WO2011014008A2 - Novel 3-phenoxy-4-pyrone, 3-phenoxy-4-pyridone, or 4-pyridone derivatives, method for preparing same, and antimicrobial composition containing same as an active ingredient - Google Patents

Novel 3-phenoxy-4-pyrone, 3-phenoxy-4-pyridone, or 4-pyridone derivatives, method for preparing same, and antimicrobial composition containing same as an active ingredient Download PDF

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WO2011014008A2
WO2011014008A2 PCT/KR2010/004966 KR2010004966W WO2011014008A2 WO 2011014008 A2 WO2011014008 A2 WO 2011014008A2 KR 2010004966 W KR2010004966 W KR 2010004966W WO 2011014008 A2 WO2011014008 A2 WO 2011014008A2
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pyridin
formula
compound
dichlorophenyl
phenoxy
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WO2011014008A3 (en
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신계정
노은주
정민경
차현주
서선희
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한국과학기술연구원
서울대학교 산학협력단
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D309/34—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D309/36—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
    • C07D309/40—Oxygen atoms attached in positions 3 and 4, e.g. maltol
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/69—Two or more oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/34—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention is a novel 3-phenoxy-4-pyrone, 3-phenoxy-4-pyridone or 4-pyridone derivative, a method for preparing the same and a fatty acid biosynthetic enzyme containing it as an active ingredient (Enoyl AC reductase ( It relates to an antimicrobial composition that inhibits enoyl-ACP reductase (Fabi).
  • Fatty acid biosynthesis plays an indispensable role in bacterial growth. And these fatty acid biosynthesis processes in cells are biochemical processes that are essential in all living cells. Fatty acid biosynthesis processes in higher animals and bacteria have some differences in enzyme-related processes. In higher animals, fatty acids are synthesized by one large polypeptide called fatty acid enzymes (FAS), but in bacterial systems several enzymes with one function are involved in each reaction. This difference leads to selectivity between the host mammal and bacteria during fatty acid biosynthesis (Campbell, JW; Cronan, JE, Jr. Bacterial fatty acid biosynthesis: Targets for antibacterial drug discovery. Annu. Rev. Microbiol. 2001, 55 , 305-332).
  • FAS fatty acid enzymes
  • Fatty acid biosynthesis consists of four steps: condensation, reduction, dehydration and reduction.
  • trans-2-enoyl-ACP is reduced to acyl-ACP by FabI, NADH (NADPH) -dependent enoyl-ACP reductase.
  • the trans-2-enoyl-ACP (FabI) enzyme used in the last step is a rate determining step and is a major regulatory point in the overall synthesis of FAS (Heath, RJ; Rock, CO Enoyl-acyl carrier protein reductase).
  • (fabI) plays a determinant role in completing cycles of fatty acid elongateion in Escherichia coli.J. Biol. Chem. 1995, 270, 26538-26542).
  • the present inventors have devised a new compound through the structural studies of existing derivatives, developed pharmacophore mapping, and developed the derivatives in order to develop a new inhibitor that can effectively inhibit the fatty acid biosynthesis of the bacteria.
  • the bacterium showed fatty acid biosynthesis inhibitory activity and completed the present invention.
  • Another object of the present invention is to provide a method for preparing a novel 3-phenoxy-4-pyrone, 3-phenoxy-4-pyridone or 4-pyridone derivative.
  • Another object of the present invention is to provide an antimicrobial composition containing the novel 3-phenoxy-4-pyrone, 3-phenoxy-4-pyridone or 4-pyridone derivative or pharmaceutically acceptable salt thereof as an active ingredient. To provide.
  • the present invention provides novel 3-phenoxy-4-pyrone, 3-phenoxy-4-pyridone or 4-pyridone derivative, or a pharmaceutically acceptable salt thereof.
  • the present invention also provides a method for preparing the novel 3-phenoxy-4-pyrone, 3-phenoxy-4-pyridone or 4-pyridone derivative.
  • the present invention provides an antimicrobial composition containing the novel 3-phenoxy-4-pyrone, 3-phenoxy-4-pyridone or 4-pyridone derivative, or a pharmaceutically acceptable salt thereof as an active ingredient. do.
  • compositions containing novel 3-phenoxy-4-pyrones, 3-phenoxy-4-pyridones or 4-pyridone derivatives according to the present invention are effective for the bacterial fatty acid biosynthetic enzyme Enoyl-ACP Reductase (FabI). Since it inhibits, it can be usefully used as an antibacterial agent.
  • FabI bacterial fatty acid biosynthetic enzyme Enoyl-ACP Reductase
  • the present invention provides novel 3-phenoxy-4-pyrone, 3-phenoxy-4-pyridone or 4-pyridone derivative represented by Formula 1 below, or a pharmaceutically acceptable salt thereof.
  • X is O or NR 3, wherein R 3 is hydrogen; C 1 -C 4 straight or branched alkyl; C 3 -C 8 cycloalkyl; C 5 -C 12 arylalkyl unsubstituted or substituted with one or more halogen, nitro, haloalkyl, C 1 -C 4 straight or branched alkyl, C 1 -C 4 alkoxy; Or C 5 -C 8 heteroaryl,
  • Y is O or -CHOH
  • R 1 is hydrogen, or wherein R 4 is C 1 -C 4 straight or branched alkyl; Or C 5 -C 8 heteroaryl,
  • R 2 is substituted with one or more C 1 -C 4 straight or branched alkyl or halogen.
  • X is O or NR 3, wherein R 3 is hydrogen, methyl, butyl, cyclopropyl, benzyl, bromobenzyl, chlorobenzyl, nitrobenzyl, trifluoromethylbenzyl, methylbenzyl, dimethylbenzyl, difluorobenzyl, Dichlorobenzyl, methoxybenzyl, t-butylbenzyl, furanyl or diphenylmethyl,
  • Y is O or -CHOH
  • R 1 is hydrogen, or Wherein R 4 is furan, thiophene, pyridine, pyrrole, isobutyl, butyl,
  • R 2 is 4-chloro- 2 -methyl, 2,3-dichloro, 2,6-dichloro, 2,4, -dichloro, 2,4-dimethyl.
  • the derivative according to the present invention may be selected from the compounds of Formulas 1a to 1d.
  • R 3 is furan, thiophene, pyridine, pyrrole, isobutyl or butyl.
  • R 4 is isobutyl or butyl
  • R 5 is hydrogen, methyl or cyclopropyl.
  • R 6 is hydrogen, methyl, cyclopropyl, butyl or benzyl
  • R 7 is 4-chloro-2-methyl, dichloro or dimethyl.
  • R 8 is benzyl, bromobenzyl, chlorobenzyl, nitrobenzyl, trifluoromethylbenzyl, methylbenzyl, dimethylbenzyl, difluorobenzyl, dichlorobenzyl, methoxybenzyl, t-butylbenzyl, Furanyl or diphenylmethyl,
  • R 9 is dichloro.
  • the derivative of the present invention represented by Formula 1 may be used in the form of a pharmaceutically acceptable salt, and acid salts formed by pharmaceutically acceptable free acid are useful as salts.
  • Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid and aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. Obtained from non-toxic organic acids such as dioates, aromatic acids, aliphatic and aromatic sulfonic acids.
  • Such pharmaceutically nontoxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, and iodide.
  • the acid addition salts according to the invention are dissolved in conventional methods, for example, by dissolving a derivative of formula 1 in an excess of aqueous acid solution and using the water miscible organic solvent, such as methanol, ethanol, acetone or acetonitrile. It can be prepared by precipitation.
  • water miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. It can be prepared by precipitation.
  • Equivalent amounts of the derivative of formula 1 and the acid or alcohol in water may be heated and then the mixture is evaporated to dryness or prepared by suction filtration of the precipitated salt.
  • Bases can also be used to make pharmaceutically acceptable metal salts.
  • Alkali metal or alkaline earth metal salts are obtained, for example, by dissolving a 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.
  • Corresponding silver salts are also obtained by reacting alkali or alkaline earth metal salts with a suitable silver salt (eg, silver nitrate).
  • the derivative represented by Chemical Formula 1 of the present invention includes not only pharmaceutically acceptable salts, but also all salts, hydrates, and solvates that can be prepared by conventional methods.
  • the addition salt according to the present invention can be prepared by a conventional method, for example, by dissolving the compound of Formula 1 in a water miscible organic solvent such as acetone, methanol, ethanol, or acetonitrile and adding an excess of an organic acid or an inorganic acid. It can be prepared by adding an acidic aqueous solution of and then precipitating or crystallizing. The solvent or excess acid may then be evaporated and dried in this mixture to obtain an addition salt or the precipitated salt may be prepared by suction filtration.
  • a water miscible organic solvent such as acetone, methanol, ethanol, or acetonitrile
  • the present invention also provides a method for preparing the derivative of Chemical Formula 1.
  • Step 2 Preparing a compound of Chemical Formula 6 by replacing the compound of Chemical Formula 5 prepared in Step 1 with a chloride group (Step 2);
  • the compound of Chemical Formula 7 prepared in Step 3 may be prepared by introducing a double bond structure through a Horner-Emons reaction (Step 4).
  • R 2 is as defined in Formula 1
  • R 3 is as defined in Formula 1a
  • Formula 1a is included in Formula 1.
  • Step 1 according to the present invention is a step of preparing a compound of Chemical Formula 5 by Ullmann reaction of the kojic acid compound of Chemical Formula 4.
  • step 1 the compound of formula 4 used as starting material and the aryl halide is reacted to produce formula 5.
  • the reaction of step 1 is commonly known in the field of organic chemistry, and reaction conditions such as reaction solvent, reaction temperature, reaction time, etc. may be appropriately selected in consideration of reactants, products, and the like.
  • dimethylformamide was used as a reaction solvent in the presence of a copper catalyst, and the compound of Chemical Formula 5 can be obtained by heating and stirring at 75 ° C. overnight.
  • step 2 is a step of preparing a compound of formula 6 by replacing the compound of formula 5 prepared in step 1 with a chloride group.
  • the compound of Chemical Formula 6 may be obtained by dissolving Chemical Formula 5 in CH 2 Cl 2 as a reaction solvent and adding thionyl chloride and triethylamine to stir at room temperature for 3 hours.
  • the phenoxyether derivative represented by Chemical Formula 5 is preferably used selected from the group consisting of the following compounds.
  • step 3 is an arbuzov reaction of the compound of formula 6 prepared in step 2 to synthesize a phosphonate to prepare a compound of formula 7.
  • step 3 the step of generating the chemical formula 7 by substituting the chloro group of the chemical formula 6.
  • the reaction of step 3 is commonly known in the organic chemistry field, and reaction conditions such as reaction solvent, reaction temperature, reaction time, and the like may be appropriately selected in consideration of reactants, products, and the like. This reaction can be accomplished by heating at reflux for 3 hours using triethylphosphite.
  • step 4 is a step of preparing a compound of Formula 1a by introducing a double bond structure through the Horner-emons reaction of the compound of Formula 7 prepared in Step 3.
  • 3-phenoxy-4-pyrone derivative (1a) may be obtained by introducing a double bond structure by reacting the phosphonate compound of Formula 5 with various substituted aldehyde compounds.
  • Step 4 is commonly known in the field of organic chemistry, and reaction conditions such as reaction solvent, reaction temperature, reaction time, etc. may be appropriately selected in consideration of reactants, products, and the like.
  • reaction solvent anhydrous tetrahydrofuran was used as a solvent, and various substituted aldehydes were added and stirred at room temperature overnight to synthesize a pyran structured compound.
  • the base may be an alkali metal hydrogen compound such as sodium hydride (NaH), lithium hydride (LiH), potassium hydride (KH), sodium methoxide, sodium ethoxide, sodium propoxide, sodium t-butoxide, potassium It is preferable to use metal alkoxides such as t-butoxide, potassium isopropoxide, lithium isopropoxide and the like, and potassium t-butoxide is more preferable.
  • NaH sodium hydride
  • LiH lithium hydride
  • KH potassium hydride
  • metal alkoxides such as t-butoxide, potassium isopropoxide, lithium isopropoxide and the like, and potassium t-butoxide is more preferable.
  • the compound of Chemical Formula 8 prepared in Step 1 may be prepared by introducing a double bond structure through a Horner-Emons reaction (Step 2).
  • step 1 is a step of preparing a compound of compound 8 by adding a phosphonate compound of formula 7 with an amine compound.
  • step 2 is a step of preparing a compound of Formula 1b by introducing a double bond structure through the Horner-emons reaction of the compound of Formula 8 prepared in Step 1.
  • This step can be carried out in the same manner as step 4 of Preparation 1.
  • the compound of formula 9 prepared in step 1 may be added to an amine compound to prepare a compound of compound 1c (step 2).
  • R 2 is as defined in Formula 1
  • R 6 and R 7 are as defined in Formula 1c
  • Formula 1c is included in Formula 1.
  • step 1 is a step of preparing a compound of formula 9 by Mitsunobu reaction of a phenoxyether compound of formula 5 with phenol and diisopropyl azodicarboxylate.
  • triphenylphosphine and phenol are added to the compound of formula 5 under anhydrous tetrahydrofuran as a solvent, diisopropyl azodicarboxylate is added at 0 ° C., and then stirred at room temperature overnight to obtain a compound of formula 9 Can be.
  • the reaction is commonly known in the field of organic chemistry under the name "Mitsunobu reaction”.
  • step 2 is a step of preparing the compound of compound 1c by the addition reaction of the compound of formula 9 prepared in step 1 with the amine compound.
  • step 1 of Preparation 2 The above step can be carried out in the same manner as step 1 of Preparation 2.
  • step 1 Preparing a compound of formula 11 by introducing a 4-chloropyridine salt of formula 10 under a methoxy structure under sodium methoxide (step 1);
  • Step 2 Preparing a compound of Compound 12 by reacting the 4-methoxypyridine compound of Formula 11 prepared in Step 1 with an aldehyde (Step 2);
  • the compound of Formula 12 prepared in Step 2 may be reacted with benzaldehyde to prepare a compound of Formula 1d (Step 3).
  • R 9 is as defined in Formula 1d, and Formula 1d is included in Formula 1.
  • step 1 is a step of preparing a compound of formula 11 by introducing a methoxy structure of the 4-chloropyridine salt of formula 10 under sodium methoxide.
  • methoxide salt is prepared by first adding solid sodium while stirring using methanol as a reaction solvent, and then adding the compound of formula 10 in an ice bath, and then heating and refluxing at 80 ° C. for 3 days to give chloro of formula 10.
  • a compound of formula 11 can be obtained in which the group is substituted with a methoxy group.
  • step 2 is a step of preparing a compound of compound 12 by reacting the 4-methoxypyridine compound of formula 11 prepared in step 1 with an aldehyde.
  • the phenylacetate derivatives or intermediates prepared according to the present invention are prepared by infrared spectroscopy, nuclear magnetic resonance spectra, mass spectroscopy, liquid chromatography, X-ray structure determination, photoluminescence measurement and elemental analysis calculations of representative compounds. The molecular structure can be confirmed by comparing with the measured values.
  • the present invention provides an antimicrobial composition containing the 3-phenoxy-4-pyrone, 3-phenoxy-4-pyridone or 4-pyridone derivative, or a pharmaceutically acceptable salt thereof as an active ingredient. .
  • the present invention also provides a therapeutically effective amount of the 3-phenoxy-4-pyrone, 3-phenoxy-4-pyridone or 4-pyridone derivative, or a pharmaceutically acceptable salt thereof. It provides a method of treating antimicrobial comprising administering to a patient.
  • the present invention provides the use of the above 3-phenoxy-4-pyrone, 3-phenoxy-4-pyridone or 4-pyridone derivative, or a pharmaceutically acceptable salt thereof.
  • 3-phenoxy-4-pyrone, 3-phenoxy-4-pyridone or 4-pyridone derivative, and pharmaceutically acceptable salts thereof, which are contained as an active ingredient in the composition according to the present invention are bacterial fatty acid biosynthetic enzymes. It has been shown to inhibit the activity of Enoyl-ACP reductase (FabI) (see Table 4). Therefore, the composition according to the present invention can be usefully used as an antimicrobial agent because it exhibits an antimicrobial effect by inhibiting an enzyme regulating fatty acid biosynthesis that plays an essential role in bacterial growth.
  • FabI Enoyl-ACP reductase
  • the pharmaceutical composition containing the derivative of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient may be formulated in various oral or parenteral dosage forms as described below. It may be administered, but is not limited thereto.
  • Formulations for oral administration include, for example, tablets, pills, hard / soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, etc. These formulations may contain, in addition to the active ingredients, diluents (e.g., lactose, dextrose). Rose, sucrose, mannitol, sorbitol, cellulose and / or glycine), lubricants such as silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycols.
  • diluents e.g., lactose, dextrose
  • Rose sucrose, mannitol, sorbitol, cellulose and / or glycine
  • lubricants such as silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycols.
  • Tablets may also contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine, and optionally such as starch, agar, alginic acid or its sodium salt. Disintegrant or boiling mixtures and / or absorbents, colorants, flavors, and sweeteners.
  • binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine, and optionally such as starch, agar, alginic acid or its sodium salt.
  • the pharmaceutical composition comprising the derivative represented by Chemical Formula 1 as an active ingredient may be administered parenterally, and the parenteral administration may be by injection of subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection.
  • the phenylacetate derivative of Formula 1 or a pharmaceutically acceptable salt thereof is mixed with water together with a stabilizer or a buffer to prepare a solution or suspension, which is an ampoule or vial unit dosage form. It can be prepared by.
  • the compositions may contain sterile and / or preservatives, stabilizers, hydrating or emulsifying accelerators, auxiliaries such as salts and / or buffers for the control of osmotic pressure, and other therapeutically useful substances, and conventional methods of mixing, granulating It may be formulated according to the formulation or coating method.
  • the dosage of the compound of the present invention to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, and generally based on an adult patient having a weight of 70 kg. It is 0.1-1,000 mg / day, Preferably it is 1-500 mg / day, It can also divide and administer once a day to several times at regular time intervals according to a decision of a doctor or a pharmacist.
  • Step 1 Preparation of 5- (4-chloro-2-methylphenoxyl) -2-hydroxymethylpyran-4-one
  • Triethylphosphite (5.79 mL, 33.79 mmol) was added to 2-chloromethyl-5- (4-chloro-2-methylphenoxy) pyran-4-one (0.8 g, 0.35 mmol) prepared in step 2 above. The reaction was then heated to reflux overnight. After the reaction was terminated, the solvent was removed under reduced pressure to obtain 5.98 g of the target compound in 44% yield.
  • Step 1 Preparation of [5- (4-chloro-2-methylphenoxy) -4-oxo-1,4-dihydropyridin-2-ylmethyl ] phosphonic acid diethyl ester
  • Step 2 Preparation of 5- (4-chloro-2-methylphenoxy) -2- (3-methylbut-1-enyl) -1H-pyridin-4-one
  • Step 1 Preparation of 5- (4-chloro-2-methyl-phenoxy) -2-phenoxymethylpyran-4-one
  • Step 2 Preparation of 5- (4-Chloro-2-methyl-phenoxy) -1-methyl-2-phenoloxymethyl-1H-pyridin-4-one
  • the reaction vessel was filled with nitrogen, contained 100 mL of anhydrous tetrahydrofuran, and 4-methoxypyridine (4.0 g, 36.65 mmol) prepared in Step 1 was added thereto.
  • the apparatus was set at ⁇ 78 ° C., and slowly added phenyllithium 1.8 M solution (44 mL, 80.64 mmol), followed by stirring at room temperature for 1 hour. After the apparatus was again set at -78 ° C, 2,6-dichlorobenzaldehyde (14.29 g, 91.64 mmol) was added slowly and stirred overnight.
  • the reaction was terminated by thin layer chromatography (TLC), and then aqueous ammonium chloride solution was added. The resulting crystals were filtered and washed with ether to obtain 4.68 g of the title compound in a yield of 45%.
  • TLC thin layer chromatography
  • the inhibitory activity of the compounds was measured by the FabI enzyme inhibition assay (FabI enzyme inhibition assay) at a degree of decrease in absorbance with NADH consumption.
  • the compound according to the present invention exhibited high inhibitory activity against fatty acid biosynthetic enzyme (FabI) against Escherichia coli strain and high antibacterial activity against Mycobacterium tuberculosis H37Rv strain.
  • FabI fatty acid biosynthetic enzyme
  • a compound having an aromatic structure of R 3 substituted in a double bond shows high FabI enzyme inhibitory activity, but MIC activity shows very low activity. It is showing.
  • the compound of the aliphatic structure of the R 3 substituent does not show high FabI enzyme inhibitory activity but shows relatively high MIC activity. Therefore, even if the compound having R 3 aliphatic structure substituted in the double bond has a low FabI enzyme inhibitory activity, MIC activity appears to be high because the cell permeability is high.
  • the 3-phenoxy-4-pyridone derivative (Formula 1b) is a compound in which a small structure such as methyl or H is substituted than a compound having a bulky structure, such as benzyl or butyl, in which R 6 is substituted for pyridone It was confirmed that the better activity, FabI enzyme inhibitory activity and MIC activity can be seen to be quite consistent. It was confirmed through the 3-phenoxy-4-pyrone derivative and the 3-phenoxy-4-pyridone derivative that the compound having a pyridone structure showed better activity than the compound having a pyrone structure. It was confirmed that the derivative having a bond had good activity.
  • 4-pyridone derivatives (formula 1c) generally showed high FabI enzyme inhibitory activity.
  • Compounds with high FabI enzyme inhibitory activity showed good MIC activity, indicating that FabI enzyme inhibitory activity and MIC activity were significantly matched.
  • the derivative of the benzyl group having a halogen group at the 3 position of the substituent substituted at the substituent R 8 showed a higher inhibitory activity than the compound having a substituent at the 2 or 4 position. And it can be seen that the R 9 substituent has a better activity than the 2,6-dichloro substituent than the 2,3-dichloro substituent.
  • composition according to the present invention can be usefully used as an antimicrobial agent because it exhibits high antimicrobial activity.
  • the compound of Formula 1 according to the present invention can be formulated in various forms according to the purpose.
  • the following are some examples of formulation methods containing the compound represented by Formula 1 according to the present invention as an active ingredient, but the present invention is not limited thereto.
  • the active ingredient After sifting 5.0 mg of the active ingredient, it was mixed with 14.8 mg of lactose, 10.0 mg of polyvinyl pyrrolidone, and 0.2 mg of magnesium stearate. The mixture was prepared using a suitable apparatus. Filled in 5 gelatin capsules.
  • Injectables were prepared by containing 100 mg as the active ingredient, followed by the addition of 180 mg of mannitol, 26 mg of Na 2 HPO 4 .12H 2 O and 2974 mg of distilled water.

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Abstract

The present invention relates to novel 3-phenoxy-4-pyrone, 3-phenoxy-4-pyridone, or 4-pyridone derivatives, or to pharmaceutically acceptable salts thereof, to a method for preparing same, and to an antibacterial composition containing same as an active ingredient. The composition containing the novel 3-phenoxy-4-pyrone, 3-phenoxy-4-pyridone, or 4-pyridone derivatives according to the present invention effectively inhibits enoyl-ACP reductase (RabI), which serves as a bacterial fatty acid biosynthesis enzyme, and thus can be effectively used as an antibacterial agent.

Description

신규 3-페녹시-4-파이론, 3-페녹시-4-피리돈 또는 4-피리돈 유도체, 이의 제조방법 및 이를 유효성분으로 함유하는 항균 조성물Novel 3-phenoxy-4-pyrone, 3-phenoxy-4-pyridone or 4-pyridone derivative, preparation method thereof and antimicrobial composition containing the same as an active ingredient
본 발명은 신규 3-페녹시-4-파이론, 3-페녹시-4-피리돈 또는 4-피리돈 유도체, 이의 제조방법 및 이를 유효성분으로 함유하는 지방산 생합성 효소인 에노일 에이씨피 환원효소(enoyl-ACP reductase; FabI)를 억제하는 항균 조성물에 관한 것이다.The present invention is a novel 3-phenoxy-4-pyrone, 3-phenoxy-4-pyridone or 4-pyridone derivative, a method for preparing the same and a fatty acid biosynthetic enzyme containing it as an active ingredient (Enoyl AC reductase ( It relates to an antimicrobial composition that inhibits enoyl-ACP reductase (Fabi).
항생제 사용이 점점 빈번해짐에 따라 내성 발전률 또한 증가하게 되었다. 이렇듯 우리의 본질적인 삶을 위협하는 문제들에 맞서기 위해서 새로운 항생물질을 찾아 발전시키는 것이 중요한 문제로 대두되고 있다. As antibiotic use became more frequent, the development rate of resistance also increased. Finding and developing new antibiotics has emerged as an important issue in order to confront these essential life-threatening problems.
새로운 항생물질을 개발하기 위하여는 기존 항생제들의 변형(modification)을 통해 유도체를 만들어내는 것보다는 완전히 새로운 타겟을 발굴하여 항생제를 개발하는 것이 내성균 극복을 위해서는 바람직한 접근 방식으로 적합하다. 이러한 면에서 잠재력 있는 박테리아 타겟 중에서 박테리아 지방산 생합성(bacterial fatty acid biosynthesis)은 새로운 항생제 타겟으로 주목받고 있다(Heath, R. J.; White, S. W.; Rock, C. O. Lipid biosynthesis as a target for antibacterial agents. Prog. Lipid Res. 2001, 40, 467-497).To develop new antibiotics, rather than to produce derivatives through modification of existing antibiotics, developing antibiotics by discovering completely new targets is a suitable approach to overcome resistant bacteria. Among these potential bacterial targets, bacterial fatty acid biosynthesis has attracted attention as a new antibiotic target (Heath, RJ; White, SW; Rock, CO Lipid biosynthesis as a target for antibacterial agents.Prog. Lipid Res 2001, 40, 467-497).
지방산 생합성은 박테리아 성장에 있어서 필수불가결한 역할을 한다. 그리고 세포내의 이들 지방산 생합성 과정은 살아있는 모든 세포 내에서는 필수적으로 존재하는 생화학적 과정이다. 고등동물과 세균에서 지방산 생합성 과정은 효소관련에 있어서 약간의 차이를 가지게 된다. 고등동물에서는 지방산은 지방산효소 (FAS)라 불리우는 하나의 큰 폴리펩타이드에 의해서 합성되나, 세균의 시스템에서는 하나의 기능을 가진 여러 효소들이 별도로 존재하여 각각의 반응에 관여하게 된다. 이러한 차이점으로 인해 지방산 생합성 과정에서 숙주인 포유동물과 박테리아 간의 선택성을 가지게 된다(Campbell, J. W.; Cronan, J. E., Jr. Bacterial fatty acid biosynthesis: Targets for antibacterial drug discovery. Annu. Rev. Microbiol. 2001, 55, 305?332).Fatty acid biosynthesis plays an indispensable role in bacterial growth. And these fatty acid biosynthesis processes in cells are biochemical processes that are essential in all living cells. Fatty acid biosynthesis processes in higher animals and bacteria have some differences in enzyme-related processes. In higher animals, fatty acids are synthesized by one large polypeptide called fatty acid enzymes (FAS), but in bacterial systems several enzymes with one function are involved in each reaction. This difference leads to selectivity between the host mammal and bacteria during fatty acid biosynthesis (Campbell, JW; Cronan, JE, Jr. Bacterial fatty acid biosynthesis: Targets for antibacterial drug discovery. Annu. Rev. Microbiol. 2001, 55 , 305-332).
지방산 생합성은 축합, 환원, 탈수, 환원의 4단계로 이루어진다. 그리고 지방산 생합성에서 마지막 단계로 NADH(NADPH)-의존 에노일-ACP 환원효소인 FabI에 의해 트랜스-2-에노일-ACP가 아실-ACP로 환원되는 과정이 일어난다. 마지막 단계에서 사용되는 트랜스-2-에노일-ACP(FabI) 효소는 속도결정단계로써 전반적인 FAS의 합성단계에서 주요한 제어 포인트(regulatory point)이다(Heath, R. J.; Rock, C. O. Enoyl-acyl carrier protein reductase (fabI) plays a determinant role in completing cycles of fatty acid elongateion in Escherichia coli. J. Biol. Chem. 1995, 270, 26538-26542).Fatty acid biosynthesis consists of four steps: condensation, reduction, dehydration and reduction. In the final step in fatty acid biosynthesis, trans-2-enoyl-ACP is reduced to acyl-ACP by FabI, NADH (NADPH) -dependent enoyl-ACP reductase. The trans-2-enoyl-ACP (FabI) enzyme used in the last step is a rate determining step and is a major regulatory point in the overall synthesis of FAS (Heath, RJ; Rock, CO Enoyl-acyl carrier protein reductase). (fabI) plays a determinant role in completing cycles of fatty acid elongateion in Escherichia coli.J. Biol. Chem. 1995, 270, 26538-26542).
이에, 본 발명자들은 상기 박테리아의 지방산 생합성을 효과적으로 억제할 수 있는 새로운 저해제를 개발하기 위하여 기존 유도체들의 구조연구를 통하여 새로운 화합물을 고안하였고, 약리작용단 맵핑(pharmacophore mapping)을 실행하였으며, 그 유도체들을 제조하여 생체외 활성 실험(in vitro assay)을 수행한 결과, 박테리아의 지방산 생합성 저해 활성을 나타냄을 확인하고 본 발명을 완성하게 되었다. Accordingly, the present inventors have devised a new compound through the structural studies of existing derivatives, developed pharmacophore mapping, and developed the derivatives in order to develop a new inhibitor that can effectively inhibit the fatty acid biosynthesis of the bacteria. As a result of performing an in vitro assay, it was confirmed that the bacterium showed fatty acid biosynthesis inhibitory activity and completed the present invention.
본 발명의 목적은 박테리아의 지방산 생합성을 효과적으로 억제할 수 있는 신규 3-페녹시-4-파이론, 3-페녹시-4-피리돈 또는 4-피리돈 유도체, 또는 이의 약학적으로 허용가능한 염을 제공하는 데 있다.It is an object of the present invention to provide novel 3-phenoxy-4-pyrones, 3-phenoxy-4-pyridones or 4-pyridone derivatives, or pharmaceutically acceptable salts thereof, which can effectively inhibit the fatty acid biosynthesis of bacteria. To provide.
본 발명의 다른 목적은 신규 3-페녹시-4-파이론, 3-페녹시-4-피리돈 또는 4-피리돈 유도체의 제조방법을 제공하는 데 있다.Another object of the present invention is to provide a method for preparing a novel 3-phenoxy-4-pyrone, 3-phenoxy-4-pyridone or 4-pyridone derivative.
본 발명의 또 다른 목적은 상기 신규 3-페녹시-4-파이론, 3-페녹시-4-피리돈 또는 4-피리돈 유도체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 항균 조성물을 제공하는 데 있다.Another object of the present invention is to provide an antimicrobial composition containing the novel 3-phenoxy-4-pyrone, 3-phenoxy-4-pyridone or 4-pyridone derivative or pharmaceutically acceptable salt thereof as an active ingredient. To provide.
상기 목적을 달성하기 위하여, 본 발명은 신규 3-페녹시-4-파이론, 3-페녹시-4-피리돈 또는 4-피리돈 유도체, 또는 이의 약학적으로 허용가능한 염을 제공한다.In order to achieve the above object, the present invention provides novel 3-phenoxy-4-pyrone, 3-phenoxy-4-pyridone or 4-pyridone derivative, or a pharmaceutically acceptable salt thereof.
또한, 본 발명은 상기 신규 3-페녹시-4-파이론, 3-페녹시-4-피리돈 또는 4-피리돈 유도체의 제조방법을 제공한다.The present invention also provides a method for preparing the novel 3-phenoxy-4-pyrone, 3-phenoxy-4-pyridone or 4-pyridone derivative.
나아가, 본 발명은 상기 신규 3-페녹시-4-파이론, 3-페녹시-4-피리돈 또는 4-피리돈 유도체, 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 항균 조성물을 제공한다.Furthermore, the present invention provides an antimicrobial composition containing the novel 3-phenoxy-4-pyrone, 3-phenoxy-4-pyridone or 4-pyridone derivative, or a pharmaceutically acceptable salt thereof as an active ingredient. do.
본 발명에 따른 신규 3-페녹시-4-파이론, 3-페녹시-4-피리돈 또는 4-피리돈 유도체를 함유하는 조성물은 박테리아 지방산 생합성 효소인 에노일-ACP 환원효소(FabI)를 효과적으로 억제하므로 항균제로서 유용하게 사용될 수 있다.Compositions containing novel 3-phenoxy-4-pyrones, 3-phenoxy-4-pyridones or 4-pyridone derivatives according to the present invention are effective for the bacterial fatty acid biosynthetic enzyme Enoyl-ACP Reductase (FabI). Since it inhibits, it can be usefully used as an antibacterial agent.
이하, 본 발명을 상세하게 설명한다.EMBODIMENT OF THE INVENTION Hereinafter, this invention is demonstrated in detail.
본 발명은 하기 화학식 1로 표시되는 신규 3-페녹시-4-파이론, 3-페녹시-4-피리돈 또는 4-피리돈 유도체, 또는 이의 약학적으로 허용가능한 염을 제공한다.The present invention provides novel 3-phenoxy-4-pyrone, 3-phenoxy-4-pyridone or 4-pyridone derivative represented by Formula 1 below, or a pharmaceutically acceptable salt thereof.
화학식 1
Figure PCTKR2010004966-appb-C000001
 Formula 1
Figure PCTKR2010004966-appb-C000001
상기 화학식 1에서In Chemical Formula 1
X는 O 또는 NR3이고, 이때 R3은 수소; C1~C4 직쇄 또는 측쇄 알킬; C3~C8 사이클로알킬; 비치환 또는 1 이상의 할로겐, 니트로, 할로알킬, C1~C4 직쇄 또는 측쇄 알킬, C1~C4 알콕시로 치환된 C5~C12 아릴알킬; 또는 C5~C8 헤테로아릴이고,X is O or NR 3, wherein R 3 is hydrogen; C 1 -C 4 straight or branched alkyl; C 3 -C 8 cycloalkyl; C 5 -C 12 arylalkyl unsubstituted or substituted with one or more halogen, nitro, haloalkyl, C 1 -C 4 straight or branched alkyl, C 1 -C 4 alkoxy; Or C 5 -C 8 heteroaryl,
Y는 O 또는 -CHOH이고,Y is O or -CHOH,
R1은 수소, 또는 이고, 이때 R4는 C1~C4 직쇄 또는 측쇄 알킬; 또는 C5~C8 헤테로아릴이고,R 1 is hydrogen, or wherein R 4 is C 1 -C 4 straight or branched alkyl; Or C 5 -C 8 heteroaryl,
R2는 1 이상의 C1~C4 직쇄 또는 측쇄 알킬 또는 할로겐으로 치환된다.R 2 is substituted with one or more C 1 -C 4 straight or branched alkyl or halogen.
바람직하게는 Preferably
X는 O 또는 NR3이고, 이때 R3은 수소, 메틸, 부틸, 사이클로프로필, 벤질, 브로모벤질, 클로로벤질, 니트로벤질, 트리플루오로메틸벤질, 메틸벤질, 디메틸벤질, 디플루오로벤질, 디클로로벤질, 메톡시벤질, t-부틸벤질, 퓨라닐 또는 디페닐메틸이고,X is O or NR 3, wherein R 3 is hydrogen, methyl, butyl, cyclopropyl, benzyl, bromobenzyl, chlorobenzyl, nitrobenzyl, trifluoromethylbenzyl, methylbenzyl, dimethylbenzyl, difluorobenzyl, Dichlorobenzyl, methoxybenzyl, t-butylbenzyl, furanyl or diphenylmethyl,
Y는 O 또는 -CHOH이고,Y is O or -CHOH,
R1은 수소,
Figure PCTKR2010004966-appb-I000001
또는
Figure PCTKR2010004966-appb-I000002
이고, 이때 R4는 퓨란, 싸이오펜, 피라딘, 파이롤, 이소부틸, 부틸이고,R 1 is hydrogen,
Figure PCTKR2010004966-appb-I000001
or
Figure PCTKR2010004966-appb-I000002
Wherein R 4 is furan, thiophene, pyridine, pyrrole, isobutyl, butyl,
R2는 4-클로로-2-메틸, 2,3-디클로로, 2,6-디클로로, 2,4,-디클로로, 2,4-디메틸이다.R 2 is 4-chloro- 2 -methyl, 2,3-dichloro, 2,6-dichloro, 2,4, -dichloro, 2,4-dimethyl.
더욱 바람직하게는 본 발명에 따른 유도체는 하기 화학식 1a~1d의 화합물 중에서 선택될 수 있다.More preferably, the derivative according to the present invention may be selected from the compounds of Formulas 1a to 1d.
[화학식 1a][Formula 1a]
Figure PCTKR2010004966-appb-I000003
Figure PCTKR2010004966-appb-I000003
(상기 화학식 1a에서, R3은 퓨란, 싸이오펜, 피라딘, 파이롤, 이소부틸 또는 부틸이다.)(In Formula 1a, R 3 is furan, thiophene, pyridine, pyrrole, isobutyl or butyl.)
[화학식 1b][Formula 1b]
Figure PCTKR2010004966-appb-I000004
Figure PCTKR2010004966-appb-I000004
(상기 화학식 1b에서 R4는 이소부틸 또는 부틸이고, R5는 수소, 메틸 또는 사이클로프로필이다.)(In Formula 1b, R 4 is isobutyl or butyl, and R 5 is hydrogen, methyl or cyclopropyl.)
[화학식 1c][Formula 1c]
Figure PCTKR2010004966-appb-I000005
Figure PCTKR2010004966-appb-I000005
(상기 화학식 1c에서, R6은 수소, 메틸, 사이클로프로필, 부틸 또는 벤질이고,(In Chemical Formula 1c, R 6 is hydrogen, methyl, cyclopropyl, butyl or benzyl,
R7은 4-클로로-2-메틸, 디클로로 또는 디메틸이다.)R 7 is 4-chloro-2-methyl, dichloro or dimethyl.)
[화학식 1d][Formula 1d]
Figure PCTKR2010004966-appb-I000006
Figure PCTKR2010004966-appb-I000006
(상기 화학식 1d에서, R8은 벤질, 브로모벤질, 클로로벤질, 니트로벤질, 트리플루오로메틸벤질, 메틸벤질, 디메틸벤질, 디플루오로벤질, 디클로로벤질, 메톡시벤질, t-부틸벤질, 퓨라닐 또는 디페닐메틸이고,(In Formula 1d, R 8 is benzyl, bromobenzyl, chlorobenzyl, nitrobenzyl, trifluoromethylbenzyl, methylbenzyl, dimethylbenzyl, difluorobenzyl, dichlorobenzyl, methoxybenzyl, t-butylbenzyl, Furanyl or diphenylmethyl,
R9는 디클로로이다.)R 9 is dichloro.)
상기 화학식 1로 표시되는 유도체를 보다 구체적으로 예시하면 다음과 같다.If more specifically exemplified the derivative represented by the formula (1) are as follows.
(1) 5-(4-클로로-2-메틸페녹시)-2-스티릴피란-4-온;(1) 5- (4-chloro-2-methylphenoxy) -2-styrylpyran-4-one;
(2) 5-(4-클로로-2-메틸페녹시)-2-(3-메틸부트-1-에닐)-1H-피리딘-4-온;(2) 5- (4-chloro-2-methylphenoxy) -2- (3-methylbut-1-enyl) -1H-pyridin-4-one;
(3) 5-(4-클로로-2-메틸페녹시)-1-메틸-2-페녹시메틸-1H-피리딘-4-온;(3) 5- (4-chloro-2-methylphenoxy) -1-methyl-2-phenoxymethyl-1H-pyridin-4-one;
(4) 1-벤질-3-[(2,6-디클로로페닐)하이드록시메틸]-1H-피리딘-4-온;(4) 1-benzyl-3-[(2,6-dichlorophenyl) hydroxymethyl] -1H-pyridin-4-one;
(5) 5-(4-클로로-2-메틸페녹시)-2-(2-퓨란-3-일비닐)피란-4-온;(5) 5- (4-chloro-2-methylphenoxy) -2- (2-furan-3-ylvinyl) pyran-4-one;
(6) 5-(4-클로로-2-메틸페녹시)-2-(2-사이오펜-2-일비닐)피란-4-온;(6) 5- (4-chloro-2-methylphenoxy) -2- (2-thiophen-2-ylvinyl) pyran-4-one;
(7) 5-(4-클로로-2-메틸페녹시)-2-펜트-1-에닐-피란-4-온;(7) 5- (4-chloro-2-methylphenoxy) -2-pent-1-enyl-pyran-4-one;
(8) 5-(4-클로로-2-메틸페녹시)-2-(2-퓨란-2-일비닐)피란-4-온;(8) 5- (4-chloro-2-methylphenoxy) -2- (2-furan-2-ylvinyl) pyran-4-one;
(9) 5-(4-클로로-2-메틸페녹시)-2-[2-(1H-파이롤-2-일)비닐]피란-4-온;(9) 5- (4-chloro-2-methylphenoxy) -2- [2- (1H-pyrrol-2-yl) vinyl] pyran-4-one;
*(10) 5-(4-클로로-2-메틸페녹시)-2-(2-사이오펜-3-일비닐)피란-4-온;* (10) 5- (4-chloro-2-methylphenoxy) -2- (2-thiophen-3-ylvinyl) pyran-4-one;
(11) 5-(4-클로로-2-메틸페녹시)-2-(3-메틸부트-1-에닐)피란-4-온;(11) 5- (4-chloro-2-methylphenoxy) -2- (3-methylbut-1-enyl) pyran-4-one;
(12) 5-(4-클로로-2-메틸페녹시)-1-메틸-2-(3-메틸부트-1-에닐)-1H-피리딘-4-온;(12) 5- (4-chloro-2-methylphenoxy) -1-methyl-2- (3-methylbut-1-enyl) -1H-pyridin-4-one;
(13) 5-(4-클로로-2-메틸페녹시)-2-(3-메틸부트-1-에닐)-1H-피리딘-4-온;(13) 5- (4-chloro-2-methylphenoxy) -2- (3-methylbut-1-enyl) -1H-pyridin-4-one;
(14) 5-(4-클로로-2-메틸페녹시)-1-사이클로프로필-2-(3-메틸부트-1-에닐)-1H-피리딘-4-온;(14) 5- (4-chloro-2-methylphenoxy) -1-cyclopropyl-2- (3-methylbut-1-enyl) -1H-pyridin-4-one;
(15) 5-(4-클로로-2-메틸페녹시)-1-메틸-2-펜트-1-에닐-1H-피리딘-4-온;(15) 5- (4-chloro-2-methylphenoxy) -1-methyl-2-pent-1-enyl-1H-pyridin-4-one;
(16) 5-(4-클로로-2-메틸페녹시)-1-사이클로프로필-2-펜트-1-에닐-1H-피리딘-4-온;(16) 5- (4-chloro-2-methylphenoxy) -1-cyclopropyl-2-pent-1-enyl-1H-pyridin-4-one;
(17) 5-(4-클로로-2-메틸페녹시)-2-페녹시메틸-1H-피리딘-4-온;(17) 5- (4-chloro-2-methylphenoxy) -2-phenoxymethyl-1H-pyridin-4-one;
(18) 1-부틸-5-(4-클로로-2-메틸페녹시)-2-페녹시메틸-1H-피리딘-4-온;(18) 1-butyl-5- (4-chloro-2-methylphenoxy) -2-phenoxymethyl-1H-pyridin-4-one;
*(19) 5-(4-클로로-2-메틸페녹시)-1-사이클로프로필-2-페녹시메틸-1H-피리딘-4-온;* (19) 5- (4-chloro-2-methylphenoxy) -1-cyclopropyl-2-phenoxymethyl-1H-pyridin-4-one;
(20) 1-벤질-5-(4-클로로-2-메틸페녹시)-2-페녹시메틸-1H-피리딘-4-온;(20) 1-benzyl-5- (4-chloro-2-methylphenoxy) -2-phenoxymethyl-1H-pyridin-4-one;
(21) 5-(2,3-디클로로페녹시)-2-페녹시메틸-1H-피리딘-4-온;(21) 5- (2,3-dichlorophenoxy) -2-phenoxymethyl-1H-pyridin-4-one;
(22) 1-사이클로프로필-5-(2,3-디클로로페녹시)-2-페녹시메틸-1H-피리딘-4-온;(22) 1-cyclopropyl-5- (2,3-dichlorophenoxy) -2-phenoxymethyl-1H-pyridin-4-one;
(23) 1-부틸-5-(2,3-디클로로페녹시)-2-페녹시메틸-1H-피리딘-4-온;(23) 1-butyl-5- (2,3-dichlorophenoxy) -2-phenoxymethyl-1H-pyridin-4-one;
(24) 1-벤질-5-(2,3-디클로로페녹시)-2-페녹시메틸-1H-피리딘-4-온;(24) 1-benzyl-5- (2,3-dichlorophenoxy) -2-phenoxymethyl-1H-pyridin-4-one;
(25) 5-(2,3-디클로로페녹시)-1-메틸-2-페녹시메틸-1H-피리딘-4-온;(25) 5- (2,3-dichlorophenoxy) -1-methyl-2-phenoxymethyl-1H-pyridin-4-one;
(26) 5-(2,4-디클로로페녹시)-2-페녹시메틸-1H-피리딘-4-온;(26) 5- (2,4-dichlorophenoxy) -2-phenoxymethyl-1H-pyridin-4-one;
(27) 5-(2,4-디클로로페녹시)-1-메틸-2-페녹시메틸-1H-피리딘-4-온;(27) 5- (2,4-dichlorophenoxy) -1-methyl-2-phenoxymethyl-1H-pyridin-4-one;
(28) 1-부틸-5-(2,4-디클로로페녹시)-2-페녹시메틸-1H-피리딘-4-온;(28) 1-butyl-5- (2,4-dichlorophenoxy) -2-phenoxymethyl-1H-pyridin-4-one;
(29) 1-벤질-5-(2,4-디클로로페녹시)-2-페녹시메틸-1H-피리딘-4-온;(29) 1-benzyl-5- (2,4-dichlorophenoxy) -2-phenoxymethyl-1H-pyridin-4-one;
(30) 1-사이클로프로필-5-(2,4-디클로로페녹시)-2-페녹시메틸-1H-피리딘-4-온;(30) 1-cyclopropyl-5- (2,4-dichlorophenoxy) -2-phenoxymethyl-1H-pyridin-4-one;
(31) 5-(2,4-디메틸페녹시)-2-페녹시메틸-1H-피리딘-4-온;(31) 5- (2,4-dimethylphenoxy) -2-phenoxymethyl-1H-pyridin-4-one;
(32) 1-벤질-5-(2,4-디메틸페녹시)-2-페녹시메틸-1H-피리딘-4-온;(32) 1-benzyl-5- (2,4-dimethylphenoxy) -2-phenoxymethyl-1H-pyridin-4-one;
(33) 5-(2,4-디메틸페녹시)-1-메틸-2-페녹시메틸-1H-피리딘-4-온;(33) 5- (2,4-dimethylphenoxy) -1-methyl-2-phenoxymethyl-1H-pyridin-4-one;
(34) 1-부틸-5-(2,4-디메틸페녹시)-2-페녹시메틸-1H-피리딘-4-온;(34) 1-butyl-5- (2,4-dimethylphenoxy) -2-phenoxymethyl-1H-pyridin-4-one;
(35) 1-사이클로프로필l-5-(2,4-디메틸페녹시)-2-페녹시메틸-1H-피리딘-4-온;(35) 1-cyclopropyll-5- (2,4-dimethylphenoxy) -2-phenoxymethyl-1H-pyridin-4-one;
(36) 1-(3-브로모벤질)-3-[(2,3-디클로로페닐)하이드록시메틸]-1H-피리딘-4-온;(36) 1- (3-bromobenzyl) -3-[(2,3-dichlorophenyl) hydroxymethyl] -1H-pyridin-4-one;
(37) 1-(4-브로모벤질)-3-[(2,3-디클로로페닐)하이드록시메틸]-1H-피리딘-4-온;(37) 1- (4-bromobenzyl) -3-[(2,3-dichlorophenyl) hydroxymethyl] -1H-pyridin-4-one;
(38) 3-[(2,3-디클로로페닐)디클로로페닐]-1-(3-트리플루오로메틸벤질)-1H-피리딘-4-온;(38) 3-[(2,3-dichlorophenyl) dichlorophenyl] -1- (3-trifluoromethylbenzyl) -1H-pyridin-4-one;
(39) 1-(4-t-부틸벤질)-3-[(2,3-디클로로페닐)하이드록시메틸]-1H-피리딘-4-온;(39) 1- (4-t-butylbenzyl) -3-[(2,3-dichlorophenyl) hydroxymethyl] -1H-pyridin-4-one;
(40) 1-(2-브로모벤질)-3-[(2,6-디클로로페닐)하이드록시메틸]-1H-피리딘-4-온;(40) 1- (2-bromobenzyl) -3-[(2,6-dichlorophenyl) hydroxymethyl] -1H-pyridin-4-one;
(41) 1-(3-브로모벤질)-3-[(2,6-디클로로페닐)하이드록시메틸]-1H-피리딘-4-온;(41) 1- (3-bromobenzyl) -3-[(2,6-dichlorophenyl) hydroxymethyl] -1H-pyridin-4-one;
(42) 1-(4-브로모벤질l)-3-[(2,6-디클로로페닐)하이드록시메틸]-1H-피리딘-4-온;(42) 1- (4-bromobenzyll) -3-[(2,6-dichlorophenyl) hydroxymethyl] -1H-pyridin-4-one;
(43) 1-(2-클로로벤질)-3-[(2,6-디클로로페닐)하이드록시메틸]-1H-피리딘-4-온;(43) 1- (2-chlorobenzyl) -3-[(2,6-dichlorophenyl) hydroxymethyl] -1H-pyridin-4-one;
(44) 1-(3-클로로벤질)-3-[(2,6-디클로로페닐)하이드록시메틸]-1H-피리딘-4-온;(44) 1- (3-chlorobenzyl) -3-[(2,6-dichlorophenyl) hydroxymethyl] -1H-pyridin-4-one;
(45) 1-(4-클로로벤질)-3-[(2,6-디클로로페닐)하이드록시메틸]-1H-피리딘-4-온;(45) 1- (4-chlorobenzyl) -3-[(2,6-dichlorophenyl) hydroxymethyl] -1H-pyridin-4-one;
(46) 3-[(2,6-디클로로페닐)하이드록시메틸]-1-(2-트리플루오로메틸벤질)-1H-피리딘-4-온;(46) 3-[(2,6-dichlorophenyl) hydroxymethyl] -1- (2-trifluoromethylbenzyl) -1H-pyridin-4-one;
(47) 3-[(2,6-디클로로페닐)하이드록시메틸]-1-(2-메톡시벤질)-1H-피리딘-4-온;(47) 3-[(2,6-dichlorophenyl) hydroxymethyl] -1- (2-methoxybenzyl) -1H-pyridin-4-one;
(48) 3-[(2,6-디클로로페닐)하이드록시메틸]-1-(3-메톡시벤질)-1H-피리딘-4-온;(48) 3-[(2,6-dichlorophenyl) hydroxymethyl] -1- (3-methoxybenzyl) -1H-pyridin-4-one;
(49) 3-[(2,6-디클로로페닐)하이드록시메틸]-1-(4-메톡시벤질)-1H-피리딘-4-온;(49) 3-[(2,6-dichlorophenyl) hydroxymethyl] -1- (4-methoxybenzyl) -1H-pyridin-4-one;
(50) 3-[(2,6-디클로로페닐)하이드록시메틸]-1-(3-메틸벤질)-1H-피리딘-4-온;(50) 3-[(2,6-dichlorophenyl) hydroxymethyl] -1- (3-methylbenzyl) -1H-pyridin-4-one;
(51) 3-[(2,6-디클로로페닐)하이드록시메틸]-1-(4-니트로벤질)-1H-피리딘-4-온;(51) 3-[(2,6-dichlorophenyl) hydroxymethyl] -1- (4-nitrobenzyl) -1H-pyridin-4-one;
(52) 1-(4-t-부틸벤질)-3-[(2,6-디클로로페닐)하이드록시메틸]-1H-피리딘-4-온;(52) 1- (4-t-butylbenzyl) -3-[(2,6-dichlorophenyl) hydroxymethyl] -1H-pyridin-4-one;
(53) 3-[(2,6-디클로로페닐)하이드록시메틸]-1-(2,6-디플루오로벤질)-1H-피리딘-4-온;(53) 3-[(2,6-dichlorophenyl) hydroxymethyl] -1- (2,6-difluorobenzyl) -1H-pyridin-4-one;
(54) 1-(3,4-디클로로벤질)-3-[(2,6-디클로로페닐)하이드록시메틸]-1H-피리딘-4-온;(54) 1- (3,4-dichlorobenzyl) -3-[(2,6-dichlorophenyl) hydroxymethyl] -1H-pyridin-4-one;
(55) 3-[(2,6-디클로로페닐)하이드록시메틸]-1-(2,6-디메틸벤질)-1H-피리딘-4-온;(55) 3-[(2,6-dichlorophenyl) hydroxymethyl] -1- (2,6-dimethylbenzyl) -1H-pyridin-4-one;
(56) 3-[(2,6-디클로로페닐)하이드록시메틸]-1-(2-메틸사이아졸-4-일메틸)-1H-피리딘-4-온;(56) 3-[(2,6-dichlorophenyl) hydroxymethyl] -1- (2-methylthiazol-4-ylmethyl) -1H-pyridin-4-one;
(57) 3-[(2,6-디클로로페닐)하이드록시메틸]-1-(3,5-디메틸이소옥사졸-4-일메틸)-1H-피리딘-4-온;(57) 3-[(2,6-dichlorophenyl) hydroxymethyl] -1- (3,5-dimethylisoxazol-4-ylmethyl) -1H-pyridin-4-one;
(58) 3-[(2,6-디클로로페닐)하이드록시메틸]-1-퓨란-3-일메틸-1H-피리딘-4-온; 및(58) 3-[(2,6-dichlorophenyl) hydroxymethyl] -1-furan-3-ylmethyl-1H-pyridin-4-one; And
(59) 1-벤즈히드릴-3-[(2,6-디클로로페닐-하이드록시메틸]-1H-피리딘-4-온.(59) 1-benzhydryl-3-[(2,6-dichlorophenyl-hydroxymethyl] -1 H-pyridin-4-one.
상기 화학식 1로 표시되는 본 발명의 유도체는 약학적으로 허용 가능한 염의 형태로 사용할 수 있으며, 염으로는 약학적으로 허용가능한 유리산(free acid)에 의해 형성된 산부가염이 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.The derivative of the present invention represented by Formula 1 may be used in the form of a pharmaceutically acceptable salt, and acid salts formed by pharmaceutically acceptable free acid are useful as salts. Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid and aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. Obtained from non-toxic organic acids such as dioates, aromatic acids, aliphatic and aromatic sulfonic acids. Such pharmaceutically nontoxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, and iodide. Id, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suverate , Sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate, meth Oxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesul Nate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1- Sulfonates, naphthalene-2-sulfonates or mandelate.
본 발명에 따른 산 부가염은 통상의 방법, 예를 들면, 화학식 1의 유도체를 과량의 산 수용액 중에 용해시키고, 이 염을 수혼화성 유기 용매, 예를 들면 메탄올, 에탄올, 아세톤 또는 아세토니트릴을 사용하여 침전시켜서 제조할 수 있다.The acid addition salts according to the invention are dissolved in conventional methods, for example, by dissolving a derivative of formula 1 in an excess of aqueous acid solution and using the water miscible organic solvent, such as methanol, ethanol, acetone or acetonitrile. It can be prepared by precipitation.
동량의 화학식 1의 유도체 및 물 중의 산 또는 알코올을 가열하고, 이어서 이 혼합물을 증발시켜서 건조시키거나 또는 석출된 염을 흡입 여과시켜 제조할 수도 있다.Equivalent amounts of the derivative of formula 1 and the acid or alcohol in water may be heated and then the mixture is evaporated to dryness or prepared by suction filtration of the precipitated salt.
또한, 염기를 사용하여 약학적으로 허용 가능한 금속염을 만들 수 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, 금속 염으로는 나트륨, 칼륨 또는 칼슘염을 제조하는 것이 제약상 적합하다. 또한, 이에 대응하는 은염은 알칼리 금속 또는 알칼리 토금속 염을 적당한 은염(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 a 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. Corresponding silver salts are also obtained by reacting alkali or alkaline earth metal salts with a suitable silver salt (eg, silver nitrate).
또한, 본 발명의 상기 화학식 1로 표시되는 유도체는 약학적으로 허용되는 염뿐만 아니라, 통상의 방법에 의해 제조될 수 있는 모든 염, 수화물 및 용매화물을 모두 포함한다.In addition, the derivative represented by Chemical Formula 1 of the present invention includes not only pharmaceutically acceptable salts, but also all salts, hydrates, and solvates that can be prepared by conventional methods.
본 발명에 따른 부가염은 통상의 방법으로 제조할 수 있으며, 예를 들면 화학식 1의 화합물을 수혼화성 유기용매, 예를 들면 아세톤, 메탄올, 에탄올, 또는 아세토니트릴 등에 녹이고 과량의 유기산을 가하거나 무기산의 산 수용액을 가한 후 침전시키거나 결정화시켜서 제조할 수 있다. 이어서 이 혼합물에서 용매나 과량의 산을 증발시킨 후 건조시켜서 부가염을 얻거나 또는 석출된 염을 흡인 여과시켜 제조할 수 있다.The addition salt according to the present invention can be prepared by a conventional method, for example, by dissolving the compound of Formula 1 in a water miscible organic solvent such as acetone, methanol, ethanol, or acetonitrile and adding an excess of an organic acid or an inorganic acid. It can be prepared by adding an acidic aqueous solution of and then precipitating or crystallizing. The solvent or excess acid may then be evaporated and dried in this mixture to obtain an addition salt or the precipitated salt may be prepared by suction filtration.
또한, 본 발명은 상기 화학식 1의 유도체의 제조방법을 제공한다.The present invention also provides a method for preparing the derivative of Chemical Formula 1.
제법 1Preparation method 1
본 발명에 따른 상기 화학식 1의 유도체 중 3-페녹시-4-파이론 유도체는 하기 반응식 1에 표시되는 바와 같이, 3-phenoxy-4-pyrone derivative of the derivative of Formula 1 according to the present invention is represented by the following Scheme 1,
화학식 4의 코직산 화합물을 울만(Ullmann) 반응시켜 화학식 5의 화합물을 제조하는 단계(단계 1);Ullmann reaction of the kojic acid compound of Formula 4 to prepare a compound of Formula 5 (Step 1);
상기 단계 1에서 제조된 화학식 5의 화합물을 클로라이드기로 치환하여 화학식 6의 화합물을 제조하는 단계(단계 2);Preparing a compound of Chemical Formula 6 by replacing the compound of Chemical Formula 5 prepared in Step 1 with a chloride group (Step 2);
상기 단계 2에서 제조한 화학식 6의 화합물을 아르부조브(Arbuzov) 반응시켜 포스포네이트를 합성하여 화학식 7의 화합물을 제조하는 단계(단계 3); 및 Preparing a compound of formula 7 by arbuzov reaction of the compound of formula 6 prepared in step 2 to synthesize phosphonate (step 3); And
상기 단계 3에서 제조한 화학식 7의 화합물을 호너-에몬스 반응을 통해 이중결합구조를 도입하여 화학식 1a의 화합물을 제조하는 단계(단계 4)를 포함할 수 있다.The compound of Chemical Formula 7 prepared in Step 3 may be prepared by introducing a double bond structure through a Horner-Emons reaction (Step 4).
[반응식 1]Scheme 1
Figure PCTKR2010004966-appb-I000007
Figure PCTKR2010004966-appb-I000007
(상기 식에서, R2는 상기 화학식 1에서 정의한 바와 같고, R3은 상기 화학식 1a에서 정의한 바와 같으며, 화학식 1a는 화학식 1에 포함된다.)Wherein R 2 is as defined in Formula 1, R 3 is as defined in Formula 1a, and Formula 1a is included in Formula 1.
본 발명에 따른 상기 단계 1은 화학식 4의 코직산 화합물을 울만(Ullmann) 반응시켜 화학식 5의 화합물을 제조하는 단계이다.Step 1 according to the present invention is a step of preparing a compound of Chemical Formula 5 by Ullmann reaction of the kojic acid compound of Chemical Formula 4.
구체적으로, 출발물질로 사용된 화학식 4의 화합물과 아릴할라이드를 반응시켜 화학식 5를 생성시킨다. 상기 단계 1의 반응은 유기화학 분야에서 통상적으로 널리 알려져 있으며, 반응 용매, 반응 온도, 반응 시간 등의 반응 조건은 반응물질, 생성물질 등을 고려하여 적절히 선택할 수 있다. 예를 들면, 상기 반응에서는 구리촉매 존재 하에서 반응 용매로서 디메틸포름아마이드를 사용하였으며 75 ℃에서 밤새동안 가열 교반함으로써 화학식 5의 화합물을 얻을 수 있다.Specifically, the compound of formula 4 used as starting material and the aryl halide is reacted to produce formula 5. The reaction of step 1 is commonly known in the field of organic chemistry, and reaction conditions such as reaction solvent, reaction temperature, reaction time, etc. may be appropriately selected in consideration of reactants, products, and the like. For example, in the above reaction, dimethylformamide was used as a reaction solvent in the presence of a copper catalyst, and the compound of Chemical Formula 5 can be obtained by heating and stirring at 75 ° C. overnight.
다음으로, 단계 2는 상기 단계 1에서 제조된 화학식 5의 화합물을 클로라이드기로 치환하여 화학식 6의 화합물을 제조하는 단계이다.Next, step 2 is a step of preparing a compound of formula 6 by replacing the compound of formula 5 prepared in step 1 with a chloride group.
화학식 6의 화합물은 화학식 5를 반응용매인 CH2Cl2에 용해시킨 후 싸이오닐클로라이드와 트리에틸아민을 첨가하여 상온에서 3시간 동안 교반하여 얻을 수 있다. 이때 상기 화학식 5인 페녹시에테르 유도체는 다음과 같은 하기 화합물로 이루어지는 군으로부터 선택되는 것을 사용하는 것이 바람직하다.The compound of Chemical Formula 6 may be obtained by dissolving Chemical Formula 5 in CH 2 Cl 2 as a reaction solvent and adding thionyl chloride and triethylamine to stir at room temperature for 3 hours. In this case, the phenoxyether derivative represented by Chemical Formula 5 is preferably used selected from the group consisting of the following compounds.
Figure PCTKR2010004966-appb-I000008
Figure PCTKR2010004966-appb-I000008
다음으로, 단계 3은 상기 단계 2에서 제조한 화학식 6의 화합물을 아르부조브(Arbuzov) 반응시켜 포스포네이트를 합성하여 화학식 7의 화합물을 제조하는 단계이다.Next, step 3 is an arbuzov reaction of the compound of formula 6 prepared in step 2 to synthesize a phosphonate to prepare a compound of formula 7.
구체적으로, 화학식 6의 클로로기를 치환시켜 화학식 7을 생성시키는 단계이다. 상기 단계 3의 반응은 유기화학 분야에서 통상적으로 널리 알려져 있으며, 반응 용매, 반응 온도, 반응 시간 등의 반응 조건은 반응물질, 생성물질 등을 고려하여 적절히 선택할 수 있다. 이 반응은 트리에틸포스파이트를 사용하여 3시간 가열 환류함으로써 이루질 수 있다.Specifically, the step of generating the chemical formula 7 by substituting the chloro group of the chemical formula 6. The reaction of step 3 is commonly known in the organic chemistry field, and reaction conditions such as reaction solvent, reaction temperature, reaction time, and the like may be appropriately selected in consideration of reactants, products, and the like. This reaction can be accomplished by heating at reflux for 3 hours using triethylphosphite.
다음으로, 단계 4는 상기 단계 3에서 제조한 화학식 7의 화합물을 호너-에몬스 반응을 통해 이중결합구조를 도입하여 화학식 1a의 화합물을 제조하는 단계이다.Next, step 4 is a step of preparing a compound of Formula 1a by introducing a double bond structure through the Horner-emons reaction of the compound of Formula 7 prepared in Step 3.
구체적으로, 상기 화학식 5의 포스포네이트 화합물에 다양하게 치환된 알데하이드 화합물을 반응시켜 이중결합 구조를 도입하여 3-페녹시-4-파이론 유도체(1a)를 얻을 수 있다.Specifically, 3-phenoxy-4-pyrone derivative (1a) may be obtained by introducing a double bond structure by reacting the phosphonate compound of Formula 5 with various substituted aldehyde compounds.
상기 단계 4의 반응은 유기화학 분야에서 통상적으로 널리 알려져 있으며, 반응 용매, 반응 온도, 반응 시간 등의 반응 조건은 반응물질, 생성물질 등을 고려하여 적절히 선택할 수 있다. 이 반응에서는 용매로서 무수 테트라하이드로퓨란을 사용하였고 다양하게 치환된 알데하이드를 첨가시켜 상온에서 밤새 교반시켜 파이란 구조의 화합물을 합성하였다. 이때, 염기는 수소화나트륨(NaH), 수소화리튬(LiH), 수소화칼륨(KH) 등의 알칼리금속수소화합물, 나트륨메톡사이드, 나트륨에톡사이드, 나트튬프로폭사이드, 나트륨 t-부톡사이드, 포타슘 t-부톡사이드, 포타슘이소프로폭사이드, 리튬이소프로폭사이드 등의 금속알콕사이드 등을 사용하는 것이 바람직하고, 포타슘 t-부톡사이드를 사용하는 것이 더욱 바람직하다.The reaction of Step 4 is commonly known in the field of organic chemistry, and reaction conditions such as reaction solvent, reaction temperature, reaction time, etc. may be appropriately selected in consideration of reactants, products, and the like. In this reaction, anhydrous tetrahydrofuran was used as a solvent, and various substituted aldehydes were added and stirred at room temperature overnight to synthesize a pyran structured compound. At this time, the base may be an alkali metal hydrogen compound such as sodium hydride (NaH), lithium hydride (LiH), potassium hydride (KH), sodium methoxide, sodium ethoxide, sodium propoxide, sodium t-butoxide, potassium It is preferable to use metal alkoxides such as t-butoxide, potassium isopropoxide, lithium isopropoxide and the like, and potassium t-butoxide is more preferable.
제법 2Preparation method 2
본 발명에 따른 상기 화학식 1의 유도체 중 3-페녹시-4-피리돈 유도체는 하기 반응식 2에 표시되는 바와 같이, 3-phenoxy-4-pyridone derivative of the derivative of Chemical Formula 1 according to the present invention is represented by the following Scheme 2,
화학식 7의 포스포네이트 화합물을 아민 화합물과 첨가반응하여 화합물 8의 화합물을 제조하는 단계(단계 1); 및 Reacting a phosphonate compound of formula 7 with an amine compound to prepare a compound of compound 8 (step 1); And
상기 단계 1에서 제조한 화학식 8의 화합물을 호너-에몬스 반응을 통해 이중결합 구조를 도입하여 화학식 1b의 화합물을 제조하는 단계(단계 2)를 포함할 수 있다.The compound of Chemical Formula 8 prepared in Step 1 may be prepared by introducing a double bond structure through a Horner-Emons reaction (Step 2).
[반응식 2]Scheme 2
Figure PCTKR2010004966-appb-I000009
Figure PCTKR2010004966-appb-I000009
(상기 식에서 R4 및 R5는 상기 화학식 1b에서 정의한 바와 같고, 화학식 1b는 화학식 1에 포함된다.)(Wherein R 4 and R 5 are as defined in Formula 1b, and Formula 1b is included in Formula 1).
먼저, 단계 1은 화학식 7의 포스포네이트 화합물을 아민 화합물과 첨가반응하여 화합물 8의 화합물을 제조하는 단계이다.First, step 1 is a step of preparing a compound of compound 8 by adding a phosphonate compound of formula 7 with an amine compound.
이때, 반응용매로서 메탄올을 사용하였고 치환된 다양한 아민을 첨가시켜 밤새동안 가열환류시켜 피리돈 구조의 화합물 8의 화합물을 합성할 수 있다. At this time, methanol was used as a reaction solvent and heated and refluxed overnight by adding various substituted amines to synthesize a compound of compound 8 having a pyridone structure.
다음으로, 단계 2는 상기 단계 1에서 제조한 화학식 8의 화합물을 호너-에몬스 반응을 통해 이중결합 구조를 도입하여 화학식 1b의 화합물을 제조하는 단계이다.Next, step 2 is a step of preparing a compound of Formula 1b by introducing a double bond structure through the Horner-emons reaction of the compound of Formula 8 prepared in Step 1.
상기 단계는 제법 1의 단계 4와 동일한 방법으로 수행될 수 있다.This step can be carried out in the same manner as step 4 of Preparation 1.
제법 3Preparation method 3
본 발명에 따른 상기 화학식 1의 유도체 중 3-페녹시-4-피리돈 유도체는 하기 반응식 3에 표시되는 바와 같이, 3-phenoxy-4-pyridone derivative of the derivative of Formula 1 according to the present invention, as shown in Scheme 3 below,
화학식 5의 페녹시에테르 화합물을 페놀과 디이소프로필 아조디카르복실레이트 하에 미츠노부(Mitsunobu) 반응시켜 화학식 9의 화합물을 제조하는 단계(단계 1);및 Preparing a compound of formula 9 by reacting a phenoxyether compound of formula 5 with phenol and diisopropyl azodicarboxylate in Mitsunobu (step 1); and
상기 단계 1에서 제조한 화학식 9의 화합물을 아민화합물과 첨가반응시켜 화합물 1c의 화합물을 제조하는 단계(단계 2)를 포함할 수 있다.The compound of formula 9 prepared in step 1 may be added to an amine compound to prepare a compound of compound 1c (step 2).
[반응식 3]Scheme 3
Figure PCTKR2010004966-appb-I000010
Figure PCTKR2010004966-appb-I000010
(상기 식에서, 상기 R2는 상기 화학식 1에서 정의한 바와 같고, R6 및 R7은 화학식 1c에서 정의한 바와 같으며, 화학식 1c는 화학식 1에 포함된다.)Wherein R 2 is as defined in Formula 1, R 6 and R 7 are as defined in Formula 1c, and Formula 1c is included in Formula 1.
먼저, 단계 1은 화학식 5의 페녹시에테르 화합물을 페놀과 디이소프로필 아조디카르복실레이트 하에 미츠노부(Mitsunobu) 반응시켜 화학식 9의 화합물을 제조하는 단계이다.First, step 1 is a step of preparing a compound of formula 9 by Mitsunobu reaction of a phenoxyether compound of formula 5 with phenol and diisopropyl azodicarboxylate.
구체적으로, 용매로서 무수 테트라하이드로퓨란 하에서 화학식 5의 화합물에 트리페닐포스핀과 페놀을 가한 후 0 ℃하에서 디이소프로필 아조디카르복실레이트를 가한 다음 상온에서 밤새동안 교반함으로써 화학식 9의 화합물을 얻을 수 있다. 상기 반응은 "미츠노부(Mitsunobu) 반응" 이라는 이름으로 유기화학 분야에서 통상 널리 알려져 있다Specifically, triphenylphosphine and phenol are added to the compound of formula 5 under anhydrous tetrahydrofuran as a solvent, diisopropyl azodicarboxylate is added at 0 ° C., and then stirred at room temperature overnight to obtain a compound of formula 9 Can be. The reaction is commonly known in the field of organic chemistry under the name "Mitsunobu reaction".
다음으로, 단계 2는 상기 단계 1에서 제조한 화학식 9의 화합물을 아민화합물과 첨가반응시켜 화합물 1c의 화합물을 제조하는 단계이다.Next, step 2 is a step of preparing the compound of compound 1c by the addition reaction of the compound of formula 9 prepared in step 1 with the amine compound.
상기 단계는 제법 2의 단계 1과 동일한 방법으로 수행될 수 있다.The above step can be carried out in the same manner as step 1 of Preparation 2.
제법 4Recipe 4
본 발명에 따른 상기 화학식 1의 유도체 중 4-피리돈 유도체는 하기 반응식 4에 표시되는 바와 같이, 4-pyridone derivative of the derivative of Formula 1 according to the present invention is represented by the following Scheme 4,
화학식 10의 4-클로로피리딘염을 소디움메톡사이드 하에서 메톡시 구조를 도입하여 화학식 11의 화합물을 제조하는 단계(단계 1);Preparing a compound of formula 11 by introducing a 4-chloropyridine salt of formula 10 under a methoxy structure under sodium methoxide (step 1);
상기 단계 1에서 제조한 화학식 11의 4-메톡시피리딘 화합물을 알데하이드와 반응시켜 화합물 12의 화합물을 제조하는 단계(단계 2);및Preparing a compound of Compound 12 by reacting the 4-methoxypyridine compound of Formula 11 prepared in Step 1 with an aldehyde (Step 2); and
상기 단계 2에서 제조한 화학식 12의 화합물을 벤즈알데하이드와 반응시켜 화학식 1d의 화합물을 제조하는 단계(단계 3)를 포함할 수 있다.The compound of Formula 12 prepared in Step 2 may be reacted with benzaldehyde to prepare a compound of Formula 1d (Step 3).
[반응식 4]Scheme 4
Figure PCTKR2010004966-appb-I000011
Figure PCTKR2010004966-appb-I000011
(상기 식에서, 상기 R9는 화학식 1d에서 정의한 바와 같고, 화학식 1d는 화학식 1에 포함된다.)Wherein R 9 is as defined in Formula 1d, and Formula 1d is included in Formula 1.
먼저, 단계 1은 화학식 10의 4-클로로피리딘염을 소디움메톡사이드 하에서 메톡시 구조를 도입하여 화학식 11의 화합물을 제조하는 단계이다.First, step 1 is a step of preparing a compound of formula 11 by introducing a methoxy structure of the 4-chloropyridine salt of formula 10 under sodium methoxide.
상기 단계에서는 우선 메탄올을 반응 용매로 사용하여 교반하면서 고체의 나트륨을 첨가시켜 메톡사이드염을 제조한 후, 얼음 중탕하에서 화학식 10의 화합물을 가한 다음 80 ℃에서 3일 동안 가열 환류시킴으로써 화학식 10의 클로로기가 메톡시기로 치환된 화학식 11의 화합물을 얻을 수 있다.In this step, methoxide salt is prepared by first adding solid sodium while stirring using methanol as a reaction solvent, and then adding the compound of formula 10 in an ice bath, and then heating and refluxing at 80 ° C. for 3 days to give chloro of formula 10. A compound of formula 11 can be obtained in which the group is substituted with a methoxy group.
다음으로, 단계 2는 상기 단계 1에서 제조한 화학식 11의 4-메톡시피리딘 화합물을 알데하이드와 반응시켜 화합물 12의 화합물을 제조하는 단계이다.Next, step 2 is a step of preparing a compound of compound 12 by reacting the 4-methoxypyridine compound of formula 11 prepared in step 1 with an aldehyde.
구체적으로, 상기 단계에서는 반응 용매로서 무수 테트라하이드로퓨란을 사용하였으며 무수상태에서 -78 ℃의 조건에서 페닐리튬 1.8 M 용액을 적가하여 0 ℃ 이하에서 충분히 교반시킨다. 그 다음 다시 -78 ℃의 조건을 만들고 해당 벤즈알데하이드를 적가하여 밤새 동안 교반하여 화합물 12의 화합물을 얻을 수 있다.Specifically, in the above step, anhydrous tetrahydrofuran was used as a reaction solvent, and in anhydrous state, phenyllithium 1.8 M solution was added dropwise at −78 ° C., and stirred sufficiently at 0 ° C. or lower. Then, again, the conditions of -78 ° C. were added dropwise to the corresponding benzaldehyde and stirred overnight to obtain the compound of Compound 12.
상기와 같이 본 발명에 따라 제조된 페닐아세테이트 유도체 또는 중간체들은 제조 후, 적외선 분광법, 핵자기 공명 스펙트럼, 질량 분광법, 액체 크로마토그래피법, X-선 구조결정법, 선광도 측정법 및 대표적인 화합물의 원소분석 계산치와 실측치의 비교에 의해 분자구조를 확인할 수 있다.As described above, the phenylacetate derivatives or intermediates prepared according to the present invention are prepared by infrared spectroscopy, nuclear magnetic resonance spectra, mass spectroscopy, liquid chromatography, X-ray structure determination, photoluminescence measurement and elemental analysis calculations of representative compounds. The molecular structure can be confirmed by comparing with the measured values.
나아가, 본 발명은 상기 3-페녹시-4-파이론, 3-페녹시-4-피리돈 또는 4-피리돈 유도체, 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 항균 조성물을 제공한다.Furthermore, the present invention provides an antimicrobial composition containing the 3-phenoxy-4-pyrone, 3-phenoxy-4-pyridone or 4-pyridone derivative, or a pharmaceutically acceptable salt thereof as an active ingredient. .
또한, 본 발명은 상기 3-페녹시-4-파이론, 3-페녹시-4-피리돈 또는 4-피리돈 유도체, 또는 이의 약학적으로 허용가능한 염을 치료적으로 유효한 양으로 이를 필요로 하는 환자에게 투여하는 단계를 포함하는 항균의 치료방법을 제공한다.The present invention also provides a therapeutically effective amount of the 3-phenoxy-4-pyrone, 3-phenoxy-4-pyridone or 4-pyridone derivative, or a pharmaceutically acceptable salt thereof. It provides a method of treating antimicrobial comprising administering to a patient.
나아가, 본 발명은 상기 3-페녹시-4-파이론, 3-페녹시-4-피리돈 또는 4-피리돈 유도체, 또는 이의 약학적으로 허용가능한 염의 용도를 제공한다.Furthermore, the present invention provides the use of the above 3-phenoxy-4-pyrone, 3-phenoxy-4-pyridone or 4-pyridone derivative, or a pharmaceutically acceptable salt thereof.
본 발명에 따른 조성물에 유효성분으로 함유되는 3-페녹시-4-파이론, 3-페녹시-4-피리돈 또는 4-피리돈 유도체, 및 이의 약학적으로 허용가능함 염은 박테리아 지방산 생합성 효소인 에노일-ACP 환원효소(FabI)의 활성을 억제하는 것으로 나타났다(표 4 참조). 따라서, 본 발명에 따른 조성물은 박테리아 성장에 있어서 필수불가결한 역할을 하는 지방산 생합성을 조절하는 효소를 저해함으로써 항균효과를 나타내므로 항균제로써 유용하게 사용될 수 있다.3-phenoxy-4-pyrone, 3-phenoxy-4-pyridone or 4-pyridone derivative, and pharmaceutically acceptable salts thereof, which are contained as an active ingredient in the composition according to the present invention are bacterial fatty acid biosynthetic enzymes. It has been shown to inhibit the activity of Enoyl-ACP reductase (FabI) (see Table 4). Therefore, the composition according to the present invention can be usefully used as an antimicrobial agent because it exhibits an antimicrobial effect by inhibiting an enzyme regulating fatty acid biosynthesis that plays an essential role in bacterial growth.
본 발명의 조성물을 의약품으로 사용하는 경우, 상기 화학식 1의 유도체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 약학적 조성물은 임상투여 시에 다양한 하기의 경구 또는 비경구 투여 형태로 제제화되어 투여될 수 있으나, 이에 한정되는 것은 아니다.When the composition of the present invention is used as a pharmaceutical, the pharmaceutical composition containing the derivative of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient may be formulated in various oral or parenteral dosage forms as described below. It may be administered, but is not limited thereto.
경구 투여용 제형으로는 예를 들면 정제, 환제, 경/연질 캅셀제, 액제, 현탁제, 유화제, 시럽제, 과립제, 엘릭시르제 등이 있는데, 이들 제형은 유효성분 이외에 희석제(예: 락토즈, 덱스트로즈, 수크로즈, 만니톨, 솔비톨, 셀룰로즈 및/ 또는 글리신), 활택제(예: 실리카, 탈크, 스테아르산 및 그의 마그네슘 또는 칼슘염 및/또는 폴리에틸렌 글리콜)를 함유하고 있다. 정제는 또한 마그네슘 알루미늄 실리케이트, 전분 페이스트, 젤라틴, 메틸셀룰로즈, 나트륨 카복시메틸셀룰로즈 및/또는 폴리비닐피롤리딘과 같은 결합제를 함유할 수 있으며, 경우에 따라 전분, 한천, 알긴산 또는 그의 나트륨 염과 같은 붕해제 또는 비등 혼합물 및/또는 흡수제, 착색제, 향미제, 및 감미제를 함유할 수 있다.Formulations for oral administration include, for example, tablets, pills, hard / soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, etc. These formulations may contain, in addition to the active ingredients, diluents (e.g., lactose, dextrose). Rose, sucrose, mannitol, sorbitol, cellulose and / or glycine), lubricants such as silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycols. Tablets may also contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine, and optionally such as starch, agar, alginic acid or its sodium salt. Disintegrant or boiling mixtures and / or absorbents, colorants, flavors, and sweeteners.
상기 화학식 1로 표시되는 유도체를 유효 성분으로 하는 약학 조성물은 비경구 투여할 수 있으며, 비경구 투여는 피하주사, 정맥주사, 근육 내 주사 또는 흉부 내 주사를 주입하는 방법에 의한다. The pharmaceutical composition comprising the derivative represented by Chemical Formula 1 as an active ingredient may be administered parenterally, and the parenteral administration may be by injection of subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection.
이때, 비경구 투여용 제형으로 제제화하기 위하여 상기 화학식 1의 페닐아세테이트 유도체 또는 이의 약학적으로 허용되는 염을 안정제 또는 완충제와 함께 물에 혼합하여 용액 또는 현탁액으로 제조하고, 이를 앰플 또는 바이알 단위 투여형으로 제조할 수 있다. 상기 조성물은 멸균되고/되거나 방부제, 안정화제, 수화제 또는 유화 촉진제, 삼투압 조절을 위한 염 및/또는 완충제 등의 보조제, 및 기타 치료적으로 유용한 물질을 함유할 수 있으며, 통상적인 방법인 혼합, 과립화 또는 코팅 방법에 따라 제제화할 수 있다.In this case, in order to formulate into a formulation for parenteral administration, the phenylacetate derivative of Formula 1 or a pharmaceutically acceptable salt thereof is mixed with water together with a stabilizer or a buffer to prepare a solution or suspension, which is an ampoule or vial unit dosage form. It can be prepared by. The compositions may contain sterile and / or preservatives, stabilizers, hydrating or emulsifying accelerators, auxiliaries such as salts and / or buffers for the control of osmotic pressure, and other therapeutically useful substances, and conventional methods of mixing, granulating It may be formulated according to the formulation or coating method.
또한, 본 발명의 화합물의 인체에 대한 투여량은 환자의 나이, 몸무게, 성별, 투여형태, 건강상태 및 질환 정도에 따라 달라질 수 있으며, 몸무게가 70 ㎏인 성인 환자를 기준으로 할 때, 일반적으로 0.1 ~ 1,000 ㎎/일이며, 바람직하게는 1 ~ 500 ㎎/일이며, 의사 또는 약사의 판단에 따라 일정시간 간격으로 1일 1회 내지 수회로 분할 투여할 수도 있다.In addition, the dosage of the compound of the present invention to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, and generally based on an adult patient having a weight of 70 kg. It is 0.1-1,000 mg / day, Preferably it is 1-500 mg / day, It can also divide and administer once a day to several times at regular time intervals according to a decision of a doctor or a pharmacist.
이하, 본 발명을 실시예 및 실험예에 의해 상세히 설명한다. 단, 하기의 실시예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기의 실시예에 의해 한정되는 것은 아니다.Hereinafter, the present invention will be described in detail by Examples and Experimental Examples. However, the following examples are merely to illustrate the present invention, but the content of the present invention is not limited by the following examples.
<실시예 1> 5-(4-클로로-2-메틸페녹시)-2-스티릴피란-4-온의 제조Example 1 Preparation of 5- (4-chloro-2-methylphenoxy) -2-styrylpyran-4-one
Figure PCTKR2010004966-appb-I000012
Figure PCTKR2010004966-appb-I000012
단계 1: 5-(4-클로로-2-메틸페녹실)-2-하이드록시메틸피란-4-온의 제조Step 1: Preparation of 5- (4-chloro-2-methylphenoxyl) -2-hydroxymethylpyran-4-one
코직산(10 g, 70 mmol)을 디메틸포름아마이드에 녹이고 2-브로모-5-클로로톨루엔(21.6 g, 10.5 mmol)과 Cu2O(10 g, 70 mmol), Cs2CO3(45.6 g, 140 mmol)을 차례로 첨가하였다. 다음으로 N-디메틸글리신염(2 g, 14 mmol)과 분자체(molecular sieve)(powder)를 모두 첨가한 후 60 ℃에서 3일 동안 가열 환류하였다. 반응이 종결되면 셀라이트(celite)를 이용하여 여과한 후 여액을 EtOAC와 H2O로 추출하였다. 유기층을 무수 MgSO4로 건조시키고 감압 하에서 용매를 제거하고 컬럼 크로마토그래피(에틸 아세테이트:n-헥산 = 1:1)를 이용하여 분리 정제하여 목적화합물을 2.1%의 수율로 400 mg 얻었다. Kojic acid (10 g, 70 mmol) was dissolved in dimethylformamide, 2-bromo-5-chlorotoluene (21.6 g, 10.5 mmol), Cu 2 O (10 g, 70 mmol), Cs 2 CO 3 (45.6 g, 140 mmol) was added sequentially. Next, N-dimethylglycine salt (2 g, 14 mmol) and molecular sieves (molecular sieve) (powder) were all added and then heated to reflux for 3 days at 60 ℃. After the reaction was completed, the resultant was filtered using celite, and the filtrate was extracted with EtOAC and H 2 O. The organic layer was dried over anhydrous MgSO 4 , the solvent was removed under reduced pressure, and purified by column chromatography (ethyl acetate: n-hexane = 1: 1) to obtain 400 mg of the target compound in 2.1% yield.
1H NMR (CDCl3, 400 MHz) δ 7.63 (s, 1H), δ 7.20 (dd, J = 2.6, 0.5 Hz, 1H), 7.09 (dd, J = 8.7, 2.6 Hz, 1H), 6.72 (d, J = 8.7 Hz, 1H), 4.52 (s, 2H), 2.29 (s, 3H) 1 H NMR (CDCl 3 , 400 MHz) δ 7.63 (s, 1H), δ 7.20 (dd, J = 2.6, 0.5 Hz, 1H), 7.09 (dd, J = 8.7, 2.6 Hz, 1H), 6.72 (d , J = 8.7 Hz, 1H), 4.52 (s, 2H), 2.29 (s, 3H)
단계 2: 2-클로로메틸-5-(4-클로로-2-메틸페녹시)피란-4-온의 제조Step 2: Preparation of 2-chloromethyl-5- (4-chloro-2-methylphenoxy) pyran-4-one
상기 단계 1에서 제조된 5-(4-클로로-2-메틸페녹실)-2-하이드록시메틸피란-4-온(100 mg, 0.375 mmol)을 CH2Cl2에 용해시킨 후 트리에틸아민(0.16 mL, 1.125 mmol)과 싸이오닐 클로라이드(0.065 mL, 0.89 mmol)를 첨가한 다음 상온에서 3시간 동안 교반하였다. 반응이 종결되면 CH2Cl2와 H2O로 추출한 후, 유기층을 무수 MgSO4로 건조시키고 감압 하에서 용매를 제거하고 컬럼 크로마토그래피(에틸 아세테이트:n-헥산 = 2:1)를 이용하여 분리 정제하여 목적화합물을 94%의 수율로 100 mg 얻었다. 5- (4-chloro-2-methylphenoxyl) -2-hydroxymethylpyran-4-one (100 mg, 0.375 mmol) prepared in step 1 was dissolved in CH 2 Cl 2 , followed by triethylamine ( 0.16 mL, 1.125 mmol) and thionyl chloride (0.065 mL, 0.89 mmol) were added, followed by stirring at room temperature for 3 hours. After completion of the reaction, the mixture was extracted with CH 2 Cl 2 and H 2 O, and then the organic layer was dried over anhydrous MgSO 4 , the solvent was removed under reduced pressure, and purified by column chromatography (ethyl acetate: n-hexane = 2: 1). 100 mg of the target compound was obtained in the yield of 94%.
1H NMR (CDCl3, 400 MHz) δ 7.64, (s, 1H), 7.09 (dd, J = 8.7, 2.6 Hz, 1H), 6.74 (d, J = 8.7 Hz), 6.56 (s, 1H), 4.34 (s, 2H), 2.29 (s, 3H) 1 H NMR (CDCl 3 , 400 MHz) δ 7.64, (s, 1H), 7.09 (dd, J = 8.7, 2.6 Hz, 1H), 6.74 (d, J = 8.7 Hz), 6.56 (s, 1H), 4.34 (s, 2H), 2.29 (s, 3H)
단계 3: [5-(4-클로로-2-메틸페녹시)-4-옥소-4H-피란-2-일메틸]포스폰산의 제조 Step 3: Preparation of [5- (4-Chloro-2-methylphenoxy) -4-oxo-4H-pyran-2-ylmethyl] phosphonic acid
상기 단계 2에서 제조한 2-클로로메틸-5-(4-클로로-2-메틸페녹시)피란-4-온(0.8 g, 0.35 mmol)에 트리에틸포스파이트(5.79 mL, 33.79 mmol)를 첨가한 후 반응물을 밤새동안 가열 환류하였다. 반응이 종결된 후 감압 하에서 용매를 제거하여 목적화합물을 44%의 수율로 5.98 g 얻었다. Triethylphosphite (5.79 mL, 33.79 mmol) was added to 2-chloromethyl-5- (4-chloro-2-methylphenoxy) pyran-4-one (0.8 g, 0.35 mmol) prepared in step 2 above. The reaction was then heated to reflux overnight. After the reaction was terminated, the solvent was removed under reduced pressure to obtain 5.98 g of the target compound in 44% yield.
1H NMR (CDCl3, 400 MHz) δ 7.62 (s, 1H), 7.21 (s, 1H), 7.09 (dd, J = 8.5, 3.3 Hz, 1H), 6.73 (d, J = 8.5 Hz, 1H), 6.44 (d, J = 3.3 Hz, 1H) 4.16 (m, 4H) 3.10 (d, J = 2.1 Hz, 2H), 2.28 (s, 3H,) 1.32 (t, J = 7.1 Hz, 6H) 1 H NMR (CDCl 3 , 400 MHz) δ 7.62 (s, 1H), 7.21 (s, 1H), 7.09 (dd, J = 8.5, 3.3 Hz, 1H), 6.73 (d, J = 8.5 Hz, 1H) , 6.44 (d, J = 3.3 Hz, 1H) 4.16 (m, 4H) 3.10 (d, J = 2.1 Hz, 2H), 2.28 (s, 3H,) 1.32 (t, J = 7.1 Hz, 6H)
단계 4: 5-(4-클로로-2-메틸페녹시)-2-스티릴피란-4-온의 제조Step 4: Preparation of 5- (4-chloro-2-methylphenoxy) -2-styrylpyran-4-one
상기 단계 3에서 제조된 5-(4-클로로-2-메틸페녹시)-4-옥소-4H-피란-2-일메틸]포스폰산(0.259 mmol, 100 mg)에 알데하이즈(1.1 eq, 0.283 mmol), tBuOK(1.5 eq, 0.387 mmol)를 첨가하고 무수 테트라하이드로퓨란 하에서 밤새동안 교반시켰다. 반응이 종결되면 EtOAC와 H2O로 추출한 후, 유기층을 무수 MgSO4로 건조시키고 감압 하에서 용매를 제거한 다음 컬럼 크로마토그래피(에틸 아세테이트:n-헥산 = 2:1)를 이용하여 분리 정제하여 목적화합물을 40%의 수율로 34.1 mg 얻었다. Aldehyde (1.1 eq, 0.283) in 5- (4-chloro-2-methylphenoxy) -4-oxo-4H-pyran-2-ylmethyl] phosphonic acid (0.259 mmol, 100 mg) prepared in step 3 mmol), tBuOK (1.5 eq, 0.387 mmol) was added and stirred overnight under anhydrous tetrahydrofuran. After completion of the reaction, the mixture was extracted with EtOAC and H 2 O, the organic layer was dried over anhydrous MgSO 4 , the solvent was removed under reduced pressure, and purified by column chromatography (ethyl acetate: n-hexane = 2: 1). 34.1 mg was obtained in a yield of 40%.
1H NMR (CDCl3, 400 MHz) δ 7.62 (s, 1H), 7.52 (d, J = 1.6 Hz, 1H), 7.53 (d, J = 1.6 Hz, 1H), 7.43 (m, 4H), 7.21 (d, J = 2.3 Hz, 1H), 7.12 (dd, J = 8.6, 2.3 Hz, 1H) 6.75 (d, J = 8.6 Hz, 1H), 6.72 (d, J = 16.1 Hz, 1H), 6.43 (s, 1H), 2.32 (s, 3H) 1 H NMR (CDCl 3 , 400 MHz) δ 7.62 (s, 1H), 7.52 (d, J = 1.6 Hz, 1H), 7.53 (d, J = 1.6 Hz, 1H), 7.43 (m, 4H), 7.21 (d, J = 2.3 Hz, 1H), 7.12 (dd, J = 8.6, 2.3 Hz, 1H) 6.75 (d, J = 8.6 Hz, 1H), 6.72 (d, J = 16.1 Hz, 1H), 6.43 ( s, 1H), 2.32 (s, 3H)
<실시예 2> 5-(4-클로로-2-메틸페녹시)-2-(3-메틸부트-1-에닐)-1H-피리딘-4-온의 제조 Example 2 Preparation of 5- (4-chloro-2-methylphenoxy) -2- (3-methylbut-1-enyl) -1H-pyridin-4- one
Figure PCTKR2010004966-appb-I000013
Figure PCTKR2010004966-appb-I000013
단계 1: [5-(4-클로로-2-메틸페녹시)-4-옥소-1,4-디하이드로피리딘-2-일메 틸]포스폰산 디에틸에스테르의 제조 Step 1: Preparation of [5- (4-chloro-2-methylphenoxy) -4-oxo-1,4-dihydropyridin-2-ylmethyl ] phosphonic acid diethyl ester
반응용매로서 메탄올 하에서 실시예 1의 상기 단계 3에서 제조한 5-(4-클로로-2-메틸페녹시)-4-옥소-4H-피란-2-일메틸]포스폰산(200 mg, 0.517 mmol)에 암모니아수(28.0-30.0%)를 2 mL 적가한 후 밤새동안 가열환류하였다. 반응이 종결된 후 감압 하에서 용매를 제거하고 컬럼 크로마토그래피(에틸 아세테이트:n-헥산 = 10:1)를 이용하여 분리 정제하여 목적화합물을 50%의 수율로 100 mg 얻었다.5- (4-chloro-2-methylphenoxy) -4-oxo-4H-pyran-2-ylmethyl] phosphonic acid (200 mg, 0.517 mmol) prepared in step 3 of Example 1 under methanol as a reaction solvent. 2 mL of ammonia water (28.0-30.0%) was added dropwise thereto, followed by heating to reflux overnight. After completion of the reaction, the solvent was removed under reduced pressure and purified by column chromatography (ethyl acetate: n-hexane = 10: 1) to obtain 100 mg of the target compound in a yield of 50%.
1H NMR (CDCl3, 400 MHz) δ 13.26 (bs, 1H), 6.99 (d, J = 2.5 Hz, 1H), 6.91 (dd, J = 8.6, 2.5 Hz, 1H), 6.54-6.41 (m, 3H), 6.04 (d, J = 16 Hz, 1H), 2.43-2.34 (m, 1H), 2.02 (s, 3H), 1.01 (d, J = 6.7 Hz, 6H) 1 H NMR (CDCl 3 , 400 MHz) δ 13.26 (bs, 1H), 6.99 (d, J = 2.5 Hz, 1H), 6.91 (dd, J = 8.6, 2.5 Hz, 1H), 6.54-6.41 (m, 3H), 6.04 (d, J = 16 Hz, 1H), 2.43-2.34 (m, 1H), 2.02 (s, 3H), 1.01 (d, J = 6.7 Hz, 6H)
단계 2: 5-(4-클로로-2-메틸페녹시)-2-(3-메틸부트-1-에닐)-1H-피리딘-4-온 의 제조 Step 2: Preparation of 5- (4-chloro-2-methylphenoxy) -2- (3-methylbut-1-enyl) -1H-pyridin-4-one
상기 단계 1에서 제조된 [5-(4-클로로-2-메틸페녹시)-4-옥소-1,4-디하이드로피리딘-2-일메틸]포스폰산 디에틸에스테르(50 mg, 0.12 mmol)에 이소부틸알데하이드(10.27 mg, 0. 1425 mmol), tBuOK (21.81 mg, 0.194 mmol)을 첨가하고 반응 용매인 무수 테트라하이드로퓨란 하에서 상온에서 교반시켰다. 반응이 종결되면 감압 하에서 용매를 제거하고 컬럼 크로마토그래피(에틸 아세테이트:n-헥산 = 1:1)를 이용하여 분리 정제하여 목적화합물을 27.9%의 수율로 11 mg 얻었다. [5- (4-Chloro-2-methylphenoxy) -4-oxo-1,4-dihydropyridin-2-ylmethyl] phosphonic acid diethyl ester (50 mg, 0.12 mmol) prepared in step 1; To isobutylaldehyde (10.27 mg, 0.125 mmol) and tBuOK (21.81 mg, 0.194 mmol) were added and stirred at room temperature under anhydrous tetrahydrofuran as a reaction solvent. When the reaction was completed, the solvent was removed under reduced pressure and purified by column chromatography (ethyl acetate: n-hexane = 1: 1) to give the target compound 11 mg in 27.9% yield.
1H NMR (CDCl3, 400 MHz) δ 10.41 (bs, 1H), 7.19 (m, 1H), 7.05 (dd, J = 8.6, 2.5 Hz, 1H), 6.69 (d, J = 8.6 Hz, 1H), 6.40 (s, 1H), 4.11 (m, 4H), 3.10 (d, J = 20.9 Hz, 2H), 2.2 (s, 3H), 1.26-1.21 (m, 6H) 1 H NMR (CDCl 3 , 400 MHz) δ 10.41 (bs, 1H), 7.19 (m, 1H), 7.05 (dd, J = 8.6, 2.5 Hz, 1H), 6.69 (d, J = 8.6 Hz, 1H) , 6.40 (s, 1H), 4.11 (m, 4H), 3.10 (d, J = 20.9 Hz, 2H), 2.2 (s, 3H), 1.26-1.21 (m, 6H)
<실시예 3> 5-(4-클로로-2-메틸페녹시)-1-메틸-2-페녹시메틸-1H-피리딘-4-온의 제조 Example 3 Preparation of 5- (4-Chloro-2-methylphenoxy) -1-methyl-2-phenoxymethyl-1H-pyridin-4-one
Figure PCTKR2010004966-appb-I000014
Figure PCTKR2010004966-appb-I000014
단계 1: 5-(4-클로로-2-메틸-페녹시)-2-페녹시메틸피란-4-온의 제조Step 1: Preparation of 5- (4-chloro-2-methyl-phenoxy) -2-phenoxymethylpyran-4-one
5-(4-클로로-2-메틸페녹실)-2-하이드로메틸피란-4-온(200 mg, 0.81 mmol)을 무수 테트라하이드로퓨란에 용해시킨 후 페놀(91.71 mg, 0.97 mmol)과 트리페닐포스핀(255.60 mg, 0.97 mmol)을 차례로 첨가하였다. 이후 0 ℃에서 디이소프로필 아조디카르복실레이트(0.19 mL, 0.97 mmol)를 천천히 가한 후 상온에서 밤새 동안 교반하였다. 반응이 종결된 후 용매를 감압 증류하고 컬럼 크로마토그래피를 이용하여 정제하여 목적화합물을 42.1%의 수율로 110 mg 얻었다.5- (4-chloro-2-methylphenoxyl) -2-hydromethylpyran-4-one (200 mg, 0.81 mmol) was dissolved in anhydrous tetrahydrofuran, followed by phenol (91.71 mg, 0.97 mmol) and triphenyl Phosphine (255.60 mg, 0.97 mmol) was added sequentially. Then diisopropyl azodicarboxylate (0.19 mL, 0.97 mmol) was slowly added at 0 ° C., and then stirred at room temperature overnight. After completion of the reaction, the solvent was distilled under reduced pressure and purified by column chromatography to give 110 mg of the target compound in a yield of 42.1%.
1H NMR (CDCl3, 400 MHz) δ 7.65 (s, 1H), 7.32 (m, 2H), 7.28 (d, J = 2.1 Hz, 1H), 7.18 (dd, J = 8.6, 2.1 Hz, 1H), 7.02 (m, 1H), 6.98 (m, 2H), 6.72 (d, J = 8.6 Hz, 1H), 6.65 (s, 1H) 4.85 (s, 2H), 2.35 (s, 3H) 1 H NMR (CDCl 3 , 400 MHz) δ 7.65 (s, 1H), 7.32 (m, 2H), 7.28 (d, J = 2.1 Hz, 1H), 7.18 (dd, J = 8.6, 2.1 Hz, 1H) , 7.02 (m, 1H), 6.98 (m, 2H), 6.72 (d, J = 8.6 Hz, 1H), 6.65 (s, 1H) 4.85 (s, 2H), 2.35 (s, 3H)
단계 2: 5-(4-클로로-2-메틸-페녹시)-1-메틸-2-페놀시메틸-1H-피리딘-4-온의 제조 Step 2: Preparation of 5- (4-Chloro-2-methyl-phenoxy) -1-methyl-2-phenoloxymethyl-1H-pyridin-4-one
상기 단계 1에서 제조한 5-(4-클로로-2-메틸-페녹시)-2-페녹시메틸피란-4-온(18 mg, 0.0525 mmol)을 메탄올에 용해시킨 후 2M 메틸아민 메탄올 용액 2방울을 적가하고 1시간 동안 가열 환류하였다. 반응이 종결한 후 H2O와 EtOAc를 이용하여 추출한 후, 무수 MgSO4로 건조하고 감압 증류하여 용매를 제거하여 목적화합물을 45.5%의 수율로 8.5 mg 얻었다.5- (4-chloro-2-methyl-phenoxy) -2-phenoxymethylpyran-4-one (18 mg, 0.0525 mmol) prepared in step 1 was dissolved in methanol, and then 2M methylamine methanol solution 2 The drop was added dropwise and heated to reflux for 1 hour. After completion of the reaction, the mixture was extracted with H 2 O and EtOAc, dried over anhydrous MgSO 4 and distilled under reduced pressure to remove the solvent to give the title compound in a yield of 45.5% 8.5 mg.
1H NMR (CDCl3, 400 MHz) δ 7.35 (dd, J = 8.6, 2.2 Hz, 2H), 7.25 (d, J = 2.2 Hz, 1H), 7.15 (s, 1H), 7.08-7.06 (m, 2H), 6.92 (d, J = 8.6 Hz, 2H,), 6.73 (d, J = 8.6 Hz, 1H), 6.65 (s, 1H), 4.95 (s, 2H), 3.64 (s, 3H), 2.3 (s, 3H) 1 H NMR (CDCl 3 , 400 MHz) δ 7.35 (dd, J = 8.6, 2.2 Hz, 2H), 7.25 (d, J = 2.2 Hz, 1H), 7.15 (s, 1H), 7.08-7.06 (m, 2H), 6.92 (d, J = 8.6 Hz, 2H,), 6.73 (d, J = 8.6 Hz, 1H), 6.65 (s, 1H), 4.95 (s, 2H), 3.64 (s, 3H), 2.3 (s, 3H)
<실시예 4> 1-벤질-3-[(2,6-디클로로-페닐)-하이드록시메틸]-1H-피리딘-4-온의 제조 Example 4 Preparation of 1-benzyl-3-[(2,6-dichloro-phenyl) -hydroxymethyl] -1 H-pyridin-4-one
Figure PCTKR2010004966-appb-I000015
Figure PCTKR2010004966-appb-I000015
단계 1: 4-메톡시피리딘의 제조Step 1: Preparation of 4-methoxypyridine
메탄올 300 mL를 교반시키면서 소디움 고체(9 g, 391 mmol)를 천천히 첨가하였다. 소디움 메톡사이드가 제조되면 얼음 중탕하에서 4-클로로피리딘 염산염(25 g, 167 mmol)을 가한 뒤 80 ℃에서 가열 환류시켰다. 반응의 종결을 박층 크로마토그래피(TLC)로 확인한 다음, 상온에서 식힌 뒤, 에테르를 넣고 추출하였다. 용매를 감압 증류하여 제거하여 4-메톡시피리딘을 67%의 수율로 12.0 g 얻었다.Sodium solid (9 g, 391 mmol) was slowly added while stirring 300 mL of methanol. When sodium methoxide was prepared, 4-chloropyridine hydrochloride (25 g, 167 mmol) was added under ice bath, followed by heating to reflux at 80 ° C. Termination of the reaction was confirmed by thin layer chromatography (TLC), and then cooled to room temperature, and ether was extracted. The solvent was distilled off under reduced pressure to obtain 12.0 g of 4-methoxypyridine in a yield of 67%.
1H NMR (300MHz) (CDCl3) δ 8.43 (dd, J = 2.0, 6.4 Hz, 2H), 6.80 (dd, J = 2.1, 6.4 Hz), 3.83 (d, J = 2.2 Hz, 3H) 1 H NMR (300 MHz) (CDCl 3 ) δ 8.43 (dd, J = 2.0, 6.4 Hz, 2H), 6.80 (dd, J = 2.1, 6.4 Hz), 3.83 (d, J = 2.2 Hz, 3H)
단계 2: 2,6-디클로로페닐-(4-메톡시피리딘-3-일)메탄올의 제조Step 2: Preparation of 2,6-dichlorophenyl- (4-methoxypyridin-3-yl) methanol
반응 용기를 질소로 채운 뒤, 무수 테트라히드로퓨란 100 mL를 담은 뒤, 상기 단계 1에서 제조된 4-메톡시피리딘(4.0 g, 36.65 mmol)을 첨가하였다. -78 ℃ 장치를 하고 페닐리튬 1.8 M 용액(44 mL, 80.64 mmol)을 서서히 가한 뒤, 상온에서 1시간 동안 교반시켰다. 다시 -78 ℃ 장치를 한 뒤, 2,6-디클로로벤즈알데하이드(14.29 g, 91.64 mmol)를 서서히 가하여 밤새 동안 교반시켰다. 반응의 종결을 박층 크로마토그래피(TLC)로 확인한 다음 암모늄클로라이드 수용액을 첨가한 후, 생성된 결정을 여과하고 에테르로 세척하여 목적화합물을 45%의 수율로 4.68 g 얻었다.The reaction vessel was filled with nitrogen, contained 100 mL of anhydrous tetrahydrofuran, and 4-methoxypyridine (4.0 g, 36.65 mmol) prepared in Step 1 was added thereto. The apparatus was set at −78 ° C., and slowly added phenyllithium 1.8 M solution (44 mL, 80.64 mmol), followed by stirring at room temperature for 1 hour. After the apparatus was again set at -78 ° C, 2,6-dichlorobenzaldehyde (14.29 g, 91.64 mmol) was added slowly and stirred overnight. The reaction was terminated by thin layer chromatography (TLC), and then aqueous ammonium chloride solution was added. The resulting crystals were filtered and washed with ether to obtain 4.68 g of the title compound in a yield of 45%.
1H NMR (300MHz) (CDCl3) δ 8.72 (s, 1H), 83.41 (d, J = 5.7 Hz, 1H), 7.28 (d, J = 7.9 Hz, 2H), 7.15 (dd, J = 0.9, 7.6 Hz, 1H), 6.72-6.74 (m, 2H), 3.74 (s, 3H) 1 H NMR (300 MHz) (CDCl 3 ) δ 8.72 (s, 1H), 83.41 (d, J = 5.7 Hz, 1H), 7.28 (d, J = 7.9 Hz, 2H), 7.15 (dd, J = 0.9, 7.6 Hz, 1H), 6.72-6.74 (m, 2H), 3.74 (s, 3H)
단계 3: 1-벤질-3-[(2,6-디클로로페닐)-하이드로메틸]-1H-피리딘-4-온의 제 조 Step 3: Preparation of 1-benzyl-3-[(2,6-dichlorophenyl) -hydromethyl] -1 H-pyridin-4-one
아세토니트릴 5 mL에 상기 단계 2에서 제조된 2,6-디클로로페닐-(4-메톡시피리딘-3-일)메탄올(100 mg, 0.352 mmol)을 용해시킨 뒤, 벤질클로라이드(0.05 mL, 0.387 mmol)와 소디움아이오다이드(106 mg, 0.704 mmol)를 첨가하여 110 ℃에서 밤새 동안 가열 환류시켰다. 반응의 종결을 박층 크로마토그래피(TLC)로 확인하고 실온으로 냉각시킨 후, Na2S2O3 수용액을 첨가하여 잠시 교반시켰다. 반응물을 H2O와 EtOAc로 추출한 다음, 감압 증류하여 용매를 제거한 뒤 컬럼 크로마토그래피(에틸 아세테이트:메탄올 = 4:1)를 이용하여 분리 및 정제하여 목적화합물을 32%의 수율로 38 mg 얻었다.Dissolve 2,6-dichlorophenyl- (4-methoxypyridin-3-yl) methanol (100 mg, 0.352 mmol) prepared in step 2 above in 5 mL of acetonitrile, and then benzyl chloride (0.05 mL, 0.387 mmol). ) And sodium iodide (106 mg, 0.704 mmol) were heated to reflux overnight at 110 ° C. The completion of the reaction was confirmed by thin layer chromatography (TLC), cooled to room temperature, and then stirred for a while by adding Na 2 S 2 O 3 aqueous solution. The reaction product was extracted with H 2 O and EtOAc, and the solvent was distilled off under reduced pressure, and the solvent was separated and purified using column chromatography (ethyl acetate: methanol = 4: 1) to obtain 38 mg of the target compound in 32% yield.
1H NMR (400MHz) (CDCl3) δ 7.38 (d, J = 1.8 Hz, 1H), 7.36 (d, J = 2.0 Hz, 2H), 7.31-7.34 (m, 3H), 7.16-7.20 (m, 1H). 7.09-7.11 (m, 2H), 6.89 (t, J = 1.2 Hz, 1H), 6.77 (s, 1H), 6.44 (d, J = 7.5 Hz, 1H), 6.26 (br s, 1H), 4.89 1 H NMR (400 MHz) (CDCl 3 ) δ 7.38 (d, J = 1.8 Hz, 1H), 7.36 (d, J = 2.0 Hz, 2H), 7.31-7.34 (m, 3H), 7.16-7.20 (m, 1H). 7.09-7.11 (m, 2H), 6.89 (t, J = 1.2 Hz, 1H), 6.77 (s, 1H), 6.44 (d, J = 7.5 Hz, 1H), 6.26 (br s, 1H), 4.89
이하에는 상기 실시예 1과 같은 방법으로 3-페녹시-4-파이론 유도체를 합성하였으며, 그 구조 및 1H NMR 데이터를 하기 표 1에 나타내었다.Hereinafter, a 3-phenoxy-4-pyrone derivative was synthesized in the same manner as in Example 1, and its structure and 1 H NMR data are shown in Table 1 below.
표 1
실시예 구조 NMR 데이터
5
Figure PCTKR2010004966-appb-I000016
 7.65 (d, J = 8.6 Hz, 1H), 7.63 (s, 1H), 7.46 (m, 1H), 7.29 (s, 1H), 7.22 (dd, J = 15.9, 1.9 Hz, 2H), 7.09 (dd, J = 8.6, 1.4 Hz, 2H), 6.75 (d, J = 8.6 Hz, 1H), 6.64 (d, J = 1.9 Hz, 1H), 6.40 (d, J = 15.9 Hz, 1H), 6.38 (s, 1H), 2.31 (s, 3H)
6
Figure PCTKR2010004966-appb-I000017
 7.65 (s, 1H), 7.46 (d, J = 1.9 Hz, 1H), 7.40-7.37 (m, 3H), 7.20 (d, J = 1.9 Hz, 1H), 7.09 (dd, J = 8.6, 2.3 Hz, 1H), 6.74 (d, J = 8.6 Hz, 1H), 6.51 (d, J = 16.0 Hz, 1H), 6.44 (s, 1H), 2.30 (s, 3H)
7
Figure PCTKR2010004966-appb-I000018
 7.59 (s, 1H), 7.21 (d, J = 2.5 Hz, 1H), 7.09 (dd, J = 8.6, 2.5 Hz, 1H), 6.72 (d, J = 8.6 Hz, 1H), 6.66-6.58 (m, 1H), 6.28 (s, 1H), 6.10 (d, J = 8.6 Hz, 1H), 2.30 (s, 3H), 2.24 (q, J = 14.5, 7.2 Hz, 2H), 1.57 (q, J = 14.5, 7.2 Hz, 2H), 0.98 (t, J = 7.2 Hz, 1H)
8
Figure PCTKR2010004966-appb-I000019
 7.62 (s, 1H), 7.50 (d, J = 2.0 Hz, 1H), 7.26 (d, J = 2.0 Hz, 1H), 7.15 (d, J = 1.8 Hz, 1H), 7.11 (dd, J = 8.6, 3.3 Hz, 1H), 6.77 (d, J = 8.6 Hz, 1H), 6.60 (d, J = 15.8 Hz, 1H), 6.58 (d, J = 3.3 Hz, 1H), 6.50-6.48 (m, 1H), 6.41 (s, 1H), 2.31 (s, 3H)
9
Figure PCTKR2010004966-appb-I000020
 8.88 (s, 1H), 7.62 (s, 1H), 7.25 (d, J = 4.2 Hz, 1H), 7.21 (m, 1H), 7.06 (dd, J = 8.6, 2.4 Hz, 1H), 6.90 (d, J = 1.2 Hz, 1H), 6.74 (d, J = 8.6 Hz, 1H), 6.54 (d, J = 1.2 Hz, 1H), 6.30 (s, 1H), 6.29 (m, 2H), 2.32 (s, 3H)
10 7.63 (s, 1H), 7.47 (d, J = 15.7 Hz, 1H), 7.38 (d, J = 5.1 Hz, 1H), 7.23 (d, J = 5.1 Hz, 2H), 7.08-7.06 (m, 2H), 6.77 (d, J = 8.6 Hz, 1H), 6.52 (d, J = 8.6 Hz, 1H), 6.48 (s, 1H). 2.31 (s, 3H)
Table 1
EXAMPLE rescue NMR data
5
Figure PCTKR2010004966-appb-I000016
 7.65 (d, J = 8.6 Hz, 1H), 7.63 (s, 1H), 7.46 (m, 1H), 7.29 (s, 1H), 7.22 (dd, J = 15.9, 1.9 Hz, 2H), 7.09 (dd , J = 8.6, 1.4 Hz, 2H), 6.75 (d, J = 8.6 Hz, 1H), 6.64 (d, J = 1.9 Hz, 1H), 6.40 (d, J = 15.9 Hz, 1H), 6.38 (s , 1H), 2.31 (s, 3H)
6
Figure PCTKR2010004966-appb-I000017
 7.65 (s, 1H), 7.46 (d, J = 1.9 Hz, 1H), 7.40-7.37 (m, 3H), 7.20 (d, J = 1.9 Hz, 1H), 7.09 (dd, J = 8.6, 2.3 Hz , 1H), 6.74 (d, J = 8.6 Hz, 1H), 6.51 (d, J = 16.0 Hz, 1H), 6.44 (s, 1H), 2.30 (s, 3H)
7
Figure PCTKR2010004966-appb-I000018
 7.59 (s, 1H), 7.21 (d, J = 2.5 Hz, 1H), 7.09 (dd, J = 8.6, 2.5 Hz, 1H), 6.72 (d, J = 8.6 Hz, 1H), 6.66-6.58 (m , 1H), 6.28 (s, 1H), 6.10 (d, J = 8.6 Hz, 1H), 2.30 (s, 3H), 2.24 (q, J = 14.5, 7.2 Hz, 2H), 1.57 (q, J = 14.5, 7.2 Hz, 2H), 0.98 (t, J = 7.2 Hz, 1H)
8
Figure PCTKR2010004966-appb-I000019
 7.62 (s, 1H), 7.50 (d, J = 2.0 Hz, 1H), 7.26 (d, J = 2.0 Hz, 1H), 7.15 (d, J = 1.8 Hz, 1H), 7.11 (dd, J = 8.6 , 3.3 Hz, 1H), 6.77 (d, J = 8.6 Hz, 1H), 6.60 (d, J = 15.8 Hz, 1H), 6.58 (d, J = 3.3 Hz, 1H), 6.50-6.48 (m, 1H ), 6.41 (s, 1 H), 2.31 (s, 3 H)
9
Figure PCTKR2010004966-appb-I000020
 8.88 (s, 1H), 7.62 (s, 1H), 7.25 (d, J = 4.2 Hz, 1H), 7.21 (m, 1H), 7.06 (dd, J = 8.6, 2.4 Hz, 1H), 6.90 (d , J = 1.2 Hz, 1H), 6.74 (d, J = 8.6 Hz, 1H), 6.54 (d, J = 1.2 Hz, 1H), 6.30 (s, 1H), 6.29 (m, 2H), 2.32 (s , 3H)
10 7.63 (s, 1H), 7.47 (d, J = 15.7 Hz, 1H), 7.38 (d, J = 5.1 Hz, 1H), 7.23 (d, J = 5.1 Hz, 2H), 7.08-7.06 (m, 2H ), 6.77 (d, J = 8.6 Hz, 1H), 6.52 (d, J = 8.6 Hz, 1H), 6.48 (s, 1H). 2.31 (s, 3 H)
이하에는 상기 실시예 2 또는 실시예 3과 같은 방법으로 3-페녹시-4-피리돈 유도체를 합성하였으며, 그 구조 및 1H NMR 데이터를 하기 표 2에 나타내었다.Hereinafter, 3-phenoxy-4-pyridone derivatives were synthesized in the same manner as in Example 2 or 3, and the structure and 1 H NMR data thereof are shown in Table 2 below.
표 2
실시예 구조 NMR 데이터
11
Figure PCTKR2010004966-appb-I000022
 7.59 (s, 1H), 7.26 (d, J = 2.5 Hz, 1H), 7.06 (dd, J = 8.6, 2.5 Hz, 1H), 6.74 (d, J = 8.6 Hz, 1H), 6.61 (dd, J = 15.8, 6.8 Hz, 1H), 6.29 (s, 1H), 6.00 (dd, J = 15.8, 1.3 Hz, 1H), 2.30 (s, 3H), 1.14 (d, J = 6.7 Hz, 6H)
12
Figure PCTKR2010004966-appb-I000023
 7.17 (d, J = 2.5Hz, 1H), 7.05 (dd, J = 8.6, 2.5 Hz, 1H), 7.02 (s, 1H), 6.70 (d, J = 8.6 Hz, 1H), 6.62 (m, 1H), 6.31-6.26 (m, 1H), 6.15 (d, J = 15.6 Hz, 1H), 2.50 (m, 1H), 2.29 (s, 3H), 1.11 (d, J = 6.6 Hz, 6H)
13
Figure PCTKR2010004966-appb-I000024
 12.92 (bs, 1H), 7.04 (d, J = 2.5 Hz, 1H), 6.93-6.91 (m, 2H), 6.49-6.40 (m, 3H), 6.08 (d, J = 15.1 Hz, 1H), 2.08-2.03 (m, 2H), 2.01 (s, 3H), 1.38 (q, J = 6.7 Hz, 2H), 0.95 (t, J = 6.7 Hz, 3H)
14
Figure PCTKR2010004966-appb-I000025
 7.23 (s, 1H), 7.18 (d, J = 2.5 Hz, 1H), 7.03 (dd, J = 8.6, 2.5 Hz, 1H), 6.67 (d, J = 8.6 Hz, 1H), 6.63 (s, 1H), 6.57-6.53 (m, 1H), 6.32-6.26 (m, 1H), 3.28-3.26 (m, 1H), 2.53-2.51 (m, 1H), 2.30 (s, 3H), 1.10 (d, J = 6.7 Hz, 6H), 0.99 (m, 2H), 0.94 (m, 2H)
15
Figure PCTKR2010004966-appb-I000026
 7.18 (d, J = 2.4 Hz, 1H), 7.05 (dd, J = 8.6, 2.4 Hz, 1H), 7.01 (s, 1H), 6.71 (d, J = 8.6 Hz, 1H), 6.64 (s, 1H), 6.33-6.20 (m, 2H), 2.26-2.20 (m, 2H), 1.50 (q, J = 7.3 Hz, 2H), 0.93 (t, J = 7.3 Hz, 3H)
16
Figure PCTKR2010004966-appb-I000027
 7.22 (s, 1H), 7.17 (d, J = 2.5 Hz, 1H), 7.03 (dd, J = 8.6, 2.5 Hz, 1H), 6.66 (d, J = 8.6 Hz, 1H), 6.64 (s, 1H), 6.61-6.58 (d, J = 15.5 Hz, 1H), 6.34-6.30 (m, 1H), 2.30 (s, 3H), 2.23 (q, J = 7.3 Hz, 2H), 1.52 (m, 2H), 1.13 (m, 2H), 1.00-0.91 (m, 5H)
17
Figure PCTKR2010004966-appb-I000028
 11.12 (bs, 1H), 7.33-7.28 (m, 2H), 7.20-7.11 (m, 2H), 7.02-6.98 (m, 2H), 6.91 (m, 2H), 6.68-6.55 (m, 2H), 5.03 (s, 2H), 2.30 (s, 2H)
18
Figure PCTKR2010004966-appb-I000029
 7.36-7.32 (m, 2H), 7.20 (d, J = 2.3 Hz, 1H), 7.12 (s, 1H), 7.08 (dd, J = 8.6, 2.3 Hz, 1H), 7.06 (dd, J = 8.6, 2.3 Hz, 1H), 7.06 (s, 1H), 6.96 (m, 2H), 6.72 (d, J = 8.6 Hz, 1H), 6.62 (s, 1H), 4.91 (s, 2H), 3.87 (m, 2H), 2.31(s, 1H), 1.78 (m, 2H), 1.37 (q, J = 7.6 Hz, 2H), 0.93 (t, J = 7.6 Hz, 3H)
19
Figure PCTKR2010004966-appb-I000030
 7.35-7.33 (m, 2H), 7.32 (s, 1H), 7.19 (d, J = 2.4 Hz, 1H), 7.06-7.02 (m, 2H), 6.96 (dd, J = 8.6, 2.4 Hz, 2H), 6.70 (s, 1H), 6.68 (d, J = 8.6 Hz, 1H), 5.10 (s, 2H), 3.51-3.48 (m,1H), 2.30 (s, 3H), 1.11-1.05 (m, 4H)
20
Figure PCTKR2010004966-appb-I000031
 7.39-7.35 (m, 3H), 7.32-7.26 (m, 2H), 7.16 (d, J = 2.2 Hz, 1H), 7.14 (s, 1H), 7.06-7.01 (m, 4H), 6.8 (dd, J = 8.6, 2.2 Hz, 2H), 6.72 (d, J = 8.6 Hz, 1H), 6.70 (s, 1H), 5.14 (s, 2H), 4.82 (s, 2H), 2.27 (s, 3H)
21
Figure PCTKR2010004966-appb-I000032
 11.83 (bs, 1H), 8.88 (s, 1H), 7.34 (t, J = 7.5 Hz, 2H), 7.29(d, J = 8.0 Hz, 1H), 7.21 (t, J = 8.3 Hz, 1H), 7.05 (d, J = 8.3 Hz, 2H), 6.97 (d, J = 7.3 Hz, 1H), 6.68-6.58 (m, 2H), 5.03(s, 2H)
22
Figure PCTKR2010004966-appb-I000033
 7.58 (s, 1H), 7.35 (dd, J = 7.4, 1.3 Hz, 1H), 7.32 (dd, J = 7.4, 1.3 Hz, 1H), 7.16 (dd, J = 8.0, 1.4 Hz, 1H), 7.06 (m, 1H), 7.03 (d, J = 1.3 Hz, 1H), 6.98 (m, 2H), 6.75 (dd, J = 8.0, 1.4 Hz, 1H), 6.73 (s, 1H), 5.12 (s, 2H), 3.53 (m, 1H), 1.12 (m, 4H)
23
Figure PCTKR2010004966-appb-I000034
 7.41 (s, 1H), 7.35 (dd, J = 7.4, 1.6 Hz, 1H), 7.33 (dd, J = 7.4, 1.6 Hz, 1H), 7.15 (dd, J = 8.2, 1.3 Hz, 1H), 7.08 (d, J = 8.2 Hz, 1H), 7.05 (d, J = 1.6 Hz, 1H), 6.97 (m, 2H), 6.77 (dd, J = 8.2, 1.3 Hz, 1H), 6.68 (s, 1H), 4.92 (s, 2H), 3.91 (m, 2H), 1.81 (m, 2H), 1.37 (q, J = 7.3 Hz, 2H), 0.95 (t, J = 7.3 Hz, 3H)
24
Figure PCTKR2010004966-appb-I000035
 7.42 (s, 1H), 7.39-7.37 (m, 3H), 7.31 (dd, J = 7.4, 1.2 Hz, 1H), 7.28 (dd, J = 7.4, 1.2 Hz, 1H), 7.16 (dd, J = 8.2, 1.4 Hz, 1H), 7.10-7.07 (m, 3H), 7.05 (d, J = 7.4 Hz, 1H), 6.87-6.85 (m, 2H), 6.78 (dd, J = 8.2, 1.4 Hz, 1H), 6.71 (s, 1H), 5.18 (s, 2H), 4.84 (s, 2H)
25
Figure PCTKR2010004966-appb-I000036
 7.38-7.33 (m, 3H), 7.17 (dd, J = 8.2, 1.2 Hz, 1H), 7.10 (m, 1H), 7.06 (d, J = 1.26 Hz, 1H), 6.97 (d, J = 8.0 Hz, 2H), 6.80 (dd, J = 8.2, 1.2 Hz, 1H), 6.70 (s, 1H), 4.93 (s, 2H), 3.74 (s, 3H)
26
Figure PCTKR2010004966-appb-I000037
 7.38 (s, 1H), 7.37-7.33 (m, 2H), 7.17 (dd, J = 8.2, 1.26 Hz, 1H), 7.10 (d, J = 8.0 Hz, 1H), 7.06 (d, J = 1.26 Hz, 1H), 6.97 (d, J = 8.0 Hz, 2H), 6.79 (dd, J = 8.2, 1.2 Hz, 1H), 6.70 (s, 1H), 4.93 (s, 2H), 3.74 (s, 3H)
27
Figure PCTKR2010004966-appb-I000038
 7.40 (d, J = 2.4 Hz, 1H), 7.36-7.32 (m, 3H), 7.11 (dd, J = 8.7, 2.4 Hz, 1H), 7.07 (m, 1H), 6.97 (d, J = 8.6 Hz, 2H), 8.82 (d, J = 8.7 Hz, 1H), 6.67 (s, 1H), 4.91 (s, 2H), 3.73 (s, 3H)
28
Figure PCTKR2010004966-appb-I000039
 7.41 (d, J = 2.4 Hz, 1H), 7.38 (s, 1H), 7.34-7.32 (m, 2H), 7.11 (dd, J = 8.8, 2.4 Hz, 1H), 7.07 (m, 1H), 6.95 (d, J = 7.7 Hz, 2H), 6.80 (d, J = 8.8 Hz, 1H), 6.66 (s, 1H), 4.91 (s, 2H), 3.90 (m, 2H), 1.82 (m, 2H), 1.38 (q, J = 7.3 Hz, 2H), 0.95 (t, J = 7.3 Hz, 3H)
29
Figure PCTKR2010004966-appb-I000040
 7.39-7.37 (m, 5H), 7.30 (d, J = 7.7 Hz, 2H), 7.12 (dd, J = 8.7, 2.4 Hz, 1H), 7.10-7.07 (m, 2H), 7.07 (m, 1H), 6.86 (d, J = 7.7 Hz, 2H), 6.81 (d, 1H), 6.70 (s, 1H), 5.17 (s, 2H), 4.83 (s, 2H)
30
Figure PCTKR2010004966-appb-I000041
 7.55 (s, 1H), 7.40 (d, J = 2.5 Hz, 1H), 7.36-7.31 (m, 2H), 7.10 (dd, J = 8.7, 2.5 Hz, 1H), 7.06-7.03 (m, 1H), 6.97 (d, J = 8.7 Hz, 2H), 6.79 (d, J = 8.7 Hz, 1H), 6.71 (s, 1H), 5.11 (s, 2H), 3.51 (m, 1H), 1.11 (m, 4H)
31
Figure PCTKR2010004966-appb-I000042
 11.73 (s, 0.6H, NH), 10.88 (s, 0.4H, OH), 7.94 (s, 0.4H), 7.60 (s, 0.6H), 7.33 (m, 2H), 7.02-6.84 (m, 5.5H), 6.50 (m, 1H), 6.38 (m, 0.5H), 5.04-5.00 (s, 2H), 2.21 (s, 6H)
32
Figure PCTKR2010004966-appb-I000043
 7.35-7.28 (m, 5H), 7.05-6.98 (m, 4H), 6.92 (s, 1H), 6.90 (m, 1H), 6.8 3(dd, J = 8.1, 4.6 Hz, 2H), 6.77 (d, J = 8.1 Hz, 1H), 6.69 (s, 1H), 5.08 (s, 2H), 4.78 (s, 2H), 2.27 (s, 3H), 2.04 (s, 3H)
33
Figure PCTKR2010004966-appb-I000044
 7.35-7.31 (m, 2H), 7.06-7.03 (m, 2H), 6.97 (m, 1H), 6.95 (dd, J = 8.1, 2.3 Hz, 2H), 6.85 (s, 1H), 6.80 (d, J = 8.1Hz, 1H), 6.66 (s, 1H), 4.89 (s, 2H), 3.63 (s, 3H), 2.30 (s, 3H), 2.24 (s, 3H)
34
Figure PCTKR2010004966-appb-I000045
 7.35-7.31 (m, 2H), 7.06-7.04 (m, 2H), 6.95 (m, 1H), 6.93 (dd, J = 8.1, 2.5 Hz, 2H), 6.89 (d, 1H), 6.78 (d, J = 8.1 Hz, 1H), 6.64 (s, 1H), 4.89 (s, 2H), 3.83 (m, 2H), 2.30 (s, 3H), 2.27 (s, 3H), 1.72 (m, 2H), 1.31 (q, J = 7.49 Hz, 2H), 0.90 (t, J = 7.4 Hz, 3H)
35
Figure PCTKR2010004966-appb-I000046
 7.31-7.27 (m, 2H), 7.09(s, 1H), 7.01-6.99 (m, 2H), 6.95 (m, 2H), 6.90 (dd, J = 8.1, 4.2 Hz, 1H), 6.71 (d, J = 8.1 Hz, 1H), 6.65 (s, 1H), 5.06 (s, 2H), 3.42 (m, 1H), 2.26 (s, 3H), 2.23 (s, 3H), 1.02-0.99 (m, 4H)
TABLE 2
EXAMPLE rescue NMR data
11
Figure PCTKR2010004966-appb-I000022
 7.59 (s, 1H), 7.26 (d, J = 2.5 Hz, 1H), 7.06 (dd, J = 8.6, 2.5 Hz, 1H), 6.74 (d, J = 8.6 Hz, 1H), 6.61 (dd, J = 15.8, 6.8 Hz, 1H), 6.29 (s, 1H), 6.00 (dd, J = 15.8, 1.3 Hz, 1H), 2.30 (s, 3H), 1.14 (d, J = 6.7 Hz, 6H)
12
Figure PCTKR2010004966-appb-I000023
 7.17 (d, J = 2.5 Hz, 1H), 7.05 (dd, J = 8.6, 2.5 Hz, 1H), 7.02 (s, 1H), 6.70 (d, J = 8.6 Hz, 1H), 6.62 (m, 1H ), 6.31-6.26 (m, 1H), 6.15 (d, J = 15.6 Hz, 1H), 2.50 (m, 1H), 2.29 (s, 3H), 1.11 (d, J = 6.6 Hz, 6H)
13
Figure PCTKR2010004966-appb-I000024
 12.92 (bs, 1H), 7.04 (d, J = 2.5 Hz, 1H), 6.93-6.91 (m, 2H), 6.49-6.40 (m, 3H), 6.08 (d, J = 15.1 Hz, 1H), 2.08 -2.03 (m, 2H), 2.01 (s, 3H), 1.38 (q, J = 6.7 Hz, 2H), 0.95 (t, J = 6.7 Hz, 3H)
14
Figure PCTKR2010004966-appb-I000025
 7.23 (s, 1H), 7.18 (d, J = 2.5 Hz, 1H), 7.03 (dd, J = 8.6, 2.5 Hz, 1H), 6.67 (d, J = 8.6 Hz, 1H), 6.63 (s, 1H ), 6.57-6.53 (m, 1H), 6.32-6.26 (m, 1H), 3.28-3.26 (m, 1H), 2.53-2.51 (m, 1H), 2.30 (s, 3H), 1.10 (d, J = 6.7 Hz, 6H), 0.99 (m, 2H), 0.94 (m, 2H)
15
Figure PCTKR2010004966-appb-I000026
 7.18 (d, J = 2.4 Hz, 1H), 7.05 (dd, J = 8.6, 2.4 Hz, 1H), 7.01 (s, 1H), 6.71 (d, J = 8.6 Hz, 1H), 6.64 (s, 1H ), 6.33-6.20 (m, 2H), 2.26-2.20 (m, 2H), 1.50 (q, J = 7.3 Hz, 2H), 0.93 (t, J = 7.3 Hz, 3H)
16
Figure PCTKR2010004966-appb-I000027
 7.22 (s, 1H), 7.17 (d, J = 2.5 Hz, 1H), 7.03 (dd, J = 8.6, 2.5 Hz, 1H), 6.66 (d, J = 8.6 Hz, 1H), 6.64 (s, 1H ), 6.61-6.58 (d, J = 15.5 Hz, 1H), 6.34-6.30 (m, 1H), 2.30 (s, 3H), 2.23 (q, J = 7.3 Hz, 2H), 1.52 (m, 2H) , 1.13 (m, 2H), 1.00-0.91 (m, 5H)
17
Figure PCTKR2010004966-appb-I000028
 11.12 (bs, 1H), 7.33-7.28 (m, 2H), 7.20-7.11 (m, 2H), 7.02-6.98 (m, 2H), 6.91 (m, 2H), 6.68-6.55 (m, 2H), 5.03 (s, 2H), 2.30 (s, 2H)
18
Figure PCTKR2010004966-appb-I000029
 7.36-7.32 (m, 2H), 7.20 (d, J = 2.3 Hz, 1H), 7.12 (s, 1H), 7.08 (dd, J = 8.6, 2.3 Hz, 1H), 7.06 (dd, J = 8.6, 2.3 Hz, 1H), 7.06 (s, 1H), 6.96 (m, 2H), 6.72 (d, J = 8.6 Hz, 1H), 6.62 (s, 1H), 4.91 (s, 2H), 3.87 (m, 2H), 2.31 (s, 1H), 1.78 (m, 2H), 1.37 (q, J = 7.6 Hz, 2H), 0.93 (t, J = 7.6 Hz, 3H)
19
Figure PCTKR2010004966-appb-I000030
 7.35-7.33 (m, 2H), 7.32 (s, 1H), 7.19 (d, J = 2.4 Hz, 1H), 7.06-7.02 (m, 2H), 6.96 (dd, J = 8.6, 2.4 Hz, 2H) , 6.70 (s, 1H), 6.68 (d, J = 8.6 Hz, 1H), 5.10 (s, 2H), 3.51-3.48 (m, 1H), 2.30 (s, 3H), 1.11-1.05 (m, 4H )
20
Figure PCTKR2010004966-appb-I000031
 7.39-7.35 (m, 3H), 7.32-7.26 (m, 2H), 7.16 (d, J = 2.2 Hz, 1H), 7.14 (s, 1H), 7.06-7.01 (m, 4H), 6.8 (dd, J = 8.6, 2.2 Hz, 2H), 6.72 (d, J = 8.6 Hz, 1H), 6.70 (s, 1H), 5.14 (s, 2H), 4.82 (s, 2H), 2.27 (s, 3H)
21
Figure PCTKR2010004966-appb-I000032
 11.83 (bs, 1H), 8.88 (s, 1H), 7.34 (t, J = 7.5 Hz, 2H), 7.29 (d, J = 8.0 Hz, 1H), 7.21 (t, J = 8.3 Hz, 1H), 7.05 (d, J = 8.3 Hz, 2H), 6.97 (d, J = 7.3 Hz, 1H), 6.68-6.58 (m, 2H), 5.03 (s, 2H)
22
Figure PCTKR2010004966-appb-I000033
 7.58 (s, 1H), 7.35 (dd, J = 7.4, 1.3 Hz, 1H), 7.32 (dd, J = 7.4, 1.3 Hz, 1H), 7.16 (dd, J = 8.0, 1.4 Hz, 1H), 7.06 (m, 1H), 7.03 (d, J = 1.3 Hz, 1H), 6.98 (m, 2H), 6.75 (dd, J = 8.0, 1.4 Hz, 1H), 6.73 (s, 1H), 5.12 (s, 2H), 3.53 (m, 1H), 1.12 (m, 4H)
23
Figure PCTKR2010004966-appb-I000034
 7.41 (s, 1H), 7.35 (dd, J = 7.4, 1.6 Hz, 1H), 7.33 (dd, J = 7.4, 1.6 Hz, 1H), 7.15 (dd, J = 8.2, 1.3 Hz, 1H), 7.08 (d, J = 8.2 Hz, 1H), 7.05 (d, J = 1.6 Hz, 1H), 6.97 (m, 2H), 6.77 (dd, J = 8.2, 1.3 Hz, 1H), 6.68 (s, 1H) , 4.92 (s, 2H), 3.91 (m, 2H), 1.81 (m, 2H), 1.37 (q, J = 7.3 Hz, 2H), 0.95 (t, J = 7.3 Hz, 3H)
24
Figure PCTKR2010004966-appb-I000035
 7.42 (s, 1H), 7.39-7.37 (m, 3H), 7.31 (dd, J = 7.4, 1.2 Hz, 1H), 7.28 (dd, J = 7.4, 1.2 Hz, 1H), 7.16 (dd, J = 8.2, 1.4 Hz, 1H), 7.10-7.07 (m, 3H), 7.05 (d, J = 7.4 Hz, 1H), 6.87-6.85 (m, 2H), 6.78 (dd, J = 8.2, 1.4 Hz, 1H ), 6.71 (s, 1H), 5.18 (s, 2H), 4.84 (s, 2H)
25
Figure PCTKR2010004966-appb-I000036
 7.38-7.33 (m, 3H), 7.17 (dd, J = 8.2, 1.2 Hz, 1H), 7.10 (m, 1H), 7.06 (d, J = 1.26 Hz, 1H), 6.97 (d, J = 8.0 Hz , 2H), 6.80 (dd, J = 8.2, 1.2 Hz, 1H), 6.70 (s, 1H), 4.93 (s, 2H), 3.74 (s, 3H)
26
Figure PCTKR2010004966-appb-I000037
 7.38 (s, 1H), 7.37-7.33 (m, 2H), 7.17 (dd, J = 8.2, 1.26 Hz, 1H), 7.10 (d, J = 8.0 Hz, 1H), 7.06 (d, J = 1.26 Hz , 1H), 6.97 (d, J = 8.0 Hz, 2H), 6.79 (dd, J = 8.2, 1.2 Hz, 1H), 6.70 (s, 1H), 4.93 (s, 2H), 3.74 (s, 3H)
27
Figure PCTKR2010004966-appb-I000038
 7.40 (d, J = 2.4 Hz, 1H), 7.36-7.32 (m, 3H), 7.11 (dd, J = 8.7, 2.4 Hz, 1H), 7.07 (m, 1H), 6.97 (d, J = 8.6 Hz , 2H), 8.82 (d, J = 8.7 Hz, 1H), 6.67 (s, 1H), 4.91 (s, 2H), 3.73 (s, 3H)
28
Figure PCTKR2010004966-appb-I000039
 7.41 (d, J = 2.4 Hz, 1H), 7.38 (s, 1H), 7.34-7.32 (m, 2H), 7.11 (dd, J = 8.8, 2.4 Hz, 1H), 7.07 (m, 1H), 6.95 (d, J = 7.7 Hz, 2H), 6.80 (d, J = 8.8 Hz, 1H), 6.66 (s, 1H), 4.91 (s, 2H), 3.90 (m, 2H), 1.82 (m, 2H) , 1.38 (q, J = 7.3 Hz, 2H), 0.95 (t, J = 7.3 Hz, 3H)
29
Figure PCTKR2010004966-appb-I000040
 7.39-7.37 (m, 5H), 7.30 (d, J = 7.7 Hz, 2H), 7.12 (dd, J = 8.7, 2.4 Hz, 1H), 7.10-7.07 (m, 2H), 7.07 (m, 1H) , 6.86 (d, J = 7.7 Hz, 2H), 6.81 (d, 1H), 6.70 (s, 1H), 5.17 (s, 2H), 4.83 (s, 2H)
30
Figure PCTKR2010004966-appb-I000041
 7.55 (s, 1H), 7.40 (d, J = 2.5 Hz, 1H), 7.36-7.31 (m, 2H), 7.10 (dd, J = 8.7, 2.5 Hz, 1H), 7.06-7.03 (m, 1H) , 6.97 (d, J = 8.7 Hz, 2H), 6.79 (d, J = 8.7 Hz, 1H), 6.71 (s, 1H), 5.11 (s, 2H), 3.51 (m, 1H), 1.11 (m, 4H)
31
Figure PCTKR2010004966-appb-I000042
 11.73 (s, 0.6H, NH), 10.88 (s, 0.4H, OH), 7.94 (s, 0.4H), 7.60 (s, 0.6H), 7.33 (m, 2H), 7.02-6.84 (m, 5.5 H), 6.50 (m, 1H), 6.38 (m, 0.5H), 5.04-5.00 (s, 2H), 2.21 (s, 6H)
32
Figure PCTKR2010004966-appb-I000043
 7.35-7.28 (m, 5H), 7.05-6.98 (m, 4H), 6.92 (s, 1H), 6.90 (m, 1H), 6.8 3 (dd, J = 8.1, 4.6 Hz, 2H), 6.77 (d , J = 8.1 Hz, 1H), 6.69 (s, 1H), 5.08 (s, 2H), 4.78 (s, 2H), 2.27 (s, 3H), 2.04 (s, 3H)
33
Figure PCTKR2010004966-appb-I000044
 7.35-7.31 (m, 2H), 7.06-7.03 (m, 2H), 6.97 (m, 1H), 6.95 (dd, J = 8.1, 2.3 Hz, 2H), 6.85 (s, 1H), 6.80 (d, J = 8.1 Hz, 1H), 6.66 (s, 1H), 4.89 (s, 2H), 3.63 (s, 3H), 2.30 (s, 3H), 2.24 (s, 3H)
34
Figure PCTKR2010004966-appb-I000045
 7.35-7.31 (m, 2H), 7.06-7.04 (m, 2H), 6.95 (m, 1H), 6.93 (dd, J = 8.1, 2.5 Hz, 2H), 6.89 (d, 1H), 6.78 (d, J = 8.1 Hz, 1H), 6.64 (s, 1H), 4.89 (s, 2H), 3.83 (m, 2H), 2.30 (s, 3H), 2.27 (s, 3H), 1.72 (m, 2H), 1.31 (q, J = 7.49 Hz, 2H), 0.90 (t, J = 7.4 Hz, 3H)
35
Figure PCTKR2010004966-appb-I000046
 7.31-7.27 (m, 2H), 7.09 (s, 1H), 7.01-6.99 (m, 2H), 6.95 (m, 2H), 6.90 (dd, J = 8.1, 4.2 Hz, 1H), 6.71 (d, J = 8.1 Hz, 1H), 6.65 (s, 1H), 5.06 (s, 2H), 3.42 (m, 1H), 2.26 (s, 3H), 2.23 (s, 3H), 1.02-0.99 (m, 4H )
이하에는 상기 실시예 4와 같은 방법으로 4-피리돈 유도체를 합성하였으며, 그 구조 및 1H NMR 데이터를 하기 표 3에 나타내었다.Hereinafter, 4-pyridone derivatives were synthesized in the same manner as in Example 4, and the structure and 1 H NMR data thereof are shown in Table 3 below.
표 3
실시예 구조 NMR 데이터
36
Figure PCTKR2010004966-appb-I000047
 8.40 (d, J = 2.4 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.41 (s, 1H), 7.33 (d, J = 7.8 Hz, 1H), 7.31 (s, 1H), 7.22-7.26 (m, 3H), 7.18 (d, J = 7.7 Hz, 1H), 6.46 (d, J = 7.8 Hz, 1H), 5.01 (s, 2H)
37
Figure PCTKR2010004966-appb-I000048
 7.77 (d, J = 7.7 Hz, 1H), 7.53 (d, J = 8.2 Hz, 2H), 7.43 (d, J = 8.0 Hz, 1H), 7.29-7.34 (m, 2H), 6.95-7.01 (m, 3H), 6.45 (d, J = 7.4 Hz, 1H), 6.22 (bs, 1H), 6.12 (s, 1H), 4.85 (s, 2H)
38
Figure PCTKR2010004966-appb-I000049
 7.75 (d, J = 7.7 Hz, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.54 (t, J = 7.3 Hz, 1H), 7.38-7.42 (m, 2H), 7.30-7.34 (m, 2H), 6.96 (s, 1H), 6.46 (dd, J = 2.5, 7.4 Hz, 1H), 6.18 (s, 1H), 6.11 (s, 1H), 4.95 (s, 2H)
39
Figure PCTKR2010004966-appb-I000050
 7.78 (d, J = 7.8 Hz, 1H), 7.40 (d, J = 8.3 Hz, 3H), 7.33 (dd, J = 2.3, 7.5 Hz, 1H), 7.05 (d, J = 8.3 Hz, 3H), 6.42-6.44 (m, 2H), 6.83 (d, J = 5.4 Hz, 1H), 4.85 (s, 2H), 1.32 (s, 9H)
40
Figure PCTKR2010004966-appb-I000051
 7.62 (d, J = 7.7 Hz, 1H), 7.31-7.37 (m, 4H), 7.19 (t, J = 7.9 Hz, 2H), 6.97 (d, J = 7.2 Hz, 1H), 6.91 (s, 1H), 6.78 (s, 1H), 6.48 (d, J = 7.4 Hz, 1H), 4.98 (s, 2H)
41
Figure PCTKR2010004966-appb-I000052
 7.49 (d, J = 8.3 Hz, 1H), 7.33 (d, J = 8.0 Hz, 3H), 7.25 (s, 2H), 7.17-7.21 (m, 1H), 7.02 (d, J = 7.9 Hz, 1H), 6.87 (q, J = 1.1 Hz, 1H), 6.77 (s, 1H), 6.45 (d, J = 7.5 Hz, 1H), 6.08 (d, J = 1.7 Hz, 1H), 4.86 (s, 2H)
42
Figure PCTKR2010004966-appb-I000053
 7.50 (d, J = 7.4 Hz, 2H), 7.32 (d, J = 7.8 Hz, 3H), 7.19 (t, J = 10.0 Hz, 1H), 6.97 (d, J = 8.0 Hz, 2H), 6.85 (s, 1H), 6.76 (s, 1H), 6.64 (d, J = 7.4 Hz, 1H), 6.11 (s, 1H), 4.84 (s, 2H)
43
Figure PCTKR2010004966-appb-I000054
 7.42 (d, J = 7.9 Hz, 1H), 7.28-7.36 (m, 5H), 7.16-7.21 (1H), 7.00 (d, J = 7.7 Hz, 1H), 6.89 (t, J = 1.1 Hz, 1H), 6.77 (s, 1H), 6.45 (dd, J = 1.3, 7.5 Hz, 1H), 6.24 (bs, 1H), 4.97 (d, J = 3.2 Hz, 2H)
44
Figure PCTKR2010004966-appb-I000055
 7.29-7.36 (m, 5H), 7.19 (t, J = 8.0 Hz, 1H), 7.09 (s, 1H), 6.98 (d, J = 6.8 Hz, 1H), 6.87 (d, J = 1.2 Hz, 1H), 6.77 (s, 1H), 6.45 (dd, J = 2.0, 7.5 Hz, 1H), 6.08 (s, 1H), 4.86 (s, 2H)
45
Figure PCTKR2010004966-appb-I000056
 7.29-7.36 (m, 5H), 7.19 (dd, J = 1.1, 7.6 Hz, 1H), 7.03 (d, J = 8.2 Hz, 2H), 6.85 (d, J = 1.1 Hz, 1H), 6.76 (s, 1H), 6.44 (dd, J = 1.8, 7.5 Hz, 1H), 6.14 (bs, 1H), 4.86 (s, 2H)
46
Figure PCTKR2010004966-appb-I000057
 7.75 (d, J = 7.7 Hz, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.54 (t, J = 7.3 Hz, 1H), 7.38-7.42 (m, 2H), 7.30-7.34 (m, 2H), 6.96 (s, 1H), 6.46 (dd, J = 2.5, 7.4 Hz, 1H), 6.18 (s, 1H), 6.11 (s, 1H), 4.95 (s, 2H)
47
Figure PCTKR2010004966-appb-I000058
 7.37-7.35 (m, 4H), 7.21 (d, J = 7.4 Hz, 1H), 7.05 (m, 1H), 6.93-6.92 (m, 1H), 6.86 (d, J = 8.3 Hz, 1H), 6.76 (s, 1H), 6.40 (d, J = 7.4 Hz, 1H), 4.82 (d, J = 5.9 Hz, 2H), 3.73 (s, 3H)
48
Figure PCTKR2010004966-appb-I000059
 7.34 (d, J = 10.3 Hz, 3H), 7.29 (s, 1H), 7.18-7.23 (m, 1H), 6.88 (t, J = 1.5 Hz, 1H), 6.79 (s, 1H), 6.98 (d, J = 10.2 Hz, 1H), 6.60 (s, 1H), 6.47 (d, J = 9.9 Hz, 1H), 6.34 (bs, 1H), 4.86 (s, 2H), 3.79 (s, 3H)
49
Figure PCTKR2010004966-appb-I000060
 7.30-7.33 (m, 3H), 7.17 (t, J = 8.0 Hz, 1H), 7.04 (d, J = 8.5 Hz, 2H), 6.86-6.89 (m, 3H), 6.75 (s, 1H), 6.42 (d, J = 7.4 Hz, 1H), 4.82 (s, 2H), 3.81 (s, 3H)
50
Figure PCTKR2010004966-appb-I000061
 7.32 (d, J = 7.7 Hz, 3H), 7.24 (d, J = 7.6 Hz, 1H), 7.15-7.20 (m, 2H), 6.97 (s, 1H), 6.99 (s, 2H), 6.78 (s, 1H), 6.44 (d, J = 7.6 Hz, 1H), 6.33 (s, 1H), 4.84 (s, 2H), 2.33 (s, 3H)
51
Figure PCTKR2010004966-appb-I000062
 8.25 (d, J = 8.7 Hz, 2H), 7.33 (d, J = 2.2 Hz, 1H), 7.31 (d, J = 2.6 Hz, 2H), 6.91-6.92 (m, 1H), 6.76 (s, 1H), 6.47 (d, J = 7.5 Hz, 1H), 5.84 (s, 1H), 5.02 (s, 2H)
52
Figure PCTKR2010004966-appb-I000063
 7.41 (d, J = 11.9 Hz, 2H), 7.31 (d, J = 7.8 Hz, 3H), 7.18 (t, J = 8.1 Hz, 1H), 7.03 (d, J = 7.8 Hz, 2H), 6.88 (s, 1H), 6.78 (s, 1H), 6.46 (d, J = 6.7 Hz, 1H), 6.33 (br s, 1H), 4.85 (s, 2H), 1.32 (s, 9H)
53
Figure PCTKR2010004966-appb-I000064
 7.44 (dd, J = 7.2, 2.2 Hz, 1H), 7.40 (s, 1H), 7.38 (s, 1H), 7.27 (s, 1H), 7.22 (t, J = 8.0 Hz, 1H), 6.94-6.98 (m, 3H), 6.74 (s, 1H), 6.41 (d, J = 7.5 Hz, 1H), 6.20 (s, 1H), 4.91 (s, 2H)
54
Figure PCTKR2010004966-appb-I000065
 7.45 (d, J = 8.3 Hz, 1H), 7.32 (d, J = 7.9 Hz, 3H), 7.17-7.21 (m, 2H), 6.93 (d, J = 6.9 Hz, 1H), 6.87 (d, J = 1.0 Hz, 1H), 6.75 (s, 1H), 6.43 (d, J = 7.4 Hz, 1H), 5.96 (s, 1H), 4.85 (s, 2H)
55
Figure PCTKR2010004966-appb-I000066
 7.50 (d, J = 7.4 Hz, 2H), 7.32 (d, J = 7.8 Hz, 3H), 7.19 (t, J = 10.0 Hz, 1H), 6.97 (d, J = 8.0 Hz, 2H), 6.85 (s, 1H), 6.76 (s, 1H), 6.64 (d, J = 7.4 Hz, 1H), 6.11 (s, 3H), 4.84 (s, 3H)
56
Figure PCTKR2010004966-appb-I000067
 7.47 (dd, J = 2.2 Hz, 1H), 7.26-7.31 (m, 3H), 7.14-7.19 (m, 1H), 7.24 (t, J = 1.1 Hz, 1H), 6.97 (s, 1H), 6.71 (s, 1H), 6.40 (d, J = 4.2 Hz, 1H), 6.28-6.35 (bs, 1H), 4.92 (s, 2H), 2.65 (s, 3H)
57
Figure PCTKR2010004966-appb-I000068
 7.77 (t, J = 1.2 Hz, 1H), 7.62 (dd, J = 2.4, 7.4 Hz, 1H), 7.28 (d, J = 7.6 Hz, 2H), 7.17-7.21 (m, 1H), 6.22 (d, J = 4.3 Hz, 1H), 6.10 (d, J = 7.4 Hz, 1H), 5.95 (d, J = 7.4 Hz, 1H), 5.04 (d, J =6.6 Hz, 2H), 2.42 (s, 3H), 2.09 (s, 3H)
58
Figure PCTKR2010004966-appb-I000069
 9.11 (s, 1H), 8.99 (d, J = 7.2 Hz, 1H), 7.96 (s, 1H), 7.71 (d, J = 1.4 Hz, 1H), 7.62 (d, J = 7.1 Hz, 1H), 7.49 (d, J = 7.6 Hz, 2H), 7.31 (t, J = 7.9 Hz, 1H), 6.92 (d, J = 2.9 Hz, 1H), 6.56 (s, 1H), 6.50 (s, 1H), 5.65 (d, J = 3.0 Hz, 2H), 3.89 (s, 3H)
59
Figure PCTKR2010004966-appb-I000070
 7.31-7.35 (m, 7H), 7.19 (dd, J = 1.5, 7.7 Hz, 2H), 6.97-7.07 (m, 5H), 6.75 (d, J =1.1 Hz, 1H), 6.70 (s, 1H), 6.39 (dd, J = 1.9, 7.6 Hz, 1H), 6.27 (s, 1H), 6.22 (s, 1H)
TABLE 3
EXAMPLE rescue NMR data
36
Figure PCTKR2010004966-appb-I000047
 8.40 (d, J = 2.4 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.41 (s, 1H), 7.33 (d, J = 7.8 Hz, 1H), 7.31 (s, 1H), 7.22-7.26 (m, 3H), 7.18 (d, J = 7.7 Hz, 1H), 6.46 (d, J = 7.8 Hz, 1H), 5.01 (s, 2H)
37
Figure PCTKR2010004966-appb-I000048
 7.77 (d, J = 7.7 Hz, 1H), 7.53 (d, J = 8.2 Hz, 2H), 7.43 (d, J = 8.0 Hz, 1H), 7.29-7.34 (m, 2H), 6.95-7.01 (m , 3H), 6.45 (d, J = 7.4 Hz, 1H), 6.22 (bs, 1H), 6.12 (s, 1H), 4.85 (s, 2H)
38
Figure PCTKR2010004966-appb-I000049
 7.75 (d, J = 7.7 Hz, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.54 (t, J = 7.3 Hz, 1H), 7.38-7.42 (m, 2H), 7.30-7.34 (m , 2H), 6.96 (s, 1H), 6.46 (dd, J = 2.5, 7.4 Hz, 1H), 6.18 (s, 1H), 6.11 (s, 1H), 4.95 (s, 2H)
39
Figure PCTKR2010004966-appb-I000050
 7.78 (d, J = 7.8 Hz, 1H), 7.40 (d, J = 8.3 Hz, 3H), 7.33 (dd, J = 2.3, 7.5 Hz, 1H), 7.05 (d, J = 8.3 Hz, 3H), 6.42-6.44 (m, 2H), 6.83 (d, J = 5.4 Hz, 1H), 4.85 (s, 2H), 1.32 (s, 9H)
40
Figure PCTKR2010004966-appb-I000051
 7.62 (d, J = 7.7 Hz, 1H), 7.31-7.37 (m, 4H), 7.19 (t, J = 7.9 Hz, 2H), 6.97 (d, J = 7.2 Hz, 1H), 6.91 (s, 1H ), 6.78 (s, 1H), 6.48 (d, J = 7.4 Hz, 1H), 4.98 (s, 2H)
41
Figure PCTKR2010004966-appb-I000052
 7.49 (d, J = 8.3 Hz, 1H), 7.33 (d, J = 8.0 Hz, 3H), 7.25 (s, 2H), 7.17-7.21 (m, 1H), 7.02 (d, J = 7.9 Hz, 1H ), 6.87 (q, J = 1.1 Hz, 1H), 6.77 (s, 1H), 6.45 (d, J = 7.5 Hz, 1H), 6.08 (d, J = 1.7 Hz, 1H), 4.86 (s, 2H )
42
Figure PCTKR2010004966-appb-I000053
 7.50 (d, J = 7.4 Hz, 2H), 7.32 (d, J = 7.8 Hz, 3H), 7.19 (t, J = 10.0 Hz, 1H), 6.97 (d, J = 8.0 Hz, 2H), 6.85 ( s, 1H), 6.76 (s, 1H), 6.64 (d, J = 7.4 Hz, 1H), 6.11 (s, 1H), 4.84 (s, 2H)
43
Figure PCTKR2010004966-appb-I000054
 7.42 (d, J = 7.9 Hz, 1H), 7.28-7.36 (m, 5H), 7.16-7.21 (1H), 7.00 (d, J = 7.7 Hz, 1H), 6.89 (t, J = 1.1 Hz, 1H ), 6.77 (s, 1H), 6.45 (dd, J = 1.3, 7.5 Hz, 1H), 6.24 (bs, 1H), 4.97 (d, J = 3.2 Hz, 2H)
44
Figure PCTKR2010004966-appb-I000055
 7.29-7.36 (m, 5H), 7.19 (t, J = 8.0 Hz, 1H), 7.09 (s, 1H), 6.98 (d, J = 6.8 Hz, 1H), 6.87 (d, J = 1.2 Hz, 1H ), 6.77 (s, 1H), 6.45 (dd, J = 2.0, 7.5 Hz, 1H), 6.08 (s, 1H), 4.86 (s, 2H)
45
Figure PCTKR2010004966-appb-I000056
 7.29-7.36 (m, 5H), 7.19 (dd, J = 1.1, 7.6 Hz, 1H), 7.03 (d, J = 8.2 Hz, 2H), 6.85 (d, J = 1.1 Hz, 1H), 6.76 (s , 1H), 6.44 (dd, J = 1.8, 7.5 Hz, 1H), 6.14 (bs, 1H), 4.86 (s, 2H)
46
Figure PCTKR2010004966-appb-I000057
 7.75 (d, J = 7.7 Hz, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.54 (t, J = 7.3 Hz, 1H), 7.38-7.42 (m, 2H), 7.30-7.34 (m , 2H), 6.96 (s, 1H), 6.46 (dd, J = 2.5, 7.4 Hz, 1H), 6.18 (s, 1H), 6.11 (s, 1H), 4.95 (s, 2H)
47
Figure PCTKR2010004966-appb-I000058
 7.37-7.35 (m, 4H), 7.21 (d, J = 7.4 Hz, 1H), 7.05 (m, 1H), 6.93-6.92 (m, 1H), 6.86 (d, J = 8.3 Hz, 1H), 6.76 (s, 1H), 6.40 (d, J = 7.4 Hz, 1H), 4.82 (d, J = 5.9 Hz, 2H), 3.73 (s, 3H)
48
Figure PCTKR2010004966-appb-I000059
 7.34 (d, J = 10.3 Hz, 3H), 7.29 (s, 1H), 7.18-7.23 (m, 1H), 6.88 (t, J = 1.5 Hz, 1H), 6.79 (s, 1H), 6.98 (d , J = 10.2 Hz, 1H), 6.60 (s, 1H), 6.47 (d, J = 9.9 Hz, 1H), 6.34 (bs, 1H), 4.86 (s, 2H), 3.79 (s, 3H)
49
Figure PCTKR2010004966-appb-I000060
 7.30-7.33 (m, 3H), 7.17 (t, J = 8.0 Hz, 1H), 7.04 (d, J = 8.5 Hz, 2H), 6.86-6.89 (m, 3H), 6.75 (s, 1H), 6.42 (d, J = 7.4 Hz, 1H), 4.82 (s, 2H), 3.81 (s, 3H)
50
Figure PCTKR2010004966-appb-I000061
 7.32 (d, J = 7.7 Hz, 3H), 7.24 (d, J = 7.6 Hz, 1H), 7.15-7.20 (m, 2H), 6.97 (s, 1H), 6.99 (s, 2H), 6.78 (s , 1H), 6.44 (d, J = 7.6 Hz, 1H), 6.33 (s, 1H), 4.84 (s, 2H), 2.33 (s, 3H)
51
Figure PCTKR2010004966-appb-I000062
 8.25 (d, J = 8.7 Hz, 2H), 7.33 (d, J = 2.2 Hz, 1H), 7.31 (d, J = 2.6 Hz, 2H), 6.91-6.92 (m, 1H), 6.76 (s, 1H ), 6.47 (d, J = 7.5 Hz, 1H), 5.84 (s, 1H), 5.02 (s, 2H)
52
Figure PCTKR2010004966-appb-I000063
 7.41 (d, J = 11.9 Hz, 2H), 7.31 (d, J = 7.8 Hz, 3H), 7.18 (t, J = 8.1 Hz, 1H), 7.03 (d, J = 7.8 Hz, 2H), 6.88 ( s, 1H), 6.78 (s, 1H), 6.46 (d, J = 6.7 Hz, 1H), 6.33 (br s, 1H), 4.85 (s, 2H), 1.32 (s, 9H)
53
Figure PCTKR2010004966-appb-I000064
 7.44 (dd, J = 7.2, 2.2 Hz, 1H), 7.40 (s, 1H), 7.38 (s, 1H), 7.27 (s, 1H), 7.22 (t, J = 8.0 Hz, 1H), 6.94-6.98 (m, 3H), 6.74 (s, 1H), 6.41 (d, J = 7.5 Hz, 1H), 6.20 (s, 1H), 4.91 (s, 2H)
54
Figure PCTKR2010004966-appb-I000065
 7.45 (d, J = 8.3 Hz, 1H), 7.32 (d, J = 7.9 Hz, 3H), 7.17-7.21 (m, 2H), 6.93 (d, J = 6.9 Hz, 1H), 6.87 (d, J = 1.0 Hz, 1H), 6.75 (s, 1H), 6.43 (d, J = 7.4 Hz, 1H), 5.96 (s, 1H), 4.85 (s, 2H)
55
Figure PCTKR2010004966-appb-I000066
 7.50 (d, J = 7.4 Hz, 2H), 7.32 (d, J = 7.8 Hz, 3H), 7.19 (t, J = 10.0 Hz, 1H), 6.97 (d, J = 8.0 Hz, 2H), 6.85 ( s, 1H), 6.76 (s, 1H), 6.64 (d, J = 7.4 Hz, 1H), 6.11 (s, 3H), 4.84 (s, 3H)
56
Figure PCTKR2010004966-appb-I000067
 7.47 (dd, J = 2.2 Hz, 1H), 7.26-7.31 (m, 3H), 7.14-7.19 (m, 1H), 7.24 (t, J = 1.1 Hz, 1H), 6.97 (s, 1H), 6.71 (s, 1H), 6.40 (d, J = 4.2 Hz, 1H), 6.28-6.35 (bs, 1H), 4.92 (s, 2H), 2.65 (s, 3H)
57
Figure PCTKR2010004966-appb-I000068
 7.77 (t, J = 1.2 Hz, 1H), 7.62 (dd, J = 2.4, 7.4 Hz, 1H), 7.28 (d, J = 7.6 Hz, 2H), 7.17-7.21 (m, 1H), 6.22 (d , J = 4.3 Hz, 1H), 6.10 (d, J = 7.4 Hz, 1H), 5.95 (d, J = 7.4 Hz, 1H), 5.04 (d, J = 6.6 Hz, 2H), 2.42 (s, 3H ), 2.09 (s, 3H)
58
Figure PCTKR2010004966-appb-I000069
 9.11 (s, 1H), 8.99 (d, J = 7.2 Hz, 1H), 7.96 (s, 1H), 7.71 (d, J = 1.4 Hz, 1H), 7.62 (d, J = 7.1 Hz, 1H), 7.49 (d, J = 7.6 Hz, 2H), 7.31 (t, J = 7.9 Hz, 1H), 6.92 (d, J = 2.9 Hz, 1H), 6.56 (s, 1H), 6.50 (s, 1H), 5.65 (d, J = 3.0 Hz, 2H), 3.89 (s, 3H)
59
Figure PCTKR2010004966-appb-I000070
 7.31-7.35 (m, 7H), 7.19 (dd, J = 1.5, 7.7 Hz, 2H), 6.97-7.07 (m, 5H), 6.75 (d, J = 1.1 Hz, 1H), 6.70 (s, 1H) , 6.39 (dd, J = 1.9, 7.6 Hz, 1H), 6.27 (s, 1H), 6.22 (s, 1H)
<< 실험예Experimental Example > > FabIFabI 효소 억제 활성 실험 Enzyme Inhibitory Activity Experiment
본 발명에 따른 신규 3-페녹시-4-파이론, 3-페녹시-4-피리돈 또는 4-피리돈 유도체의 FabI 효소의 억제 활성을 알아보기 위하여 다음과 같은 실험을 수행하였다.In order to investigate the inhibitory activity of FabI enzyme of novel 3-phenoxy-4-pyrone, 3-phenoxy-4-pyridone or 4-pyridone derivative according to the present invention, the following experiment was performed.
화합물의 억제 활성은 FabI 효소 억제 실험(FabI enzyme inhibition assay)법으로 340 nm에서 NADH의 소비에 따른 흡광도의 감소 정도로 측정하였다. The inhibitory activity of the compounds was measured by the FabI enzyme inhibition assay (FabI enzyme inhibition assay) at a degree of decrease in absorbance with NADH consumption.
구체적으로, FabI에 대한 기질로서 200 μM 농도의 (E)-2-디세논산-N-아세틸시스테아민 티오에스테르((E)-2-decenoic acid-N-acetyl-cysteamine thioester)를 사용하였고, 수소공여체인 NADH 50 μM과 FabI 효소 60 nM을 혼합해 상온에서 10분 동안 전배양시킨 후, 340 nm에서 NADH의 흡광도를 측정하였다. 여기에 실시예 1~59에서 제조된 유도체들을 45 μM부터 3배씩 희석하여 농도를 변화시키면서 30 ℃에서 20분간 반응시킨 뒤, 다시 340 nm에서 NADH의 흡광도를 측정하여 감소된 NADH 양을 정량하므로서 FabI 효소 저해 활성 정도를 측정하였다. 또한, 이미 FabI 저해제로 알려진 트리클로산(triclosan)을 대조물질로 함께 실험시켜 이들의 활성도를 비교하였다. 세균에 대한 항생제의 최소 저해 농도 MIC(Minimum inhibitory concentration)는 아가 희석법(agar dilution method)에 의해서 측정되었다. 실험에는 Mycobacterium tuberculosis H37Rv가 사용되었다. 그리고 최근에 개발되어진 옥사졸리이논(oxazolidinone) 계통의 항생제인 리네졸리드(linezolid)를 대조물질로 함께 실험하여 활성도를 비교할 수 있었다. 얻어진 결과를 표 4에 정리하였다. Specifically, 200 μM concentration of (E) -2-disenoic acid-N-acetylcysteamine thioester ((E) -2-decenoic acid-N-acetyl-cysteamine thioester) was used as a substrate for FabI. 50 μM of hydrogen donor NADH and 60 nM of FabI enzyme were mixed and preincubated at room temperature for 10 minutes, and then absorbance of NADH was measured at 340 nm. Here, the derivatives prepared in Examples 1 to 59 were diluted three times from 45 μM and reacted at 30 ° C. for 20 minutes while varying the concentration, and then the absorbance of NADH was measured at 340 nm to quantify the reduced amount of NADH. The degree of enzyme inhibitory activity was measured. In addition, triclosan, already known as FabI inhibitor, was tested together as a control to compare their activity. The minimum inhibitory concentration (MIC) of antibiotics against bacteria was determined by the agar dilution method. Mycobacterium tuberculosis H37Rv was used in the experiment. In addition, the activity of the recently developed oxazolidinone strain, linezolid, an antibiotic, was compared with the control material. The obtained results are summarized in Table 4.
표 4
구분 대장균 FabI IC50(μM) MIC (㎍/㎕)
실시예 1 2.87±1.53 > 128
실시예 2 NT NT
실시예 3 0.11±0.11 16
실시예 4 3.55 32
실시예 5 > 10 > 128
실시예 6 - > 128
실시예 7 1.22±0.06 64
실시예 8 > 10 > 128
실시예 9 0.14±0.02 64
실시예 10 1.09±0.29 > 128
실시예 11 3.61±0.57 32
실시예 12 NT NT
실시예 13 NT NT
실시예 14 NT NT
실시예 15 NT NT
실시예 16 NT NT
실시예 17 0.40±0.01 4
실시예 18 NT 128
실시예 19 NT 64
실시예 20 NT 64
실시예 21 NT > 128
실시예 22 NT 32
실시예 23 NT > 128
실시예 24 NT 16
실시예 25 NT 16
실시예 26 NT 4
실시예 27 NT > 128
실시예 28 NT > 128
실시예 29 NT > 128
실시예 30 NT > 128
실시예 31 NT NT
실시예 32 NT NT
실시예 33 NT NT
실시예 34 NT NT
실시예 35 NT NT
실시예 36 > 50 NT
실시예 37 1.61 16
실시예 38 > 50 NT
실시예 39 > 50 NT
실시예 40 5.92 32
실시예 41 0.43 2
실시예 42 1.61 16
실시예 43 1.34 NT
실시예 44 0.59 4
실시예 45 2.28 16
실시예 46 3.06 64
실시예 47 NT 8
실시예 48 NT NT
실시예 49 NT 16
실시예 50 NT 16
실시예 51 11.66 64
실시예 52 1.29 16
실시예 53 11.66 64
실시예 54 2.93 4
실시예 55 6.30 32
실시예 56 8.89 > 128
실시예 57 17.92 NT
실시예 58 > 30 NT
실시예 59 2.90 128
비교군(트리클로산) 0.44±0.02
비교군(리네졸리드) 1
NT: Assay test is in process
Table 4
division E. coli FabI IC 50 (μM) MIC (μg / μl)
Example 1 2.87 ± 1.53 > 128
Example 2 NT NT
Example 3 0.11 ± 0.11 16
Example 4 3.55 32
Example 5 > 10 > 128
Example 6 - > 128
Example 7 1.22 ± 0.06 64
Example 8 > 10 > 128
Example 9 0.14 ± 0.02 64
Example 10 1.09 ± 0.29 > 128
Example 11 3.61 ± 0.57 32
Example 12 NT NT
Example 13 NT NT
Example 14 NT NT
Example 15 NT NT
Example 16 NT NT
Example 17 0.40 ± 0.01 4
Example 18 NT 128
Example 19 NT 64
Example 20 NT 64
Example 21 NT > 128
Example 22 NT 32
Example 23 NT > 128
Example 24 NT 16
Example 25 NT 16
Example 26 NT 4
Example 27 NT > 128
Example 28 NT > 128
Example 29 NT > 128
Example 30 NT > 128
Example 31 NT NT
Example 32 NT NT
Example 33 NT NT
Example 34 NT NT
Example 35 NT NT
Example 36 > 50 NT
Example 37 1.61 16
Example 38 > 50 NT
Example 39 > 50 NT
Example 40 5.92 32
Example 41 0.43 2
Example 42 1.61 16
Example 43 1.34 NT
Example 44 0.59 4
Example 45 2.28 16
Example 46 3.06 64
Example 47 NT 8
Example 48 NT NT
Example 49 NT 16
Example 50 NT 16
Example 51 11.66 64
Example 52 1.29 16
Example 53 11.66 64
Example 54 2.93 4
Example 55 6.30 32
Example 56 8.89 > 128
Example 57 17.92 NT
Example 58 > 30 NT
Example 59 2.90 128
Comparative group (Triclosan) 0.44 ± 0.02
Comparative group (linezolid) One
NT: Assay test is in process
표 4에 나타낸 바와 같이, 본 발명에 따른 화합물은 Escherichia coli 균주에 대하여 지방산 생합성 효소(FabI)에 대하여 높은 억제활성을 나타내며, Mycobacterium tuberculosis H37Rv 균주에 대해서 높은 항균활성을 나타내었다.As shown in Table 4, the compound according to the present invention exhibited high inhibitory activity against fatty acid biosynthetic enzyme (FabI) against Escherichia coli strain and high antibacterial activity against Mycobacterium tuberculosis H37Rv strain.
구체적으로, 3-페녹시-4-파이론 유도체(화학식 1a)에서 이중결합에 치환된 R3가 방향족(aromatic) 구조를 갖는 화합물이 높은 FabI 효소 저해활성을 보여주고 있으나 MIC 활성은 매우 낮은 활성을 보이고 있다. 그러나 R3 치환기가 지방족(aliphatic) 구조의 화합물은 높은 FabI 효소 저해활성을 보이고 있지는 않지만 상대적으로 높은 MIC 활성을 보이고 있음을 알 수 있다. 따라서 이중결합에 치환된 R3가 지방족 구조를 가지는 화합물이 FabI 효소 저해활성이 낮아도 세포 투과율이 높으므로 MIC활성이 나타나는 것으로 사료된다. Specifically, in the 3-phenoxy-4-pyrone derivative (Chemical Formula 1a), a compound having an aromatic structure of R 3 substituted in a double bond shows high FabI enzyme inhibitory activity, but MIC activity shows very low activity. It is showing. However, it can be seen that the compound of the aliphatic structure of the R 3 substituent does not show high FabI enzyme inhibitory activity but shows relatively high MIC activity. Therefore, even if the compound having R 3 aliphatic structure substituted in the double bond has a low FabI enzyme inhibitory activity, MIC activity appears to be high because the cell permeability is high.
또한, 3-페녹시-4-피리돈 유도체(화학식 1b)는 피리돈에 치환된 R6가 벤질기나 부틸기와 같이 부피가 큰 구조를 가지는 화합물보다 메틸기나 H와 같은 작은 구조가 치환된 화합물이 더 좋은 활성을 나타내고 있음을 확인하였고, FabI 효소 저해활성과 MIC 활성이 상당히 일치함을 알 수 있다. 3-페녹시-4-파이론 유도체와 3-페녹시-4-피리돈 유도체를 통해서 피리돈 구조를 가지는 화합물이 파이론 구조를 가지는 화합물보다 더 좋은 활성을 나타내고 있음을 확인하였으며, 피리돈 구조에 이중결합을 가지는 유도체가 좋은 활성을 가지는 것을 확인하였다. In addition, the 3-phenoxy-4-pyridone derivative (Formula 1b) is a compound in which a small structure such as methyl or H is substituted than a compound having a bulky structure, such as benzyl or butyl, in which R 6 is substituted for pyridone It was confirmed that the better activity, FabI enzyme inhibitory activity and MIC activity can be seen to be quite consistent. It was confirmed through the 3-phenoxy-4-pyrone derivative and the 3-phenoxy-4-pyridone derivative that the compound having a pyridone structure showed better activity than the compound having a pyrone structure. It was confirmed that the derivative having a bond had good activity.
4-피리돈 유도체(화학식 1c)는 대체로 높은 FabI 효소 저해활성을 보였다. 높은 FabI 효소 저해활성을 가지는 화합물이 좋은 MIC 활성을 보여주는 것을 통해 FabI 효소 저해활성과 MIC 활성이 상당히 일치함을 확인할 수 있었다. 치환기 R8에 치환된 치환체가 3번 위치에 할로겐 그룹을 가지는 벤질기의 유도체가 2번이나 4번 위치에 치환기를 갖는 화합물보다 더 높은 저해활성을 나타내었다. 그리고 R9 치환기는 2,3-디클로로 치환기보다는 2,6-디클로로 치환기가 더 좋은 활성을 가지는 것을 알 수 있다. 4-pyridone derivatives (formula 1c) generally showed high FabI enzyme inhibitory activity. Compounds with high FabI enzyme inhibitory activity showed good MIC activity, indicating that FabI enzyme inhibitory activity and MIC activity were significantly matched. The derivative of the benzyl group having a halogen group at the 3 position of the substituent substituted at the substituent R 8 showed a higher inhibitory activity than the compound having a substituent at the 2 or 4 position. And it can be seen that the R 9 substituent has a better activity than the 2,6-dichloro substituent than the 2,3-dichloro substituent.
따라서, 본 발명에 따른 조성물은 높은 항균활성을 나타내므로 항균제로서 유용하게 사용될 수 있다.Therefore, the composition according to the present invention can be usefully used as an antimicrobial agent because it exhibits high antimicrobial activity.
한편, 본 발명에 따른 상기 화학식 1의 화합물은 목적에 따라 여러 형태로 제제화가 가능하다. 하기는 본 발명에 따른 상기 화학식 1로 표시되는 화합물을 활성성분으로 함유시킨 몇몇 제제화 방법을 예시한 것으로 본 발명이 이에 한정되는 것은 아니다.On the other hand, the compound of Formula 1 according to the present invention can be formulated in various forms according to the purpose. The following are some examples of formulation methods containing the compound represented by Formula 1 according to the present invention as an active ingredient, but the present invention is not limited thereto.
<제제예 1> 정제(직접 가압)Preparation Example 1 Tablet (Direct Pressurization)
활성성분 5.0 ㎎을 체로 친 후, 락토스 14.1 ㎎, 크로스포비돈 USNF 0.8 ㎎ 및 마그네슘 스테아레이트 0.1 ㎎을 혼합하고 가압하여 정제로 제조하였다.After sifting 5.0 mg of the active ingredient, 14.1 mg of lactose, 0.8 mg of crospovidone USNF, and 0.1 mg of magnesium stearate were mixed and pressed to prepare a tablet.
<제제예 2> 정제(습식 조립)Preparation Example 2 Tablet (Wet Assembly)
활성성분 5.0 ㎎을 체로 친 후, 락토스 16.0 ㎎과 녹말 4.0 ㎎을 섞었다. 폴리솔베이트 80 0.3 ㎎을 순수한 물에 녹인 후 이 용액의 적당량을 첨가한 다음, 미립화하였다. 건조 후에 미립을 체질한 후 콜로이달 실리콘 디옥사이드 2.7 ㎎ 및 마그네슘 스테아레이트 2.0 ㎎과 섞었다. 미립을 가압하여 정제로 제조하였다.After sifting 5.0 mg of the active ingredient, 16.0 mg of lactose and 4.0 mg of starch were mixed. 0.3 mg of polysorbate 80 was dissolved in pure water and then an appropriate amount of this solution was added and then atomized. After drying, the fine particles were sieved and mixed with 2.7 mg of colloidal silicon dioxide and 2.0 mg of magnesium stearate. The granules were pressed to make tablets.
<제제예 3> 분말과 캡슐제Preparation Example 3 Powder and Capsule
활성성분 5.0 ㎎을 체로 친 후에, 락토스 14.8 ㎎, 폴리비닐 피롤리돈 10.0 ㎎, 마그네슘 스테아레이트 0.2 ㎎와 함께 혼합하였다. 상기 혼합물을 적당한 장치를 사용하여 단단한 No. 5 젤라틴 캡슐에 채웠다.After sifting 5.0 mg of the active ingredient, it was mixed with 14.8 mg of lactose, 10.0 mg of polyvinyl pyrrolidone, and 0.2 mg of magnesium stearate. The mixture was prepared using a suitable apparatus. Filled in 5 gelatin capsules.
<제제예 4> 주사제<Example 4> Injection
활성성분으로서 100 mg을 함유시키고, 그 밖에도 만니톨 180 mg, Na2HPO4·12H2O 26 mg 및 증류수 2974 mg를 함유시켜 주사제를 제조하였다.Injectables were prepared by containing 100 mg as the active ingredient, followed by the addition of 180 mg of mannitol, 26 mg of Na 2 HPO 4 .12H 2 O and 2974 mg of distilled water.

Claims (16)

  1. 하기 화학식 1로 표시되는 신규 3-페녹시-4-파이론, 3-페녹시-4-피리돈 또는 4-피리돈 유도체, 또는 이의 약학적으로 허용가능한 염:New 3-phenoxy-4-pyrones, 3-phenoxy-4-pyridones or 4-pyridone derivatives represented by the following formula (1), or pharmaceutically acceptable salts thereof:
    [화학식 1][Formula 1]
    Figure PCTKR2010004966-appb-I000071
    .
    Figure PCTKR2010004966-appb-I000071
    .
    (상기 화학식 1에서,(In Formula 1,
    X는 O 또는 NR3이고, 이때 R3은 수소; C1~C4 직쇄 또는 측쇄 알킬; C3~C8 사이클로알킬; 비치환 또는 1 이상의 할로겐, 니트로, 할로알킬, C1~C4 직쇄 또는 측쇄 알킬, C1~C4 알콕시로 치환된 C5~C12 아릴알킬; 또는 C5~C8 헤테로아릴이고,X is O or NR 3, wherein R 3 is hydrogen; C 1 -C 4 straight or branched alkyl; C 3 -C 8 cycloalkyl; C 5 -C 12 arylalkyl unsubstituted or substituted with one or more halogen, nitro, haloalkyl, C 1 -C 4 straight or branched alkyl, C 1 -C 4 alkoxy; Or C 5 -C 8 heteroaryl,
    Y는 O 또는 -CHOH이고,Y is O or -CHOH,
    R1은 수소,
    Figure PCTKR2010004966-appb-I000072
    또는
    Figure PCTKR2010004966-appb-I000073
    이고, 이때 R4는 C1~C4 직쇄 또는 측쇄 알킬; 또는 C5~C8 헤테로아릴이고,    R 1 is hydrogen,
    Figure PCTKR2010004966-appb-I000072
    or
    Figure PCTKR2010004966-appb-I000073
    Wherein R 4 is C 1 -C 4 straight or branched alkyl; Or C 5 -C 8 heteroaryl,
    R2는 1 이상의 C1~C4 직쇄 또는 측쇄 알킬 또는 할로겐으로 치환된다.)R 2 is substituted with one or more C 1 -C 4 straight or branched alkyl or halogen.)
  2. 제 1항에 있어서, 상기 X는 O 또는 NR3이고, 이때 R3은 수소, 메틸, 부틸, 사이클로프로필, 벤질, 브로모벤질, 클로로벤질, 니트로벤질, 트리플루오로메틸벤질, 메틸벤질, 디메틸벤질, 디플루오로벤질, 디클로로벤질, 메톡시벤질, t-부틸벤질, 퓨라닐 또는 디페닐메틸이고,The compound of claim 1, wherein X is O or NR 3 , wherein R 3 is hydrogen, methyl, butyl, cyclopropyl, benzyl, bromobenzyl, chlorobenzyl, nitrobenzyl, trifluoromethylbenzyl, methylbenzyl, dimethyl Benzyl, difluorobenzyl, dichlorobenzyl, methoxybenzyl, t-butylbenzyl, furanyl or diphenylmethyl,
    Y는 O 또는 -CHOH이고,Y is O or -CHOH,
    R1은 수소,
    Figure PCTKR2010004966-appb-I000074
    또는
    Figure PCTKR2010004966-appb-I000075
    이고, 이때 R4는 퓨란, 싸이오펜, 피라딘, 파이롤, 이소부틸, 부틸이고,    R 1 is hydrogen,
    Figure PCTKR2010004966-appb-I000074
    or
    Figure PCTKR2010004966-appb-I000075
    Wherein R 4 is furan, thiophene, pyridine, pyrrole, isobutyl, butyl,
    R2는 4-클로로-2-메틸, 2,3-디클로로, 2,6-디클로로, 2,4,-디클로로, 2,4-디메틸인 것을 특징으로 하는 신규 3-페녹시-4-파이론, 3-페녹시-4-피리돈 또는 4-피리돈 유도체, 또는 이의 약학적으로 허용가능한 염.New 3-phenoxy-4-pyrone, wherein R 2 is 4-chloro- 2 -methyl, 2,3-dichloro, 2,6-dichloro, 2,4, -dichloro, 2,4-dimethyl, 3-phenoxy-4-pyridone or 4-pyridone derivative, or a pharmaceutically acceptable salt thereof.
  3. 제 1항에 있어서, 상기 유도체는 하기 화학식 1a~1d의 화합물 중에서 선택되는 것을 특징으로 하는 것을 특징으로 하는 신규 3-페녹시-4-파이론, 3-페녹시-4-피리돈 또는 4-피리돈 유도체, 또는 이의 약학적으로 허용가능한 염.The novel 3-phenoxy-4-pyrone, 3-phenoxy-4-pyridone or 4-pyrier according to claim 1, wherein the derivative is selected from compounds of the general formulas 1a to 1d. Don derivatives, or pharmaceutically acceptable salts thereof.
    [화학식 1a][Formula 1a]
    Figure PCTKR2010004966-appb-I000076
    Figure PCTKR2010004966-appb-I000076
    (상기 화학식 1a에서, R3은 퓨란, 싸이오펜, 피라딘, 파이롤, 이소부틸 또는 부틸이다.)(In Formula 1a, R 3 is furan, thiophene, pyridine, pyrrole, isobutyl or butyl.)
    [화학식 1b][Formula 1b]
    Figure PCTKR2010004966-appb-I000077
    Figure PCTKR2010004966-appb-I000077
    (상기 화학식 1b에서 R4는 이소부틸 또는 부틸이고, R5는 수소, 메틸 또는 사이클로프로필이다.)(In Formula 1b, R 4 is isobutyl or butyl, and R 5 is hydrogen, methyl or cyclopropyl.)
    [화학식 1c][Formula 1c]
    Figure PCTKR2010004966-appb-I000078
    Figure PCTKR2010004966-appb-I000078
    (상기 화학식 1c에서, R6은 수소, 메틸, 사이클로프로필, 부틸 또는 벤질이고,(In Chemical Formula 1c, R 6 is hydrogen, methyl, cyclopropyl, butyl or benzyl,
    R7은 4-클로로-2-메틸, 디클로로 또는 디메틸이다.)R 7 is 4-chloro-2-methyl, dichloro or dimethyl.)
    [화학식 1d][Formula 1d]
    Figure PCTKR2010004966-appb-I000079
    Figure PCTKR2010004966-appb-I000079
    (상기 화학식 1d에서, R8은 벤질, 브로모벤질, 클로로벤질, 니트로벤질, 트리플루오로메틸벤질, 메틸벤질, 디메틸벤질, 디플루오로벤질, 디클로로벤질, 메톡시벤질, t-부틸벤질, 퓨라닐 또는 디페닐메틸이고,(In Formula 1d, R 8 is benzyl, bromobenzyl, chlorobenzyl, nitrobenzyl, trifluoromethylbenzyl, methylbenzyl, dimethylbenzyl, difluorobenzyl, dichlorobenzyl, methoxybenzyl, t-butylbenzyl, Furanyl or diphenylmethyl,
    R9는 디클로로이다.) R 9 is dichloro.)
  4. 제 1항에 있어서, 상기 유도체는The method of claim 1, wherein the derivative
    (1) 5-(4-클로로-2-메틸페녹시)-2-스티릴피란-4-온;(1) 5- (4-chloro-2-methylphenoxy) -2-styrylpyran-4-one;
    (2) 5-(4-클로로-2-메틸페녹시)-2-(3-메틸부트-1-에닐)-1H-피리딘-4-온;(2) 5- (4-chloro-2-methylphenoxy) -2- (3-methylbut-1-enyl) -1H-pyridin-4-one;
    (3) 5-(4-클로로-2-메틸페녹시)-1-메틸-2-페녹시메틸-1H-피리딘-4-온;(3) 5- (4-chloro-2-methylphenoxy) -1-methyl-2-phenoxymethyl-1H-pyridin-4-one;
    (4) 1-벤질-3-[(2,6-디클로로페닐)하이드록시메틸]-1H-피리딘-4-온;(4) 1-benzyl-3-[(2,6-dichlorophenyl) hydroxymethyl] -1H-pyridin-4-one;
    (5) 5-(4-클로로-2-메틸페녹시)-2-(2-퓨란-3-일비닐)피란-4-온;(5) 5- (4-chloro-2-methylphenoxy) -2- (2-furan-3-ylvinyl) pyran-4-one;
    (6) 5-(4-클로로-2-메틸페녹시)-2-(2-사이오펜-2-일비닐)피란-4-온;(6) 5- (4-chloro-2-methylphenoxy) -2- (2-thiophen-2-ylvinyl) pyran-4-one;
    (7) 5-(4-클로로-2-메틸페녹시)-2-펜트-1-에닐-피란-4-온;(7) 5- (4-chloro-2-methylphenoxy) -2-pent-1-enyl-pyran-4-one;
    (8) 5-(4-클로로-2-메틸페녹시)-2-(2-퓨란-2-일비닐)피란-4-온;(8) 5- (4-chloro-2-methylphenoxy) -2- (2-furan-2-ylvinyl) pyran-4-one;
    (9) 5-(4-클로로-2-메틸페녹시)-2-[2-(1H-파이롤-2-일)비닐]피란-4-온;(9) 5- (4-chloro-2-methylphenoxy) -2- [2- (1H-pyrrol-2-yl) vinyl] pyran-4-one;
    (10) 5-(4-클로로-2-메틸페녹시)-2-(2-사이오펜-3-일비닐)피란-4-온;(10) 5- (4-chloro-2-methylphenoxy) -2- (2-thiophen-3-ylvinyl) pyran-4-one;
    (11) 5-(4-클로로-2-메틸페녹시)-2-(3-메틸부트-1-에닐)피란-4-온;(11) 5- (4-chloro-2-methylphenoxy) -2- (3-methylbut-1-enyl) pyran-4-one;
    (12) 5-(4-클로로-2-메틸페녹시)-1-메틸-2-(3-메틸부트-1-에닐)-1H-피리딘-4-온;(12) 5- (4-chloro-2-methylphenoxy) -1-methyl-2- (3-methylbut-1-enyl) -1H-pyridin-4-one;
    (13) 5-(4-클로로-2-메틸페녹시)-2-(3-메틸부트-1-에닐)-1H-피리딘-4-온;(13) 5- (4-chloro-2-methylphenoxy) -2- (3-methylbut-1-enyl) -1H-pyridin-4-one;
    (14) 5-(4-클로로-2-메틸페녹시)-1-사이클로프로필-2-(3-메틸부트-1-에닐)-1H-피리딘-4-온;(14) 5- (4-chloro-2-methylphenoxy) -1-cyclopropyl-2- (3-methylbut-1-enyl) -1H-pyridin-4-one;
    (15) 5-(4-클로로-2-메틸페녹시)-1-메틸-2-펜트-1-에닐-1H-피리딘-4-온;(15) 5- (4-chloro-2-methylphenoxy) -1-methyl-2-pent-1-enyl-1H-pyridin-4-one;
    (16) 5-(4-클로로-2-메틸페녹시)-1-사이클로프로필-2-펜트-1-에닐-1H-피리딘-4-온;(16) 5- (4-chloro-2-methylphenoxy) -1-cyclopropyl-2-pent-1-enyl-1H-pyridin-4-one;
    (17) 5-(4-클로로-2-메틸페녹시)-2-페녹시메틸-1H-피리딘-4-온;(17) 5- (4-chloro-2-methylphenoxy) -2-phenoxymethyl-1H-pyridin-4-one;
    (18) 1-부틸-5-(4-클로로-2-메틸페녹시)-2-페녹시메틸-1H-피리딘-4-온;(18) 1-butyl-5- (4-chloro-2-methylphenoxy) -2-phenoxymethyl-1H-pyridin-4-one;
    (19) 5-(4-클로로-2-메틸페녹시)-1-사이클로프로필-2-페녹시메틸-1H-피리딘-4-온;(19) 5- (4-chloro-2-methylphenoxy) -1-cyclopropyl-2-phenoxymethyl-1H-pyridin-4-one;
    (20) 1-벤질-5-(4-클로로-2-메틸페녹시)-2-페녹시메틸-1H-피리딘-4-온;(20) 1-benzyl-5- (4-chloro-2-methylphenoxy) -2-phenoxymethyl-1H-pyridin-4-one;
    (21) 5-(2,3-디클로로페녹시)-2-페녹시메틸-1H-피리딘-4-온;(21) 5- (2,3-dichlorophenoxy) -2-phenoxymethyl-1H-pyridin-4-one;
    (22) 1-사이클로프로필-5-(2,3-디클로로페녹시)-2-페녹시메틸-1H-피리딘-4-온;(22) 1-cyclopropyl-5- (2,3-dichlorophenoxy) -2-phenoxymethyl-1H-pyridin-4-one;
    (23) 1-부틸-5-(2,3-디클로로페녹시)-2-페녹시메틸-1H-피리딘-4-온;(23) 1-butyl-5- (2,3-dichlorophenoxy) -2-phenoxymethyl-1H-pyridin-4-one;
    (24) 1-벤질-5-(2,3-디클로로페녹시)-2-페녹시메틸-1H-피리딘-4-온;(24) 1-benzyl-5- (2,3-dichlorophenoxy) -2-phenoxymethyl-1H-pyridin-4-one;
    (25) 5-(2,3-디클로로페녹시)-1-메틸-2-페녹시메틸-1H-피리딘-4-온;(25) 5- (2,3-dichlorophenoxy) -1-methyl-2-phenoxymethyl-1H-pyridin-4-one;
    (26) 5-(2,4-디클로로페녹시)-2-페녹시메틸-1H-피리딘-4-온;(26) 5- (2,4-dichlorophenoxy) -2-phenoxymethyl-1H-pyridin-4-one;
    (27) 5-(2,4-디클로로페녹시)-1-메틸-2-페녹시메틸-1H-피리딘-4-온;(27) 5- (2,4-dichlorophenoxy) -1-methyl-2-phenoxymethyl-1H-pyridin-4-one;
    (28) 1-부틸-5-(2,4-디클로로페녹시)-2-페녹시메틸-1H-피리딘-4-온;(28) 1-butyl-5- (2,4-dichlorophenoxy) -2-phenoxymethyl-1H-pyridin-4-one;
    (29) 1-벤질-5-(2,4-디클로로페녹시)-2-페녹시메틸-1H-피리딘-4-온;(29) 1-benzyl-5- (2,4-dichlorophenoxy) -2-phenoxymethyl-1H-pyridin-4-one;
    (30) 1-사이클로프로필-5-(2,4-디클로로페녹시)-2-페녹시메틸-1H-피리딘-4-온;(30) 1-cyclopropyl-5- (2,4-dichlorophenoxy) -2-phenoxymethyl-1H-pyridin-4-one;
    (31) 5-(2,4-디메틸페녹시)-2-페녹시메틸-1H-피리딘-4-온;(31) 5- (2,4-dimethylphenoxy) -2-phenoxymethyl-1H-pyridin-4-one;
    (32) 1-벤질-5-(2,4-디메틸페녹시)-2-페녹시메틸-1H-피리딘-4-온;(32) 1-benzyl-5- (2,4-dimethylphenoxy) -2-phenoxymethyl-1H-pyridin-4-one;
    (33) 5-(2,4-디메틸페녹시)-1-메틸-2-페녹시메틸-1H-피리딘-4-온;(33) 5- (2,4-dimethylphenoxy) -1-methyl-2-phenoxymethyl-1H-pyridin-4-one;
    (34) 1-부틸-5-(2,4-디메틸페녹시)-2-페녹시메틸-1H-피리딘-4-온;(34) 1-butyl-5- (2,4-dimethylphenoxy) -2-phenoxymethyl-1H-pyridin-4-one;
    (35) 1-사이클로프로필l-5-(2,4-디메틸페녹시)-2-페녹시메틸-1H-피리딘-4-온;(35) 1-cyclopropyll-5- (2,4-dimethylphenoxy) -2-phenoxymethyl-1H-pyridin-4-one;
    (36) 1-(3-브로모벤질)-3-[(2,3-디클로로페닐)하이드록시메틸]-1H-피리딘-4-온;(36) 1- (3-bromobenzyl) -3-[(2,3-dichlorophenyl) hydroxymethyl] -1H-pyridin-4-one;
    (37) 1-(4-브로모벤질)-3-[(2,3-디클로로페닐)하이드록시메틸]-1H-피리딘-4-온;(37) 1- (4-bromobenzyl) -3-[(2,3-dichlorophenyl) hydroxymethyl] -1H-pyridin-4-one;
    (38) 3-[(2,3-디클로로페닐)디클로로페닐]-1-(3-트리플루오로메틸벤질)-1H-피리딘-4-온;(38) 3-[(2,3-dichlorophenyl) dichlorophenyl] -1- (3-trifluoromethylbenzyl) -1H-pyridin-4-one;
    (39) 1-(4-t-부틸벤질)-3-[(2,3-디클로로페닐)하이드록시메틸]-1H-피리딘-4-온;(39) 1- (4-t-butylbenzyl) -3-[(2,3-dichlorophenyl) hydroxymethyl] -1H-pyridin-4-one;
    (40) 1-(2-브로모벤질)-3-[(2,6-디클로로페닐)하이드록시메틸]-1H-피리딘-4-온;(40) 1- (2-bromobenzyl) -3-[(2,6-dichlorophenyl) hydroxymethyl] -1H-pyridin-4-one;
    (41) 1-(3-브로모벤질)-3-[(2,6-디클로로페닐)하이드록시메틸]-1H-피리딘-4-온;(41) 1- (3-bromobenzyl) -3-[(2,6-dichlorophenyl) hydroxymethyl] -1H-pyridin-4-one;
    (42) 1-(4-브로모벤질l)-3-[(2,6-디클로로페닐)하이드록시메틸]-1H-피리딘-4-온;(42) 1- (4-bromobenzyll) -3-[(2,6-dichlorophenyl) hydroxymethyl] -1H-pyridin-4-one;
    (43) 1-(2-클로로벤질)-3-[(2,6-디클로로페닐)하이드록시메틸]-1H-피리딘-4-온;(43) 1- (2-chlorobenzyl) -3-[(2,6-dichlorophenyl) hydroxymethyl] -1H-pyridin-4-one;
    (44) 1-(3-클로로벤질)-3-[(2,6-디클로로페닐)하이드록시메틸]-1H-피리딘-4-온;(44) 1- (3-chlorobenzyl) -3-[(2,6-dichlorophenyl) hydroxymethyl] -1H-pyridin-4-one;
    (45) 1-(4-클로로벤질)-3-[(2,6-디클로로페닐)하이드록시메틸]-1H-피리딘-4-온;(45) 1- (4-chlorobenzyl) -3-[(2,6-dichlorophenyl) hydroxymethyl] -1H-pyridin-4-one;
    (46) 3-[(2,6-디클로로페닐)하이드록시메틸]-1-(2-트리플루오로메틸벤질)-1H-피리딘-4-온;(46) 3-[(2,6-dichlorophenyl) hydroxymethyl] -1- (2-trifluoromethylbenzyl) -1H-pyridin-4-one;
    (47) 3-[(2,6-디클로로페닐)하이드록시메틸]-1-(2-메톡시벤질)-1H-피리딘-4-온;(47) 3-[(2,6-dichlorophenyl) hydroxymethyl] -1- (2-methoxybenzyl) -1H-pyridin-4-one;
    (48) 3-[(2,6-디클로로페닐)하이드록시메틸]-1-(3-메톡시벤질)-1H-피리딘-4-온;(48) 3-[(2,6-dichlorophenyl) hydroxymethyl] -1- (3-methoxybenzyl) -1H-pyridin-4-one;
    (49) 3-[(2,6-디클로로페닐)하이드록시메틸]-1-(4-메톡시벤질)-1H-피리딘-4-온;(49) 3-[(2,6-dichlorophenyl) hydroxymethyl] -1- (4-methoxybenzyl) -1H-pyridin-4-one;
    (50) 3-[(2,6-디클로로페닐)하이드록시메틸]-1-(3-메틸벤질)-1H-피리딘-4-온;(50) 3-[(2,6-dichlorophenyl) hydroxymethyl] -1- (3-methylbenzyl) -1H-pyridin-4-one;
    (51) 3-[(2,6-디클로로페닐)하이드록시메틸]-1-(4-니트로벤질)-1H-피리딘-4-온;(51) 3-[(2,6-dichlorophenyl) hydroxymethyl] -1- (4-nitrobenzyl) -1H-pyridin-4-one;
    (52) 1-(4-t-부틸벤질)-3-[(2,6-디클로로페닐)하이드록시메틸]-1H-피리딘-4-온;(52) 1- (4-t-butylbenzyl) -3-[(2,6-dichlorophenyl) hydroxymethyl] -1H-pyridin-4-one;
    (53) 3-[(2,6-디클로로페닐)하이드록시메틸]-1-(2,6-디플루오로벤질)-1H-피리딘-4-온;(53) 3-[(2,6-dichlorophenyl) hydroxymethyl] -1- (2,6-difluorobenzyl) -1H-pyridin-4-one;
    (54) 1-(3,4-디클로로벤질)-3-[(2,6-디클로로페닐)하이드록시메틸]-1H-피리딘-4-온;(54) 1- (3,4-dichlorobenzyl) -3-[(2,6-dichlorophenyl) hydroxymethyl] -1H-pyridin-4-one;
    (55) 3-[(2,6-디클로로페닐)하이드록시메틸]-1-(2,6-디메틸벤질)-1H-피리딘-4-온;(55) 3-[(2,6-dichlorophenyl) hydroxymethyl] -1- (2,6-dimethylbenzyl) -1H-pyridin-4-one;
    (56) 3-[(2,6-디클로로페닐)하이드록시메틸]-1-(2-메틸사이아졸-4-일메틸)-1H-피리딘-4-온;(56) 3-[(2,6-dichlorophenyl) hydroxymethyl] -1- (2-methylthiazol-4-ylmethyl) -1H-pyridin-4-one;
    (57) 3-[(2,6-디클로로페닐)하이드록시메틸]-1-(3,5-디메틸이소옥사졸-4-일메틸)-1H-피리딘-4-온;(57) 3-[(2,6-dichlorophenyl) hydroxymethyl] -1- (3,5-dimethylisoxazol-4-ylmethyl) -1H-pyridin-4-one;
    (58) 3-[(2,6-디클로로페닐)하이드록시메틸]-1-퓨란-3-일메틸-1H-피리딘-4-온; 및(58) 3-[(2,6-dichlorophenyl) hydroxymethyl] -1-furan-3-ylmethyl-1H-pyridin-4-one; And
    (59) 1-벤즈히드릴-3-[(2,6-디클로로페닐-하이드록시메틸]-1H-피리딘-4-온으로 이루어지는 군으로부터 선택되는 것을 특징으로 하는 신규 3-페녹시-4-파이론, 3-페녹시-4-피리돈 또는 4-피리돈 유도체, 또는 이의 약학적으로 허용가능한 염.(59) Novel 3-phenoxy-4-, characterized in that it is selected from the group consisting of 1-benzhydryl-3-[(2,6-dichlorophenyl-hydroxymethyl] -1H-pyridin-4-one. Pyrone, 3-phenoxy-4-pyridone or 4-pyridone derivative, or a pharmaceutically acceptable salt thereof.
  5. 하기 반응식 1에 표시되는 바와 같이, As shown in Scheme 1 below,
    화학식 4의 코직산 화합물을 울만(Ullmann) 반응시켜 화학식 5의 화합물을 제조하는 단계(단계 1);Ullmann reaction of the kojic acid compound of Formula 4 to prepare a compound of Formula 5 (Step 1);
    상기 단계 1에서 제조된 화학식 5의 화합물을 클로라이드기로 치환하여 화학식 6의 화합물을 제조하는 단계(단계 2);Preparing a compound of Chemical Formula 6 by replacing the compound of Chemical Formula 5 prepared in Step 1 with a chloride group (Step 2);
    상기 단계 2에서 제조한 화학식 6의 화합물을 아르부조브(Arbuzov) 반응시켜 포스포네이트를 합성하여 화학식 7의 화합물을 제조하는 단계(단계 3); 및 Preparing a compound of formula 7 by arbuzov reaction of the compound of formula 6 prepared in step 2 to synthesize phosphonate (step 3); And
    상기 단계 3에서 제조한 화학식 7의 화합물을 호너-에몬스 반응을 통해 이중결합구조를 도입하여 화학식 1a의 화합물을 제조하는 단계(단계 4)를 포함하는 제1항의 신규 3-페녹시-4-파이론 유도체의 제조방법:The novel 3-phenoxy-4-pyrone of claim 1 comprising preparing a compound of Formula 1a by introducing a double bond structure through a Horner-Emons reaction (Step 4). Preparation of Derivatives:
    [반응식 1]Scheme 1
    Figure PCTKR2010004966-appb-I000080
    Figure PCTKR2010004966-appb-I000080
    (상기 식에서, R2는 상기 제1항의 화학식 1에서 정의한 바와 같고, R3은 상기 화학식 1a에서 정의한 바와 같으며, 화학식 1a는 제3항의 화학식 1에 포함된다.)(Wherein R 2 is as defined in formula 1 of claim 1, R 3 is as defined in formula 1a, and formula 1a is included in formula 1 of claim 3)
  6. 제 5항에 있어서, 상기 단계 1의 반응은 구리촉매, 리간드로서 N,N-디메틸글리신 염, 염기로서 Cs2CO3, 용매로서 디메틸 포름아마이드에서 수행되는 것을 특징으로 하는 제조방법.The method of claim 5, wherein the reaction of Step 1 is performed in a copper catalyst, N, N-dimethylglycine salt as ligand, Cs 2 CO 3 as base, and dimethyl formamide as solvent.
  7. 제 5항에 있어서, 상기 단계 2의 반응 용매는 무수 테트라하이드로퓨란이고, 염기는 포타슘 t-부톡사이드인 것을 특징으로 하는 제조방법.6. The process according to claim 5, wherein the reaction solvent of step 2 is anhydrous tetrahydrofuran and the base is potassium t-butoxide.
  8. 하기 반응식 2에 표시되는 바와 같이, As shown in Scheme 2 below,
    화학식 7의 포스포네이트 화합물을 아민 화합물과 첨가반응하여 화합물 8의 화합물을 제조하는 단계(단계 1); 및 Reacting a phosphonate compound of formula 7 with an amine compound to prepare a compound of compound 8 (step 1); And
    상기 단계 1에서 제조한 화학식 8의 화합물을 호너-에몬스 반응을 통해 이중결합 구조를 도입하여 화학식 1b의 화합물을 제조하는 단계(단계 2)를 포함하는 제1항의 3-페녹시-4-피리돈 유도체의 제조방법:The 3-phenoxy-4-pyridone of claim 1 comprising preparing a compound of Formula 1b by introducing a double bond structure through a Horner-Emons reaction of the compound of Formula 8 prepared in Step 1 (Step 2). Preparation of Derivatives:
    [반응식 2]Scheme 2
    Figure PCTKR2010004966-appb-I000081
    Figure PCTKR2010004966-appb-I000081
    (상기 식에서 R4 및 R5는 상기 화학식 1b에서 정의한 바와 같고, 화학식 1b는 화학식 1에 포함된다.)(Wherein R 4 and R 5 are as defined in Formula 1b, and Formula 1b is included in Formula 1).
  9. 하기 반응식 3에 표시되는 바와 같이, As shown in Scheme 3 below,
    화학식 5의 페녹시에테르 화합물을 페놀과 디이소프로필 아조디카르복실레이트 하에 미츠노부(Mitsunobu) 반응시켜 화학식 9의 화합물을 제조하는 단계(단계 1);및 Preparing a compound of formula 9 by reacting a phenoxyether compound of formula 5 with phenol and diisopropyl azodicarboxylate in Mitsunobu (step 1); and
    상기 단계 1에서 제조한 화학식 9의 화합물을 아민화합물과 첨가반응시켜 화합물 1c의 화합물을 제조하는 단계(단계 2)를 포함하는 제1항의 3-페녹시-4-피리돈 유도체의 제조방법:Method of preparing a 3-phenoxy-4-pyridone derivative of claim 1 comprising the step (step 2) of preparing a compound of compound 1c by the reaction of the compound of formula 9 prepared in step 1 with an amine compound:
    [반응식 3]Scheme 3
    Figure PCTKR2010004966-appb-I000082
    Figure PCTKR2010004966-appb-I000082
    (상기 식에서, 상기 R2는 상기 화학식 1에서 정의한 바와 같고, R6 및 R7은 화학식 1c에서 정의한 바와 같으며, 화학식 1c는 화학식 1에 포함된다.)Wherein R 2 is as defined in Formula 1, R 6 and R 7 are as defined in Formula 1c, and Formula 1c is included in Formula 1.
  10. 제 9항에 있어서, 상기 단계 1의 반응 용매는 무수 테트라하이드로퓨란이고, 반응물질로서 디이소프로필 아조디카르복실레이트와 트리페닐포스핀을 사용하는 것을 특징으로 하는 제조방법.10. The method of claim 9, wherein the reaction solvent of step 1 is anhydrous tetrahydrofuran, and diisopropyl azodicarboxylate and triphenylphosphine are used as reactants.
  11. 제 9항에 있어서, 상기 단계 2의 반응 용매는 메탄올인 것을 특징으로 하는 제조방법.10. The process according to claim 9, wherein the reaction solvent of step 2 is methanol.
  12. 하기 반응식 4에 표시되는 바와 같이, As shown in Scheme 4 below,
    화학식 10의 4-클로로피리딘염을 소디움메톡사이드 하에서 메톡시 구조를 도입하여 화학식 11의 화합물을 제조하는 단계(단계 1);Preparing a compound of formula 11 by introducing a 4-chloropyridine salt of formula 10 under a methoxy structure under sodium methoxide (step 1);
    상기 단계 1에서 제조한 화학식 11의 4-메톡시피리딘 화합물을 알데하이드와 반응시켜 화합물 12의 화합물을 제조하는 단계(단계 2);및Preparing a compound of Compound 12 by reacting the 4-methoxypyridine compound of Formula 11 prepared in Step 1 with an aldehyde (Step 2); and
    상기 단계 2에서 제조한 화학식 12의 화합물을 벤즈알데하이드와 반응시켜 화학식 1d의 화합물을 제조하는 단계(단계 3)를 포함하는 제1항의 4-피리돈 유도체의 제조방법:Method of preparing a 4-pyridone derivative of claim 1 comprising the step (step 3) of reacting the compound of formula 12 prepared in step 2 with benzaldehyde to prepare a compound of formula 1d:
    [반응식 4]Scheme 4
    Figure PCTKR2010004966-appb-I000083
    Figure PCTKR2010004966-appb-I000083
    (상기 식에서, 상기 R9는 화학식 1d에서 정의한 바와 같고, 화학식 1d는 화학식 1에 포함된다.)Wherein R 9 is as defined in Formula 1d, and Formula 1d is included in Formula 1.
  13. 제 1항의 신규 3-페녹시-4-파이론, 3-페녹시-4-피리돈 또는 4-피리돈 유도체, 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 항균 조성물.An antimicrobial composition comprising the novel 3-phenoxy-4-pyrone, 3-phenoxy-4-pyridone or 4-pyridone derivative of claim 1, or a pharmaceutically acceptable salt thereof as an active ingredient.
  14. 제 13항에 있어서, 상기 항균 조성물은 박테리아 지방산 생합성 효소인 에노일-ACP 환원효소(FabI)의 활성을 억제하는 것을 특징으로 하는 조성물.The composition of claim 13, wherein the antimicrobial composition inhibits the activity of Enoyl-ACP Reductase (FabI), a bacterial fatty acid biosynthetic enzyme.
  15. 제 1항의 화학식 1로 표시되는 신규 3-페녹시-4-파이론, 3-페녹시-4-피리돈, 4-피리돈 유도체, 또는 이의 약학적으로 허용가능한 염의 치료적으로 유효한 양으로 이를 필요로 하는 환자에게 투여하는 단계를 포함하는 항균의 치료방법.A therapeutically effective amount of the novel 3-phenoxy-4-pyrone, 3-phenoxy-4-pyridone, 4-pyridone derivative, or a pharmaceutically acceptable salt thereof represented by Formula 1 of claim 1 is required. A method of treating antibacterial comprising administering to a patient.
  16. 항균 치료용 항균제의 제조에 있어서, 제 1항의 화학식 1로 표시되는 3-페녹시-4-파이론, 3-페녹시-4-피리돈, 4-피리돈 유도체, 또는 이의 약학적으로 허용가능한 염의 용도.In preparing an antimicrobial agent for antimicrobial treatment, 3-phenoxy-4-pyrone, 3-phenoxy-4-pyridone, 4-pyridone derivative represented by Formula 1 of claim 1, or a pharmaceutically acceptable salt thereof Usage.
PCT/KR2010/004966 2009-07-28 2010-07-28 Novel 3-phenoxy-4-pyrone, 3-phenoxy-4-pyridone, or 4-pyridone derivatives, method for preparing same, and antimicrobial composition containing same as an active ingredient WO2011014008A2 (en)

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WO2017155052A1 (en) * 2016-03-09 2017-09-14 日本曹達株式会社 Pyridine compound and use thereof

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GB9107973D0 (en) * 1991-04-15 1991-05-29 Fujisawa Pharmaceutical Co New cephem compounds and process for preparation thereof

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017155052A1 (en) * 2016-03-09 2017-09-14 日本曹達株式会社 Pyridine compound and use thereof
JPWO2017155052A1 (en) * 2016-03-09 2019-01-17 日本曹達株式会社 Pyridine compounds and uses thereof
US10781177B2 (en) 2016-03-09 2020-09-22 Nippon Soda Co., Ltd. Pyridine compound and use thereof

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WO2011014008A3 (en) 2011-06-30
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