KR100222082B1 - Novel quinoline carboxylic acid derivatives with 7-(3-aminomethyl-4-alkyloxime) pyrrolidine substituent and process for preparation thereof - Google Patents

Abstract

In particular, the present invention is a compound having a derivative of a 4-alkyloximepyrrolidine group at the 7-position of the quinolone mother nucleus, which has excellent antibacterial activity and broad antibacterial spectrum, and is superior to conventional quinolone antibiotics. Novel quinoline (naphthyridine) carboxylic acid derivatives represented by the following structural formula (I) having properties, pharmaceutically acceptable salts thereof, and methods for their preparation.

Wherein R is hydrogen, methyl or amino, Q is CH, CF, C-Cl, C-CH ₃ , CO-CH ₃ or N; R ₁ is cyclopropyl, ethyl, a phenyl group substituted with one or more fluorine atoms; R ₂ is C ₃ -C ₄ branched chain alkyl group including t-butyl group or cyclopropylmethyl or C ₃ -C ₆ alkyl having triple bond including propazyl or homopropazyl, or 2-haloethyl, It is a methoxymethyl or methoxycarbonylmethyl group, or represents the group of the following general formula,

Wherein n is 0 or 1, m is 0, 1 or 2, X is methylene, 0 or N, and R ₃ and R ₄ are each independently hydrogen or an alkyl group of C ₁ -C ₃ , or to which they are attached It may form a ring with each other with the nitrogen atom.

Description

Novel quinoline carboxylic acid derivatives having 7- (3-aminomethyl-4-alkyloxime) pyrrolidine substituents and preparation methods thereof

The present invention relates to a novel quinolone compound exhibiting excellent antimicrobial activity, in particular, a compound having a derivative of a 4-alkyloxime pyrrolidine group at the 7-position of the quinolone mother nucleus, which has excellent antibacterial activity and broad antibacterial spectrum, The present invention relates to a novel quinoline (nathyridine) carboxylic acid derivative represented by the following general formula (I), which has superior pharmacokinetic properties than conventional quinolone antibiotics, a pharmaceutically acceptable salt thereof, and a preparation method thereof.

Wherein Q is CH, CF, C-Cl, C-CH ₃ , CO-CH ₃ or N, R is hydrogen, methyl or amino group, R ₁ is cyclopropyl, ethyl, one or more fluorine atoms Is a substituted phenyl group, R ₂ is a C ₃ -C ₄ branched alkyl, C ₃ -C ₆ alkynyl, 2-chloroethyl, methoxymethyl, or methoxycarbonylmethyl group, or a group of the formula:

Wherein n is 0 or 1, m is 0, 1 or 2, X is methylene, 0 or N, and R ₃ and R ₄ are each independently hydrogen or an alkyl group of C ₁ -C ₃ , or to which they are attached It may form a ring with each other with the nitrogen atom.

Since the emergence of nalidic acid (GY Lesher, et al., J. Med. Chem. 5, 1063-1065 (1962)) as a treatment for urinary tract infections in 1962, many quinoline carboxylic acid-based antimicrobials, oxolinic acid ), Rosoxacin and Pipemidic acid were developed. These early antimicrobial agents (Albrecht R., Prog. Drug Res., 21, 9 (1977)) have little activity against Gram-positive bacteria. It has been mainly used only as an antimicrobial agent for Gram-negative bacteria.

Recently, a new generation of quinolones-containing nofloxacin (H. Koga, et al., J. Med. Chem. 23, 1358-63 (1980)) containing fluorine at position 6 has been developed. Research on antibiotics has been very extensively attempted. However, nofloxacin was used only for the treatment of Gram-negative bacteria because of its low antimicrobial activity against Gram-positive bacteria and poor distribution and absorption. Cyprofloxacin (R. Wise, et al., J. Antimicrob. Agents Chemother., 23, 559 (1983)), and ofloxacin (K. Sata, et al., Antimicrob. Agents). Chemother., 22, 548 (1982), and the like, which have a broader antimicrobial activity than earlier antimicrobial agents, are now widely used in clinical and therapeutic practice today.

On the other hand, currently used or clinical compounds are mainly piperazine derivatives, such as ciprofloxacin or oploxacin at position 7 of the quinolone hair nucleus. However, as a result of efforts to develop more powerful and broad antibacterial quinolone antibiotics, the introduction of 3-amino or 3-amino methylpyrrolidin group at position 7 compared to compounds having piperazine group at position 7 The antimicrobial activity against gram positive bacteria was found to be increased while maintaining the antimicrobial activity against gram negative bacteria. Unfortunately, in general, compounds having a pyrrolidine substituent do not show strong antimicrobial activity such as in vitro antibacterial activity due to low solubility in water compared to a compound having a piperazine substituent. Thus, efforts have been made to increase this disadvantage of compounds with pyrrolidine substituents, ie to increase solubility in water and also to improve pharmacokinetic properties.

Examples of such studies are shown in several reports. For example, ((2S, 4S) -4-amino-2-methylpyrrolidinyl) naphthyridine derivatives (Rosen, T; Chu, DTW etc. J. Med. Chem. 1988, 31, 1598-1611) or ( Trans-3-amino-4-methylpyrrolidinyl) naphthyridine derivatives (Matsumoto, J. et. Al., Proceedings of the 14th International Congress of Chemotherapy; Ishigami, J., Ed .; University of Tokyo Press: Tokyo, 1985; pp 1519-1520) showed similar in vitro antimicrobial activity and 20- and 40-fold increase in solubility in water, respectively, compared to the compound without methyl group, indicating that bioavailability and pharmacokinetic properties were improved. .

On the other hand, instead of the amino group in pyrrolidine or piperazine, other functional groups are introduced to improve the disadvantages of quinolone compounds, such as relatively weak antimicrobial activity against Gram-positive bacteria and solubility in water, thereby improving pharmacokinetic properties. Efforts have been made to improve. As part of this effort, there have been several examples of introducing an oxime group to the amine at position 7 of the quinolone compound.

In other words, Abbott's researchers published in a professional magazine (J. Med. Chem. 1992, 35, 1392-1398), according to the following general formula [A], 3-oxime (or methyl oxime) pyrroli When a dine or 4-oxime (or methyloxime) piperidine group is substituted at position 7 of quinolone, it has excellent antimicrobial activity against Gram-positive bacteria.

Wherein R is a cyclopropyl or 2,4-difluorophenyl group: R 'is hydrogen or methyl; X is C-H, C-F, or N, and n represents 1 or 2.

However, these compounds show relatively weak antimicrobial activity against Gram-negative bacteria, and also have a disadvantage of showing a relatively low antimicrobial activity in in vivo experiments.

On the other hand, Japanese Patent Application Laid-Open No. 01-100165 (1989) describes a quinolone compound of the following general formula [B].

Wherein R is a cyclopropyl, 2,4-difluorophenyl or 4-hydroxyphenyl group; R 'represents an oxime or hydroxyaminopyrrolidine substituent; X represents C-H, C-F or C-C1.

In the above report, like the compound of general formula (I) according to the present invention, the position 3 has an oxime structure and does not include a compound having an aminomethyl group at the 4-position.

In addition, European Patent Publication No. 0 541 086 describes quinolone compounds of the general formula [C].

Wherein R and R ₁ are each independently hydrogen or C ₁ -C ₅ alkyl; R ₂ is hydrogen, amino, fluorine or hydroxy; R ₃ is a cycloalkyl group of C ₃ -C ₇ ; R ₄ is methoxy or fluorine; R ₅ and R ₆ may be the same as or different from each other with hydrogen or an alkyl group, and are cycloalkyl groups of C ₃ -C ₅ , m is 0 or 1; n is an integer of 1-3.

In this case, the representative substituent at position 7 is the structure shown below, and in the case of the compound of the general formula [C], the compound of the present invention does not include a compound in which an oxime group and an aminomethyl group are simultaneously introduced at position 7 Is different.

Common characteristics of the known oxime or hydroxyamine-based compounds mentioned above, Gram-positive bacteria including MRSA (Methicillin Resistant Staphylococcus aureus) bacteria shows excellent antimicrobial activity compared to the previous quinolone antibiotics, Gram-negative bacteria It has a weak antimicrobial activity against, suggesting that the antimicrobial spectrum is narrower than conventional oploxacin or cyprofloxacin.

Accordingly, the present inventors have developed a new quinolone compound substituted with 3-aminomethyl-4-oxime (or C1-C4 straight alkyl oxime) pyrrolidine group at position 7, which can solve this problem, and these are resistant bacteria It has recently been found to have antimicrobial activity against a wide range of pathogens, including gram positive and negative (including Korean Patent Application No. 94-13604).

Wherein Q is CH, CF, C-Cl, C-OH, CO-methyl or N, R is hydrogen, methyl, or amino, R ₁ is cyclopropyl, ethyl, substituted with one or more fluorine atoms Is phenyl, R ₂ is hydrogen, C ₁ -C ₄ straight alkyl group or allyl group, R ₃ and R ₄ are each independently hydrogen or C ₁ -C ₃ alkyl or ring together with the nitrogen atom to which they are attached Can be formed.

Therefore, the present inventors based on this prior art, while maintaining the strong antibacterial activity and broad antibacterial spectrum of these oxime-aminomethyl-based compounds, a new oxime-aminomethyl-based which can show a high absorption with more excellent pharmacokinetic properties As a result of efforts to develop the compounds, it has been found that quinolone compounds having a side chain alkyl group containing a t-butyl group or an alkyl group having other substituents attached to the R ₂ position of oxime meet this purpose and complete the present invention. Was done.

It is therefore an object of the present invention to provide novel quinolone compounds of the general formula (I), pharmaceutically acceptable non-toxic salts thereof, physiologically hydrolysable esters, solvates and isomers thereof.

Wherein Q is CH, CF, C- (Cl), C-CH ₃ , CO-CH ₃ or N, R is hydrogen, methyl or amino group, R ₁ is cyclopropyl, ethyl, one or more A phenyl group substituted with a fluorine atom, R ₂ is a C ₃ -C ₄ branched alkyl, a C ₃ -C ₆ alkynyl, 2-chloroethyl, methoxymethyl, or a methoxycarbonylmethyl group, or a group of the following general formula:

Wherein n is 0 or 1, m is 0, 1 or 2, X is methylene, 0 or N, and R ₃ and R ₄ are each independently hydrogen or an alkyl group of C ₁ -C ₃ , or to which they are attached It may form a ring with each other with the nitrogen atom.

Among the compounds of formula (I) having excellent antimicrobial activity and broad antibacterial spectrum and excellent pharmacokinetic properties, preferred compounds are Q, CH, CF, C-Cl, C-OMe, or N, R is hydrogen, R ₁ is cyclopropyl or 2,4-difluorophenyl, R ₂ is t-butyl, i-propyl, propazyl, homopropazol or 2-chloroethyl, and R ₃ and R ₄ are hydrogen .

More preferred compounds are Q is CH, CF or N, R is hydrogen, R ₁ is cyclopropyl, R ₂ is t-butyl, homopropazol, 2-chloroethyl, and R ₃ and R ₄ are hydrogen to be.

Position 4 in which the aminomethyl group is substituted in the pyrrolidine group of the general formula (I) is an asymmetric carbon, R or S form, and R, S mixture form. In addition, in the case of the alkyl oxime group substituted at the 3 position of pyrrolidine, there exist geometric isomers of syn and anti according to the geometric form, and each of these geometric isomers and mixtures thereof is included in the present invention. do.

Pharmaceutically acceptable non-toxic salts of the compounds of formula (I) according to the invention are salts with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid or acetic acid, trifluoroacetic acid, citric acid, maleic acid, hydroxyl acid, succinic acid, benzoic acid Salts with organic carboxylic acids such as tartaric acid, fumaric acid, manderic acid, ascorbic acid or dried acid or with sulfonic acids such as methanesulfonic acid, para-toluenesulfonic acid, and salts with other acids known and used in the quinolone-based art. Include. These acid addition salts can be prepared by conventional conversion processes.

Compounds of formula (I) according to the invention are prepared according to the scheme of Scheme 1 (JM Domagala et al. J. Med. Chem. 1991, 34, 1142; JM Domagala et. al. J. Med. Chem. 1988, 31, 991; D. Bouzard et al. J. Med. Chem. 1992, 35, 518) and the compound of formula (III) are added to a suitable base in the presence of a solvent and It can be prepared by stirring for 1 to 20 hours at a temperature of 200 to 200 ℃, it is also an object of the present invention to provide a method for preparing a new compound of formula (I).

Wherein Q, R, R ₁ , R ₂ are the same as described above; X is a halogen atom (preferably chlorine, bromine or fluorine); The compound of formula (III) can be used on its own or in the form of a salt with hydrochloric acid, bromic acid or trifluoroacetic acid or the like.

As the solvent used in the reaction, acetonitrile, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), pyridine or hexamethylphosphoamide (HMPA) and the like are preferable.

The reaction is generally carried out in the presence of an acid acceptor, wherein in order to increase the reaction efficiency of the relatively expensive starting material (II), the reactant (III) is used in an equimolar amount or 10 molar amount relative to the starting material (II), Preferably equimolar or 5 molar amounts are used and after the reaction the remaining compound of formula (III) is recovered and reused. At this time, usable acid acceptors include inorganic bases such as sodium hydrogen carbonate and potassium carbonate, triethylamine, diisopropylethylamine, pyridine, N, N-dimethylaniline, N, N-dimethylaminopyridine, 1,8- Organic bases such as diazabicyclo [5,4,0] unde-7-cene (DBU) and 1,4-diazabicyclo [2,2,2] octane (DABCO) are preferred.

The compound of formula (I) according to the present invention may be prepared according to Scheme 1, but in some cases, as shown in Scheme 2 below, R ₃ and 4-aminomethyl in the compound of formula (III) When R ₄ is hydrogen, reacted under the same conditions as in Scheme 1 using the compound of formula (III ′) in which the amino group is protected, and then the compound of formula (I ′) obtained is deprotected. Vaporization may also be carried out to synthesize the desired compound of general formula (I).

Wherein Q, R, R ₁ , R ₂ are the same as described above; X is a halogen atom (preferably chlorine, bromine or fluorine); The compound of formula (III) may be used on its own or in the form of a salt with hydrochloric acid, bromic acid or trifluoroacetic acid or the like; P represents an aminoprotecting group.

The amino protecting group which can be used at this time may be any conventionally used in the field of organic chemistry as long as it can be removed without destroying the structure of the target compound obtained as a result of the reaction. Specific examples thereof include formyl, acetyl, trifluoroacetyl, benzoyl, para-toluenesulfonyl, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, benzyloxycarbonyl, para-methoxybenzyloxy Carbonyl, trichloroethoxycarbonyl, beta-iodineethoxycarbonyl group, benzyl, paramethoxybenzyl, trityl, tetrahydropyranyl group and the like.

Removal of the amino protecting group in the target compound (I ′) obtained after completion of the reaction can be carried out using a solvolysis or reduction reaction including hydrolysis, depending on the nature of the group. For example, it is carried out in the presence or absence of an acid or a base at a temperature of 0 to 130 ℃. The inorganic acid that can be used may include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as acetic acid, trifluoroacetic acid, formic acid, toluenesulfonic acid, and Lewis acids such as boron tribromide and aluminum chloride may also be used. Examples of the base include hydroxides of alkali metals or alkaline earth metals such as sodium hydroxide and barium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, and alkali metal alkoxides such as sodium methoxide and sodium ethoxide and sodium acetate. have. As the solvent, depending on the water and the compound, a solvent such as ethanol, tetrahydrofuran, dioxane, ethylene glycol, acetic acid, or a mixed solvent of these solvents and water may be used, or in some cases, may be reacted without a solvent.

When the protecting group is para-toluenesulfonyl, benzyl, trityl, paramethoxybenzyl, benzyloxycarbonyl, para-methoxybenzyloxycarbonyl, trichloroethoxycarbonyl, beta-ioethoxycarbonyl, or the like It can be effectively removed using a reduction reaction. The removal of the protecting group by the reduction reaction may vary slightly depending on the nature of the protecting group, but by blowing hydrogen stream at a temperature of 10 to 100 ℃ in the presence of a catalyst such as platinum, palladium, nickel and the like in an inert solvent or It is generally carried out by treatment with metallic sodium or metallic lithium in liquid ammonia at a temperature of -50 to -10 ° C.

Compounds of formula (II) used as starting materials in the present invention are described in JM Domagala, et al., J. Med. Chem. 34, 1142 (1991); JM Domagala, et al., J. Med. Chem. 31, 991 (1988); D, Bouzard, et al., J. Med. Chem. 35, 518 (1992) and the like) can be prepared easily by proceeding the reaction.

On the other hand, the compound of the general formula (III) used as a reaction material in the present invention can be easily prepared by the method shown in Schemes 3, 4 and 5.

In Schemes 3 and 4, protecting groups P and P ′ are amino protecting groups having the same meaning as described above, and may be the same or different from each other; Py represents pyridine.

The preparation method is described in detail in Schemes 3 and 4.

According to Scheme 3, 3-keto-4-cyanopyrrolidine [2] can be obtained by reacting cyano ester [1] with an amino group in a solvent such as ethanol using sodium ethoxide. The cyanopyrrolidine [2] is reduced by passing through a stream of hydrogen under a platinum catalyst to produce aminoalcohol [3]. In this case, aminoalcohol [3] may be prepared using another reducing agent. That is, the ketone group and the cyano group can be reduced by using lithium aluminum hydride (LAH), sodium borohydride-cobalt chloride mixture (NaBH ₄ -CoCl ₃ ) or lithium borohydride (LiBH ₄ ). In addition, aminoalcohol [3] may be synthesized using sodium brohydride (NaBH ₄ ) or the like by first reducing a ketone group with a hydroxyl group and then a cyano group. By selectively protecting the amino group of the amino alcohol [3], a protected amine [4] is obtained. The amine [4] was treated in a sulfur trioxide-pyridine mixture with a dimethylsulfoxide solvent (Parikh, JR and Doering, WvEJ Am. Chem. Soc., 1967, 89, 5505) or oxidized with other oxidants to ketones [5] This is easily generated. The ketone compound [5] can be reacted with hydroxyamine having the structure of R ₂ described above to obtain the desired alkyl oxime compound [6]. The oxime compound [6] is deprotected by a suitable method depending on the protecting group to give the desired oxime. Compound (III) can be obtained.

Alternatively, the reaction of this ketone [5] with hydroxyamine gives the desired oxime compound [7], which is reacted with various alkyl electrophiles in the presence of a base to prepare an alkyl oxime derivative of the general formula [6]. Thereafter, the alkyl oxime compound [6] is deprotected in a suitable manner according to the protecting group as in Scheme 3 to obtain the desired oxime compound (III).

On the other hand, the compound of the general formula (II) in which the aminomethyl group at position 4 of pyrrolidine is substituted by alkyl may be prepared by the following Scheme 5.

According to the above method, the amine compound [3] is _first treated with an aldehyde of C ₁ -C ₃ and then reduced to obtain a new amine [8], and then protected. Then, the same method as in Schemes 3 and 4 is used. Thus, the compound of formula (III) can be easily synthesized.

The synthetic methods mentioned above will be explained in more detail in the preparation examples described below.

The compounds prepared according to the present invention can be administered in a variety of oral, parenteral and topical dosage forms, wherein, as active ingredients, pharmaceutically acceptable salts corresponding to the compounds of formula (I) are of course constituted.

Inert, pharmaceutically acceptable carriers for the preparation of pharmaceutical compositions from the compounds of formula (I) described herein may be solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, suppositories, and ointments. The solid carrier can be one or more of a substance that can act as a diluent, flavor, solubilizer, lubricant, suspending agent, binder, tableting agent. It may also be an encapsulating material. In the case of powders, the carrier preferably contains 5 or 10 to 70% of the finely divided component. Suitable solid carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, trigacanth, methylcellulose, sodium carboxymethylcellulose, low melting wax, cocoa butter and the like.

The term "formulation" refers to a combination of the encapsulating material and the active compound as a carrier which provides a capsule in which the active ingredient (with or without other carriers) is surrounded by a carrier and bound thereto. Similarly include casein. Tablets, powders, cachets, and capsules can be used in solid dosage forms suitable for oral administration.

Formulations in liquid form include solutions, suspensions, and emulsions. For example, water or water-propylene glycol solutions may be used for parenteral injection. Such solutions are prepared such that isotonicity, pH, and the like are suitable for the biological system. Liquid formulations may also be formed into solutions in aqueous polyethylene glycol solution. Aqueous solutions suitable for oral use can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavors, stabilizers and thickening agents. Aqueous suspensions suitable for oral use can be prepared by dispersing the finely divided active component in a viscous material such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose and known suspending agents.

Preferred pharmaceutical preparations are in unit dosage form. In such forms, the preparation is subdivided into unit forms containing the appropriate amount of active ingredient. The unit dosage form may be a packaged preparation, the package containing discrete quantities of the preparation, for example packaged tablets, capsules, powders and vials in vials or ampoules, or plasters in vials. The unit dosage form can also be a capsule, casein, tablet, gel or cream or any suitable number of seedlings in this package.

The amount of active compound in the unit dosage of the formulation is variable and can be adjusted from 1 to 100 mg depending on the efficacy of the particular active ingredient.

For therapeutic purposes used as a medicament for the treatment of bacterial infectivity, the compound used in the pharmaceutical method of the present invention is preferably initially in a dosage of about 6 to 14 mg per kilogram. However, the dosage may vary depending on the needs of the patient, the extent of the condition to be treated and the compound to be used.

It is known to determine the desired dosage in a particular state. Treatment usually begins with a dosage that is less than the optimal amount of the compound. Then increase the dosage in small increments until the optimum effect occurs. For convenience, the total daily dose may be divided in part for one day.

Compounds according to the present invention mentioned above exhibit a broad spectrum of antimicrobial spectrum and stronger antimicrobial activity against pathogens including gram-positive bacteria and gram-negative bacteria. For gram-negative bacteria, conventional compounds (eg cyprofloxacin) and It shows the same or more antimicrobial activity, especially against Gram-positive bacteria shows excellent activity compared to the existing drugs, and also shows very good antimicrobial activity against strains that are resistant to quinolone compounds.

The compound according to the present invention has a high solubility in water in terms of pharmacokinetics, so it is better absorbed than conventional quinolone compounds, has a very high bioavailability, and has a half-life in vivo that is much longer than conventional quinolone compounds. It is suitable for use as an antimicrobial agent for administration purposes.

Moreover, it is less toxic and can be used very effectively for the prevention and treatment of vaginal infection caused by bacterial infection in animals including humans.

Hereinafter, the present invention will be described in more detail with reference to Examples. However, the following Preparation Examples and Examples are only to aid the understanding of the present invention, and the scope of the present invention is not limited thereto unless the main configuration is changed.

Preparation Example 1: Synthesis of (2-cyano-ethylamino) -acetic acid ethyl ester

139.6 g (1 mol) of glycine ethyl ester hydrochloride is dissolved in 80 ml of distilled water, and 230 ml of an aqueous solution of 67.3 g (1.2 molar equivalents) of potassium hydroxide is added to the solution, followed by heating and stirring to 50 to 60 ° C. 106.2 g (2 molar equivalents) of nitrile are added dropwise. The reaction mixture is heated and stirred for 5 hours, the organic layer is separated, the water layer is extracted with ethyl ether and mixed with the organic layer. The mixed organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure, the solvent was removed and distilled under reduced pressure (100 to 150 ° C / 10.25 torr) to give 65.6 g (yield: 48%) of the title compound.

¹ H NMR (CDCl ₃ , ppm): δ 4.20 (2H, q), 3.48 (2H, s), 2.96 (2H, t), 2.54 (2H, t), 1.30 (3H, t)

Mass (FAB, m / e): 157 (M + H)

Preparation Example: Synthesis of 4-cyano-1- (N-t-butoxycarbonyl) -pyrrolidin-3-one]

In the above formula, Boc represents t-butoxycarbonyl and is used in the same sense below.

29 g (0.186 mole) of the compound obtained in Preparation Example 1 was dissolved in 200 ml of chloroform, placed in a 1 L flask, and 45 g (1.1 molar equivalent) of di-t-butoxycarbonylcarbonate was added little by little and stirred at room temperature for 17 hours. The reaction is concentrated and diluted in 250 ml of absolute ethanol. This solution is added to a solution prepared by slicing 6 g of sodium (Na) metal in a solution of sodium ethoxide (NaOEt), that is, 220 ml of anhydrous ethanol, while heating to reflux. The mixture was further heated to reflux for 1 hour, concentrated under reduced pressure, diluted with water, and washed with methylene chloride. Adjust the pH of the water layer to 4 again with 1N HCl, extract with ethyl acetate, and combine. Drying over anhydrous magnesium sulfate, filtration and concentration yields the title compound in a crude state quantitatively.

¹ H NMR (CDCl ₃ , ppm): δ 4.5 ~ 3.5 (5H, m), 1.5 (9H, s)

Mass (FAB, m / e): 211 (M + H)

Preparation Example 3: Synthesis of 4-aminomethyl-1- (N-t-butoxycarbonyl) pyrrolidine-3-ol hydrochloride

3 g (14 mmol) of the compound obtained in Preparation Example 2 were dissolved in a mixed solution of 357 ml of anhydrous ethanol and 7 ml of chloroform, and placed in a flask, followed by catalytic amount of platinum oxide (Pt ₂ O). After the air was removed under reduced pressure, a balloon filled with hydrogen gas was attached and stirred at room temperature for 17 hours. The reaction is filtered and concentrated to yield the title compound quantitatively.

¹ H NMR (CDCl ₃ , ppm): δ 8.0 (2H, bs), 3.5 ~ 2.0 (7H, m), 3.3 (2H, s), 1.38 (9H, s)

Mass (FAB, m / e): 216 (M + H)

Preparation Example 4 Synthesis of 4- (N-t-butoxycarbonyl) aminomethyl-1- (N-t-butoxycarbonyl) pyrrolidin-3-ol]

Method A: 20 g (0.094 mol) of the compound obtained in Preparation Example 3 was dissolved in a mixed solution of 456 ml of dioxane and 268 ml of distilled water, and then the pH was adjusted to 9 by adding 1N aqueous sodium hydroxide solution. 30.9 g (1.5 molar equivalents) of di-t-butoxycarbonylcarbonate was added thereto, followed by stirring at room temperature for 30 minutes.

The reaction is concentrated under reduced pressure and diluted with methylene chloride, then water is added and the pH of the water layer is acidified to about 4. The water layer was extracted with methylene chloride, combined, dried over anhydrous magnesium sulfate, concentrated and purified by column chromatography to obtain 17 g (yield 57%) of the title compound.

¹ H NMR (CDCl ₃ , ppm): δ 4.95 (1H, m), 4.6 ~ 4.1 (2H, m), 3.5 (5H, m), 3.0 (1H, m)

Mass (FAB, m / e): 317 (M + H)

Method B: 10 g (0.047 mol) of the material obtained in Preparation Example 2 was added to a 1 L flask and dissolved in 500 ml of dry tetrahydrofuran. After cooling to minus 3 ° C. in an ice-sodium chloride bath, 3.8 g (0.094 mol) of lithium aluminum hydride (LAH) is added in small portions over 20 minutes. After the addition, the mixture was stirred for 1 hour in an ice-water bath. After completion of the reaction, 4 ml of water, 4 ml of 15% aqueous sodium hydroxide solution and 12 ml of water were carefully added in this order. After stirring vigorously at room temperature for 3 hours, 10 g of anhydrous magnesium sulfate was added thereto, stirred, and concentrated by filtration. The product obtained quantitatively was diluted in 200 ml of dioxane-water (2: 1 volume ratio) and 12.3 g (0.056 mol) of di-t-butyl carbonate was added at room temperature. After completion of the reaction by stirring at room temperature for 1 hour, the reaction mixture was concentrated, diluted with ethyl acetate, and washed with saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, filtration and concentration, and purified by column chromatography using eluent hexane-ethyl acetate (2: 1 volume ratio) to give the title compound 8.2g (yield: 55%).

Method C: A thermometer was installed in a 6 L container, and 210 g (1 mol) of the material obtained in Preparation Example 2 was dissolved in 4 L of methanol. The reaction vessel was cooled to 10 DEG C with a dry ice-acetone bath. 76 g (2 mol) of sodium borohydride (NaBH ₄ ) were added little by little over 1.5 hours. At this time, the internal temperature was maintained at 10 to 13 ℃. After the addition, the mixture was stirred for another 30 minutes at the same temperature to reduce all the ketones to alcohol, and then 243 g (1 mol) of cobalt chloride hydrate was added over 10 minutes. After completion of the reaction, the resulting solid complex was dissolved in 4 L of ammonia water, diluted with 8 L of water, extracted with ethyl acetate, and combined. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The mixture was mixed with 1.5 L of dioxane and 0.5 L of distilled water, and then 212 g of di-butyl carbonate was added thereto, followed by stirring at room temperature for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, diluted with dichloromethane, and washed with water. After drying over anhydrous magnesium sulfate, filtration and concentration were purified using silica gel-filled column chromatography (hexane-ethyl acetate 2: 1 by volume) to give 202 g (yield: 64%) of the title compound.

Method D: 10 g (0.047 mol) of the compound obtained in Preparation Example 2 was added to a 1 L flask and dissolved in 500 ml of methanol. It was cooled in an ice bath and 3.6 g (0.094 mol) of sodium borohydride were added in portions over 20 minutes. The mixture was stirred for 30 minutes to complete the reaction, and then concentrated under reduced pressure, and diluted with ethyl acetate. The mixture was washed with water, dried over anhydrous magnesium sulfate, and concentrated by filtration to obtain a compound in which only the desired ketone group was reduced with alcohol. 10.1 g (0.047 mol) of this alcohol compound was dissolved in 200 ml of dry tetrahydrofuran, and then cooled to −5 ° C. in an ice-salt bath. 2.6 g (0.066 mol) of lithium aluminum hydride was added over 20 minutes. The mixture was stirred at the same temperature for 30 minutes to complete the reaction, and then 2.6 ml of water, 2.6 ml of 15% sodium hydroxide and 7.8 ml of water were added in this order and stirred at room temperature for 1 hour. 6 g of anhydrous magnesium sulfate was added, and after stirring for 30 more minutes, it filtered and concentrated to obtain a product. The product was diluted with 200 ml of dioxane-water (2: 1 volume ratio), 12.3 g (0.56 mol) of di t-butyl carbonate was added little by little, followed by stirring for 30 minutes to complete the reaction. After concentration, the mixture was diluted with ethyl acetate and washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. Purified by column chromatography to give 12.3g (83%) of the title compound.

Preparation Example 5 Synthesis of 4- (N-t-butoxycarbonyl) aminomethyl-1- (N-t-butoxycarbonyl) pyrrolidin-3-one]

14 g (0.044 mol) of the compound obtained in Preparation Example 4 was dissolved in 64 ml of dimethyl sulfoxide, and then 18.5 ml (3 mol equivalent) of triethylamine was added and cooled with an ice bath. When the bottom wall of the flask begins to freeze, 12.7 g (1.8 molar equivalents) of an oxidizing agent pyridine-sulfotrioxide (Py-SO ₃ ) is added in small portions. After the addition, remove the bath and stir at room temperature for 3 hours. The reaction is diluted with water and then extracted with methylene-chloride, combined, dried over anhydrous magnesium sulfate and concentrated to give the title compound in quantitative form without purification.

¹ H NMR (CDCl ₃ , ppm): δ 4.95 (1H, bs), 4.15 to 2.7 (6H, m), 1.45 (9H, s), 1.40 (9H, s)

Mass (FAB, m / e): 315 (M + H)

Preparation Example 6 Synthesis of 1- (N-t-butoxycarbonyl) -4- (N-t-butoxycarbonyl) aminomethyl-pyrrolidin-3-one t-butyloxime

300 mg of the compound obtained in Preparation Example 5 was dissolved in a 30 ml reaction vessel in 6 ml of 95% ethanol and 3 ml of tetrahydroleuran (THF). 487 mg (3.5 molar equivalents) of o-t-butylhydroxy amine hydrochloride was added thereto, and 281 mg (3.5 molar equivalents) of sodium bicarbonate was dissolved in 1.5 ml of distilled water and added. The reaction was completed by stirring for 40 minutes in a 40 ℃ oil bath, and then concentrated under reduced pressure after cooling. The reaction mixture was diluted with methylene chloride, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then filtered and concentrated. Silica gel-filled column chromatography was used for elution with hexane-ethyl acetate (1: 1 volume ratio) to obtain 285 mg (yield 80%) of the title compound.

¹ H NMR (CDCl 3): δ 5.10 (1H, bs), 4.05 (2H, s), 3.71 (1H, dd), 3.43 (1H, br), 3.0 (1H, m), 1.42 (18H, s), 1.30 (9H, s)

MS (m / e, FAB): 385 (M + H)

Preparation Example 7 Synthesis of 1- (N-t-butoxycarbonyl) -4- (N-t-butoxycarbonyl) aminomethyl-pyrrolidin-3-one 3-butynyl oxime

[A. Synthesis of 3-butynyl hydroxyamine]

3-butynol (0.35 g, 5 mmol), N-hydroxyphthalimide (0.86 g, 5.25 mmol) and triphenylphosphine (1.44 g, 5.5 mmol) were dissolved in 15 ml of anhydrous tetrahydrofuran, followed by diethylazodica Reboxyllade (1.05 g, 6 mmol) was added for 30 minutes. After stirring for 10 minutes at room temperature, the solvent was distilled under reduced pressure, 50 ml of ethyl acetate-hexane (1: 1 v / v) was added thereto, the solid formed was filtered off, the filtrate was concentrated, and then column chromatography (hexane-ethyl acetate 9 : 1 v / v). White solid obtained [0.54 g, yield 50%, ¹ H NMR (CDCl ₃ ): δ 7.85 (2H, m), 7.75 (2H, m), 4.2 (2H, t), 2.8 (2H, dd), 2.5 ( 2H, dd), 2.1 (1H, s) FAB MS (POS): [M + H] ^- = 216] was dissolved in 12 ml of methylene chloride, 0.25 g (5 mmol) of hydrazine hydrate was added dropwise in 4 ml of methanol, and the solid was added dropwise. After filtration was removed, the filtrate was concentrated under reduced pressure at low temperature to obtain the target compound (0.2 g yield 93%).

¹ H NMR (CDCl 3): δ 9.5 (2H, br), 4.5 (2H, t), 2.8 (2H, m), 2.4 (2H, m), 2.05 (1H, s)

FAB MS (POS): [M + H] ⁺ = 86

[B. Synthesis of 3-butynyl oxime]

Ketone (0.45 g, 1.43 mmol) and 3-butynyl hydroxyamine (0.2 g, 2.35 mmol) were dissolved in 5 ml of methanol, and then reacted at 60 ° C. for 12 hours, followed by concentration under reduced pressure, followed by column chromatography (ethyl acetate-hexane 1: 4). v / v) to obtain 0.59 g of the target compound (yield: quantitative).

¹ H NMR (CDCl ₃ δ, ppm): 5.0 (1H, m), 4.15 (2H, t), 4.5 (2H, s), 3.75 (1H, m), 3.6-3.2 (3H, m), 3.0 ( 1H, m), 2.5 (2H, m), 2.0 (1H, s), 1.45 (18H, s)

FAB MS (POS): 382 (M + H) ⁺ = 382

Production Example 8-17

In the same manner as in Preparation Example 7, instead of 3-butynol, by reacting the alcohol derivative having the structure of R ₂ described above, to obtain the amine compound of Table 1, respectively.

Preparation Example 14 Synthesis of 1- (N-t-butoxycarbonyl) -4- (N-t-butoxycarbonyl) aminomethyl-pyrrolidin-3-one oxime

300 mg of the compound obtained in Preparation Example 5 was dissolved in a 30 ml reaction vessel in 6 ml of 95% ethanol and 3 ml of tetrahydrofuran (THF). 232 mg (3.5 molar equivalents) of hydroxyamine hydrochloride (NH ₂ OH.HCl) was added thereto, and 281 mg of sodium bicarbonate (3.5 molar equivalents) was added to 1.5 ml of distilled water. The reaction was completed by stirring for 40 minutes in a 40 ℃ oil bath, and then concentrated under reduced pressure after cooling. The reaction mixture was diluted with methylene chloride and concentrated under reduced pressure. The reaction mixture was diluted with methylene chloride, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Silica gel-filled column chromatography was used to separate the hexane-ethyl acetate (1: 1 volume ratio) eluent to give 230 mg (yield 73%) of the title compound.

¹ H NMR (CDCl ₃ ): δ 9.70 (1H, bs), 5.05 (1H, bs), 3.83-2.79 (7H, m), 1.42 (18H, s)

MS (m / e, FAB): 329 (M + H)

Preparation Example 15 Synthesis of 1- (N-t-butoxycarbonyl) -4- (N-t-butoxycarbonyl) aminomethyl-pyrrolidin-3-one propazol oxime

659 mg of the title compound of Preparation Example 6, 193 mg of tetra-n-butyl ammonium bromide and 855 mg of propazyl bromide were added to 15 ml of dichloromethane, and 5 ml of 15% aqueous sodium hydroxide solution was added thereto, followed by stirring at room temperature for 30 minutes. The organic layer of the reaction mixture was separated, dried over anhydrous magnesium sulfate, filtered and the residue obtained by distillation under reduced pressure was purified by glass column chromatography to obtain 776 mg (yield: 92%) of the target compound.

¹ H NMR (CDCl ₃ ): 4.92 (1H, m), 4.13 (2H, m), 3.76 (1H, m), 3.41 (1H, m), 3.25 (2H, m), 3.02 (1H, m), 1.50 (9H, s), 1.49 (9H, s)

MS (m / e, FAB): 370 (M + H)

Production Examples 16 to 18

In the same manner as in Preparation Example 7, but instead of 3-butynol by reacting the alcohol derivative having the structure of R ₂ described above, to obtain the amine compounds of Table 2, respectively.

[Production Example 19]

[Synthesis of 4-aminomethyl-pyrrolidin-3-one t-butyl oxime hydrochloride]

After cooling 5 ml of methanol to 0 ° C. and slowly adding 3 ml of acetyl chloride and stirring for 10 minutes, a solution of 640 mg of the title compound of Preparation Example 6 in 10 ml of methanol was added thereto. The reaction mixture was stirred at room temperature for 20 minutes, and the residue obtained by distillation under reduced pressure was washed with ethyl ether. The residue was dried to obtain 390 mg (yield: 91%) of the target compound as a white solid.

¹ H NMR (DMSO-d ₆ ): 10.0-9.6 (2H, bsX2), 8.20 (7H, m), 3.90 (2H, m), 3.61 (1H, bs), 3.40 (2H, bs), 3.12 (2H , bs), 1.25 (9H, s)

MS (m / e, FAB): 186 (M + H)

Production Example 20-29

In the same manner as in Preparation Example 19, the compounds of Preparation Examples 20 to 29 were obtained from the compounds obtained in Preparation Examples 7 to 13 and 16 to 18, respectively, as shown in Table 3.

Example 1 7- (4-Aminomethyl-3-t-butyloxyimino-pyrrolidin-1-yl) -1-cyclopropyl-6-fluor-1,4-dihydro-4-oxo- Synthesis of 1,8-naphthyridine-3-carboxylic acid]

7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro [1,8] naphthyridine-3-carboxylic acid (141 mg, 0.5 mmol) and (3-amino obtained in Preparation Example 19 Methyl-4-t-butyloxyiminopyrrolidine dihydrochloride (2HCl) (143 mg, 0.55 mmol) was well suspended in 2.5 ml of acetonitrile, followed by diazabicyclo [5.4.0] undec-7-cene ( 230 mg, 1.5 mmol) was slowly added dropwise and stirred at room temperature for 30 minutes, 1 ml of water was added to the reaction mixture, vigorously stirred for 10 minutes, filtered and acetonitrile-water (4: 1 v / v, 2 ml) and acetonitrile (2 ml x). 2) After washing in order, washed with ether and dried to give the target compound 132mg (yield 61%).

¹ H NMR (DMSO-d 6); 8.6 (1H, s), 8.1 (1H, d), 4.6 (2H, s), 4.2 (1H, dd), 3.9 (1H, m), 3.7 (1H, m), 3.1 (1H, m), 2.9 -2.7 (2H, m), 1.3 (9H, s), 1.2 (2H, m), 1.1 (2H, m)

FAB MS (POS): 432

Example 2 7- (3-Aminomethyl-4-t-butyloxyiminopyrrolidin-1-yl) -1-cyclopropyl-6,8-difluoro-4-oxo-1,4- Synthesis of Dihydroquinoline-3-carboxylic Acid]

1-cyclopropyl-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (141 mg, 0.5 mmol) and 3-aminomethyl-4-t-butyloxy Minofyrrolidine dihydrochloride (143 mg, 0.55 mmol) was heated to reflux for 2.5 hours, cooled to room temperature and treated in the same manner as in Example 1 to obtain 151 mg (yield 67%) of the title compound.

¹ H NMR (DMSO-d 6); 8.6 (1H, s), 7.7 (1H, d), 4.3 (2H, s), 4.1 (1H, m), 3.9 (1H, m), 3.8 (1H, m), 2.9 (1H, m), 2.8 -2.7 (2H, m), 1.3 (9H, s), 1.15 (4H, s)

FAB MS (POS): [M + H] ⁺ = 449

Example 3 8-Chloro-1-cyclopropyl-6-fluoro- [7- (3-aminomethyl-4-t-butyloxyiminopyrrolidin-1-yl)]-4-oxo-1 Synthesis of, 4-dihydroquinoline-3-carboxylic acid]

In the same manner as in Example 1 using 8-chloro-1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (150 mg, 0.5 mmol) The reaction mixture was concentrated and the residue was separated and purified by preparative HPLC to give 148 mg (yield 64%) of the title compound.

¹ H NMR (DMSO-d ₆ δ ppm); 8.7 (1H, s), 7.9 (1H, d), 4.4 (2H, s), 4.3 (1H, m), 3.8 (1H, m), 3.7 (1H, m), 3.0 (1H, m), 2.9 -2.7 (2H, m), 1.3 (9H, s), 1.2 ~ 0.9 (4H, m)

FAB MS (POS): [M + H] ⁺ = 465

Example 4 7- (3-Aminomethyl-4-t-butyloxyiminopyrrolidin-1-yl) -1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline Preparation of 3-carboxylic Acid]

Heat reflux for 3.5 hours in the same manner as in Example 1 using 1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (132 mg, 0.5 mmol) The resulting residue was treated with preparative HPLC to give 129 mg (yield: 60%) of the title compound.

¹ H NMR (DMSO-d ₆ δ ppm); 8.6 (1H, s), 7.8 (1H, d), 7.2 (1H, d), 4.4 (2H, s), 3.9 (1H, m), 3.8 (1H, m), 3.7 (1H, m), 3.0 (1H, m), 2.9-2.7 (2H, m), 1.4 (9H, s), 1.3-1.1 (4H, m)

FAB MS (POS): [M + H] ⁺ = 431

Example 5 5-Amino-7- (3-aminomethyl-4-t-butyloxyiminopyrrolidin-1-yl) -1-cyclopropyl-6, 8-difluoro-4-oxo- Preparation of 1,4-dihydroquinoline-3-carboxylic acid]

Same method as Example 3 using 5-amino-1-cyclopropyl-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (148 mg, 0.5 mmol) The residue produced by heating under reflux for 8 hours was purified by preparative HPLC to give 151 mg (yield: 65%) of the title compound.

¹ H NMR (DMSO-d ₆ ); 8.4 (1H, s), 7.5 (2H, br), 4.3 (2H, s), 4.0-3.8 (3H, m), 3.2 (1H, m), 2.8-2.6 (2H, m), 1.3 (9H, s), 1.1 (4H, m)

FAB MS (POS): [M + H] ⁺ = 464

Example 6 7- (3-Aminomethyl-4-t-butyloxyiminopyrrolidin-1-yl) -1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1, Preparation of 4-dihydroquinoline-3-carboxylic acid]

In the same manner as in Example 3 using 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (148 mg, 0.5 mmol) After heating at reflux for 10 hours, the resulting residue was purified by preparative HPLC to obtain 92 mg (yield: 40%) of the title compound.

¹ H NMR (DMSO-d ₆ δ ppm): 8.9 (1H, s), 7.8 (1H, d), 4.5 (2H, s), 4.3 (1H, m), 4.1 (1H, m), 3.9 (1H , m), 3.0 (1H, m), 2.8-2.7 (2H, m), 2.7 (3H, s), 1.3 (9H, s), 1.25 (2H, m), 0.9 (2H, s)

FAB MS (POS): [M + H] ⁺ = 461

Example 7 7- (3-Aminomethyl-4-t-butyloxyiminopyrrolidin-1-yl) -1- (2,4-difluorophenyl) -6-fluoro-4-oxo Preparation of -1,4-dihydro-1,8-naphthyridine-3-carboxylic acid]

6,7-difluoro-1- (2,4-difluorophenyl) -4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (168 mg, 0.5 mmol) And 3-aminomethyl-4-t-butyloxyiminopyrrolidine dihydrochloride (143 mg, 0.55 mmole) in 3 ml of anhydrous acetonitrile followed by 1,8-diazabicyclo [5,4,0] -undec -7-Sene (230 mg, 1.5 mmol) was added thereto, stirred at room temperature for 15 minutes, and treated in the same manner as in Example 1 to obtain 203 mg (yield: 81%) of the title compound.

¹ H NMR (DMSO-d ₆ ): 8.8 (1H, s), 8.1 (1H, d), 7.8 (1H, m), 7.6 (1H, dd), 7.3 (1H, dd), 4.3 (2H, s ), 4.0 (1H, m), 3.9 (1H, m), 3.0 (1H, m), 2.8-2.6 (2H, m), 1.3 (9H, s)

FAB MS (POS): [M + H] ⁺ = 504

Example 8 7- (3-Aminomethyl-4-t-butyloxyiminopyrrolidin-1-yl) -6,8-difluoro-1-ethyl-4-oxo-1,4-di Preparation of Hydroquinoline-3-carboxylic Acid]

Heated for 5 hours in the same manner as in Example 3 using 1-ethyl-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (136 mg, 0.5 mmol) After the reflux, the resulting residue was separated and purified through preparative HPLC to obtain 170 mg (yield: 78%) of the title compound.

¹ H NMR (DMSO-d ₆ ); 8.8 (1H, s), 7.8 (1H, d), 4.5 (2H, q), 4.4 (2H, s), 4.2 (1H, m), 3.9 (1H, m), 3.1 (1H, m), 2.9 -2.7 (2H, m), 1.45 (3H, t), 1.3 (9H, s)

FAB MS (POS): [M + H] ⁺ = 437

[Examples 9 to 88]

From the amine compounds obtained in Preparation Examples 20 to 30, each of the following Compounds 9 to 88 was obtained using the same method as Examples 1 to 8, and the respective NMR data and Mass data are shown in Tables 4 to 11 below. .

Biological Example 1: In vitro Antimicrobial Activity Assay

The usefulness of the compounds according to the present invention is based on the known compounds Ofloxacin and Ciprofloxacin as a control agent against standard strains, clinically isolated strains, strains resistant to some antibiotics. Minimum Inhibitory Concentration (MIC, ug / ml) was obtained and evaluated. The minimum inhibitory concentration was determined by diluting the test compound by a 2-fold dilution method and then dispersing it in Muller-Hinton agar medium and then 10 per ml. 5 μl of standard strains containing CFU were inoculated and incubated at 37 ° C. for 18 hours. The results are shown in Table 12.

Biological Example 2: Pharmacokinetic Experiments

Pharmacokinetic parameters for rats were determined using SD rats (males) weighing approximately 230 ± 10 g. That is, the compounds according to the present invention were administered through the femoral vein at a dose of 20 mg / kg to 4 to 5 mice, and blood was collected through the femoral artery at regular intervals after administration. The concentration of blood was calculated by the method, and the calculated pharmacokinetic parameter values, half-life (T1 / 2) and area under the curve (ALC) values are shown in Table 13.

Claims (3)

Novel quinoline carboxylic acid derivatives represented by the following general formula (I), pharmaceutically acceptable salts thereof and solvates thereof including hydrates: Wherein R is hydrogen, methyl or an amino group; Q is CH, CF, C-Cl, C-CH ₃ , CO-CH ₃ or N; R ₁ is cyclopropyl, ethyl, a phenyl group substituted with one or more fluorine atoms, R ₂ is C ₃ -C ₄ branched alkyl, C ₃ -C ₆ alkynyl, 2-chloroethyl, methoxymethyl, or A methoxycarbonylmethyl group, or a group of the following general formula: Wherein n is 0 or 1, m is 0, 1 or 2, X is methylene, O or N, and R ₃ and R ₄ are each independently hydrogen or an alkyl group of C ₁ -C ₃ , or to which they are attached It may form a ring with each other with the nitrogen atom. The compound of claim 1 wherein Q is CH, CF, C-OMe or N, R is hydrogen, R ₁ is cyclopropyl or 2,4-difluorophenyl, R ₂ is i-propyl, t- Butyl, propazyl, homopropazol, or 2-chloroethyl. The compound of claim 2, wherein Q is CH, CF or N, R is hydrogen, R ₁ is cyclopropyl, and R ₂ is t-butyl, homopropazol, or 2-chloroethyl.