KR20110011271A - Novel 3-phenoxy-4-pyrone, 3-phenoxy-4-pyridone or 4-pyridone derivatives, preparation method thereof and antibiotic composition containing the same as an active ingredient - Google Patents

Abstract

PURPOSE: A novel 3-phenoxy-4-pyrone, 3-penoxy-4-pyridone or 4-pyridoen derivative and an antibacterial composition are provided to effectively suppress enoyl-ACP reductase(Fabl). CONSTITUTION: A novel 3-penoxy-4-pyrone, 3-phenoxy-4-pyridone or 4-pyridone derivative is denoted by chemical formula 1. A method for preparing the novel 3-phenoxy-4-pyrone derivative of chemical formula 1 comprises: a step of performing Ullmann reaction of kojic acid compound of chemical formula 4 to obtain a compound of chemical formula 5; a step of substituting the compound of chemical formula 5 with a chloride group to prepare a compound of chemical formula 6; a step of performing Arbuzov reation of the compound of chemical formula 6 to obtain a compound of chemical formula 7; and a step of performing Horner-Emmons reaction of compound of chemical formula 7 to introduce a double bond structure to prepare a compound of chemical formula 1a. An antibacterial composition contains the novel 3-phenoxy-4-pyrone, 3-phenoxy-4-pyridone or 4-pyridone derivative or pharmaceutically acceptable salt thereof as an active ingredient.

Description

Novel 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 {Novel 3-phenoxy-4-pyrone, 3- phenoxy-4-pyridone or 4-pyridone derivatives, preparation method approximately and antibiotic composition containing the same as an active ingredient}

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).

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.

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 is drawing 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).

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).

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).

Therefore, the inventors of the present invention devised a new compound through the study of the structure of the existing derivatives in order to develop a new inhibitor that can effectively inhibit the fatty acid biosynthesis of the bacteria, and carried out pharmacophore mapping, the derivatives 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.

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.

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 a pharmaceutically acceptable salt thereof as an active ingredient. To provide.

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.

The present invention also provides a method for preparing the novel 3-phenoxy-4-pyrone, 3-phenoxy-4-pyridone or 4-pyridone derivative.

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.

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.

EMBODIMENT OF THE INVENTION Hereinafter, this invention is demonstrated in detail.

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.

In Chemical Formula 1

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,

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,

R ² is substituted with one or more C ₁ -C ₄ straight or branched alkyl or halogen.

Preferably

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,

또는

이고, 이때 R⁴는 퓨란, 싸이오펜, 피라딘, 파이롤, 이소부틸, 부틸이고,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.

More preferably, the derivative according to the present invention may be selected from the compounds of Formulas 1a to 1d.

(In Formula 1a, R ³ is furan, thiophene, pyridine, pyrrole, isobutyl or butyl.)

(In Formula 1b, R ⁴ is isobutyl or butyl, and R ⁵ is hydrogen, methyl or cyclopropyl.)

(In Chemical Formula 1c, R ⁶ is hydrogen, methyl, cyclopropyl, butyl or benzyl,

R ⁷ is 4-chloro-2-methyl, dichloro or dimethyl.)

(In Formula 1d, R ⁸ is benzyl, bromobenzyl, chlorobenzyl, nitrobenzyl, trifluoromethylbenzyl, methylbenzyl, dimethylbenzyl, difluorobenzyl, dichlorobenzyl, methoxybenzyl, t-butylbenzyl, Furanyl or diphenylmethyl,

R ⁹ is dichloro.)

If more specifically exemplified the derivative represented by the formula (1) are as follows.

(1) 5- (4-chloro-2-methylphenoxy) -2-styrylpyran-4-one;

(2) 5- (4-chloro-2-methylphenoxy) -2- (3-methylbut-1-enyl) -1H-pyridin-4-one;

(3) 5- (4-chloro-2-methylphenoxy) -1-methyl-2-phenoxymethyl-1H-pyridin-4-one;

(4) 1-benzyl-3-[(2,6-dichlorophenyl) hydroxymethyl] -1H-pyridin-4-one;

(5) 5- (4-chloro-2-methylphenoxy) -2- (2-furan-3-ylvinyl) pyran-4-one;

(6) 5- (4-chloro-2-methylphenoxy) -2- (2-thiophen-2-ylvinyl) pyran-4-one;

(7) 5- (4-chloro-2-methylphenoxy) -2-pent-1-enyl-pyran-4-one;

(8) 5- (4-chloro-2-methylphenoxy) -2- (2-furan-2-ylvinyl) pyran-4-one;

(9) 5- (4-chloro-2-methylphenoxy) -2- [2- (1H-pyrrol-2-yl) vinyl] pyran-4-one;

(10) 5- (4-chloro-2-methylphenoxy) -2- (2-thiophen-3-ylvinyl) pyran-4-one;

(11) 5- (4-chloro-2-methylphenoxy) -2- (3-methylbut-1-enyl) pyran-4-one;

(12) 5- (4-chloro-2-methylphenoxy) -1-methyl-2- (3-methylbut-1-enyl) -1H-pyridin-4-one;

(13) 5- (4-chloro-2-methylphenoxy) -2- (3-methylbut-1-enyl) -1H-pyridin-4-one;

(14) 5- (4-chloro-2-methylphenoxy) -1-cyclopropyl-2- (3-methylbut-1-enyl) -1H-pyridin-4-one;

(15) 5- (4-chloro-2-methylphenoxy) -1-methyl-2-pent-1-enyl-1H-pyridin-4-one;

(16) 5- (4-chloro-2-methylphenoxy) -1-cyclopropyl-2-pent-1-enyl-1H-pyridin-4-one;

(17) 5- (4-chloro-2-methylphenoxy) -2-phenoxymethyl-1H-pyridin-4-one;

(18) 1-butyl-5- (4-chloro-2-methylphenoxy) -2-phenoxymethyl-1H-pyridin-4-one;

(19) 5- (4-chloro-2-methylphenoxy) -1-cyclopropyl-2-phenoxymethyl-1H-pyridin-4-one;

(20) 1-benzyl-5- (4-chloro-2-methylphenoxy) -2-phenoxymethyl-1H-pyridin-4-one;

(21) 5- (2,3-dichlorophenoxy) -2-phenoxymethyl-1H-pyridin-4-one;

(22) 1-cyclopropyl-5- (2,3-dichlorophenoxy) -2-phenoxymethyl-1H-pyridin-4-one;

(23) 1-butyl-5- (2,3-dichlorophenoxy) -2-phenoxymethyl-1H-pyridin-4-one;

(24) 1-benzyl-5- (2,3-dichlorophenoxy) -2-phenoxymethyl-1H-pyridin-4-one;

(25) 5- (2,3-dichlorophenoxy) -1-methyl-2-phenoxymethyl-1H-pyridin-4-one;

(26) 5- (2,4-dichlorophenoxy) -2-phenoxymethyl-1H-pyridin-4-one;

(27) 5- (2,4-dichlorophenoxy) -1-methyl-2-phenoxymethyl-1H-pyridin-4-one;

(28) 1-butyl-5- (2,4-dichlorophenoxy) -2-phenoxymethyl-1H-pyridin-4-one;

(29) 1-benzyl-5- (2,4-dichlorophenoxy) -2-phenoxymethyl-1H-pyridin-4-one;

(30) 1-cyclopropyl-5- (2,4-dichlorophenoxy) -2-phenoxymethyl-1H-pyridin-4-one;

(31) 5- (2,4-dimethylphenoxy) -2-phenoxymethyl-1H-pyridin-4-one;

(32) 1-benzyl-5- (2,4-dimethylphenoxy) -2-phenoxymethyl-1H-pyridin-4-one;

(33) 5- (2,4-dimethylphenoxy) -1-methyl-2-phenoxymethyl-1H-pyridin-4-one;

(34) 1-butyl-5- (2,4-dimethylphenoxy) -2-phenoxymethyl-1H-pyridin-4-one;

(35) 1-cyclopropyll-5- (2,4-dimethylphenoxy) -2-phenoxymethyl-1H-pyridin-4-one;

(36) 1- (3-bromobenzyl) -3-[(2,3-dichlorophenyl) hydroxymethyl] -1H-pyridin-4-one;

(37) 1- (4-bromobenzyl) -3-[(2,3-dichlorophenyl) hydroxymethyl] -1H-pyridin-4-one;

(38) 3-[(2,3-dichlorophenyl) dichlorophenyl] -1- (3-trifluoromethylbenzyl) -1H-pyridin-4-one;

(39) 1- (4-t-butylbenzyl) -3-[(2,3-dichlorophenyl) hydroxymethyl] -1H-pyridin-4-one;

(40) 1- (2-bromobenzyl) -3-[(2,6-dichlorophenyl) hydroxymethyl] -1H-pyridin-4-one;

(41) 1- (3-bromobenzyl) -3-[(2,6-dichlorophenyl) hydroxymethyl] -1H-pyridin-4-one;

(42) 1- (4-bromobenzyll) -3-[(2,6-dichlorophenyl) hydroxymethyl] -1H-pyridin-4-one;

(43) 1- (2-chlorobenzyl) -3-[(2,6-dichlorophenyl) hydroxymethyl] -1H-pyridin-4-one;

(44) 1- (3-chlorobenzyl) -3-[(2,6-dichlorophenyl) hydroxymethyl] -1H-pyridin-4-one;

(45) 1- (4-chlorobenzyl) -3-[(2,6-dichlorophenyl) hydroxymethyl] -1H-pyridin-4-one;

(46) 3-[(2,6-dichlorophenyl) hydroxymethyl] -1- (2-trifluoromethylbenzyl) -1H-pyridin-4-one;

(47) 3-[(2,6-dichlorophenyl) hydroxymethyl] -1- (2-methoxybenzyl) -1H-pyridin-4-one;

(48) 3-[(2,6-dichlorophenyl) hydroxymethyl] -1- (3-methoxybenzyl) -1H-pyridin-4-one;

(49) 3-[(2,6-dichlorophenyl) hydroxymethyl] -1- (4-methoxybenzyl) -1H-pyridin-4-one;

(50) 3-[(2,6-dichlorophenyl) hydroxymethyl] -1- (3-methylbenzyl) -1H-pyridin-4-one;

(51) 3-[(2,6-dichlorophenyl) hydroxymethyl] -1- (4-nitrobenzyl) -1H-pyridin-4-one;

(52) 1- (4-t-butylbenzyl) -3-[(2,6-dichlorophenyl) hydroxymethyl] -1H-pyridin-4-one;

(53) 3-[(2,6-dichlorophenyl) hydroxymethyl] -1- (2,6-difluorobenzyl) -1H-pyridin-4-one;

(54) 1- (3,4-dichlorobenzyl) -3-[(2,6-dichlorophenyl) hydroxymethyl] -1H-pyridin-4-one;

(55) 3-[(2,6-dichlorophenyl) hydroxymethyl] -1- (2,6-dimethylbenzyl) -1H-pyridin-4-one;

(56) 3-[(2,6-dichlorophenyl) hydroxymethyl] -1- (2-methylthiazol-4-ylmethyl) -1H-pyridin-4-one;

(57) 3-[(2,6-dichlorophenyl) hydroxymethyl] -1- (3,5-dimethylisoxazol-4-yl methyl) -1H-pyridin-4-one;

(58) 3-[(2,6-dichlorophenyl) hydroxymethyl] -1-furan-3-ylmethyl-1H-pyridin-4-one; And

(59) 1-benzhydryl-3-[(2,6-dichlorophenyl-hydroxymethyl] -1 H-pyridin-4-one.

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 those derived from 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, hydroxyalkanoates, Dioleate, aromatic acid, 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.

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.

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.

In addition, bases can 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).

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.

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.

The present invention also provides a method for preparing the derivative of Chemical Formula 1.

Preparation method 1

3-phenoxy-4-pyrone derivative of the derivative of Formula 1 according to the present invention is represented by the following Scheme 1,

Ullmann reaction of the kojic acid compound of Formula 4 to prepare a compound of Formula 5 (Step 1);

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);

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

The compound of Formula 7 prepared in step 3 may include a step (step 4) of preparing a compound of Formula 1a by introducing a double bond structure through a Horner-emons reaction.

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.

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.

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.

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.

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.

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.

Specifically, the step of generating the formula (7) by substituting the chloro group of the 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.

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.

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.

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 is 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.

Preparation method 2

3-phenoxy-4-pyridone derivative of the derivative of Chemical Formula 1 according to the present invention is represented by the following Scheme 2,

Reacting a phosphonate compound of formula 7 with an amine compound to prepare a compound of compound 8 (step 1); And

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).

(Wherein R ⁴ and R ⁵ are as defined in Formula 1b, and Formula 1b is included in Formula 1).

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.

 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.

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.

This step can be carried out in the same manner as step 4 of Preparation 1.

Preparation method 3

3-phenoxy-4-pyridone derivative of the derivative of Formula 1 according to the present invention, as shown in Scheme 3 below,

Preparing a compound of formula 9 by reacting a phenoxyether compound of formula 5 with phenol and diisopropyl azodicarboxylate in Mitsunobu (step 1); and

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).

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.

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.

Specifically, 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".

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.

The above step can be carried out in the same manner as step 1 of Preparation 2.

Recipe 4

4-pyridone derivative of the derivative of Formula 1 according to the present invention is represented by the following Scheme 4,

Preparing a compound of formula 11 by introducing a 4-chloropyridine salt of formula 10 under a methoxy structure under sodium methoxide (step 1);

Preparing a compound of Compound 12 by reacting the 4-methoxypyridine compound of Formula 11 prepared in Step 1 with an aldehyde (Step 2); and

The compound of Formula 12 prepared in Step 2 may be reacted with benzaldehyde to prepare a compound of Formula 1d (Step 3).

Wherein R ⁹ is as defined in Formula 1d, and Formula 1d is included in Formula 1.

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.

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.

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.

Specifically, in the above step, anhydrous tetrahydrofuran was used as a reaction solvent, and in anhydrous state, a 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.

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.

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. .

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.

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.

Formulations for oral administration include, for example, tablets, pills, hard / soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, and the like. 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, optionally with starch, agar, alginic acid or its sodium salt. Such disintegrating or boiling mixtures and / or absorbents, colorants, flavors, and sweeteners.

The pharmaceutical composition comprising the derivative represented by 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.

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.

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.

Hereinafter, the present invention will be described in detail with reference to Examples and Experimental Examples. However, the following examples are only for exemplifying the present invention, and the content of the present invention is not limited by the following examples.

< Example  1> 5- (4- Chloro -2- Methylphenoxy )-2- Styrylpyran Preparation of 4-one

Step 1: 5- (4- Chloro -2- Methylphenoxyl )-2- Hydroxymethylpyran Preparation of 4-one

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.

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)

Step 2: 2- Chloromethyl -5- (4- Chloro -2- Methylphenoxy Preparation of Pyran-4-one

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%.

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)

Step 3: [5- (4- Chloro -2- Methylphenoxy ) -4-oxo-4H-pyran-2- Yl methyl ] Production of Phosphonic Acid

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.

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)

Step 4: 5- (4- Chloro -2- Methylphenoxy )-2- Styrylpyran Preparation of 4-one

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%.

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)

< Example  2> 5- (4- Chloro -2- Methylphenoxy ) -2- (3- Methyl Boot -One- Enil Preparation of 1-1H-pyridin-4-one

Step 1: [5- (4- Chloro -2- Methylphenoxy ) -4-oxo-1,4- Dihydropyridine -2- Yl methyl Phosphonic acid Diethyl ester  Produce

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%.

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)

Step 2: 5- (4- Chloro -2- Methylphenoxy ) -2- (3- Methyl Boot -One- Enil Preparation of 1-1H-pyridin-4-one

[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.

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)

< Example  3> 5- (4- Chloro -2- Methylphenoxy )-One- methyl -2- Phenoxymethyl Preparation of -1H-pyridin-4-one

Step 1: 5- (4- Chloro -2- methyl - Phenoxy )-2- Phenoxymethylpyran Preparation of 4-one

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 the title compound 110 mg in 42.1% yield.

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)

Step 2: 5- (4- Chloro -2- methyl - Phenoxy )-One- methyl -2- Phenolicmethyl Preparation of -1H-pyridin-4-one

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.

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)

< Example  4> 1-benzyl-3-[(2,6- Dichloro - Phenyl ) - Hydroxymethyl ] -1H-pyridin-4-one

Step 1: 4- Methoxypyridine  Produce

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, ether and extracted. The solvent was distilled off under reduced pressure to obtain 12.0 g of 4-methoxypyridine in a yield of 67%.

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)

Step 2: 2,6- Dichlorophenyl -(4- Methoxypyridine Preparation of -3-yl) methanol

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%.

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)

Step 3: 1-benzyl-3-[(2,6- Dichlorophenyl ) - Hydromethyl ] -1H-pyridin-4-one

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.

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

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.

Example rescue NMR data 5

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

7.65 (s, 1 H), 7.46 (d, J = 1.9 Hz, 1 H), 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

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

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

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)

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.

Example rescue NMR data 11

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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 )

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.

Example rescue NMR data 36

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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)

< Experimental Example > FabI  Enzyme Inhibitory Activity Experiment

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.

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.

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.

division E. coli FabI IC ₅₀ (μM) MIC (µg / mL) 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

As shown in Table 4, the compounds according to the invention are Escherichia coli Mycobacterium tuberculosis showed high inhibitory activity against fatty acid biosynthetic enzyme (FabI) It showed high antimicrobial activity against H37Rv strain.

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.

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-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.

Therefore, the composition according to the present invention can be usefully used as an antimicrobial agent because it exhibits high antimicrobial activity.

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.

< Formulation example  1> tablet (direct pressure)

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.

< Formulation example  2> tablets (wet assembly)

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.

< Formulation example  3> with powder Capsule

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.

< Formulation example  4> Injection

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 (14)

New 3-phenoxy-4-pyrones, 3-phenoxy-4-pyridones or 4-pyridone derivatives represented by the following formula (1), or pharmaceutically acceptable salts thereof: [Formula 1]

. (In the formula 1, 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.) 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, Y is O or -CHOH, R ¹ is hydrogen,

or

Wherein R ⁴ is furan, thiophene, pyridine, pyrrole, isobutyl, butyl, 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. The novel 3-phenoxy-4-pyrone, 3-phenoxy-4-pyridone or 4-pyrile according to claim 1, wherein the derivative is selected from the compounds of Formulas 1a to 1d. Don derivatives, or pharmaceutically acceptable salts thereof. [Formula 1a]

(In Formula 1a, R ³ is furan, thiophene, pyridine, pyrrole, isobutyl or butyl.) [Chemical Formula 1b]

(In Formula 1b, R ⁴ is isobutyl or butyl, and R ⁵ is hydrogen, methyl or cyclopropyl.) [Formula 1c]

(In Chemical Formula 1c, R ⁶ is hydrogen, methyl, cyclopropyl, butyl or benzyl, R ⁷ is 4-chloro-2-methyl, dichloro or dimethyl.) &Lt; RTI ID = 0.0 &

(In Formula 1d, R ⁸ is benzyl, bromobenzyl, chlorobenzyl, nitrobenzyl, trifluoromethylbenzyl, methylbenzyl, dimethylbenzyl, difluorobenzyl, dichlorobenzyl, methoxybenzyl, t-butylbenzyl, Furanyl or diphenylmethyl, R ⁹ is dichloro.) The method of claim 1, wherein the derivative (1) 5- (4-chloro-2-methylphenoxy) -2-styrylpyran-4-one; (2) 5- (4-chloro-2-methylphenoxy) -2- (3-methylbut-1-enyl) -1H-pyridin-4-one; (3) 5- (4-chloro-2-methylphenoxy) -1-methyl-2-phenoxymethyl-1H-pyridin-4-one; (4) 1-benzyl-3-[(2,6-dichlorophenyl) hydroxymethyl] -1H-pyridin-4-one; (5) 5- (4-chloro-2-methylphenoxy) -2- (2-furan-3-ylvinyl) pyran-4-one; (6) 5- (4-chloro-2-methylphenoxy) -2- (2-thiophen-2-ylvinyl) pyran-4-one; (7) 5- (4-chloro-2-methylphenoxy) -2-pent-1-enyl-pyran-4-one; (8) 5- (4-chloro-2-methylphenoxy) -2- (2-furan-2-ylvinyl) pyran-4-one; (9) 5- (4-chloro-2-methylphenoxy) -2- [2- (1H-pyrrol-2-yl) vinyl] pyran-4-one; (10) 5- (4-chloro-2-methylphenoxy) -2- (2-thiophen-3-ylvinyl) pyran-4-one; (11) 5- (4-chloro-2-methylphenoxy) -2- (3-methylbut-1-enyl) pyran-4-one; (12) 5- (4-chloro-2-methylphenoxy) -1-methyl-2- (3-methylbut-1-enyl) -1H-pyridin-4-one; (13) 5- (4-chloro-2-methylphenoxy) -2- (3-methylbut-1-enyl) -1H-pyridin-4-one; (14) 5- (4-chloro-2-methylphenoxy) -1-cyclopropyl-2- (3-methylbut-1-enyl) -1H-pyridin-4-one; (15) 5- (4-chloro-2-methylphenoxy) -1-methyl-2-pent-1-enyl-1H-pyridin-4-one; (16) 5- (4-chloro-2-methylphenoxy) -1-cyclopropyl-2-pent-1-enyl-1H-pyridin-4-one; (17) 5- (4-chloro-2-methylphenoxy) -2-phenoxymethyl-1H-pyridin-4-one; (18) 1-butyl-5- (4-chloro-2-methylphenoxy) -2-phenoxymethyl-1H-pyridin-4-one; (19) 5- (4-chloro-2-methylphenoxy) -1-cyclopropyl-2-phenoxymethyl-1H-pyridin-4-one; (20) 1-benzyl-5- (4-chloro-2-methylphenoxy) -2-phenoxymethyl-1H-pyridin-4-one; (21) 5- (2,3-dichlorophenoxy) -2-phenoxymethyl-1H-pyridin-4-one; (22) 1-cyclopropyl-5- (2,3-dichlorophenoxy) -2-phenoxymethyl-1H-pyridin-4-one; (23) 1-butyl-5- (2,3-dichlorophenoxy) -2-phenoxymethyl-1H-pyridin-4-one; (24) 1-benzyl-5- (2,3-dichlorophenoxy) -2-phenoxymethyl-1H-pyridin-4-one; (25) 5- (2,3-dichlorophenoxy) -1-methyl-2-phenoxymethyl-1H-pyridin-4-one; (26) 5- (2,4-dichlorophenoxy) -2-phenoxymethyl-1H-pyridin-4-one; (27) 5- (2,4-dichlorophenoxy) -1-methyl-2-phenoxymethyl-1H-pyridin-4-one; (28) 1-butyl-5- (2,4-dichlorophenoxy) -2-phenoxymethyl-1H-pyridin-4-one; (29) 1-benzyl-5- (2,4-dichlorophenoxy) -2-phenoxymethyl-1H-pyridin-4-one; (30) 1-cyclopropyl-5- (2,4-dichlorophenoxy) -2-phenoxymethyl-1H-pyridin-4-one; (31) 5- (2,4-dimethylphenoxy) -2-phenoxymethyl-1H-pyridin-4-one; (32) 1-benzyl-5- (2,4-dimethylphenoxy) -2-phenoxymethyl-1H-pyridin-4-one; (33) 5- (2,4-dimethylphenoxy) -1-methyl-2-phenoxymethyl-1H-pyridin-4-one; (34) 1-butyl-5- (2,4-dimethylphenoxy) -2-phenoxymethyl-1H-pyridin-4-one; (35) 1-cyclopropyll-5- (2,4-dimethylphenoxy) -2-phenoxymethyl-1H-pyridin-4-one; (36) 1- (3-bromobenzyl) -3-[(2,3-dichlorophenyl) hydroxymethyl] -1H-pyridin-4-one; (37) 1- (4-bromobenzyl) -3-[(2,3-dichlorophenyl) hydroxymethyl] -1H-pyridin-4-one; (38) 3-[(2,3-dichlorophenyl) dichlorophenyl] -1- (3-trifluoromethylbenzyl) -1H-pyridin-4-one; (39) 1- (4-t-butylbenzyl) -3-[(2,3-dichlorophenyl) hydroxymethyl] -1H-pyridin-4-one; (40) 1- (2-bromobenzyl) -3-[(2,6-dichlorophenyl) hydroxymethyl] -1H-pyridin-4-one; (41) 1- (3-bromobenzyl) -3-[(2,6-dichlorophenyl) hydroxymethyl] -1H-pyridin-4-one; (42) 1- (4-bromobenzyll) -3-[(2,6-dichlorophenyl) hydroxymethyl] -1H-pyridin-4-one; (43) 1- (2-chlorobenzyl) -3-[(2,6-dichlorophenyl) hydroxymethyl] -1H-pyridin-4-one; (44) 1- (3-chlorobenzyl) -3-[(2,6-dichlorophenyl) hydroxymethyl] -1H-pyridin-4-one; (45) 1- (4-chlorobenzyl) -3-[(2,6-dichlorophenyl) hydroxymethyl] -1H-pyridin-4-one; (46) 3-[(2,6-dichlorophenyl) hydroxymethyl] -1- (2-trifluoromethylbenzyl) -1H-pyridin-4-one; (47) 3-[(2,6-dichlorophenyl) hydroxymethyl] -1- (2-methoxybenzyl) -1H-pyridin-4-one; (48) 3-[(2,6-dichlorophenyl) hydroxymethyl] -1- (3-methoxybenzyl) -1H-pyridin-4-one; (49) 3-[(2,6-dichlorophenyl) hydroxymethyl] -1- (4-methoxybenzyl) -1H-pyridin-4-one; (50) 3-[(2,6-dichlorophenyl) hydroxymethyl] -1- (3-methylbenzyl) -1H-pyridin-4-one; (51) 3-[(2,6-dichlorophenyl) hydroxymethyl] -1- (4-nitrobenzyl) -1H-pyridin-4-one; (52) 1- (4-t-butylbenzyl) -3-[(2,6-dichlorophenyl) hydroxymethyl] -1H-pyridin-4-one; (53) 3-[(2,6-dichlorophenyl) hydroxymethyl] -1- (2,6-difluorobenzyl) -1H-pyridin-4-one; (54) 1- (3,4-dichlorobenzyl) -3-[(2,6-dichlorophenyl) hydroxymethyl] -1H-pyridin-4-one; (55) 3-[(2,6-dichlorophenyl) hydroxymethyl] -1- (2,6-dimethylbenzyl) -1H-pyridin-4-one; (56) 3-[(2,6-dichlorophenyl) hydroxymethyl] -1- (2-methylthiazol-4-ylmethyl) -1H-pyridin-4-one; (57) 3-[(2,6-dichlorophenyl) hydroxymethyl] -1- (3,5-dimethylisoxazol-4-ylmethyl) -1H-pyridin-4-one; (58) 3-[(2,6-dichlorophenyl) hydroxymethyl] -1-furan-3-ylmethyl-1H-pyridin-4-one; And (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. As shown in Scheme 1 below, Ullmann reaction of the kojic acid compound of Formula 4 to prepare a compound of Formula 5 (Step 1); 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); 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 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: Scheme 1

(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) The method of claim 5, wherein the reaction of Step 1 is carried out in a copper catalyst, N, N-dimethylglycine salt as ligand, Cs ₂ CO ₃ as base, and dimethyl formamide as solvent. The method of claim 5, wherein the reaction solvent of step 2 is anhydrous tetrahydrofuran, and the base is potassium t-butoxide. As shown in Scheme 2 below, Reacting a phosphonate compound of formula 7 with an amine compound to prepare a compound of compound 8 (step 1); And The 3-phenoxy-4-pyridone of claim 1 comprising the step (2) of 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 Preparation of Derivatives: Scheme 2

(Wherein R ⁴ and R ⁵ are as defined in Formula 1b, and Formula 1b is included in Formula 1). As shown in Scheme 3 below, Preparing a compound of formula 9 by reacting a phenoxyether compound of formula 5 with phenol and diisopropyl azodicarboxylate in Mitsunobu (step 1); and 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: Scheme 3

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. The method according to claim 9, wherein the reaction solvent of step 1 is anhydrous tetrahydrofuran, and diisopropyl azodicarboxylate and triphenylphosphine are used as reactants. 10. The process according to claim 9, wherein the reaction solvent of step 2 is methanol. As shown in Scheme 4 below, Preparing a compound of formula 11 by introducing a 4-chloropyridine salt of formula 10 under a methoxy structure under sodium methoxide (step 1); Preparing a compound of Compound 12 by reacting the 4-methoxypyridine compound of Formula 11 prepared in Step 1 with an aldehyde (Step 2); and 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: Scheme 4

Wherein R ⁹ is as defined in Formula 1d, and Formula 1d is included in Formula 1. 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. The composition of claim 13, wherein the antimicrobial composition inhibits the activity of Enoyl-ACP Reductase (FabI), a bacterial fatty acid biosynthetic enzyme.