WO2001066542A1 - Pyridonecarboxylic acid derivatives - Google Patents

Abstract

Novel pyridonecarboxylic acid derivatives of the general formula (I), or esters or salts thereof; and use of the derivatives, the esters or the salts as antimicrobial agents, particularly therapeutic or preventive agents for methicillin-resitant (Staphylococcus aureus infections, wherein X is chloro or bromo.

Description

 Description Pyridonecarboxylic acid derivative Technical field

 The present invention relates to pathogenic bacteria, especially methicillin-resistant Staphylococcus aureus

 (.methici 11 in-resistant Staphylococcus aureus, hereafter referred to as “MRSA”), which has excellent antibacterial activity and high safety as a pharmaceutical. The present invention relates to a carboxylic acid derivative, a drug containing the compound, and a novel intermediate useful for producing the compound. Background art

 MRSA is a bacterium with low sensitivity to various antibiotics such as methicillin / 3 / 3-lactam antibiotics, and hospital-acquired infection by these bacteria is a very serious problem in medical practice. ing.

 Traditionally, various quinolone synthetic antibacterial agents have been used in clinical settings against a wide range of infectious diseases and have achieved excellent results. However, MRSA is not only resistant to β-lactam antibiotics but also to other chemotherapeutic agents including quinolone drugs (multidrug resistance) in many cases. Antibiotics were less effective against MRS III infection.

Under these circumstances, in the medical field, there is a demand for the development of a drug that is more effective and safer against MRSA infection. For example, WO97 / 40036 discloses the following general formula (A)

 Where:

R ¹ is a hydrogen atom, a nitrogen atom, etc.

R ² is a hydrogen atom, etc.

R ³ is a hydroxyl group or the like;

A compound represented by R ⁴ is a hydrogen atom, a lower alkyl group or the like is disclosed.

The WO 96/23 7 75 5 publication states that the following formula (B)

 Where:

R ¹ is a hydrogen atom, etc.

R ² is an amino group, etc.

R ³ is a halogen atom,

R ⁴ and R ⁵ are hydrogen atom, halogen atom, etc. R ⁶ is a hydrogen atom, a lower alkyl group, etc.

R ⁷ is a halogen atom, etc.

 A is — C X = (where X is a hydrogen atom, a halogen atom, etc.)

 Z is a halogen atom or a saturated cyclic amino group which may have a substituent,

Are disclosed. In addition, the publication W0982 35992 discloses the following formula (C)

 Where:

R ¹ is a group—OR ⁹ (where R ⁹ is a hydrogen atom, etc.),

R ² is a hydrogen atom, a lower alkyl group, etc.

R ³ is a halogen atom, etc.

R ⁴ is a nitro group, an azide group, a hydrazino group which may have a substituent, a group NR ^ R ¹¹ (where R ^ID and R ' ¹ are the same or different A hydrogen atom, a lower alkyl group, a lower alkenyl group, a cyclo-lower alkyl group, a saturated heterocyclic group or an amino-protecting group which may have a substituent), a lower alkoxyl group Group or hydroxy A sil group,

R ⁵ , R ⁶ and R ⁷ are a hydrogen atom, a nitrogen atom, etc., and R ⁸ is an amino group, etc.

A is a group C—R ¹² (where R ¹² is a hydrogen atom, a halogen atom, etc.), and the like.

B is a nitrogen atom or a group C—R ^u (where R ¹³ is a hydrogen atom or a halogen atom);

Are disclosed. Further, WO 9710068 discloses the following general formula (D)

D)

 Where:

R ¹ is a hydrogen atom, etc.

R ² is an amino group, etc.

R ³ is a hydrogen atom or a halogen atom,

R ⁴ is an octogen atom, etc.

R ⁵ is a halogen atom or a saturated cyclic amino group which may have a substituent,

R ⁶ is a hydrogen atom, a halogen atom, a nitro group or an amino group which may be protected,

X, Y and Z may be the same or different Nitrogen atom, — CH = or one CR ⁷ = (where R ⁷ is a lower alkyl group, ノ, or a halogen atom) (provided that X, Y, and Z are less W is a nitrogen atom or one CR ⁸ = (where R ⁸ is a hydrogen atom, a halogen atom or a lower alkyl group),

Are disclosed.

 Examples 12 and 13 of the publication describe two kinds of salts of the following compound (D-1) (see Comparative Example 1 described later).

Although the above four publications disclose that the compounds of the above formulas (A) to (D) have antibacterial activity against various pathogens, MRSA No antimicrobial activity is described. Disclosure of the invention

The present inventors have conducted various searches to develop pyridonecarbonic acid derivatives having excellent antibacterial activity, in particular, antibacterial activity against MRSA and high safety. As a result, this time, the following general formula (I) I)

 Wherein X is a chlorine atom or a bromine atom,

A novel pyridone carboxylic acid derivative (hereinafter sometimes referred to as compound (I)) represented by the formula (I) or its ester or salt is an excellent antibacterial agent against pathogenic bacteria, especially MRSA. The compound (I) of the present invention or a salt thereof, which has been found to have activity, exhibits strong antibacterial activity against various pathogens and is useful as an antibacterial agent. Furthermore, the compound (I) or a salt thereof exhibits excellent antibacterial activity, particularly against MRSA, and is valuable as an agent for treating or preventing MRSA infection. The excellent antibacterial action of compound (I) or a salt thereof, particularly the strong antibacterial action against MRSA, is due to the combination of the methyl group at the 5-position of compound (I) and the remaining characteristic structural part. it is conceivable that.

The 3-carboxylate of compound (I) is valuable as a precursor of the corresponding 3-carboxylate, and the 3-carboxylate isomer is in vivo. When easily converted to a carboxylic acid derivative, it exerts the same action and effect as the carboxylic acid derivative, and can be used as an antibacterial agent (prodrug). In this specification, unless stated otherwise, the term "lower" means that the group to which this term is attached contains 1 to 7 carbon atoms. The term “halogen atom” refers to chlorine, fluorine, bromine and iodine, with the former being particularly preferred.

 The “ester” of the compound (I) of the present invention is desorbed in vivo or in vitro by a chemical or enzymatic means to give a free carboxylic acid compound represented by the above formula (I) or a free carboxylic acid derivative thereof. Those that can be converted to salts are preferred.

Examples of the ester which can be converted to the corresponding free carboxylic acid compound or its salt by elimination by a chemical means such as hydrolysis include lower alkyl esters such as methyl ester and ethyl ester; and esters such as benzyl ester. Aralkyl esters; lower alkenyl esters such as vinyl ester and aryl ester; and aryl esters such as phenyl ester and naphthyl ester. Esters that can be converted into free carboxylic acids or salts thereof by enzymatic means as well as by chemical means include, for example, 2- (N, N-dimethylamino) Ethyl ester, 2-((N, N-Jetylamino) ethyl ester, 1-dimethylamino-1-2-Di-lower alkylamino lower alkyl ester such as propyl ester; 2-((1-pyrrolidinyl) ethyl ester, 2 — (1 — piberidinyl) ethyl ester, 2 — (1 — pyrrolyl) ethyl ester, 2 — pyridylmethyl ester, 3 — pyridylmethyl ester, 2 — (4-morpholinyl) ethyl ester Cyclic amino lower alkyl esters such as acetoximetyl ester, 1-acetoxethylester, and vivaloy methoxymethyl ester Lower alkanoyloxy lower alkyl esters, such as alkenyl; lower alkoxy carbonyloxy lower alkyl esters, such as 1-ethoxycarbonyloxyshethyl ester; , 2 — (N, N — getylamino) 1 2 — oxoethyl ester, 3 — butyrolactonyl ester, cholester ester, phthalidyl ester, (5 — methyl — 2 — oxo 1 1 , 3 — Jokiso Lu 4-yl) Methyl ester and the like.

 The “salt” of the compound (I) of the present invention includes both an acid addition salt and a carboxylate. Examples of the acid addition salt include methanesulfonic acid and p-toluenesulfonic acid. Organic acids such as carboxylic acids such as sulfonic acid, trifluoroacetic acid, acetic acid, lactic acid, succinic acid, maleic acid, malonic acid and dalconic acid, and amino acids such as aspartic acid or daltamic acid. Salts with acids; salts with inorganic acids such as hydrochloric acid and phosphoric acid. Examples of the capronate include salts with metals such as sodium, potassium, zinc, and silver; ethanolamine, diethanamine, 2-amino-1-propanol. 1,3-Diamino-2-propanol, piperazine, N-methylbiperazine, 1-1 (2-hydroxyshethyl) piperazine, 1,3-Diaminopropane, trimethylamine, tri Salts with organic bases such as ethylamine, N-methylmorpholine, prolinol, and 2-piperidinemethanol; ammonium salts and choline salts. Of these, physiologically acceptable salts are particularly preferred.

The compound (I) of the present invention may exist as a hydrate or a solvate, and may be an optically active isomer, a stereoisomer (cis type, trans type) or a mixture thereof. It may exist in the form. All of these compounds are included in the compound (I) of the present invention. Among the compounds (I) of the present invention, preferred compounds are those in which X is a chlorine atom in the aforementioned general formula (I), that is, 1- (6-amino-3,5-difluoro-). 2 — pyridyl) 1 8 — black mouth 6 — fluoro-1, 4 — dihydro 7 — (3 — hydroxyazetidine 1 1 — yl) 1 5 — methyl — 4 oxoquinoline 1 3 — Carboxylic acids, and their physiologically acceptable. The compound (I) of the present invention or an ester or a salt thereof is, for example, a compound represented by the following general formula (II)

式中、 Y は脱離 し得る基である、

Wherein Y is a leaving group,

Is reacted with 3 -hydroxyazetidine, and depending on the case, the resulting ester of compound (I) is converted to compound (I), or compound (I) is converted to compound (I). It can be manufactured by changing to salt.

The term "removable group" in the definition of the substituent Y in the above formula (II) is any which can be removed by substituting with 3-hydroxyazetidine and leading to the compound (I) '. Although there is no particular limitation, specific examples include a halogen atom, a lower alkoxy group, a lower alkylthio group, a lower alkylsulfonyl group, a lower alkylsulfinyl group, a lower alkylsulfonyloxy group, and a benzenesulfonyloxy group. And a halogen atom such as fluorine or chlorine is preferable. The reaction of the compound (（) or its ester with 3—hydroxyxazetidine is usually carried out in a solvent at about 10 to 180 ° C., preferably at about 20 to 130 ° C. It can be carried out by stirring for about 10 minutes to 7 days, preferably for about 30 minutes to 3 days. Examples of the solvent used in this case include water and methanol. , Ethanol, acetonitril, black mouth form, pyridin, N, N-dimethylformamide, dimethylsulfoxide, 1-methyl-2-pyrrolidone, etc. Are mentioned. These solvents may be used alone or as a mixture.

 This reaction is generally performed in the presence of an acid acceptor. Examples of the acid acceptor used at that time include 1,8-diazapicocyclo [5.4.0] —7_dedecen (DBU), triethylamine, pyridin, and the like. Organic bases such as quinoline and picolin, or sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, hydrogen bicarbonate And inorganic bases. These acid acceptors can usually be used in a molar amount of about 1 to about 3 times the amount of 3-hydroxyazetidine. It is also possible to use 3-hydroxyazetidine in a large excess to also serve as an acid receptor.

 In the above reaction, 3-hydroxyazetidine can usually be used in a ratio of 1 to 5 mol per 1 mol of the compound (III) or its ester.

 The ester of compound (I) thus obtained can be easily converted to compound (I) or a salt thereof by, for example, hydrolyzing the ester according to a conventional method.

The free compound (I) can be converted to a salt, if necessary, and the salt of the compound (I) can be converted to the corresponding free compound or ester according to a conventional method. be able to. The compound (I) or an ester or a salt thereof produced in this way can be isolated and purified according to a conventional method. These compounds may be obtained in the form of a salt, a free form or a hydrate, depending on the conditions of isolation and purification. However, these can be converted into each other depending on the purpose, and can lead to the desired form of the compound according to the present invention.

 The stereoisomers of the compound (I) can be separated from each other by a usual method, for example, fractional crystallization, a chromatographic method, and the like, and the optically active substance can be obtained by a known optical resolution method. It can be isolated by applying. The compound (Π) or an ester thereof used as a starting material in the production of the compound (I) is, for example, a compound represented by the following formula (m)

 In the formula, L is a group capable of leaving,

 R is a carboxyl protecting group,

 X and Y are as defined above,

Is reacted with an orthoformate and then with 2,6 diamino 35 difluoropyridine to give the following formula (IV)

式中、 L 、 X 、 Y及び Rは前記定義のとおり である、 で表される化合物と し、 次いで該化合物 （ IV ) を閉環させ、 そして所望 によ り 、 加水分解反応に付す こ と によ り 製造する こ とができ る。

In the formula, L, X, Y and R are as defined above, a compound represented by the following formula: Thus, it can be produced by subjecting it to a hydrolysis reaction.

 Further, the term "removable group" in the definition of L in the above formula (m) includes the same groups as those capable of leaving in the substituent γ of the formula (π), for example, fluorine. Halogen atoms such as elemental and chlorine are preferred.

 5 Further, the “carboxyl-protecting group” in the definition of R in the above formula (m) includes a group which is eliminated by a hydrolysis reaction, and examples thereof include lower alkyl such as methyl and ethyl. Groups are preferred. The reaction of compound (m) with ortho-formate such as ethyl orthoformate or methyl orthoformate is generally carried out at 0 to 160 ° C in the presence of carboxylic anhydride such as acetic anhydride. It can be carried out by mixing and stirring at a temperature of preferably 50 to 150 ° C., usually for 10 minutes to 50 hours, preferably for 1 to 10 hours. The amount of orthoformate used at this time can be usually at least equimolar to the compound (m), preferably 1 to 10 times the molar amount of the compound (m). The carboxylic anhydride can be used usually in an equimolar amount or more, preferably 1 to 10 times the molar amount of the compound (m).

 Subsequent reaction with 2,6—diamino 3,5—difluoropyridine can be carried out, for example, by an equimolar amount or more of 2,6—diamino 3,5 with respect to compound (IE).

20—Difluoropyridine, in a suitable solvent, usually at a temperature of 0 to 150 ° C, preferably at a temperature of 10 to 100 ° C, usually 10 minutes to 48 hours Preferably, the reaction can be carried out by mixing and stirring for 30 minutes to 10 hours.The solvent used in this reaction is any solvent that does not affect the reaction. Can be used, for example, benzene, toluene, xylene

Aromatic hydrocarbons such as 25; ethers such as getyl ether, diisopropyl ether, tetrahydrofuran, and dioxane; pentane, hexane Aliphatic hydrocarbons such as methylene chloride; halogenated hydrocarbons such as methylene chloride, chloroform-form, and dichloroethane; methanol, ethanol, and propanol And the like; dimethylformamide, 11-methyl-2-amide and the like; pyrrolidone; and sulfoxides such as dimethylsulfoxide.

 2,6—Diamino—3,5—Difluoropyridine is a compound known per se, for example, the method described in WO 09/11068, or a method described therein. It can be manufactured by a similar method. The ring closure reaction of the obtained compound (IV) can be carried out by heating appropriately in a suitable solvent in the presence or absence of a base. The reaction temperature of the ring closure reaction is generally selected from the range of 0 to 180 ° C, preferably 20 to 150 ° C, and the reaction time is usually 10 minutes to 48 hours. It is preferably selected from the range of 30 minutes to 30 hours. Examples of the base optionally used in this reaction include metal hydrides such as sodium hydride and calcium hydride; sodium hydroxide, potassium hydroxide, and sodium carbonate. Inorganic bases such as sodium, potassium carbonate and sodium hydrogencarbonate; alcohols such as sodium methoxide, sodium ethoxide, and potassium t_butoxide Xides; metal fluorides such as sodium fluoride and potassium fluoride; 'triethylamine, 1,8-diazabicyclo [5.4.0]-7— ゥOrganic bases such as ndecene (DBU). These bases can be used usually in an equimolar amount or more, preferably in an amount of 1 to 2 moles, per 1 mole of the compound (IV).

The solvent used in the above ring closure reaction is not particularly limited as long as it does not affect the reaction. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene, and xylene; Chilether, diisopropirate Ethers such as toluene, tetrahydrofuran and dioxane; aliphatic hydrocarbons such as pentane and hexane; halogenated hydrocarbons such as methylene chloride, chloroform, and dichloroethane; methanol Alcohols such as ethanol, ethanol, and propanol; amides such as dimethylformamide and 1-methyl-2-pyrrolidone; and sulfoxides such as dimethyl sulfoxide. The deprotection reaction of the thus-obtained compound (III) in which the propyloxyl group is protected by hydrolysis can be carried out under the conditions used in ordinary hydrolysis reactions. This reaction is usually performed in an appropriate solvent in the presence of an acid or a base in the sense of accelerating the reaction. Examples of usable acids include inorganic acids such as hydrochloric acid, sulfuric acid, hydrobromic acid, and phosphoric acid; and organic acids such as acetic acid, formic acid, trifluoroacetic acid, and p-toluenesulfonic acid. Examples of the base include inorganic bases such as potassium hydroxide, sodium hydroxide, sodium carbonate and potassium carbonate. The reaction temperature is usually from 20 to 150, preferably from 30 to 120, and the reaction time is usually from 10 minutes to 48 hours, preferably. Can be about 30 minutes to 24 hours.

As the solvent used in this reaction, water is usually used, but an organic solvent can be used as long as it does not affect the reaction. For example, alcohols such as methanol, ethanol, and propanol can be used. And ethers such as tetrahydrofuran and dioxane; and ketones such as acetate and methylethylketone. These solvents are used alone or as a mixture. The compound (I) or a salt thereof provided by the present invention has excellent antibacterial activity, In particular, it not only has remarkable antibacterial activity against MRSA, but also has extremely low toxicity and is useful as a highly safe antibacterial agent. The results of the in vitro antibacterial test and the acute mouse toxicity test of the compound (I) of the present invention are described below with reference to data. The compounds used for the test are as follows.

The present invention

 Compound

 Example 2 (B) Example 4 (B)

Comparison

 Compound

 Comparative Example 1 Comparative Example 2

 * The compound of Comparative Example 1 is the compound of Example 12 in the above-mentioned W0971 / 11068 publication (but a free form). The compound of Comparative Example 2 is included in the general formula (D) described in WO97 / 11668, but is not specifically disclosed in the publication.

Antibacterial test The minimum inhibitory concentration (MIC) of the test compound against bacteria was measured according to the description in Chemotherapy II (1), 76 (1981). In the calculation of the geometric mean, if the MIC value is ≤0.003, the calculation is performed as 0.016. did. The results are shown in Tables 1 and 2 below.

 Table 1 shows the minimum inhibitory concentrations for various bacteria, and Table 2 shows the minimum inhibitory concentrations for MRSA.

 The MRSA (28 strains) used in the tests in Table 2 is a methicillin-resistant clinical strain isolated from patients and showing a MIC of 12.5 zg / ml or more for methicillin. The strain numbers of MRSA in Table 2 are uniquely numbered by Dainippon Pharmaceuticals Discovery Research Institute, and specify the patient and date from which the bacteria were isolated. The activity ratio in the table means the ratio of the antibacterial activity of the compound of the present invention to each comparative compound. Table 1: Antibacterial activity against various pathogens (MIC: ng / ml) _

上記表 1 は、 本発明の化合物 （ I ) が、 種々の菌に対して強い抗菌活 性を備えてお り 、 各種の病原菌に対して有効な抗菌剤とな り う る こ とを 示している。 ： M R S A臨床分離株に対する抗菌活性 （MIC: g/ml) 実施例化合物 比較化合物

Table 1 shows that the compound (I) of the present invention has strong antibacterial activity against various bacteria, and can be an effective antibacterial agent against various pathogenic bacteria. I have. : Antibacterial activity against MRSA clinical isolate (MIC: g / ml) Example compound Comparative compound

 Strain number

 2 (B) 4 (B) Comparative Example 1 Comparative Example 2

1 0.05 0.05 0.78 0.39

 0.05 0.05 0.78 0.39

0. 025 0. 025 0.2. 2 0.2

 A f 0.025 0 025 0.2 0.2 0.2

 C

 D 0.05 0.05 0.78 0.39

 Ό c 0.05 0.05 0.78 0.39

 7 0. 025 0. 025 0. 1 0.1.

Q

 O 0.05 0.025 0.22 0.2

 Q 0. 025 0. 025 0.2 2 0.2

1 n 0.Ω 50Ω 50.3 0.3 ^Q 0.2

1 1 0 05 O 05 0.

11 L 0.39 0.2 3.13 1.56

1 Q 0 Π 25 0 Ο 25 0.2 0.2

1> 41 0.05 0 025 0.78 0.39

1 O <0 Ω 03 0 O06 0. 025 0. 013 0 <0. 003 <0. 003 0. 013

 1 f 0.05 0.O

 Ω 5 0.39 0.39

 1 Q O

1 o 0.025 0.025 0.22 0.2 ''

1 Q 3 0. 025 0. 025 0. 2 0.2

 U <0. 003 <0. 003 0. 013 0. 013 k 1 ≤ 0. 003 <0. 003 0. 013 0. 013 k ≤ 0. 003 ≤ 0. 003 0. 025 0. 013 k 3 0 . 025 0. 025 0. 2 0. 1

 2 4 ≤ 0. 003 ≤ 0. 003 0. 013 0. 013

2 5 ≤ 0. 003 ≤ 0. 003 0. 1 ≤ 0. 003

2 6 0. 025 0. 025 0. 2 0.2

2 7 0. 025 0.05 0.2 0.2

2 8 0. 025 0. 025 0. 2 0.1 Geometric mean value 0.0173 0. 0173 0.164 0.108

 Activity ratio 1 9.48 9.48 1

Activity ratio 2 6.24 6.24 1 Table 2 shows that the compound (I) of the present invention exerts an antibacterial activity 6.2 to 9.5 times stronger than that of the compounds of Comparative Examples 1 and 2 against MRSA. It indicates that it is useful as a therapeutic or prophylactic agent for infectious diseases. Acute toxicity test

 Std-ddY male mice (body weight: about 17 to 20 g) were administered with the compound of Example 2 (B) or 4 (B) dissolved in physiological saline in the tail vein at a dose of 100 mg / kg to 5 mice each. Until the next day, convulsions and deaths were observed. As a result, no convulsions or deaths were observed at all, confirming that the compound of the present invention has high safety. Thus, the compound of the present invention can be suitably used as an antibacterial agent for the treatment, treatment or prevention of bacterial diseases in humans or non-human animals.

 When the compound of the present invention is used in humans as an antibacterial agent, its dosage varies depending on age, body weight, symptoms, administration route and the like, but is generally 5 mg to 5 g per day. It is recommended that the drug be administered once or several times. The route of administration may be oral, parenteral, or topical, but it is preferable to administer it as an external preparation such as an ointment to the skin or nasal mucosa.

The compound of the present invention may be administered to humans or the like as it is, but is usually administered in a dosage form (pharmaceutical composition) prepared with pharmaceutically acceptable additives. You. Such dosage forms include, for example, tablets, solutions, capsules, granules, fine granules, powders, syrups, injections, suppositories, ointments, lotions, sprays, drops. Agents and the like. These preparations can be produced according to a conventional method using ordinary pharmaceutical additives. For example, additives commonly used in the field of ointments, such as white petrolatum, macrogol, and glycerin, are mentioned as additives for ointments. The compound of the present invention is contained in the ointment at a ratio of usually not more than 20%, preferably from 0.01% to 10%. Examples of additives for oral preparations include those commonly used in the field of preparations such as starch, mannite, microcrystalline cellulose, carboxymethylcellulose Ca, water and ethanol, and compounds of the present invention. Unreacted solid or liquid carriers or diluent materials are used. Examples of injection additives include those commonly used in the field of injections, such as water, physiological saline, glucose solutions, and infusions. The above nebulizers and ointments may also be used in the treatment, treatment or prevention of infectious diseases in otolaryngology and ophthalmology. Example

 Next, the present invention will be described more specifically with reference to examples. Examples 1 to 31 relate to a method for producing the compound (I) of the present invention or an ester or a salt thereof, and Examples A and B relate to a preparation. Example 1

(6-amino-3,5-difluoro-2-pyridyl) —8-chloro mouth-6,7 difluoro 1,4-dihydro-5-methyl-4-oxoquino Lin-3-ethyl carboxylate

Triethyl orthoformate (42.3 m) was added to 50 g of 3-chloro-2,4,5-trifluoro-6-methylbenzoyl acetate, and 40.1 ml of acetic anhydride was added, followed by refluxing for 2 hours. The reaction solution was concentrated under reduced pressure, and toluene was further added to azeotrope. The residue was dissolved in 150 ml of 1-methyl-2-pi-or-don, and this was dissolved in 2,6-diamino-3,5-difluoropyridine 25.8 g of 1-methyl-2- The solution was added dropwise to a 350 ml solution of pyrrodon under ice-cooling. The mixture was stirred at room temperature for 1 hour. 25.8 g of potassium carbonate was added, and the mixture was stirred at 60 ° C for 4.5 hours and at room temperature overnight. The mixture was poured into 1500 ml of water, and the precipitated crystals were collected by filtration and washed sequentially with water and acetonitrile to obtain 51.1 g of the title compound.

Melting point: 198-199 ° C

IR (KBr) cm— ': 1726, 1614

NMR-NMR (DMS0-d ₆ ) δ: 1.27 (t, 3Η, J = 7 Hz), 2.73 (d, 3Η, J = 3 Hz), 4.23 (q, 2Η, J = 7 Hz), 6.74 (s, 2Η) , 7.95 (t, 1Η, J = 9Hz,), 8.50 (s, 1Η) Example 2 (A)

2- (3-amino-3,5-difluoro-2-pyridyl) —8—mouth Mouth—6—fluoro-1,4-dihydro-7- (3-hydroxyazetidine-trily ) -5-Methyl-4-oxoquinoline-3-carboxylate

 A solution of 1.5 g of the compound obtained in Example 1, 460 mg of 3-hydroxyazetidine and 530 mg of triethylamine in 15 ml of dimethyl sulfoxide was stirred at room temperature overnight. After adding 30 ml of cold water, the precipitated crystals were collected by filtration and washed with ethanol to give 1.42 g of the title compound.

Melting point: 266-268 ° C

Ή-NMR (DMS0-d ₆ ) δ: 1.25 (t, 3Η, J = 7 Hz), 2.61 (d, 3Η, J = 3 Hz), 4.00-4.12 (m, 2Η), 4.21 (q, 2Η, J = 7Hz), 4.36-4.52 (m, 1Η), 4.53-4.68 (m, 2Η), 5.66 (d, 1H, J = 5Hz), 6.65 (s, 2H), 7.88 (t, 1H, J = 10Hz) ), 8.28 (s, 1H)

MS (m / z): 483, 485 (MH ¹ ) Example 2 (B)

U- (6-amino-3,5-difluoro-2-pyridyl) -1-8-black mouth-6-full-year l-1,4-dihydro-7- (3-hydroxyazetidin -1-yl)-5-methyl-4-oxoquino Lin-3-butyric acid

 1.4 g of the compound obtained in Example 2 (A), 14 ml of ethanol, and 28 ml of a sodium hydroxide aqueous solution were heated at 60 ° C. for 4.5 hours. The reaction solution was treated with activated carbon, and 28 ml of an aqueous solution of acetic acid was added dropwise to the filtrate heated at 80 ° C. After cooling, the precipitated crystals were collected by filtration and washed with water to give 1.1 g of the title compound.

Melting point: 277-280

IR (KBr) cm— ¹ : 3377, 1716, 1622

Ή-NMR (DMS0-d ₆ ) δ: 2.69 (d, 3H, J = 4 Hz), 4.12-4.23 (m, 2H), 4.39-4.54 (m, 1H), 4.64-4.78 (m, 2H), 5.71 (d, 1H, J = 6Hz), 6.72 (s, 2H), 7.91 (t, 1H, J = 10Hz), 8.62 (s, 1H), 15.00 (s, 1H)

MS (m / z): 455, 457 (MH ⁺ ) Example 3

l- (6-Amino-3,5-difluoro-2, -pyridyl) -8-bromo-6,7-difluoro-1,4-dihydro-5-methyl-4-oxo -3-Ethyl carboxylate) V_

 (1) 42.8 g of potassium nitrate was slowly added to 58 g of 3,4,6-trifluoro-2-methylbenzoic acid and 420 ml of concentrated sulfuric acid under ice cooling, followed by stirring at the same temperature for 2 hours. This was poured into 2500 ml of ice water, extracted with a black hole form, washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain crude crystals. This was washed with a mixed solution of n-hexane and chloroform at a ratio of 10: 1 to obtain 27.5 g of 2,4,5-trifluoro-6-methyl-3-nittobenzoic acid.

Melting point: 108-109 ° C

IR (KBr) cm " ¹ : 1717, 1558, 1372

_{Ή-NMR (CDC 1 3)} δ: 2.52 (d, 3H, J = 3Hz)

MS (m / z): 234 (M—H) — (2) 20.8 g of oxalyl chloride was added dropwise to a solution of 27.5 g of the compound obtained in the preceding section and 0.3 ml of N, N-dimethylformamide in 400 ml of dichloromethane, and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure to obtain an acid chloride. To a solution of 15 g of benzyl alcohol and 17.8 g of triethylamine in 300 ml of dichloromethane was added dropwise a 200 ml solution of the previously synthesized acid chloride in dichloromethane under ice-cooling. The mixture was stirred at the same temperature for 2 hours. 1N-hydrochloric acid and black-mouthed form were added, and the mixture was separated. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane: ethyl acetate = 50: 1), and the 2,4,5-trifluoro-6-methyl-3-nitro-2-port was obtained. 29.2 g of benzyl benzoate were obtained as an oil.

_{Ή-NMR (CDC 1 3)} δ: 2.38 (d, 3H, J = 3 Hz), 5.42 (s, 2Η), 7.35 - 7.45 (m, 5Η)

 MS (m / z): 324 (M-H) "

(3) To a solution of 29.2 g of the compound obtained in the preceding section in 400 ml of ethanol was added 3 g of 5% paradigm-carbon, and the mixture was stirred under a hydrogen stream for 7 hours. The catalyst was removed by filtration, and the solvent was distilled off under reduced pressure to obtain a crude crystal. This was washed with chloroform to obtain 16 g of 3-amino-2,4,5-trifluoro-6-methylbenzoic acid.

Melting point: 144-1 5 ° C

Ή-NMR (DMS0-d ₆ ) δ: 2.1 (d, 3H, J = 3 Hz), 5.57 (brs, 2H)

MS (m / z): 206 (MH ⁺ )

(4) 16 g of the compound obtained in the preceding paragraph and 87 g of cupric bromide are suspended in 320 ml of 10% hydrobromic acid, and a solution of 6.5 g of sodium nitrite in 40 ml of water is added dropwise with ice cooling. Stirred overnight at room temperature. After cooling on ice again, the crystals were collected by filtration and washed with water. Coarse crystals into n- The residue was washed with sun to obtain 16.4 g of 1,3-, 4-, 5-trifluoro-6-methylbenzoic acid.

Melting point: 122—1 M ° C

_{Ή-NMR (CDC1 3) 6} : 2.43 (d, 3H, J = 3Hz)

MS (ra / z): 267, 269 (M—H)-

(5) 9.4 g of oxalyl chloride was added dropwise to a solution of 10.5 g of the compound obtained in the preceding section and 0.3 ml of N, N-dimethylformamide in 140 ml of dicumone, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure to obtain an acid chloride. Separately, 9.3 g of ethyl malonate, 6.3 g of magnesium chloride, and 13.8 g of triethylamine were suspended in 150 ml of ethyl acetate and stirred at room temperature for 7 hours. This was cooled on ice, a 50 ml solution of the previously synthesized acid chloride in ethyl acetate was added dropwise, and the mixture was stirred at room temperature overnight. Ethyl acetate and 1N-hydrochloric acid were added to separate the layers. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: n-hexane: ethyl acetate-10: 1), and then purified by 3-butane -2,4,5-trifluoro- 11.5 g of 6-methylbenzoyl ethyl acetate was obtained.

Melting point: 37-39 ° C

MS (m / z): 339, 341 (MH +)

(6) Triethyl orthoformate (2.9 ml) and acetic anhydride (3.3 / n1) were added to 4.4 g of the compound obtained in the preceding section, and the mixture was heated under reflux for 1 hour. The reaction solution was concentrated under reduced pressure, and toluene was further added to azeotrope. The residue was used as a 25 ml ethanol solution, and the solution was added dropwise to a solution of 1.9 g of 2,6-diamino-3,5-difluoropyridine in 40 ml of ethanol under ice-cooling. After stirring at the same temperature for 1 hour, the crystals were collected by filtration and dissolved in 60 ml of N, N-dimethylformamide. To this, add 2.9 g of potassium carbonate and stir at room temperature overnight. Was. The reaction solution was poured into 12 Om1 of ice water, the precipitated crystals were collected by filtration, ethanol was added and the mixture was heated, and the crystals were collected by filtration to obtain 3.9 g of the title compound.

Melting point: 228-229 ° C

H-NMR (DMS0-d ₆ ) δ: 1.26 (t, 3H, J = 8 Hz), 2.72 (d, 3H, J = 3 Hz), 4.24 (q, 2H, J = 8 Hz), 6.72 (s, 2H ), 7.93 (t, 1H, J = 10 Hz), 8.50 (s, 1H) MS (ni / z): 474, 476 (MH Example 4 (A)

(6-amino-3,5-difluoro-2-pyridyl) -8-bromo-6-fluoro-1, 4-dihydro-7- (3-hydroxyazetidine-1 Yl) -5-methyl-4-oxoquinoline-3-ethyl carboxylate

 A solution of 1.5 g of the compound obtained in Example 3, 330 mg of 3-hydroxyazetidine and 460 mg of triethylamine in 15 ml of dimethyl sulfoxide was stirred at room temperature overnight. After adding 30 ml of cold water, the precipitated crystals were collected by filtration and washed with ethanol to give 1.2 g of the title compound.

Melting point: 257-2591:

Ή-NMR (DMS0-d ₆ ) δ: 1.25 (t, 3H, J = 7 Hz), 2.60 (d, 3H, J = 3 Hz), 3.96-4.12 (m, 2H), 4.21 (q, 2H, J = 7Hz), 4.33-4.68 (m, 3H), 5.66 (d, 1H, J = 5Hz), 7.88 (t, 1H, J = 10Hz), 8.33 (s, 1H)

MS (ra / z): 527, 529 (MH +) Example 4 (B)

2- (3-amino-3,5-difluoro-2-pyridyl) -8-bromo-6-fluoro-1,4—dihydro-7- (3-hydroxyazetidine- -5-methyl-4-oxoquinoline-3-butyric acid

Example 4 1.2 g of the compound obtained in (A), 12 m of ethanol and 2% 28 ml of the aqueous stream solution was heated at 60 ° C for 6 hours. The reaction solution is treated with activated carbon,

56 ml of a 1% aqueous acetic acid solution was added dropwise to the filtrate heated at 80 ° C. After allowing to cool, the precipitated crystals were collected by filtration and washed with water to obtain 700 mg of the title compound.

Melting point: 257—260 ° C

 IR (KBr) cm— ': 3349, 1698, 1620

Ή-NMR (DMS0-d ₆ ) δ: 2.69 (d, 3Η, J = 4 Hz), 4.08-4.21 (m, 2H), 4.37-4.52 (in, 1H), 4.61-4.76 (m, 2H), 5.71 (d, 1H, J = 5Hz), 6.70 (s, 2H), 7.92 (t, 1H, J = 10Hz), 8.65 (s, 1H), 15.00 (s, 1H)

MS (m / z): 499, 501 (MH ⁺ ) Example 5

(6—Amino—3,5-difuryleo mouth—2-pyridyl) —8-cu Mouth mouth—6-fluoro-1,4-dihydro-7- (3-hydroxyazetidine- (Til)-5-methyl-4-oxoquinoline-3-carbonic acid choline

 To 300 mg of the compound obtained in Example 2 (B) were added 4 ml of methanol and 0.3 ml of a 45% solution of methanol in methanol, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and a mixed solution of ethyl acetate and methanol was added and dissolved by heating. After cooling at room temperature, the precipitated crystals were collected by filtration and washed with ethyl acetate to obtain 316 mg of the title compound.

Melting point: 152-155 ° C (decomposition)

IR (KBr) cm " ¹ : 3449, 1641

Ή-NMR (DMS0-d ₆ ) δ: 2.58 (d, 3H, J = 3.3 Hz), 3.11 (s, 9H), 3.39-3.44 (m, 2H), 3.80-3.89 (m, 2H), 3.94-4.05 (m, 2H), 4.36-4.5 (m, 1H), 4.47-4.60 (m, 2H), 5.66 (brs, 1H), 5.83 (brs, 1H), 6.50 (s, 2H), 7.72 (s, 1H), 7.82 0, 2H, J = 9.5 Hz)

MS m / z: 454 (MH ⁺ ) Example 6

(6-Amino-3,5-difluoro-2-pyridyl) -8-Port Mouth-6-Fluoro-1,4,1-Hydrogen Mouth- 7- (3-Hydroxyazetidine- ) -5-Methyl-4-oxoquinoline-3-capronic acid 1,3-diamino-2-propanol salt

 To 200 mg of the compound obtained in Example 2 (B) were added 15 ml of methanol and 400 mg of 1,3-diammino-2-propanol, and the mixture was heated and dissolved at 65. After maintaining at the same temperature for 15 minutes, 15 ml of ethyl acetate was added, and methanol was distilled off at normal pressure. After cooling at room temperature, the precipitated crystals were collected by filtration and washed with ethyl acetate to obtain 198 mg of the title compound.

Melting point: 122-123 ° C

 IR (KBr) cm— ': 3380, 1639

Ή-NMR (DMS0-d ₆ ) δ: 2.38-2.63 (m, 4H), 2.67 (d, 3H, J = 3.3 Hz), 3.21-3.45 (m, 2H), 4.11-4.23 (m, 2H), 4.0-4.53 (m, 2H), 4.59-4.68 (m, 2H), 5.58 (brs, lH), 6.68 (s, 2H), 7.89 (t, 1H, J = 9.6Hz), 8.42 (s, 1H)

MS (m / z): 455 (MH ⁺ ), 91 Example 7 — 15

In the same manner as described in Example 6, the following 1- (6-amino-3,5-difluoro port—2-pyridylile) —8—k port port—6—fluor port— 1,4-dihydroxy-7- (3-hydroxyxazetidine-1-yl) -5-methyl-4-oxoquinoline-3-potassium salt Obtained. Example Salt type Melting point (in)

 7 Ethanol amine salt 265-267 (decomposed)

8 (S) -2-Amino-1-propanol salt 270-272 (decomposed)

9 Diethanolamine 157-158 (decomposed)

10 N-methyl biperazine salt 266—268 (decomposed)

1 1 Piperazine (1/2 molecule) Salt 218-219 (decomposition)

1 2 1,3-Diamino propane (1/2 molecule) salt

 1 3 1- (2-Hydroxychetyl) Piperazine salt 175-177 (decomposed)

1 4 (S) -Prolinole salt 161-163 (decomposed)

1 52 2-Pyridine Methanol Salt 182-183 (decomposed)

Example 16

(6-amino-3, 5-difluoro-2-pyridyl)-8-mouth-6-fluoro-1,4-dihydro-7- (3-hydroxyazetidine- ) -5-Methyl-4-oxoquinoline-3-potassium sodium salt

Example 2 (B) in the resulting compound 300mg Water 10m was 1N- Na Application Benefits U anhydrous solution 0.66ml hydroxide and § Seto D Application Benefits Le 5ml addition, _c sub dissolved by heating at 65

Most of the solvent was distilled off under reduced pressure, and acetonitrile 15 ra 1 was added, followed by heating at 70 ° C. After allowing to cool at room temperature, the crystals were collected by filtration and washed with acetonitrile to obtain 243 mg of the title compound. Melting point: 240-242 ° C (decomposition)

IR (KBr) cm— ': 3344, 1632

Ή-NMR (DMS0-d ₆ ) δ: 2.63 (d, 3Η, J-3.3 Hz), 3.93-4.09 (in, 2Η), 4.34-4.62 (m, 3Η), 5.64 (brs, 1Η), 6.56 ( s, 2H), 7.84 (t, 1H, J = 9.6Hz), 8.03 (s, 1H)

MS (m / z): 477 (MUNa), 455 (MH +)

Example 17

The following compound was obtained in the same manner as described in Example 16. (6—Amino—3,5-difluoro—2—pyridyl) -8—Cu Mouth Mouth—6—Fluoro Mouth—1,4—Dihydro-7- (3-Hydroxyazetidin -1-yl) -5-methyl-4-oxoquinoline -3-potassium phosphate salt

Melting point: 221-223 ° C (decomposition) Example 18 (A)

(6—Amino—3,5-difluoro—2—pyridyl) —8—Cu Mouth—6—Fluoro—1,4—Dihydro-Ί- (3-Hydroxyazetidin- 2- (N, N-dimethylamino) ethyl ester of 5- (methyl) -4-oxoquinoline-3-hydroxycarboxylic acid

 300 mg of the compound obtained in Example 2 (B) was added to N, N-dimethylformamide

Dissolve it in 15 ml, add thereto N, N-dimethylaminoethyl chloride hydrochloride (114 mg), carbonic acid (RI) 218 mg and iodide (RI) 1 lrag, stir for 10 minutes, and add 50 ml — Stirred at 60 for 4 hours. Ice water was added, and the mixture was extracted with a black hole form, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatograph (eluent black-mouthed form: methanol = 20: 1) to obtain 309 mg of the title compound. Melting point: 106-107 ° C Example 18 (B)

(6-Amino-3,5-difluoro-2-pyridyl) -8-c Mouth Mouth-6-Fluoro-1,4-dihydro-7- (3-hydroxyazetidine- Yl) -5-methyl-4-oxoquinoline-3-carboxylic acid 2- (N, N-dimethylamino) ethyl ester hydrochloride To the compound obtained in Example 18 (A) 309 mg Then, 8 ml of ethanol and 0.08 ml of 30% ethanol monohydrochloride were added under ice-cooling, and the mixture was stirred for 10 minutes. 8 ml of diisopropyl ether was added, and the crystals were collected by filtration and washed with diisopropyl ether to obtain 259 mg of the title compound. Melting point: 162—1631:

IR (KBr) cnr ¹ : 3367, 1728, 1618

Ή-NMR (DMS0-d ₆ ) δ: 2.62 (d, 3H, J = 3.3 Hz), 2.85 (s, 6H), 3.38-3.48 (m, 2H), 3.98-4.13 (ra, 2H), 4.32- 4.68 (m, 5H), 5.68 (d, 1H, J = 5, 5 Hz), 6.62 (s, 2H), 7.90 (t, 1H, J = 9.8 Hz), 8.42 (s, 1H)

MS (tn / z): 526 (MH ÷)

Example 1 9 — 3 1

 Example 18 In the same manner as in the methods described in (A) and (B), the following 1- (6-amino-3,5-difluoro-2-2-pyridyl) -8-8 —6 Fluoro mouth— 1, 4-Dihydro mouth -7- (3-Hydroxyazetidine-1-yl) -5-Methyl-4-oxoquinoline-3-3-Hydronic acid The ester was obtained.

Example Type of ester Melting point (^)

1 9 2- (N, N-Jethylamino) ethyl ester 108-109

 2- (N, N-Jethylamino) ethyl ester

 2 0

 Methanesulfonate o

2 1 2-(1 -pyrrolidinyl) ethyl ester 112-113

2 22 2- (1-Pyrrolidinyl) ethyl ester hydrochloride 155-156 o

2 3 2- (4-morpholinyl) tyl ester

 2 4 2- (4-morpholinyl) ethyl ester hydrochloride 154-155

2 52 2- (1-Pyrrolyl) ethyl ester 210- 211

 2- (N, N-Jetylamino) -2-year-old

2 6

 Tell (disassembly)

 157-159

2 7 2- (1-Piberidinyl) ethyl ester hydrochloride

 (Disassembly)

167-168

2 8 1-Dimethylamino-2-propyl ester hydrochloride

 (Disassembly)

2 92-Pyridylmethyl ester hydrochloride 125-126

3 0 3-Pyridyl methyl ester hydrochloride 138-139

3 1 2- (aminocarbonylamino) ethyl ester 108-109 Example A

Tablet manufacturing method

Example 2 Compound (B) 250 g

Corn starch 54 g

Carboxymethylserylose 1 C a 40 g

Microcrystalline cellulose 50 g

Magnesium stearate 6 g

 Each of the above components was mixed with ethanol, granulated by a conventional method, and tableted to obtain 2,000 tablets weighing 200 mg. Example B

Preparation of ointment

Example 2 Compound (B) 5 mg

Flow paraffin 100 mg

White petrolatum qs

 The above components were mixed in a conventional manner to obtain 100 mg of ointment. Industrial applicability

 The compound of the present invention has excellent antibacterial activity against various pathogens, has high safety as a medicine, and is useful as an antibacterial agent. The compound of the present invention exhibits extremely excellent antibacterial activity against MRSA, and is particularly useful as an agent for treating or preventing MRSA infection.

Claims

The scope of the claims 1. The following general formula (I)

Wherein X is a chlorine atom or a bromine atom, A pyridonecarboxylic acid derivative represented by or a ester or salt thereof. 2. The pyridone carboxylic acid derivative or the ester or salt thereof according to claim 1, wherein X is a chlorine atom. 3. A drug containing the pyridonecarboxylic acid derivative or the physiologically acceptable salt thereof according to claim 1 or 2 as an active ingredient. 4. A pharmaceutical composition comprising the pyridone carboxylic acid derivative according to claim 1 or 2, or a physiologically acceptable salt thereof, and a pharmaceutically acceptable additive. 5. Methicillin-resistant Staphylococcus aureus infection containing the pyridonecarboxylic acid derivative or the physiologically acceptable salt thereof according to claim 1 or 2 as an active ingredient. For treating or preventing sickness. 6. The therapeutic or prophylactic agent according to claim 5, which is in the form of an external preparation. 7. The therapeutic or prophylactic agent according to claim 6, which is in the form of an ointment. 8. Infect methicillin-resistant Staphylococcus aureus with an effective amount of a pyridone carboxylic acid derivative or a physiologically acceptable salt thereof according to claim 1 or 2. A method for treating or preventing methicillin-resistant Staphylococcus aureus infection of a patient, comprising administering to a patient who is or may have a risk. 9. Use of a pyridone carboxylic acid derivative or an ester or a salt thereof according to claim 1 or 2 for the manufacture of a medicament. 10. The following general formula (Π)

 In the formula, X is a chlorine atom or a bromine atom  Y is a group capable of leaving, Or a compound or an ester or salt thereof. 11. The compound according to claim 10, wherein Y is a fluorine atom or a chlorine atom, or an ester or salt thereof.