KR100361832B1 - Novel quinolone carboxylic acid derivatives having (4-aminomethyl-3-substituted oxime-2-methyl)pyrrolidine - Google Patents

Abstract

The present invention has a superior antibacterial activity and a broad spectrum of antibacterial spectrum, and (4-aminomethyl-3-substituted as a substituent at the 7-position of the quinolone mother nucleus, which shows pharmacokinetic properties superior to conventional quinolone antibiotics. Novel quinolone carboxylic acid derivatives of formula (1) having an oxime-2-methyl) pyrrolidine group, pharmaceutically acceptable salts, esters, solvates and isomers thereof, preparation methods thereof and containing the compounds as active ingredients Relates to an antimicrobial composition comprising:

Where

R ₁ is C ₁ -C ₅ alkyl, C ₃ -C ₆ cycloalkyl or dihalophenyl;

R ₂ is hydrogen, C ₁ -C ₅ alkyl or amino;

Q is CH, CF, C-Cl, C-CH ₃ , CO-CH ₃ or N;

R ₃ is C ₁ -C ₅ alkyl, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkylC ₁ -C ₅ alkyl, C ₃ -C ₆ alkenyl, C ₃ -C ₆ alkynyl, C ₁ -C ₅ haloalkyl, or substituted or unsubstituted phenyl or benzyl.

Description

Novel quinolone carboxylic acid derivatives having (4-aminomethyl-3-substituted oxime-2-methyl) pyrrolidine} (4-aminomethyl-3-substituted oxime-2-methyl) pyrrolidine}

The present invention relates to novel quinolone compounds exhibiting excellent antimicrobial activity. More specifically, the present invention provides a compound having (4-aminomethyl-3-substituted oxime-2-methyl) pyrrolidine at the 7-position of the quinolone mother nucleus as a substituent, which has excellent antibacterial activity and broad antibacterial spectrum. Novel quinolone carboxylic acid derivatives of formula (1), pharmaceutically acceptable salts, esters, solvates and isomers thereof, methods for their preparation and antimicrobial compositions containing these compounds as active ingredients:

Formula 1

Where

R ₁ is C ₁ -C ₅ alkyl, C ₃ -C ₆ cycloalkyl or dihalophenyl;

R ₂ is hydrogen, C ₁ -C ₅ alkyl or amino;

Q is CH, CF, C-Cl, C-CH ₃ , CO-CH ₃ or N;

R ₃ is C ₁ -C ₅ alkyl, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkylC ₁ -C ₅ alkyl, C ₃ -C ₆ alkenyl, C ₃ -C ₆ alkynyl, C ₁ -C ₅ haloalkyl, or substituted or unsubstituted phenyl or benzyl.

Alkyl used in the present invention is straight or branched chain.

In the structure of the above formula (1), position 4 substituted by aminomethyl in the pyrrolidin group at position 7 of the parent nucleus is an asymmetric carbon in R or S form, and includes R / S mixture form. In addition, in the case of the oxime group substituted at the 3 position, syn- and anti-isomers exist according to geometric shapes, and each of these geometric isomers and mixtures thereof is included in the present invention.

Since the emergence of nalidixic acid (G, Y. Lesher, et al., J. Med. Chem. 5, 1063-1065 (1962)) as a therapeutic agent for urinary tract infections in 1962, numerous quinoline carboxylic acid-based antimicrobials, oxols Oxolinic acid, Roxoxacin, and Pipemidic acid were developed. These early antimicrobials have little activity against Gram-positive bacteria and have been used only as antimicrobial agents for Gram-negative bacteria. Albrecht R., Prog. Drug Res., 21, 9 (1977).

Recently developed by Norfloxacin, H. Koga, et al., J. Med. Chem. 23, 1358-1363 (1980), a new generation of quinolone compounds containing fluorine at position 6 As a result, research on quinolone antibiotics has been very extensive. However, nofloxacin is still used only for the treatment of diseases caused by Gram-negative bacteria because of its low antimicrobial activity against Gram-positive bacteria and poor distribution and absorption. Ciprofloxacin; see R. Wise, et al., J. Antimicrob. Agents Chemother., 23, 559 (1983), and ofloxacin; K. Sata, et al. , Antimicrob. Agents Chemother., 22, 548 (1982)) have been developed, and these antimicrobials have broader antimicrobial activity than earlier antimicrobials, and are widely used in clinical and therapeutic practice today.

On the other hand, compounds currently in use or in clinical trials mainly have piperazine derivatives at position 7 of the quinolone hair nucleus, such as cyprofloxacin or opfloxacin. However, as a result of efforts to develop more powerful and broader antibacterial quinolone antibiotics, the introduction of 3-amino or 3-aminomethyl pyrrolidine groups at position 7 results in compounds with piperazine groups at position 7. In comparison, the antimicrobial activity against gram-positive bacteria was increased while maintaining the antimicrobial activity against gram-negative bacteria. However, in general, compounds having these pyrrolidine substituents exhibit problems such as low solubility in water compared to compounds having piperazine substituents, and thus do not exhibit strong antimicrobial effects such as in vitro antibacterial activity. Thus, efforts have been made to increase this disadvantage of compounds with pyrrolidine substituents, ie solubility in water.

On the other hand, pharmacokinetic properties are improved by introducing other functional groups instead of amino groups in pyrrolidine or piperazine to improve the disadvantages of quinolone compounds, such as relatively weak antimicrobial activity against Gram-positive bacteria and low solubility in water. Efforts have also been made to improve this. As part of this effort, there is an example in which an oxime group is introduced into the amine structure at position 7 of the quinolone compound. In other words, Abott's team is a professional magazine [J. Med. Chem. 1992, 35, 1392-1398 reported that the 3-oxime (or methyloxime) pyrrolidine or 4-oxime (or methyloxime) piperidine group is located at position 7 of quinolone as shown in the following structural formula (1a): When substituted for, it shows increased antimicrobial activity against Gram-positive bacteria.

Where

R is cyclopropyl or 2,4-difluorophenyl,

X is C-H, C-F or N,

n is 1 or 2,

R 'is hydrogen or methyl.

However, the compound is excellent in efficacy against Gram-positive bacteria, but exhibits low antibacterial activity against Gram-negative bacteria and does not show a broad spectrum, and also has a disadvantage of showing low antimicrobial activity in in vivo experiments.

In other words, known compounds with oxime structure exhibit increased antimicrobial activity against Gram-negative bacteria including MRSA (methicillin-resistant Staphylococcus aureus) bacteria compared to previous quinolone antimicrobial agents, The antimicrobial spectrum is weaker than conventional oploxacin or cyprofloxacin.

Therefore, the present inventors have conducted intensive studies to solve these problems and develop compounds exhibiting strong antimicrobial activity against a wide range of pathogens. As a result, position 4 of the pyrrolidine structure is substituted by an aminomethyl group, Synthesis of a new quinolone compound of the following formula substituted by an oxime substituted at position 3, and found that these compounds have a strong antimicrobial activity against a wide range of Gram-positive and negative pathogens, including resistant bacteria It was completed.

Accordingly, it is an object of the present invention to provide novel quinolone carboxylic acid compounds of formula (1), pharmaceutically acceptable non-toxic salts thereof, physiologically hydrolysable esters, solvates and isomers.

Formula 1

Where

R ₁ is C ₁ -C ₅ alkyl, C ₃ -C ₆ cycloalkyl or dihalophenyl;

R ₂ is hydrogen, C ₁ -C ₅ alkyl or amino;

Q is CH, CF, C-Cl, C-CH ₃ , CO-CH ₃ or N;

R ₃ is C ₁ -C ₅ alkyl, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkylC ₁ -C ₅ alkyl, C ₃ -C ₆ alkenyl, C ₃ -C ₆ alkynyl, C ₁ -C ₅ haloalkyl, or substituted or unsubstituted phenyl or benzyl.

Among the compounds of the formula (1) showing excellent antimicrobial activity and broad antibacterial spectrum and excellent efficacy, preferred compounds are those wherein Q is CH, CF, C-Cl or N, R ₂ is hydrogen or amino, and R ₁ is cyclopropyl or 2,4-difluorophenyl and R ₃ is methyl, ethyl, t-butyl, i-propyl, allyl, phenyl, propargyl or 2-fluoroethyl.

More preferred compounds of formula (1) are compounds wherein Q is CH, CF or N, R ₂ is hydrogen, R ₁ is cyclopropyl, R ₃ is methyl, ethyl, 2-fluoroethyl or t-butyl .

Most preferred compounds of formula (1) are compounds wherein Q is CF or N, R ₂ is hydrogen, R ₁ is cyclopropyl, and R ₃ is methyl.

In the compound of Formula (1), the carbon atom at position 4 and at position 2 with methyl group in the pyrrolidin group at the parent nucleus position 7 is asymmetric carbon and is in the form of R or S form or R / S mixture. May exist. The present invention also encompasses both these individual isomers and isomer mixtures. In addition, in the case of the oxime group substituted at the 3 position, syn- and anti-isomers exist according to geometric shapes, and each of these geometric isomers and mixtures thereof is included in the present invention.

The compound of formula (1) according to the present invention may also form non-toxic salts with pharmaceutically acceptable inorganic or organic acids. These pharmaceutically acceptable non-toxic salts include, for example, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid or acetic acid, trifluoroacetic acid, citric acid, maleic acid, oxalic acid, succinic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid Salts with organic carboxylic acids such as ascorbic acid or dried acid or with sulfonic acids such as methanesulfonic acid, para-toluenesulfonic acid and with other acids known and used in the quinolone-based art. These acid addition salts can be prepared by conventional conversion processes.

Another object of the present invention is to provide a method for preparing the compound of formula (1).

The compound of formula (1) according to the present invention can be prepared by reacting a compound of formula (2) with a compound of formula (3) according to the method shown in Scheme 1 below.

In the above scheme,

R ₁ , R ₂ , R ₃ and Q are as defined above,

X represents halogen, preferably chlorine, bromine or fluorine.

As shown in Scheme 1, the compound of formula (1) can be prepared by reacting a quinolone compound of formula (2) with a compound of formula (3). In this reaction, the compound of formula (3) can be used on its own or in the form of a salt with hydrochloric acid, hydrobromic acid or trifluoroacetic acid or the like.

This reaction is generally carried out in a solvent. Examples of solvents which are preferably used for this purpose may include acetonitrile, dimethylformamide (DMF), dimethylsulfoxide (DMSO), pyridine or hexamethylphosphoramide (HMPA) and the like.

The reaction also generally proceeds in the presence of a base, wherein the compound of formula (3) is reacted with respect to 1 mole of the starting material (2) in order to increase the reaction efficiency of the relatively expensive starting compound (2). It is used in the ratio of equimolar amount to 5 molar amount, and after the reaction, the remaining compound of formula (3) is recovered and reused. The base that can be used includes inorganic bases such as sodium hydrogen carbonate, sodium carbonate and potassium carbonate and triethylamine, diisopropylethylamine, pyridine, N, N-dimethylaniline, N, N-dimethylaminopyridine, 1,8- Organic bases, such as a diazabicyclo [5.4.0] undec-7-ene (DBU) and a 1, 4- diazabicyclo [2.2.2] octane (DABCO), are preferable.

In the reaction according to Scheme 1, the reaction temperature is not particularly limited and generally, the reaction is carried out by stirring at a temperature of room temperature to 200 ° C. for 1 to 20 hours.

Compounds of formula (2) used as starting materials in the process of the invention are compounds known in the prior art or can be readily prepared by known methods. See J. M. Domagala, et al., J. Med. Chem., 34, 1142 (1991); J. M. Domagala, et al., J. Med. Chem., 31, 991 (1988); In D. Bouzard, et al., J. Med. Chem., 35, 518 (1992) and the like].

The compound of formula (3) used as another starting material in the method of the present invention can be easily prepared by the method as shown in the following Scheme 2.

In the above scheme,

R ₃ is as mentioned above,

P and P 'each represent the same or different amino protecting group.

As the amino protecting group in Scheme 2, any one can be used as long as it can be easily removed without destroying the structure of the target compound obtained by the reaction as commonly used in the field of organic chemistry. Specific examples thereof include formyl, acetyl, trifluoroacetyl, benzoyl, para-toluenesulfonyl, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, benzyloxycarbonyl, para-methoxybenzyloxy Carbonyl, trichloroethoxycarbonyl, beta-iodoethoxycarbonyl, benzyl, paramethoxybenzyl, trityl, tetrahydropyranyl and the like.

Referring to the preparation method of Scheme 2 in detail.

According to Scheme 2, (l)-or (d) -ethylalanine and acrylonitrile were reacted in the presence of a mixture of potassium hydroxide-water to obtain compound (1 '), and then immediately protected with an amine group to selectively cyano Ester compound 2 'is obtained in 90% yield. This compound (2 ') is cyclized in the presence of sodium ethoxide to give cyano ketone (3'), and the ketone group of this compound is reduced with sodium borohydride (NaBH ₄ ) to give cyano alcohol ( 4) is obtained. Thereafter, the cyano group is reduced with a reducing agent such as lithium aluminum hydride (LiAlH ₄ ) to obtain an amine (5), and the amino group of the compound is selectively protected to obtain a protected alcohol (6). Treatment in a sulfur trioxide-pyridine mixture with a dimethylsulfoxide solvent or oxidation with another oxidant yields the ketone compound (7). The obtained ketone compound (7) is reacted with O-substituted hydroxyamine hydrochloride having the structure of R ₃ described above to give the desired substituted oxime compound (8), which is derivatized with hydrochloric acid. Protection can give the desired compound of formula (3).

The novel quinolone carboxylic acid compounds according to the present invention can be administered in the form of various pharmaceutical preparations, such as oral, parenteral and topical dosage forms, wherein the active ingredients are the compounds of formula (1) as well as the corresponding pharmaceutical Acceptable salts or hydrates may be used.

The carrier used to prepare the pharmaceutical composition from the compound of formula (1) according to the present invention may be an inert, pharmaceutically acceptable solid or liquid carrier which is commonly used in the pharmaceutical art according to the formulation to be prepared. have. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, suppositories, and ointments, and the solid carriers used for their preparation include diluents, flavors, solubilizers, lubricants, suspending agents, binders, boraxes It may be one or more substances selected from the group consisting of release, encapsulant, and the like. In the case of powders, the carrier preferably comprises finely divided active ingredients in a ratio of 5 to 70%, preferably 10 to 70%, and suitable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose , Pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting wax, cocoa butter and the like. 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. As the liquid carrier used for the preparation of such liquid formulations, for example, water or water-propylene glycol solutions may be used for parenteral injection. Such solutions are prepared such that isotonicity, pH, etc. are suitable for the biological system. Liquid formulations may also be prepared in the form of solutions dissolved in aqueous polyethylene glycol solution. Aqueous solutions suitable for oral use can be prepared by dissolving the active ingredient in water and adding the appropriate 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 rubbers, resins, methylcellulose, sodium carboxymethylcellulose and known suspending agents.

Pharmaceutical formulations are preferably in unit dosage forms containing an appropriate amount of active ingredient. The unit dosage form may be a packaged preparation, the package containing discrete quantities of the preparation, such as tablets, capsules, powders and plasters in tubes or bottles, packaged in vials or ampoules. The unit dosage form may also be a capsule, casein, tablet, gel, or cream.

The amount of active compound in the unit dosage of the formulation is variable and can be adjusted to 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 infectious diseases, the compound used in the pharmaceutical method of the present invention preferably initially has a dosage of about 6 to 14 mg per kg of body weight. However, the dosage may vary depending on the needs of the patient, the degree of condition to be treated, and the compound to be used.

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

The above-mentioned compounds according to the present invention exhibit a broad spectrum of antimicrobial spectrum and stronger antimicrobial activity against various Gram-positive bacteria and Gram-negative bacteria, and for Gram-negative bacteria, they exhibit the same or higher antimicrobial activity, Gram-negative bacteria show excellent activity compared to conventional drugs, and also shows very good antibacterial activity against strains that are resistant to quinolone compounds.

The compound according to the present invention also has a merit in that it has better solubility in water than the conventional quinolone compound in terms of pharmacokinetics. Moreover, it is less toxic and can be used very effectively for the purpose of preventing and treating diseases caused by bacterial infection in animals including humans.

The invention is explained in more detail by the following preparation examples and examples. However, the following Preparation Examples and Examples are only provided to aid the understanding of the present invention, and the scope of the present invention is not limited by them in any way unless the main configuration is changed.

Preparation Example 1 Synthesis of Ethyl (2S) 2-[(t-butoxycarbonyl)-(2-cyano-ethyl) -amino] -propionate

8.5 g (0.056 mol) of L-ethylalanine was added to 11.7 ml of water, stirred well, and 3.7 g (1 mol equivalent) of potassium hydroxide was added thereto. 5.9 g (2.0 molar equivalents) of acrylonitrile was added thereto, followed by stirring for 5 hours in a bath at 50 to 60 ° C. After completion of the reaction, the resulting two layers were separated. The water layer was extracted with methylene chloride, collected, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrated residue was diluted with methylene chloride and 12 g (1 molar equivalent) of di-t-butoxycarbonyldicarbonate was added and stirred at room temperature. After completion of the reaction, the mixture was washed with 0.1N aqueous hydrochloric acid solution, dried over anhydrous magnesium sulfate, filtered and concentrated to give 13.6 g (yield 90%) of the title compound.

¹ H NMR (CDCl ₃ , ppm): δ 4.5 (1H, m), 4.15 (3H, m), 3.6 (1H, m), 3.4 (1H, m), 2.68 (2H, m), 1.5 (9H, s), 1.47 (3H, m), 1.41 (3H, m).

FAB MS (Pos): [M + H] = 271

Preparation Example 2 Synthesis of t-butyl (2S) -4-cyano-2-methyl-3-oxo-1-pyrrolidinecarboxylate

Sodium ethoxide obtained by dissolving 13.6 g (0.05 mol) of the compound synthesized in Preparation Example 1 in 39 ml of anhydrous ethanol and heating to reflux, followed by heating and refluxing 1.29 g (1.1 molar equivalent) of sodium metal in 39 ml of anhydrous ethanol. NaOEt was added little by little. All were added and heated to reflux for 1 hour until the reaction was completed, then cooled to room temperature and concentrated under reduced pressure. The remaining concentrate was dissolved in water and washed with ethyl acetate. The aqueous layer was acidified to pH-4 using 6N, 3N, and 1N HCl, and collected by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to give 6.4 g (56% yield) of the title compound as a white solid.

¹ H NMR (CDCl ₃ , ppm): δ 4.4 (1H, m), 4.2-4.0 (2H, m), 3.9-3.4 (3H, m), 1.48, 1.49 (9H, s, s), 1.40, 1.38 (d, d, 3H).

FAB MS (Pos): [M + H] = 225

Preparation Example 3 Synthesis of t-butyl (2S) -4-{[(t-butoxycarbonyl) amino] methyl} -3-hydroxy-2-methyl-1-pyrrolidinecarboxylate

3.2 g (0.014 mmol) of the compound synthesized in Preparation Example 2 was dissolved in 90 mL of anhydrous ethanol, and 540 mg (1.0 mmol) of sodium borohydride (NaBH ₄ ) was added little by little at room temperature. After the reaction was completed, the mixture was concentrated under reduced pressure and diluted with 30 ml of ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated to give 2.5 g (0.011 mol) of a primary intermediate compound.

The primary intermediate compound was dried well under reduced pressure, dissolved in 45 ml of anhydrous tetrahydrofuran, and 432 mg (0.011 mol) of lithium aluminum hydride (LiAlH ₄ ) was added little by little at room temperature. The reaction was completed by stirring at room temperature for 2 hours. After cooling with ice water bath, 0.4 ml of water, 0.4 ml of 1N sodium hydroxide solution, and 1.2 ml of water were added little by little, followed by stirring at room temperature for 17 hours. Anhydrous magnesium sulfate was added to the reaction mixture, followed by filtration and concentration under reduced pressure to obtain 1.8 g (7.8 mmol) of the secondary intermediate compound.

The secondary intermediate compound was dissolved in dioxane-water (2: 1 volume ratio), 1.7 g (7.8 mmol) of di-t-butoxycarbonyldicarbonate was added thereto, and the mixture was basified to pH-10 with sodium bicarbonate, followed by stirring at room temperature. After the reaction was completed, the mixture was concentrated under reduced pressure and diluted with 30 ml of ethyl acetate. Washed with 0.1N aqueous hydrochloric acid solution and water, dried over anhydrous magnesium sulfate, filtered and concentrated to give the title compound 2.3g (total yield 49%).

¹ H NMR (CDCl ₃ , ppm): δ 4.9 (1H, m), 4.1 to 3.8 (2H, m), 3.7 to 3.3 (2H, m), 3.2 to 2.9 (2H, m), 1.8 (1H, m) ), 1.42 (9H, s), 1.43 (9H, s), 1.4-1.1 (3H, m).

FAB MS (Pos): [M + H] = 331

Preparation Example 4 Synthesis of t-butyl (2S) -4-{[(t-butoxycarbonyl) amino] methyl} -3- (methoxyimino) -2-methyl-1-pyrrolidinecarboxylate

0.5 g (1.5 mmol) of the compound synthesized in Preparation Example 3 was dissolved in 1.58 ml of dimethyl sulfoxide, and 0.63 ml (3 mol equivalent) of triethylamine was added thereto. 443 mg (1.8 molar equivalents) of pyridine sulfur trioxide was added little by little when the wall started to freeze by cooling with an ice-water bath. After the addition, the mixture was stirred for 1 hour at room temperature. After completion of the reaction, the reaction mixture was cooled with ice-water bath and diluted with 10 ml of water and 20 ml of ethyl acetate. The layers were separated, the aqueous layer was extracted with ethyl acetate, collected, dried over anhydrous magnesium sulfate, filtered and concentrated to give 380 mg (yield 78%) of an intermediate compound.

380 mg (1.15 mmol) of the compound synthesized in the above reaction was dissolved in 10 mL of a mixed solution of ethanol-tetrahydrofuran-water (4: 2: 1, volume ratio), and 152 mg (1.5 mmol) of methylhydroxyamine hydrochloride and sodium bicarbonate were dissolved. 152 mg (1.5 mmol) was added. After stirring for 1 hour at room temperature to complete the reaction and concentrated under reduced pressure. Diluted with 20 ml of ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated to give 300 mg (yield 72%) of the title compound.

¹ H NMR ((CDCl ₃ , ppm): δ 5.0 to 4.8 (1H, m), 3.9,3.8 (3H, s, s), 3.7 to 2.9 (6H, m), 1.47, 1.46 (9H, s, s ), 1.46, 1.45 (9H, s, s), 1.3 (1H, m).

FAB MS (Pos): [M + H] = 358

Preparation Example 5 Synthesis of (2S) -4- (aminomethyl) -2-methyl-3-pyrrolidinone O-methyloxime Dihydrochloride

300 mg (0.84 mmol) of the compound synthesized in Preparation Example 4 was dissolved in 10 ml of methanol and cooled in an iced water bath. 3 ml of acetyl chloride was added thereto, and after 20 minutes, the bath was removed and stirred for 30 minutes at room temperature. After the reaction was completed, the resultant was concentrated under reduced pressure to obtain 193 mg (yield quantitative) of the title compound.

¹ H NMR (CDCl ₃ , ppm): δ 4.6 (1H, m), 3.97, 3.95, 3.94 (3H, s, s, s), 3.84 (1H, m), 3.63 (1H, m), 3.48 (1H m), 3.4 to 3.2 (2H, m), 1.60 to 1.54 (3H, m).

FAB MS (Pos): [M + H] = 158

Preparation Example 6 Synthesis of Ethyl (2R) 2-[(t-butoxycarbonyl)-(2-cyano-ethyl) -amino] -propionate

In the same manner as in Preparation Example 1, 12 g (yield 85%) of the title compound was synthesized using 8 g (0.053 mol) of D-ethylalanine.

¹ H NMR (CDCl ₃ , ppm): δ 4.5 (1H, m), 4.15 (3H, m), 3.6 (1H, m), 3.4 (1H, m), 2.68 (2H, m), 1.5 (9H, s), 1.47 (3H, m), 1.41 (3H, m).

FAB MS (Pos): [M + H] = 271

Preparation Example 7 Synthesis of t-butyl (2R) -4-cyano-2-methyl-3-oxo-1-pyrrolidinecarboxylate

In the same manner as in Preparation Example 2, 4.4 g (yield 53%) of the title compound was synthesized using 10 g (0.036 mol) of the compound prepared in Preparation Example 6.

¹ H NMR (CDCl ₃ , ppm): δ 4.5 (1H, m), 4.2-4.0 (2H, m), 3.9-3.4 (3H, m), 1.48,1.47 (9H, s, s), 1.39 (3H , m).

FAB MS (Pos): [M + H] = 225

Preparation Example 8 Synthesis of t-butyl (2R) -4-{[(t-butoxycarbonyl) amino] methyl} -3-hydroxy-2-methyl-1-pyrrolidinecarboxylate

In the same manner as in Preparation Example 3, 2.1 g (yield 50%) of the title compound was synthesized using 3.0 g (0.013 mol) of the compound prepared in Preparation Example 7.

¹ H NMR (CDCl ₃ , ppm): δ 4.9 (1H, m), 4.1 to 3.8 (2H, m), 3.5 to 3.3 (2H, m), 3.2 to 2.9 (2H, m), 1.8 (1H, m) ), 1.45 (9H, s), 1.44 (9H, s), 1.4-1.1 (3H, m).

FAB MS (Pos): [M + H] = 331

Preparation Example 9 Synthesis of t-butyl (2R) -4-{[(t-butoxycarbonyl) amino] methyl} -2-methyl 3-oxo-1-pyrrolidinecarboxylate

In the same manner as in Preparation Example 4, 0.39 g (yield 80%) of the title compound was synthesized using 0.5 g (1.5 mmol) of the compound obtained in Preparation Example 8.

¹ H NMR (CDCl ₃ , ppm): δ 5.0 to 4.8 (1H, m), 3.9,3.8 (3H, s, s), 3.7 to 2.9 (6H, m), 1.47,1.46 (9H, s, s) , 1.46, 1.45 (9H, s, s), 1.3 (1H, m).

FAB MS (Pos): [M + H] = 329

Preparation Example 10 Synthesis of t-butyl (2R) -4-{[(t-butoxycarbonyl) amino] methyl} -3- (methoxyimino) -2-methyl-1-pyrrolidinecarboxylate

0.23 g (yield 70%) of the title compound was synthesized using 300 mg (0.9 mmol) of the compound obtained in Preparation Example 9, in the same manner as in Preparation Example 5.

¹ H NMR (CDCl ₃ , ppm): δ 5.0 to 4.8 (1H, m), 3.9,3.8 (3H, s, s), 3.7 to 2.9 (6H, m), 1.47,1.46 (9H, s, s) , 1.46, 1.45 (9H, s, s), 1.35, 1.31 (1H, d, d).

FAB MS (Pos): [M + H] = 358

Preparation Example 11 Synthesis of (2R) -4- (aminomethyl) -2-methyl-3-pyrrolidinone O-methyloxime Dihydrochloride

0.13 g (quantitative yield) of the title compound was synthesized using 200 mg (0.56 mmol) of the compound synthesized in Preparation 10 in the same manner as in Preparation Example 5.

¹ H NMR (CD ₃ OD, ppm): δ 4.7,4.6 (1H, m, m), 3.98,3.96,3.95 (3H, s, s, s), 3.85 (1H, m), 3.65 (1H, m) ), 3.48 (1H, m), 3.4-3.2 (2H, m), 1.60, 1.59, 1.54 (3H, d, d, d).

FAB MS (Pos): [M + H] = 158

Example 1 7-[(2R) -4- (aminomethyl) -3- (methoxyimino) -2-methylpyrrolidinyl] -1-cyclopropyl-6-fluoro-4-oxo-1, Synthesis of 4-dihydro [1,8] naphthyridine-3-quinolidinecarboxylic acid

50 mg (0.17 mmol) of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid and synthesized in Preparation Example 49 MG (1.2 molar equivalent) was added to 3 ml of dry acetonitrile and stirred well. 80 mg (3 mol equivalent) of 1,8- diazabicyclo [5.4.0] undec-7-ene (DBU) was added little by little, and it stirred at room temperature for 2 hours. After the reaction was completed, diluted with water and neutralized with 0.1N aqueous hydrochloric acid solution. Concentration under reduced pressure and purification by recovery plate chromatography gave 42 mg (yield 62%) of the title compound.

¹ H NMR (CD ₃ OD-CDCl ₃ , ppm): δ 8.68,8.65 (1H, s, s), 8.0,7.98 (1H, d, d), 5.4 (1H, m), 4.5-4.3 (1H, m), 4.0 (1H, m), 3.92, 3.91 (3H, s, s), 3.8-3.5 (2H, m), 3.2-3.0 (2H, m), 1.5-1.0 (7H, m).

FAB MS (Pos): [M + H] = 404

Example 2 7-[(2R) -4- (aminomethyl) -3- (methoxyimino) -2-methylpyrrolidinyl] -1-cyclopropyl-6,8-difluoro-4-oxo Synthesis of -1,4-dihydro-3-quinolidinecarboxylic acid

50 mg (0.16 mmol) of 7-chloro-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-carboxylic acid and 48 mg (1.2 mol) of the compound synthesized in Preparation Example 11 Equivalent) into 3 ml of dry acetonitrile and stirred well. 80 mg (3 mol equivalent) of 1,8- diazabicyclo [5.4.0] undec-7-ene (DBU) was added little by little, and it stirred at 80 degreeC for 2 hours. After the reaction was completed, diluted with water and neutralized with 0.1N aqueous hydrochloric acid solution. Concentration under reduced pressure and purification with recovered plate chromatography to obtain 31 mg (46% yield) of the title compound.

¹ H NMR (CDCl ₃ , ppm): δ 8.65,8.64 (1H, s, s), 7.75,7.74 (1H, d, d), 4.35 (1H, m), 4.1-3.9 (2H, m), 3.8 3.79 (3H, s, s), 3.7 (1H, m), 3.35 (1H, m), 2.9-2.6 (2H, m), 1.25-0.95 (7H, m)

FAB MS (Pos): [M + H] = 421

Examples 3-6 :

Using the compound synthesized in Preparation Example 11, the compound of Examples 3 to 6 was synthesized in the same manner as in Example 2.

Examples 7-12 :

Example 7 was synthesized in the same manner as in Example 1, and Examples 8 to 12 were synthesized using the compound synthesized in Preparation Example 5 in the same manner as in Example 2.

Biological Example 1 : In vitro Antimicrobial Activity Assay

In order to confirm the usefulness of the compound according to the present invention, using the known compound Cyprofloxacin (Ciprofloxacin) as a control agent, the minimum inhibitory concentration for the standard strain, clinically isolated strains, strains resistant to some antibiotics ( Minimum Inhibitory Concentration (MIC, µg / ml) was obtained and evaluated. The minimum inhibitory concentration was obtained by diluting the test compound by a 2-fold dilution method and dispersing it in a Mueller-Hinton agar medium, inoculating 5 μl of standard strain with 10 ⁷ CFU / ml for 18 hours at 37 ° C. It was obtained by culturing, and the results are shown in Table 1.

Minimum Inhibition Concentration (MIC, ug / mL) Example 1 Example 2 Example 3 Cyprofloxacin Staphylococcus aureus 6538P Staphylococcus aureus giorgio Staphylococcus aureus 77 Staphylococcus aureus 241 Staphylococcus pneumoniae PN010 Staphylococcus epidermidis 887E 0.0630.0160.1320.250.0630.25 0.130.0160.1340.250.0630.25 0.016 <= 0.0080.01610.0630.0160.13 0.130.250.256410.130.5 Escherichia coli 10536 Escherichia coli 3190Y Escherichia coli 851E Escherichia coli TEM3 3455E Escherichia coli TEM9 2639E 0.0630.0310.1310.25 0.0630.0630.1310.25 0.0630.0160.0160.250.063 0.016 <= 0.008 <= 0.0080.250.016 Pseudomonas Aruginosa 1912E Pseudomonas Aruginosa 6065Y 28 416 18 0.254 Acinetobacter Calcoaceticus 15473 Citrobacter Diversus 2046E Enterobacter Cloacca 1194E Enterobacter Cloacca P99 Cleveciella Aerogenes 1976E Cleveciella Aerogenes 1082EProteus Bulgari 6059 Serratia Marker Sense 1826E Salmonella typhimurium 14028 0.250.250.250.0630.50.250.130.50.25 0.250.250.50.0630.250.250.1320.5 0.250.0630.0630.0160.130.0630.250.130.063 0.250.0310.016 <= 0.0080.130.0160.0310.0630.031

Biological Example 2: Acute Toxicity Test (LD50)

Acute toxicity studies in rats were conducted using SD rats (males) weighing approximately 230 + 10 g. That is, the compound according to the present invention was administered to 4 to 5 mice and observed clinical observation and mortality.

Example 1 Example 2 Cyprofloxacin LD50 5000 mg 3000 mg 3000 mg

Claims (6)

Quinolone carboxylic acid derivatives of formula (1), pharmaceutically acceptable salts, esters, solvates and isomers thereof: Formula 1 Where R ₁ is C ₁ -C ₅ alkyl, C ₃ -C ₆ cycloalkyl or dihalophenyl; R ₂ is hydrogen, C ₁ -C ₅ alkyl or amino; Q is CH, CF, C-Cl, C-CH ₃ , CO-CH ₃ or N; R ₃ is C ₁ -C ₅ alkyl, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkylC ₁ -C ₅ alkyl, C ₃ -C ₆ alkenyl, C ₃ -C ₆ alkynyl, C ₁ -C ₅ haloalkyl, or substituted or unsubstituted phenyl or benzyl. The compound of claim 1 wherein R_OneIs cyclopropyl or 2,4-difluorophenyl, R₂Is hydrogen or amino, Q is C-H, C-F, C-Cl or N, R₃ Is methyl, ethyl, i-propyl, t-butyl, allyl, phenyl, propargyl or 2-fluoroethyl. The compound of claim 2, wherein R ₁ is cyclopropyl, R ₂ is hydrogen, Q is CH, CF or N, and R ₃ is methyl or 2-fluoroethyl. The compound of claim 3, wherein R ₁ is cyclopropyl, R ₂ is hydrogen, Q is CF or N, and R ₃ is methyl. An antimicrobial composition comprising a compound of formula (1) according to claim 1 as an active ingredient together with a pharmaceutically acceptable carrier. A process for preparing a compound according to claim 1, characterized by reacting a compound of formula (2) with a compound of formula (3) in the presence of a base in a solvent. Where R ₁ , R ₂ , R ₃ and Q are as defined in claim 1, X represents a halogen.