KR19990010427A - Quinoline carboxylic acid derivative with 7- [3-aminomethyl-4- (Z) -substituted oxymer] pyrrolidine substituent - Google Patents

Abstract

The present invention has an excellent antibacterial activity and a broad spectrum of antimicrobial spectrum, and (Z) -4-substituted oximepi as a substituent at the 7-position of the quinolone mother nucleus, which shows pharmacokinetic properties superior to conventional quinolone antibiotics. A quinoline carboxylic acid derivative in the form of a novel Z-isomer represented by the following general formula (I) having a lollidine group, a pharmaceutically acceptable salt thereof, a method for preparing the same, and an antimicrobial composition containing the compound as an active ingredient :

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, or phenyl substituted by one or more fluorine atoms; R 2 is C ₁ -C ₅ straight or branched alkyl, cyclopropyl, cyclopropylmethyl, C ₃ -C ₆ alkenal, C ₃ -C ₆ alkynyl, haloalkyl, substituted or unsubstituted phenyl or benzyl, or the following general Is a group of expressions,

Wherein n is O or 1, m is 0,1 or 2 and X is methylene, O or NH; R ₃ and R ₄ each independently represent hydrogen or C ₁ -C ₃ alkyl, or R ₃ and R ₄ together with the nitrogen atom to which they are attached may form a 5-6 membered heterocycle.

Description

Quinoline carboxylic acid derivative with 7- [3-aminomethyl-4- (Z) -substituted oxymer] pyrrolidine substituent

The present invention relates to novel quinolone compounds exhibiting excellent antimicrobial activity. More specifically, the present invention provides a compound having a pyrrolidin group substituted with a 3-aminomethyl group and a 4- (Z) -substituted oxime group at the 7-position of the quinolone mother nucleus as a substituent. A novel quinoline carboxylic acid derivative represented by the following general formula (I) and a pharmaceutically acceptable salt thereof, as well as a broad antimicrobial spectrum and exhibiting pharmacokinetic properties superior to conventional quinolone antibiotics, and methods for preparing the same An antimicrobial composition comprising a compound as an active ingredient:

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, or phenyl substituted by one or more fluorine atoms; R ₂ is C ₁ -C ₅ straight or branched alkyl, cyclopropyl, cyclopropylmethyl, C ₃ -C ₆ alkenyl, C ₃ -C ₆ alkynyl, haloalkyl, substituted or unsubstituted phenyl or benzyl, or Is a group of general formulas,

Wherein n is 0 or 1, m is 0, 1 or 2 and X is methylene, O or NH; R ₃ and R ₄ each independently represent hydrogen or C ₁ -C ₃ alkyl, or R ₃ and R ₄ together with the nitrogen atom to which they are attached may form a 5-6 membered heterocycle.

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, jade Soxolinic acid, Roxoxacin, and Pipemidic acid have been 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, a new generation of quinolone compounds containing fluorine at position 6 (Norfloxacin; H. Koga, et al., J. Med. Chem. 1980, 23, 1358) were developed. Research on antibiotics has been very extensively attempted. 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 (R. Wise, et al., J. Antimicrob. Agents Chemother., 1983, 23, 559), Ofioxacin (K. Sata, et al., Antimicrob. Agents Chemother., 1982, 22, 548) have been developed, and these antimicrobial agents have broader antimicrobial activity than earlier antimicrobial agents, and are widely used in the treatment of various indications 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 have problems such as low solubility in water compared to compounds having piperazine substituents, and thus do not exhibit strong antibacterial effects such as in vitro antibacterial activity. Thus, efforts have been made to improve these disadvantages of compounds with pyrrolidine substituents, ie to increase solubility in water and to improve pharmacokinetic properties.

Therefore, the present inventors have conducted intensive studies to solve these problems and to develop compounds exhibiting strong antimicrobial activity against a wide range of pathogens, and as a result, aminomethyl-4-oxime (or alkyl oxime) pyrrolidine at position 7 A new quinolone compound of the following general formula substituted with a group is synthesized, and it has been found that the compound has a strong antibacterial activity against a wide range of Gram-positive and negative pathogens including resistant bacteria, and has applied for a patent application (see Republic of Korea Patent Application No. 94-13604

Wherein R is hydrogen, methyl or amino; Q is CH, CF, C-Cl, C-OH, CO-methyl or N; R ₁ is cyclopropyl, ethyl, phenyl substituted with one or more fluorine atoms; R ₂ is hydrogen, C ₁ -C ₆ straight or branched chain alkyl, aryl or allyl; R ₃ and R ₄ are each independently hydrogen or C ₁ -C ₃ alkyl, or may form a ring with the nitrogen atom to which they are attached.

Based on these prior arts, the present inventors have found that pyrrolidine may exist as E and Z isomers depending on the orientation of the oxime group present at the 4 position of the pyrrolidine structure. As a result of the separation and searching for the antimicrobial activity, it was confirmed that the Z isomer exhibits not only an excellent antimicrobial activity, but also an excellent antimicrobial activity compared to the Z / E isomer mixture.

It is therefore an object of the present invention to provide quinoline carboxylic acid derivatives of the novel Z-isomeric form of the general formula (I) and pharmaceutically acceptable salts thereof.

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, or phenyl substituted by one or more fluorine atoms; R ₂ is C ₁ -C ₅ straight or branched alkyl, cyclopropyl, cyclopropylmethyl, C ₃ -C ₆ alkenyl, C ₃ -C ₆ alkynyl, haloalkyl, substituted or unsubstituted phenyl or benzyl, or Is a group of general formulas,

Wherein n is 0 or 1, m is 0,1 or 2 and X is methylene, O or NH; R ₃ and R ₄ each independently represent hydrogen or C ₁ -C ₃ alkyl, or R ₃ and R ₄ together with the nitrogen atom to which they are attached may form a 5-6 membered heterocycle.

Among the compounds of the general formula (I) having excellent antibacterial action and broad antibacterial spectrum and excellent pharmacokinetic properties, preferred compounds are those wherein Q is CH, CF, C-Cl or N, R is hydrogen or amino, and R ₁ is Cyclopropyl or 2,4-difluorophenyl, R ₂ is methyl, ethyl, t-butyl, i-propyl, allyl, phenyl, propazyl, or 2-fluoroethyl, and R ₃ and R ₄ are hydrogen Or methyl.

More preferred compounds of formula (I) are those wherein Q is CH, CF or N, R is hydrogen, R ₁ is cyclopropyl, R ₂ is methyl, 2-fluoroethyl or t-butyl, R ₃ and R ₄ is a compound that is hydrogen.

In the compound of formula (I), the carbon atom at position 3 of the pyrrolidin substituted with the aminoalkyl group may be present as an asymmetric carbon in R or S form or R / S mixture form. The present invention also encompasses both these individual isomers and isomer mixtures.

Formula (I) compounds according to the invention may also form salts with pharmaceutically acceptable inorganic or organic acids. These pharmaceutically acceptable 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, hydroxyl, succinic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, Organic carboxylic acids such as ascorbic acid or dried acid or salts with sulfonic acids such as methanesulfonic acid, para-toluenesulfonic acid and salts with other acids known and used in the quinolone-based art. Solvents which can be used when preparing a pharmaceutically acceptable acid addition salt according to the present invention include those in which 5 to 95% of chloroform is mixed with methanol, ethanol, t-butanol or isopropanol in a volume ratio, wherein chloroform Instead, dichloromethane or ethyl acetate can be used in the same way. In addition to mixed solvents, acid addition salts may be prepared under single solvent conditions, and chloroform, dichloromethane, lower alcohols or water may be used for this purpose. These acid addition salts may be prepared according to conventional processes for converting free base to acid addition salts under the above solvent conditions.

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

Compounds of formula (I) according to the invention can be readily prepared by using the corresponding Z-isomers as starting materials. That is, the compound of general formula (I) can be manufactured by reacting the compound of general formula (II) with the z-isomeric compound of general formula (III) according to the method shown by following Reaction Scheme 1.

Scheme 1

Was the reaction formula, R, R _l, R _2, R _3, R ₄ and Q are the same as defined above, Y represents a halogen, preferably chlorine, bromine or fluorine.

As shown in Scheme 1, the compound of general formula (I) can be prepared by reacting a quinolone compound of general formula (II) with a pyrrolidine derivative of general formula (III) having a (Z) -oxime group. . In this reaction, the compound of general formula (III) can be used on its own or in the form of a salt with hydrochloric acid, hydrobromic acid or trifluoroacetic acid.

This reaction is generally carried out in a solvent. Examples of solvents which are preferably used for this purpose may include acetonitrile, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), pyridine or hexamethylphosphoramide (HMPA) and the like. The reaction also generally proceeds in the presence of an acid acceptor, in which the pyrrolidin derivatives of the general formula (II) are reacted with a starting material (II) in order to increase the reaction efficiency of the relatively expensive starting compound (II). II) It is suitable to use it in the ratio of equimolar to 10 mol with respect to 1 mol, Preferably it is used in ratio of equimolar to 5 mol, and after reaction, the compound of general formula (III) which remain | survives is collect | recovered and reused. The acid acceptors that can be used include inorganic bases such as sodium hydrogen carbonate and potassium carbonate, triethylamine, diisopropylethylamine, pyridine, N, N-dimethylaniline, N, N-dimethylaminopyridine, 1,8-dia Organic bases, such as zabicyclo [5.4.0] undec-7-ene (DBU) and 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 performed by stirring for 1 to 20 hours at a temperature of room temperature to 200 ° C.

Compounds of formula (II) used as starting materials in the process of the present 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.

Compounds of formula (III) used as another starting material in the process of the present invention can be readily prepared by the method as shown in Schemes 3 or 4.

Scheme 3

Scheme 4

In Schemes 3 and 4, R ₂ is as defined above, Y represents halogen, P and P 'each represent the same or different amino protecting group, Py represents pyridine, TBAB represents tetrabutylammonium bromide Indicates.

As the amino protecting group in Schemes 3 and 4, 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 Schemes 3 and 4 in detail.

According to Scheme 3, the cyano ester (1) in which the amine group is protected is reacted using a sodium ethoxide in a solvent such as ethanol to obtain 3-keto-4-cyanopyrrolidine [2], and the obtained cya Nopirrolidine (2) is reduced with a reducing agent such as sodium borohydride to give cyanoalcohol (3), and selectively protecting the amino group of the cyanoalcohol (3) to obtain a protected amine (4). do. The obtained amine (4) was treated in a sulfur trioxide-pyridine mixture and a dimethyl sulfoxide solvent (Parikh, JR and Doering, WvEJ Am. Chem. Soc., 1967, 89, 5505) or oxidized with another oxidizing agent to give a ketone compound. (5) is generated. The resulting ketone compound (5) is reacted with an alkoxylamine derivative having the structure of R ₂ described above to give a substituted oxime compound (6), which is suitable from the oxime compound (6) according to the type of protecting group. Deprotection can yield the desired pyrrolidine oxime compound of formula (III).

As another method of preparing a compound of formula (III), ketone compound (5) is first reacted with hydroxyamine to produce oxime compound (7), as shown in Scheme 4, which is general in the presence of a base. After reacting with an electrophilic compound of formula R ₂ -X to obtain a substituted oxime compound (6), deprotected the substituted oxime compound (6) by a suitable method according to the type of protecting group as in Scheme 3 The pyrrolidine oxime compound of general formula (III) can also be obtained.

The novel quinolone compounds according to the 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 (I) as well as the corresponding pharmaceuticals. Acceptable salts may be used.

The carrier used to prepare the pharmaceutical composition from the compound of formula (I) according to the invention is an inert, pharmaceutically acceptable solid or liquid carrier which is commonly used in the pharmaceutical art according to the formulation to be prepared. Can be. 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. Preparation of such liquid formulations

As the liquid carrier used for the purpose, for example, water or water-propylene glycol solution 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 rubber, 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 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, which are equivalent to conventional drugs (for example, cyprofloxacin). Or more than the antibacterial activity, and also shows a very good antibacterial activity against strains that are resistant to the quinolone compound.

In addition, the compound according to the present invention also has high solubility in water in terms of pharmacokinetics, and thus is better absorbed than conventional quinolone compounds, has a very high bioavailability, and has an in vivo half-life that is much longer than conventional quinolone compounds. It can be used as an antimicrobial agent for single use.

Moreover, the compound of general formula (I) according to the present invention is less toxic and can be used very effectively for the prevention and treatment of 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 (2-cyano-ethylamino) -acetic acid ethyl ester

139.6 g (1 mol) of glycine ethyl ester hydrochloride was dissolved in 80 ml of distilled water, and 230 ml of an aqueous solution containing 67.3 g (1.2 molar equivalents) of potassium hydroxide was added to the resulting solution, followed by heating to 50 to 60 ° C. 106.2 g (2 molar equivalents) of acrylonitrile was added dropwise while stirring. The reaction mixture was heated and stirred for 5 hours, the organic layer was separated, and the aqueous layer was extracted with ethyl ether and combined with the organic layer. The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent, and then 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, J = 7.1 Hz), 3.48 (2H, s), 2.96 (2H, t, J = 6.7 Hz), 254 (2H, t, J = 6.7 Hz), 1.30 (3H, t, J = 7.1 Hz)

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

Preparation Example 2 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 was concentrated and diluted with 250 mL of absolute ethanol. The resulting solution was added to a solution prepared by slicing 6 g of sodium (Na) metal in a sodium ethoxide solution (NaOEt) solution, that is, 220 mL of anhydrous ethanol while heating and refluxing. The reaction mixture was further reacted under heating under reflux for 1 hour, concentrated under reduced pressure, diluted with water, and washed with methylene chloride. The pH of the aqueous layer was adjusted to 4 again using 1N HCl, and then extracted with ethyl acetate and combined. After drying over anhydrous magnesium sulfate, it was filtered and concentrated to give quantitatively the title compound in the crude state.

¹ H-NMR (CDCl ₃ , ppm): δ 4.5 (1H, m), 4.05 (1H, m), 3.9-3.5 (3H, m), 1.5 (9H, s) MS (FAB, m / e): 211 (M + H)

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

Method A:

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 anhydrous tetrahydrofuran. After cooling to minus 3 ° C. in an ice-sodium chloride bath, 3.8 g (0.094 mol) of lithium aluminum hydride (LAH) was added in portions over 20 minutes. After all was added, the mixture was stirred for 1 hour in an ice-water bath. After the reaction was completed, 4 ml of water, 4 ml of 15% aqueous sodium hydroxide solution and 12 ml of water were carefully added in sequence. After stirring vigorously at room temperature for 3 hours, 10 g of anhydrous magnesium sulfate was added thereto, stirred, and filtered and concentrated. The product obtained quantitatively was diluted with 200 mL of dioxane-water (2: 1 volume ratio) and 12.3 g (0.056 mol) of di-t-butylcarbonate were added at room temperature. The reaction solution was stirred at room temperature for 1 hour to complete the reaction, concentrated, diluted with ethyl acetate and washed with saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, filtration and concentration, the residue was purified by column chromatography [eluent: hexane / ethyl acetate = 2/1, v / v] to give 8.2 g (yield: 55%) of the title compound. It was.

¹ H-NMR (CDCl ₃ , ppm): δ 4.95 (1H, m), 4.1 (1H, m), 3.5 (2H, m), 3.3-3.0 (4H, m), 2.1 (1H, m), 1.45 (18H, s)

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

Method B:

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. The resulting solution was cooled in an ice bath and 3.6 g (0.094 mol) of sodium borohydride were added in portions over 20 minutes. After stirring for 30 minutes to complete the reaction, the reaction solution was concentrated under reduced pressure and diluted with ethyl acetate again. Washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated to obtain a compound in which only the desired ketone group was reduced with alcohol. 10.lg (0.047 mol) of the obtained alcohol compound was dissolved in 200 ml of anhydrous tetrahydrofuran, and then cooled to -5 DEG C with an ice-salt bath and 2.6 g (0.066 mol) of lithium aluminum hydride was added over 20 minutes. It was. After further stirring for 30 minutes at the same temperature to complete the reaction, 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 were added and stirred for 30 more minutes, followed by filtration and concentration to give the product. The product was diluted with 200 mL of dioxane-water (2: 1 volume ratio), 12.3 g (0.056 mol) of di-t-butylcarbonate was added little by little, followed by stirring for 30 minutes to complete the reaction. The reaction solution was concentrated and then diluted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography [eluent: hexane / ethyl acetate = 2/1, v / v] to give 12.3 g (yield: 83%) of the title compound.

Preparation Example 4 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 3 was dissolved in 64 ml of dimethyl sulfoxide, and then 18.5 ml (3 molar equivalents) of triethylamine was added and cooled with an ice bath.

12.7 g (1.8 molar equivalents) of an oxidizing agent pyridine-sulfur trioxide (Py-SO ₃ ) was added little by little when the flask wall began to freeze. After the addition was completed, the ice bath was removed and stirred at room temperature for 3 hours. The reaction solution was diluted with water and extracted with methylene chloride. The extracts were combined, dried over anhydrous magnesium sulfate, and concentrated to give quantitatively the title compound in an unpurified state.

¹ H-NMR (CDCl ₃ , ppm): δ 4.95 (1H, bs), 4.11 (1H, m), 3.90 (1H, m), 3.69 (1H, m), 3.40 (3H, m), 2.78 (1H) , m), 1.45 (9H, s), 1.40 (9H, s)

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

Preparation Example 5 Synthesis of 4- (N-t-butoxycarbonyl) aminomethyl-1- (N-t-butoxycarbonyl) pyrrolidine-3-one-O-methyloxime

260 mg (8.28 x 10 ^-4 mole) of the compound obtained in Preparation Example 4 was dissolved in a mixture of ⁵ ml of 95% ethanol and 2.5 ml of tetrahydrofuran, and then 256 mg (3.7 molar equivalents) of methoxyamine hydrochloride were added to the reaction vessel. It was. To this was added 257 mg (3.7 molar equivalents) of sodium bicarbonate dissolved in 2.5 ml of distilled water. The resulting solution was stirred for 17 h in an oil bath at 40 ° C. After the reaction solution was concentrated under reduced pressure, the residue was washed successively with an aqueous ammonium chloride solution and an aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated to give 250 mg (yield: 88%) of the title compound.

¹ H-NMR (CDCl ₃ , ppm): δ 4.98 (1H, bs), 4.08 (2H, s), 3.81 (3H, s), 3.75 (1H, m), 3.75 (1H, m), 3.50 (1H , bs), 3.41 (1H, bs), 3.28 (1H, m), 3.00 (1H, m), 1.40 (18H, s)

Mass (FAB, m / e): 344 (M + H)

Preparation Example 6 Synthesis of 4-Aminomethyl-pyrrolidin-3-one-benzyl oxime hydrochloride

After cooling 20 ml of methanol to 5 ° C, 10 ml of acetyl chloride was slowly added and stirred for 30 minutes, and then 990 mg of the compound obtained in Preparation Example 5 was dissolved in 10 ml of methanol and added. The reaction mixture was stirred at room temperature for 50 minutes, and the residue obtained by distillation under reduced pressure was washed with ethyl ether and dried to give 648 mg (yield: 94%) of the title compound as a yellow solid.

¹ H-NMR (DMSO-d ₆ , ppm): δ 10.0 (1H, m), 8.35 (2H, m), 7.40 (5H, m), 5.18 (2H, s), 4.00 (2H, m), 3.69 (1H, m), 3.40 (2H, m), 3.12 (2H, s)

MS (m / e, FAB): 220 (M + H)

Example 1 7- [4-Aminomethyl-3- (Z) -methyloxyimino-pyrrolidin-1-yl] -1-cyclopropyl-6-fluoro-1,4-dihydro-4- Synthesis of oxo-1,8-naphthyridine-3-carboxylic acid

141 mg of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid and 4-aminomethyl-pyrroli obtained in Preparation Example 6 110 mg of din-3-one benzyloxime hydrochloride was suspended in 15 ml of acetonitrile and then cooled under ice-water bath. Thereafter, 4.6 g of 1,8-diazabicyclo [5.4.0] -undec-7-ene (DBU) was slowly added to the reaction mixture, stirred at room temperature for 0.5 hour, and then 15 ml of water was added and concentrated. . The solid obtained by filtration of the concentrated suspension was washed with water and ethanol to give 167 mg (yield: 85%) of the title compound.

¹ H-NMR (DMSO-d ₆ , ppm): δ 8.61 (1H, s), 8.05 (1H, d, J = 13.0 Hz), 4.55 (2H, s), 3.85 (3H, s), 3.84 (1H , s), 3.70 (1H, m), 3.05 (1H, m), 2.85-2.75 (2H, m), 1.20-1.10 (4H, m)

MS (FAB, m / e): 390 (M + H)

Example 2 7- [4-Aminomethyl-3- (Z) -methyloxyimino-pyrrolidin-1-yl] -1-cyclopropyl-6-fluoro-1,4-dihydro-4- Synthesis of oxo-1,8-naphthyridine-3-carboxylic acid methanesulfonate

7- [4-Aminomethyl-3- (Z) -methyloxyimino-pyrrolidin-1-yl] -1-cyclopropyl-6-fluoro-1,4-dihydro- obtained in Example 1 0.5 g (1.284 mmol) of 4-oxo-1,8-naphthyridine-3-carboxylic acid was added to a mixture of 10 ml of chloroform and 2 ml of ethanol, and then gently warmed to dissolve and cooled to room temperature. While stirring the mixture well, 0.12 g (0.95 molar equivalents) of methanesulfonic acid was added dropwise to 1 ml of ethanol. The mixture was stirred well for 1 hour while the solid precipitated, filtered, washed with ethyl acetate and dried with nitrogen to obtain 0.46 g (yield: 74%) of the title compound.

¹ H-NMR (CDCl ₃ , ppm): δ 8.69 (1H, s), 8.04 (1H, d, J = 12.0 Hz), 4.61 (2H, m), 4.26 (1H, m), 4.17 (1H, m) ), 3.99 (3H, s), 3.71 (1H, m), 3.55 (1H, m), 3.11 (2H, d), 1.35 (2H, m), 1.14 (2H, m)

MS (FAB, m / e): 390 (M + H)

Biological Example 1: In vitro Antimicrobial Activity Assay

In order to confirm the usefulness of the compound obtained in Example 1 as a representative compound according to the present invention, E-isomer corresponding to the title compound of Example 1 and ciprofloxacin, a known compound, were used as a reference agent. Minimum Inhibitory Concentration (MIC, μl / ml) for strains, clinically isolated strains and strains resistant to some antibiotics were 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 per ml and incubating at 37 ° C. for 18 hours. It was obtained by culturing, and the results are shown in Table 1.

Minimum Inhibition Concentration (MIC, μl / mL)

TABLE 1

Claims (6)

Quinoline carboxylic acid derivatives represented by the following general formula (I) having a 4- (Z) -substituted oxime pyrrolidine group and pharmaceutically acceptable salts thereof: 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, or phenyl substituted by one or more fluorine atoms; R ₂ is C ₁ -C ₅ straight or branched alkyl, cyclopropyl, cyclopropylmethyl, C ₃ -C ₆ alkenyl, C ₃ -C ₆ alkynyl, haloalkyl, substituted or unsubstituted phenyl or benzyl, or Is a group of general formulas, Wherein n is 0 or 1, m is 0, 1 or 2 and X is methylene, O or NH; R ₃ and R ₄ each independently represent hydrogen or C ₁ -C ₃ alkyl, or R ₃ and R ₄ together with the nitrogen atom to which they are attached may form a 5-6 membered heterocycle. The compound of claim 1 wherein Q is CH, CF, C-Cl or N, R is hydrogen or amino, R ₁ is cyclopropyl or 2,4-difluorophenyl, and R ₂ is methyl, ethyl, i -Propyl, t-butyl, allyl, phenyl, propazyl or 2-fluoroethyl, and R ₃ and R ₄ are each hydrogen or methyl. The compound of claim 2, wherein Q is CH, CF or N, R is hydrogen, R ₁ is cyclopropyl, R ₂ is methyl, 2-fluoroethyl or t-butyl, and R ₃ and R ₄ are each A compound that is hydrogen. The compound of claim 2, wherein Q is N, R is hydrogen, R ₁ is cyclopropyl, R ₂ is methyl, and R ₃ and R ₄ are each hydrogen. An antimicrobial composition comprising a compound of formula (I) according to claim 1 as an active ingredient together with a pharmaceutically acceptable carrier. A process for preparing the compound according to claim 1 and salts thereof, characterized by reacting the compound of formula (II) with the Z-isomer of the compound of formula (III). Wherein R, R ₁ , R ₂ , R ₃ , R ₄ and Q are as defined in claim 1 and Y represents halogen.