JPH07196657A - 1,4-dihydro-4-oxonaphthyridine derivative or its salt - Google Patents

Abstract

PURPOSE:To obtain 1,4-dihydro-4-oxonaphthyridine derivative of a specific formula useful as a naphthyridine-based synthetic antibacterial agent showing a strongly antibacterial action on gram-positive and gram negative bacteria, especially on antibiotic-resistant bacterium. CONSTITUTION:The compound of containing I [R<1> is H or a carboxylprotecting group; R<2> is a halogen or a (substituted) cyclic amino; R<3> is a (substituted) aryl; A is a lower alkylene] such as 2-(2,6-dichloro-5-fluoronicotinoyl)-3-(3- fluorobenzylamino)acrylic acid ethyl ester, etc. The compound is preferably obtained by reacting a compound of formula II with ethyl orthoformate in acetic anhydride, and then with an amine to give a compound of formula III, subjecting the compound of formula III to ring closure reaction and reacting the prepared compound of formula IV with a cyclic amine in the presence of an inert solvent such as benzene.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention has the general formula

[Chemical 2] "In the formula, R ¹ is a hydrogen atom or a carboxyl protecting group; R ² is a halogen atom or an optionally substituted cyclic amino group; R ³ is a substituted aryl group;
Represents a lower alkylene group. , 1,4
It relates to a dihydro-4-oxonaphthyridine derivative or a salt thereof.

[0002]

2. Description of the Related Art Conventionally, nalidixic acid has been widely used as a naphthyridine-based synthetic antibacterial agent, but its antibacterial spectrum and absorption are still insufficient. In particular, Pseudomonas aeruginosa, which is a gram-positive bacterial infection or intractable disease, The effect on the treatment of infectious diseases was not satisfactory.

[0003]

A naphthyridine-based synthetic antibacterial agent showing a strong antibacterial action against Gram-positive bacteria and Gram-negative bacteria, especially against antibiotic-resistant bacteria and having high safety has been demanded.

[0004]

Under these circumstances, the inventors of the present invention have conducted diligent research and as a result, found that a 1,4-dihydro-4-oxonaphthyridine derivative represented by the general formula [1] or a salt thereof was obtained. The inventors have found that the above objects can be achieved and completed the present invention. In the present specification, unless otherwise specified, the halogen atom means, for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. And, even when a term such as halogen is included in various terms, it has the above-described meaning unless otherwise specified. Hereinafter, the compound of the present invention will be described.

The compound of the present invention is represented by the following general formula [1].

[Chemical 3]"In the formula, R¹, R², R³And A have the same meanings as above.
Have. Odor of the compound of the general formula [1] or a salt thereof
And R¹Examples of the carboxyl protecting group of
Treated by catalytic reduction, chemical reduction or other mild conditions
Ester-forming group that is eliminated by
An ester-forming group that is easily eliminated at
It can be easily desorbed by treating it with alcohol.
Such as silyl group, organophosphorus group or organotin group
Other various known ester-forming groups are mentioned. these
Among the carboxyl protecting groups of, suitable protecting groups include
For example, the method described in JP-A-59-80665
Examples include boxyl protecting groups. R²Is a halogen atom
Or a cyclic amino group which may be substituted,
Examples of the gen atom include a fluorine atom, a chlorine atom,
A bromine atom, and examples of the cyclic amino group include the ring
In addition to one or more nitrogen atoms as foreign atoms forming
A 5-membered member which may further contain one or more oxygen atoms
Or a 6-membered cyclic amino group, for example 1-pyrrolidini
Le, piperidino, 1-piperazinyl, morpholino, etc.
Can be mentioned. The cyclic amino group described above is an alkyl group,
For example, methyl, ethyl, n-propyl, isopropyl,
n-butyl, isobutyl, sec-butyl, tert-butyl, etc.
C_1-4Alkyl group; amino group; aminoalkyl group
For example, aminomethyl, 2-aminoethyl, 3-amino
Amino C such as propyl_1-4Alkyl group; hydroxya
Alkyl group, for example hydroxymethyl, 2-hydroxy
Hydroxy- such as cyethyl and 3-hydroxypropyl
C_1-4Alkyl group; hydroxyl group; alkenyl group;
For example, C such as vinyl and allyl_2-4Alkenyl group;
Silyl groups such as formyl, acetyl, propioni
C such as le, butyryl_{1- Four}Acyl group; trifluoroacetate
A tyl group; an alkylamino group such as methylamino,
Ethylamino, n-propylamino, isopropylamino
Such as C_1-4Alkylamino group; dialkylamino group,
For example, dimethylamino, diethylamino, di-n-propyl
Di-C such as ropylamino and methylethylamino_1-4A
Alkylamino group; cyano group; oxo group; aralkyl group
Mino groups such as benzylamino, phenethylami
Al-C such as no, tritylamino_1-4Alkylamino
Groups; acylamino groups such as formylamino, acetamin
Tylamino, propionylamino, butyrylamino, te
C such as rt-butoxycarbonylamino_1-4Acylamino
Group; alkoxycarbonyl group, for example, methoxycarl
Bonyl, ethoxycarbonyl, n-propoxycarbonyl
, Isopropoxycarbonyl, tert-butoxycarbo
C such as nil_1-4Alkoxycarbonyl group; N-acyl
An -N-alkylamino group, such as
The nitrogen atom of the kylamino group is an acyl group, such as acetyl
C such as le, propionyl, butyryl_1-4Set with an acyl group
Is it a substituted N-acyl-N-alkylamino group or the like?
It may be substituted with one or more substituents selected from

R ³ represents a substituted aryl group,
Examples of the aryl group include phenyl and naphthyl. These aryl groups are halogen atoms; alkyl groups, for example, C _1-10 such as methyl, ethyl, isopropyl, tert-butyl, pentyl and octyl.
An alkyl group; an optionally protected hydroxyl group; an alkoxy group, for example, a C _1-10 alkoxy group such as methoxy, ethoxy, isopropoxy, tert-butoxy, pentyloxy, octyloxy; a cyano group, an amino group,
Acyl groups, for example, C _1-4 acyl groups such as formyl, acetyl, propionyl, butyryl; aralkyl groups,
For example, it is substituted with one or more substituents selected from benzyl, phenethyl and the like.

Examples of the lower alkylene for A include C _1-4 alkylene groups such as methylene, ethylene and propylene. Examples of the salt of the compound of the general formula [1] include salts of commonly known basic groups such as amino groups or acidic groups such as hydroxyl groups or carboxyl groups. Examples of the salt in the basic group include salts with mineral acids such as hydrochloric acid and sulfuric acid; salts with organic carboxylic acids such as formic acid, trichloroacetic acid and trifluoroacetic acid; methanesulfonic acid, p-toluenesulfonic acid, naphthalenesulfone. A salt with a sulfonic acid such as an acid,
Examples of the salt in the acidic group include salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; procaine, dibenzylamine, N-benzyl-β.
-Nitrogen-containing organics such as phenethylamine, 1-ephenamine, N, N-dibenzylethylenediamine, trimethylamine, triethylamine, tributylamine, pyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine Mention may be made of salts with bases. Also,
When the compound of the general formula [1] or a salt thereof has isomers (for example, optical isomers, geometric isomers, tautomers, etc.), the present invention includes all isomers thereof, and It extends to all crystalline forms and hydrates. Next, a method for producing the compound of the present invention is described.

As a method for producing the compound of the present invention, a method known per se can be mentioned, but a typical production method will be described in detail below. The compound of the present invention can be produced, for example, according to the following production route.

[Chemical 4]

[In the formula, R ^1a represents a carboxyl protecting group similar to R ¹ ; R ^2a represents a halogen atom similar to R ² ;
^2b is an ^optionally substituted cyclic amino group similar to R ^2, and R ¹ , R ³ and A have the same meanings as described above. "

As the salts of the compounds of the general formulas [1a], [1b] and [3], the same salts as those mentioned as the salts of the compounds of the general formula [1] can be mentioned. (1) The compound of the general formula [3] or a salt thereof is disclosed in
7-72981, JP-A-58-74638 and JP-A-58-74667, the compound of the general formula [2] is added to ethyl orthoformate or orthoformate in acetic anhydride. It is obtained by reacting methyl and then reacting an amine represented by the general formula: R ³ —A—NH ₂ [4] “wherein R ³ and A have the same meanings as described above”. . The solvent used in this reaction is not particularly limited as long as it is an inert solvent in the reaction, for example,
Aromatic hydrocarbons such as benzene, toluene, xylene; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol dimethyl ether, dimethyl cellosolve; alcohols such as methanol, ethanol, propanol; halogenated carbonization such as methylene chloride, chloroform, dichloroethane Hydrogens;
Examples thereof include amides such as N, N-dimethylformamide and N, N-dimethylacetamide; sulfoxides such as dimethylsulfoxide, and the like, and two or more kinds of these solvents may be mixed and used. The amount of ethyl orthoformate or methyl orthoformate used is preferably equimolar or more, especially about 1 to 10 times the molar amount of the compound of the general formula [2].
This reaction is usually carried out at 0 to 150 ° C., preferably 50 to 150 ° C., and the reaction time is usually 20 minutes to 50 hours, preferably 1 to
3 hours. Then, in order to react the amines of the general formula [4], the amines are used in an equimolar amount or an equimolar amount or more with respect to the compound of the general formula [2], and usually 0 to 100 ° C.
Preferably, the reaction is carried out at 10 to 60 ° C. for usually 20 minutes to 30 hours, preferably 1 to 5 hours. Alternatively, after reacting the compound of the general formula [2] with an acetal such as N, N-dimethylformamide dimethyl acetal or N, N-dimethylformamide diethyl acetal,
The compound of the general formula [4] can be reacted to lead to the compound of the general formula [3] or a salt thereof. The solvent used in this reaction is not particularly limited as long as it is a solvent inert to the reaction, and specific examples thereof include the same solvents as described above. The amount of acetal used is preferably equimolar or more, particularly about 1.0 to 1.3 times the molar amount of the compound of the general formula [2]. This reaction is generally 0-100 ° C, preferably 50
The reaction time is usually 20 minutes to 50 hours, preferably 1 to 3 hours. Then, in order to react the amines of the general formula [4], the amines are used in an equimolar amount or an equimolar amount or more with respect to the compound of the general formula [2], and usually 0 to 100 ° C., preferably 10 to The reaction is carried out at 60 ° C. for usually 20 minutes to 30 hours, preferably 1 to 5 hours. (2) The compound of the general formula [1a] or a salt thereof can be obtained by subjecting the compound of the general formula [3] or a salt thereof to a ring closure reaction (preferably under heating) in the presence or absence of a base. . The solvent used in this reaction is not particularly limited as long as it is an inert solvent for the reaction, but for example, amides such as N, N-dimethylformamide, N, N-dimethylacetamide; dioxane, anisole, diethylene glycol dimethyl ether. , Ethers such as dimethyl cellosolve; sulfoxides such as dimethyl sulfoxide, and the like.
You may use it in mixture of 2 or more types. Examples of the base include sodium hydrogen carbonate, potassium carbonate, potassium te
rt-butoxide, sodium hydride and the like can be mentioned, and the amount thereof is preferably 0.5 to 5 times mol relative to the compound of the general formula [3] or a salt thereof, and this reaction is usually 20 to 160 times.
C., preferably 80 to 150.degree. C., and the reaction time is generally 5 minutes to 30 hours, preferably 5 minutes to 5 hours. (3) The compound of the general formula [1b] or a salt thereof is the same as the compound of the general formula [1a] or a salt thereof in the general formula R ^2b —H [5] “wherein R ^2b is the same substituent as R ^2. It represents a cyclic amino group which may be formed by a reaction with a cyclic amine or a salt thereof. The solvent used in this reaction is not particularly limited as long as it is a solvent inert to the reaction, for example, benzene, toluene,
Aromatic hydrocarbons such as xylene; alcohols such as methanol, ethanol, propanol; dioxane,
Ethers such as tetrahydrofuran, anisole, diethylene glycol diethyl ether; methylene chloride,
Halogenated hydrocarbons such as chloroform and dichloroethane; amides such as N, N-dimethylformamide and N, N-dimethylacetamide, sulfoxides such as dimethylsulfoxide, and the like.
You may use it in mixture of 2 or more types. The cyclic amine of the general formula [5] or a salt thereof is used in an excess amount, particularly preferably 2 to 5 times by mole, based on the compound of the general formula [1a] or a salt thereof, and the amount of the cyclic amine to be used is about 1 to 1. If the mole is 1.3 times,
An equimolar amount of the deoxidizing agent may be used with respect to the compound of the general formula [1a] or a salt thereof. Examples of the deoxidizing agent include organic or inorganic bases such as triethylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), potassium tert-butoxide, potassium carbonate, sodium carbonate, sodium hydride and the like. Can be mentioned. This reaction is generally performed at 0 to 150 ° C., preferably 20 to 100 ° C., and the reaction time is generally 5 minutes to 30 hours, preferably 30 minutes to 10 hours. In the compound of the general formula [1a], [1b] or [3] or a salt thereof, the carboxyl protecting group of R ¹ is usually 0 in the presence of a usual acid or alkali used in the hydrolysis reaction. The corresponding carboxyl group can be obtained by hydrolysis at ˜110 ° C., preferably 20 to 110 ° C. for 5 minutes to 50 hours, preferably 5 minutes to 5 hours. Furthermore, general formulas [1a] and [1
If desired, the compound of b] or [3] or a salt thereof can be subjected to a salt formation reaction or an esterification reaction known per se to give a salt or ester of the corresponding compound. The general formulas [1a] and [1b]
Alternatively, when the compound of [3] or a salt thereof has an active group (for example, a hydroxyl group) at a site other than the reaction site, the active group is protected in advance by a conventional method, and after the reaction is completed, the protecting group is protected. It may be detached. The compound obtained as described above may be subjected to usual isolation and purification operations such as column chromatography, recrystallization and extraction. In the general formula [1], a compound in which R ² is a halogen atom (corresponding to the compound of the general formula [1a]) is
It is also useful as an intermediate for obtaining a compound in which R ² is an optionally substituted cyclic amino group. When the compound of the present invention is used as a medicine, a carrier usually used for formulation is appropriately used, and tablets, capsules,
It is prepared into powder, syrup, granule, suppository, ointment, injection and the like. In addition, the administration method, dose and frequency of administration can be appropriately selected according to the symptoms of the patient, and usually for adults, oral or parenteral (for example, injection administration,
0.1 to 100 by topical administration (infusion, administration to rectal site, etc.)
It may be administered by dividing mg / kg / day into 1 to several times.

Next, the antibacterial action of the representative compounds of the present invention will be shown. Antibacterial activity test method Japanese Society of Chemotherapy Standard Method [CHEMOTHERA
PY) Vol. 29, No. 1, pp. 76-79 (1981)]] Heart Infusion
Broth) (manufactured by Eiken Chemical Co., Ltd.) at 37 ° C for 20 hours
t Infusion agar) medium (Eiken Chemical Co., Ltd.)
After culturing at 20 ° C. for 20 hours, the presence or absence of bacterial growth was observed, and the minimum concentration at which bacterial growth was inhibited was defined as MIC (μg / ml). However, the inoculum is 10 ⁴ cells / plate (10 ⁶ cells / m
l). The results are shown in Table 1.

Test compound

[Chemical 5]

[0013]

[Table 1] Note) *: Penicillinase-producing bacterium **: Cephalosporinase-producing bacterium

[0014]

EXAMPLES Next, the present invention will be described with reference to Reference Examples and Examples. The symbols used in Reference Examples and Examples have the following meanings. Me; methyl group, Et; ethyl group

Reference Example 1 2,6-Dichloro-5-fluoronicotinic acid (150 g) is dissolved in chloroform (450 ml), thionyl chloride (127 g) and N, N-dimethylformamide (1.5 g) are added, and the mixture is heated and refluxed for 4 hours. After completion of the reaction, the solvent is distilled off under reduced pressure. Dissolve 120 g of diethyl malonate in 1.05 l of toluene, add 90 g of magnesium ethoxide, and heat under reflux to
After reacting for a time, after the reaction is completed, it is cooled to -12 to -10 ° C.
The 2,6-dichloro-5-fluoronicotinic acid chloride prepared previously was added dropwise to this solution at -12 to -10 ° C over 30 minutes, and the mixture was reacted at the same temperature for 30 minutes, then gradually warmed to room temperature. The temperature is raised and the reaction is carried out for 1 hour. After the reaction is completed, 1.5 l of water is added, the pH is adjusted to 0.5 with concentrated hydrochloric acid, and the organic layer is separated. The aqueous layer is extracted with 75 ml of toluene, the obtained organic layer is combined with the previous organic layer, washed with 200 ml of water, and the solvent is distilled off under reduced pressure.
377 ml of water and p-toluenesulfonic acid were added to the obtained residue.
1.11 g is added, and the mixture is reacted with heating under reflux for 5 hours with vigorous stirring. After completion of the reaction, add 300 ml of chloroform,
The organic layer is separated, washed successively with 100 ml of water and 100 ml of saturated saline and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was n-hexane (300 ml).
Was added, and the mixture was stirred under ice cooling for 1 hour, and then the precipitated crystals were collected by filtration to obtain 118 g of 2,6-dichloro-5-fluoronicotinoyl acetic acid ethyl ester (yield 60.0%). Melting point; 64-65 ° C IR (KBr) cm ^-1 ; ν _{c = o} 1650,1630,1620 NMR (CDCl ₃ ) δ value; 1.25 (1.29H, t, J = 7Hz), 1.33 (1.71H, t, J
= 7Hz), 4.07 (1.14H, s), 4.28 (2H, q, J = 7Hz), 5.82 (0.43H,
s), 7.80 (1H, d, J = 7Hz), 12.62 (0.43H, s)

Example 1 A mixture of 3.0 g of 2,6-dichloro-5-fluoronicotinoyl acetic acid ethyl ester, 4.37 g of acetic anhydride and 6.35 g of ethyl orthoformate is reacted under heating under reflux for 1 hour. After completion of the reaction, the solvent was distilled off under reduced pressure, the obtained residue was dissolved in 15 ml of ethanol, and m-fluorobenzylamine 1.38 was added.
Add g and react at room temperature for 1.5 hours. After completion of the reaction, the mixture was stirred for 30 minutes under ice cooling, and the precipitated crystals were collected by filtration to give 2-
(2,6-dichloro-5-fluoronicotinoyl) -3
4.10 g (yield 92.2%) of-(3-fluorobenzylamino) acrylic acid ethyl ester is obtained. Melting point; 137-138 ° C (resolving solvent; methanol) IR (KBr) cm ^-1 ; ν _{c = o} 1690 NMR (CDCl ₃ ) δ value; [0.88 (t, J = 7Hz), 1.05 (t, J = 7Hz)] 3H,
[4.00 (q, J = 7Hz), 4.03 (q, J = 7Hz)] 2H, 4.68 (2H, d, J = 7H
z), 6.80 ~ 7.60 (5H, m), 8.05 ~ 8.55 (1H, m), 10.90 ~ 11.70
(1H, m) Similarly, the compounds shown in Table 2 are obtained.

[0017]

[Table 2]

The physical properties of the compounds shown in Table 2 are shown below. 1. Melting point: 149 to 149.5 ° C (resolving solvent: ethanol) IR (KBr) cm ^-1 ; ν _{c = o} 1675 2. Melting point: 136 to 137 ° C (resolving solvent: methanol) IR (KBr) cm ^-1 ; ν _{c = o} 1685 3. Melting point; Oily substance IR (neat) cm ^-1 ; ν _{c = o} 1680

Example 2 2- (2,6-dichloro-5-fluoronicotinoyl)
3.95 g of 3- (3-fluorobenzylamino) acrylic acid ethyl ester was added to 20 ml of N, N-dimethylformamide.
, 960 mg of sodium hydrogen carbonate is added, and the mixture is reacted at 120 ° C for 2 hours. After completion of the reaction, 80 ml of water was added, the mixture was stirred at room temperature for 1 hour, and the precipitated crystals were collected by filtration to give 7-chloro-6-fluoro-1- (3-fluorobenzyl) -1,
4-dihydro-4-oxo-1,8-naphthyridine-3
-3.38 g (yield 93.8 g) of carboxylic acid ethyl ester are obtained. Melting point: 211-212 ° C (resolving solvent: ethyl acetate) IR (KBr) cm ^-1 ; ν _{c = o} 1695 NMR (CDCl ₃ ) δ value; 1.38 (3H, t, J = 7Hz), 4.37 (2H, q, J = 7Hz),
5.52 (2H, s), 6.63-7.55 (4H, m), 8.40 (1H, d, J = 7.5Hz), 8.6
5 (1H, s) Similarly, the compounds shown in Table 3 are obtained.

[0020]

[Table 3]

The physical properties of the compounds shown in Table 3 are shown below. 1. Melting point; 190.5 to 192 ° C (resolving solvent; isopropanol-N, N-dimethylformamide) IR (KBr) cm ^-1 ; ν _{c = o} 1670 2. Melting point; 194 to 194.5 ° C (resolving solvent; methanol) IR (KBr) cm ^-1 ; ν _{c = o} 1730,1695 3. Melting point; 240-244 ℃ (resolving solvent; methanol) IR (KBr) cm ^-1 ; ν _{c = o} 1730,1690

Example 3 250 mg of 3-aminopyrrolidine dihydrochloride and 530 mg of triethylamine were dissolved in 5 ml of ethanol to give 7-chloro-6-fluoro-1- (3-fluorobenzyl)-.
After adding 1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester (500 mg), chloroform (5 ml) was added to make a uniform solution, and the mixture was reacted at room temperature for 5 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, 2 ml of ethanol was added to the obtained residue, and 10 ml of water was further added.
After stirring at room temperature for 30 minutes, the precipitated crystals are filtered to give 7-
(3-Amino-1-pyrrolidinyl) -6-fluoro-1
-(3-Fluorobenzyl) -1,4-dihydro-4-
470 mg (yield 83.1%) of oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester is obtained. Melting point; 218 to 225 ° C (decomposition) (resolving solvent; methanol) IR (KBr) cm ^-1 ; ν _{c = o} 1700 NMR (DMSO-d ₆ ) δ value; 1.28 (3H, t, J = 7Hz), 1.95 ~ 2.15 (2H,
m), 3.35 ~ 4.65 (9H, m), 5.52 (2H, s), 6.90 ~ 7.90 (5H, m), 8.
80 (1H, s) Similarly, the compounds shown in Table 4 are obtained.

[0023]

[Table 4]

The physical properties of the compounds shown in Table 4 are shown below. 1. Melting point; 218-225 ° C (resolving solvent; ethyl acetate) IR (KBr) cm ^-1 ; ν _{c = o} 1700 2. Melting point; 254-255.5 ° C (decomposition) (resolving solvent: chloroform-isopropanol) IR (KBr) cm ^-1 ; ν _{c = o} 1710 3. Melting point; 134.5-135.5 ° C (resolving solvent; ethyl acetate) IR (KBr) cm ^-1 ; ν _{c = o} 1715,1685 4. Melting point; 240-245 ℃ (resolving solvent; methanol) IR (KBr) cm ^-1 ; ν _{c = o} 1715,1690 5. Melting point; 160-162 ℃ (resolving solvent; isopropanol-isopropyl ether) IR (KBr) cm ^-1 ; ν _{c = o} 1735 6. Melting point; 230 to 241 ° C (resolving solvent; chloroform-ethanol) IR (KBr) cm ^-1 ; ν _{c = o} 1715

Example 4 (1) 7- (3-Amino-1-pyrrolidinyl) -6-fluoro-1- (3-fluorobenzyl) -1,4-dihydro-4-oxo-1,8-naphthyridine- 300 mg of 3-carboxylic acid ethyl ester was suspended in 3 ml of 6N hydrochloric acid,
The mixture is reacted under heating under reflux for 9 hours. After completion of the reaction, the precipitated crystals were collected by filtration to give 7- (3-amino-1-pyrrolidinyl)-
6-fluoro-1- (3-fluorobenzyl) -1,4
-Dihydro-4-oxo-1,8-naphthyridine-3-
220 mg (yield 71.9%) of carboxylic acid hydrochloride is obtained. Melting point: 203-204 ° C (resolving solvent: 2N hydrochloric acid) IR (KBr) cm ^-1 ; ν _{c = o} 1720 NMR (TFA-d ₁ ) δ value; 2.28-3.08 (2H, m), 3.65-5.00 ( 5H,
m), 5.93 (2H, s), 6.75-7.85 (4H, m), 8.12 (1H, d, J = 11Hz),
9.18 (1H, s) Similarly, the compounds shown in Table 5 were obtained.

[0026]

[Table 5]

The physical properties of the compounds shown in Table 5 are shown below. 1. mp;> 280 ° C. (recrystallization solvent; 6N hydrochloric ^{acid) IR (KBr) cm -1;} ν c = o 1720 2. mp; 205 to 209 ° C. (recrystallization solvent; 2N hydrochloric acid) IR (KBr) cm ^{- 1} ; ν _{c = o} 1715 3. Melting point; 275-277 ° C (decomposition) (resolving solvent; 6N hydrochloric acid-ethanol) IR (KBr) cm ^-1 ; ν _{c = o} 1720 4. Melting point; 250-257 ° C ( Resolving solvent; 2N hydrochloric acid) IR (KBr) cm ^-1 ; ν _{c = o} 1710 5. Melting point; 257-263 ° C (resolving solvent; 2N hydrochloric acid) IR (KBr) cm ^-1 ; ν _{c = o} 1715

(2) 7- (3-amino-1-pyrrolidinyl) -1- (2,4-dimethoxybenzyl) -6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3 200 mg of carboxylic acid ethyl ester is dissolved in a mixed solvent of 2 ml of 1N sodium hydroxide aqueous solution and 4 ml of ethanol and reacted at room temperature for 2 hours. After completion of the reaction, the reaction solution was concentrated, 10 ml of water was added, the pH was adjusted to 7 with 1N hydrochloric acid, and the precipitated crystals were collected by filtration to give 7- (3-amino-1
-Pyrrolidinyl) -1- (2,4-dimethoxybenzyl) -6-fluoro-1,4-dihydro-4-oxo-
120 mg of 1,8-naphthyridine-3-carboxylic acid (yield 63.
8%). Melting point: 210-212 ° C (resolving solvent: dimethylsulfoxide) IR (KBr) cm ^-1 ; ν _{c = o} 1710

[0029]

INDUSTRIAL APPLICABILITY The 1,4-dihydro-4-oxonaphthyridine derivative of the present invention or a salt thereof exhibits a strong antibacterial action against Gram-positive bacteria and Gram-negative bacteria, especially antibiotic-resistant bacteria, and is synthesized by naphthyridine synthesis. It is a compound useful as an antibacterial agent.

 ─────────────────────────────────────────────────── --- Continuation of the front page (72) Inventor Fumihiko Iino 9-1 Matsuwaka-cho, Toyama City, Toyama Prefecture (72) Inventor Junko Kobayashi 5242-6 Gofu, Toyama City, Toyama Prefecture (72) Inventor Isamu Saikawa Toyama City, Toyama Prefecture 7-52 Oizumi Nakamachi

Claims (1)

[Claims] Claims: "In the formula, R ¹ is a hydrogen atom or a carboxyl protecting group; R ² is a halogen atom or an optionally substituted cyclic amino group; R ³ is a substituted aryl group;
Represents a lower alkylene group. , 1,4
A dihydro-4-oxonaphthyridine derivative or a salt thereof.