JP2787704B2 - Novel pyridonecarboxylic acid derivatives and salts thereof - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] Wherein R ¹ is a hydrogen atom or a carboxyl protecting group;
² represents a hydrogen atom, a halogen atom, an alkoxy group, an optionally protected hydroxyl group, an optionally protected amino group, an optionally protected lower alkylamino group or a di-lower alkylamino group; ³ is a hydrogen atom,
Lower alkyl group, optionally protected amino group, optionally protected lower alkylamino group, di-lower alkylamino group, optionally protected carboxyl group,
An optionally protected amino lower alkyl group, an optionally protected lower alkylamino lower alkyl group, di-
One or more groups selected from a lower alkylamino lower alkyl group and an optionally protected hydroxy lower alkyl group; A represents an imino group optionally substituted with an oxygen atom, a sulfur atom or a lower alkyl group; And X represent a halogen atom. And a salt thereof.

An object of the present invention is to provide Gram-positive and Gram-negative bacteria,
In particular, it is an object of the present invention to provide a novel compound represented by the general formula [I] and a salt thereof, which exert a strong antibacterial action against antibiotic-resistant bacteria.

[Related Art] Ofloxacin has been widely used clinically as a pyridobenzoxazine-based synthetic antibacterial agent, but its antibacterial activity is still insufficient.

[Problems to be Solved by the Invention] Therefore, it has been desired to develop a synthetic antibacterial agent which is effective not only against gram-negative bacteria but also against gram-positive bacteria and has a wide antibacterial spectrum.

[Means for Solving the Problems] Under such circumstances, the present inventors have conducted intensive studies and have found that the pyridonecarboxylic acid derivative of the general formula [I] and a salt thereof achieve the above object. Heading,
The present invention has been completed.

In the present specification, unless otherwise specified, a halogen atom is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom; an alkyl group is, for example, methyl,
Ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec- butyl, tert- butyl, pentyl, C _{1 to 10} alkyl group such as hexyl or octyl; a lower alkyl group, for example, alkyl groups as described above Of these, a C _1-5 alkyl group; an alkoxy group is, for example, an —O-alkyl group (the alkyl group is
_{Shows a 1-10} alkyl group. Lower alkylamino group means, for example, a _C1-5 alkylamino group such as methylamino, ethylamino or propylamino;
A lower alkylamino group is, for example, a di- _C1-5 alkylamino group such as dimethylamino; an amino-lower alkyl group is, for example, amino- _C1-5 alkyl such as aminomethyl, aminoethyl or aminopropyl. group; and lower alkylamino-lower alkyl group, for example, methylaminomethyl, methylaminoethyl, ethylaminomethyl, a C _{1 to 5} alkyl amino -C _{1 to 5} alkyl groups such as methyl aminopropyl or propyl aminoethyl; di - lower alkyl amino lower alkyl group, for example, dimethylaminomethyl, diethylaminomethyl, di -C _{1 to 5} alkylamino -C _{1 to 5} alkyl group such as diethylaminoethyl or dimethylaminopropyl; and hydroxy lower alkyl group Is, for example, hydroxy Chill means respectively hydroxyalkyl -C _{1 to 5} alkyl groups, such as hydroxyethyl or hydroxypropyl.

 Hereinafter, the present invention will be described in detail.

Carboxyl protecting groups include, for example, catalytic reduction,
An ester-forming group which is eliminated by chemical reduction or other mild treatment; an ester-forming group which is easily eliminated in vivo; or an organic silyl which is easily eliminated by treatment with water or alcohol; Examples thereof include ordinary carboxyl protecting groups described in JP-A-59-80665, such as organic phosphorus or organic tin groups.

Examples of the protecting group for the amino group, lower alkylamino group, amino lower alkyl group and lower alkylamino lower alkyl group include protecting groups usually used in the art, such as formyl, acetyl, benzyl and And ordinary amino protecting groups described in JP-80665.

Examples of the protecting group for the hydroxyl group and the hydroxy lower alkyl group include protecting groups usually used in the art, for example, an organic silyl group which is easily eliminated by treatment with water or an alcohol, and formyl, acetyl and benzyl. And ordinary hydroxyl protecting groups described in JP-A-59-80665.

Examples of the salt of the pyridonecarboxylic acid derivative of the general formula [I] include a salt of a generally known basic group such as an amino group or an acidic group such as a hydroxyl or carboxyl group.

Salts in basic groups include, for example, salts with mineral acids such as hydrochloric acid, hydrobromic acid or sulfuric acid; tartaric acid, formic acid,
Salts with organic carboxylic acids such as citric acid, trichloroacetic acid or trifluoroacetic acid; or methanesulfonic acid,
Benzenesulfonic acid, p-toluenesulfonic acid, a salt with a sulfonic acid such as mesitylenesulfonic acid or naphthalenesulfonic acid, and a salt in the acidic group,
For example, salts with alkali metals such as sodium or potassium; salts with alkaline earth metals such as calcium or magnesium; ammonium salts; or trimethylamine, triethylamine, tributylamine, pyridine, N, N-dimethylaniline, N-methylpiperidine , N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-
Examples thereof include salts with a nitrogen-containing organic base such as benzyl-β-phenethylamine, 1-ephenamine or N, N′-dibenzylethylenediamine.

When isomers (for example, optical isomers, geometric isomers, tautomers, and the like) are present in the pyridonecarboxylic acid derivative of the general formula [I] and salts thereof, the present invention relates to all of the isomers And also a solvate,
It includes hydrates and all crystal forms.

Next, a method for producing the pyridonecarboxylic derivative of the general formula [I] and a salt thereof will be described.

The pyridonecarboxylic acid derivative of the general formula [I] and a salt thereof can be obtained by combining methods known per se. For example, they can be produced according to the following production route.

Wherein R ¹ , R ³ , A and X have the same meanings as described above; R ^2a represents a hydrogen atom or a halogen atom similar to R ² ; R ^2b represents the same as R ² alkoxy or optionally protected hydroxyl group; R ^2c is similar optionally protected amino group and R ^2, which may be protected lower alkylamino group or a di - lower alkylamino group; R ⁴ is
Shows a hydrogen atom or a protecting group. The protecting group in "R ^4, a hydroxyl protecting group or amino protecting group, or The Chemistry Of The
Chiol Group Pad 2 Soul Patai Edition; John Willi and Sons (The Chemistry of the
thiol group part2 Edited by Saul Patai; JOHN WILEY
& SONS) at page 669.

General formulas [Ia], [Ib], [Ic], [II], [III]
And salts of the compound of [IV] include the same salts as described for the salts of the compound of general formula [I].

(1) The compound of the general formula [Ia] or a salt thereof can be obtained by subjecting the compound of the general formula [II] or a salt thereof to a ring closure reaction in the presence or absence of a fluoride salt or a base. it can.

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, anisole ,
Ethers such as diethylene glycol dimethyl ether and dimethyl cellosolve; alcohols such as methanol and ethanol; and sulfoxides such as dimethyl sulfoxide. These solvents may be used alone or in combination of two or more.

Examples of the fluoride used as necessary in this reaction include sodium fluoride and potassium fluoride. Examples of the base used as needed include sodium hydrogen carbonate, potassium carbonate, and sodium methoxy. , Sodium ethoxide, potassium
Examples thereof include tert-butoxide and sodium hydride, and the amount of each used is at least equimolar to the compound of the general formula [II] or a salt thereof, preferably 1.
0 to 2.5 times mol.

This reaction may be usually performed at 0 to 180 ° C. for 5 minutes to 30 hours.

(2) The compound of the general formula [Ib] or a salt thereof, in the presence or absence of a base, can be prepared by adding the compound of the general formula [Ia] or a salt thereof, wherein R ^2a is a halogen atom, By reacting an alcohol 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 examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene; dioxane, tetrahydrofuran and diethyl ether. Ethers; halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; nitriles such as acetonitrile; and amides such as N, N-dimethylformamide and N, N-dimethylacetamide. One or a mixture of two or more solvents may be used.

Further, as the base used as necessary in this reaction, for example, sodium, potassium, potassium tert-
Butoxide or sodium hydride.

The amount of the alcohol of the general formula [III] or a salt thereof and the base to be used if necessary is at least equimolar to the compound of the general formula [Ia] or a salt thereof, wherein R ^2a is a halogen atom. It is.

This reaction may be usually performed at 0 to 150 ° C. for 10 minutes to 20 hours.

(3) The compound of the general formula [Ic] or a salt thereof can be prepared by adding a compound of the general formula [Ia] or a salt thereof, wherein R ^2a is a halogen atom, in the presence or absence of a base. It can be obtained by reacting an amine 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 examples thereof include the same solvents as those described in the above (2).

Bases used as necessary in this reaction include, for example, triethylamine, diisopropylethylamine, 1,8-diazabicyclo- [5.4.0] undec-
Organic or inorganic bases such as 7-ene (DBU), pyridine, potassium tert-butoxide, potassium carbonate, sodium carbonate or sodium hydride.

The amount of the amines represented by the general formula [IV] or a salt thereof is represented by R
The compound of the general formula [Ia] or a salt thereof, wherein ^2a is a halogen atom, is preferably 2 to 10 moles,
By appropriately using a base, the amount of the amines represented by the general formula [IV] or a salt thereof can be reduced.

This reaction is usually carried out at 0 to 150 ° C., preferably 15 to 100 ° C.
C. for 5 minutes to 30 hours.

Alternatively, the compound of the general formula [I] or a salt thereof is subjected to a reaction known per se such as, for example, oxidation, reduction, rearrangement, substitution, halogenation and hydrolysis, or by appropriately combining them to obtain another compound. It can be converted to a compound of the general formula [I] or a salt thereof.

In the compound of [II] in the above-mentioned production method,
When isomers exist (eg, optical isomers, geometric isomers, tautomers, and the like), all of these isomers can be used, and solvates, hydrates, and all crystalline forms Can be used.

In the compounds of the general formulas [II], [III] and [IV], compounds having an amino group, a hydroxyl group or a carboxyl group may be protected beforehand by protecting these groups with a usual protecting group. Accordingly, these protecting groups can be eliminated by a method known per se.

The compound of the general formula [I] or a salt thereof thus obtained can be isolated and purified according to a conventional method such as extraction, crystallization, and column chromatography.

The general formula [I] which is a raw material for producing the compound of the present invention
The compound [I] or a salt thereof is a novel compound and can be obtained by combining methods known per se. For example, it can be produced according to the following production route.

Wherein R ¹ , R ^2a , R ⁴ , A and X have the same meanings as described above; R ^1a and R ^1b have the same carboxyl protecting group as R ¹ ; R ^3a has hydrogen atoms or R ³ the same optionally protected amino group, unprotected or protected lower alkylamino group, di - lower alkylamino group, a protected or unprotected amino-lower alkyl group, which may be protected One or more groups selected from good lower alkylamino lower alkyl groups, di-lower alkylamino lower alkyl groups and optionally protected hydroxy lower alkyl groups;
^3b is a lower alkyl group similar to R ^3; R ^3c shows the same lower alkyl group and a hydrogen atom or R ^3. In the compounds of the general formulas [VI], [VII] or [IIc] or salts thereof, two R ^1b may be the same or different.

Formulas [V], [VII], [VIII], [IX],
[X], [XI], [XII], [IIa], [IIb], [II
c], [II d] and the salt of the compound of [II e]
Salts similar to those described for the salt of the compound of the general formula [I] can be mentioned.

Examples of the salt of active methylene of the compounds of the general formulas [VI] and [VIII] include salts with an alkali metal such as sodium, potassium or lithium.

Next, a method for producing the compound of the general formula [II] or a salt thereof will be described in more detail according to the aforementioned production route.

The compound of the general formula [V] or a salt thereof is disclosed in JP-A-58-10
It can be obtained by the method described in No. 3393.

The compound of the general formula [V] or a salt thereof is prepared according to US Pat.
The compound of the general formula [VI] can be reacted with the compound of the general formula [VI] or a salt thereof according to the method described in 590,036.
I] or a salt thereof, which is subjected to deprotection and decarboxylation by a conventional method, followed by introduction of a carboxyl-protecting group, thereby obtaining a compound of the general formula [VI]
II] or a salt thereof.

The compound of the general formula [VIII] is converted to Chemiché Berichte (Ch
em. Ber.) Vol. 99, p. 2407 (1966), and can be derived into a compound of the general formula [IX] or a salt thereof.

Furthermore, the compound of the general formula [IX] or a salt thereof can be derived by reacting the compound of the general formula [IX] or a salt thereof with a diazoalkane.

Further, the compound of the general formula [XI] or a salt thereof can be prepared by a conventional method by converting the compound of the general formula [IX] or a salt thereof or the compound of the general formula [X] or a salt thereof in the presence of a base such as sodium hydride. And trimethylsulfoxonium iodide.

The compound of the general formula [IIa] or a salt thereof has the general formula [X
Compound [I] or a salt thereof can be obtained by subjecting the compound to a known reaction such as deprotection, reduction, amination, Curtius reaction or alkylation, or by appropriately combining these reactions.

The compound of the general formula [IIb] or a salt thereof has the general formula [I
X] or a salt thereof by subjecting the compound of the general formula [XI] to deprotection and decarboxylation by a conventional method.
I] or a salt thereof, which is then subjected to a 1,3-dipole addition reaction with a diazoalkane, followed by a thermal denitrification reaction.

Alternatively, the compound of the general formula [IIb] or a salt thereof can be obtained by subjecting the compound of the general formula [XI] or a salt thereof to a usual deprotection and decarboxylation reaction.

The compound of the general formula [IIc] or a salt thereof is represented by the general formula [XI:
After subjecting the compound of the formula I] or a salt thereof to a bromination or chlorination reaction, for example, a base such as DBU is allowed to act thereon, and then the compound of the general formula [VI] or a salt thereof is reacted. it can.

The compound of the general formula [II d] or a salt thereof has the general formula [II d
Compound [c] or a salt thereof is subjected to a conventional deprotection reaction and decarboxylation reaction, and further, a carboxyl protecting group is introduced.

Further, by subjecting the compound of the general formula [II d] or a salt thereof to a reaction known per se such as deprotection, reduction, amination, Curtius reaction or alkylation, or by appropriately combining these reactions, A compound of the formula [IIe] or a salt thereof can be obtained.

The general formulas [V], [VII],
In the compounds of [VIII], [IX], [X], [XI] and [XII], when isomers (for example, optical isomers, geometric isomers, tautomers and the like) are present, all of these areomers are used. Isomers can be used, and solvates, hydrates and all crystalline forms can be used.

Further, general formulas [V], [VII], [VIII], [I
X], [X], [XI], [XII], [IIc] and [II
In the compound d), the compound having an amino group, a hydroxyl group or a carboxyl group may be protected with a conventional protecting group in advance, and after the reaction, if necessary, by a method known per se. Can also be desorbed.

The thus-obtained compound of the general formula [I] and a salt thereof can be isolated and purified according to a conventional method such as extraction, crystallization and column chromatography.

When the compound of the present invention is used as a medicament, excipients usually used in the preparation, formulation aids such as carriers and diluents may be appropriately mixed, and these are tablet, capsule, powder, and the like by a conventional method. It can be administered orally or parenterally in the form of syrups, fine granules, granules, pills, suspensions, emulsions, solutions, powders, suppositories, ointments or injections. In addition, the administration method, dosage and number of administration can be appropriately selected according to the patient's age, body weight and symptoms,
Usually, for adults, oral or parenteral (eg, injection, infusion, administration to rectal site, etc.)
The daily dose of 0.1 to 100 mg / Kg may be administered in one to several divided doses.

Next, the pharmacological action of the representative compound of the present invention will be described.

1. Antimicrobial activity test method Japanese Society of Chemotherapy standard method [CHEMOTHERA
PY) Vol. 29, No. 1, pp. 76-79 (1981)], and Heart Infuture Broth (Heart Infu
sion broth) (manufactured by Eiken Chemical Co., Ltd.) at 37 ° C for 20 hours.
One platinum loop of the bacterial solution adjusted to a cell count of 10 ⁶ cells / ml was added to a heart infusion agar containing a test compound (Heart Infugen).
sion agar) medium (manufactured by Eiken Chemical Co., Ltd.)
After culturing for a period of time, the presence or absence of the growth of the bacteria was observed, and the MIC (μg / ml) was defined as the minimum concentration at which the growth of the bacteria was inhibited.

 Table 1 shows the results.

 The symbols in Table 1 have the following meanings.

*: Β-lactamase-producing bacteria Test compound A: 8- (1-aminocyclopropyl) -9,1-epoxy:
Methano-7-fluoro-5-oxo-5H-thiazolo [3,
2-a] quinoline-4-carboxylic acid B: 8-cyclopropyl-9,1-epoxy: methano-7-fluoro-5-oxo-5H-thiazolo [3,2-a] quinoline-4-carboxylic acid [Effects of the Invention] From the above results, it is clear that the compound of the present invention exhibits an excellent antibacterial action, and can be used as an antibacterial agent.

[Examples] Next, the production method of the compound of the present invention will be specifically described with reference to Reference Examples and Examples, but the present invention is not limited thereto.

The mixing ratios in the eluent are all volume ratios, and the carrier in column chromatography is
Unless otherwise specified, Kieselgel 60, Art.7734
(Kieselgel 60, Art.7734, manufactured by Merck) was used.

Reference Example 1 1.16 g of 60% sodium hydride was added to dimethyl sulfoxide 6
Suspended in water, and 6.30 g of malonic acid di-tert-butyl ester was added dropwise over 20 minutes under cooling with water. After stirring at the same temperature for 1 hour, 1-acetoxymethyl-7,8,9-triester was added. 2.9 g of fluoro-5-oxo-5H-thiazolo [3,2-a] quinoline-4-carboxylic acid ethyl ester was added, and the mixture was added at room temperature.
Stir for hours. The reaction solution was mixed with 100 ml of water and 100 ml of ethyl acetate.
The mixture is adjusted to pH 2 with 2N hydrochloric acid, and the organic layer is separated. The separated organic layer is sequentially washed with water and saturated saline, and then 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 = 3: 1) to give 1-acetoxymethyl-8-di-tert-butoxycarbonylmethyl. 4.3 g (99.4% yield) of -7,9-difluoro-5-oxo-5H-thiazolo [3,2-a] quinoline-4-carboxylic acid ethyl ester is obtained.

IR (neat) cm ^-1 ; v _{c = 0} 1735 Reference Example 2 1-acetoxymethyl-8-di-tert-butoxycarbonylmethyl-7,9-difluoro-5-oxo-5H-thiazolo [3,2-a 20 ml of trifluoroacetic acid is added to 4.25 g of quinoline-4-carboxylic acid ethyl ester, and the mixture is stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and diisopropyl ether was added to the obtained residue to collect crystals, whereby 1-acetoxymethyl-8-carboxymethyl-
7,9-difluoro-5-oxo-5H-thiazolo [3,2-
a] Quinoline-4-carboxylic acid ethyl ester 2.94 g
(93.8% yield).

IR (KBr) cm ^-1 ; v _{c = 0} 1740 Reference Example 3 1-acetoxymethyl-8-carboxymethyl-7,9
-Difluoro-5-oxo-5H-thiazolo [3,2-a]
Quinoline-4-carboxylic acid ethyl ester (2.90 g) is suspended in chloroform (30 ml), and a diphenyldiazomethane-ethyl acetate solution is added dropwise at room temperature until the red color disappears. The reaction solution was concentrated under reduced pressure, and diethyl ether was added to the obtained residue to collect crystals, whereby 1-acetoxymethyl-7,9-difluoro-8-diphenylmethoxycarbonylmethyl-5-oxo-5H- Thiazolo [3,2-
a] Quinoline-4-carboxylic acid ethyl ester 3.44 g
(86.1% yield).

IR (KBr) cm ^-1 ; v _{c = 0} 1735 Reference Example 4 1-acetoxymethyl-7,9-difluoro-8-diphenylmethoxycarbonylmethyl-5-oxo-5H-thiazolo [3,2-a] quinoline- 2.90 g of 4-carboxylic acid ethyl ester was suspended in 29 ml of dimethyl sulfoxide, and 3
0.78 g of a 7% aqueous formaldehyde solution and 20 mg of sodium hydrogen carbonate are added, and the mixture is stirred at 50 ° C. for 1 hour. After adding 300 ml of ethyl acetate and 200 ml of water to the reaction solution, the organic layer is separated. The separated organic layer is sequentially washed with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (eluent; chloroform: ethyl acetate = 1: 1) to give 1-acetoxymethyl-7,9-difluoro-8.
2.25 g of-(1-diphenylmethoxycarbonyl-2-hydroxyethyl) -5-oxo-5H-thiazolo [3,2-a] quinoline-4-carboxylic acid ethyl ester (yield 73.
9%).

IR (KBr) cm ^-1 ; ν _{c = 0} 1745,1730 (sh) Reference Example 5 1-acetoxymethyl-7,9-difluoro-8- (1
-Diphenylmethoxycarbonyl-2-hydroxyethyl) -5-oxo-5H-thiazolo [3,2-a] quinoline-4-carboxylic acid ethyl ester 2.18 g in methylene chloride 2
Suspended in 2 ml, and cooled with ice under methanesulfonyl chloride 0.4
After adding 7 g, 0.83 g of triethylamine is added dropwise over 5 minutes, and the mixture is stirred at room temperature for 30 minutes. After adding 20 ml of water to the reaction solution and adjusting the pH to 2 with 2N hydrochloric acid, the organic layer is separated. After sequentially washing the separated organic layer with water and saturated saline,
Dry 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 = 3: 1) to give 1
-Acetoxymethyl-7,9-difluoro-8- (1-diphenylmethoxycarbonylvinyl) -5-oxo-5H
1.77 g (83.6% yield) of ethyl thiazolo [3,2-a] quinoline-4-carboxylate were obtained.

IR (KBr) cm ^-1 ; ν _{c = 0} 1735,1715 Reference Example 6 0.73 g of trimethylsulfoxonium iodide was suspended in 17 ml of dimethyl sulfoxide, and 0.5% of 60% sodium hydride was added.
After adding 13 g and stirring at room temperature for 40 minutes, 1-acetoxymethyl-7,9-difluoro-8- (1-diphenylmethoxycarbonylvinyl) -5-oxo-5H-thiozolo [3,2-a] quinoline- 4-carboxylic acid ethyl ester
Add 1.70 g and stir at the same temperature for 1 hour. 100 ml of ethyl acetate and 100 ml of water are added to the reaction solution, the pH is adjusted to 2 with 2N hydrochloric acid, and then the organic layer is separated. The separated organic layer is sequentially washed with water and saturated saline, and then 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 = 3: 1) to give 1-acetoxymethyl-7,9.
-Difluoro-8- (1-diphenylmethoxycarbonylcyclopropyl) -5-oxo-5H-thiazolo [3,2
-A] Quinoline-4-carboxylic acid ethyl ester 1.14 g
(65.6% yield).

IR (KBr) cm ^-1 ; ν _{c = 0} 1740,1720 Reference Example 7 1-acetoxymethyl-7,9-difluoro-8- (1
-Diphenylmethoxycarbonylcyclopropyl) -5
1.09 g of -oxo-5H-thiozolo [3,2-a] quinoline-4-carboxylic acid ethyl ester was suspended in 10 ml of anisole, 10 ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and diethyl ether was added to the obtained residue to collect crystals, whereby 1-acetoxymethyl-8- (1-carboxycyclopropyl) -7,
9-difluoro-5-oxo-5H-thiazolo [3,2-a]
0.76 g of quinoline-4-carboxylic acid ethyl ester (yield 9
4.6%).

IR (KBr) cm ^-1 ; v _{c =} 1760,1735 Reference Example 8 1-acetoxymethyl-8- (1-carboxycyclopropyl) -7,9-difluoro-5-oxo-5H-thiozolo [3,2 -A] 400 mg of ethyl quinoline-4-carboxylate suspended in 5 ml of acetone, triethylamine
Add 105 mg. Then, the reaction solution is cooled to -20 ° C, 115 mg of ethyl chlorocarbonate is added, and the mixture is stirred at -20 to -10 ° C for 30 minutes. Then, 0.3 ml of an aqueous solution containing 73 mg of sodium azide is added at -20 ° C, and the mixture is stirred for 30 minutes under ice cooling. 20 ml of ethyl acetate and 20 ml of water are added to the reaction solution, the pH is adjusted to 2 with 2N hydrochloric acid, and the organic layer is separated. The separated organic layer is sequentially washed with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and 5 ml of dioxane and 190 mg of benzyl alcohol were added to the obtained residue, followed by refluxing for 1 hour. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (eluent; toluene: ethyl acetate 1: 1) to give 1-acetoxymethyl-8- (1-benzyloxycarbonylaminocyclohexane). Propyl) -7,9-difluoro-5-oxo-5H-thiazolo [3,2-a] quinoline-4-carboxylic acid ethyl ester (340 mg, yield 69.3%) was obtained.

IR (KBr) cm ^-1 ; v _{c =} 1745,1720 Reference Example 9 1-acetoxymethyl-8- (1-carboxycyclopropyl) -7,9-difluoro-5-oxo-5H-thiazolo [3,2 -A] React 280 mg of quinoline-4-carboxylic acid ethyl ester over a direct burner for about 30 seconds to complete decarboxylation. The obtained residue was purified by column chromatography (eluent; toluene: ethyl acetate = 3: 1) to give 1-acetoxymethyl-8-cyclopropyl-7,
9-difluoro-5-oxo-5H-thiazolo [3,2-a]
Quinoline-4-carboxylic acid ethyl ester 95 mg (yield 3
7.5%).

IR (KBr) cm ^-1 ; v _{c = 0} 1745 Example 1 1-acetoxymethyl-8- (1-benzyloxycarbonylaminocyclopropyl) -7,9-difluoro-
5-oxo-5H-thiazolo [3,2-a] quinoline-4-
330 mg of carboxylic acid ethyl ester is suspended in 10 ml of ethanol, 90 mg of sodium ethoxide is added under ice cooling, and the mixture is stirred at room temperature for 1 hour. 100 ml of chloroform and 100 ml of water are added to the reaction solution, the pH is adjusted to 2 with 2N hydrochloric acid, and the organic layer is separated. The separated organic layer is sequentially washed with water and saturated saline, and then 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 to give 8- (1-benzyloxycarbonylaminocyclopropyl) -9,1-epoxy.
Methano-7-fluoro-5-oxo-5H-thiazolo [3,
2-a] quinoline-4-carboxylic acid ethyl ester 250 mg
(85.0% yield).

IR (KBr) cm ^-1 ; v _{c = 0} 1720 Example 2 1-acetoxymethyl-8-cyclopropyl-7,9-
85 mg of difluoro-5-oxo-5H-thiazolo [3,2-a] quinoline-4-carboxylic acid ethyl ester was suspended in 2 ml of ethanol, and 34 mg of sodium ethoxide was added under ice-cooling.
And stirred at room temperature for 1 hour. If the precipitated crystal is removed, 8-cyclopropyl-9,1-epoxy: methano-7
-Fluoro-5-oxo-5H-thiazolo [3,2-a] quinoline-4-carboxylic acid ethyl ester 65 mg (89.7 yield)
%).

IR (KBr) cm ^-1 ; v _{c = 0} 1710 Example 3 To a 30% hydrogen bromide-acetic acid solution (2 ml) was added 8- (1-
Benzyloxycarbonylaminocyclopropyl) -9,
1-epoxy: methano-7-fluoro-5-oxo-5H
200 mg of -thiazolo [3,2-a] quinoline-4-carboxylic acid ethyl ester is added, and the mixture is stirred at room temperature for 2 hours. The reaction solution is concentrated under reduced pressure, chloroform is added to the obtained residue, and the crystals are collected to give 8- (1-aminocyclopropyl) -9,1-epoxy: methano-7-fluoro-5-.
175 mg of the hydrobromide of oxo-5H-thiazolo [3,2-a] quinoline-4-carboxylic acid ethyl ester (yield 97.7%)
%).

IR (KBr) cm ^-1 ; v _{c = 0} 1670 Example 4 8- (1-Aminocyclopropyl) -9,1-epoxy: methano-7-fluoro-5-oxo-5H-thiazolo [3,2-] a] 100 mg of hydrobromide of quinoline-4-carboxylic acid ethyl ester in 1 ml of ethanol and dioxane
Suspended in a mixture of 1 ml, 1 ml of 1N sodium hydroxide aqueous solution
And stirred at 40 ° C. for 1.5 hours. The reaction solution was concentrated under reduced pressure, 2 ml of water was added to the obtained residue, and the mixture was adjusted to pH 7 with 2N hydrochloric acid, and the crystals were collected to give 8- (1-aminocyclopropyl) -9,1-epoxy. : Methano-7-fluoro-
5-oxo-5H-thiazolo [3,2-a] quinoline-4-
45 mg of carboxylic acid (59.2% yield) are obtained.

Melting point: 270 to 275 ° C (recrystallization solvent: chloroform-ethanol) IR (KBr) cm ^-1 ; v _{c =} 1680 NMR (d ₁ -TFA) δ value: 1.30 to 2.20 (4H, m), 5.97 (2H) , s), 7.70 to 8.30 (2H, m) Example 5 8-Cyclopropyl-9,1-epoxy: methano-7-
60 mg of fluoro-5-oxo-5H-thiazolo [3,2-a] quinoline-4-carboxylic acid ethyl ester was added to ethanol
It is suspended in a mixture of 5 ml and 5 ml of dioxane, 1 ml of a 1N aqueous sodium hydroxide solution is added, and the mixture is stirred at 40 ° C. for 1.5 hours.
The reaction solution is concentrated under reduced pressure, 5 ml of water and 50 ml of chloroform are added to the obtained residue, the pH is adjusted to 2 with 2N hydrochloric acid, and the organic layer is separated. The separated organic layer is sequentially washed with water and saturated saline, and then 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 to give 8-cyclopropyl-9,1-epoxy: methano-7-fluoro-5-.
50 mg (90.4% yield) of oxo-5H-thiazolo [3,2-a] quinoline-4-carboxylic acid are obtained.

Melting point: 265 to 268 ° C (recrystallization solvent; chloroform-ethanol) IR (KBr) cm ^-1 ; v _{c =} 1680 NMR (d ₁ -TFA) δ value: 0.80 to 1.80 (4H, m), 1.90 to 2.70 (1H, m), 5.72 (2H, s), 7.50-8.10 (2H, m)

──────────────────────────────────────────────────続 き Continuation of the front page (56) References JP-A-1-117888 (JP, A) JP-A-57-136588 (JP, A) JP-A-62-175485 (JP, A) (58) Field (Int. Cl. ⁶ , DB name) C07D 513 / 06,513 / 16 C07D 498 / 06,498 / 16 CA (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] (1) General formula Wherein R ¹ is a hydrogen atom or a carboxyl protecting group;
² represents a hydrogen atom, a halogen atom, an alkoxy group, an optionally protected hydroxyl group, an optionally protected amino group, an optionally protected lower alkylamino group or a di-lower alkylamino group; ³ is a hydrogen atom,
Lower alkyl group, optionally protected amino group, optionally protected lower alkylamino group, di-lower alkylamino group, optionally protected carboxyl group,
An optionally protected amino lower alkyl group, an optionally protected lower alkylamino lower alkyl group, di-
One or more groups selected from a lower alkylamino lower alkyl group and an optionally protected hydroxy lower alkyl group; A represents an imino group optionally substituted with an oxygen atom, a sulfur atom or a lower alkyl group; And X represent a halogen atom. The pyridonecarboxylic acid derivative represented by these, and its salt.