JPH0543464A - Antibacterial agent containing pyridonecarboxylic acid derivative or salt thereof - Google Patents

Abstract

(57) [Summary] [Purpose] The present invention has the formula: Another object of the present invention is to provide an antibacterial agent containing the pyridonecarboxylic acid derivative represented by or a salt thereof. [Effect] The above-mentioned antibacterial agent of the present invention is effective not only for Gram-negative bacteria including Pseudomonas aeruginosa but also for Gram-positive bacteria and has a broad antibacterial spectrum, and at the same time has excellent solubility and high blood concentration It is useful for treating bacterial infections because of its high safety such as the fact that it has no effect on the central system.

Description

Detailed Description of the Invention

[0001]

The present invention relates to the formula [1].

[Chemical 2] The present invention relates to an antibacterial agent containing a pyridonecarboxylic acid derivative represented by or a salt thereof. The object of the present invention is to exert a strong antibacterial action against Gram-positive bacteria and Gram-negative bacteria, especially antibiotic-resistant bacteria, and to obtain high blood concentration by oral or parenteral administration, and safety. Another object of the present invention is to provide an antibacterial agent containing a novel compound represented by the formula [1] or a salt thereof, which has excellent properties such as high content.

[0002]

2. Description of the Related Art Conventionally, ofloxacin has been widely used clinically as a pyridobenzoxazine-based synthetic antibacterial agent, but its antibacterial activity is still insufficient. Among them, the effect on the treatment of particularly intractable Pseudomonas aeruginosa infection is not satisfactory.

[0003]

Therefore, it is effective not only against Gram-negative bacteria including Pseudomonas aeruginosa but also against Gram-positive bacteria and has a broad antibacterial spectrum, and at the same time, it has excellent solubility and high blood concentration. It has been desired to develop a synthetic antibacterial agent which is highly safe and has no effect on the central system.

[0004]

Under the circumstances, as a result of intensive studies by the present inventors, an antibacterial agent containing the pyridonecarboxylic acid derivative of the formula [1] or a salt thereof has the above-mentioned object. The present invention has been completed and the present invention has been completed.

The present invention will be described in detail below. Examples of the salt of the compound of the formula [1] include salts of a generally known basic group such as amino group or acidic group such as carboxyl group. Examples of the salt in the basic group include salts with mineral acids such as hydrochloric acid, hydrobromic acid or sulfuric acid; salts with organic carboxylic acids such as tartaric acid, formic acid, citric acid, trichloroacetic acid or trifluoroacetic acid; methanesulfone. Acid, benzenesulfonic acid, p-toluenesulfonic acid, a salt with a sulfonic acid such as mesitylenesulfonic acid or naphthalenesulfonic acid, and as the salt in the acidic group, for example, a salt with an alkali metal such as sodium or potassium; Salts with alkaline earth metals such as calcium or magnesium; ammonium salts; trimethylamine, triethylamine, tributylamine, pyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzyl. Min, N- benzyl -β- phenethylamine, 1-Efenamin or N, N'and salts with nitrogen-containing organic bases such as di-dibenzylethylenediamine and the like.

When isomers (for example, optical isomers, geometric isomers, tautomers, etc.) exist in the compound of the formula [1] and salts thereof, the present invention includes all of those isomers. It also includes all crystalline forms, solvates and hydrates.

Next, a method for producing the compound of the formula [1] and a salt thereof will be described. The compound of the formula [1] and salts thereof can be produced, for example, by the production route shown below.

[0008]

[Chemical 3]"In the formula, R1 Is a hydrogen atom or a carboxyl protecting group
R;_1aIs a carboxyl protecting group similar to R1; R_Two
Represents an optionally protected amino group. "

R₁As a carboxyl protecting group in
Is, for example, catalytic reduction, chemical reduction or other
Ester formation which is eliminated by treatment under mild conditions
Group or ester formation that is easily eliminated in vivo
By treating with a base, or water or alcohol
Organic silyl group, organic phosphorus group or organic that can be easily eliminated
For example, the tin group₅₉−₈₀₆₆₅No.
Examples thereof include a ruboxyl protecting group. R2 Ami in
The protecting group for the no group is a protective group usually used in the art.
Groups, for example formyl, acetyl, benzyl.
And JP Sho₅₉−₈₀₆₆₅Ordinary amino listed in No.
Protecting groups and the like can be mentioned. General formulas [2], [3],
Of the compounds of [5] and [6] and the compound of formula [4]
As the salt, the same as those described for the salt of the compound of the formula [1] can be used.
Salt can be mentioned.

Next, each step will be described. (1) The compound of the general formula [3] or a salt thereof can be obtained by subjecting the compound of the general formula [2] or a salt thereof to a ketoesterification reaction generally known in the art. (a) For example, the carboxyl group of the compound of the general formula [2] or a salt thereof is converted into an acid halide with a halogenating agent such as thionyl chloride, and then reacted with a metal salt of malonic acid diester such as sodium or ethoxymagnesium. A compound of the general formula [3] or a salt thereof can be derived by partially removing and decarboxylating a carboxyl protecting group using _p- toluenesulfonic acid or trifluoroacetic acid in a water-containing solvent. it can. The solvent used in the reaction between the acid halide and the metal salt of malonic acid diester is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene. Ethers such as dioxane, tetrahydrofuran and diethyl ether; halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; and amides such as N, N-dimethylformamide and N, N-dimethylacetamide. These solvents may be used alone or in combination of two or more. The amount of the metal salt of malonic acid diester used is equimolar or more, preferably 1 to 3 with respect to the acid halide of the compound of the general formula [2].
It is twice the mole. This reaction is usually performed at _-50 to ₁₀₀ ° C for 5
It may be carried out for ₃₀ minutes to ₃₀ minutes.

(B) Alternatively, for example, _{Angew. Chem. Int. Ed. Engl. 18th}
Vol. _72, p. ₁₉₇₉ , the carboxyl group of the compound of the general formula [2] or a salt thereof is derivatized into an active acid amide with, for example, N, N'-carbonyldiimidazole. Then, the compound of the general formula [3] or a salt thereof can be obtained by reacting with a magnesium salt of malonic acid monoester. The solvent used in the reaction of the active acid amide and the magnesium salt of malonic acid monoester is not particularly limited as long as it does not adversely affect the reaction, and specifically, the above-mentioned _{(1) (a} The same solvent as the above ₎ can be mentioned. The amount of magnesium salt of N, N′-carbonyldiimidazole and malonic acid monoester used is at least equimolar, preferably 1 to 2 times the molar amount of the compound of the general formula [2] or the salt thereof. Is. This reaction may be carried out usually at 0 to ₁₀₀ ° C, preferably ₁₀ to ₈₀ ° C for 5 minutes to ₃₀ hours.

_{(2) (a)} The compound of the general formula [5] or a salt thereof is obtained by reacting the compound of the general formula [3] or a salt thereof with methyl orthoformate or ethyl orthoformate in acetic anhydride. The compound of the formula [4] or a salt thereof is reacted (the optically active compound of the formula [4] or a salt thereof can be converted into an optically active pyridonecarboxylic acid derivative of the formula [1]. Can be obtained by The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction, and for example, aromatic hydrocarbons such as benzene, toluene and xylene; dioxane, tetrahydrofuran, anisole, Ethers such as diethylene glycol diethyl ether and dimethyl cellosolve; alcohols such as methanol, ethanol and propanol; halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; N, N Examples include amides such as dimethylformamide and N, N-dimethylacetamide; and sulfoxides such as dimethyl sulfoxide. These solvents may be used alone or in combination of two or more. The amount of methyl orthoformate or ethyl orthoformate used is equimolar or more, preferably about 1 to the compound of the general formula [3] or a salt thereof.
_{It is 10} times the mole. This reaction may be carried out usually at 0 to ₁₅₀ ° C., preferably at ₅₀ to ₁₅₀ ° C. for ₂₀ minutes to ₅₀ hours.
Then, in order to react the compound of the formula [4] or a salt thereof, the compound of the formula [4] or a salt thereof is used in an equimolar amount or more with respect to the compound of the general formula [3] or a salt thereof. It may be carried out at 0 to ₁₀₀ ° C., preferably ₁₀ to ₆₀ ° C. for ₂₀ minutes to ₃₀ hours.

(B) Alternatively, an acetal such as N, N-dimethylformamide dimethyl acetal or N, N-dimethylformamide diethyl acetal is added to the compound of the general formula [3] or a salt thereof. After reacting the compounds, a compound of the formula [4] or a salt thereof (when the optically active compound of the formula [4] or a salt thereof is used, it is converted into an optically active pyridonecarboxylic acid derivative of the formula [1]. Can be done.)
Can also be reacted to induce the compound of the general formula [5] or a salt thereof. The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction, and specific examples thereof include the same solvents as those described above in _{(2) (a)} . The amount of acetal used is at least equimolar to the compound of the general formula [3] or a salt thereof, preferably,
It is about _1.0 to _5.0 times mol. This reaction is usually 0-
_It may be carried out at ₁₀₀ ° C., preferably ₅₀ to ₈₅ ° C. for ₂₀ minutes to ₅₀ hours. Then, in order to react the compound of the formula [4] or a salt thereof, the compound of the formula [4] or a salt thereof is
It is used in an equimolar amount or more with respect to the compound of the general formula [3] or a salt thereof, and is usually 0 to ₁₀₀ ° C, preferably ₁₀ to ₆₀ ° C.
Then, it may be carried out for ₂₀ minutes to ₃₀ hours.

(3) The compound of the general formula [6] or a salt thereof can be obtained by subjecting the compound of the general formula [5] or a salt thereof to a ring closure reaction in the presence or absence of a fluoride salt or a base. be able to. The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction. For example, amides such as N, N-dimethylformamide and N, N-dimethylacetamide; dioxane, anisoso. -Le, diethyleneglycol-
Examples thereof include ethers such as dimethyl ether and dimethyl cellosolve; and sulfoxides such as dimethyl sulfoxide. These solvents may be used alone or in combination of two or more. Examples of the fluoride salt optionally used in this reaction include sodium fluoride or potassium fluoride, and examples of the base optionally used include sodium hydrogen carbonate, potassium carbonate, potassium _tert. -Butoxide, sodium hydride and the like can be mentioned, and the amount thereof is based on the compound of the general formula [5] or a salt thereof.
They are equimolar or more, preferably _1.0 to _1.5 times by mole. This reaction may be carried out usually at 0 to ₁₈₀ ° C. for 5 minutes to ₃₀ hours.

(4) (a) A compound of the formula [1] or a salt thereof is obtained by subjecting a compound of the general formula [6] or a salt thereof to a ring closure reaction in the presence or absence of a fluoride salt or a base. Can be obtained by This reaction may be carried out under the same reaction conditions as the ring closure reaction described in ₍₃₎ above.

(B) Alternatively, the compound of the formula [1] or a salt thereof is subjected to a ring closure reaction of the compound of the general formula [5] or a salt thereof in the presence or absence of a fluoride salt or a base. It can also be obtained. The amount of the fluorinated salt or base used as desired in this reaction is at least twice the molar amount of the compound of the general formula [5] or the salt thereof. This reaction is usually performed at 0 to ₁₈₀ ° C for 5
It may be carried out for ₃₀ minutes to ₃₀ minutes.

In the compounds having an amino group in the compounds of the general formulas [2], [3], [5] and [6] and the formula [4], the amino group is previously protected with a usual protecting group, After the reaction, the protecting group can be removed by a method known per se. The compound of the formula [1] or a salt thereof thus obtained can be isolated and purified according to a conventional method such as extraction, crystallization, column chromatography and the like.

The compound of the general formula [2] or a salt thereof, which is a raw material for producing the compound of the formula [1], is a novel compound and can be synthesized, for example, according to the following production route. ..

[0019]

[Chemical 4]"In the formula, R1 , R1a And R2 Respectively, as described above
Has the same meaning; R1b Is R1 Carboxyl similar to
Indicates a protecting group. The compound of general formula [8] or [9]
Or in their salts, two R1b Are the same or different
It may be. General formulas [7], [9], [₁₁] And
And [₁₂] The salt of the compound of formula [1] is a salt of the compound of formula [1]
The same salt as described in 1. can be mentioned. Also, the general formula
[8] and [_Ten] As an active methylene salt of the compound
Is, for example, sodium, potassium or lithium.
Examples include salts with any alkali metal. Then, each process
Will be described. Compound of general formula [7] or salt thereof
The US Patent No._3,590,036According to the method described in No.
By reacting with a compound of formula [8] or a salt thereof
To a compound of the general formula [9] or a salt thereof.
Deprotection and decarboxylation reactions by the usual methods.
Then, by introducing a carboxyl protecting group,
General formula [_Ten] Compounds or salts thereof
You can This is Chemiche Berichte (_{Chem. Ber.)}
First₉₉Volume, No.₂₄₀₇page(₁₉₆₆Year)
General formula [₁₁] Compound or salt thereof
It Furthermore, the general formula [₁₁] Or a salt thereof with hydrogen
In the presence of a base such as sodium iodide, trimethyl iodide
By reacting with sulfoxonium, the general formula [
₁₂] Or a salt thereof. one
The compound of the general formula [2] or a salt thereof has the general formula [₁₂]
Compound or its salt, deprotection reaction, reduction reaction, amination
Reaction, Curtius (_Curtius)Reaction or anti-alkylation
By subjecting it to a reaction known per se, such as
Can be obtained by combining these reactions as appropriate
it can.

[0020]

The effects of the antibacterial agent of the present invention are as follows.
The pharmacological action of the compound of the formula [1] or a salt thereof is shown. 1. Antibacterial activity test method Japanese Society of Chemotherapy standard method [chemotherapy_{(CHEMOTHERAPY)}
First₂₉Volume, No. 1, No.₇₆~₇₉page(₁₉₈₁Year)],
Heart Infusion Broth
_{(Heart Infusion broth) (}Manufactured by Eiken Chemical Co., Ltd.₃₇℃,₂₀Time
Culture for a period of time_Ten6 Individual/_mlBacteria solution adjusted to 1 platinum loop
A heart infusion agar containing a drug
_{(Heart Infusion agar)}Inoculate the medium (Eiken Chemical Co., Ltd.)
Then₃₇At ℃₂₀Observe the growth of bacteria after culturing for a long time
However, with the minimum concentration at which the growth of bacteria was blocked_{MIC (}μ_{g
/ ml}). The results are shown in Table-1. Table-1
The symbols inside have the following meanings. *: Β-lactamase-producing bacterium

Test Compound 1. _10- (1-aminocyclopropyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-
Pyrido [1,2,3- _de ] [1,4] benzoxazine-6-carboxylic acid hydrochloride 1. (S) - ₁₀ - (1- amino-cyclopropyl) -9-
Fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3- _de ] [1,4] benzoxazine-6-carboxylic acid hydrochloride Control compound: (±) 9 -Fluoro-2,3-dihydro-
3-Methyl- _10- (4-methyl-1-piperazinyl)-
7-oxo-7H-pyrido [1,2,3- _de ] [1,
4] Benzoxazine-6-carboxylic acid (ofloxacin) (hereinafter, blank)

[0022]

[Table-1] MIC (μ_g/_ml) ────────────────────────────────────     Compound number  Strain_{─────────────────────}  1 2 Ofloxacin (control) ─────────────────────────────────────  E. coli_{(E.coli) NIHJ}≤_0.05≤_0.05≤_0.05  E. coli_{(E.coli) TK-111}≤_0.05≤_0.05≤_0.05  Klebsiella pneumoniae_{(K.pneumoniae) Y-4}*_0.2≤_{0.05 0.39}  Serratia_{(S.marcescens) W-134 0.1}≤_{0.05 0.2}  Transforming fungus_{(P.mirabilis) T-111 0.1}≤_{0.05 0.39}  Morgan fungus_{(M.morganii) T-216}≤_0.05≤_{0.05 0.1}  Citrobacter_{(C.freundii) N-7}≤_0.05≤_{0.05 0.39}  Pseudomonas aeruginosa_{(P.aeruginosa) GN-918}*_{0.2 0.1 3.13 ────────────────────────────────────}

2. Acute toxicity 1 _ICR male mice (body weight: ₂₂ ± _{1 g} ) each consisting of 3 test compounds. 2 was intravenously administered to examine acute toxicity.
The test compound No. 2 was prepared by dissolving it in a _0.1 N sodium hydroxide aqueous solution. As a result, the test compound N
o. The ₅₀ % lethal dose ( _LD50 ) of 2 was 1000 mg / kg or more.

For the antibacterial agent of the present invention, the compound of the formula [1] or a salt thereof is appropriately used in a carrier usually used for formulation,
It may be prepared into tablets, capsules, powders, syrups, granules, suppositories, ointments, injections and the like according to a conventional method. In addition, the administration method, dose and frequency of administration can be appropriately selected according to the symptoms of the patient. Ordinarily for adults, oral or parenteral (eg injection, infusion, administration to the rectal site, etc.) administration Depending on 0.1 to 100 mg / kg /
The dose may be divided into one to several times for administration.

[0025]

EXAMPLES The present invention will be described below with reference to reference examples and examples, but the present invention is not limited to these. The symbols used in Reference Examples and Examples are
Each has the following meanings. TFA: trifluoroacetic acid, D ₂ O: heavy water In addition, unless otherwise specified, the carrier for column chromatography is Kieselgel 60, Art.7734 (Kieselgel 60).
elgel 60, Art.7734, manufactured by Merck) was used. further,
All mixing ratios in the eluent are volume ratios.

Reference Example 1 5.57 g of 60% sodium hydride was suspended in 260 ml of N, N-dimethylformamide, and 30.0 g of malonic acid di-tert-butyl ester was added to this suspension under ice cooling for 1 hour. Then, the mixture is added dropwise and stirred for 10 minutes at the same temperature, 25.7 g of 2,3,4,5-tetrafluorobenzoic acid ethyl ester is added to the resulting mixture, and the mixture is stirred for 10 hours at room temperature. The reaction mixture was added to a mixed solvent of 800 ml of water and 300 ml of ethyl acetate, and 6N was added.
After adjusting the pH to 3 with hydrochloric acid, the organic layer is separated. The separated organic layer is washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure,
The obtained residue was dissolved in 100 ml of trifluoroacetic acid,
Stir at room temperature for 20 hours. Concentrate the reaction mixture under reduced pressure,
150 ml of diethyl ether and 400 ml of water are added to the obtained residue.
Are sequentially added, and the organic layer is separated. The separated organic layer is washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, 60 ml of toluene is added to the obtained residue, and the mixture is refluxed for 1.5 hours. The reaction mixture was concentrated under reduced pressure, n-hexane was added to the obtained residue, and crystals were collected by filtration to give 4-carboxymethyl-2.
3,5-Trifluorobenzoic acid ethyl ester 15.4g
(Yield 50.8%) is obtained. IR (KBr) cm ^-1 ; ν _{C = O} 1710

Reference Example 2 4-Carboxymethyl-2,3,5-trifluorobenzoic acid ethyl ester (15.0 g) is dissolved in diethyl ether (25 ml), and a diphenyldiazomethane-petroleum ether solution is added dropwise at room temperature until the red color disappears. .. If the precipitated crystals are collected, 4-diphenylmethoxycarbonylmethyl-
2,3,5-Trifluorobenzoic acid ethyl ester 22.2
g (yield 90.6%) are obtained. IR (KBr) cm ^-1 ; ν _{C = O} 1730

Reference Example 3 4-diphenylmethoxycarbonylmethyl-2,3,5
-Trifluorobenzoic acid ethyl ester 32.3 g N, N
Dissolve in 240 ml of dimethylformamide, add 2.38 g of paraformaldehyde and 51 mg of sodium ethylate to this solution and stir for 2 hours at room temperature. 250 ml of ethyl acetate and 600 ml of water are sequentially added to the reaction mixture, and the organic layer is separated. The separated organic layer is washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (eluent: toluene: ethyl acetate = 10: 1) to give 4- (1-diphenylmethoxycarbonyl-
2-4.0 g of 2-hydroxyethyl) -2,3,5-trifluorobenzoic acid ethyl ester (yield 69.4%) is obtained. IR (neat) cm ^-1 ; ν _{C = O} 1720

Reference Example 4 24.0 g of 4- (1-diphenylmethoxycarbonyl-2-hydroxyethyl) -2,3,5-trifluorobenzoic acid ethyl ester was dissolved in 240 ml of methylene chloride, and this solution was cooled with ice, After adding 6.6 g of methanesulfonyl chloride, 11.6 g of triethylamine was added dropwise over 10 minutes, and the mixture was stirred at the same temperature for 1 hour. After adding 200 ml of water to the reaction mixture and adjusting the pH to 1 with 2N hydrochloric acid, the organic layer is separated. The separated organic layer is washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. Then, the solvent is distilled off under reduced pressure to obtain 22.9 g of 4- (1-diphenylmethoxycarbonylvinyl) -2,3,5-trifluorobenzoic acid ethyl ester (yield 99.3%). IR (neat) cm ^-1 ; ν _{C = O} 1720

Reference Example 5 2.5 g of 60% sodium hydride was suspended in 230 ml of N, N-dimethylformamide, and 13.7 g of trimethylsulfoxonium iodide was added to this suspension under ice cooling, and the suspension was allowed to stand at room temperature for 1 hour. After stirring, 22.9 g of 4- (1-diphenylmethoxycarbonylvinyl) -2,3,5-trifluorobenzoic acid ethyl ester was added to the obtained mixture, and the mixture was stirred at the same temperature for 2 hours. 250 ml ethyl acetate and 700 water in the reaction mixture
ml was added sequentially, the pH was adjusted to 1 with 2N hydrochloric acid, and the organic layer was separated. The separated organic layer is washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (eluent: toluene) to give 4- (1
-Diphenylmethoxycarbonylcyclopropyl)-
2,3,5-Trifluorobenzoic acid ethyl ester 15.8
g (yield 66.9%) is obtained. IR (neat) cm ^-1 ; ν _{C = O} 1725

Reference Example 6 12.2 g of 4- (1-diphenylmethoxycarbonylcyclopropyl) -2,3,5-trifluorobenzoic acid ethyl ester was dissolved in 60 ml of anisole, and 60 ml of trifluoroacetic acid was added to this solution. , Stir at room temperature for 2 hours.
The reaction mixture was concentrated under reduced pressure, n-hexane was added to the obtained residue, and the crystals were collected by filtration to give 4- (1-carboxycyclopropyl) -2,3,5-trifluorobenzoic acid ethyl ester. 7.1 g (yield 91.7%) are obtained. IR (KBr) cm ^-1 ; ν _{C = O} 1715,1685

Reference Example 7 4- (1-Carboxycyclopropyl) -2,3,5-
6.6 g of trifluorobenzoic acid ethyl ester was added to N, N-
Dissolve in 66 ml of dimethylformamide, and in this solution under ice cooling, 3.0 g of ethyl chlorocarbonate and 2.8 of triethylamine.
After adding g, the mixture is stirred at the same temperature for 30 minutes. Then, 1.9 g of sodium azide is added under ice cooling, and the mixture is stirred at the same temperature for 1 hour. To the reaction mixture, 120 ml of ethyl acetate and 250 ml of water were sequentially added, the pH was adjusted to 1 with 2N hydrochloric acid, and the organic layer was separated. The separated organic layer is washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, the obtained residue is dissolved in a mixed solvent of 60 ml of dioxane and 4.9 g of benzyl alcohol, and the mixture is refluxed for 1 hour. The reaction mixture was concentrated under reduced pressure, and the obtained residue was subjected to column chromatography (eluent: toluene).
When purified with, 4- (1-benzyloxycarbonylaminocyclopropyl) -2,3,5-trifluorobenzoic acid ethyl ester (7.8 g, yield 86.7%) is obtained. IR (KBr) cm ^-1 ; ν _{C = O} 1735,1700

Reference Example 8 4- (1-benzyloxycarbonylaminocyclopropyl) -2,3,5-trifluorobenzoic acid ethyl ester (5.6 g) was dissolved in a mixed solvent of ethanol (34 ml) and dioxane (34 ml) to prepare 1N sodium hydroxide. After adding 34 ml of the aqueous solution, the mixture is stirred at room temperature for 1 hour. Water 150m in the reaction mixture
After adding 1L and adjusting to pH 1 with 2N hydrochloric acid, ethyl acetate 150
ml is added and the organic layer is separated. The separated organic layer is washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, n-hexane was added to the obtained residue, and crystals were collected by filtration to give 4- (1-benzyloxycarbonylaminocyclopropyl) -2.
5.17 g (yield 99.4%) of 3,5-trifluorobenzoic acid is obtained. IR (KBr) cm ^-1 ; ν _{C = O} 1710,1675

Reference Example 9 7.50 g of 4- (1-benzyloxycarbonylaminocyclopropyl) -2,3,5-trifluorobenzoic acid was dissolved in 75 ml of anhydrous tetrahydrofuran, and this solution was cooled with ice under N, N '. After adding 4.99 g of carbonyldiimidazole and stirring at room temperature for 1 hour, 4.40 g of magnesium salt of ethoxycarbonylacetic acid is added to the obtained mixture and stirring at the same temperature for 20 hours. The reaction mixture is added to a mixed solvent of 150 ml of ethyl acetate and 200 ml of water, the pH is adjusted to 1 with 2N hydrochloric acid, and the organic layer is separated. The separated organic layer is washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (eluent; toluene: ethyl acetate = 50: 1) to give 4- (1-benzyloxycarbonylaminocyclopropyl) -2. 8.10 g (yield 90.6%) of 3,5-trifluorobenzoyl acetic acid ethyl ester is obtained. IR (neat) cm ^-1 ; ν _{C = O} 1725,1700 (sh)

Reference Example 10 4- (1-benzyloxycarbonylaminocyclopropyl) -2,3,5-trifluorobenzoyl acetic acid ethyl ester (3.00 g) was dissolved in benzene (30 ml) to prepare N, N-
Add 3.69 g of dimethylformamide dimethyl acetal and reflux for 30 minutes. The reaction mixture is concentrated under reduced pressure, the obtained residue is dissolved in 15 ml of toluene, 518 mg of DL-2-amino-1-propanol is added, and the mixture is stirred at room temperature for 17 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (eluent; toluene: ethyl acetate = 5: 1) to give 2- [4- (1-benzyloxycarbonylaminocyclopropyl). ) -2, 3, 5
-Trifluorobenzoyl] -3- (2-hydroxy-
1-Methylethylamino) acrylic acid ethyl ester 3.
09 g (yield 86.1%) are obtained. IR (KBr) cm ⁻¹ ; ν _C═O 1690 Similarly, the following compound is obtained. (S) -2- [4- (1-Benzyloxycarbonylaminocyclopropyl) -2,3,5-trifluorobenzoyl] -3- (2-hydroxy-1-methylethylamino) acrylic acid ethyl ester IR ( KBr) cm ^-1 ； ν _{C = O} 1695

Reference Example 11 2- [4- (1-benzyloxycarbonylaminocyclopropyl) -2,3,5-trifluorobenzoyl]
-3.0- (2-Hydroxy-1-methylethylamino) acrylic acid ethyl ester (3.07 g) was dissolved in N, N-dimethylformamide (25 ml), and 60% sodium hydride (519 mg) was added under ice-cooling at room temperature for 18 hours. Stir. The reaction mixture is added to a mixed solvent of 50 ml of ethyl acetate and 50 ml of water, the pH is adjusted to 1 with 2N hydrochloric acid, and the organic layer is separated. The separated organic layer is washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (eluent: toluene: ethyl acetate = 1: 1) to give 10- (1
-Benzyloxycarbonylaminocyclopropyl)-
9-Fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid ethyl ester 760 mg
(Yield 26.9%) is obtained. IR (KBr) cm ^-1 ; ν _{C = O} 1715

Reference Example 12 (S) -2- [4- (1-benzyloxycarbonylaminocyclopropyl) -2,3,5-trifluorobenzoyl] -3- (2-hydroxy-1-methylethylamino) Dissolve 1.13 g of acrylic acid ethyl ester in 11 ml of N, N-dimethylformamide to give 660 mg of potassium carbonate.
And stir at 90-100 ° C for 3.5 hours. The reaction mixture is added to a mixed solvent of 40 ml of ethyl acetate and 40 ml of water, the pH is adjusted to 1.5 with 2N hydrochloric acid, and the organic layer is separated. The separated organic layer is washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure,
Diethyl ether was added to the obtained residue and the crystals were collected by filtration to give (S) -10- (1-benzyloxycarbonylaminocyclopropyl) -9-fluoro-3-methyl-
7-oxo-2,3-dihydro-7H-pyrido [1,
800 mg (yield 76.7%) of 2,3-de] [1,4] benzoxazine-6-carboxylic acid ethyl ester is obtained. IR (KBr) cm ^-1 ; ν _{C = O} 1715

Reference Example 13 (S) -10- (1-Benzyloxycarbonylaminocyclopropyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3] -D
10 g of e] [1,4] benzoxazine-6-carboxylic acid ethyl ester was dissolved in 100 ml of acetic acid, 2 g of 5% palladium-carbon was added, and the mixture was stirred at room temperature under normal pressure in a hydrogen stream for 2 hours. After the reaction mixture was filtered, the filtrate was concentrated to dryness under reduced pressure, 200 ml of methylene chloride and 200 ml of water were added to the obtained residue, and the mixture was saturated with saturated aqueous sodium hydrogen carbonate solution.
Adjust to H7.7. The organic layer is separated, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, diethyl ether was added to the obtained residue, and the crystals were collected by filtration to obtain (S) -10- (1
-Aminocyclopropyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,
6.43 g (yield 89.2%) of 2,3-de] [1,4] benzoxazine-6-carboxylic acid ethyl ester is obtained. IR (KBr) cm ^-1 ; ν _{C = O} 1705

Reference Example 14 (S) -10- (1-benzyloxycarbonylaminocyclopropyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3] -D
e] [1,4] benzoxazine-6-carboxylic acid ethyl ester 800 mg, 1N aqueous sodium hydroxide solution 8 ml,
Add 8 ml of ethanol and 4 ml of dioxane, and add 1.
Stir for 5 hours. After adding 30 ml of water to the reaction mixture and adjusting the pH to 3 with 2N hydrochloric acid, 60 ml of ethyl acetate is added and the organic layer is separated. The separated organic layer is washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, diethyl ether was added to the obtained residue, and the crystals were collected by filtration to give (S) -10- (1-benzyloxycarbonylaminocyclopropyl) -9-fluoro-3- Methyl-7-oxo-2,3-dihydro-7
690 mg (yield 91.6%) of H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid is obtained. Melting point: 180 to 182 ° C. IR (KBr) cm ⁻¹ ; ν _C═O 1705 Similarly, the following compound is obtained. 10- (1-benzyloxycarbonylaminocyclopropyl) -9-fluoro-3-methyl-7-oxo-2
3-dihydro-7H-pyrido [1,2,3-de] [1,
4] Benzoxazine-6-carboxylic acid IR (KBr) cm ^-1 ; ν _{C = O} 1705

Example 1 (S) -10- (1-benzyloxycarbonylaminocyclopropyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3 -D
e] [1,4] benzoxazine-6-carboxylic acid 690mg
Was dissolved in 30 ml of acetic acid, 650 mg of 5% palladium-carbon was added, and the mixture was stirred at room temperature under normal pressure in a hydrogen stream for 2 hours. After filtering the reaction mixture, the filtrate was concentrated under reduced pressure, 5 ml of 2N hydrochloric acid was added to the obtained residue, and the mixture was further concentrated under reduced pressure.
Ethanol was added to the obtained residue and the crystals were collected by filtration to obtain (S) -10- (1-aminocyclopropyl) -9-
Fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid hydrochloride 470 mg (yield 86.9
%). Melting point: 243.5-247.5 ° C (resolving solvent: ethanol-methanol) IR (KBr) cm ^-1 ; ν _{C = O} 1710 NMR (d ₁ -TFA) δ value; 1.30-2.30 (7H, m), 4.70-5.60 (3H,
m), 8.05 (1H, d, J = 9.5Hz), 9.43 (1H, s) Optical rotation -32.5 ° (25 ° C, C = 0.5, water) Similarly, the following compound is obtained. 10- (1-aminocyclopropyl) -9-fluoro-3
-Methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6
-Carboxylic acid hydrochloride Melting point; 254 to 257 ° C (resolving solvent; methanol) IR (KBr) cm ^-1 ; ν _{C = O} 1715 NMR (d ₁ -TFA) δ value; 1.20 to 2.20 (7H, m) , 4.60 ~ 5.60 (3H,
m), 8.06 (1H, d, J = 10.0Hz), 9.43 (1H, s)

Example 2 (S) -10- (1-aminocyclopropyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7
730 mg of H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid hydrochloride are dissolved in 8.57 ml of water, and 242 mg of potassium hydroxide and 5.84 ml of ethanol are added. Subsequently, 0.19 ml of concentrated hydrochloric acid was added dropwise at 60 ° C over 30 minutes, and then cooled to 20 ° C over 2 hours. At 20 ℃
After stirring for 30 minutes and collecting the precipitated crystals by filtration, (S) -10-
(1-Aminocyclopropyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-
570 mg of carboxylic acid (yield 87.0%) are obtained. Melting point: 269-271.5 ° C IR (KBr) cm ^-1 ; ν _{C = O} 1705 NMR (d ₁ -TFA) δ value: 1.30-2.20 (7H, m), 4.45-5.55 (3H,
m), 8.06 (1H, d, J = 9.5Hz), 9.42 (1H, s) Optical rotation -88.0 ° (25 ° C, C = 0.5,0.05N sodium hydroxide aqueous solution)

Example 3 (S) -10- (1-aminocyclopropyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7
3.00 g of H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid was suspended in 120 ml of ethanol, and 996 mg of methanesulfonic acid was added at 50 ° C., followed by 2
If it takes time to cool to 20 ° C, and the precipitated crystals are collected by filtration,
(S) -10- (1-Aminocyclopropyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7
3.05 g (yield 78.1%) of methanesulfonate of H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid is obtained. Melting point: 263-265 ° C IR (KBr) cm ^-1 ; ν _{C = O} 1710 NMR (D ₂ O) δ value; 1.30-1.90 (7H, m), 2.84 (3H, s), 4.25-5.
20 (3H, m), 7.53 (1H, d, J = 10.0Hz), 8.84 (1H, s)

 ─────────────────────────────────────────────────── ─── Continued Front Page (72) Inventor Fumihiko Iino 1-6-30 Shimookui, Toyama City, Toyama Prefecture (72) Inventor Mikako Miyajima 3-2-5 Ishigane, Toyama City, Toyama Prefecture (72) Inventor Yoshikazu Toyama, Fukuoka 141 Inujima Suzukakedai, Toyama City, Toyama Prefecture (72) Inventor Isamu Saikawa 7-52 Oizumi Nakamachi, Toyama City, Toyama Prefecture

Claims (2)

[Claims] 1. The formula: An antibacterial agent containing the pyridonecarboxylic acid derivative represented by or a salt thereof. Wherein (S) - ₁₀ - (1- amino-cyclopropyl) methyl-7-oxo-2,3
-Dihydro-7H-pyrido [1,2,3- _de ] [1,
4] An antibacterial agent containing benzoxazine-6-carboxylic acid or a salt thereof.