J = 9.0 Hz, 2H), 6.88 (d, J = 8.5 Hz, 2H), 4.35 (t, J = 5.0 Hz, 2H), 3.95 (s, 3H), 2.91 ( t, J = 5.5 Hz, 2H), 2.72 (s, 2H), 1.35 (s, 6H), 0.72 (s, 9H); 13 C-NMR (125 MHz, CDCl 3 ) δ 169.7, 165.5, 155.4, 146.3, 144.8, 143.7, 127.7, 127.4, 113.8, 63.9, 56.9, 52.6, 38.0, 37.6, 32.3, 31.8, 31.7.
화합물 9-9. :Compound 9-9. :
N N
-(3-(모르폴린-4-카보닐)페닐)-3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)프로판아마이드(-(3- (morpholin-4-carbonyl) phenyl) -3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamide (
NN
-(3-(Morpholine-4-carbonyl)phenyl)-3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)propanamide) -(3- (Morpholine-4-carbonyl) phenyl) -3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamide)
3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)propanoic acid (1.0 equiv) 및 (3-aminophenyl)(morpholino)methanone (1.2 equiv)를 THF에 혼합하여 이를 EDC·HCl (1.5 equiv), HOBT (1.5 equiv) 및 DIPEA (1.5 equiv)에 첨가하였다. 반응 혼합물을 상온에서 밤새 교반한 후, 감압하여 농축한 뒤, 얻어진 잔사를 EtOAc로 희석하고, 물 및 brine으로 세척하였다. 유기층을 모아 무수 황산마그네슘 (anhydrous MgSO4)으로 수분을 제거한 후, 감압하에 농축하였다. 상기 농축액을 실리카겔 컬럼 크로마토그래피로 정제하여 N-(3-(모르폴린-4-카보닐)페닐)-3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)프로판아마이드를 수득하였다(흰색 고체, 0.08 g, 53.0 % 수율).3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanoic acid (1.0 equiv) and (3-aminophenyl) (morpholino) methanone (1.2 equiv) were mixed with THF and EDC-HCl ( 1.5 equiv), HOBT (1.5 equiv) and DIPEA (1.5 equiv). The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the residue obtained was diluted with EtOAc and washed with water and brine. After collection of the organic layer was removed, the dried over anhydrous magnesium sulfate (anhydrous MgSO 4), and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to obtain N- (3- (morpholine-4-carbonyl) phenyl) -3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propane Amide was obtained (white solid, 0.08 g, 53.0% yield).
1H-NMR (500 MHz, CDCl3)δ 8.56 (s, 1H), 7.57 - 7.60 (m, 2H), 7.27 - 7.33 (m, 3H), 7.10 (d, J = 8.0 Hz, 1H), 6.85 (d, J = 8.5 Hz, 2H), 4.30 (t, J = 5.5 Hz, 2H), 3.46 - 3.77 (m, 8H), 2.81 (t, J = 5.5 Hz, 2H), 1.71 (s, 2H), 1.35 (s, 6H), 0.72 (s, 9H); 13C-NMR (125 MHz, CDCl3)δ 170.1, 169.3, 155.7, 143.2, 138.3, 135.7, 129.3, 127.3, 122.5, 121.4, 118.7, 113.7, 66.9, 64.0, 56.9, 38.0, 37.6, 32.3, 31.8, 31.7, 22.7, 14.2. 1 H-NMR (500 MHz, CDCl 3 ) δ 8.56 (s, 1H), 7.57-7.60 (m, 2H), 7.27-7.33 (m, 3H), 7.10 (d, J = 8.0 Hz, 1H), 6.85 (d, J = 8.5 Hz, 2H), 4.30 (t, J = 5.5 Hz, 2H), 3.46-3.77 (m, 8H), 2.81 (t, J = 5.5 Hz, 2H), 1.71 (s, 2H) , 1.35 (s, 6 H), 0.72 (s, 9 H); 13 C-NMR (125 MHz, CDCl 3 ) δ 170.1, 169.3, 155.7, 143.2, 138.3, 135.7, 129.3, 127.3, 122.5, 121.4, 118.7, 113.7, 66.9, 64.0, 56.9, 38.0, 37.6, 32.3, 31.8, 31.7, 22.7, 14.2.
화합물 9-10. : 에틸 2-(3-(3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)프로판아미도)벤즈아미도)아세테이트(Ethyl 2-(3-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)propanamido)benzamido)acetate) Compound 9-10. : Ethyl 2- (3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) benzamido) acetate (Ethyl 2- (3- (3- ( 4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamido) benzamido) acetate)
3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)propanoic acid (1.0 equiv) 및 ethyl 2-(3-aminobenzamido)acetate (1.2 equiv)를 THF에 혼합하여 이를 EDC·HCl (1.5 equiv), HOBT (1.5 equiv) 및 DIPEA (1.5 equiv)에 첨가하였다. 반응 혼합물을 상온에서 밤새 교반한 후, 감압하여 농축한 뒤, 얻어진 잔사를 EtOAc로 희석하고, 물 및 brine으로 세척하였다. 유기층을 모아 무수 황산마그네슘 (anhydrous MgSO4)으로 수분을 제거한 후, 감압하에 농축하였다. 상기 농축액을 실리카겔 컬럼 크로마토그래피로 정제하여 에틸 2-(3-(3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)프로판아미도)벤즈아미도)아세테이트를 수득하였다 (흰색 고체, 0.14 g, 64.4 % 수율).3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanoic acid (1.0 equiv) and ethyl 2- (3-aminobenzamido) acetate (1.2 equiv) were mixed with THF to give EDCHCl ( 1.5 equiv), HOBT (1.5 equiv) and DIPEA (1.5 equiv). The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the residue obtained was diluted with EtOAc and washed with water and brine. After collection of the organic layer was removed, the dried over anhydrous magnesium sulfate (anhydrous MgSO 4), and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to give ethyl 2- (3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) benzamido) acetate (White solid, 0.14 g, 64.4% yield).
1H-NMR (500 MHz, CDCl3)δ 8.47 (s, 1H), 7.86 (s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.28-7.34 (m, 3H), 6.99 (s, 1H), 6.86 (d, J = 8.5 Hz, 2H), 4.32 (t, J = 5.5 Hz, 2H), 4.20-4.26 (m, 4H), 2.85 (d, J = 5.0 Hz, 2H), 1.70 (s, 2H), 1.34 (s, 6H), 1.30 (t, J = 7.0 Hz, 3H), 0.71 (s, 9H); 13C-NMR (125 MHz, CDCl3)δ 170.2, 169.4, 167.4, 155.7, 143.2, 138.4, 134.2, 129.3, 127.3, 123.2, 122.6, 118.4, 113.8, 64.0, 61.7, 56.9, 41.9, 38.0, 37.6, 32.3, 31.8, 31.7, 14.2. 1 H-NMR (500 MHz, CDCl 3 ) δ 8.47 (s, 1H), 7.86 (s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.28-7.34 (m, 3H), 6.99 (s, 1H), 6.86 (d, J = 8.5 Hz, 2H), 4.32 (t, J = 5.5 Hz, 2H), 4.20-4.26 (m, 4H), 2.85 (d, J = 5.0 Hz, 2H), 1.70 (s, 2H), 1.34 (s, 6H), 1.30 (t, J = 7.0 Hz, 3H), 0.71 (s, 9H); 13 C-NMR (125 MHz, CDCl 3 ) δ 170.2, 169.4, 167.4, 155.7, 143.2, 138.4, 134.2, 129.3, 127.3, 123.2, 122.6, 118.4, 113.8, 64.0, 61.7, 56.9, 41.9, 38.0, 37.6, 32.3, 31.8, 31.7, 14.2.
화합물 9-11. : (Compound 9-11. : (
SS
)-)-
메틸methyl
3- 3-
메틸methyl
-2-(3-(3-(4-(2,4,4--2- (3- (3- (4- (2,4,4-
트리메틸펜탄Trimethylpentane
-2-일)-2 days)
페녹시Phenoxy
)프로판아미도)벤즈아미도)부타노에이트((Propane amido benz amido butanoate
SS
)-methyl 3-methyl-2-(3-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)propanamido)benzamido)butanoate) ) -methyl 3-methyl-2- (3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamido) benzamido) butanoate)
3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)propanoic acid (1.0 equiv) 및 (S)-methyl 2-(3-aminobenzamido)-3-methylbutanoate (1.2 equiv)를 THF에 혼합하여 이를 EDC·HCl (1.5 equiv), HOBT (1.5 equiv) 및 DIPEA (1.5 equiv)에 첨가하였다. 반응 혼합물을 상온에서 밤새 교반한 후, 감압하여 농축한 뒤, 얻어진 잔사를 EtOAc로 희석하고, 물 및 brine으로 세척하였다. 유기층을 모아 무수 황산마그네슘 (anhydrous MgSO4)으로 수분을 제거한 후, 감압 하에 농축하였다. 상기 농축액을 실리카겔 컬럼 크로마토그래피로 정제하여 (S)-메틸3-메틸-2-(3-(3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)프로판아미도)벤즈아미도)부타노에이트를 수득하였다 (흰색 고체, 0.15 g, 73.3 % 수율).3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanoic acid (1.0 equiv) and ( S ) -methyl 2- (3-aminobenzamido) -3-methylbutanoate (1.2 equiv) in THF It was mixed and added to EDC.HCl (1.5 equiv), HOBT (1.5 equiv) and DIPEA (1.5 equiv). The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the residue obtained was diluted with EtOAc and washed with water and brine. The organic layers were combined, water was removed with anhydrous magnesium sulfate (anhydrous MgSO 4 ), and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to give ( S ) -methyl3-methyl-2- (3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamido ) Benzamido) butanoate was obtained (white solid, 0.15 g, 73.3% yield).
1H-NMR (500 MHz, CDCl3)δ 8.60 (s, 1H), 7.90 (s, 1H), 7.89 (s, 1H), 7.47 (d, J = 7.5 Hz, 1H), 7.34 (t, J = 8.0 Hz, 1H), 7.27 (d, J = 9.0 Hz, 2H), 6.81 - 6.86 (m, 3H), 4.72-4.75 (m, 1H), 4.31 (t, J = 5.5 Hz, 2H), 3.75 (s, 3H), 2.85 (t, J = 5.5 Hz, 2H), 2.33-2.30 (m, 1H), 1.70 (s, 2H), 1.34 (s, 6H), 0.99 (t, J = 6.5 Hz, 6H), 0.71 (s, 9H); 13C-NMR (125 MHz, CDCl3)δ 172.6, 169.4, 167.3, 155.8, 143.0, 138.6, 134.7, 129.3, 127.2, 123.2, 122.4, 118.5, 113.8, 64.0, 57.8, 56.9, 52.3, 38.0, 37.6, 32.3, 31.8, 31.7, 31.4, 19.1, 18.1. 1 H-NMR (500 MHz, CDCl 3 ) δ 8.60 (s, 1H), 7.90 (s, 1H), 7.89 (s, 1H), 7.47 (d, J = 7.5 Hz, 1H), 7.34 (t, J = 8.0 Hz, 1H), 7.27 (d, J = 9.0 Hz, 2H), 6.81-6.86 (m, 3H), 4.72-4.75 (m, 1H), 4.31 (t, J = 5.5 Hz, 2H), 3.75 (s, 3H), 2.85 (t, J = 5.5 Hz, 2H), 2.33-2.30 (m, 1H), 1.70 (s, 2H), 1.34 (s, 6H), 0.99 (t, J = 6.5 Hz, 6H), 0.71 (s, 9H); 13 C-NMR (125 MHz, CDCl 3 ) δ 172.6, 169.4, 167.3, 155.8, 143.0, 138.6, 134.7, 129.3, 127.2, 123.2, 122.4, 118.5, 113.8, 64.0, 57.8, 56.9, 52.3, 38.0, 37.6, 32.3, 31.8, 31.7, 31.4, 19.1, 18.1.
[실험예]Experimental Example
실험예 1. 제조된 화합물의 MDH 억제 활성 확인Experimental Example 1. Confirmation of MDH inhibitory activity of the prepared compound
1-1. MDH2의 유전자 클로닝 및 재조합 단백질 분리 및 정제1-1. Gene Cloning and Recombinant Protein Isolation and Purification of MDH2
상기 실시예 1에 따라 제조된 화합물의 MDH2 억제 활성을 확인하기 위하여, MDH2 재조합 (recombinant) 단백질을 제작하였다. MDH2 유전자는 한국생명공학연구원 인간유전자 뱅크 (Korean HumanGeneBank, KUGI, NM_005918)에서 구입하였으며, 이를 PCR로 증폭한 후 pET28a vector (Merck, Germany)에 클로닝하였다. 그 후, 플라스미드 벡터를 E. coli Rosetta 2 (DE3)에 도입한 후 IPTG 처리하여 MDH2 recombinant 단백질을 과발현하였다.In order to confirm the MDH2 inhibitory activity of the compound prepared according to Example 1, an MDH2 recombinant protein was prepared. The MDH2 gene was purchased from the Korea Human Genetics Bank (Korean Human GeneBank, KUGI, NM_005918), and amplified by PCR and cloned into the pET28a vector (Merck, Germany). Thereafter, the plasmid vector was introduced into E. coli Rosetta 2 (DE3), followed by IPTG treatment to overexpress MDH2 recombinant protein.
그 결과, 도 2에 나타낸 바와 같이, 과발현된 recombinant MDH2 단백질은 Ni-NTA affinity chromatography, TEV 효소 cleavage, 및 size-exclusion chromatography 과정을 통해 분리 정제하였다.As a result, as shown in FIG. 2, the overexpressed recombinant MDH2 protein was purified by Ni-NTA affinity chromatography, TEV enzyme cleavage, and size-exclusion chromatography.
1-2. 제조된 화합물의 1-2. Of the prepared compound
MDH1MDH1
및 And
MDH2MDH2
억제 활성 확인 (in vitro) Confirmation of inhibitory activity (in vitro)
MDH1 및 상기 실험예 1-1, 1-2, 1-3 및 1-4에서 제작한 MDH2 재조합 단백질에 대한 화합물의 억제 활성을 측정하였다. 보다 구체적으로, 0.25 nM MDH1 재조합 단백질 (바이오비젼 사) 또는 MDH2 재조합 단백질을 200 μM 옥살로아세트산 (oxaloacetate), 니코틴아마이드 아데닌 다이뉴클레오타이드 (NADH), 상기 실시예 1에서 제조된 화합물 및 MDH 어세이 버퍼 (100 mM potassium phosphate, pH 7.4)에서 30 분 동안 반응시켰다. 그 후, MDH1 또는 MDH2 효소에 의한 NADH의 산화 (NAD+) 에 의한 용액 내 NADH 농도변화를 흡광도 340 ㎚에서 측정하였다.The inhibitory activity of the compounds against MDH1 and MDH2 recombinant proteins produced in Experimental Examples 1-1, 1-2, 1-3 and 1-4 were measured. More specifically, 0.25 nM MDH1 recombinant protein (Biovision) or MDH2 recombinant protein was prepared using 200 μM oxaloacetate, nicotinamide adenine dinucleotide (NADH), the compound prepared in Example 1, and MDH assay buffer (100 mM potassium phosphate, pH 7.4) for 30 minutes. Thereafter, the change in NADH concentration in the solution by oxidation of NADH (NAD + ) by MDH1 or MDH2 enzyme was measured at absorbance 340 nm.
그 결과, 하기 표 1에 나타낸 바와 같이, 상기 실시예 1에 기재된 화합물 55종의 SAR 결과를 확인하였다.As a result, as shown in Table 1 below, SAR results of 55 compounds described in Example 1 were confirmed.
Comp. No.Comp. No. | MDH1IC50(μM)MDH1IC 50 (μM) | MDH2IC50(μM)MDH2IC 50 (μM) |
3-13-1 | ++ | ++ |
3-23-2 | ++ | ++ |
3-33-3 | ++ | ++ |
3-43-4 | ++ | ++ |
3-53-5 | ++ | ++ |
3-63-6 | ++ | ++ |
3-73-7 | ++++ | ++ |
3-83-8 | ++++ | ++ |
3-93-9 | ++ | ++ |
3-103-10 | ++ | ++ |
3-113-11 | ++++ | ++++ |
3-123-12 | ++++++ | ++++++ |
3-133-13 | ++++++ | ++++++ |
3-143-14 | ++++++ | ++++++ |
3-153-15 | ++++++ | ++++ |
3-163-16 | ++ | ++ |
3-173-17 | ++++++ | ++++ |
3-183-18 | ++ | ++ |
3-193-19 | ++ | ++ |
3-203-20 | ++++++ | ++++ |
3-213-21 | ++ | ++ |
3-223-22 | ++ | ++ |
3-233-23 | ++ | ++ |
3-243-24 | ++++++ | ++ |
3-253-25 | ++ | ++ |
3-263-26 | ++ | ++ |
3-273-27 | ++++++ | ++++++ |
3-283-28 | ++++++ | ++++++ |
3-293-29 | ++++++ | ++++++ |
3-303-30 | ++++++ | ++++++ |
3-313-31 | ++++++ | ++ |
3-323-32 | ++++++ | ++++++ |
3-333-33 | ++++++ | ++++++ |
3-343-34 | ++++ | ++++++ |
6-16-1 | ++ | ++++++ |
6-26-2 | ++++++ | ++++++ |
6-36-3 | ++++ | ++++ |
6-46-4 | ++ | ++ |
6-56-5 | ++ | ++ |
6-66-6 | ++ | ++ |
6-76-7 | ++++ | ++ |
6-86-8 | ++++ | ++++ |
6-96-9 | ++ | ++ |
6-106-10 | ++++++ | ++++++ |
9-19-1 | ++++++ | ++++ |
9-29-2 | ++++++ | ++++++ |
9-39-3 | ++++++ | ++++++ |
9-49-4 | ++++ | ++++ |
9-59-5 | ++ | ++ |
9-69-6 | ++ | ++ |
9-79-7 | ++ | ++ |
9-89-8 | ++++ | ++++ |
9-99-9 | ++ | ++ |
9-109-10 | ++ | ++ |
9-119-11 | ++ | ++ |
1 ~ 5 μM : +++, 5 ~ 10 μM : ++, >10 μM : +1 to 5 μM: +++, 5 to 10 μM: ++,> 10 μM: +
실험예 2. 제조된 화합물 9-2의 MDH 억제 기전 확인 Experimental Example 2. Confirmation of MDH inhibition mechanism of the prepared compound 9-2
상기 실시예 1-3에서 제조한 화합물 9-2, 즉 메틸 3-(3-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)프로판아미도)벤조에이트의 MDH 억제 기전을 확인하였다. 보다 구체적으로, 상기 실험예 1-2에 기재된 바와 같이, 다양한 농도의 니코틴아마이드 아데닌 다이뉴클레오타이드 (60, 75, 100, 150 및 300 μM) 및 600 μM 옥살로아세트산을 사용하여 효소반응속도 (enzyme kinetics) 실험을 수행하였다. 또한, 라인위버-버크 플롯법을 통해 최대속도 (Vmax) 및 미카엘리스 상수 (Km)를 측정하였다.MDH of compound 9-2 prepared in Example 1-3, ie, methyl 3- (3- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) propaneamido) benzoate The inhibition mechanism was confirmed. More specifically, as described in Experimental Example 1-2, enzyme kinetics using various concentrations of nicotinamide adenine dinucleotide (60, 75, 100, 150 and 300 μM) and 600 μM oxaloacetic acid ) Experiments were performed. In addition, the maximum velocity (Vmax) and the Michaelis constant (Km) were measured through the Lineweaver-Burk plot method.
그 결과, 도 3에 나타낸 바와 같이, MDH1 및 MDH2 효소반응에서 세 종류의 상이한 농도의 화합물 9-2로부터 얻은 라인은 x축에 교차되었으며, NADH 농도가 변함에 따라, Vmax 값은 변하지 않지만, 결합친화도 (Km)값은 농도 의존적으로 감소하였다. 따라서 화합물 9-2는 NADH와 동일한 결합부위에 결합하여 경쟁적으로 MDH 저해제함을 확인하였다.As a result, as shown in FIG. 3, lines from three different concentrations of compound 9-2 in the MDH1 and MDH2 enzymatic reactions crossed the x-axis, and as the NADH concentration changed, the V max value did not change. The binding affinity (Km) value decreased in a concentration dependent manner. Thus, compound 9-2 was found to bind to the same binding site as NADH competitively MDH inhibitors.
실험예 3. 제조된 화합물 9-2의 HIF-1α 억제 활성 확인Experimental Example 3. Confirmation of HIF-1α inhibitory activity of the prepared compound 9-2
상기 실시예 1-3에서 제조한 화합물 9-2의 HIF-1α 억제 활성을 확인하였다. HIF-1α (hypoxia-inducible factor-1α)는 고형암의 방사선 저항성 및 항암제 저항성에 영향을 미치며, 암의 악성화에 영향을 주는 인자이다. 보다 구체적으로, HCT-116 대장암 세포주를 우태아혈청 5 % (FBS)를 포함하는 DMEM 배지에 현탁시킨 후 6 well 플레이트 (5 × 105 cells/well)에 옮겨 5 % 이산화탄소를 유지하는 37 ℃ 세포 배양기에서 24 시간 배양하였다. 저산소에 의한 HIF-1α 단백질의 축적 유도를 위해 1 % 산소, 94 % 질소 및 5 % 이산화탄소 조건에서 세포를 6 시간 배양하였다. 방사선면역 침전 분석 완충용액 (radioimmuno precipitation assay buffer,RIPA buffer,밀리포어사)을 이용해 HCT-116 세포를 파쇄하여 세포 추출물을 수득후, 세포 추출물 각 10 ㎍을 SDS-PAGE에 전개하여 분리한 다음, PVDF 막 (polyvinylidene fluoride membrane)에 옮겨 HIF-1α 항체 (BD사이언스 사), HIF-1β 항체 (BD사이언스사), β-Actin (산타크루즈 사) 및 horseradish peroxidase (HRP) 표지 2차 항체 (산타크루즈 사)를 순차적으로 결합시켜 단백질 발현을 확인하였다.The HIF-1α inhibitory activity of the compound 9-2 prepared in Example 1-3 was confirmed. HIF-1α (hypoxia-inducible factor-1α) affects radiation resistance and anticancer drug resistance in solid cancers and is a factor influencing cancer malignancy. More specifically, the HCT-116 colon cancer cell line was suspended in DMEM medium containing 5% fetal calf serum (FBS) and transferred to 6 well plates (5 × 10 5 cells / well) at 37 ° C. to maintain 5% carbon dioxide. The cells were incubated for 24 hours in a cell incubator. Cells were incubated for 6 hours at 1% oxygen, 94% nitrogen and 5% carbon dioxide conditions to induce accumulation of HIF-1α protein by hypoxia. After cell disruption was obtained by disrupting HCT-116 cells using radioimmuno precipitation assay buffer (RIPA buffer, Millipore), 10 μg of each cell extract was developed on SDS-PAGE, and then separated. Transferred to a PVDF membrane (polyvinylidene fluoride membrane), HIF-1α antibody (BD Science), HIF-1β antibody (BD Science), β-Actin (Santa Cruz) and horseradish peroxidase (HRP) labeled secondary antibody (Santa Cruz) G) were sequentially combined to confirm protein expression.
그 결과, 도 4에 나타낸 바와 같이, 화합물 9-2는 2.5, 5, 및 10 μM에서 HIF-1β 단백질 발현에는 영향없이 HIF-1α 단백질 축적을 농도의존적으로 억제함을 확인하였다.As a result, as shown in FIG. 4, it was confirmed that Compound 9-2 inhibited HIF-1α protein accumulation in a concentration-dependent manner without affecting HIF-1β protein expression at 2.5, 5, and 10 μM.
실험예 4. 화합물 9-2의 미토콘드리아 호흡 억제 확인Experimental Example 4. Confirmation of mitochondrial respiration inhibition of compound 9-2
4-1. 화합물 9-2의 산소 소비율 억제 확인4-1. Confirmation of Inhibition of Oxygen Consumption of Compound 9-2
상기 실시예 1-3에 기재된 화합물 9-2의 미토콘드리아 호흡에 억제 활성을 검토하기 위하여 산소 소비율 변화를 측정하였다. 보다 구체적으로, XF24 extracellular flux analyzer (씨홀스 사)를 이용하여 미토콘드리아의 산소 소비율 (OCR)을 측정하였다. HCT-116 세포 (1 × 105 cells)를 측정 플레이트 (XF24 cell cultureplate)에서24 시간 배양한 뒤, 배양액을 XF 측정 배지로 교환하고 이산화탄소가 없는 상태의 세포 배양기에서 1 시간 배양하였다. 미토콘드리아의 산소 소비율은 약물 비투여 상태의 세포에서 3 회 측정한 뒤, ATP 합성 저해제 oligomycin (1 μM)을 투여 후 3 회, 화학적 짝풀림제 carbonyl cyanide p-trifluoromethoxyphenylhydrazone (0.5 μM)을 투여 후 3 회, 전자전달계 저해제 rotenone (1 μM) 및 antimycin A (1 μM)를 투여 후 3 회 산소 소비율을 측정하였다.In order to examine the inhibitory activity on mitochondrial respiration of compound 9-2 described in Example 1-3, the change in oxygen consumption rate was measured. More specifically, the oxygen consumption rate (OCR) of the mitochondria was measured using an XF24 extracellular flux analyzer (Seaholes). After HCT-116 cells (1 × 10 5 cells) were incubated for 24 hours in a measuring plate (XF24 cell cultureplate), the culture medium was exchanged with XF measuring medium and incubated for 1 hour in a cell incubator without carbon dioxide. The oxygen consumption rate of mitochondria was measured three times in non-drug cells, three times after administration of the ATP synthesis inhibitor oligomycin (1 μM), and three times after administration of the chemical decoupling agent carbonyl cyanide p -trifluoromethoxyphenylhydrazone (0.5 μM). Oxygen consumption was measured three times after administration of rotenone (1 μM) and antimycin A (1 μM).
그 결과, 도 5에 나타낸 바와 같이, 화합물 9-2는 암세포내 미토콘드리아의 산소 소비율을 억제하였으며, 기초 호흡량 및 최대 호흡량이 농도의존적으로 감소하는 것을 확인하였다.As a result, as shown in Figure 5, Compound 9-2 suppressed the oxygen consumption rate of mitochondria in cancer cells, it was confirmed that the basal respiratory rate and the maximum respiratory rate decreases in a concentration-dependent manner.
4-1. 화합물 9-2에 의한 세포 내 산소 증가 확인4-1. Confirmation of Increased Intracellular Oxygen by Compound 9-2
상기 실시예 1-3에 기재된 화합물 9-2의 미토콘드리아의 산소 소비율 억제에 의한 세포내 산소 농도 증가를 확인하기 위하여 산소 감응 형광 프로브를 활용한 실험을 수행하였다. 보다 구체적으로 HCT-116 세포 (1 × 105 cells)에 화합물 9-2 및 저산소 특이적 감응 형광 프로브 MAR (고료 사, 0.5 μM)를 처리한 후, 저산소 조건의 세포 배양기에서 6 시간 배양하였다. 그 후, 저산소에 의한 세포 내 형광 세기의 변화를 실시간 세포관찰 분석 시스템 (인큐사이트, 에센 사)로 측정 및 정량화하였다.In order to confirm the increase in the intracellular oxygen concentration by inhibiting the oxygen consumption rate of the mitochondria of the compound 9-2 described in Example 1-3, an experiment using an oxygen-sensitive fluorescent probe was performed. More specifically, HCT-116 cells (1 × 10 5 cells) were treated with compound 9-2 and hypoxic specific sensitive fluorescent probe MAR (Gray, 0.5 μM), and then incubated for 6 hours in a cell incubator under hypoxic conditions. Thereafter, changes in intracellular fluorescence intensity due to hypoxia were measured and quantified by a real-time cell observation analysis system (Incusite, Essen).
그 결과, 도 6에서 나타낸 바와 같이, 세포 내 산소 농도는 화합물 9-2에 의해 증가됨을 확인하였다.As a result, as shown in Figure 6, it was confirmed that the oxygen concentration in the cell is increased by the compound 9-2.
실험예 5. 화합물 9-2의 항종양 효과 확인Experimental Example 5. Confirmation of antitumor effect of compound 9-2
생체 내에서 화합물 9-2의 암세포 성장을 억제하는 효과를 확인하기 위하여, 암세포 이식 마우스 모델을 활용하여 실험하였다. 보다 구체적으로, 플레이트 배양 HCT-116 대장암 세포주를 트립신(trypsin) 처리하여 수득한 뒤, 무혈청 배지(serum-free medium)로 세척 후 2.5 × 107 cells/㎖ 농도로 희석하였다. 그 후, Balb/c 계통의 특정병원체 부재(specific pathogen free; SPF) 마우스인 6 주령의 암컷 누드마우스 (SLC-중앙실험동물 사, 한국) 7 마리의 옆구리에 상기 희석한 세포 5 × 106 cells/200 ㎕를 각각 피하 주사 (subcutaneous injection)로 주입하였다. 종양 크기가 약 100 ㎣ 정도 자란 뒤, 화합물 9-2를 20 ㎎/㎏ 농도로 1일 1회 경구 투여하고, 3, 5, 7, 10, 12, 14, 17, 19, 21, 및 24 일에 상기 누드마우스의 체중 및 종양 크기를 하기 수학식 1을 사용하여 측정하였다. 화합물 9-2 투여 후 24 일에 마우스를 희생시켜 적출한 종양의 무게 및 크기를 확인하였다.In order to confirm the effect of inhibiting cancer cell growth of compound 9-2 in vivo, experiments were carried out using a cancer cell transplant mouse model. More specifically, plate culture HCT-116 colon cancer cell line was obtained by trypsin treatment, and then washed with serum-free medium and diluted to 2.5 × 10 7 cells / ml. Subsequently, the diluted cells of the 6-week-old female nude mice (SLC-Central Animal Co., South Korea), which are specific pathogen free (SPF) mice of the Balb / c strain, were 5 × 10 6 cells. / 200 μl was injected by subcutaneous injection, respectively. After tumor growth was about 100 mm 3, compound 9-2 was orally administered once daily at a concentration of 20 mg / kg, and 3, 5, 7, 10, 12, 14, 17, 19, 21, and 24 days Body weight and tumor size of the nude mouse were measured using Equation 1 below. Mice were sacrificed 24 days after Compound 9-2 administration to determine the weight and size of the extracted tumor.
그 결과, 하기 표 2에 나타낸 바와 같이, 종양을 이식한 후 마우스의 체중에 유의적인 변화가 나타나지 않았으며, 도 7a, 도 7b 및 하기 표 3에 나타낸 바와 같이, 화합물 9-2의 생체 내 항종양 효능을 확인한 결과, 화합물 9-2 투여 마우스에서 종양의 형성 정도 (크기 또는 부피)가 76.4 % 감소하는 것을 확인하였으며, 도 7c에 나타낸 바와 같이, 화합물 9-2 투여 24 일 후 종양의 무게가 163.0 ± 117.5 ㎎으로 나타났으며, 비투여 마우스의 종양 무게인 493.5 ± 216.5 ㎎에 비하여 67.0 % 감소한 것을 확인하였다.As a result, as shown in Table 2, after the tumor was transplanted, there was no significant change in the body weight of the mouse, as shown in Figure 7a, 7b and Table 3, in vivo term of the compound 9-2 As a result of confirming the tumor efficacy, it was confirmed that the degree of tumor formation (size or volume) was reduced by 76.4% in the compound 9-2 administration mice, and as shown in FIG. 163.0 ± 117.5 mg, which was 67.0% less than the tumor weight of 493.5 ± 216.5 mg of non-administered mice.
시간 (일)Hours (days) | 체중 (g)Body weight (g) | |
VehicleVehicle | 화합물 9-2Compound 9-2 | |
00 | 21.2±0.921.2 ± 0.9 | 21.2±0.621.2 ± 0.6 |
33 | 21.7±0.821.7 ± 0.8 | 21.5±0.821.5 ± 0.8 |
55 | 21.9±0.721.9 ± 0.7 | 21.8±0.721.8 ± 0.7 |
77 | 21.9±0.921.9 ± 0.9 | 21.6±1.121.6 ± 1.1 |
1010 | 22.4±0.922.4 ± 0.9 | 22.2±1.022.2 ± 1.0 |
1212 | 22.9±0.922.9 ± 0.9 | 22.7±0.722.7 ± 0.7 |
1414 | 22.9±1.022.9 ± 1.0 | 22.7±1.022.7 ± 1.0 |
1717 | 23.0±1.023.0 ± 1.0 | 22.6±0.822.6 ± 0.8 |
1919 | 22.6±0.922.6 ± 0.9 | 22.4±0.522.4 ± 0.5 |
2121 | 23.0±0.923.0 ± 0.9 | 22.5±0.722.5 ± 0.7 |
2424 | 22.7±0.722.7 ± 0.7 | 22.3±0.822.3 ± 0.8 |
시간 (일)Hours (days) | 종양크기 (㎣)Tumor size (㎣) | |
VehicleVehicle | 화합물 9-2Compound 9-2 | |
00 | 102.5±11.0102.5 ± 11.0 | 94.1±11.094.1 ± 11.0 |
33 | 138.9±38.9138.9 ± 38.9 | 97.3±9.897.3 ± 9.8 |
55 | 151.7±32.8151.7 ± 32.8 | 101.6±15.7101.6 ± 15.7 |
77 | 177.9±49.2177.9 ± 49.2 | 119.9±29.3119.9 ± 29.3 |
1010 | 248.5±82.2248.5 ± 82.2 | 111.0±19.0111.0 ± 19.0 |
1212 | 308.7±94.7308.7 ± 94.7 | 124.2±35.5124.2 ± 35.5 |
1414 | 351.3±186.4351.3 ± 186.4 | 159.9±44.6159.9 ± 44.6 |
1717 | 432.3±248.9432.3 ± 248.9 | 187.9±78.5187.9 ± 78.5 |
1919 | 631.8±394.3631.8 ± 394.3 | 241.4±162.8241.4 ± 162.8 |
2121 | 822.1±484.1822.1 ± 484.1 | 258.3±195.7258.3 ± 195.7 |
2424 | 1175.1±630.51175.1 ± 630.5 | 277.5±216.0277.5 ± 216.0 |
전술한 본 발명의 설명은 예시를 위한 것이며, 본 발명이 속하는 기술분야의 통상의 지식을 가진 자는 본 발명의 기술적 사상이나 필수적인 특징을 변경하지 않고서 다른 구체적인 형태로 쉽게 변형이 가능하다는 것을 이해할 수 있을 것이다. 그러므로 이상에서 기술한 실시예들은 모든 면에서 예시적인 것이며 한정적이 아닌 것으로 이해해야만 한다.The foregoing description of the present invention is intended for illustration, and it will be understood by those skilled in the art that the present invention may be easily modified in other specific forms without changing the technical spirit or essential features of the present invention. will be. Therefore, it should be understood that the embodiments described above are exemplary in all respects and not restrictive.
실험예 6. 화합물 9-2의 세포증식 억제 활성 확인Experimental Example 6. Confirmation of cell proliferation inhibitory activity of compound 9-2
상기 실시예에 따라 제조된 화합물 9-2의 세포증식 억제 활성을 확인하였다.실험에 사용된 세포주는 폐암 (lung cancer) 세포주 A549 및 H1703, 결장직장암 (colorectal cancer) 세포주 HCT116 및 HT29, 간암 (liver cancer) 세포주 Hep3B 및 HepG2, 위암종 (gastric or stomach cancer) 세포주 NUGC-3 및 AGS, 신장암 (kidney and renal cancer) 세포주 786-O 및 Caki-1, 유방암 (breast cancer) 세포주 MCF-7 및 MDA-MB-231, 전립선암 (prostate cancer) 세포주 PC3, 췌장암 (pancreatic cancer) 세포주 MIA-PaCa-2, 자궁경부암 (cervical cancer) 세포주 HeLa, 정상세포 WI-38 및 CCD-32Lu 세포주이다. 구체적으로 상기 세포주를 우태아혈청 5 % (FBS)를 포함하는 DMEM 배지에 현탁시킨 후 96 well 플레이트 (3 × 103 cells/well)에 옮겨 5 % 이산화탄소를 유지하는 37 ℃ 세포 배양기에서 24 시간 배양하였다. 화합물 9-2를 다양한 농도로 처리하여 72 시간 배양하고 10 % 포르말린 수용액으로 세포를 고정 후, 0.5 % 메틸렌블루 용액으로 세포를 염색하였다. 그 뒤, 0.5 % 염산 수용액으로 추출된 메틸렌블루의 농도 변화를 흡광도 600 nm 에서 측정하였다.The cell proliferation inhibitory activity of the compound 9-2 prepared according to the above Example was confirmed. The cell lines used in the experiment were lung cancer cell lines A549 and H1703, colorectal cancer cell lines HCT116 and HT29, liver cancer (liver). cancer cell lines Hep3B and HepG2, gastric or stomach cancer cell lines NUGC-3 and AGS, kidney and renal cancer cell lines 786-O and Caki-1, breast cancer cell lines MCF-7 and MDA -MB-231, prostate cancer cell line PC3, pancreatic cancer cell line MIA-PaCa-2, cervical cancer cell line HeLa, normal cell WI-38 and CCD-32Lu cell lines. Specifically, the cell line was suspended in DMEM medium containing 5% fetal bovine serum (FBS), and then transferred to a 96 well plate (3 × 10 3 cells / well) for 24 hours in a 37 ° C. cell incubator maintaining 5% carbon dioxide. It was. Compound 9-2 was treated at various concentrations, incubated for 72 hours, and the cells were fixed with an aqueous 10% formalin solution, followed by staining with 0.5% methylene blue solution. Thereafter, the concentration change of methylene blue extracted with an aqueous 0.5% hydrochloric acid solution was measured at an absorbance of 600 nm.
그 결과, 표 4에 나타낸 바와 같이, 화합물 9-2는 정상세포주인 다양한 암세포주의 증식을 억제하였으며, 특히 A549, HCT116, HepG2 세포에서 강한 억제 효과를 나타내었다. 화합물 9-2는 암세포 증식을 억제하는 농도 범위에서, 정상세포주의 증식에는 영향이 없음을 확인하였다.As a result, as shown in Table 4, Compound 9-2 inhibited the proliferation of various cancer cell lines that are normal cell lines, and showed a particularly strong inhibitory effect in A549, HCT116, HepG2 cells. Compound 9-2 was found to have no effect on the proliferation of normal cell lines in a concentration range that inhibits cancer cell proliferation.
CellsCells | ViabilityViability GI50(GI50 ( μMμM )) |
A549A549 | ++++++ |
H1703H1703 | ++++ |
HCT116HCT116 | ++++++ |
HT29HT29 | ++++ |
Hep3BHep3B | ++ |
HepG2HepG2 | ++++++ |
NUGC-3NUGC-3 | ++++ |
AGSAGS | ++ |
786-O786-O | ++ |
Caki-1Caki-1 | ++ |
MCF-7MCF-7 | ++ |
MDA-MB-231MDA-MB-231 | ++ |
PC3PC3 | ++ |
MIA PaCa-2MIA PaCa-2 | ++++ |
HeLaHeLa | ++ |
WI-38WI-38 | -- |
CCD-32LuCCD-32Lu | -- |
1 ~ 5 μM : +++, 5 ~ 10 μM : ++, 10 ~ 20 μM : +, > 20 μM : -1 to 5 μM: +++, 5 to 10 μM: ++, 10 to 20 μM: +,> 20 μM:-
Claims (11)
- 하기 화학식 1로 표시되는 화합물, 이의 이성질체 또는 이의 약학적 허용가능한 염:A compound represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof:[화학식 1][Formula 1](상기 화학식 1에 있어서,(In the above formula 1,X는 메틸렌기, 에테인기, 에틸렌기, n-프로필렌기 또는 아이소프로필렌이고;X is methylene group, ethane group, ethylene group, n -propylene group or isopropylene;R1은 니트로기, 트리플루오로메틸기, C1-C20 알킬 또는 C1-C20 사이클로알킬이고; 및R 1 is a nitro group, trifluoromethyl group, C 1 -C 20 alkyl or C 1 -C 20 cycloalkyl; And상기 R3는 메틸 또는 2-프로핀일이고; R 3 is methyl or 2-propynyl;상기 R4는 메틸, 수소, 하이드록시, 메톡시, 2-프로핀일, , , , , , 또는 이고; R 4 is methyl, hydrogen, hydroxy, methoxy, 2-propynyl, , , , , , or ego;상기 R6는 메틸 또는 하이드록시이고; 및R 6 is methyl or hydroxy; And상기 R7는 C 또는 N임.)R 7 is C or N.
- 제 1항에 있어서,The method of claim 1,상기 R1은 니트로기, 트리플루오로메틸기, 아다만틸, tert-부틸, 펜틸, 사이클로펜틸, 사이클로헥실, 또는 2,4,4-트리메틸펜테인-2-일인 것을 특징으로 하는, 화합물, 이의 이성질체 또는 이의 약학적 허용가능한 염.R 1 is a nitro group, trifluoromethyl group, adamantyl, tert -butyl, pentyl, cyclopentyl, cyclohexyl, or 2,4,4-trimethylpentin-2-yl, a compound thereof, Isomers or pharmaceutically acceptable salts thereof.
- 제 1항에 있어서, The method of claim 1,상기 R1은 아다만틸이고;R 1 is adamantyl;X는 메틸렌기, 에테인기, 에틸렌기, n-프로필렌기 또는 아이소프로필렌이고; 및 X is methylene group, ethane group, ethylene group, n -propylene group or isopropylene; And상기 R3는 메틸인 것을 특징으로 하는, 화합물, 이의 이성질체 또는 이의 약학적 허용가능한 염. R 3 is methyl, a compound, an isomer thereof, or a pharmaceutically acceptable salt thereof.
- 제 1항에 있어서, 상기 화합물은 하기 화학식 2로 표시되는 화합물인 것을 특징으로 하는, 화합물, 이의 이성질체 또는 이의 약학적 허용가능한 염.The compound, isomer thereof or pharmaceutically acceptable salt thereof, characterized in that the compound is represented by the following formula (2).[화학식 2][Formula 2](상기 화학식 2에 있어서,(In the above formula 2,상기 R1은 아다만틸 또는 tert-부틸이고; 및 R 1 is adamantyl or tert -butyl; And상기 R3는 메틸 또는 2-프로핀일이고; R 3 is methyl or 2-propynyl;상기 R4는 메틸, 수소 또는 하이드록시이고; R 4 is methyl, hydrogen or hydroxy;상기 R6는 메틸 또는 하이드록시이고; 및R 6 is methyl or hydroxy; And상기 R7는 C 또는 N임).R 7 is C or N).
- 제 1항에 있어서, 상기 화합물은 하기 화학식 3으로 표시되는 화합물인 것을 특징으로 하는, 화합물, 이의 이성질체 또는 이의 약학적 허용가능한 염.The compound, isomer thereof or pharmaceutically acceptable salt thereof, according to claim 1, wherein the compound is a compound represented by the following Chemical Formula 3.[화학식 3][Formula 3](상기 화학식 3에 있어서,(In Formula 3,상기 R1은 니트로기, 트리플루오로메틸기, 아다만틸, tert-부틸, 펜틸, 사이클로펜틸, 사이클로헥실, 또는 2,4,4-트리메틸펜테인-2-일이고;R 1 is a nitro group, trifluoromethyl group, adamantyl, tert -butyl, pentyl, cyclopentyl, cyclohexyl, or 2,4,4-trimethylpentin-2-yl;상기 R3는 메틸 또는 2-프로핀일이고; 및R 3 is methyl or 2-propynyl; And
- 제 1항에 있어서,The method of claim 1,상기 화학식 1로 표시되는 화합물은 하기 화합물들로 이루어진 군으로부터 선택되는 어느 하나인 것을 특징으로 하는 화합물, 이의 이성질체 또는 이의 약학적 허용가능한 염:The compound represented by Formula 1 is any one selected from the group consisting of the following compounds, isomers thereof or pharmaceutically acceptable salts thereof:(1) 메틸 3-(2-(4-니트로페녹시)아세트아미도)벤조네이트(Methyl 3-(2-(4-nitrophenoxy)acetamido)benzoate);(1) Methyl 3- (2- (4-nitrophenoxy) acetamido) benzoate (Methyl 3- (2- (4-nitrophenoxy) acetamido) benzoate);(2) 메틸 3-(2-(4-트리플루오로메틸)페녹시)아세트아미도)벤조에이트(Methyl 3-(2-(4-(trifluoromethyl)phenoxy)acetamido)benzoate);(2) methyl 3- (2- (4-trifluoromethyl) phenoxy) acetamido) benzoate (Methyl 3- (2- (4- (trifluoromethyl) phenoxy) acetamido) benzoate);(3) 메틸 3-(2-(4-tert-부틸페녹시)아세트아미도)벤조에이트 (Methyl 3-(2-(4-tert-butylphenoxy)acetamido)benzoate) ;(3) methyl 3- (2- (4-tert-butylphenoxy) acetamido) benzoate (Methyl 3- (2- (4-tert-butylphenoxy) acetamido) benzoate);(4) 메틸 3-(2-(p-톨리록시)아세트아미도)벤조에이트(Methyl 3-(2-(p-tolyloxy)acetamido)benzoate);(4) Methyl 3- (2- (p-tolyloxy) acetamido) benzoate (Methyl 3- (2- (p-tolyloxy) acetamido) benzoate);(5) 메틸 3-(2-(4-에틸페녹시)아세트아미도)벤조에이트 (Methyl 3-(2-(4-ethylphenoxy)acetamido)benzoate) ;(5) methyl 3- (2- (4-ethylphenoxy) acetamido) benzoate (Methyl 3- (2- (4-ethylphenoxy) acetamido) benzoate);(6) 메틸 3-(2-(4-프로필페녹시)아세트아미도)벤조에이트 (Methyl 3-(2-(4-propylphenoxy)acetamido)benzoate);(6) methyl 3- (2- (4-propylphenoxy) acetamido) benzoate (Methyl 3- (2- (4-propylphenoxy) acetamido) benzoate);(7) 메틸 3-(2-(4-부틸 페녹시)아세트아미도)벤조에이트;(7) methyl 3- (2- (4-butyl phenoxy) acetamido) benzoate;(8) 메틸 3-(2-(4-펜틸페녹시)아세트아미도)벤조에이트 (Methyl 3-(2-(4-pentylphenoxy)acetamido)benzoate) ;(8) methyl 3- (2- (4-pentylphenoxy) acetamido) benzoate (Methyl 3- (2- (4-pentylphenoxy) acetamido) benzoate);(9) 메틸 3-(2-(4-사이클로펜틸페녹시)아세트아미도)벤조에이트 (Methyl 3-(2-(4-cyclopentylphenoxy)acetamido)benzoate) ;(9) methyl 3- (2- (4-cyclopentylphenoxy) acetamido) benzoate (Methyl 3- (2- (4-cyclopentylphenoxy) acetamido) benzoate);(10) 메틸 3-(2-(4-사이클로헥실페녹시)아세트아미도)벤조에이트 (Methyl 3-(2-(4-cyclohexylphenoxy)acetamido)benzoate);(10) methyl 3- (2- (4-cyclohexylphenoxy) acetamido) benzoate (Methyl 3- (2- (4-cyclohexylphenoxy) acetamido) benzoate);(11) 메틸 3-(2-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)아세트아미도)벤조에이트 (Methyl 3-(2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acetamido)benzoate);(11) Methyl 3- (2- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) acetamido) benzoate (Methyl 3- (2- (4- (2,4) , 4-trimethylpentan-2-yl) phenoxy) acetamido) benzoate);(12) 메틸 4-하이드록시-3-(2-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)아세트아미도)벤조에이트 (Methyl 4-hydroxy-3-(2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acetamido)benzoate); (12) Methyl 4-hydroxy-3- (2- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) acetamido) benzoate (Methyl 4-hydroxy-3- ( 2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamido) benzoate);(13) N-(4-(트리플루오로메틸)페닐)-2-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)아세트아마이드 (N-(4-(trifluoromethyl)phenyl)-2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acetamide) ;(13) N- (4- (trifluoromethyl) phenyl) -2- (4- (2,4,4-trimethylpentin-2-yl) phenoxy) acetamide (N- (4- (trifluoromethyl ) phenyl) -2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamide);(14) N-(4-(4-메틸피페라진-1-일)페닐)-2-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)아세트아마이드 (N-(4-(4-methylpiperazin-1-yl)phenyl)-2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acetamide);(14) N- (4- (4-methylpiperazin-1-yl) phenyl) -2- (4- (2,4,4-trimethylpentin-2-yl) phenoxy) acetamide (N- (4- (4-methylpiperazin-1-yl) phenyl) -2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamide);(15) 1-(4-(4-(트리플루오로메틸)벤질)피페라진-1-일)-2-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)에탄온 (1-(4-(4-(trifluoromethyl)benzyl)piperazin-1-yl)-2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)ethanone) ;(15) 1- (4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) -2- (4- (2,4,4-trimethylpentane-2-yl) phenoxy) Ethanone (1- (4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) -2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) ethanone);(16) 1-(4-(프로프-2-인일)피페라진-1-일)-2-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)에탄온 (1-(4-(prop-2-ynyl)piperazin-1-yl)-2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)ethanone);(16) 1- (4- (prop-2-ynyl) piperazin-1-yl) -2- (4- (2,4,4-trimethylpentane-2-yl) phenoxy) ethanone ( 1- (4- (prop-2-ynyl) piperazin-1-yl) -2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) ethanone);(17) 프로프-2-인일 4-하이드록시-3-(2-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)아세트아미도)벤조에이트 (Prop-2-ynyl 4-hydroxy-3-(2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acetamido)benzoate);(17) Prop-2-ynyl 4-hydroxy-3- (2- (4- (2,4,4-trimethylpentane-2-yl) phenoxy) acetamido) benzoate (Prop-2 -ynyl 4-hydroxy-3- (2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamido) benzoate);(18) N-(3-하이드록시-아다만테인-1-일)-2-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)아세트아마이드 (N-(3-hydroxy-adamantan-1-yl)-2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acetamide) ;(18) N- (3-hydroxy-adamantane-1-yl) -2- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) acetamide (N- (3 -hydroxy-adamantan-1-yl) -2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamide);(19) 메틸 3-(2-(4-아다만테인-1-일-페녹시)아세트아미도)벤조에이트 (Methyl 3-(2-(4-adamantan-1-yl-phenoxy)acetamido)benzoate) ;(19) Methyl 3- (2- (4-adamantane-1-yl-phenoxy) acetamido) benzoate (Methyl 3- (2- (4-adamantan-1-yl-phenoxy) acetamido) benzoate );(20) 메틸 3-(2-(4-아다만테인-1-일-페녹시)아세트아미도 4-하이드록시벤조에이트(Methyl 3-(2-(4-adamantan-1-yl-phenoxy)acetamido)-4-hydroxybenzoate);(20) Methyl 3- (2- (4-adamantane-1-yl-phenoxy) acetamido 4-hydroxybenzoate (Methyl 3- (2- (4-adamantan-1-yl-phenoxy) acetamido) -4-hydroxybenzoate);(21) 메틸 3-(2-(4-아다만테인-1-일-페녹시)아세트아미도)-4-(2-에톡시-2-옥소에톡시)벤조에이트(Methyl 3-(2-(4-adamantan-1-yl-phenoxy)acetamido)-4-(2-ethoxy-2-oxoethoxy)benzoate) ;(21) Methyl 3- (2- (4-adamantane-1-yl-phenoxy) acetamido) -4- (2-ethoxy-2-oxoethoxy) benzoate (Methyl 3- (2 -(4-adamantan-1-yl-phenoxy) acetamido) -4- (2-ethoxy-2-oxoethoxy) benzoate);(22) 메틸 3-(2-(4-아다만테인-1-일-페녹시)아세트아미도)-4-(2-(피롤리딘-1-일)에톡시)벤조에이트 (Methyl 3-(2-(4-adamantan-1-yl-phenoxy)acetamido)-4-(2-(pyrrolidin-1-yl)ethoxy)benzoate);(22) Methyl 3- (2- (4-adamantane-1-yl-phenoxy) acetamido) -4- (2- (pyrrolidin-1-yl) ethoxy) benzoate (Methyl 3 -(2- (4-adamantan-1-yl-phenoxy) acetamido) -4- (2- (pyrrolidin-1-yl) ethoxy) benzoate);(23) 메틸 3-(2-(4-아다만테인-1-일-페녹시)아세트아미도)-4-(3-모르폴리노프로폭시)벤조에이트 (Methyl 3-(2-(4-adamantan-1-yl-phenoxy)acetamido)-4-(3-morpholinopropoxy)benzoate);(23) Methyl 3- (2- (4-adamantane-1-yl-phenoxy) acetamido) -4- (3-morpholinopropoxy) benzoate (Methyl 3- (2- (4 -adamantan-1-yl-phenoxy) acetamido) -4- (3-morpholinopropoxy) benzoate);(24) 메틸 4-메톡시-3-(2-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)아세트아미도)벤조에이트 (Methyl 4-methoxy-3-(2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acetamido)benzoate); (24) Methyl 4-methoxy-3- (2- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) acetamido) benzoate (Methyl 4-methoxy-3- ( 2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamido) benzoate);(25) 메틸 4-(2-메톡시에톡시)-3-(2-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)아세트아미도)벤조에이트 (Methyl 4-(2-methoxyethoxy)-3-(2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acetamido)benzoate); (25) Methyl 4- (2-methoxyethoxy) -3- (2- (4- (2,4,4-trimethylpentane-2-yl) phenoxy) acetamido) benzoate (Methyl 4 -(2-methoxyethoxy) -3- (2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamido) benzoate);(26) 메틸 4-(2-모르폴리노에톡시)-3-(2-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)아세트아미도)벤조에이트 (Methyl 4-(2-morpholinoethoxy)-3-(2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acetamido)benzoate);(26) Methyl 4- (2-morpholinoethoxy) -3- (2- (4- (2,4,4-trimethylpentane-2-yl) phenoxy) acetamido) benzoate (Methyl 4- (2-morpholinoethoxy) -3- (2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamido) benzoate);(27) 메틸 4-(프로프-2-인일옥시)-3-(2-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)아세트아미도)벤조에이트 (Methyl 4-(prop-2-ynyloxy)-3-(2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acetamido)benzoate) ;(27) Methyl 4- (prop-2-ynyloxy) -3- (2- (4- (2,4,4-trimethylpentane-2-yl) phenoxy) acetamido) benzoate (Methyl 4- (prop-2-ynyloxy) -3- (2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamido) benzoate);(28) 메틸 4-(4-메톡시벤질옥시)-3-(2-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)아세트아미도)벤조에이트 (Methyl 4-(4-methoxybenzyloxy)-3-(2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acetamido)benzoate) ;(28) Methyl 4- (4-methoxybenzyloxy) -3- (2- (4- (2,4,4-trimethylpentane-2-yl) phenoxy) acetamido) benzoate (Methyl 4 -(4-methoxybenzyloxy) -3- (2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamido) benzoate);(29) 메틸 3-(2-(4-아다만테인-1-일-페녹시)-2-메틸프로판아미도)벤조에이트 (Methyl 3-(2-(4-adamantan-1-yl-phenoxy)-2-methylpropanamido)benzoate) ;(29) Methyl 3- (2- (4-adamantane-1-yl-phenoxy) -2-methylpropaneamido) benzoate (Methyl 3- (2- (4-adamantan-1-yl-phenoxy ) -2-methylpropanamido) benzoate);(30) 메틸 3-(2-메틸-2-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)프로판아미도)벤조에이트 (Methyl 3-(2-methyl-2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)propanamido)benzoate) ;(30) Methyl 3- (2-methyl-2- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) propaneamido) benzoate (Methyl 3- (2-methyl-2 -(4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamido) benzoate);(31) 메틸- 4-하이드록시-3-(2-메틸-2-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)프로판아미도)벤조에이트(Methyl 4-hydroxy-3-(2-methyl-2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)propanamido)benzoate) ;(31) Methyl-4-hydroxy-3- (2-methyl-2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) benzoate (Methyl 4-hydroxy -3- (2-methyl-2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamido) benzoate);(32) 메틸 3-[4-(4-아다만테인-1-일-페녹시)부탄아미도]벤조에이트 (Methyl 3-[4-(4-adamantan-1-yl-phenoxy)butanamido]benzoate) ;(32) Methyl 3- [4- (4-adamantane-1-yl-phenoxy) butanamido] benzoate (Methyl 3- [4- (4-adamantan-1-yl-phenoxy) butanamido] benzoate );(33) 메틸 3-(4-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)부탄아미도)벤조에이트 (Methyl 3-(4-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)butanamido)benzoate) ;(33) Methyl 3- (4- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) butanamido) benzoate (Methyl 3- (4- (4- (2,4) , 4-trimethylpentan-2-yl) phenoxy) butanamido) benzoate);(34) 메틸 4-하이드록시-3-(4-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)부탄아미도)벤조에이트 (Methyl 4-hydroxy-3-(4-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)butanamido)benzoate); (34) Methyl 4-hydroxy-3- (4- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) butanamido) benzoate (Methyl 4-hydroxy-3- ( 4- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) butanamido) benzoate);(35) (E)-3-[3-(4-아다만테인-1-일-페녹시)-아크릴오일아미노]-벤조익 산 메틸 에스테르((E)-3-[3-(4-Adamantan-1-yl-phenoxy)-acryloylamino]-benzoic acid methyl ester);(35) (E) -3- [3- (4-adamantane-1-yl-phenoxy) -acryloylamino] -benzoic acid methyl ester ((E) -3- [3- (4- Adamantan-1-yl-phenoxy) -acryloylamino] -benzoic acid methyl ester);(36) (E)-3-{3-[4-(2,4,4-트리메틸펜탄-2-일)페녹시]아크릴아미도}벤조익 산 메틸 에스테르((E)-3-{3-[4-(2,4,4-Trimethylpentan-2-yl)phenoxy]acrylamido}benzoic acid methyl ester) ;(36) (E) -3- {3- [4- (2,4,4-trimethylpentan-2-yl) phenoxy] acrylamido} benzoic acid methyl ester ((E) -3- {3 -[4- (2,4,4-Trimethylpentan-2-yl) phenoxy] acrylamido} benzoic acid methyl ester);(37) (E)-메틸4-메틸-3-(3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)아크릴아미도)벤조에이트((E)-methyl 4-methyl-3-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acrylamido)benzoate) ;(37) (E) -methyl4-methyl-3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate ((E) -methyl 4 -methyl-3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate);(38) (E)-메틸2-메틸-5-(3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)아크릴아미도)벤조에이트((E)-methyl 2-methyl-5-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acrylamido)benzoate) ;(38) (E) -methyl2-methyl-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate ((E) -methyl 2 -methyl-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate);(39) (E)-메틸2-하이드록시-5-(3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)아크릴아미도)벤조에이트((E)-methyl 2-hydroxy-5-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acrylamido)benzoate) ;(39) (E) -methyl2-hydroxy-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate ((E) -methyl 2-hydroxy-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate);(40) (E)-이소프로필 3-(3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)아크릴아미도)벤조에이트((E)-isopropyl 3-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acrylamido)benzoate);(40) (E) -isopropyl 3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate ((E) -isopropyl 3- (3 -(4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate);(41) (E)-메틸 2,4-다이메틸-5-(3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)아크릴아미도)벤조에이트((E)-methyl 2,4-dimethyl-5-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acrylamido)benzoate); (41) (E) -methyl 2,4-dimethyl-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate ((E) -methyl 2,4-dimethyl-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate);(42) (E)-3H-[1,2,3]트리아졸로[4,5-b]피리딘-3-일 3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)아크릴레이트((E)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl 3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acrylate) ;(42) (E) -3H- [1,2,3] triazolo [4,5-b] pyridin-3-yl 3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy Acrylate ((E) -3H- [1,2,3] triazolo [4,5-b] pyridin-3-yl 3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy ) acrylate);(43) (E)-1H-벤조[d][1,2,3]트리아졸-1-일 3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)아크릴레이트((E)-1H-benzo[d][1,2,3]triazol-1-yl 3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acrylate) ;(43) (E) -1H-benzo [d] [1,2,3] triazol-1-yl 3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylate ((E) -1H-benzo [d] [1,2,3] triazol-1-yl 3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylate);(44) (E)-메틸 4-하이드록시-3-(3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)아크릴아미도)벤조에이트((E)-methyl 4-hydroxy-3-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)acrylamido)benzoate);(44) (E) -methyl 4-hydroxy-3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate ((E) -methyl 4-hydroxy-3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate);(45) 메틸 3-[3-(4-아다만테인-1-일-페녹시)프로판아미도]벤조에이트 (Methyl 3-(3-(4-(adamantan-1-yl)phenoxy)propanamido)benzoate);(45) Methyl 3- [3- (4-adamantane-1-yl-phenoxy) propanamido] benzoate (Methyl 3- (3- (4- (adamantan-1-yl) phenoxy) propanamido) benzoate);(46) 메틸 3-(3-(4-(2,4,4-트리메틸펜테인-2-일)페녹시)프로판아미도)벤조에이트 (Methyl 3-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)propanamido)benzoate) ;(46) Methyl 3- (3- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) propaneamido) benzoate (Methyl 3- (3- (4- (2,4) , 4-trimethylpentan-2-yl) phenoxy) propanamido) benzoate);(47) 메틸 4-하이드록시-3-(3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)프로판아미도)벤조에이트(Methyl 4-hydroxy-3-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)propanamido)benzoate) ;(47) Methyl 4-hydroxy-3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) benzoate (Methyl 4-hydroxy-3- (3 -(4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamido) benzoate);(48)메틸 4-메틸-3-(3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)프로판아미도)벤조에이트(Methyl 4-methyl-3-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)propanamido)benzoate) ;(48) methyl 4-methyl-3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) benzoate (Methyl 4-methyl-3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamido) benzoate);(49) 메틸 2-메틸-5-(3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)프로판아미도)벤조에이트(Methyl 2-methyl-5-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)propanamido)benzoate) ;(49) Methyl 2-methyl-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) benzoate (Methyl 2-methyl-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamido) benzoate);(50)메틸 2-하이드록시-5-(3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)프로판아미도)벤조에이트(Methyl 2-hydroxy-5-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)propanamido)benzoate) ;(50) Methyl 2-hydroxy-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) benzoate (Methyl 2-hydroxy-5- (3 -(4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamido) benzoate);(51) 이소프로필 3-(3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)프로판아미도)벤조에이트(Isopropyl 3-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)propanamido)benzoate);(51) Isopropyl 3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) benzoate (Isopropyl 3- (3- (4- (2,4 , 4-trimethylpentan-2-yl) phenoxy) propanamido) benzoate);(52) 메틸 5-(3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)프로판아미도)니코티네이트; (Methyl 5-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)propanamido)nicotinate) (52) methyl 5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) nicotinate; (Methyl 5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamido) nicotinate)(53) N-(3-(모르폴린-4-카보닐)페닐)-3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)프로판아마이드(N-(3-(Morpholine-4-carbonyl)phenyl)-3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)propanamide) ;(53) N- (3- (morpholin-4-carbonyl) phenyl) -3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamide (N- (3- (Morpholine-4-carbonyl) phenyl) -3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamide);(54) 에틸 2-(3-(3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)프로판아미도)벤즈아미도)아세테이트(Ethyl 2-(3-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)propanamido)benzamido)acetate) ; 또는(54) ethyl 2- (3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) benzamido) acetate (Ethyl 2- (3- (3 -(4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamido) benzamido) acetate); or(55) (S)-메틸 3-메틸-2-(3-(3-(4-(2,4,4-트리메틸펜탄-2-일)페녹시)프로판아미도)벤즈아미도)부타노에이트((S)-methyl 3-methyl-2-(3-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)propanamido)benzamido)butanoate).(55) (S) -methyl 3-methyl-2- (3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) benzamido) butano Ate ((S) -methyl 3-methyl-2- (3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamido) benzamido) butanoate).
- 제 1항 내지 제 6항 중 어느 한 항의 화합물, 이의 이성질체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는, 암 예방 또는 치료용 약학적 조성물.The compound of any one of claims 1 to 6, an isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient, cancer prevention or treatment pharmaceutical composition.
- 제 7항에 있어서,The method of claim 7, wherein상기 조성물은 MDH1 (malate dehydrogenases 1) 및 MDH2 (malate dehydrogenases 2) 중 어느 하나 이상의 활성을 동시에 저해시키는 것을 특징으로 하는, 암 예방 또는 치료용 약학적 조성물.The composition is characterized in that simultaneously inhibiting the activity of any one or more of MDH1 (malate dehydrogenases 1) and MDH2 (malate dehydrogenases 2), cancer prevention or treatment pharmaceutical composition.
- 제 7항에 있어서, 상기 암은 암종(carcinoma), 림프종 (lymphoma), 모세포종 (blastoma), 육종 (sarcoma), 지방육종 (liposarcoma), 신경내분비종 (neuroendocrine tumor),중피종(mesothelioma), 신경초종 (schwanoma), 수막종 (meningioma), 샘암종(adenocarcinoma), 흑색종 (melanoma), 백혈병 (leukemia), 악성 림프종 (lymphoidmalignancy), 편평세포암종 (squamous cell cancer), 편평상피세포암 (epithelial squamous cell cancer), 폐암 (lung cancer), 소세포폐암 (small-cell lungcancer), 비소세포폐암 (non-small cell lungcancer),폐샘암종 (adenocarcinoma of the lung),폐편평암종(squamous carcinoma of the lung),복막종 (cancer of the peritoneum), 간세포성종 (hepatocellular cancer), 위암종 (gastric or stomach cancer), 위장관종 (gastrointestinal cancer), 췌장암(pancreatic cancer), 뇌암 (brain cancer), 아교모세포종 (glioblastoma), 자궁경부암 (cervical cancer), 난소암 (ovarian cancer), 간암 (liver cancer), 방광암 (bladder cancer), 간암 (hepatoma), 유방암 (breast cancer), 결장암 (colon cancer), 직장암 (rectal cancer), 결장직장암 (colorectal cancer), 자궁내막 또는 자궁암 (endometrial or uterine carcinoma), 침샘암 (salivary gland carcinoma), 신장암 (kidney and renal cancer), 전립선암 (prostate cancer), 외음암 (vulval cancer), 갑상선암 (thyroid cancer), 간암종 (hepatic carcinoma), 항문암종 (anal carcinoma), 음경암종 (penile carcinoma), 고환암 (testicular cancer), 식도정맥류암 (esophageal cancer), 담도암 (biliary tract), 대장암(colorectal cancer) 및 두경부암 (head and neck cancer)으로 구성되는 군으로부터 선택되는 것을 특징으로 하는, 암 예방 또는 치료용 약학적 조성물. The method of claim 7, wherein the cancer is carcinoma, lymphoma, blastoma, sarcoma, liposarcoma, neuroendocrine tumor, mesothelioma, neurocholia ( schwanoma, meningioma, adenocarcinoma, melanoma, melanoma, leukemia, lymphoidmalignancy, squamous cell cancer, squamous cell cancer, epithelial squamous cell cancer, Lung cancer, small-cell lungcancer, non-small cell lungcancer, adenocarcinoma of the lung, squamous carcinoma of the lung, peritoneal tumor of the peritoneum, hepatocellular cancer, gastric or stomach cancer, gastrointestinal cancer, pancreatic cancer, brain cancer, glioblastoma, cervical cancer cancer, ovarian cancer, liver cancer ancer, bladder cancer, hepatoma, breast cancer, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, Salivary gland carcinoma, kidney and renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatocarcinoma, anal carcinoma Selected from the group consisting of penile carcinoma, testicular cancer, esophageal cancer, biliary tract, colorectal cancer and head and neck cancer Characterized in that the pharmaceutical composition for preventing or treating cancer.
- 제 1항 내지 제 6항 중 어느 한 항의 화합물, 이의 이성질체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는, 암 예방 또는 치료용 약학적 조성물을 개체에 투여하는 단계를 포함하는, 암 치료방법. A cancer treatment comprising administering to a subject a pharmaceutical composition for preventing or treating cancer, comprising the compound of any one of claims 1 to 6, an isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient. Way.
- 제 1항 내지 제 6항 중 어느 한 항의 화합물, 이의 이성질체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는, 암 예방 또는 치료용 약학적 조성물의 암 예방 또는 치료용도.Use of the compound of any one of claims 1 to 6, an isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient, cancer prevention or treatment of cancer of the pharmaceutical composition for preventing or treating cancer.
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