JP2630566B2 - 1,4-dihydro-4-oxonaphthyridine derivative or salt thereof - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a compound of the general formula

Embedded image Wherein R ¹ represents a hydrogen atom or a carboxyl protecting group; R ² represents a halogen atom or an optionally substituted cyclic amino group; R ³ represents a halogen atom or an alkoxy group.
A phenyl group substituted with shea group; A represents a lower alkylene group. 1,4-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 synthetic antibacterial agent, but its antibacterial spectrum and absorption are still insufficient. The effect on the treatment of infections was not satisfactory.

[0003]

There is a need for a naphthyridine-based synthetic antibacterial agent which exhibits a strong antibacterial action against Gram-positive bacteria and Gram-negative bacteria, especially antibiotic-resistant bacteria, and is highly safe.

[0004]

Under such circumstances, the present inventors have conducted intensive studies and as a result, have found that the 1,4-dihydro-4-oxonaphthyridine derivative represented by the general formula [1] or a salt thereof has been obtained. The inventors have found that the above objects have been achieved, and have completed the present invention. In the present specification, unless otherwise specified, a halogen atom means, for example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like. And, when various terms include, for example, a term such as halogen, the meaning is as described above 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].

Embedded image"Where R¹, R^Two, R^ThreeAnd A are as defined above
Having. The compound of general formula [1] or a salt thereof
And R¹Examples of carboxyl protecting groups include
Processed by catalytic reduction, chemical reduction or other mild conditions
Ester forming groups that are eliminated by
An ester-forming group that readily leaves at
Or easily desorbed by treatment with alcohol
Organic silyl groups, organic phosphorus groups or organic tin groups
Various other known ester-forming groups are included. these
Among the carboxyl protecting groups of the preferred protective groups include
For example, a card described in JP-A-59-80665 is disclosed.
Boxyl protecting groups. R^TwoIs a halogen atom or
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 a cyclic amino group,
Other than one or more nitrogen atoms as hetero atoms forming
And 5 members which may further contain one or more oxygen atoms
Or a 6-membered cyclic amino group such as 1-pyrrolidinyl
, Piperidino, 1-piperazinyl, morpholino, etc.
No. The above-mentioned cyclic amino group 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 such as hydroxymethyl, 2-hydroxy
Hydroxy- such as silethyl, 3-hydroxypropyl
C_1-4Alkyl group; hydroxyl group; alkenyl group;
For example, C such as vinyl and allyl_2-4Alkenyl group;
Sil groups such as formyl, acetyl, propioni
C such as 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 propylamino and methylethylamino_1-4A
Alkylamino group; cyano group; oxo group;
Amino groups such as benzylamino, phenethylami
Al-C, such as rho and tritylamino_1-4Alkylamino
An acylamino group such as formylamino, ace
Tylamino, propionylamino, butyrylamino, te
C such as rt-butoxycarbonylamino_1-4Acylamino
A group; an alkoxycarbonyl group, for example, methoxycal
Bonyl, ethoxycarbonyl, n-propoxycarboni
, Isopropoxycarbonyl, tert-butoxycarbo
C such as nil_1-4Alkoxycarbonyl group; N-acyl
-N-alkylamino group, for example,
A nitrogen atom of a killamino group is an acyl group such as acetyl
, Propionyl, butyryl and other C_1-4Substitute with acyl group
Replaced N-acyl-N-alkylamino group, etc.
It may be substituted with one or more substituents selected from the group consisting of

[0006] as a substituent of the phenyl group in R ³
Examples of the alkoxy group include methoxy and ethoxy.
Si, propoxy, tert-butoxy, pentyloxy
And C _1-10 alkoxy groups such as octyloxy.
I can do it.

The lower alkylene in A includes, for example, C _1-4 alkylene groups such as methylene, ethylene and propylene. Examples of the salt of the compound represented by the general formula [1] include a commonly known salt in a basic group such as an amino group or an acidic group such as a hydroxyl group or a carboxyl group. 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, and naphthalenesulfonic acid. A salt with a sulfonic acid such as an acid,
Examples of the salt in the acidic group include salts with an alkali metal such as sodium and potassium; salts with an alkaline earth metal 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 The salt with a base can be mentioned. Also,
When isomers (for example, optical isomers, geometric isomers, tautomers, and the like) exist in the compound of the general formula [1] or a salt thereof, the present invention includes all such isomers, It covers all crystal forms and hydrates. Next, a method for producing the compound of the present invention will be described.

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

Embedded image

Wherein R ^1a has the same carboxyl protecting group as R ¹ ; R ^2a has the same halogen atom as R ² ;
^2b is a similar optionally substituted cyclic amino group and R ^2, R ^1, R ³ and A are each as defined above. "

The salts of the compounds of the general formulas [1a], [1b] and [3] include the same salts as the salts of the compounds of the general formula [1]. (1) The compound of the general formula [3] or a salt thereof is disclosed in
7-72981, JP-A-58-74638, JP-A-58-74667, and the like. The compound of the general formula [2] is added to ethyl orthoformate or orthoformate in acetic anhydride. After reacting with methyl, it is obtained by reacting an amine represented by the general formula R ³ -A-NH ₂ [4] wherein R ³ and A have the same meaning as described above. . The solvent used in this reaction is not particularly limited as long as it is a solvent inert to the reaction.
Aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol dimethyl ether and dimethyl cellosolve; alcohols such as methanol, ethanol and propanol; halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane Hydrogens;
Examples thereof include amides such as N, N-dimethylformamide and N, N-dimethylacetamide; sulfoxides such as dimethyl sulfoxide; and these solvents may be used as a mixture of two or more kinds. The amount of ethyl orthoformate or methyl orthoformate to be used is preferably at least equimolar, particularly preferably about 1 to 10 times, the molar amount of the compound of the formula [2].
This reaction is usually performed at 0 to 150 ° C., preferably 50 to 150 ° C., and the reaction time is generally 20 minutes to 50 hours, preferably 1 to 50 hours.
3 hours. Then, in order to react the amines of the general formula [4], the amines are used in an equimolar amount or in an equimolar amount or more with respect to the compound of the general formula [2].
The reaction is preferably performed at 10 to 60 ° C., usually for 20 minutes to 30 hours, preferably for 1 to 5 hours. Alternatively, the compound of the general formula [2] is reacted with an acetal such as N, N-dimethylformamide dimethyl acetal or N, N-dimethylformamide diethyl acetal.
The amine of the general formula [4] can be reacted to give a 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 the acetal used is preferably at least equimolar to the compound of the general formula [2], particularly preferably about 1.0 to 1.3 moles. The reaction is usually carried out at 0 to 100 ° C., preferably at 50
The reaction is carried out at a temperature of usually from 20 minutes to 50 hours, preferably from 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 in an equimolar amount or more with respect to the compound of the general formula [2]. 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 is 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 a solvent inert to the reaction. For example, amides such as N, N-dimethylformamide and N, N-dimethylacetamide; dioxane, anisole, diethylene glycol dimethyl ether And ethers such as dimethyl cellosolve; and sulfoxides such as dimethyl sulfoxide.
You may mix and use more than one kind. As the base, for example, sodium hydrogen carbonate, potassium carbonate, potassium te
rt-butoxide, sodium hydride, and the like, and the amount thereof is preferably 0.5 to 5 moles per mole of the compound of the general formula [3] or a salt thereof.
C., preferably at 80 to 150.degree. C., and the reaction time is usually 5 minutes to 30 hours, preferably 5 minutes to 5 hours. (3) The compound of the general formula [1b] or a salt thereof is obtained by adding a compound of the general formula [1a] or a salt thereof to the general formula R ^2b -H [5] wherein R ^2b is the same as R ² And a cyclic amino group represented by the formula: "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, and propanol; dioxane;
Ethers such as tetrahydrofuran, anisole and diethylene glycol diethyl ether; methylene chloride;
Halogenated hydrocarbons such as chloroform and dichloroethane; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; and sulfoxides such as dimethylsulfoxide.
You may mix and use more than one kind. The amount of the cyclic amines of the general formula [5] or a salt thereof to be used is preferably an excess amount, particularly preferably 2 to 5 times mol, of the compound of the general formula [1a] or a salt thereof. 1.3 moles,
The deoxidizing agent may be used in an equimolar amount 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, and sodium hydride. No. This reaction is usually 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 may be optionally 0 in the presence of a usual acid or alkali used in a hydrolysis reaction, if desired. Hydrolysis at で 110 ° C., preferably 20-110 ° C. for 5 minutes to 50 hours, preferably 5 minutes to 5 hours can lead to the corresponding carboxyl group. Further, the general formulas [1a] and [1]
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, if necessary, to lead to 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 position other than the reaction site, the active group is protected in advance by a conventional method, and after completion of the reaction, the protective group is removed. It may be detached. The compound obtained as described above may be subjected to ordinary 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])
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 preparation is appropriately used, and a tablet, a capsule,
It is prepared into powders, syrups, granules, suppositories, ointments, injections and the like. In addition, the administration method, dosage and number of administration can be appropriately selected according to the symptoms of the patient.
Drip, rectal site, etc.)
mg / kg / day may be administered once or several times.

Next, the antibacterial activity of the representative compounds of the present invention will be described. Antibacterial activity test method Japanese Society of Chemotherapy standard method [CHEMOTHERA
PY) Vol. 29, No. 1, pp. 76-79 (1981)]
broth) (manufactured by Eiken Chemical Co., Ltd.) at 37 ° C for 20 hours. The drug-containing Heart Infusion Agar (Hear
t Infusion agar) Medium (Eiken Chemical Co., Ltd.)
After culturing at 20 ° C. for 20 hours, 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. However, inoculum amount 10 ⁴ cells / plate ⁽¹⁰⁶ cells / m
l) Table 1 shows the results.

Test compound

Embedded image

[0013]

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

[0014]

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 1 150 g of 2,6-dichloro-5-fluoronicotinic acid was dissolved in 450 ml of chloroform, 127 g of thionyl chloride and 1.5 g of N, N-dimethylformamide were added, and the mixture was reacted under heating and reflux 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 add
The reaction is carried out for an hour, and after the reaction is completed, the mixture is cooled to -12 to -10C.
To this solution, 2,6-dichloro-5-fluoronicotinic acid chloride prepared above was added dropwise at −12 to −10 ° C. over 30 minutes, and allowed to react at the same temperature for 30 minutes, and then gradually brought to room temperature. Raise the temperature and react for 1 hour. After completion of the reaction, 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, and the obtained organic layer is combined with the previous organic layer, washed with 200 ml of water, and then 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 under heating and reflux for 5 hours while stirring vigorously. After completion of the reaction, 300 ml of chloroform was added,
The organic layer is separated, washed successively with 100 ml of water and 100 ml of saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was n-hexane 300 ml.
After stirring for 1 hour under ice cooling, the precipitated crystals are collected by filtration to obtain 118 g of ethyl 2,6-dichloro-5-fluoronicotinoyl acetic acid (60.0% yield). Melting point: 64 to 65 ° C IR (KBr) cm ^-1 ; v _{c = o} 1650, 1630, 1620 NMR (CDCl ₃ ) δ value: 1.25 (1.29 H, t, J = 7 Hz), 1.33 (1.71 H, t, J
= 7Hz), 4.07 (1.14H, s), 4.28 (2H, q, J = 7Hz), 5.82 (0.43H, s
s), 7.80 (1H, d, J = 7Hz), 12.62 (0.43H, s)

EXAMPLE 1 A mixture of 3.0 g of ethyl 2,6-dichloro-5-fluoronicotinoylacetate, 4.37 g of acetic anhydride and 6.35 g of ethyl orthoformate is reacted under heating and reflux for 1 hour. After completion of the reaction, the solvent was distilled off under reduced pressure, and the obtained residue was dissolved in ethanol (15 ml) to give m-fluorobenzylamine (1.38).
g and react at room temperature for 1.5 hours. After completion of the reaction, the mixture was stirred under ice-cooling for 30 minutes, and the precipitated crystals were collected by filtration to give 2-
(2,6-dichloro-5-fluoronicotinoyl) -3
4.10 g (92.2% yield) of-(3-fluorobenzylamino) acrylic acid ethyl ester are obtained. Melting point: 137 to 138 ° C (resolved solvent; methanol) IR (KBr) cm ^-1 ; ν _{c = o} 1690 NMR (CDCl ₃ ) δ value; [0.88 (t, J = 7 Hz), 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: 149-149.5 ° C. (reconstitution solvent; ethanol) IR (KBr) cm ⁻¹ ; v _{c = o} 1675 2. Melting point: 136-137 ° C. (reconstitution solvent: methanol) IR (KBr) cm ⁻¹ ; v _{c = o} 1685 3.Melting point; oil IR (nith) cm ^-1 ; ν _{c = o} 1680

Example 2 2- (2,6-dichloro-5-fluoronicotinoyl)
3.95 g of ethyl 3- (3-fluorobenzylamino) acrylate was added to 20 ml of N, N-dimethylformamide.
960 mg of sodium hydrogen carbonate, and the mixture is reacted at 120 ° C. for 2 hours. After completion of the reaction, 80 ml of water was added, and the mixture was stirred at room temperature for 1 hour. 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 of carboxylic acid ethyl ester (93.8 g yield) are obtained. Melting point: 211-212 ° C. (resolved solvent; ethyl acetate) IR (KBr) cm ⁻¹ ; v _{c = o} 1695 NMR (CDCl ₃ ) δ value: 1.38 (3H, t, J = 7 Hz), 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 (reconstituted solvent: isopropanol-N, N-dimethylformamide) IR (KBr) cm ^-1 ; vc _{= o} 1670 2. Melting point: 194 to 194.5 ° C (reconstituted solvent; Methanol) IR (KBr) cm ^-1 ; ν _{c = o} 1730,1695 3. Melting point; 240 to 244 ° C (reconstituted 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, and 7-chloro-6-fluoro-1- (3-fluorobenzyl)-
After 500 mg of 1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester is added, 5 ml of chloroform is added to make a homogeneous solution, and the mixture is reacted at room temperature for 5 hours. After completion of the reaction, 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 collected by filtration.
(3-amino-1-pyrrolidinyl) -6-fluoro-1
-(3-Fluorobenzyl) -1,4-dihydro-4-
470 mg (yield 83.1%) of ethyl oxo-1,8-naphthyridine-3-carboxylate was obtained. Melting point: 218 to 225 ° C (decomposition) (solvent: methanol) IR (KBr) cm ^-1 ; ν _{c = o} 1700 NMR (DMSO-d ₆ ) δ value: 1.28 (3H, t, J = 7 Hz), 1.95 to 2.15 (2H,
m), 3.35-4.65 (9H, m), 5.52 (2H, s), 6.90-7.90 (5H, m), 8.
80 (1H, s) In the same manner, 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 to 225 ° C (resolved solvent; ethyl acetate) IR (KBr) cm ^-1 ; v _{c = o} 1700 2. Melting point: 254 to 255.5 ° C (decomposed) (resolved solvent: chloroform-isopropanol) IR (KBr) cm ^-1 ; ν _{c = o} 1710 3. Melting point: 134.5 to 135.5 ° C (reconstitution solvent: ethyl acetate) IR (KBr) cm ^-1 ; ν _{c = o} 1715,1685 4. Melting point: 240 to 245 ° C (reconstituted solvent; methanol) IR (KBr) cm ^-1 ; ν _{c = o} 1715,1690 5. Melting point; 160-162 ° C (reconstituted solvent: isopropanol-isopropyl ether) IR (KBr) cm ^-1 ; ν _{c = o} 1735 6. Melting point: 230-241 ° C (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 reaction is performed for 9 hours under reflux. After completion of the reaction, the precipitated crystals are 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 (71.9% yield) of the hydrochloride of the carboxylic acid are obtained. Melting point: 203-204 ° C. (resolved solvent; 2N hydrochloric acid) IR (KBr) cm ⁻¹ ; v _{c = o} 1720 NMR (TFA-d ₁ ) δ value: 2.28 to 3.08 (2H, m), 3.65 to 5.00 ( 5H,
m), 5.93 (2H, s), 6.75-7.85 (4H, m), 8.12 (1H, d, J = 11Hz),
9.18 (1H, s) In the same manner, the compounds shown in Table 5 are obtained.

[0026]

[Table 5]

The physical properties of the compounds shown in Table 5 are shown below. 1. Melting point:> 280 ° C. (reconstituted solvent; 6N hydrochloric acid) IR (KBr) cm ⁻¹ ; v _{c = o} 1720 2. Melting point: 205-209 ° C. (reconstituted solvent: 2N hydrochloric acid) IR (KBr) cm ^{− 1} ; ν _{c = o} 1715 3. Melting point: 275-277 ° C (decomposition) (reconstituted solvent: 6N hydrochloric acid-ethanol) IR (KBr) cm ^-1 ; ν _{c = o} 1720 4. Melting point: 250-257 ° C ( Reconstituted solvent: 2N hydrochloric acid) IR (KBr) cm ^-1 ; ν _{c = o} 1710 5. Melting point: 257 to 263 ° C (Reconstituted 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 aqueous sodium hydroxide 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 (reconstitution solvent: dimethyl sulfoxide) IR (KBr) cm ^-1 ; v _{c = o} 1710

[0029]

Industrial Applicability The 1,4-dihydro-4-oxonaphthyridine derivative or a salt thereof according to the present invention exhibits a strong antibacterial activity against Gram-positive bacteria and Gram-negative bacteria, especially antibiotic-resistant bacteria, and exhibits naphthyridine-based synthesis. It is a compound useful as an antibacterial agent.

 ──────────────────────────────────────────────────続 き Continuation of the front page (72) Inventor Isamu Isakawa 7-52 Oizuminakacho, Toyama-shi, Toyama Examiner Koichi Seshita (56) References Japanese Patent Publication 7-17642 (JP, B2)

Claims (1)

(57) [Claims] [Claim 1] Wherein R ¹ represents a hydrogen atom or a carboxyl protecting group; R ² represents a halogen atom or an optionally substituted cyclic amino group; R ³ represents a halogen atom or an alkoxy group.
A phenyl group substituted with shea group; A represents a lower alkylene group. A 1,4-dihydro-4-oxonaphthyridine derivative or a salt thereof.