KR0150742B1 - Novel quinoline carboxylic acid derivative and process for preparing thereof - Google Patents

Abstract

The present invention relates to novel quinoline compounds having good antibacterial activity. More particularly, the present invention is a compound having a 4-substituted aminomethyl-3-substituted or unsubstituted oximepyrrolidine substituent at position 7 of the quinolone mother nucleus, and has excellent antimicrobial activity and broad antibacterial spectrum, Novel quinoline (naphthyridine) carboxylic acid derivatives represented by the following general formula (I), which have significantly superior absorption and pharmacokinetic properties than quinolone antibiotics of pharmaceutically acceptable nontoxic salts thereof, and physiologically hydrolyzable Degradable esters thereof, solvates including hydrates and isomers.

Wherein Q, R, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , and R ₆ are as defined in the specification.

Description

Novel quinoline carboxylic acid derivatives and preparation method thereof

The present invention relates to a novel quinolone compound exhibiting excellent antimicrobial activity, in particular a compound having a 4-substituted aminomethyl-3-substituted or unsubstituted oxime pyrrolidine substituent at position 7 of the quinolone mother nucleus, A novel quinoline (naphthyridine) carboxylic acid derivative represented by the following general formula (I), which has not only an action and a broad spectrum of antimicrobial spectrum, but also an excellent absorption and pharmacokinetic property of conventional quinolone antibiotics, pharmaceutical And non-toxic salts thereof, physiologically hydrolysable esters thereof, solvates including hydrates and isomers.

Wherein R represents hydrogen, methyl or amino; Q represents CH, CF, C-C1, C-CH ₃ , CO-CH ₃ or N; R ₁ represents cyclopropyl, ethyl or phenyl substituted with one or more fluorine atoms; R ₂ represents hydrogen, C ₁ -C ₅ alkyl, cyclopropyl, cyclopropylmethyl, C ₃ -C ₆ alkenyl, C ₃ -C ₆ alkynyl, substituted or unsubstituted phenyl or benzyl, or a compound of formula Represent;

Wherein n is 0 or 1, m is 0, 1 or 2 and X is methylene, O or N.

R ₃ and R ₄ each independently represent hydrogen, C ₁ -C ₃ alkyl or together with the nitrogen atom to which they are attached may form a ring of C ₃ -C ₅ ; R ₅ and R ₆ each independently represent C ₁ -C ₃ alkyl or haloalkyl or they may be linked to one another to form a cycloalkyl group, provided that R ₅ and R ₆ are not simultaneously hydrogen.

The present invention also relates to a process for the preparation of the above general formula (I) compounds and to antimicrobial compositions containing these compounds as active ingredients.

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 ), Rosoxzcin 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 used only as an antimicrobial agent for gram negative bacteria.

Recently, a new generation of quinolone compounds containing fluorine at position 6, norfloxacin (H. Koga, et al., J. Med. Chem. 23, 1358-1363 (1980)), was developed Research on antibiotics has been very extensively attempted. However, nofloxacin still has weak antimicrobial activity against Gram-positive bacteria and does not have good distribution and absorption, so it has been used only for the treatment of diseases caused by Gram-negative bacteria. Ci-profloxacin (R. Wise, et al., J. Antimicrob. Agents Chemother, 23, 559 (1983)), and ofloxacin (K. Sata, et al., Antimicrob. Agents Chemother. , 22,548 (1982)), and these antimicrobial agents have broader antimicrobial activity than earlier antimicrobial agents, and are widely used in clinical and therapeutic practice today.

On the other hand, compounds currently in use or in clinical trials are mainly derivatives having piperazine substituents at position 7 of the quinolone nucleotides, as in ciprofloxacin or oploxacin. However, as a result of efforts to develop more powerful and broad antibacterial quinolone antibiotics, the introduction of 3-amino or 3-amino methyl pyrrolidine 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. However, in general, the compounds having these pyrrolidine substituents were not as potent as the antibacterial effects in vivo due to the low solubility in water and the like, compared to the compounds having piperazine substituents. Accordingly, 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 Chenotherapy; Ishigami, J., Ed .; University of Tokyo Press: Tokyo, 1985 pp1519-1520) showed similar in vitro antimicrobial activity and increased solubility in water by 20 and 40 times compared to compounds without methyl group, resulting in increased bioavailability and improved pharmacokinetic properties.

On the other hand, by introducing other functional groups instead of the amino groups in pyrrolidine or peperazine, it is possible to improve the disadvantages of quinolone compounds, such as relatively weak antimicrobial activity against Gram-positive bacteria and low solubility in water, thereby improving pharmacokinetic properties. Efforts have also 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. That is, Abbott 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 the quinolone, these quinolone compounds show excellent antibacterial activity against Gram-positive bacteria.

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

However, the compounds show relatively weak antimicrobial activity against gram-negative bacteria, and also has 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 quinolone compounds of the general formula [B]:

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

Particularly, the Japanese Patent Laid-Open Patent Publication refers to oxime or hydroxy aminopyrrolidine-based compounds as a substituent of R 'very widely, but has a 3-position having an oxime structure and at the same time a blood having an aminomethyl group at 4-position. There is no specific reference to the lollidine substituent.

In addition, European Patent Publication No. 0 541 086 discloses 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 a hydroxy group; R ₃ is a C ₃ -C ₇ cycloalkyl group; R ₄ is methoxy or fluorine; R ₅ and R ₆ may each be the same or different or hydrogen or an alkyl group, or together are a C ₃ -C ₅ cycloalkyl group; m is 0 or 1; n is an integer of 1-3.

A representative substituent at position 7 of the quinolone nucleus in compound [C] described in the European Patent Publication is the structure shown below, and in the case of the compound of formula [C], oxime at pyrrolidin at position 7 Compounds in which the group and the aminoalkyl group were introduced at the same time were not included and are therefore different from the compounds of the present invention.

The common features of the known oxime or hydroxyamine-based compounds mentioned above show Gram-positive bacteria including Gram-positive bacteria including MRSA (Methicillin Resistant Staphylococcus aureus) bacteria, compared to previous quinolone antibiotics, but are Gram-negative bacteria. It has a weak antimicrobial activity against the field, which means that the antimicrobial spectrum is narrower than that of conventional oploxacin or ciprofloxacin.

On the other hand, in the case of aminomethylpyrrolidin-based quinolone compounds that showed excellent in vitro antibacterial activity, methyl or dimethyl groups were introduced at the methylene position of the aminomethyl group to have disadvantages such as low solubility in water and relatively low in vivo. Efforts have also been made to improve antimicrobial activity. In other words, as published by Warner La-mbert, a researcher published in a professional magazine (J. Med. Chem. 1993, 37, 871-881; J. Med. Chem. 1994, 37, 733-738) As shown in the general formula [D], when methyl or dimethyl group is substituted at the methylene position of the aminomethylpyrrolidin group, it shows high in vivo antibacterial activity and low cytotoxicity.

Wherein R ₁ is cypropropyl or 2,4-difluorophenyl; Q is CH, C-C1, C-OMe or N, and R ₂ and R ₃ represent hydrogen or a methyl group.

Therefore, based on these prior arts, the present inventors have a new oxime capable of exhibiting high solubility and absorption in water while having superior pharmacokinetic properties while maintaining the strong antibacterial activity and broad antibacterial spectrum of these aminomethyl compounds. Efforts to develop aminomethyl compounds have resulted in the introduction of a (1-amino-1-alkyl) ethyl group at the 4-position of the pyrrolidine structure and a quinolone-based structure in which the alkyloxime group is simultaneously introduced at the 3-position. The discovery that the compound meets these objectives has led to the completion of the present invention.

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 R represents hydrogen, methyl, or amino;

Q represents CH, CF, C-C1, C-CH ₃ , CO-CH ₃ or N; R ₁ represents cyclopropyl, ethyl or phenyl substituted with one or more fluorine atoms; R ₂ represents hydrogen, C ₁ -C ₅ alkyl, cyclopropyl, cyclopropylmethyl, C ₃ -C ₆ alkenyl, C ₃ -C ₆ alkynyl, substituted or unsubstituted phenyl or benzyl, or a compound of formula Represent;

Wherein n is 0 or 1, m is 0, 1 or 2 and X is methylene, O or N. R ₃ and R ₄ each independently represent hydrogen, C ₁ -C ₃ alkyl or together with the nitrogen atom to which they are attached may form a ring of C ₃ -C ₅ ; R ₅ and R ₆ each independently represent C ₁ -C ₃ alkyl or haloalkyl or they may be linked to one another to form a cycloalkyl group, provided that R ₅ and R ₆ are not simultaneously hydrogen.

Among the compounds of the general formula (I) having excellent antibacterial action and broad antibacterial spectrum and excellent pharmacokinetic properties, preferred compounds are Q, CH, CF, C-Cl or N; R is hydrogen or amino; R ₁ is cyclopropyl or 2,4-difluophenyl; R ₂ is hydrogen, methyl, ethyl, t-butyl, i-propyl, allyl, phenyl or propazyl; R ₃ and R ₄ are hydrogen; R ₅ and R ₅ are each independently methyl or fluoromethyl or they are linked to one another to represent cyclopropyl.

More preferred compounds Q is CH, CF or N; R is hydrogen or amino and R ₁ is cyclopropyl; R ₂ is hydrogen, methyl or t-butyl, and R ₃ and R ₄ are hydrogen; R ₅ and R ₆ are each a compound which is methyl.

R position in which the (1-amino-1-alkyl) ethyl group is substituted in the pyrrolidine group of the compound of general formula (I) may be present in the form of R or S as an asymmetric carbon, or in the form of a mixture of R and S. In addition, when there is a substituted alkyloxime group at position 3 of pyrrolidine, there are geometric isomers of syn- and anti- depending on the geometric form, and each of these geometric isomers and Mixtures thereof are also included.

Pharmaceutically acceptable non-toxic salts of the compounds of general formula (i) according to the invention are salts with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid or the like 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 other acids known and used in the quinolone-based art. Salts. These acid addition salts can be prepared by conventional conversion processes.

According to the invention there is also provided a process for the preparation of the novel compounds of the general formula (I).

According to the present invention, the compound of general formula (I) can be prepared by reacting the compound of general formula (II) with a compound of general formula (III) or a salt thereof according to the method of Scheme 1 below.

Wherein R, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ and Q are the same as described above;

X represents a halogen atom, preferably chlorine, bromine or fluorine.

According to Scheme 1, the compound of formula (I) of the present invention is a compound of formula (II) and a compound of formula (III) at a temperature of room temperature to 200 ℃ by adding a suitable base in the presence of a solvent It can be prepared by stirring for 1 to 20 hours. In this reaction, the compound of general formula (III) can be used in the form of a free compound or in the form of a salt with an acid such as hydrochloric acid, hydrobromic acid or trifluoroacetic acid.

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

The reaction is generally carried out in the presence of an acid acceptor, in which the reactant (III) is in excess of the starting material (II), for example equimolar amounts, in order to increase the reaction efficiency of the relatively expensive starting material (II). It is used in 10 to 10 times the molar amount, Preferably it is used in the equimolar amount to 5 times molar amount. When the reactant (III) is used in excess, the compound of the general formula (III) remaining after the reaction can be recovered and reused. The acid acceptors that can be used include inorganic bases such as sodium hydrogen carbonate and potassium carbonate, trientylamine, 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.

As a compound represented by the general formula (I) according to the invention it can also be illustrated in the following reaction scheme 2, R ₃ and R ₄ in the 4-aminomethyl the R ₃ and R ₄ in the compound of formula (III) hydrogen A compound of formula (III ′) in which a protecting group P was introduced into one to form an amino group in a protected form was reacted with a compound of formula (II) under the same conditions as in Scheme 1, It can also be manufactured by the method of synthesizing the compound of general formula (I) of interest by deprotecting the compound of I ') and removing protecting group P.

Wherein R, R ₁ , R ₂ , R ₅ , R ₆ Q and X are the same as described above; P represents an aminoprotecting group.

The compound of general formula (III ′) in the reaction of Scheme 2, like the compound of general formula (III) in Scheme 1, is a free compound or in the form of a salt with an acid such as hydrochloric acid, hydrobromic acid or trifluoroacetic acid. Can be used as

The amino protecting group P usable in the compound of the general formula (III ′) may be any one that can be removed without destroying the structure of the target compound obtained as a result of reaction as commonly used in organic chemistry. Specific examples of protecting groups that can be used for this purpose include formyl, acetyl, trifluoroacetyl, benzoyl, para-nitrobenzoyl, para-toluenesulfonyl, methoxycarbonyl, ethoxycarbonyl, t-butoxycar Carbonyl, benzyloxycarbonyl, para-methoxybenzyloxycarbonyl, trichloroethoxycarbonyl, beta-iodineethoxycarbonyl, benzyl, paramethoxybenzyl, trityl, tetrahydropyranyl groups and the like.

After the reaction is completed, the amino protecting group present in the target compound (I ′) produced can be removed using a solvolysis or reduction reaction including hydrolysis, depending on the nature of the protecting group. For example, the compound of general formula (I ′) may be carried out by treating at a temperature of 0 to 130 ° C. in a solvent in the presence or absence of an acid or base. 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 alkali metal or alkaline earth metal hydroxides 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, sodium acetate, and the like. . As a solvent, a solvent such as ethanol, tetrahydrofuran, dioxane, ethylene glycol, acetic acid, or a mixed solvent of these solvents and water may be used depending on the compound, or may be reacted without solvent in some cases.

In addition, when the protecting group is para-toluenesulfonyl, benzyl, trityl, paramethoxybenzyl, benzyloxycarbonyl, para-methoxybenzyloxycarbonyl, trichloroethoxycarbonyl, beta-ioethoxycarbonyl group or the like, reduction The reaction can be used to effectively remove it. The removal of the protecting group by the reduction reaction may vary slightly depending on the nature of the protecting group, but may be carried out by blowing a 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 In general, it is carried out by treatment with metallic sodium or metallic lithium in liquid ammonia at -50 to -10 ° C.

Compounds of formula (II) used as starting materials in the present invention are known compounds (JM Domagala, et al., J. Med. Chem. 34, 1142 (1991); JM Domagala, et al., J) Med. Chem. 31,991 (1998); D. Bouzard, et al., J. Med. Chem. 35, 518 (1992) and the like).

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

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

Referring to the preparation method of Schemes 3 and 4 in detail.

First, according to Scheme 3, 3-keto-4-cyanopinolidine [2] can be obtained by reacting cyanoester [1] in which the amine group is protected with benzyl group with sodium ethoxide in a solvent such as ethanol. Can be. Cyanoalcohol [3] is prepared by reducing the produced cyanopinolidine [2] with a reducing agent such as sodium borohydride, and reacting cyanoalcohol [3] with methyllidium or dimethylcerium chloride at low temperature to give mono Or dimethylated aminoalcohol [4]. The amine [5] obtained by protecting the amino group and the alcohol group of the obtained aminoalcohol [4] simultaneously with t-butoxycarbonyl etc. was obtained, and the benzyl group of the amine [5] was removed by passing through a hydrogen stream under a palladium catalyst. Protected amine [6] is synthesized by protecting and vaporizing with t-butoxycarbonyl anhydride in the same vessel. The amine [6] was treated in an anti-trioxide tripyridine mixture with a dimethylsulfoxide solvent (Parikh, JR and Doering, W. v. EJ Am. Chem. Soc. 1967, 89, 5505) or oxidized with another oxidizing agent to ketone [ 7] is generated. The ketone compound [7] can be obtained by reacting with an amine having the structure of R ₂ described above to obtain the desired oxime compound [8]. The oxime compound [8] is deprotected by a suitable method depending on the type of protecting group to give the desired oxime. Compound (III) can be obtained.

As another method, according to Scheme 4, ketone [7] is reacted with hydroxylamine to produce the desired oxime compound [9], and this compound [9] is introduced into the desired R ₂ in the presence of a base. After reacting with an appropriate electrophilic compound to prepare an oxime derivative of the general formula [8], the resulting oxime compound [8] is deprotected in a suitable manner according to the type of protecting group in the same manner as in Scheme 3. It is also possible to obtain the desired oxime compound (III).

On the other hand, the compound of the general formula (III) in which the amino group of the aminomethyl group of the pyrrolidin 4 position is substituted by alkyl can be prepared by the following Scheme 5.

According to the above method, the amine compound [4] is _first treated with an aldehyde of C ₁ -C ₃ and then reduced to obtain a substituted amine compound [9], which is then protected, and then the same method as in Schemes 3 and 4 It can be used to synthesize the compound of the general formula (III) easily.

Synthesis methods mentioned above will be described in more detail in the following Production Examples.

According to the present invention, there is also provided an antimicrobial composition containing as an active ingredient the novel compound of formula (I) or a pharmaceutically acceptable salt thereof.

Such antimicrobial compositions are formulated into pharmaceutical formulations in solid, semisolid or liquid form suitable for oral, parenteral and topical administration by combining a compound of formula (I) with a pharmaceutically acceptable inert carrier upon clinical administration. Can be administered. Pharmaceutically acceptable inert carriers which may suitably be used for this purpose may be solid or liquid. Solid or semisolid forms of pharmaceutical preparations, including powders, tablets, dispersible granules, capsules, cachets, suppositories, and ointments, are generally used as solid carriers, and solid carriers which can be used favorably include diluents, flavors, It may be one or more of a solubilizer, a lubricant, a suspending agent, a binder, a tablet swelling agent, or a substance for encapsulation. In the case of powders, the carrier preferably comprises 5 or 10 to 70% of the finely divided active component. Specific examples of 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. 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 a water-propylene glycol solution may be used for oral 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 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 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 plasters in tubes or bottles in vials or ampoules. The unit dosage form may also be a capsule, casein, tablet, gel or cream or may also be 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 infections, the compound used in the pharmaceutical methods of the present invention is preferably initially at a dosage of about 6-14 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.

Determining the desired dosage in a particular condition is well known to those skilled in the art. 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 dosage may be divided several times and administered throughout the day.

As mentioned above, the compounds according to the present invention exhibit an antimicrobial spectrum and stronger antimicrobial activity against various gram-positive and gram-negative pathogens. For gram-negative bacteria, conventional compounds (eg ciprofloxacin) and It shows the same or more antimicrobial activity, especially for Gram-positive bacteria shows excellent activity compared to conventional drugs, and also shows very good antimicrobial activity against strains that are resistant to quinolone compounds.

The compound according to the present invention 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 a half-life in vivo that is significantly longer than that of conventional quinolone compounds. Suitable for use as an antimicrobial agent for single use.

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

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

[Production Example 1]

[Synthesis of (N-benzyl-2-cyanoethylamino) acetic acid ethyl ester]

(2-cyanoethylamino) acetic acid ethyl ester (54.48 g, 0.35 mol) was dissolved in 500 ml of N, N-dimethylformamide, and 62.65 g (1.05 molar equivalent) of benzylbromide was added to the solution, followed by sodium carbonate (Na 37 g (1 molar equivalent) of ₂ CO ₃ ) was added thereto, and the resultant was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, dissolved in water, extracted with ethyl ester, dried, filtered and concentrated, and purified by short column chromatography (eluent: hexane / ethyl acetate (2: 1)) to give the title compound 83.57 as a yellow liquid. g was obtained. (Yield 97%).

[Production Example 2]

[Synthesis of 1-benzyl-4-cyanopyrrolidin-3-one]

A sodium ethoxide (NaOEt) solution was prepared by pulverizing 8 g of sodium (Na) metal in 500 ml of anhydrous ethanol and refluxing the mixture. To this solution, 83.57 g (0.34 mol) of the compound obtained in Preparation Example 1 was dissolved in 500 ml of anhydrous ethanol and added while heating under reflux. The mixture was further heated to reflux for 1 hour, concentrated under reduced pressure, dissolved in water, and washed with methylene chloride. The pH of the water layer was adjusted to 4 with 3 N HC1, then extracted three times with methylene chloride, combined, and the extract was dried over anhydrous magnesium sulfate. The dried solution was filtered and concentrated to give 60.21 g (yield: 89%) of the title compound in an unpurified state.

[Manufacture example 3]

[Synthesis of 1-benzyl-4-cyanopyrrolidin-3-ol]

60.21 g (0.3 mol) of the compound obtained in Preparation Example 2 was dissolved in 1 L of ethanol, and sodium borohydride (NaBH ₄ ; 22.8 g, 2 molar equivalents) was slowly added while stirring at room temperature. After further stirring at room temperature for 2 hours, the mixture was concentrated under reduced pressure. The mixture was diluted with dilute acid, extracted three times with methylene chloride, combined, washed with dilute acid and brine, dried over anhydrous magnesium sulfate, filtered and concentrated to afford the title compound. This was purified by column chromatography (eluent; hexane / ethyl acetate = 1: 1) (60 g, quantitative). When the obtained compound is left in the internal compartment, the sticky oil is changed into a solid, which is washed with hexane and dried under reduced pressure to be a pale yellow solid, which can be stored in this state.

[Production Example 4]

[Synthesis of 4- (1-amino-1-methyl) ethyl-1-benzylpyrrolidin-3-ol]

Cerium chloride (CeCl ₃ 7H ₂ O) was slowly heated to 14 ° C. under vacuum (0.1 Torr) for about 2 hours, and then stirred overnight while maintaining 150 ° C. After the reaction was completely dried, the temperature was lowered to room temperature, and anhydrous cerium chloride (CeC1 ₃ ) was weighed under nitrogen to find 8.82 g (35.8 mmol, 5 molar equivalents). Dilute anhydrous cerium chloride with 90 ml of anhydrous tetrahydrofuran (THF) under nitrogen and stir well for 3 to 3.5 hours, then lower the temperature of the reaction mixture to 78 ° C. and add methyllithium (MeLi, 1.4 M / ethyl ether solution). , 25.5 ml) was added slowly dropwise. At the same temperature, 1.45 g (7.1 mmol) of the compound obtained in Preparation Example 3 was dissolved in 20 ml of anhydrous tetrahydrofuran and slowly added dropwise to the mixture. Stirred for 3 hours while maintaining the reaction temperature between -70 and -60 ℃. After 5.4 ml of ammonia water (28%) was dropped dropwise to terminate the reaction, the temperature was raised to the phase mixing. 44 ml of methylene chloride was added thereto, stirred well, filtered, the slurry and the solid were discarded, and concentrated under reduced pressure. The reaction was concentrated with a solution of 1.27 g of acetic acid diluted in 69 ml of distilled water and dissolved twice with methylene chloride. The water layer was neutralized with 4.4 ml of ammonia water and extracted with methylene chloride. The organic layers were combined, dried, concentrated and concentrated under reduced pressure to yield 1.20 g of the crude title compound.

Production Example 5

[Synthesis of 1-benzyl-4- (1-t-butoxycarbonylamino-1-methyl) ethyl-3-t-butoxycarbonyloxypyrrolidine]

After dissolving the compound obtained in Preparation Example 4 in a mixed solution of 20 ml of dioxane and 10 ml of distilled water, 1.55 g (7.1 mmol) of di-t-butoxycarbonylcarbonate was added to 5 ml of dioxane and added to the mixture at room temperature. Stirred for a minute. At this time, if the reaction is not completed, a small amount of sodium bicarbonate (NaHCO ₃ ) is added. The reaction was concentrated under reduced pressure, diluted with ethyl acetate, washed with distilled water, dried, condensed and concentrated. The residue was purified by column chromatography (eluent; 20% ethyl acetate / hexane) to give 1.23 g of the title compound (total yield of 2 steps of Preparation Examples 4 and 5: 40%).

[Manufacture example 6]

[Synthesis of 1-t-butoxycarbonyl-4- (1-t-butoxycarbonylamino-1-methyl) ethyl-3-t-butoxycarbonyloxypyrrolidine]

920 mg (2.1 mmol) of 1-benzyl-4- (1-t-butoxycarbonylamino-1-methyl) ethyl-3-t-butoxycarbonyloxypyrrolidine obtained in Preparation Example 5 was added to 50 ml of methanol. After dissolving, 50 mg of Pb (OH) ₂ and 550 g (2.5 mmol) of di-t-butoxycarbonylcarbonate were added thereto. After the reaction mixture was stirred under a hydrogen gas pressure using a balloon for 12 hours, the reaction mixture was filtered and concentrated under reduced pressure to obtain the title compound quantitatively (1.1 g).

[Manufacture example 7]

[Synthesis of 1-t-butoxycarbonyl-4- (1-t-butoxycarbonylamino-1-methyl) ethylpyrrolidin-3-ol]

1-t-butoxycarbonyl-4- (1-t-butoxycarbonylamino-1-methyl) ethyl-3-t-butoxycarbonyloxypyrroli obtained in crude state without purification 1.1 g of Dean was dissolved in 50 ml of methanol, and 10 ml of 10% KOH solution was added thereto, followed by stirring at room temperature. After 2 hours, the reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate, and washed with brine. The organic layer was dried, filtered and concentrated and purified by column chromatography (eluent; 30% ethyl acetate / hexane) to yield 0.61 g of the title compound (total yield of Preparation 6 and 7 two steps: 79%).

[Manufacture example 8]

[Synthesis of 1-t-butoxycarbonyl-4- (1-t-butoxycarbonylamino-1-methyl) ethylpyrrolidin-3-one]

600 mg (1.63 mmol) of the compound obtained in Preparation Example 7 were dissolved in 15 ml of dimethyl sulfoxide, and then 0.7 ml (3 molar equivalents) of trimethylamine was added and cooled in an ice bath. When the base wall of the flask began to freeze, 2.60 g (10 molar dang) of pyridine-sulfotrioxide (Py-SO ₃ ) oxidizer was added little by little, and after that, the ice bath was removed and stirred at room temperature for 3 hours. The temperature was lowered again with an ice bath, further diluted with 50 ml of jeongdong water, extracted with ethyl acetate, and combined. The extract was dried, filtered and concentrated and purified by silica gel column chromatography (eluent; hexane / ethyl acetate (2: 1)) to give 330 mg of the title compound (yield: 55%).

[Manufacture example 9]

[Synthesis of 1-t-butoxycarbonyl-4- (1-t-butoxycarbonylamino-1-methyl) ethylpyrrolidin-3-one-O-methyloxime]

330 mg (0.91 mmol) of the compound obtained in Preparation Example 8 were dissolved in a mixture of 6 ml of ethanol and 3 ml of tetrahydrofuran, followed by addition of 0.33 g (3.7 molar equivalents) of methoxylamine hydrochloride. 300 mg of sodium hydrogen carbonate was added to 1.5 ml of distilled water in the reaction mixture, and the mixture was stirred overnight at room temperature. The reaction was concentrated under reduced pressure, diluted with ethyl acetate and washed with an aqueous ammonium chloride solution and an aqueous sodium chloride solution.

The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated and purified by column chromatography to give 303 mg of the title compound (yield: 90%).

Preparation Example 10

[10: Synthesis of 4- (1-amino-1-methyl) ethylpyrrolidin-3-one-O-methyloxime dihydrochloride]

After dissolving 303 mg (0.82 mmol) of the compound obtained in Preparation Example 9 in 2 ml of methanol, the temperature was lowered to -5 ° C. 1 ml of acetyl chloride was slowly added dropwise thereto, and the mixture was stirred for 30 minutes while raising the temperature to room temperature. The oily substance obtained by concentrating the reaction under reduced pressure was washed 3-4 times with ethyl ether, dissolved in a minimum amount of methanol, and acetonitrile was slowly dropped therein to precipitate a solid. Filtration, washing with ethyl ether and drying with nitrogen gave 158 mg of the title compound (yield: 79%).

Example 1

[7- [4- (1-amino-1-methyl) ethyl-3-methoxyiminopyrrolidin-1-yl] -1-cyclopropyl-6-fluoro-4-oxo-1,4-di Synthesis of Hydro [1,8] naphthyridine-3-carboxylic Acid]

85 mg (0.35 mmol) of 4- (1-amino-1-methyl) ethylpyrrolidin-3-one-O-methyloxime dihydrochloride obtained in Preparation Example 10 and 1-cyclopropyl-7-chloro-6-fluoro 81 mg (0.29 mmol) of r-4--4-o-1,4-dihydro [1-8] naphthyridine-3-carboxylic acid were added to 2.0 ml of dried acetonitrile, and 1,8-diazabicyclo [ 5.4.0] Undecase-7-ene 136 mg (3.1 molar equivalents) were added and stirred at room temperature for 1 hour. 1 ml of distilled water was added thereto, stirred, and the precipitated solid was filtered, washed with 80% ethanol, and dried to yield 80 mg of the title compound (yield: 66%).

Example 2

[7- [4- (1-amino-1-methyl) ethyl-3-methoxyiminopyrrolidin-1-yl] -1-cyclopropyl-6,8-difluoro-4-oxo-1, Synthesis of 4-dihydroquinoline-3-carboxylic acid]

272 mg (1 mmol) of 1-cyclopropyl-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid and 4- (1-amino-1-methyl) ethyl 258 mg (1.2 molar equivalents) of pyrrolidin-3-one-O-methyloxime dihydrochloride was added to 3 ml of dried acetonitrile and 440 mg (3.1) of 1,8-diazabicyclo [5.4.0] undec-7-ene Molar equivalents) was added thereto, and the mixture was heated to reflux for 1.5 hours, and then cooled to room temperature. 2 ml of distilled water was added to the reaction and stirred for 20 minutes. The precipitated solid was filtered and purified using preparative HPLC to give 252 mg of the title compound (yield: 58%).

Example 3

[7- [4- (amino-1-methyl) ethyl-3-methoxyiminopyrrolidin-1-yl] -1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline Synthesis of 3-carboxylic Acid]

265 mg (1 mmol) of 1-cyclopropyl-6.7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid and 4- (1-amino-1-methyl) ethylpyrrolidine- 258 mg (1.2 molar equivalent) of 3-one-O-methyloximedihydrochloride was reacted for 2 hours in the same manner as in Example 2. The reaction mixture was cooled to room temperature, water was added, and the resulting solid was purified by preparative HPLC to give 229 mg of the title compound (yield: 55%).

Example 4

[5-amino-7- [4- (1-amino-1-methyl) ethyl-3-methoxyiminopyrrolidin-1-yl] -1-cyclopropyl-6,8-difluoro-4- Synthesis of Oxo-1,4-dihydroquinoline-3-carboxylic Acid]

298 mg (1 mmol) of 5-amino-1-cyclopropyl-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid and 4- (1-amino-1 258 mg (1.2 molar equivalents) of -methyl) ethylpyrrolidin-3-one-O-methyloxime dihydrochloride was added to 2 ml of dried acetonitrile and 1,8-diazabicyclo [5.4.0] undec-7- 440 mg (3.1 molar equivalent) of ene was added and heated to reflux for 2 hours. After cooling the reaction mixture to room temperature, 2ml of distilled water was added and stirred for 15 minutes. Filtration gave a solid, which was then purified by preparative HPLC to give 193 mg of the title compound (yield: 43%).

Biological Example 1

[In vitro Antimicrobial Activity Assay]

The usefulness of the compounds according to the present invention is the minimum inhibitory concentration against standard strains, clinically isolated strains, and strains resistant to some antibiotics using known compounds of Ofloxacin and Ciprofloxacin as control agents. Minimum Inhibitory Concentration (Mic, µg / ml) was obtained and evaluated. The minimum inhibitory concentration was obtained by diluting the test compound by 2-fold dilution method, dispersing it in Mueller-Hinton agar medium, and inoculating 5 μl of standard strain having 10 ⁷ CFU / ml at 37 ° C. Incubation was performed for 18 hours, and the results are shown in Table 1 below.

Biological Example 2

[Acute Oral Toxicity Test]

To investigate the acute oral toxicity of the compounds obtained in Examples 1 and 4, solutions containing the compounds in different concentrations were orally administered to male mice of the ICR strain at a dose of 10 ml per kg. The mortality and symptoms for 7 days after oral administration were observed and the median lethal dose (LD, mg / kg) was calculated according to the Litchfield-Wilcoxon method and the results are shown in Table 2 below.

Claims (13)

Quinoline carboxylic acid derivatives represented by the following general formula (I), pharmaceutically acceptable salts thereof, physiologically hydrolysable esters, solvates and isomers. Wherein R represents hydrogen, methyl or amino; Q represents CH, CF, C-C1, C-CH ₃ , CO-CH ₃ or N; R ₁ represents cyclopropyl, ethyl or phenyl substituted with one or more fluorine atoms; R ₂ represents hydrogen, C ₁ -C ₅ alkyl, cyclopropyl, cyclopropylmethyl, C ₃ -C ₆ alkenyl, or C ₃ -C ₆ alkynyl; R ₃ and R ₄ each independently represent hydrogen or C ₁ -C ₃ alkyl; R ₅ and R ₆ each independently represent C ₁ -C ₃ alkyl. The compound of claim 1, wherein Q is CH CF, C—C 1 or N; R is hydrogen or amino; R ₁ is cyclopropyl or 2,4-difluorophenyl; R ₂ is hydrogen, methyl, ethyl, t-butyl, i-propyl, allyl, phenyl or propazyl; R ₃ and R ₄ are hydrogen; R ₅ and R ₅ each independently represent methyl. The compound of claim 2, wherein Q is CH, CF or N; R is hydrogen or amino; R ₁ is cyclopropyl; R ₂ is hydrogen, methyl or t-butyl; R ₃ and R ₄ are hydrogen; R ₅ and R ₆ are each methyl. A process for preparing a compound of formula (I), wherein the compound of formula (II) is reacted with a compound of formula (III) in the presence of an acid acceptor in a solvent. Wherein Q, R, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and R ₆ are as defined in claim 1 and X is halogen. The process according to claim 4, wherein the compound of formula (III) is used in salt form with hydrochloric acid, hydrobromic acid or trifluoroacetic acid. The method according to claim 4, wherein the compound of general formula (III) is used in an equimolar amount to 10 molar times with respect to the compound of general formula (II). The process of claim 4 wherein the solvent is selected from acetonitrile, dimethylformamide (DMF), dimethylsulfoxide (DMSO), pyridine or hexamethylphosphoamide (HMPA). The acid acceptor according to claim 4, wherein the acid acceptor is sodium hydrogencarbonate as an inorganic base, triethylamine, diisopropylethylamine, pyridine, N, N-dimethylaniline, N, N-dimethylaminopyridine, 1 as an inorganic base. , 8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,4-diazabicyclo [2.2.2] octane (DABCO). The method of claim 4 wherein the reaction temperature is from room temperature to 200 ° C. 6. A method for preparing a compound of formula (I), wherein the compound of formula (III ') is reacted with the compound of formula (II) in the presence of an acid acceptor, and then the amino protecting group is removed. Wherein R ₂ , R ₅ and R ₆ are as defined in claim 1 and P represents an aminoprotecting group. The aminoprotecting group of claim 10, wherein the aminoprotecting group is formyl, acetyl, trifluoroacetyl, benzoyl, para-nitrobenzoyl, para-toluenesulfonyl, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, benzyl Oxycarbonyl, para-methoxybenzyloxycarbonyl, trichloroethoxycarbonyl, beta-iodoethoxycarbonyl, benzyl, paramethoxybenzyl, trityl, tetrahydropyranyl. An antimicrobial composition comprising the compound of formula (I) according to claim 1 as an active ingredient. 13. The composition of claim 12, wherein the compound of formula (I) contains 1 to 10 mg in unit dosage.