KR0134940B1 - Novel 7-aminooxypyrrolidine quinoline carboxylic acid derivatives and preparation method thereof - Google Patents

Abstract

The present invention is a compound having a derivative of a pyrrolidine group substituted with an aminooxy group at the 7-position of the quinolone mother nucleus, and has a novel quinoline and naphthyridine carboxyl of formula (I) having excellent antibacterial action and broad antibacterial spectrum. Acid derivatives, pharmaceutically acceptable salts thereof, solvates thereof, and methods for their preparation.

Wherein Q is CH, CF, C-Cl, CO-alkyl (C ₁ -C ₄ ), or N, R ₁ is ethyl, cyclopropyl or phenyl substituted with one or more fluorine atoms, R ₂ is Hydrogen, methyl, or amino, R ₃ is hydrogen, hydroxy, C ₁ -C ₄ alkoxy, or NR ₆ R ₇ , wherein R ₆ and R ₇ are each independently hydrogen or C ₁ -C ₄ alkyl, or R ₆ and R ₇ may be linked together with the nitrogen atom to which they are attached to form a 4 to 8 membered ring which may optionally contain one or more additional heteroatoms selected from N, O or S). , n is 0 or 1, and R ₄ and R ₅ may each independently form hydrogen, C ₁ -C ₄ alkyl, or C ₁ -C ₄ alkenes in which two groups are connected together by a double bond to a nitrogen atom.

Description

Novel 7-aminooxypyrrolidine quinoline carboxylic acid derivatives and preparation method thereof

The present invention relates to novel quinolone compounds exhibiting excellent antimicrobial activity.

In particular, the present invention is a compound having a derivative of a pyrrolidine group substituted with an aminooxy group at the 7-position of quinolone hair nucleus, and has novel quinoline and naphti of the general formula (I) having excellent antibacterial tension and broad antibacterial spectrum. Lidine carboxylic acid derivatives, pharmaceutically acceptable salts thereof, solvates thereof, and methods for their preparation.

Wherein Q is CH, CF, C-Cl, CO-alkyl (C ₁ -C ₄ ), or N, R ₁ is ethyl, cyclopropyl or phenyl substituted with one or more fluorine atoms, R ₂ is hydrogen , Methyl, or amino, R ₃ is hydrogen, hydroxy, C ₁ -C ₄ alkoxy, or NR ₆ R ₇ , wherein R ₆ and R ₇ are each independently hydrogen or C ₁ -C ₄ alkyl, or R ₆ and R ₇ may be linked together with the nitrogen atom to which they are attached to form a 4-8 membered ring which may optionally contain one or more additional heteroatoms selected from N, O or S), n is 0 or 1, and R ₄ and R ₅ may each independently form hydrogen, C ₁ -C ₄ alkyl, or C ₁ -C ₄ alkenes in which two groups are linked together by a double bond to a nitrogen atom.

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

Recently, a new generation of quinolones-containing nofloxacin (H. Koga, et al., J. Med. Chem. 23, 1358-63 (1980)) containing fluorine at position 6 has been developed. Research on antibiotics has been very extensively attempted. However, nofloxacin has a relatively low antimicrobial activity against Gram-positive bacteria and is poorly distributed and absorbed, resulting in urinary tract infections, gastro-intestinal infections or sexually transmitted infections caused by Gram-negative bacteria. mainly used for transmitted desaeae). However, thereafter, ciprofloxacin (R. Wise, et al., J. Antimicrob. Agents Chemother, 3, 559 (1983)), ofloxacin (K. Sata, et al., Antimicrob. Agents Chemother, 22, 548 (1982), and the like, which have a broader antimicrobial activity than earlier antimicrobials, and are widely used in practice today.

On the other hand, piperazine-substituted derivatives such as ciprofloxacin or oploxacin are mainly formed at position 7 of the quinolone mother nucleus, but as a result of continuous efforts to develop more powerful and broad-spectrum antibacterial antibiotics, position 7 It was found that the antimicrobial activity against Gram-positive bacteria was increased while maintaining the antimicrobial activity against Gram-negative bacteria compared to the compound having 3-amino or 3-amino methylpyrrolidine group and having a piperazine group at position 7. Unfortunately, in general, compounds having pyrrolidin substituents do not show strong antimicrobial properties in vitro, such as antibacterial activity, due to low solubility in water compared to compounds having piperazine substituents. Thus, efforts have been made to improve these shortcomings of compounds with pyrrolidine substituents to increase their solubility in water and also to improve their pharmacokinetic properties, examples of which are shown in several reports. For example, ((2S, 4S) -4-amino-methylpyrrolidinyl) naphthyridine derivatives (Rosen, T; Chu, DTW etc. J. Med. Chem. 1988, 31, 1598-1611) or (trans- 3-amino-4-mitelpyrrolidinyl) naphthyridine derivatives (Matsumoto. J etc. Proceedings of the 14th International Congress of Chemotherapy; Ishigami, J., Ed .: University of Tokyo Press: Tokyo, 1985; pp 1519-1520 ) Showed similar in vitro antimicrobial activity and 20- and 40-fold solubility in water, respectively, compared to the compound without methyl group in pyrrolidine, which increased oral absorption and improved pharmacokinetic properties.

On the other hand, efforts to improve pharmacokinetic properties by introducing other functional groups into pyrrolidine or piperazine by improving the disadvantages of quinolone compounds, that is, relatively weak antimicrobial activity and low solubility in water against gram-positive bacteria In this effort, for example, European Patent No. 288519-A (1988) discloses a quinolone compound represented by the following general formula [A].

Wherein R _1,2,3 each independently represent hydrogen, alkyl, amino, fluoro, chlorine, phenyl or hydroxy; X represents a halogen element such as fluoro; Y represents hydrogen or a halogen element.

As another example, Japanese Patent No. 01-100165 (1989) describes a quinolone compound represented by the following general formula [B].

Wherein R is cyclopropyl, 2,4-difluorophenyl, 4-hydroxy, or phenyl, and R ₄ is hydrogen, fluorine or chlorine; R ₃ is 3-hydroxyaminopyrrolidine, 3-methoxyaminopyrrolidine, 3-amino-4-methoxyaminopyrrolidine, 3-oximepyrrolidine (formula a below), or 3-methyl Oximepyrrolidine (formula b)

In the above-mentioned prior document, the amine group of oxime is characterized by being directly connected to the pyrrolidine ring. On the other hand, Japanese Patent No. 028998 (85) describes a quinolone compound represented by the following general formula [C].

Wherein R represents hydrogen or lower alkyl; R 'represents a benzene group substituted with cyclic lower alkyl or fluorine such as lower alkyl, cyclopropyl; X represents a halogen element such as fluorine or chlorine.

As another example, European Patent No. 0551653 of Bayer AG. Describes a quinolone compound represented by the following general formula [D].

Wherein R represents lower alkyl. The compound of the formula shows excellent antimicrobial activity against gram-positive bacteria, while relatively weak antimicrobial activity against gram-negative bacteria.

Another Japanese Patent No. 2-69474 of Bayer AG. Discloses a quinolone compound represented by the following general formula [E].

Wherein R corresponds to an ester forming group of hydrogen and lower alkyl; X represents a reactive element such as hydrogen or fluorine; R ₁ is benzene substituted with halogen such as cyclopropyl or fluorine; R ₂ , R ₃ and R ₄ each represent the same or different hydrogen or lower alkyl group.

The structural features of the compounds represented by the above formulas are those in which an amino group is directly bonded to a pyrrolidine group substituted at position 7 of the quinolone, such that the oxygen of the aminooxy group, like the target compound of the present invention, is directly or through a methylene group. It does not contain any compound having an aminooxypyrrolidine group linked to lollidine.

Accordingly, the present inventors have made efforts to develop a quinolone compound having strong antibacterial activity against a wide range of pathogens including gram-positive bacteria and gram-negative bacteria as well as resistant bacteria and having improved pharmacokinetic properties based on these prior arts. The present invention has been accomplished by discovering that a compound in which an aminooxy group is bonded directly or via methylene to the pyrrolidine group at the position of the quinolone mother nucleus 7 meets this goal.

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

Wherein Q is CH, CF, C-Cl, CO-alkyl (C ₁ -C ₄ ), or N, R ₁ is ethyl, cyclopropyl or phenyl substituted with one or more fluorine atoms, R ₂ is hydrogen , Methyl, or amino, R ₃ is hydrogen, hydroxy, C ₁ -C ₄ alkoxy, or NR ₆ R ₇ , wherein R ₆ and R ₇ are each independently hydrogen or C ₁ -C ₄ alkyl, or R ₆ and R ₇ may be linked together with the nitrogen atom to which they are attached to form a 4-8 membered ring which may optionally contain one or more additional heteroatoms selected from N, O or S), and Is 0 or 1, and R ₄ and R ₅ may each independently form hydrogen, C ₁ -C ₄ alkyl, or C ₁ -C ₄ alkenes in which two groups are connected together by a double bond with a nitrogen atom.

Among the compounds of the general formula (I) showing excellent antimicrobial activity and broad antimicrobial spectrum, preferred compounds are Q, CH, CF or N, R ₁ is cyclopropyl or 2,4-difluorophenyl, and R ₂ is hydrogen R ₃ is hydrogen, C ₁ -C ₄ alkoxy, or NR ₆ R ₇ , wherein R ₆ and R ₇ are each independently hydrogen or C ₁ -C ₄ alkyl, or R ₆ and R ₇ are attached thereto Or N is 0 or 1, and R ₄ and R ₅ are each hydrogen, or two groups are linked together by a double bond to a nitrogen atom. Compound forming _1- C ₄ alkene.

More preferred compounds are Q is CH or CF, R ₁ is cyclopropyl, R ₂ is hydrogen, R ₃ is hydrogen or NH ₂ , n is 0 or 1 and R ₄ and R ₅ are each hydrogen, Two groups are compounds that together form isopropylidene linked to a nitrogen atom by a double bond.

In the pyrrolidine group of the general formula (I), positions 3 and 4 where the -R ₃ group or the-(CH ₂ ) _n ONR ₄ R ₅ group are substituted are asymmetric carbons or R or S isomers respectively, or R And S in the form of a mixture. Therefore, in the present invention, each of these isomers and mixtures thereof is also included.

Pharmaceutically acceptable non-toxic salts of the general formula (I) compounds according to the present invention are inorganic acids such as hydrochloric acid, bromic acid, phosphoric acid, sulfuric acid, acetic acid, trifluoroacetic acid, citric acid, maleic acid, hydroxyl, succinic acid, benzoic acid, tartaric acid And other carboxylic acids such as fumaric acid, manderinic acid, ascorbic acid or dried acid, or salts with sulfonic acids such as methanesulfonic acid and para-toluenesulfonic acid. Contains salts. These acid addition salts can be prepared by conventional conversion processes.

Compound of formula (I) according to the present invention is added to the compound of formula (II) and the compound of formula (III) in the presence of a solvent according to the method of Scheme 1 below to a temperature of room temperature to 200 ℃ It is also an object of the present invention to provide a method for preparing a compound of general formula (I), which can be prepared by stirring for 1 to 20 hours.

Wherein Q, R ₁ , R ₂ , n, R ₃ , R ₄ and R ₅ are the same as those matured, X is a halogen atom (preferably chlorine, bromine or fluorine), and The compounds may be used on their own or in the form of salts with hydrochloric acid, bromic acid or trifluoroacetic acid and the like.

As the solvent used in the reaction, acetonitrile, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), pyridine or hexamethylphosphoamide (HMPA), and the like are preferable. In order to increase the reaction efficiency of the released material (II), the reaction material (III) is used in an amount of from 10 to 10 molar times, preferably 1.2 to 10 molar times, more preferably from 1.2 to 10 moles. It is good to make it react using 5 mol times.

In addition, the reaction is carried out in the presence of an acid acceptor, which may be used as an inorganic acceptor such as sodium bicarbonate, potassium carbonate, triethylamine, diisopropylethylamine, pyridine, N, N-dimethylaniline, N , N-dimethylaminopyridine, 1,8-diazabicyclo [5,4,0] undec-7-ene (DBU), 1,4-diazabicyclo [2,2,2] octane (DABCO) Organic bases, such as these, are preferable.

The compound of formula (I) according to the present invention may be prepared according to Scheme 1, but in some cases, as shown in Scheme 2 below, when R ₃ is an amino group in the compound of formula (III), the amino group After reacting under the same conditions as in Scheme 1 using the compound of general formula (III ') in protected form, the compound of general formula (I) obtained by deprotecting the obtained compound of general formula (I') May be obtained.

Wherein Q, R ₁ , R ₂ , n, R ₃ , R ₄ and R ₅ are the same as described above, and X is a halogen atom (preferably chlorine, bromine or fluorine); P represents an aminoprotecting group.

The amino protecting group which can be used at this time may be any thing as long as it is commonly used in the field of organic chemistry and can be easily removed without destroying the structure of the target compound obtained by the reaction. Specific examples thereof include formyl, acetyl, trifluoroacetyl, methoxycarbonyl, benzyloxycarbonyl, para-methoxybenzyloxycarbonyl, trityl, trimethylsilyl, diphenylphosphinyl, tetrahydropyranyl, t -Butyloxycarbonyl group, and the like.

Removal of the amino protecting group contained in the obtained compound (I ′) after completion of the reaction can be carried out using a solvolysis or reduction reaction including hydrolysis, for example, from 0 to 130, depending on the nature of the group. In the presence or absence of an acid or base in a solvent at a temperature of < RTI ID = 0.0 > In this case, examples of the inorganic acid which may be used include hydrochloric acid, bromic acid, sulfuric acid, and phosphoric acid. 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. As the base, hydroxides of alkali metals or alkaline earth metals such as sodium hydroxide and barium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate or alkali metal alkoxides such as sodium methoxide and sodium ethoxide, sodium acetate and the like can be used. have. As the solvent, a solvent such as ethanol, dioxane, ethylene glycol, acetic acid, or a mixed solvent of these solvents and water may be used depending on the kind of the water or the compound, and in some cases, it may be reacted without the solvent.

Further, when the protecting group is para-toluenesulfonyl, benzyl, trityl, benzylcarbonyl, benzyloxycarbonyl, para-methoxybenzyloxycarbonyl, trichloroethoxycarbonyl, beta-iodineethoxycarbonyl or the like, reduction The reaction can be used to effectively remove it. The removal of the protecting group by the reduction reaction may be slightly different depending on the nature of the protecting group, but is 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 by treatment with metallic sodium or metallic lithium in liquid ammonia at a temperature of -50 to -10 ° C.

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

Compounds of the general formula (III) used as reactants in this study can be easily prepared by the method shown in the following schemes. First, for example, pyrrolidin-3-yl-hydroxylamine (IIIa) Can be prepared by the reaction of Scheme 3 below.

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

According to Scheme 3, 3-hydroxypyrrolidine derivative [1] was reacted with N-hydroxyphthalamide, triphenylphosphine and diethylazodicarboxylate (DEAD) in an organic solvent such as tetrahydrofuran or methylene chloride. ) To a temperature of 10 to 50 ° C. for 1 to 10 hours to obtain a compound [2] in which the N-hydroxyphthalimide group is substituted with a pyrrolidine group in high yield. The phthalamino group of the amino group protecting group of the compound [2] is hydrazine (T. Sasaki, K, Minamoto and H. Itoh, J. Org. Chem., 1978, 43, 2320) or phenylhydrazine (I. Schumann and RA Boissinnas, Helv. Chim. Acta, 1952, 35, 2235) or sodium sulfide (S. Kukolja and SR Lammert, J. Am. Chem. Soc., 1975, 97, 5582) and the like with high yields It can be easily deprotected. In addition, the protecting group of the amino group in the pyrrolidine ring can be easily deprotected by using the aforementioned methods to obtain the desired compound (IIIa) in high yield.

As another method, 4-aminopyrrolidin-3-ylhydroxylamine (IIIb) can be obtained from the pyrroline compound [3] by the method of Scheme 4.

According to Scheme 4, 3-pyrroline compound [3] is generally used to synthesize epoxide, such as chloroform using meta-chloroperoxybenzoic acid (mCPBA) or hydrogen peroxide (H ₂ O ₂ ) as an oxidizing agent. It can be easily converted to the epoxide compound [4] by reacting in an organic solvent, water, or a mixture thereof, and the epoxide compound [4] is a known method using azide chloride in acetone, water or a mixture thereof (J. Org. Chem. 1985, 50, 5696) can be used to quantitatively obtain azido compounds [5] by reacting at room temperature or under reflux conditions. The azido group of compound [5] obtained using hydrogen in the presence of a metal catalyst such as palladium or platinum (MK Eberhardt, Tetrahedron 1967, 23, 3029) or lithium aluminum hydride (JH Boyer, J. Am. Chem. Soc., 1951, 73, 5865), sodium chloride (BA Belinka and AJ Hassner, J. Org. Chem., 1979, 44, 4,712) or triphenylphosphine (R. Carrie, etc., Tet-rahedron Letters 1983, 4 763) and the like, easily reduced to amine groups, and the reduced amine groups are protected with t-butylcarbonyl groups and then hydroxyphthalimide, tri, in an organic solvent such as tetrahydrofuran or methylene chloride. A compound in which an N-hydroxyphthalimide group is substituted with a pyrrolidine group by reacting with phenylphosphine and diethylazodicarboxylate (DEAD) at a temperature of 10 to 50 ° C. for 1 to 10 hours [7] Can be obtained in high yield. The amino group protecting group of the obtained compound is a phthalimino group and a t-butoxycarbonyl group, which is an amino protecting group on the pyrrolidine ring structure, by deprotecting the group in the same manner as in Scheme 3 to obtain the target compound (IIIb).

[1,3 '] bipyrrolidinyl-4'-ylhydroxylamine (IIIc) can be synthesized by the same method as in Scheme 5.

According to Scheme 5, the starting material epoxide compound [4] was reacted with pyrrolidine in an aqueous solution or an organic solvent such as dimethylformimide at a temperature of 20 to 120 ° C. for 1 to 10 hours in quantitative yield. Hydroxy compound [9] can be obtained, and then 3-hydroxypyrrolidine compound [9] is added to N-hydroxyphthalimide, triphenylphosphine, in an organic solvent such as tetrahydrofuran or methylene chloride. And 85% of the compound [10] in which the N-hydroxyphthalimide group is substituted with a pyrrolidine group by reacting with diethylazodicarboxylate (DEAD) at a temperature of 10 to 50 ° C. for 1 to 10 hours. It can be obtained in yield. The amino protecting group of the obtained compound [10] is a phthalimino group and a t-butoxycarbonyl group, which is an amino protecting group having a pyrrolidine ring structure, by deprotection in the same manner as in Scheme 3 to obtain the target compound (IIIc). do.

As another example of the amine, 4-methoxypyrrolidin-3-ylhydroxylamine (IIId) may be prepared by the same method as in Scheme 6.

According to Scheme 6, the epoxide compound [4] was reacted with sodium methoxide in an organic solvent such as aqueous solution or methanol at a temperature of 20 to 120 ° C. for 1 to 10 hours to obtain a hydroxy compound [11] in high yield. And 3-hydroxypyrrolidine compound [11] was subsequently added to N-hydroxyphthalimide, triphenylphosphine, and diethylazodicarboxyl in an organic solvent such as tetrahydrofuran or methylene chloride. Reaction with DEAD may be carried out at a temperature of 10 to 50 ° C. for 1 to 10 hours to obtain compound [12] in which the N-hydroxyphthalimide group is substituted with a pyrrolidine group. The amino protecting group of the obtained compound [12] is a phthalamide group and a t-butoxycarbonyl group, which is an amino protecting group having a pyrrolidine ring structure, by deprotecting the group to give the target compound (IIId) as an inorganic compound. Obtained in acid form.

In addition, as another example of the amine, pyrrolidin-3-ylmethylhydroxylamine (IIIe) may be synthesized by the same method as in Scheme 7.

According to Scheme 7, the pyrrolidin derivative [13] obtained by reacting benzylamine and itaconic acid was reduced to lithium aluminum hydride in an organic solvent such as tetrahydrofuran to convert the alcohol compound [14]. The benzyl group, which is a protecting group of the alcohol compound [14], can then be deprotected by the aforementioned method, and protected again with t-butoxycarbonate to obtain the alcohol compound [15] in high yield. . Amino group-protected alcohol compounds [15] together with N-hydroxyphthalimide, triphenylphosphine, and diethylazodicarboxylate (DEAD) in organic solvents such as tetrahydrofuran or methylene chloride, 10 to 50 The reaction was carried out at a temperature of 1 ° C. for 1 to 10 hours to obtain a compound [16] in which the N-hydroxyphthalimide group was substituted with a pyrrolidine group, and the phthalimino group which is an amino protecting group in the obtained compound [16] The t-butoxycarbonyl group, an amino protecting group of the lollidine ring structure, is deprotected in the same manner as in Scheme 3 to obtain the target compound (IIIe) in the form of an inorganic acid salt.

As another amine, 3-amino-4-isopropylideneiminooxypyrrolidine (IIIf) can be obtained from the aminooxypyrrolidine derivative [8] by the same method as in Scheme 8.

According to Scheme 8, when the aminooxypyrrolidine derivative [8] is reacted with acetone at a temperature of 10 to 50 ° C., the oxime compound [17] can be obtained in high yield (92%), and then the oxime compound is continued. By removing the protecting group of [17] using the aforementioned method, the target compound (IIIf) is obtained in the form of a salt.

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

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

Inert and pharmaceutically acceptable carriers for the preparation of pharmaceutical compositions from the compounds of general formula (I) described herein can be either solid or liquid.

Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, suppositories, and ointments, among which solid dosage forms suitable for oral administration include tablets, powders, cachets, and capsules. The solid carrier is selected from one or more of diluents, flavors, solubilizers, lubricants, suspending agents, binders, substances which can act as tableting agents or encapsulating materials. In the case of powders, the carrier contains from 5 to 70%, preferably from 10 to 70%, of finely divided active ingredients, and 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.

Formulations in liquid form include solutions, suspensions, and emulsions. For example, water or a mixed solution of water-propylene glycol may be used for parenteral injection, which is prepared such that isotonicity, pH, and the like are suitable for a biological system. Liquid formulations may also be formed from aqueous polyethylene glycol solutions. Aqueous solutions suitable for oral use can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavors, stabilizers and thickening agents. Aqueous suspensions suitable for oral use can be prepared by dispersing the undivided active ingredient in viscous materials 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 containing discrete amounts of the preparation, for example tablets, capsules, powders and vials packaged in vials or ampoules, or plasters in tubes or bottles. The unit dosage form may also be a capsule, casein, tablet, gel or cream or any suitable number of several types of such packaging forms.

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 the purpose of treating bacterial infectious diseases, the compound used in the pharmaceutical method according to the present invention is preferably initially in a dosage of about 6 to 14 mg per kilogram. Dosages, however, vary depending on the needs of the patient, the extent of the condition to be treated, and the compound to be used. It is known to determine the desired dosage in a particular state. In general, treatment begins with a dosage less than the optimal amount of the compound. Then increase the dosage in small increments when the optimal effect occurs. For convenience, it is also possible to partially divide the total daily dose for the day.

The compounds according to the present invention mentioned above 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 are equivalent to conventional drugs (for example, oploxacin). Or more than the antimicrobial activity, especially for Gram-positive bacteria shows excellent activity compared to the existing drugs, and also shows a very good antimicrobial activity against strains that are resistant to quinolone compounds.

Furthermore, the compound according to the present invention is better absorbed than conventional quinolone compounds in terms of pharmacokinetics and is less toxic and can be used very effectively for the prevention and treatment of diseases by bacterial infection of animals including humans.

EMBODIMENT OF THE INVENTION Hereinafter, this invention is demonstrated more concretely based on an Example. However, the following Preparation Examples and Examples are only to aid the understanding of the present invention, and the scope of the present invention is not limited thereto unless the main configuration is changed.

[Production Example 1]

Preparation of 1-t-butoxycarbonyl-3-pinolin

18 g (0.26 mol) of 3-pyrroline was added to 130 ml of chloroform, and 62.51 g (0.28 mol) of di-t-butoxycarbonyldicarbonate dissolved in 50 ml of chloroform was added thereto, followed by stirring at room temperature for 1.5 hours. The reaction was washed with dilute aqueous hydrochloric acid solution, water and brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was distilled under reduced pressure to obtain the title compound almost yield (yield 99%).

¹ H NMR (CDCl ₃ , ppm): δ 5.77 (2H, d, J = 7.29 Hz), 4.11 (4H, d, J = 7.56 Hz), 1.48 (9H, s)

MS (FAB, pos): [M + 1] ⁺ = 170

[Production Example 2]

Preparation of 3-t-butoxycarbonyl-6-oxa-3-azabicyclo [3,1,0] hexane

49.8 g (0.26 mol) of 3-t-butoxycarbonyl pyrroline was dissolved in 250 ml of chloroform, and 97.21 g (0.34 mol) of meta-croperoxybenzoic acid (mCPBA) dissolved in 1 liter of chloroform was added thereto. The reaction was stirred at room temperature for 10 hours and then washed with 5% aqueous sodium hydrosulfite solution and with saturated aqueous sodium hydrogen carbonate solution. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure to obtain the title compound in a yield of 82%.

¹ H NMR (CDCl ₃ , ppm): δ3.9-3.6 (4H, m), 3.32 (2H, dd), 1.46 (9H, s)

MS (FAB, pos): [M + 1] ⁺ = 186

[Manufacture example 3]

Preparation of 1-t-butoxycarbonyl-4-azido-3-pyrrolidinol

7.41 g (0.04 mol) of the compound synthesized in Preparation Example 2 was added to 60 ml of a mixed solution of acetone: mol (1: 1), where 13 g (0.2 mol) of sodium azide and 4.28 g (0.008 mol) of ammonium chloride were added. Heated to reflux for the next 15 hours. The reaction was diluted with 50 ml of ethyl acetate and added with saturated brine to extract the organic layer. The organic layer was dried over anhydrous magnesium sulfate, filtered and the filtrate was distilled under reduced pressure to give the title compound in a yield of 96%.

¹ H NMR (CDCl ₃ , ppm): δ 4.25 (1H, s), 3.92 (1H, s), 3.8-3.2 (2H, m), 3.5-3.2 (2H, m), 2.6-2.3 (1H, d), 1.46 (9H, s)

MS (FAB, pos): [M + 1] ⁺ = 229

[Production Example 4]

Preparation of 1-t-butoxycarbonyl-4-amino-3-pyrrolidinol

8.57 g (37.5 mmol) of the compound synthesized in Preparation Example 3 was dissolved in 85 ml of tetrahydrofuran, and 9.84 g (37.5 mmol) of triphenylphosphine was added thereto, followed by stirring at room temperature for 1.5 hours. 3 ml of water was added to the reaction, followed by further stirring for 13 hours, and the reaction was distilled under reduced pressure to obtain a residue, which was purified by column chromatography to give 6.86 g (yield 90%) of the title compound.

¹ H NMR (CDCl ₃ , ppm): δ 3.98 (1H, m), 3.70 (2H, m), 3.40-3.05 (3H, m), 1.80 (3H, br), 1.47 (9H, s)

MS (FAB, pos): [M + 1] ⁺ = 203

Production Example 5

Preparation of 1-t-butoxycarbonyl-4- (N-t-butoxycarbonyl) amino-3-pyrrolidinol

6.86 g (33.9 mol) of the compound synthesized in Preparation Example 4 and 6.65 ml (47.5 mmol) of triethylamine were dissolved in 20 ml of chloroform, and 20 ml of chloroform in which 8.98 g (40.7 mmol) of di-t-butyldicarbonate was dissolved therein. The solution was added. The reaction mixture was stirred at room temperature for 2 hours, diluted with 30 ml of dichloromethane and washed with diluted aqueous hydrochloric acid solution, water and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure to obtain the title compound in a yield of 92%.

¹ H NMR (CDCl ₃ , ppm): δ4.72 (1H, s), 4.21 (1H, s), 3.91 (1H, s), 3.85-3.60 (3H, m), 3.40-3.10 (2H, m) , 1.46 (18H, s)

MS (FAB, pos): [M + 1] ⁺ = 303

[Manufacture example 6]

Preparation of 1-t-butoxycarbonyl-3- (N-t-butoxycarbonyl) amino-4- (1,3-dioxo-1,3-dihydroisoindol-2-yloxy) pyrrolidine

A 30 ml solution of tetrahydrofuran in which 2.02 g (7.7 mmol) of triphenylphosphine was dissolved was cooled in a water-ice container, and after adding 1.21 ml (7.7 mmol) of diethylazodicarboxylate (DEAD) to the water for 20 minutes Stirred. To this solution, 2.12 g (7 mmol) of the compound synthesized in Preparation Example 5 and 1.26 g (7.7 mmol) of N-hydroxyphthalimide were added and stirred at room temperature for 2.5 hours. The residue obtained by distillation under reduced pressure was purified by column chromatography to give 2.51 g (yield 80%) of the title compound.

¹ H NMR (CDCl ₃ , ppm): δ 7.80 (4H, m), 5.80 (1H, dd, J = 8.6 Hz), 4.33 (1H, m), 4.70 (1H, m), 3.98 (1H, dd) , J = 5.94 Hz), 3.86 (1H, t, J = 9.72 Hz) 3.58 (1H, m), 3.31 (1H, m), 1.48 (9H, s), 1.42 (9H, s)

MS (FAB, pos): [M + 1] ⁺ = 449

[Manufacture example 7]

Preparation of 1-t-butoxycarbonyl-3- (N-t-butoxycarbonyl) amino-4-aminooxypyrrolidine

0.23 g (0.51 mmol) of the compound synthesized in Preparation Example 6 was added to 4 ml of ethanol, and 0.12 g (2.44 mmol) of hydrazine (80%) was added thereto, followed by stirring at room temperature for 330 minutes. The residue obtained by distillation under reduced pressure was diluted with ethyl ether and washed with 5% aqueous sodium carbonate solution, followed by water and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure to obtain 161 mg (yield 100%) of the title compound.

¹ H NMR (CDCl ₃ , ppm): δ5.50 (1H, s), 5.20-4.90 (1H, m), 4.16 (2H, m), 3.80-3.50 (2H, m), 3.39 (1H, dd, J = 4.2 Hz), 3.08 (1H, m), 1.46 (18H, s)

MS (FAB, pos): [M + 1] ⁺ = 318

[Manufacture example 8]

Preparation of 4-amino-pyrrolidin-3-yl-hydroxylamine dihydrochloride

5 ml of methanol was cooled to 0 ° C., 2 ml of acetyl chloride was slowly added, followed by stirring at room temperature for 30 minutes, and 0.19 g (0.6 mmol) of the compound synthesized in Preparation Example 7 was added thereto by dissolving in 2 ml of methanol. The reaction mixture was stirred for 30 minutes at room temperature, distilled under reduced pressure, and the residue was washed with ethyl ether and dried to give 100 mg (yield 75%) of the title compound as a white solid.

¹ H NMR (DMSO-d ₆ ): δ 9.79 (2H, s), 8.90 (4H, s), 4.75 (1H, s), 3.95 (1H, m), 3.68 (1H, d, J = 12.96 Hz ), 3.50 (2H, m), 3.25 (1H, t, J = 10.53 Hz)

MS (FAB, pos): [M + 1] ⁺ = 318

[Manufacture example 9]

Preparation of 1-t-butoxycarbonyl-4-methoxy-3-pyrrolidinol

3.71 g (20 mmol) of the compound synthesized in Preparation Example 2 and 6.51 g (0.1 mol) of potassium cyanide were added to 50 ml of methanol, and the mixture was heated and stirred at 60 ° C. After 1.5 hours, the reaction was heated to reflux for 13 hours, concentrated by distillation under reduced pressure, and the concentrate was purified by chromatography to give 2.86 g (yield 66%) of the title compound.

¹ H NMR (CDCl ₃ , ppm): δ 4.25 (1H, s), 3.72 (1H, s), 3.65-3.45 (3H, m), 3.45-3.25 (5H, m), 1.47 (9H, s) .

MS (FAB, pos): [M + 1] ⁺ = 218

[Production Example 10]

Preparation of 1-t-butoxycarbonyl-3-methoxy-4- (1,3-dioxo-1,3-dihydro-isoindol-2-yloxy) pyrrolidine

652 mg (3 mmol) of the compound synthesized in Preparation Example 9, 866 mg (3.3 mmol) of triphenylphosphine, and 538 mg (3.3 mmol) of N-hydroxyphthalimide were added to 20 ml of tetrahydrofuran and stirred at room temperature for 20 minutes. Then, 0.47 ml (3.6 mmol) of diethyl azodicarboxylate (DEAD) was added thereto and stirred for 24 hours. The reaction was concentrated by distillation under reduced pressure and purified by column chromatography to give 440 mg (41% yield) of the title compound.

¹ H NMR (CDCl ₃ , ppm): δ 7.80 (4H, m), 4.90 (1H, m), 3.90-3.30 (4H, m), 3.50 (3H, s), 1.48 (9H, s).

MS (FAB, pos): [M + 1] ⁺ = 363

[Production Example 11]

Preparation of 1-t-butoxycarbonyl-3-methoxy-4-aminooxypyrrolidine

440 mg (1.21 mmol) of the compound synthesized in Preparation Example 10 and 365 mg (5.83 mmol) of hydrazine (80%) were added to 6 ml of ethanol and stirred at room temperature for 1 hour. The concentrate obtained by distillation under reduced pressure was diluted with ethyl ether and washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure to obtain 171 mg (yield 61%) of the title compound.

¹ H NMR (CDCl ₃ , ppm): δ 4.28 (1H, m), 3.90 (1H, m), 3.65-3.20 (4H, m), 3.45 (3H, s), 1.45 (9H, s).

MS (FAB, pos): [M + 1] ⁺ = 233

[Manufacture example 12]

Preparation of 3-methoxypyrrolidin-4-ylhydroxylamine hydrochloride

4 ml of methanol was cooled to 0 ° C., 2 ml of acetyl chloride was slowly added, followed by stirring at room temperature for 20 minutes, and a solution of 165 mg (0.71 mmol) of the compound synthesized in Preparation Example 11 was dissolved in 10 ml of methanol. The reaction was stirred at room temperature for 1 hour and the residue obtained by distillation under reduced pressure was washed with ethanol and ethyl ether to give 92 mg (64% yield) of the title compound.

¹ H NMR (DMSO-d ₆ , ppm): δ9.80 (5H, s), 3.92 (1H, m), 3.80-3.30 (4H, m), 3.46 (3H, s).

MS (FAB, pos): [M + 1] ⁺ = 133

[Production Example 13]

Preparation of 1-t-butoxycarbonyl-4- (pyrrolidin-1-yl) -3-pyrrolidinol

1.00 g (5.4 mmol) of the compound synthesized in Preparation Example 2 and 3.0 g (54 mmol) of pyrrolidine were mixed with 1 ml of distilled water, and then stirred at 80 ° C. for 2.5 hours. The reaction was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure to obtain the title compound in a yield of 99%.

¹ H NMR (CDCl ₃ , ppm): δ 4.31 (1H, m), 3.80-3.10 (4H, m), 2.71 (1H, s), 2.61 (4Hs), 2.80 (4H, s) 1.46 (9H, s).

MS (FAB, pos): [M + 1] ⁺ = 257

Production Example 14

Preparation of 1-t-butoxycarbonyl-3- (pyrrolidin-1-yl) -4- (1,3-dioxo-1,3-dihydroisoindol-2-yloxy) pyrrolidine

866 mg (3.3 mol) of triphenylphosphine was dissolved in 10 ml of tetrahydrofuran, cooled to 0 ° C., and 0.52 ml (3.3 mmol) of diethyl azodicarboxylate (DEAD) was added thereto and stirred for 20 minutes. A 10 ml solution of 768 mg (3 mmol) of tetrahydrofuran synthesized in Preparation Example 13 was added thereto, and 538 mg of N-hydroxyphthalimide was added thereto, followed by stirring at room temperature for 1.5 hours. The residue obtained by distillation under reduced pressure was purified by column chromatography to give 971 mg (yield 81%) of the title compound.

¹ H NMR (CDCl ₃ , ppm): δ 7.58 (4H, m), 4.90 (1H, s), 3.74 (3H, m), 3.51 (1H, m), 3.18 (1H, m), 2.70-2.50 (4H, m), 1.75 (4H, s), 1.47 (9H, s).

MS (FAB, pos): [M + 1] ⁺ = 402

[Production Example 15]

Preparation of 1-t-butoxycarbonyl-3-aminooxy-4- (pyrrolidin-1-yl) rollidine

1.67 g (4.2 mmol) of the compound synthesized in Preparation Example 14 and 1.25 g (20 mmol) of hydrazine (80%) were added to 35 ml of ethanol and stirred at room temperature for 1 hour. The filtrate was filtered, and the filtrate was concentrated by distillation under reduced pressure. The concentrated solution was diluted with ethyl ether, washed with 5% aqueous sodium carbonate solution, water, and brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure to give 734 mg (yield 64%) of the title compound.

¹ H NMR (CDCl ₃ , ppm): δ5.41 (2H, s), 4.22 (1H, m), 3.70-3.30 (4H, m), 2.89 (1H, s), 2.60 (4H, s), 1.80 (4H, s), 1.48 (9 H, s).

MS (FAB, pos): [M + 1] ⁺ = 272

[Production Example 16]

Preparation of [1,3 '] bipyrrolidinyl-4'-yl-hydroxylamine hydrochloride

734 mg (2.7 mmol) of the compound synthesized in Preparation Example 15 was dissolved in 10 ml of methanol, and this was added to a solution prepared by adding 5 ml of acetyl chloride to 10 ml of methanol, followed by stirring at room temperature for 1 hour. The reaction was distilled under reduced pressure and the residue was washed with ethanol and ethyl ether to give 0.393 g (60% yield) of the title compound.

¹ H NMR (DMSO-d ₆ , ppm): δ9.70 (2H, s), 5.11 (1H, s), 4.14 (1HMs), 3.75 (3H, m) 3.50-3.30 (5H, m), 1.95 ( 4H, s).

MS (FAB, pos): [M + 1] ⁺ = 172

[Production Example 17]

Preparation of 1-t-butoxycarbonyl-3- (N-t-butoxycarbonyl) amino-4-isopropylidene aminooxypyrrolidine

32 mg (0.1 mmol) of the compound synthesized in Preparation Example 7 was added to 1 ml of acetone, and stirred at room temperature for 1 hour, followed by distillation under reduced pressure to obtain 40 mg (yield 10%) of the title compound.

¹ H NMR (CDCl ₃ , ppm): δ 5.03 (1H, m), 4.61 (1H, m), 4.29 (1H, m), 3.80 (1H, t), 3.75-3.40 (2H, m), 3.10 (1H, m), 1.89 (3H, s), 1.85 (3H, s), 1.48 (18H, s).

MS (FAB, pos): [M + 1] ⁺ = 358

[Production Example 18]

Preparation of 3-amino-4-isopropylideneaminooxy-pyrrolidine ditrifluoroacetic acid salt

40 mg (0.1 mmol) of the compound obtained in Preparation Example 17 was added to 0.5 ml of trifluoroacetic acid, stirred for 10 minutes, and the residue obtained by distillation under reduced pressure was washed with ethyl ether, thereby obtaining 32 mg (yield 83%) of the title compound. .

¹ H NMR (DMSO-d ₆ , ppm): δ9.3 (3H, s), 8.40 (3H, s), 4.76 (1H, s), 3.98 (1H, m), 3.60-3.20 (4H, m) , 1.89 (3H, s), 1.84 (3H, s).

MS (FAB, pos): [M + 1] ⁺ = 158

[Production Example 19]

Preparation of 1-benzyl-5-oxopyrrolidine-3-carboxylic acid

107.2 g (1.0 mole) of benzylamine and 130.1 g (1.0 mole) of itaconic acid were mixed, heated and stirred at 110 to 120 ° C. for 2.5 hours, and then suspended in 500 ml of ice water. The resulting solid was filtered, washed with ethyl ether and dried to give 199.4 g (91% yield) of the title compound.

¹ H NMR (CDCl ₃ , ppm): δ 7.32 (5H, m), 4.46 (2H, dd, J = 14.65, 15.26 Hz), 3.50 (2H, m), 3.27 (1H, m), 2.83 (2H) , m).

MS (FAB, pos): [M + 1] ⁺ = 220

[Production Example 20]

Preparation of 1-benzyl-3-hydroxymethylpyrrolidine

4.74 g (0.125 mol) of lithium aluminum hydride was added to 200 ml of tetrahydrofuran, cooled to 0 ° C., and then 10.96 g (50 mmol) of the compound synthesized in Preparation Example 19 was added slowly. The reaction was heated to reflux for 3 hours and then cooled to 0 ° C., added in the order of 5 ml of water, 5 ml of 15% aqueous sodium hydroxide solution and 5 ml of water and filtered. The filtrate was distilled under reduced pressure to give 9.37 g (yield 98%) of the title compound.

¹ H NMR (CDCl ₃ , ppm): δ 7.29 (5H, s), 3.67 (1H, dd, J = 4.32, 4.05 Hz), 3.59 (2H, s), 3.51 (1H, dd, J = 4.32, 5.13 Hz), 2.82 (1 H, m), 2.64 (1 H, m), 2.50 (1 H, t, J = 6.75 Hz), 2.30 (2 H, m), 2.01 (1 H, m), 1.72 (1 H, m) .

MS (FAB, pos): [M + 1] ⁺ = 192

[Production Example 21]

Preparation of 1-t-butoxycarbonyl-3-hydroxymethylpyrrolidine

5.74 g (30 mmol) of the compound synthesized in Preparation Example 20 was added to 60 ml of a mixture of methanol / acetic acid (6/4), and 2,87 g of 10% palladium / carbon was added thereto, followed by heating to 70 ° C. under hydrogen gas (400 psi). Stirred. After 2 hours, the reaction was filtered, and the residue obtained by distillation of the filtrate under reduced pressure was dissolved in 80 ml of chloroform, and 7.59 g (75 mmol) of triethylamine was added thereto, followed by 7.86 g of 3-t-butyldicarbonate. (36 mmol) was added. The reaction was stirred at room temperature for 30 minutes, washed with dilute aqueous hydrochloric acid solution and water, washed with saturated aqueous sodium hydrogen carbonate solution, water, and brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure to give 5.25 g (87% yield) of the title compound.

¹ H NMR (CDCl ₃ , ppm): δ3.61 (2H, m), 3.55-3.25 (3H, m), 3.10 (1H, m), 2.41 (1H, m), 1.97 (1H, m), 1.64 (1H, m), 1.46 (9H, s).

MS (FAB, pos): [M + 1] ⁺ = 202

[Production Example 22]

Preparation of 1-t-butoxycarbonyl-3- (1,3-dioxo-1,3-dihydroisoindol-2-yloxy) methylpyrrolidine

1.57 g (6 mmol) of triphenylphosphine was dissolved in 15 ml of tetrahydrofuran, cooled to 0 ° C., and 1.04 ml (6.6 mmol) of diethylazodicarboxylate (DEAD) were added. The reaction was stirred for 10 minutes, and 1.21 g (6 mmol) of the compound synthesized in Preparation Example 21 and 0.98 g (6 mmol) of N-hydroxyphthalimide were dissolved in 15 ml of tetrahydrofuran and added thereto. The reaction mixture was stirred at room temperature for 30 minutes and distilled under reduced pressure to purify the residue by column chromatography to give 1.85 g (89% yield) of the title compound.

¹ H NMR (CDCl ₃ , ppm): δ 7.80 (4H, m), 4.17 (2H, m), 3.62 (1H, dd, J = 7.83 Hz), 3.55-3.15 (3H, m), 2.70 (1H) m), 2.16 (1 H, m), 1.90 (1 H, m), 1.47 (9 H, s).

MS (FAB, pos): [M + 1] ⁺ = 347

[Manufacture example 23]

Preparation of 1-t-butoxycarbonyl-3-aminooxymethylpyrrolidine

1.08 g (3.13 mmol) of the compound synthesized in Preparation Example 22 was added to 20 ml of ethanol, and 0.78 g (15.7 mmol) of hydrazine (80%) was added thereto, followed by stirring at room temperature for 1 hour. The reaction was distilled under reduced pressure, the residue was diluted with ethyl acetate, washed with 5% aqueous potassium carbonate solution, and the organic layer was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure to obtain 680 mg (yield 100%) of the title compound.

¹ H NMR (CDCl ₃ , ppm): δ5.42 (2H, s), 3.70-3.20 (5H, m), 3.04 (1H, m), 2.52 (1H, m), 1.95 (1H, m), 1.60 (1H, m), 1.46 (9H, s).

MS (FAB, pos): [M + 1] ⁺ = 217

[Manufacture example 24]

Preparation of Pyrrolidin-3-ylmethylhydroxylamine Hydrochloride

10 ml of methanol was cooled to 0 ° C., 3.5 ml of acetyl chloride was slowly added, followed by stirring at room temperature for 20 minutes, followed by dissolving 580 mg of the compound synthesized in Preparation Example 23 in 10 ml of methanol. The reaction was stirred at room temperature for 1 hour, distilled under reduced pressure, and the residue obtained was washed with ethanol and ethyl ether and dried to give 402 mg (yield 79%) of the title compound.

¹ H NMR (DMSO-d ₆ , ppm): δ 10.90 (3Hs), 9.29 (2H, m), 4.01 (2H, m), 3.30-3.00 (3H, m), 2.91 (2H, m), 2.60 (1 Hm), 2.00 (1 H, m), 1.63 (1 H, m).

MS (FAB, pos): [M + 1] ⁺ = 117

Production Example 25

Preparation of 1-t-butoxycarbonyl-3- (1,3-dioxo-1,3-dihydroisoindol-2-yloxy) pyrrolidine

A 25 ml solution of tetrahydrofuran in which 2.88 g (10.9 mmol) of triphenylphosphine was dissolved was cooled to 0 ° C., followed by slowly adding 1.73 ml (10.9 mmol) of diethylazodicarboxylate (DEAD) to 1 1.71 g (9.15 mmol) of -t-butoxycarbonyl-3-pyrrolidinol and 1.64 g (10.1 mmol) of N-hydroxyphthalimide were dissolved in 35 ml of tetrahydrofuran and added. The reaction mixture was stirred at room temperature for 1 hour and then distilled under reduced pressure to give a residue, which was purified by column chromatography to give 2.62 g (yield 86%) of the title compound.

¹ H NMR (CDCl ₃ , ppm): δ 7.80 (4H, m), 4.95 (1H, m), 3.90-3.50 (4H, m), 2.25 (1H, m), 1.99 (1H, m), 1.49 (9H, s).

MS (FAB, pos): [M + 1] ⁺ = 333

Production Example 26

Preparation of Pyrrolidin-3-yl Hydroxylamine Hydrochloride

2.62 g (7.89 mmol) of the compound synthesized in Preparation Example 25 was added to 30 ml of ethanol, and 1.98 g (39.5 mmol) of hydrazine (80%) was added thereto at room temperature, followed by stirring for 40 minutes. The reaction was distilled under reduced pressure to give a residue, which was diluted with ethyl ether, washed with 5% aqueous sodium carbonate solution, water, and brine, dried over anhydrous magnesium sulfate and filtered. The residue obtained by distillation of the filtrate under reduced pressure was carried out in the same manner as in Preparation Example 24 to obtain 963 mg (yield 70%) of the title compound.

¹ H NMR (DMSO-d ₆ , ppm): δ 10.46 (3H, s), 9.63 (2H, s), 4.94 (1H, s), 3.49 (1H, d), 3.40-3.10 (3H, m) , 2.26 (1 H, m), 2.09 (1 H, m).

MS (FAB, pos): [M + 1] ⁺ = 103

Example 1

Preparation of 7- (3-aminooxypyrrolidin-1-yl) -1-cyclopropyl-6,8-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

1-cyclopropyl-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (141 mg, 0.5 mmol) and pyrrolidin-3-ylhydroxylamine hydrochloride (105 mg, 0.6 mmol) was suspended in 1.5 ml of anhydrous acetonitrile. To this was added 1,8-diazabicyclo [5,4,0] -undec-7-ene (DBU, 228 mg, 1.5 mmol), heated to reflux for 1 hour, and then cooled to room temperature and filtered. The obtained residue was washed with a water / acetonitrile (2/8) mixed solution and dried to give 150 mg (yield 82%) of the title compound.

¹ H NMR (DMSO-d ₆ , ppm): δ8.6 (1H, s), 7.7 (1H, d), 6.1 (2H, br), 4.25 (1H, m), 4.1 (1H, m), 3.9 (2H, m), 4.75-4.55 (2H, m), 2.15 (1H, m), 1.9 (1H, m), 1.15 (4H, s).

MS (FAB, pos): [M + 1] ⁺ = 366

Example 2

Preparation of 7- (3-aminooxypyrrolidin-1-yl) -1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (133 mg, 0.5 mmol) and pyrrolidine-ylhydroxylamine hydrochloride (88 mg, 0.5 mmol) was reacted for 0.5 hour in the same manner as in Example 1, filtered and dried to give 66 mg (yield 38%) of the title compound.

¹ H NMR (DMSO-d ₆ , ppm): δ8.6 (1H, s), 7.85 (1H, d), 7.1 (1H, d), 6.1 (2H, s), 4.3 (1H, m), 3.75 (3H, m), 3.6 (2H, m), 2.25-1.95 (2H, m), 1.25 (2H, m), 1.1 (2H, d).

MS (FAB, pos): [M + 1] ⁺ = 348

Example 3

Preparation of 7- (3-aminopyrrolidin-1-yl) -1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro [1,8] naphthyridine-3-carboxylic acid

7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro [1,8] naphthyridine-3-carboxylic acid (141 mg, 0.5 mmol) and pyrrolidine-3- Monohydroxylamine hydrochloride (105 mg, 0.6 mmol) was reacted for 20 minutes in the same manner as in Example 1, filtered and dried to give 137 mg (yield 79%) of the title compound.

¹ H NMR (DMSO-d ₆ , ppm): δ8.55 (1H, s), 8.0 (1H, d), 6.1 (2H, s), 4.3 (1H, s), 4.05 (1H, m), 3.85 -3.65 (3H, m), 2.2-1.9 (2H, m), 1.15 (2H, d), 1.05 (2H, d).

MS (FAB, pos): [M + 1] ⁺ = 349

Example 4

Preparation of 7- (3-aminooxypyrrolidin-1-yl) -1-cyclopropyl-6,8-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

1-cyclopropyl-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (71 mg, 0.25 mmol) and 4-aminopyrrolidin-3-ylhydride The reaction of loxylamine dihydrochloride (57 mg, 0.6 mmol) in the same manner as in Example 1 was carried out for 2 hours, followed by filtration and drying to give 63 mg (yield 66%) of the title compound.

¹ H NMR (DMSO-d ₆ , ppm): δ8.6 (H, s), 7.7 (1H, d), 6.5-5.8 (2H, br), 4.1 (1H, m), 3.95 (1H, s) , 3.85 (2H, s), 3.7 (1H, m), 3.45 (2H, m), 1.15 (4H, s).

MS (FAB, pos): [M + 1] ⁺ = 381

Example 5

7- (3-amino-4-aminooxypyrrolidin-1-yl) -1- (2,4-difluorophenyl) -6-fluoro-4-oxo-1, 4-dihydro [1 , 8] Preparation of naphthyridine-3-carboxylic acid

7-chloro-1- (2,4-difluorophenyl) -6-fluoro-4-oxo-1,4-dihydro [1,8] naphthyridine-3-capric acid (35 mg, 0.1 mmol ) And 4-aminopyrrolidin-3-ylhydroxylamine dihydrochloride (30 mg, 0.13 mmol) in the same manner as in Example 1 for 20 minutes and then filtered and dried to give 31 mg (71% yield) of the title compound. Obtained.

¹ H NMR (DMSO-d ₆ , ppm): δ 8.8 (1H, s), 8.05 (1H, d), 7.8 (1H, dd), 7.35 (1H, dd), 7.6 (1H, dd), 7.35 (1H, dd), 4.1-3.8 (3H, m), 3.6 (3H, m).

MS (FAB, pos): [M + 1] ⁺ = 436

Example 6

7- [3-aminooxy-4- (pyrrolidin-1-yl) pyrrolidin-1-yl] -1-cyclopropyl-6,8-difluoro-4-oxo-1,4-di Preparation of Hydroquinoline-3-carboxylic Acid

1-cyclopropyl-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (141 mg, 0.5 mmol) and (1.3 ') bipyrrolidinyl-4'- Monohydroxylamine hydrochloride (168 mg, 0.6 mmol) was reacted for 45 minutes in the same manner as in Example 1, filtered and dried to obtain 120 mg (yield 55%) of the title compound.

¹ H NMR (DMSO-d ₆ , ppm): δ8.6 (1H, s), 7.75 (1H, d), 6.2 (2H, s), 4.3 (1H, s), 4.1 (1H, m), 3.95 (2H, m), 3.7 (2H, m), 2.9 (1H, m).

MS (FAB, pos): [M + 1] ⁺ = 435

Example 7

7- (3-aminooxy-4-methoxypyrrolidin-1-yl) -1-cyclopropyl-6,8-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid Manufacture

1-cyclopropyl-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (71 mg, 0.225 mmol) and 4-methoxypyrrolidin-3-ylhydro Oxylamine hydrochloride (62 mg, 0.6 mmol) was reacted for 2 hours in the same manner as in Example 1, filtered, and dried to obtain 32 mg (yield 32%) of the title compound.

¹ H NMR (DMSO-d ₆ , ppm): δ8.62 (1H, s), 7.7 (1H, d), 6.2 (2H, s), 4.3 (1H, m), 4.0 (1H, m), 3.85 (3H, m), 3.6 (1H, m), 3.4 (4H, s), 1.2 (4H, m).

MS (FAB, pos): [M + 1] ⁺ = 396

Example 8

7- (3-amino-4-isopropylideneaminooxypyrrolidin-1-yl) -1-cyclopropyl-6,8-difluoro-4-oxo-1,4-dihydroquinoline-3- Preparation of Carboxylic Acids

1-cyclopropyl-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (21 mg, 0.076 mmol) and 3-amino-4-isopropylideneaminooxy Pyrrolidine ditrifluoroacetic acid salt (32 mg, 0.084 mmol) was reacted for 1.5 hours in the same manner as in Example 1, filtered and dried to obtain 12 mg (yield 39%) of the title compound.

¹ H NMR (DMSO-d ₆ , ppm): δ8.6 (1H, s), 7.7 (1H, d), 4.5 (1H, m), 4.05 (2H, m), 3.75 (2H, m), 3.5 (3H, m), 3.35 (2H, m), 1.05 (6H, d), 1.2 (4H, s).

MS (FAB, pos): [M + 1] ⁺ = 421

Example 9

Preparation of 7- (3-aminooxymethylpyrrolidin-1-yl) -1-cyclopropyl-6,8-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

1-cyclopropyl-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (141 mg, 0.5 mmol) and pyrrolidin-3-ylmethylhydroxylamine Hydrochloride (113 mg, 0.6 mmol) was reacted for 1 hour in the same manner as in Example 1, filtered and dried to give 141 mg (yield 74%) of the title compound.

¹ H NMR (DMSO-d ₆ , ppm): δ8.6 (1H, s), 7.7 (1H, d), 6.05 (2H, br), 4.05 (1H, m), 3.7 (3H, m), 3.6 (3H, m), 2.0 (1H, m), 1.6 (1H, m), 1.15 (4H, s).

MS (FAB, pos): [M + 1] ⁺ = 380

Example 10

Preparation of 7- (3-aminooxymethylpyrrolidin-1-yl) -cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (66 mg, 0.25 mmol) was reacted in the same manner as in Example 9 to 35 mg of the title compound. (Yield 39%) was obtained.

¹ H NMR (DMSO-d ₆ , ppm): δ8.6 (1H, s), 7.8 (1H, D), 6.05 (2H, s), 3.7-3.5 (6H, m), 3.4 (1H, m) , 2.6 (1H, m), 2.1 (1H, m), 1.7 (1H, m), 1.25 (2H, m), 1.15 (2H, s).

MS (FAB, pos): [M + 1] ⁺ = 362

Example 11

In vitro antibacterial 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 the known compound of Ofloxacin as a control agent (Minimum Inhibitory Concentration: MIC, μg / ml) was obtained and evaluated. The highest inhibitory concentration was obtained by diluting the test compound by a 2-fold dilution method, dispersing it in Mueller-Hinton agar medium, inoculating 5 μl of a standard strain having 10 ⁷ CFU per ml, and incubating at 37 ° C. for 18 hours. The results are shown in Table 1.

Example 12

Acute Oral Toxicity Test

In order to investigate the acute oral toxicity of Compounds 1 and 8 among the compounds of the present invention, a solution containing various concentrations of the compounds in different concentrations was orally administered to a male mouse of the ICR strain at a dose of 10 ml / kg body weight. After oral administration, mortality and symptoms for 7 days were observed, and the average lethal dose (LD ₅₀ , mg / kg) was calculated according to the Litchfield-Wilcoxon method and the results are shown in Table 2.

Claims (9)

Quinoline carboxylic acid derivatives of the following general formula (I), pharmaceutically acceptable salts thereof and solvates thereof. Wherein Q is CH, CF, C-Cl, CO-alkyl (C ₁ -C ₄ ), or N, R ₁ is ethyl, cyclopropyl or phenyl substituted with one or more fluorine atoms, R ₂ is hydrogen , Methyl, or amino, R ₃ represents hydrogen, C ₁ -C ₄ alkoxy, or NR ₆ R ₇ , wherein R ₆ and R ₇ each independently represent hydrogen or C ₁ -C ₄ alkyl, or Together they form a 5-membered heterocyclo together with the nitrogen atom to which they are attached, n is 0 or 1, and R ₄ and R ₅ are each independently hydrogen, or C ₁ together with a double bond to a nitrogen atom; -C ₄ alkylidene can be formed. The compound of claim 1, wherein Q is CH, CF, or N, R ₁ is cyclopropyl or 2,4-difluorophenyl, R ₂ is hydrogen, R ₃ is hydrogen, C ₁ -C ₄ alkoxy, Amino or pyrrolidine, n is 0 or 1, and R ₄ and R ₅ are each independently hydrogen or together form a C ₁ -C ₄ alkylidene linked by a double bond to a nitrogen atom. 3. The compound of claim 2, wherein Q is CH or CF, R ₁ is cyclopropyl, R ₂ is hydrogen or NH ₂ , n is 0 or 1, and R ₄ and R ₅ are each hydrogen or two groups together A compound that forms isopropylidene linked by a double bond to a nitrogen atom. A process for preparing a compound of formula (I), characterized by reacting a compound of formula (II) with a compound of formula (III) in the presence of an acid acceptor in a solvent. How to feature. The method of claim 4 wherein the solvent is selected from acetonitrile, dimethylformamide, dimethylsulfoxide, pyridine, and hexamethylphosphoamide. The acid acceptor according to claim 4, wherein the acid acceptor is sodium bicarbonate, potassium carbonate, triethylamine, diisopropylethylamine, pyridine, N, N-dimethylaniline, N, N-dimethylaminopyridine, 1,8-diazabicyclo Characterized in that it is selected from [5,4,0] uns-7-ene, 1,4-diazabicyclo [2,2,2] octane. 5. The compound of formula (III) according to claim 4, wherein when R ₂ is amino, the compound of formula (III) reacts with the compound of formula (II) in the form of formula (III ') Removal method. Wherein R ₄ and R ₅ are as mentioned in claim 1 and P represents an aminoprotecting group. An antimicrobial composition comprising as an active substance a compound of formula (I) according to claim 1, a pharmaceutically acceptable salt thereof, or a solvate thereof. The composition according to claim 10, wherein the composition contains 1 to 10 mg of active substance in a unit dose.