JPH0544949B2 - - Google Patents

Description

[Detailed description of the invention]

[Industrial Field of Application] The present invention is based on the general formula [In the formula, R ¹ represents a hydrogen atom or a carboxyl protecting group, R ² represents an optionally substituted heterocyclic group, and R ³ represents a halogen atom or an optionally substituted cyclic amino group. ] This relates to a 1,4-dihydro-4-oxonaphthyridine derivative represented by the following and a salt thereof. The purpose of the present invention is to exhibit a strong antibacterial effect against Gram-positive bacteria and Gram-negative bacteria, especially antibiotic-resistant bacteria, to obtain high blood concentrations when administered orally or parenterally, and to be safe. The object of the present invention is to provide a novel compound represented by the general formula [] which has excellent properties such as high viscosity and high viscosity. [Conventional technology] Conventionally, nalidixic acid has been widely used as a naphthyridine-based synthetic antibacterial agent, but its antibacterial spectrum and absorption are still insufficient, and it is particularly effective against Gram-positive bacterial infections and Pseudomonas aeruginosa, which is an intractable disease. The effect on the treatment of infectious diseases was not satisfactory. [Problems to be Solved by the Invention] It has been desired to develop a synthetic antibacterial agent having a broad antibacterial spectrum that is effective against not only Gram-negative bacteria including Pseudomonas aeruginosa but also Gram-positive bacteria. [Means for Solving the Problem] Under these circumstances, the present inventors conducted intensive research and found that the 1,4-dihydro-4-oxonaphthyridine derivative represented by the general formula [] and its salt The inventors have found that the above objects can be achieved, and have completed the present invention. The compounds of the present invention will be explained in detail below. The compound of the present invention is represented by the following general formula []. In the compound of general formula [] and its salt,
As the carboxyl protecting group for R ¹ , for example,
Ester-forming groups that are eliminated by catalytic reduction, chemical reduction, or treatment with other mild conditions, or ester-forming groups that are easily eliminated in vivo, or easily eliminated by treatment with water or alcohol. Various other known ester-forming groups such as an organosilyl group, an organophosphorus group or an organotin group can be mentioned. Among these carboxyl protecting groups, suitable protecting groups include, for example, the carboxyl protecting groups described in JP-A-59-80665. Also
The heterocyclic group for R ² is a 5- or 6-membered ring containing one or more heteroatoms selected from oxygen atom, nitrogen atom, and sulfur atom as a heteroatom forming the ring, or a fused ring thereof. Examples include groups such as furyl, pyrrolyl, thienyl, oxazolyl, imidazolyl, thiazolyl, 1-pyrrolidinyl, benzofuryl, benzothiazolyl, pyridyl, quinolyl, pyrimidinyl, and morpholino. These heterocyclic groups include halogen atoms, such as fluorine, chlorine, bromine, iodine, etc.; alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- butyl, tert-butyl,
Straight or branched C _1-10 alkyl groups such as pentyl, hexyl, heptyl, octyl; hydroxyl groups; alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy , tert−
Straight chain or branched C _1-10 alkoxy groups such as butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy; cyano group; amino group; acylamino group, such as formylamino, acetylamino, propionylamino group, butyrylamino group C _1-4 acylamino groups such as; trihalogenoalkyl groups, e.g. trihalogeno-C _1-4 such as trifluoromethyl, trichloromethyl;
It may be substituted with one or more substituents selected from alkyl groups and the like. Furthermore, examples of the halogen atom for R ³ include a fluorine atom, a chlorine atom, and a bromine atom, and for the cyclic amino group, in addition to one or more nitrogen atoms as the heteroatoms forming the ring, , a 5- or 6-membered cyclic amino group which may further contain one or more oxygen atoms, such as 1-pyrrolidinyl, piperidino, 1-piperazinyl, morpholino, and the like. The above-mentioned cyclic amino group is an alkyl group, such as methyl, ethyl, n
- straight-chain or branched C _1-4 alkyl groups such as propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl; amino groups; aminoalkyl groups, such as aminomethyl, 2-aminoethyl, Amino C _1-4 alkyl groups such as 3-aminopropyl; hydroxyalkyl groups, e.g. hydroxy-C _1-4 alkyl groups such as hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl; hydroxyl groups; alkenyl groups, e.g. _C2-4 alkenyl groups such as , vinyl, allyl; acyl groups, e.g. _C1-4 acyl groups such as formyl, acetyl, propionyl, butyryl; alkylamino groups, e.g. methylamino, ethylamino, n-propylamino , C _1-4 alkylamino groups such as isopropylamino; dialkylamino groups, for example, di-C _1-4 alkylamino groups such as dimethylamino, diethylamino, di-n-propylamino, methylethylamino; cyano groups; Oxo group; aralkylamino group, for example, an Al-C _1-4 alkylamino group such as benzylamino, phenethylamino; acylamino group, for example, C _1-4 acylamino group such as formylamino, acetylamino, propionylamino, butyrylamino; Alkoxycarbonyl groups, such as methoxycarbonyl, ethoxycarbonyl,
C _1-4 alkoxycarbonyl group such as n-propoxycarbonyl, isopropoxycarbonyl; N-
Acyl-N-alkylamino group, for example N-acyl-N-, in which the nitrogen atom of the alkylamino group as above is substituted with an acyl group, for example a C _1-4 acyl group such as acetyl, propionyl, butyryl, etc. It may be substituted with one or more substituents selected from alkylamino groups and the like. Examples of the salt of the compound of general formula [] include commonly known salts of basic groups such as amino groups or acidic groups such as hydroxyl groups or carboxyl groups. Examples of salts with basic groups include salts with mineral acids such as hydrochloric acid and sulfuric acid; salts with organic carboxylic acids such as oxalic acid, formic acid, trichloroacetic acid, and trifluoroacetic acid; methanesulfonic acid and p-toluenesulfonic acid. Salts with sulfonic acids such as naphthalenesulfonic acid, salts with acidic groups include, for example, salts with alkali metals such as sodium and potassium; calcium,
Salts with alkaline earth metals such as magnesium; ammonium salts; procaine, dibenzylamine,
N-benzyl-β-phenethylamine, 1-ephenamine, N,N-dibenzylethylenediamine, triethylamine, trimethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine Salts with nitrogen-containing organic bases such as In addition, when isomers (e.g., optical isomers, geometric isomers, tautomers, etc.) exist in the compound of general formula [] and its salt, the present invention includes all such isomers, It also covers all crystal forms and hydrates. [Effects of the Invention] Next, the antibacterial effects of representative compounds of the present invention will be shown. Antibacterial activity test method Japanese Society of Chemotherapy Standard Method [CHEMOTHERAPY Vol. 29, No. 1, No. 76-
p. 79 (1981)], a bacterial suspension cultured at 37°C for 20 hours in Heart Infusion broth (manufactured by Eiken Chemical Co., Ltd.) was incubated with Heart Infusion Agar containing the drug.
Infusion ager) medium (manufactured by Eiken Kagaku Co., Ltd.).
After culturing at 37°C for 20 hours, the presence or absence of bacterial growth was observed, and the minimum concentration that inhibited bacterial growth was determined.
It was defined as MIC (μg/ml). However, the amount of inoculated bacteria is 10 ⁴
cells/plate ( ¹⁰⁶ cells/ml). The results are shown in Table-1. The symbols used in Table 1 have the following meanings. * Penicillinase-producing bacteria ** Cephalosporinase-producing bacteria Me: Methyl group

【table】

【table】

〔Example〕

Next, the present invention will be explained by giving reference examples and examples. Note that the symbols used in Reference Examples and Examples have the following meanings. Me: methyl group; Et: ethyl group; ∧; methylene group; Under ice-cooling, 0.86 ml of concentrated hydrochloric acid was added dropwise over 10 minutes, and the mixture was allowed to react at 45°C for 1 hour. After the reaction was completed, the insoluble materials were removed, and the solvent was distilled off under reduced pressure. 10.3 g (yield: 88.8%) of 3-amino-6-fluoropyridine having a melting point of 95.5-96.5°C is obtained. IR (KBr) cm ^-1 ; 3320, 3200, 1595 NMR (d ₆ -DMSO) δ value; 4.13 (2H, bs), 6.82 (1H, dd, J=3Hz, J
=9Hz), 7.02~7.32 (1H, m), 7.48~7.55
(1H, m) In the same manner, the following compound is obtained. 〇3-amino-2-fluoropyridine (oil) IR (neat) cm ^-1 ; 3350, 3220, 1615, 1590 〇3-amino-2,6-difluoropyridine Melting point: 61.5-62.5°C (reconsolidation solvent; n-hexane) IR (KBr) cm ^-1 ; 3400, 3325, 3200, 1610,
1590 Example 1 (1) 2,6-dichloro-5-fluoronicotinoyl acetic acid ethyl ester 1.00 g, acetic anhydride 1.46 g
and 2.11 g of ethyl orthoformate are reacted for 1.5 hours under heating and reflux. After the reaction is complete, the solvent is distilled off under reduced pressure, and the resulting residue is dissolved in 5 ml of ethanol. Then, 370 mg of 2-aminothiophene was added, and the mixture was allowed to react at room temperature for 1 hour. After the reaction is complete, the solvent is distilled off under reduced pressure, and 30 ml of ethyl acetate and 10 ml of water are added to the resulting residue. The organic layer is separated, washed with 10 ml of saturated brine, and then dried over anhydrous magnesium sulfate.
The solvent was distilled off under reduced pressure, and the resulting residue was subjected to column chromatography (Merck Kiesel gel).
2-(2,
6-dichloro-5-fluoronicotinoyl)-
1.07 g (yield 77.0%) of 3-(2-thienylamino)acrylic acid ethyl ester is obtained. Melting point: 103-104°C (resolidification solvent: ethanol) IR (KBr) cm ^-1 ; c=o 1710, 1685 NMR (CDCl ₃ ) δ value: 1.08 (3H, t, J = 7.5Hz), 4.07 ( 2H, q,
Similarly, the following table A compound shown in -2 is obtained.

[Table] (2) Dissolve 600 mg of 2-(2,6-dichloro-5-fluoronicotinoyl)-3-(2-thienylamino)acrylic acid ethyl ester in 3 ml of N,N-dimethylformamide and add sodium hydrocarbon. Add 140 mg and react at 90°C for 2.5 hours.
After the reaction is complete, add 20 ml of water, stir at room temperature for 1 hour, and remove the precipitated crystals to obtain 7-chloro-
6-fluoro-1,4-dihydro-4-oxo-1-(2-thienyl)-1,8-naphthyridine-3-carboxylic acid ethyl ester 480 mg (yield
88.3%). Melting point: 195-196°C (reconsolidation solvent: methanol) IR (KBr) cm ^-1 ; c = o 1735, 1690 NMR (CDCl ₃ ) δ value: 1.39 (3H, t, J = 7Hz), 4.39 (2H ,q,J
=7Hz), 6.97-7.60 (3H, m), 8.43 (1H,
d, J=7Hz), 8.71 (1H, s) Similarly, the compounds shown in Table 3 below are obtained.

【table】

[Table] (3) Dissolve 170 mg of 3-aminopyrrolidine dihydrochloride and 350 mg of triethylamine in 5 ml of ethanol, and dissolve 7-chloro-6-fluoro-1,4
-dihydro-4-oxo-1-(2-thienyl)
After adding 200 mg of -1,8-naphthyridine-3-carboxylic acid ethyl ester, chloroform 10
ml to make a homogeneous solution, and react at room temperature for 7 hours. After the reaction is complete, 10 ml of chloroform and 10 ml of saturated saline are added, and the organic layer is separated. The aqueous layer was further extracted twice with 10 ml of chloroform each time.
Combine with the previous organic layer, wash twice with 10 ml of saturated brine, and dry over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and 10 ml of ethyl acetate was added to the resulting residue to collect crystals.
-(3-amino-1-pyrrolidinyl)-6-fluoro-1,4-dihydro-4-oxo-1-
(2-thienyl)-1,8-naphthyridine-3-
Carboxylic acid ethyl ester 160mg (yield 69.6%)
get. Melting point: 228-233°C (resolidification solvent: ethanol) IR (KBr) cm ^-1 ; c = o 1710 NMR (d ₁ -TFA) δ value: 1.50 (3H, t, J = 7Hz), 2.33-2.95 (2H,
m), 3.53-4.95 (7H, m), 7.05-7.76 (3H,
m), 8.18 (1H, d, J = 12Hz), 9.18 (1H,
s) In the same manner, the compounds shown in Table 4 below are obtained.

【table】

【table】

[Table] (4)(i) 7-(3-amino-1-pyrrolidinyl)-6
-fluoro-1,4-dihydro-4-oxo-1-(2-thienyl)-1,8-naphthyridine-3-carboxylic acid ethyl ester 140 mg
Dissolve in 5.6 ml of 6N hydrochloric acid and react under heating and reflux for 4 hours. After the reaction is complete, the solvent is distilled off under reduced pressure, and 10 ml of diethyl ether is added to collect crystals to obtain 7-(3-amino-1-pyrrolidinyl)-6-fluoro-1,4-dihydro-4-oxo. -1-(2-thienyl)-1,
8-Naphthyridine-3-carboxylic acid hydrochloride
Obtain 140 mg (97.9% yield). Melting point: 259-264℃ (decomposition) (reconsolidation solvent: water-
ethanol) IR (KBr) cm ^-1 ; c=o 1720 NMR (d ₁ -TFA) δ value; 2.20-2.97 (2H, m), 3.53-4.95 (5H,
m), 7.04-7.90 (3H, m), 8.17 (1H, d,
J=12Hz), 9.30 (1H, s) In the same manner, the compounds shown in Table 5 below are obtained.

[Table] (ii) 6-fluoro-1-(6-fluoro-3-
94mg
Dissolved in 2 ml of ethanol and 1 ml of water,
1 mg of 2.5N sodium hydroxide aqueous solution under ice cooling
and react for 30 minutes at room temperature. After the reaction is complete, adjust the pH to 1 with 2N hydrochloric acid under ice-cooling and remove the precipitated crystals to obtain 6-fluoro-1-(6-
Fluoro-3-pyridyl)1,4-dihydro-4-oxo-7-(1-piperazinyl)-
88 mg (yield 91.8%) of 1,8-naphthyridine-3-carboxylic acid hydrochloride is obtained. Melting point: >280°C (reconsolidation solvent: concentrated hydrochloric acid-ethanol) IR (KBr) cm ^-1 ; 〓c=o 1720 NMR (d ₁ -TFA) δ value: 3.30-4.00 (4H, m), 4.00-4.70 (4H,
m), 7.40-7.68 (1H, m), 8.00-9.00
(3H, m), 9.35 (1H, s) In the same manner, the compounds shown in Table 6 below are obtained.

【table】

[Table] (iii) 7-[(3-N,N-dimethylamino)-1
-pyrrolidinyl]-6-fluoro-1-(6-
Fluoro-3-pyridyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3
-Dissolve 190 mg of carboxylic acid ethyl ester in 2 ml of ethanol and 0.5 ml of water, add 0.33 ml of 10% aqueous sodium hydroxide solution, and react at room temperature for 5 hours. After the reaction is complete, cool on ice for 2N.
Adjust the pH to 7 with hydrochloric acid and remove the precipitated crystals to obtain 7-[(3-N,N-dimethylamino)-
1-pyrrolidinyl]-6-fluoro-1-(6
-fluoro-3-pyridyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-
70 mg (yield 34.5%) of 3-carboxylic acid is obtained. Melting point: 268-269°C (recrystallization solvent: methanol) IR (KBr) cm ^-1 ; 〓c=o 1720 NMR (d ₁ -TFA) δ value: 2.20-2.95 (2H, m), 3.15 (6H, s ), 3.50
~4.90 (5H, m), 7.35 ~ 7.70 (1H, m,),
8.00-8.90 (3H, m), 9.2 (1H, s) In the same manner, the compounds shown in Table 7 below are obtained.

[Table] Example 2 (1) 500 mg of 2,6-dichloro-5-fluoronicotinoyl acetic acid ethyl ester was dissolved in 50 mg of chloroform.
ml of 3-aminopyrrolidine dihydrochloric acid
After adding 341 mg, triethylamine 720 under ice cooling.
mg was added, and the mixture was allowed to react under heating and reflux for 2 hours. After the reaction is complete, add 5 ml of water and adjust the pH with 2N hydrochloric acid under ice cooling.
After adjusting to 6, the organic layer is separated. The aqueous layer is further extracted twice with 5 ml of chloroform each time, combined with the organic layer, washed with 5 ml of saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography [Wako silica gel C-200, elution solvent: chloroform:ethanol = 30:1 (volume ratio)] to obtain an oily 6- (3-amino-
430 mg (yield: 66.0%) of ethyl ester (1-pyrrolidinyl)-2-chloro-5-fluoronicotinoyl acetate is obtained. IR (neat) cm ^-1 ; c = o 1725 NMR (CDCl ₃ ) δ value; 1.28 (3H, t, J = 7Hz), 1.50 ~ 2.70 (4H,
m), 3.00-4.50 (9H, m), 7.61 (1H, d,
J = 13 Hz) (2) After reacting a mixed solution of 760 mg of 99% formic acid and 790 mg of acetic anhydride at 45°C for 1 hour,
A solution of 900 mg of (3-amino-1-pyrrolidinyl)-2-chloro-5-fluoronicotinoyl acetic acid ethyl ester in 2 ml of chloroform was added dropwise over 5 minutes, and the mixture was allowed to react at room temperature for 2 hours. After the reaction, the solvent is distilled off under reduced pressure, 10 ml of ethyl acetate and 5 ml of water are added to the resulting residue, the organic layer is separated, washed with 5 ml of saturated brine, and then dried over anhydrous magnesium sulfate. . The solvent was distilled off under reduced pressure, and the resulting residue was subjected to column chromatography [Wako silica gel C-200, elution solvent: benzene: ethyl acetate = 2:1 (volume ratio)]
If purified by
(yield 92.9%). IR (neat) cm ^-1 ; c = o 1730, 1650 NMR (CDCl ₃ ) δ value; 1.25 (3H, t, J = 7Hz), 1.80 ~ 2.40 (2H,
m), 3.50-4.90 (9H, m), 6.30-6.70 (1H,
m), 7.63 (1H, d, J = 13Hz), 8.10 (1H,
s) (3) Dissolve 100 mg of 2-chloro-5-fluoro-6-(3-formylamino-1-pyrrolidinyl) nicotinoylacetic acid ethyl ester in 1.2 ml of benzene, add 40 mg of N,N-dimethylformamide dimethyl acetal, Heat and react under reflux for 30 minutes. After the reaction, the solvent was distilled off under reduced pressure, the resulting residue was dissolved in 2 ml of benzene, and 3-amino-2,6-difluoropyridine was dissolved.
Add 36 mg and react under heating and reflux for 3 hours.
After the reaction is complete, the solvent is distilled off under reduced pressure, and the resulting residue is purified by column chromatography [Wako silica gel C-200, elution solvent: benzene:ethyl acetate = 1:1 (volume ratio)]. , melting point 70
100 mg of 2-[2-chloro-5-fluoro-6-(3-formylamino-1-pyrrolidinyl)nicotinoyl]-3-(2,6-difluoro-3-pyridylamino)acrylic ethyl ester exhibiting a temperature of ~73°C ( Yield: 79.0%). IR (KBr) cm ^-1 ; νc=o 1665 NMR (d ₆ -DMSO) δ value; 1.07 (3H, t, J=7Hz), 1.75-2.35 (2H,
m), 3.20-4.60 (7H, m), 7.00-8.80 (6H,
m), 10.87 (d, J = 13Hz) 12.27 (d, J = 13Hz) (1H) Similarly, using hydrazine hydrate instead of 3-amino-2,6-difluoropyridine,
2-[2-chloro-5- with a melting point of 116-117°C
Fluoro-6-(3-formylamino-1-pyrrolidinyl)nicotinoyl]-3-hydrazinoacrylic acid ethyl ester is obtained. IR (KBr) cm ^-1 ; c=o 1700, 1680, 1650 (4) 2-[2-chloro-5-fluoro6-(3-
150 mg of formylamino-1-pyrrolidinyl)nicotinoyl]-3-(2,6-difluoro-3-pyridylamino)acrylic acid ethyl ester was dissolved in 0.75 ml of N,N-dimethylformamide, 30 mg of sodium bicarbonate was added, and the mixture was heated at 90°C. in
Incubate for 3.5 hours. After the reaction is complete, add 10 ml of water, stir for 1 hour, and remove the precipitated crystals to obtain 1-(2,6-difluoro-3-pyridyl).
-6-fluoro-7-(3-formylamino-
1-pyrrolidinyl)-1,4-dihydro-4-
96 mg (yield 69.1%) of oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester is obtained. Melting point: 131-132°C (re-solidification solvent: chloroform) IR (KBr) cm ^-1 ; 〓c=o 1725, 1670 NMR (d ₆ -DMSO) δ value: 1.26 (3H, t, J = 7Hz), 1.65 ~2.20 (2H,
m), 2.95-3.90 (5H, m), 4.21 (2H, q,
J=7Hz), 7.20~7.60 (1H, m), 7.60~8.75
(5H, m) Similarly, 1-amino-6-fluoro-7-(3-formylamino-1-pyrrolidinyl)-1,4-dihydro- exhibiting a melting point of 150.5-152°C
4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester is obtained. IR (KBr) cm ^-1 ; c=o 1710, 1660 (5) 1-(2,6-difluoro-3-pyridyl)-
6-Fluoro-7-(3-formylamino-1
-pyrrolidinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester (100 mg) is suspended in 1 ml of dioxane and 0.1 ml of concentrated hydrochloric acid, and reacted at 60-70°C for 10 hours. After the reaction is complete, add 1 ml of water and 1 ml of ethyl acetate, adjust the pH to 7 with a saturated aqueous sodium bicarbonate solution under ice cooling, and remove the precipitated crystals to obtain 7-(3-amino-1
-pyrrolidinyl)-1-(2,6-difluoro-
3-pyridyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3
- 60 mg (yield 68.3%) of carboxylic acid are obtained. IR (KBr) cm ^-1 ; c=o 1720 NMR (d ₁ -TFA) δ value; 2.20 to 3.00 (2H, m), 3.40 to 4.85 (5H, m),
7.00~7.50 (1H, m), 7.80~8.60 (2H, m),
9.20(1H,s) (6) 1-amino-6-fluoro-7-(3-formylamino-1-pyrrolidinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-
170mg of 3-carboxylic acid ethyl ester to 0.5mg of acetic acid
ml, add 62 mg of 2,5-dimethoxytetrahydrofuran, and react under heating under reflux for 3 hours. After the reaction was completed, the solvent was distilled off under reduced pressure.
The obtained residue was dissolved in 2 ml of 6N hydrochloric acid and reacted under heating under reflux for 5 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to column chromatography [Merck Kieselgel 60,
Elution solvent; chloroform:ethanol = 7:1
(volume ratio)], 7-(3-amino-1-pyrrolidinyl)-6-fluoro-1,4-dihydro-4-
Oxo-1-(1-pyrrolyl)-1,8-naphthyridine-3-carboxylic acid hydrochloride 15 mg (yield
8.1%). IR (KBr) cm ^-1 ; νc=o 1670 NMR (d ₁ -TFA) δ value; 2.31 to 3.30 (2H, m), 3.87 to 5.06 (5H, m),
7.30~8.82 (5H, m), 9.14 (1H, s)

Claims (1)

[Claims] 1. General formula [In the formula, R ¹ represents a hydrogen atom or a carboxyl protecting group, R ² represents an optionally substituted heterocyclic group, and R ³ represents a halogen atom or an optionally substituted cyclic amino group. ] A 1,4-dihydro-4-oxonaphthyridine derivative and a salt thereof.