KR100937738B1 - Quinoline-carboxylic acid-amide derivatives or pharmaceutically acceptable salts thereof, preparation method thereof and antibiotic composition containing the same as an active ingredient - Google Patents

Abstract

The present invention relates to a quinoline carboxylic acid amide derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof, a method for preparing the same and an antimicrobial composition containing the same as an active ingredient, and a quinoline carboxylic acid amide derivative according to the present invention or a pharmaceutical composition thereof As a composition containing an acceptable salt as an active ingredient, it can effectively be used as an antimicrobial agent because it effectively inhibits the activity of Fab I, which is a target of the antimicrobial agent, involved in the last step of the fatty acid biosynthesis process of bacteria.

[Formula 1]

(In the above formula, R ¹ And R ² is as defined in the specification.)

Quinoline carboxylic acid amide, fatty acid biosynthetic enzyme, antibacterial substance

Description

Quinoline-carboxylic acid-amide derivatives or pharmaceutically acceptable salts etc, preparation method including and antibiotic composition containing the same as an active ingredient}

The present invention relates to a quinoline carboxylic acid amide derivative or a pharmaceutically acceptable salt thereof, a preparation method thereof and an antimicrobial composition containing the same as an active ingredient.

The area of interest in the field of antibiotic research and development is the emergence of resistant bacteria, and the future development direction is to develop new antibiotics with chemical structures that are completely different from existing antibiotics, or to modify the structure of natural antibiotics to develop new semisynthetic derivatives. will be. Recent technological trends in the development of new antibiotics to overcome resistant bacteria are based on essential gene target information from major bacteria whose genomes have been fully decoded, rather than structurally similar approaches such as simple structural modifications of existing antibiotics. From this the mainstream is to develop new target-oriented screening systems and to develop antimicrobial agents with new chemical structures and new mechanisms of action. In this respect, the fatty acid biosynthesis process (FAS) of bacteria has attracted attention as a new antimicrobial target.

Fatty acid plays an essential role in the maintenance of life phenomena as a major component of cell membranes as well as an energy source in life. Thus, these fatty acid biosynthesis processes in cells are biochemical processes that are indispensable in all living cells, and the genes involved are essential genes that are indispensable from bacteria to humans.

The overall pathway of saturated fatty acid biosynthesis is similar in all organisms, while the fatty acid synthase (FAS) system differs considerably depending on its structural organization. Vertebrate and yeast have FAS in which all enzymatic activities are encoded in one or two polypeptide chains respectively and acyl carrier protein (ACP) is an integral part of the complex. In contrast, in bacterial FAS, each reaction is catalyzed by a separate monofunctional enzyme, and ACP is an isolated protein. Therefore, a substance that inhibits the enzyme action involved in the bacterial FAS can be usefully used as an antibacterial agent.

Fab I acts as an anoyl-ACP reductase at the final stage of the four reactions involved in each cycle of bacterial fatty acid biosynthesis [Bergler, et al, (1994), J. Biol . Chem . 269, 5493-5496. In this pathway, the first step is catalyzed by β-ketoacyl-ACP synthase and the malonyl-ACP condenses with acetyl-CoA (FabH, synthetase III). In the next step, malonyl-ACP condenses with growth chain acyl-ACP (FabB and FabF, synthetase I and II, respectively). The second stage of the extension cycle is ketoester reduction by NADPH-dependent β-ketoacyl-ACP reductase (FabG).

Subsequent dehydration by β-hydroxyacyl-ACP dehydratase (either FabA or FabZ) induces trans-2-enoyl-ACP, which in turn results in NADH-dependent enoyl-ACP reductase (Fab I) To acyl-ACP. Additional repetition of this cycle, adding two carbon atoms per cycle, results in palmitoyl-ACP (16C), which immediately stops the cycle, largely due to feedback suppression of Fab I by palmitoyl-ACP Heath, et al, (1996), J. Biol . Chem . 271, 1833-1836. Fab I is thus a major biosynthetic enzyme and an important regulatory point in the overall synthetic pathway of bacterial fatty acid biosynthesis. Therefore, Fab I is an ideal target for antimicrobials.

Previous studies have shown that diazaborin antibiotics inhibit fatty acid, phospholipids and lipopolysaccharide (LPS) biosynthesis, and that the antimicrobial target of these compounds is Fab I. See, eg, Grasssberger, et al (1984) J. Med . Chem . 27 947-953] derivative 2b18 is reported to be a noncompetitive inhibitor of Fab I [Bergler, et al, (1994), J. Biol . Chem . 269, 5493-5496. In addition, plasmids containing Fab I gene from S. typhimurium are endowed with diazaborin resistance of E. coli [Turnowsky, et al, (1989), J. Bacteriol . , 171, 6555-6565.

Moreover, in Fab I temperature sensitive mutations, inhibition of Fab I by elevated temperature or by diazaborin is fatal. These results demonstrate that Fab I is essential for the survival of microorganisms [Bergler, et al (1994), J. Biol . Chem . 269, 5493-5496.

In addition, recent studies have shown that Fab I is also a target for a wide range of antimicrobials, triclosan [McMurry, et al, (1998). Nature , 394, 531-532. The crystal structure of Escherichia coli Fab I complexed with NAD and Triclozan showed that Triclozan replicates its natural substrate and acts as a site-specific, very potent inhibitor of Fab I [Levy, et al, (1999), Nature , 398, 383-384.

Therefore, the present inventors have studied to develop a novel Fab I inhibitor that can effectively inhibit the Fab I activity of bacteria, synthesizes a new quinoline carboxylic acid amide derivative, the quinoline carboxylic acid amide derivatives significantly significantly Fab I inhibitory activity After confirming that the present invention was completed.

An object of the present invention is to provide a quinoline carboxylic acid amide derivative or a pharmaceutically acceptable salt thereof that can effectively inhibit the Fab I activity of bacteria.

Another object of the present invention is to provide a method for preparing the quinoline carboxylic acid amide derivative.

Furthermore, another object of the present invention is to provide an intermediate produced during the preparation of the quinoline carboxylic acid amide derivative.

In addition, another object of the present invention to provide an antimicrobial composition containing the quinoline carboxylic acid amide derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

In order to achieve the above object, the present invention provides a quinoline carboxylic acid amide derivative or a pharmaceutically acceptable salt thereof.

The present invention also provides a method for preparing the quinoline carboxylic acid amide derivative.

Furthermore, the present invention provides an intermediate produced during the preparation of the quinoline carboxylic acid amide derivative.

The present invention also provides an antimicrobial composition containing the quinoline carboxylic acid amide derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

A composition containing a quinoline carboxylic acid amide derivative according to the present invention or a pharmaceutically acceptable salt thereof as an active ingredient is effective in the activity of Fab I, a target of an antimicrobial agent, involved in the last step (speed regulation step) of the fatty acid biosynthesis process of bacteria. Since it effectively inhibits, it can be usefully used as an antimicrobial agent.

The present invention provides a quinoline carboxylic acid amide derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof.

In the above formula,

R ¹ is a C _{5 ~ 10} unsubstituted or substituted by one or more C _{1 ~ 4} straight or branched chain alkyl, or one or more C _{1 ~ 4} alkoxy-aryl; Or unsubstituted or one or more C _{1 ~ 4} straight or branched chain alkyl, a C _{5 ~ 10} heteroaryl substituted by one or more C _{1 ~ 4} alkoxy aryl,

이고, 이때 R³은 C_{1 ~4} 직쇄 또는 측쇄 알킬 또는 NHR⁴이고, 이때 R⁴는 C_{1 ~4} 직쇄 또는 측쇄 알킬; 또는 비치환 또는 1 또는 그 이상의 C_{1 ~4} 직쇄 또는 측쇄 알킬, 1 또는 그 이상의 C_{1 ~4} 알콕시로 치환된 C_{5 ~10} 아릴; 또는 비치환 또는 1 또는 그 이상의 C_{1 ~4} 직쇄 또는 측쇄 알킬, 1 또는 그 이상의 C_{1 ~4} 알콕시로 치환된 C_{5 ~10} 헤테로아릴이다.R ² is hydrogen or

And, wherein R ³ is C _{1 ~ 4} is a straight or branched chain alkyl, or NHR ^4, wherein R ⁴ is C _{1 ~ 4} alkyl; Or a C _{5 ~ 10} unsubstituted or substituted by one or more C _{1 ~ 4} straight or branched alkyl, one or more of C _{1 ~ 4} alkoxy-aryl; Or it is a _{5 ~} C ₁₀ heteroaryl group unsubstituted or substituted by one or more C _{1 ~ 4} straight or branched alkyl, one or more of C _{1 ~ 4} alkoxy.

Preferably,

Wherein R ¹ is unsubstituted or one or more C _{1 ~ 4} straight or branched alkyl, one or more of C _{1 ~ 4} alkoxy-substituted phenyl; Or is an indole unsubstituted or substituted by one or more C _{1 ~ 4} straight or branched chain alkyl,

이고, 이때 R³은 C_{1 ~4} 직쇄 또는 측쇄 알킬 또는 NHR⁴이고, 이때 R⁴는 C_{1 ~4} 직쇄 또는 측쇄 알킬; 또는 비치환 또는 1 또는 그 이상의 C_{1 ~4} 직쇄 또는 측쇄 알킬, 1 또는 그 이상의 C_{1 ~4} 알콕시로 치환된 페닐이다.R ² is hydrogen or

And, wherein R ³ is C _{1 ~ 4} is a straight or branched chain alkyl, or NHR ^4, wherein R ⁴ is C _{1 ~ 4} alkyl; Or it is unsubstituted or one or more C _{1 ~ 4} straight or branched alkyl, one or more of C _{1 ~ 4} alkoxy-substituted phenyl.

More preferably,

R ¹ is unsubstituted or phenyl substituted with one or more methyl, ethyl, propyl, isopropyl or butyl, or one or more methoxy, ethoxy, propoxy, isopropoxy or butoxy; Or indole unsubstituted or substituted with one or more methyl or ethyl,

이고, 이때 R³은 메틸, 에틸, 프로필, 또는 NHR⁴이고, 이때 R⁴는 메틸, 에틸, 프로필, 이소프로필, 부틸 또는 이소부틸; 비치환 또는 1 또는 그 이상의 메틸, 에틸 또는 프로필, 또는 1 또는 그 이상의 메톡시, 에톡시로 치환된 페닐이다.R ² is hydrogen or

Wherein R ³ is methyl, ethyl, propyl, or NHR ^4, wherein R ⁴ is methyl, ethyl, propyl, isopropyl, butyl or isobutyl; Phenyl unsubstituted or substituted with one or more methyl, ethyl or propyl, or one or more methoxy, ethoxy.

Most preferably,

또는

이고,R ¹ is

or

ego,

R ² is H, acetyl, N -methylamido, N -isopropylamido, N -phenylamido or N- (4-methoxyphenyl) amido,

Amido groups substituted with R ¹ are located at positions 6 or 7 of quinoline.

More specifically exemplified carboxylic acid amide derivative represented by the formula (1) are as follows.

(1) N- (4-methoxybenzyl) -N -methyl-2-aminoquinoline-7-carboxylic acid amide;

(2) N -methyl-N- (4-methoxybenzyl) -2- (3-methylureido) quinoline-7-carboxylic acid amide;

(3) N- (4-methoxybenzyl) -N -methyl-2- (3- (4-methoxyphenyl) ureido) quinoline-7-carboxylic acid amide;

(4) N -methyl-N- (4-methoxybenzyl) -2- (3-phenylureido) quinoline-7-carboxylic acid amide;

(5) N- (4-methoxybenzyl) -N -methyl-2- (3-isopropylureido) quinoline-7-carboxylic acid amide;

(6) N- (4-methoxybenzyl) -N -methyl-2-acetamidoquinoline-7-carboxylic acid amide;

(7) N- (1,2-dimethyl-1H-indol-3-yl) methyl- N -methyl-2-aminoquinoline-6-carboxylic acid amide;

(8) N- (1,2-dimethyl-1H-indol-3-yl) methyl- N -methyl-2- (3-methylureido) quinoline-6-carboxylic acid amide;

(9) N- (1,2-dimethyl-1H-indol-3-yl) methyl- N -methyl-2- (3- (4-methoxyphenyl) ureido) quinoline-6-carboxylic acid amide;

(10) N- (1,2-dimethyl-1H-indol-3-yl) methyl- N -methyl-2- (3-phenylureido) quinoline-6-carboxylic acid amide;

(11) N- (1,2-dimethyl-1H-indol-3-yl) methyl- N -methyl-2- (3-isopropylureido) quinoline-6-carboxylic acid amide; And

(12) N- (1,2-dimethyl-1H-indol-3-yl) methyl- N -methyl-2-acetamidoquinoline-6-carboxylic acid amide.

The quinoline carboxylic acid amide derivative of the present invention represented by Chemical Formula 1 may be used in the form of a pharmaceutically acceptable salt, and an acid addition salt formed by a pharmaceutically acceptable free acid is useful as a salt. As salts are acid addition salts formed with pharmaceutically acceptable free acids. Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid and aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. Obtained from non-toxic organic acids such as dioates, aromatic acids, aliphatic and aromatic sulfonic acids. Such pharmaceutically nontoxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, and iodide. Id, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, Suverate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate , Methoxybenzoate, 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.

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, as the metal salt, it is pharmaceutically suitable to prepare sodium, potassium or calcium salt. Corresponding silver salts are also obtained by reacting alkali or alkaline earth metal salts with a suitable negative salt (eg, silver nitrate).

In addition, the quinoline carboxylic acid amide derivative represented by 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.

In addition, the present invention, as shown in Scheme 1,

Preparing a compound of Chemical Formula 3 by reacting an aldehyde group of a compound of Chemical Formula 2, which is a starting material, with phosphate substituted with a cyano group (Step 1);

Preparing a quinoline compound of formula 4 by performing intramolecular cyclization of the compound of formula 3 prepared in step 1 (step 2); And

It provides a method for producing a quinoline carboxylic acid amide derivative comprising the step (step 3) of preparing a compound of formula (1a) by reacting the compound of formula 4 prepared in step 2 with a secondary amine.

(Wherein R ¹ is as defined in Formula 1, and Formula 1a is included in Formula 1 according to the present invention.)

Hereinafter, the manufacturing method according to the present invention will be described in detail step by step.

Step 1

Step 1 according to the present invention is a step of preparing a compound of formula 3 by reacting an aldehyde group of the compound of formula 2 as a starting material with phosphate substituted with a cyano group.

The starting compound of Formula 2 can be obtained from known methods (Vetelino, et al, (1994) Tetrahedron Letters, 35, 219-222).

The reaction of Step 1 is commonly known in the field of organic chemistry as a "Horner-Wadsworth-Emmons" reaction, and reaction conditions such as reaction solvent, reaction temperature and reaction time may be appropriately selected in consideration of reactants and products. have. For example, in the present invention, dimethylformamide was used as a reaction solvent, and stirred at room temperature overnight in the presence of a base to obtain the compound of Formula 3.

Step 2

Step 2 according to the present invention is a step of preparing a quinoline compound of Formula 4 by intramolecular cyclization of the compound of Formula 3 prepared in Step 1.

At this time, it is preferable to use iron and concentrated hydrochloric acid to prepare the formula (4) in which the basic skeleton quinoline is formed. The iron and concentrated hydrochloric acid serves to reduce the nitro group of the compound of Formula 3 and to cause intramolecular cyclization. At this time, the reaction solvent may be alcohol such as methanol, ethanol, the reaction temperature is preferably reacted at 80 ~ 120 ℃.

Thereafter, it is preferable to further carry out a process of adding NaOH aqueous solution dropwise to the alcohol solvent, and cooling the solution after the reaction is completed, and then neutralizing by adding hydrochloric acid.

Step 3

Step 3 according to the present invention is a step of preparing a compound of formula 5 by reacting the compound of formula 4 prepared in step 2 with a secondary amine.

In this case, dimethylformamide, tetrahydrofuran, and the like may be used as the reaction solvent, and the amine, HOBt.H ₂ O, and EDC [1- (3-dimethylaminopropyl) -3-ethylcarbodiimide)] may be added dropwise to form a solvent. The phosphorus method can be used to react within appropriate reaction conditions.

In addition, as shown in Scheme 2 below, the preparation method according to the present invention further comprises the step of preparing a compound of formula 1 by reacting the compound of formula 1a prepared in step 3 with an isocyanate derivative (step 4) Can be done.

Wherein R ¹ And R ² is as defined in Formula 1.)

Step 4 according to the present invention is a step of preparing a compound of Formula 1 by reacting the compound of Formula 1a prepared in Step 3 with an isocyanate derivative.

Methylene chloride, dimethylformamide, etc. may be used as a reaction solvent to synthesize a quinoline carboxylic acid amide derivative, which is a final compound, and a compound having a ureido structure may be synthesized by reacting with various substituted isocyanate derivatives. The introduction of the acetyl group can be obtained by dropwise addition of acetic anhydride and Et ₃ N in the same solvent and stirring at room temperature.

Furthermore, the present invention provides a compound represented by the following Chemical Formula 3 or 4 produced as an intermediate in the preparation of the quinoline carboxylic acid amide derivative.

As described above, the quinoline carboxylic acid amide 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 of representative compounds. The molecular structure can be confirmed by comparing the calculated value with the measured value.

Furthermore, the present invention provides an antimicrobial composition comprising the quinoline carboxylic acid amide derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

Fab I acts as an anoyl-ACP reductase at the final stage of the four reactions involved in each cycle of bacterial fatty acid biosynthesis [Bergler, et al, (1994), J. Biol. Chem. 269, 5493-5496. In this pathway, the first step is catalyzed by β-ketoacyl-ACP synthase and the malonyl-ACP condenses with acetyl-CoA (FabH, synthetase III). In the next step, malonyl-ACP condenses with growth chain acyl-ACP (FabB and FabF, synthetase I and II, respectively). The second stage of the extension cycle is ketoester reduction by NADPH-dependent β-ketoacyl-ACP reductase (FabG).

Subsequent dehydration by β-hydroxyacyl-ACP dehydratase (either FabA or FabZ) induces trans-2-enoyl-ACP, which in turn results in NADH-dependent enoyl-ACP reductase (Fab I) To acyl-ACP. Additional repetition of this cycle, adding two carbon atoms per cycle, results in palmitoyl-ACP (16C), which immediately stops the cycle, largely due to feedback suppression of Fab I by palmitoyl-ACP Heath, et al, (1996), J. Biol. Chem. 271, 1833-1836. Fab I is thus a major biosynthetic enzyme and an important regulatory point in the overall synthetic pathway of bacterial fatty acid biosynthesis. Therefore, Fab I is an ideal target for antimicrobials.

Quinoline carboxylic acid amide derivatives and their pharmaceutically acceptable salts contained in the compositions according to the present invention have been shown to significantly inhibit the fatty acid biosynthetic enzyme (Fab Ι) activity of bacteria (see Experimental Example 1 and Table 1). ). Therefore, the composition according to the present invention can effectively be used as an antimicrobial agent because it effectively inhibits the activity of Fab I.

The compound of the present invention may be administered in various oral and parenteral dosage forms for clinical administration, and when formulated, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, surfactants, etc., which are commonly used, may be used. Are manufactured.

Solid form preparations for oral administration include tablets, patients, powders, granules, capsules, troches, and the like, which form at least one excipient such as starch, calcium carbonate, water, or the like. It is prepared by mixing cross, lactose or gelatin. In addition to simple excipients, lubricants such as magnesium styrate talc are also used. Liquid preparations for oral administration include suspensions, solvents, emulsions or syrups, and include various excipients such as wetting agents, sweeteners, fragrances, and preservatives in addition to the commonly used simple diluents, water and liquid paraffin. Can be.

Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories, and the like. As the non-aqueous solvent and the suspension solvent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerol, gelatin and the like can be used.

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 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.

< Example  1> N -(4-methoxybenzyl)- N - methyl -2- Aminoquinoline -7- Carboxylic acid Amide  synthesis

Step 1: 4- (2- Cyanovinyl ) -3- Nitrobenzoic acid Methyl ester  synthesis

After dissolving 5.88 g (50.2 mmol) of diethyl cyanomethylphosphate in 90 mL of anhydrous dimethylformamide, 9.91 g (71.7 mmol) of K ₂ CO ₃ was slowly added dropwise under an ice bath. 10.0 g (47.8 mmol) of 4-formyl-3-nitrobenzoic acid methyl ester dissolved in anhydrous dimethylformamide was slowly added dropwise and stirred overnight. The reaction was terminated by thin layer chromatography (TLC), then saturated aqueous NH ₄ Cl solution was added, and the precipitate was filtered to give 4- (2-cyanovinyl) -3-nitrobenzoic acid methyl ester in a yield of 28%. 3.1 g was obtained.

¹ H NMR (400 MHz) (CDCl ₃ ) δ 8.84 (d, J = 1.6 Hz, 1H), 8.75 (d, J = 1.6 Hz, 1H), 8.40 (dd, J = 8.0, 1.6 Hz, 1H), 8.33 (dd, J = 8.1, 1.6 Hz, 1H), 8.00 (d, J = 16.5 HZ, 1H), 7.94 (d, J = 8.1 HZ, 1H), 7.74 (d, J = 8.1 Hz, 1H), 7.66 (d, J = 8.1 Hz, 1H), 5.73, (d, J = 16.8 Hz, 1H), 5.80 (d, J = 11.7 Hz, 1H), 4.01 (s, 3H), 4.00 (s, 3H) , 1.58 (s, 2 H).

Step 2: 2- Aminoquinoline -7- Carboxylic acid  synthesis

3.1 g (12.9 mmol) of 4- (2-cyanovinyl) -3-nitrobenzoic acid methyl ester prepared in step 1 was dissolved in ethanol, and 2.16 g (38.8 mmol) of iron was added thereto, followed by concentration. Hydrochloric acid was added dropwise by dropping one or two chambers and then heated to reflux overnight at 100 ℃. After confirming the completion of the reaction, the reaction solution was cooled to room temperature, the iron was filtered, and the solvent was removed under reduced pressure to obtain 1.99 g of 2-aminoquinoline-7-carboxylic acid methyl ester in a yield of 76%. The resulting compound was dissolved in 20 ml of methanol, and 30 ml of 1N NaOH was added dropwise to reflux at 100 ° C. for 1 hour, and the reaction was terminated by thin layer chromatography (TLC), and then cooled to room temperature, followed by 1N hydrochloric acid. Was added to make the liquid acidic to pH = 2. The resulting precipitate was filtered to give 1.22 g of 2-aminoquinoline-7-carboxylic acid in 66% yield.

^{1 H NMR (400MHz) (DMSO-} d 6) δ 8.04 (s, 1H), 7.97 (d, J = 8.9 Hz, 1H), 7.94-7.73 (m, 2H), 6.86 (d, J = 8.9 Hz, 3H).

Step 3: N - methyl - N -(4-methoxybenzyl) -2- Aminoquinoline -7- Carboxylic acid Amide  synthesis

After dissolving 0.30 g (1.59 mmol) of 2-aminoquinoline-7-carboxylic acid prepared in Step 2 above in 40 ml of anhydrous dimethylformamide, 0.24 g (1.59 N -methyl- N- (4-methoxybenzyl) amine mmol), 0.22 g (1.59 mmol) of HOBt.H ₂ O, 0.22 mL (1.59 mmol) of Et ₃ N, and 0.3 g (1.59 mmol) of EDC were added dropwise and stirred at room temperature for 3 days. The reaction was terminated by thin layer chromatography (TLC), extracted with ethyl acetate, and then evaporated under reduced pressure to remove the solvent. Then purified by column chromatography (ethyl acetate: methanol = 9: 1) to give the target compound N -methyl- N- (4-methoxybenzyl) -2-aminoquinoline-7-carboxylic acid amide in 82% yield. 0.41 g was obtained.

^{1 H NMR (400MHz) (DMSO-} d 6) δ 7.90 (d, J = 6.7 Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.40 (s, 1H), 7.28 (s, 1H), 7.14 (d, J = 8.1 Hz, 2H), 6.93 (s, 1H), 6.78 (d, J = 8.0 Hz, 1H), 6.55 (s, 2H), 4.61 & 4.43 (s, 2H, conformer), 3.74 (s, 3H), 2.87 & 2.80 (s , 3h, conformer).

< Example  2> N - methyl - N -(4-methoxybenzyl) -2- (3- Methylureido Quinoline-7- Carboxylic acid  Synthesis of Amide

Step 1 to Step 3

N -methyl- N- (4-methoxybenzyl) -2-aminoquinoline-7-carboxylic acid amide was prepared in the same manner as in the steps 1 to 3 of Example 1.

Step 4: N - methyl - N -(4-methoxybenzyl) 2- (3- Methylureido Quinoline-7- Carboxylic acid Amide  synthesis

After filling the flask with nitrogen, 50.0 mg (0.16 mmol) of N -methyl- N- (4-methoxybenzyl) -2-aminoquinoline-7-carboxylic acid amide prepared in Step 3 was dissolved in 5 ml of dimethyl chloride. Next, 0.1 ml (1.63 mmol) of methyl isocyanate was added dropwise and stirred at room temperature for 4 days. The reaction was terminated by thin layer chromatography (TLC), the solvent was distilled off under reduced pressure, and then purified by column chromatography to obtain N -methyl- N- (4-methoxybenzyl) -2- (3- as the target compound. Methylureido) quinoline-7-carboxylic acid amide was obtained 46 mg in 78% yield.

^{1 H NMR (300MHz) (DMSO-} d 6) δ 9.80 (s, 1H), 9.19 (m, 1H), 8.22 (d, J = 9.6 Hz, 1H), 7.92 (s, 1H), 7.86 (d, J = 8.7 Hz, 1H), 7.41 (dd, J = 8.0, 1.4 Hz, 1H), 7.26-7.34 (m, 2H), 7.11 (d, J = 7.0 Hz, 1H), 6.94 (t, J = 8.7 Hz, 2H), 4.64 & 4.44 (s, 2H, conformer), 3.74 (s, 3H), 3.33 (s, 3H), 2.91 (s, 1H), 2.82 (s, 3H).

< Example  3> N -(4-methoxybenzyl)- N - methyl -2- (3- (4- Methoxyphenyl ) Ureido Quinoline-7-car Fidelity mountain Amide  synthesis

Step 1 to Step 3

N -methyl- N- (4-methoxybenzyl) -2-aminoquinoline-7-carboxylic acid amide was prepared in the same manner as in the steps 1 to 3 of Example 1.

Step 4

Example 2 except that 4-methoxyphenylisocyanate is used instead of methylisocyanate for N -methyl- N- (4-methoxybenzyl) -2-aminoquinoline-7-carboxylic acid amide prepared in Step 3 above N- (4-methoxybenzyl) -N -methyl-2- (3- (4-methoxyphenyl) ureido) quinoline-7-carboxylic acid amide (white crystal, 94%) was obtained.

< Example  4> N - methyl - N -(4-methoxybenzyl) -2- (3- Phenylureido Quinoline-7- Carboxylic acid  Synthesis of Amide

Step 1 to Step 3

N -methyl- N- (4-methoxybenzyl) -2-aminoquinoline-7-carboxylic acid amide was prepared in the same manner as in the steps 1 to 3 of Example 1.

Step 4

The N prepared as described in Step 3 - methyl - N - (4- methoxybenzyl) amino-2-methyl-quinoline-7-carboxylic acid amide in place of isocyanate the same as in the method of Example 2 but using phenyl isocyanate The method was carried out to obtain N -methyl- N- (4-methoxybenzyl) -2- (3-phenylureido) quinoline-7-carboxylic acid amide (white crystals, 85%) as a target compound.

< Example  5> N -(4-methoxybenzyl)- N - methyl -2- (3- Isopropylureido Quinoline-7- Carboxylic acid  Synthesis of Amide

Step 1 to Step 3

N -methyl- N- (4-methoxybenzyl) -2-aminoquinoline-7-carboxylic acid amide was prepared in the same manner as in the steps 1 to 3 of Example 1.

Step 4

Except for using isopropyl isocyanate instead of methyl isocyanate to N -methyl- N- (4-methoxybenzyl) -2-aminoquinoline-7-carboxylic acid amide prepared in step 3 and The same procedure was followed to obtain N- (4-methoxybenzyl) -N -methyl-2- (3-isopropylureido) quinoline-7-carboxylic acid amide (white crystals, 61%) as a target compound.

< Example  6> N- (4-methoxybenzyl) -N- methyl -2- Acetamidoquinoline -7- Carboxylic acid Amide  synthesis

Step 1 to Step 3

N -methyl- N- (4-methoxybenzyl) -2-aminoquinoline-7-carboxylic acid amide was prepared in the same manner as in the steps 1 to 3 of Example 1.

Step 4

Except for using acetyl chloride instead of methyl isocyanate to N -methyl- N- (4-methoxybenzyl) -2-aminoquinoline-7-carboxylic acid amide prepared in Step 3, the same method as in Example 2 The method was carried out to obtain N- (4-methoxybenzyl) -N -methyl-2-acetamidoquinoline-7-carboxylic acid amide (white solid, 56%) as a target compound.

< Example  7> N -(1,2-dimethyl-1H-indol-3-yl) methyl - N - methyl -2- Aminoquinoline -6- Carboxylic acid Amide  synthesis

Step 1: 3- (2- Cyanovinyl )-4- Nitrobenzoic acid Methyl ester  synthesis

Except for using 4-formyl-3-nitrobenzoic acid methyl ester of Example 1 except that 3-formyl-4-nitrobenzoic acid methyl ester was used in the same manner as in Example 1 3- (2-cyanovinyl) -4-nitrobenzoic acid methyl ester was obtained in 25% yield.

Step 2: 2- Aminoquinoline -6- Carboxylic acid  synthesis

Example 1 except that 3- (2-cyanovinyl) -4-nitrobenzoic acid methyl ester is used instead of 4- (2-cyanovinyl) -3-nitrobenzoic acid methyl ester of Example 1 By the same method as the method to give the target compound 2-aminoquinoline-6-carboxylic acid in a yield of 56%.

Step 3: N -(1,2-dimethyl-1H-indol-3-yl) methyl - N - methyl -2- Aminoquinoline -6- Carboxylic acid Amide  synthesis

N - methyl - N - (4- methoxybenzyl) amine instead of N - methyl - N - (1,2- dimethyl -1H- indol-3-yl) as 2-amino-quinoline-7-carboxylic acid using methylamine Instead of using the 2-aminoquinoline-6-carboxylic acid except in the same manner as in Example 1 to the target compound N- (1,2-dimethyl-1H- indol-3-yl) methyl- N- Methyl-2-aminoquinoline-6-carboxylic acid amide was obtained in 77% yield.

< Example  8> N -(1,2-dimethyl-1H-indol-3-yl) methyl - N - methyl -2- (3- Methylureido Quinoline-6- Carboxylic acid Amide  synthesis

Step 1 to Step 3

N- (1,2-dimethyl-1H-indol-3-yl) methyl- N -methyl-2-aminoquinoline-6-carboxylic acid amide was carried out in the same manner as in the steps 1 to 3 of Example 7. Prepared.

Step 4

After filling the flask with nitrogen, N- (1,2-dimethyl-1H-indol-3-yl) methyl- N -methyl-2-aminoquinoline-6-carboxylic acid amide prepared in step 3 was added to 5 ml of dimethyl chloride. 50.0 mg (0.16 mmol) was dissolved, and 0.1 ml (1.63 mmol) of methylisocyanate was added dropwise, followed by stirring at room temperature for 4 days. The reaction was terminated by thin layer chromatography (TLC), the solvent was distilled off under reduced pressure, and then purified by column chromatography to obtain N- (1,2-dimethyl-1H-indol-3-yl) methyl- as a target compound. N -methyl-2- (3-methylureido) quinoline-6-carboxylic acid amide (white solid, 78%) was obtained.

< Example  9> N -(1,2-dimethyl-1H-indol-3-yl) methyl - N - methyl -2- (3- (4- Methoxyphenyl ) Ureido Quinoline-6- Carboxylic acid Amide  synthesis

Step 1 to Step 3

N- (1,2-dimethyl-1H-indol-3-yl) methyl- N -methyl-2-aminoquinoline-6-carboxylic acid amide was carried out in the same manner as in the steps 1 to 3 of Example 7. Prepared.

Step 4

N- (1,2-dimethyl-1H-indol-3-yl) methyl- N -methyl-2-aminoquinoline-6-carboxylic acid amide prepared in step 3 was substituted with 4-methoxyphenylisocyanate instead of methylisocyanate. Except for using the same method as in Step 4 of Example 8 was carried out in the same manner as the target compound N -((1,2-dimethyl-1H-indol-3-yl) methyl- N -methyl-2- ( 3- (4-methoxyphenyl) ureido) quinoline-6-carboxylic acid amide (white solid, 24%) was obtained.

< Example  10> N -(1,2-dimethyl-1H-indol-3-yl) methyl - N - methyl -2- (3- Phenylureido Quinoline-6- Carboxylic acid Amide  synthesis

Step 1 to Step 3

N- (1,2-dimethyl-1H-indol-3-yl) methyl- N -methyl-2-aminoquinoline-6-carboxylic acid amide was carried out in the same manner as in the steps 1 to 3 of Example 7. Prepared.

Step 4

Except for using phenyl isocyanate instead of methylisocyanate in N- (1,2-dimethyl-1H-indol-3-yl) methyl- N -methyl-2-aminoquinoline-6-carboxylic acid amide prepared in step 3 above Then, the procedure was carried out in the same manner as in Step 4 of Example 8 to obtain N- (1,2-dimethyl-1H-indol-3-yl) methyl- N -methyl-2- (3-phenylureido as a target compound. ) Quinoline-6-carboxylic acid amide (white solid, 95%) was obtained.

< Example  11> N -(1,2-dimethyl-1H-indol-3-yl) methyl - N - methyl -2- (3- Isopropylureido Quinoline-6- Carboxylic acid Amide  synthesis

Step 1 to Step 3

N- (1,2-dimethyl-1H-indol-3-yl) methyl- N -methyl-2-aminoquinoline-6-carboxylic acid amide was carried out in the same manner as in the steps 1 to 3 of Example 7. Prepared.

Step 4

Using isopropyl isocyanate instead of methyl isocyanate in N- (1,2-dimethyl-1H-indol-3-yl) methyl- N -methyl-2-aminoquinoline-6-carboxylic acid amide prepared in step 3 above Except for the same method as in Step 4 of Example 8, except that N- (1,2-dimethyl-1H-indol-3-yl) methyl- N -methyl-2- (3-isopropyl) was the target compound. Ureido) quinoline-6-carboxylic acid amide (white solid, 32%) was obtained.

< Example  12> N -(1,2-dimethyl-1H-indol-3-yl) methyl - N - methyl -2- Acetamidoquinoline -6-ka Fidelity mountain Amide  synthesis

Step 1 to Step 3

N- (1,2-dimethyl-1H-indol-3-yl) methyl- N -methyl-2-aminoquinoline-6-carboxylic acid amide was carried out in the same manner as in the steps 1 to 3 of Example 7. Prepared.

Step 4

Except for using acetyl chloride instead of methyl isocyanate in N- (1,2-dimethyl-1H-indol-3-yl) methyl- N -methyl-2-aminoquinoline-6-carboxylic acid amide prepared in step 3 above Then, the procedure was carried out in the same manner as in Step 4 of Example 8 to obtain N- (1,2-dimethyl-1H-indol-3-yl) methyl- N -methyl-2-acetamidoquinoline-6 as a target compound. -Carboxylic acid amide (white solid, 76%) was obtained.

The chemical formula and NMR data of the compound prepared in the above example are summarized in Table 1.

< Experimental Example  1> Quinoline according to the present invention Carboxylic acid Amide  Inhibitory Effect of Fatty Acid Biosynthetic Enzyme (Fab I) on Derivatives

In order to investigate the inhibitory activity of Fab I of the quinoline carboxylic acid amide derivative according to the present invention, the following experiment was performed.

As a substrate for Fab I of E. coli, 200 μM concentration of ( E ) -2-decenoic acid- N -acetyl-cysteamine thioester was used, and a mixture of 50 μM hydrogen donor NADH and 60 nM Fab I enzyme was mixed at room temperature. After 10 minutes of incubation, the absorbance of NADH at 340 nm was measured. Herein, the compounds prepared in Examples 7, 8, 11 and 12 were diluted 4 times from 30 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 reduce NADH amount. By quantifying the degree of inhibitory activity of Fab I enzyme of E. coli was measured by the IC ₅₀ value is shown in Table 2.

Example Inhibitory Activity of Fab I Enzyme in Escherichia Coli (IC ₅₀ , μM) 7 1.76 ± 0.12 8 3.97 ± 0.36 11 3.66 ± 1.25 12 6.49 ± 0.55

As shown in Table 2, the carboxylic acid amide derivative according to the present invention or a pharmaceutically acceptable salt thereof has antibacterial activity against Escherichia coli by showing an inhibitory activity of Fab I enzyme from 1.76 ± 0.12 to 6.49 ± 0.55 μM. Able to know. Therefore, the carboxylic acid amide derivative of the present invention or a pharmaceutically acceptable salt thereof can be usefully used as an antimicrobial agent because it effectively inhibits the activity of Fab I.

Meanwhile, the quinoline carboxylic acid amide derivative represented by Chemical Formula 1 according to the present invention may be formulated in various forms according to the purpose. The following are some examples of formulation methods containing the derivative represented by Chemical 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 sieving 5.0 mg of the derivative of Formula 1, 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 sieving 5.0 mg of the derivative of Formula 1, 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 180 mg of mannitol, 26 mg of Na ₂ HPO ₄ .12H ₂ O and 2974 mg of distilled water.

Claims (14)

Carboxylic acid amide derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof: [Formula 1]

. (In the above formula, R ¹ is

or

ego, R ² is H, acetyl, N -methylamido, N -isopropylamido, N -phenylamido or N- (4-methoxyphenyl) amido, Amido groups substituted with R ¹ are located at positions 6 or 7 of quinoline.) delete delete delete The method of claim 1, wherein the carboxylic acid amide derivative is (1) N- (4-methoxybenzyl) -N -methyl-2-aminoquinoline-7-carboxylic acid amide; (2) N -methyl-N- (4-methoxybenzyl) -2- (3-methylureido) quinoline-7-carboxylic acid amide; (3) N- (4-methoxybenzyl) -N -methyl-2- (3- (4-methoxyphenyl) ureido) quinoline-7-carboxylic acid amide; (4) N -methyl-N- (4-methoxybenzyl) -2- (3-phenylureido) quinoline-7-carboxylic acid amide; (5) N- (4-methoxybenzyl) -N -methyl-2- (3-isopropylureido) quinoline-7-carboxylic acid amide; (6) N- (4-methoxybenzyl) -N -methyl-2-acetamidoquinoline-7-carboxylic acid amide; (7) N- (1,2-dimethyl-1H-indol-3-yl) methyl- N -methyl-2-aminoquinoline-6-carboxylic acid amide; (8) N- (1,2-dimethyl-1H-indol-3-yl) methyl- N -methyl-2- (3-methylureido) quinoline-6-carboxylic acid amide; (9) N- (1,2-dimethyl-1H-indol-3-yl) methyl- N -methyl-2- (3- (4-methoxyphenyl) ureido) quinoline-6-carboxylic acid amide; (10) N- (1,2-dimethyl-1H-indol-3-yl) methyl- N -methyl-2- (3-phenylureido) quinoline-6-carboxylic acid amide; (11) N- (1,2-dimethyl-1H-indol-3-yl) methyl- N -methyl-2- (3-isopropylureido) quinoline-6-carboxylic acid amide; And (12) N- (1,2-dimethyl-1H-indol-3-yl) methyl- N -methyl-2-acetamidoquinoline-6-carboxylic acid amide, characterized in that any one selected from the group consisting of Carboxylic acid amide derivatives or pharmaceutically acceptable salts thereof. As shown in Scheme 1 below, Preparing a compound of Chemical Formula 3 by reacting an aldehyde group of a compound of Chemical Formula 2, which is a starting material, with phosphate substituted with a cyano group (Step 1); Preparing a quinoline compound of formula 4 by performing intramolecular cyclization of the compound of formula 3 prepared in step 1 (step 2); And Method of preparing a quinoline carboxylic acid amide derivative comprising the step (step 3) of preparing a compound of formula 1 (1a) by reacting the compound of formula 4 prepared in step 2 with a secondary amine: Scheme 1

. (Wherein R ¹ is as defined in formula 1 of claim 1, and formula 1a is included in formula 1 of claim 1). The quinoline carboxylic acid of claim 6, further comprising the step (step 4) of preparing the compound of formula 1 by reacting the compound of formula 1a prepared in step 3 with an isocyanate derivative, as shown in Scheme 2 below. Preparation of Amide Derivatives: Scheme 2

. (Wherein R ¹ and R ² are as defined in formula 1 of claim 1). The method of claim 6, wherein step 2 is a method for producing a quinoline carboxylic acid amide derivative, characterized in that the reflux at 80 ~ 120 ℃ using iron and hydrochloric acid in the alcohol solvent. The method of claim 6, wherein the step 3 is reacted with an amine by using dimethylformamide as a reaction solvent and adding HOBt.H ₂ O and EDC [1- (3-dimethylaminopropyl) -3-ethylcarbodiimide) as a base. Method for producing a quinoline carboxylic acid amide derivative, characterized in that. 8. The method of claim 7, wherein methylene chloride is used as the reaction solvent of step 4. 9. Intermediates of carboxylic acid amide derivatives represented by the following general formula (3): [Formula 3]

. delete An antimicrobial composition comprising the carboxylic acid amide derivative of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. The antimicrobial composition of claim 13 wherein the composition inhibits the activity of the Fab I of the bacterium.