JPS61143383A - Antibacterial agent containing 1,4-dihydro-4-oxo-naphthyridine derivative or salt thereof - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I (R<1> is H, or carboxyl protecting group; R<2> is aryl which may be replaced; R<3> is halogen, cyclic amino which may be replaced, with the proviso that a case where R<1> is H, and R<2> is 2,3-difluorophenyl is omitted). EXAMPLE:6-Fluorophenyl-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthy ridine-3- carboxylic acid. USE:An antibacterial agent. showing strong antibacterial action on Gram-positive and Gran-negative bacteria, especially bacteria resistant to antibiotics. PREPARATION:A compound shown by the formula II and a compound shown by the formula III in the presence or absence of a base(e.g., sodium hydrogencarbonate) are subjected to ring closure in an inert solvent at 20-160 deg.C to give a compound shown by the formula I. Optionally, a salt-forming reaction and esterification reaction is carried out.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to an antibacterial agent containing a 1,4-dihydro-4-oxonaphthyridine derivative represented by the general formula or a salt thereof.

The purpose of the present invention is to exhibit a strong antibacterial effect against Durham-positive bacteria and Durham-negative bacteria, especially antibiotic-resistant bacteria, to obtain high blood concentrations by oral or parenteral administration, and to be safe. The object of the present invention is to provide an antibacterial agent containing a strong compound represented by the general formula [I] or a salt thereof, which has excellent properties such as high temperature.

[Conventional technology]

Conventionally, synthetic antibacterial agents such as nalidixic acid, pyromidic acid, and pipemidic acid have been widely used, but their effectiveness in treating intractable diseases such as Pseudomonas aeruginosa infection and Durham-positive bacterial infection is not satisfactory. There wasn't. For this reason, various pyridonecarboxylic acid compounds, such as 1
-Ethyl-6-fluoro-1,4-dihydro-4-oxo-7-+1-piperazinyl)-3-quinolinecarvone fi (Tsurua 0xazine) and others are being developed as alternatives to conventional synthetic antibacterial agents. Although these compounds have excellent antibacterial activity against various Durham-negative bacteria including Pseudomonas aeruginosa, their antibacterial activity against Durham-positive bacteria has not yet been sufficient.

[Problem that the invention seeks to solve]

Therefore, as a result of extensive research, the present inventors found that the antibacterial agent expressed by general formula (1) has a wide range of antibacterial spectrum and is effective against not only Durham-negative bacteria but also Durham-positive bacteria. The present inventors have discovered that an antibacterial agent containing a 1°4-dihydro-4-oxonaphthyridine derivative or a salt thereof achieves the above object, and has completed the present invention.

The present invention will be explained in detail below.

The antibacterial agent of the present invention contains a compound represented by the following general formula CI or a salt thereof as an active ingredient.

In the compound of general formula CI) and its salts, the carboxyl protecting group for R1 is, for example, an ester-forming group that is removed by treatment under catalytic reduction, chemical reduction or other mild conditions, or an ester-forming group that is easily removed in vivo. an ester-forming group that is easily eliminated by treatment with water or alcohol;
Other commonly known ester-forming groups may be mentioned, such as organophosphorus or organotin groups.

Among these carboxyl protecting groups, suitable protecting groups include, for example, the carboxyl protecting groups described in Japanese Patent Application No. 188930/1983.

Examples of the aryl group for R1 include phenyl and naphthyl groups. This aryl group is
Halogen atoms, such as fluorine, chlorine, bromine, iodine, etc.; alkyl groups, such as methyl, ethyl, n-propyl, inpropyl, n-butyl,
Straight chain or branched C31, such as isobutyl, 5ec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl. Alkyl group; hydroxyl group; alkoxy group, such as methoxy, ethoxy, n-propoxy, isopropoxy, n'-butoxy, isobutoxy,
Straight chain or branched chain C1-7. such as 5ec-butoxy, tart-butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy. Alkoxy group; cyano group; amino group; acylamino group, e.g., C2-4 acylamino group such as formylamino, acetylamino, globionylamino, butyrylamino; trihalogenoalkyl group, e.g., trifluoromethyl, trichloromethyl, etc. It may be substituted with one or more substituents selected from halogen-C0-4 alkyl groups and the like.

Further, examples of the halogen atom of R1 include a fluorine atom, a chlorine atom, and a bromine atom, and as a cyclic amino group, in addition to one or more nitrogen atoms as heteroatoms forming the ring, It may further contain one or more oxygen atoms, and includes, for example, 5- or 6-membered cyclic amino groups such as 1-pyrrolidinyl, piperidino, 1-piperazinyl, and morpholino. The above-mentioned cyclic amino group is an alkyl group, such as methyl, ethyl, n-propyl, inpropyl, n-butyl, isobutyl, 5ea
- Straight chain or branched chain C such as butyl, tert-butyl, etc.
1-4 alkyl group; amino group; aminoalkyl group, e.g., aminomethyl, 2-aminoe f/L/, 3-aminopropyl, etc.; hydroxyalkyl group, e.g., hydroxymethyl, Hydroxy C1-4 alkyl groups such as 2-hydroxyethyl and 3-hydroxypropyl; hydroxyl groups; alkenyl groups, e.g. C1-, alkenyl groups such as vinyl and allyl; acyl groups, e.g. formyl, acetyl, glopionyl, C2-4 acyl groups such as butyryl; alkylamino groups, such as methylamino, ethyl 1-mino,
C1~ such as n-propylamino and inglobylamino
4 alkylamino group; dialkylamino group, e.g.
Di-C7-4 alkylamino groups such as dimethylamino, diethylamino, di-n-propylamine, and methylethylamino; cyano groups; oxo groups; aralkylamino groups, such as aru CI-4 such as benzylamino and phenethyl amino; Alkylamino group; C8-4 acylamino group such as acylamino group, acetylamino, propionylamino, butyrylamino; alkoxycarbonyl group, such as methoxycarbonyl, ethoxycarbonyl, n-7' loboxycarbonyl, isopropoxycarbonyl, etc. C8~.

Alkoxycarbonyl group; N-acyl-N-alkylamino group, for example, N in which the nitrogen atom of the same alkylamino group as above is substituted with an acyl group, for example, a C1-4 acyl group such as acetyl, glopionyl, butyryl, etc.
It may be substituted with one or more substituents selected from -acyl-N-alkylamino groups and the like. However, this excludes cases where R1 is a hydrogen atom and R'' is a 2,4-difluorophenyl group.

Examples of the salt of the compound of general formula CD include commonly known salts of basic groups such as amino groups or acidic groups such as carboxyl groups. Salts with basic groups include, for example, salts with mineral acids such as hydrochloric acid and sulfuric acid;
Salts of organic carboxylic acids such as formic acid, trichloroacetic acid, and trifluoroacetic acid with sulfonic acids such as methanesulfone, p-)luenesulfonic acid and naphthalenesulfonic acid are salts with acidic groups, such as sodium chloride. , salts with alkali metals such as potassium; salts with alkaline earth metals such as calcium, magnesium; ammonium salts; procaine, dibenzylamine/-1N-benzyl-β-7enethylamine, 1-ephenamine, N,N-
Dibenzylethylenediamine, triethylamine, trimethylamine, tributylamine, pyridine, N, N-
Salts with mousine-containing organic bases such as dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, and dicyclohexylamine can be mentioned.

Furthermore, when isomers (e.g., optical isomers, geometric isomers, tautomers, etc.) exist in the compound of general formula (1) and its salt, the present invention includes all such isomers. , and all crystalline forms and hydrates.

Next, a method for producing the compound of general formula C1) and its salt will be explained.

Methods for producing the compound of general formula [1) and its salts include methods known per se, and representative production methods will be explained in detail below.

The compound of general formula (1) and its salt can be produced, for example, according to the following production route.

(t[) (IV) or a salt thereof ([3 or a salt thereof CV) or a salt thereof PK,'' [ta: or a salt thereof [I] or a salt thereof General formula (ta], Cl), [■'l and Examples of the salt of the compound (V) include the same salts as those listed as the salt of the compound of general formula (1).

(1) The compound of the general formula CD or its salt, or the compound of the general formula (V) or its salt, respectively, is a compound of the general formula (
After reacting the compound of II) or the compound of general formula CIV) or a salt thereof with an acetal such as N,N-dimethylformamide dimethyl acetal or IN,N-dimethylformamide diethyl acetal,
It can be obtained by reacting amines represented by -NH, (R1 has the same meaning as above).

The insolvent used in this reaction is not particularly limited as long as it is inert to the reaction, but examples include benzene,
Aromatic hydrocarbons such as toluene and xylene; ethers such as dioxane, tetrahydro7rane, anisole, diethylene glycol dimethyl ether, and dimethyl cellosolve; halogenated hydrocarbons such as methylene chloride, chloroform, and dichloroethane IN.

Examples include amides such as N-dimethylformamide and N,N-dimethylacetamide; sulfoxides such as dimethylsulfoxide, and two or more of these solvents may be used as a mixture. The amount of acetals to be used is at least equimolar, particularly about 1.0 to 1.3 molar based on the compound of general formula (If) or the compound of general formula J] or its salt.
Double molar ratio is preferred. This reaction is usually carried out at 0 to 100°C, preferably 50 to 80°C, and the reaction time is usually 20°C.
minutes to 50 hours, preferably 1 to 3 hours. Then, in order to react the amines R1-NH, the amines are used in an equimolar amount or more than the equimolar amount based on the compound of the monomer formula [ll) or the compound of the general formula C1a) or a salt thereof, and usually O ~100°C, preferably 10-60°
C, the reaction is usually carried out for 20 minutes to 30 hours, preferably for 1 to 5 hours.

Alternatively, after reacting the compound of general formula 1'' [) or the compound of general formula [■] or its salt with ethyl orthoformate or methyl orthoformate in acetic anhydride, R
By reacting amines of 1-NHt, the respective general formulas [
This can lead to the compound of [Summer] or its salt, or the compound of general formula [■] or its salt.

(11) The compound of the general formula [1a] or its salt or the compound of the general formula m or its salt is each a compound of the general formula C
It can be obtained by subjecting the compound of I) or its salt or the compound of general formula [■] or its salt to a ring-closing 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 inert to the reaction, but for example, N.

Amides such as N-dimethylformamide and N,N-dimethylacetamide; ethers such as dioxane, anisole, diethylene glycol dimethyl ether, and dimethyl cellosolve; and sulfoxides such as dimethyl sulfoxide. You may also use it. Examples of the base include sodium hydrogen carbonate, potassium carbonate, potassium tert-butoxy, sodium hydride, etc., and the amount used is 0 to 0 for the compound of -12 formula (1) or CV) or a salt thereof. The reaction temperature is preferably 20 to 160°C, preferably 100 to 1
The reaction time is usually 5 minutes to 30 hours, preferably 5 minutes to 1 hour.

(B1) A compound of general formula CIV) or a salt thereof, in which R3 is an optionally substituted cyclic amino group, general formula [V
) or a salt thereof or a compound of general formula [l) or a salt thereof is a compound of general formula [■], a compound of general formula CI] or a salt thereof, or a compound of general formula C1a, respectively.
) or a salt thereof with an amine V represented by the formula 3jb-H (H3b represents an optionally substituted cyclic amine group similar to Bs). The solvent used in this reaction is not particularly limited as long as it is inert to the reaction, but examples include aromatic hydrocarbons such as benzene, toluene, and xylenato;
Ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether; methylene chloride, chloroform, dichloroethane natonohalokenated hydrocarbons; N,N-dimethylformamide N
.

Examples include amides such as N-dimethylacetamide; sulfoxides such as dimethyl sulfoxide; alcohols such as methanol and ethanol; and nitrites such as acetonitrile. These solvents may be used in a mixture of 2fi or more. The amount of cyclic amines used is based on general formula C
It is preferable to use an excess amount, particularly 2 to 5 times the molar amount, of the compound u), the compound of the general formula CI) or its salt, or the compound of the general formula CIA''l or its salt, and the amount used is about 1 to 1. In the case of 3 times the molar amount, if an equimolar amount of deoxidizing agent is used for the compound of general formula Cl1), -eZ compound of formula (1) or its salt, or the compound of general formula (ta) or its salt. good.

As a deoxidizing agent, triethylamine, 1,8-diazabicyclo-(5,4,Ol-undec-7-xone (DBU
), tert-butoxypotassium, potassium carbonate, sodium carbonate, sodium hydride, and other inorganic or organic bases. This reaction is usually carried out at 0 to 150°C, preferably 50 to 100°C, and the reaction time is usually 5 minutes to 30 hours, preferably 30 minutes to 3 hours.

Further, general formula (1) in which R1 is a carboxyl protecting group,
(IJL), C1) or (V) or a salt thereof, as desired, in the presence of a usual acid or alkali used in a hydrolysis reaction, usually 0 to 10
5 minutes to 50 hours at 0°C, preferably 20 to 100°C,
Preferably, by hydrolyzing for 5 minutes to 4 hours, the corresponding compounds can be converted to free carboxylic acids. Furthermore, the compound of general formula C1), [■a], [■] or (V) or a salt thereof may be subjected to a salt-forming reaction or an esterification reaction known per se as desired to form a corresponding compound. Can lead to salts or esters.

In addition, general formula (IL), [I], (IV) or [■
] or their salts have an active group (e.g., hydroxyl group, amino group, etc.) other than the reaction site, the active group is retained in advance using a conventional method, and after the reaction is completed, the protective group is removed. may be removed.

The compound obtained as described above may be subjected to conventional isolation and construction operations such as column chromatography, recrystallization, and extraction.

Next, the antibacterial activity of typical compounds of general formula CI) or salts thereof, which are the active ingredients of the antibacterial agent of the present invention, will be shown.

1. Antibacterial activity test method Japanese Society of Chemotherapy standard method [CHE THERAPY Pack 2
Hea according to Vol. 9, No. 1, pp. 76-79 (19th year)]
A bacterial solution cultured in rt Infusion broth (manufactured by Eiken Kagaku Co., Ltd.) at 37°C for 20 hours was added to Hea containing the drug.
rt Infusion agar medium (manufactured by Eiken Kagaku Co., Ltd.) was inoculated and cultured at 37°C for 20 hours, and the presence or absence of bacterial growth was observed, and the minimum concentration at which bacterial growth was inhibited was defined as MIC (μV Hani). .

However, the amount of inoculated bacteria is 10'lli/' plate (106
1 [ii1/Id). The results are shown in Table-1.

The symbols used in Table 1 have the following meanings.

* Penicillinase-producing bacteria ** Cephalosporinase-producing bacteria Me2 Methyl group, -n-Pr:n-
Propyl group, 1-Pr: Isoprobyl group *1 Amount of bacteria in contact with PA 2>"10' i hard/M Tablets, capsules, powders, syrups, granules,
Prepared as suppositories, ointments, injections, etc. In addition, the administration method, dose, and frequency of administration can be selected as appropriate depending on the patient's symptoms, and usually for adults, oral or parenteral administration (e.g., injection administration, infusion, rectal administration, etc.) Depending on the target administration, 0.1 to 100 II #g/7 days may be administered in one to several divided doses.

〔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: z-thyl group, n-Pr: n-propyl group, 1-Pr: isopropyl group, AC niacetyl group, N: allyl group, N: ethylene group Reference Example 2, 6-cyclo-5-fluoro Nicotinic acid 21? was dissolved in 210 #L of chloroform, and thionyl chloride 2
3.85' and N,N-dimethylformamide 0.1
and react at 70°C for 2 hours.

The solvent and excess thionyl chloride are distilled off under reduced pressure, and the resulting residue is dissolved in 21 dK of tetrahydrofuran.

Magnesium λ67? Ethoxymagnesium diethyl malonate 25.1) prepared from v4 was added to tetrahydro7 run 1101! Dissolve in Ll and cool to -40 to -30°C. Add the previously prepared 2,6-dichloro-5-
A solution of fluoronicotinyl chloride in tetrahydrofuran is added dropwise at the same temperature over 30 minutes. After stirring this mixed solution at the same temperature for 1 hour, the temperature was gradually raised to room temperature. The solvent was distilled off under reduced pressure, and to the resulting residue were added 200 tj of chloroform and 10 Cl/l of water, and the pH was adjusted to 1 with 6N hydrochloric acid. Separate the organic layer and add 5Qi of water, 50d of 5% aqueous sodium bicarbonate solution and 50d of saturated brine.
After washing with water, dry with anhydrous magnesium sulfate.

The solvent was distilled off under reduced pressure, and 53m of water and p-toluenesulfoheptaic acid were added to the obtained oil, and the mixture was reacted at 100°C for 2 hours with vigorous stirring, followed by extraction with 100m of chloroform. do. The organic layer was diluted with saturated saline solution for 50 min.
After washing with m/ and drying with anhydrous sulfuric acid magne ram, the medium was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (Wako silica gel C-200, eluent: toluene). For example, it shows a melting point of 64-65°C2,
6-cyclo5-fluoronicotinoyl acetic acid ethyl ester 21551't-4.

IR(KBr)z-': sic-0 1650.163
0.162ONMR (CDC131: 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 (IH, d, J-7Hz).

1242 (0,43H, s) Example 1 (1) 2,6-cyclo-5-fluoronicotinoyl acetic acid ethyl ester s, oil benzene 40! Dissolve in ILl, N,N-dimethylformamide dimethyl acetal 4.1? and react at 70°C for 1.5 hours. Then, 3.25% of 4-fluoroaniline was added to this reaction solution.
't-Additionally, after reacting at room temperature for 4 hours, the solvent was distilled off under reduced pressure. If the obtained residue is purified by column chromatography (Wako silica gel C-200, eluent: chloroform), 2-(
2,6-dichloro-5-fluoronicotinoyl)-3-
(4-fluorophenylamino)acrylic acid ethyl ester 7.8? get.

IR(KBr)crn-' svc-o 1710.
In the same manner as No. 1680, the compounds shown in Table 2 below were obtained.

Margin below Table-2 H Desire Table-・2 (continued) Table-2 (continued) Table-2 (continued) Six using NEET instead of true KBrO.

(2) 2-(2,6-dichloro-5-fluoronicotinoyl l-3-(4-fluorophenylamino)acrylic acid ethyl ester 7.0) IN, dissolved in 90 m of N-dimethylformamide, sodium hydrogen carbonate 1.76)
was added and reacted at 120°C for 20 minutes, then the solvent was distilled off under reduced pressure, and the resulting residue was dissolved in chloroform 5.
Dissolve in 0-. This reaction solution is washed with 30 d of water and 3 d of saturated saline (1/3) in sequence, and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting crystalline substance is washed with 30 d of diethyl ether. , melting point 23
7-chloro-6-fluoro-1-( exhibiting a temperature of 1 to 232°C
6.0y-4-fluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester.

IR(KBrlz-';I/ 1730.170
5C! 0 In the same manner, the compounds shown in Table 3 below were obtained.

Table -3 Table -3 (continued) Table -3fffl+ Table -3 (continued) (3) 7-chloro-6-fluoro-1-(4-fluorophenyl l-1+4-dihydro-4-oxo-1,8-
Naphthyridine-3-carboxylic acid ethyl ester 2.01
was dissolved in 35 ml of chloroform and 8 ml of VCf, and added with 0.77 ml of N-acetylpiperazine. and triethylamine 0
．． 61% and reacted at 60°C for 1 hour. Then, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to column chromatography [Wako Silica Gel C-200, Solvent 11].
1:'roloform:ethanol = 30:1 (volume ratio)]
7-(4-
Acetyl-1-piperazinyl)-6-fluoro-1-(
4-Fluorophenyl l-1,4-dihydro-4-oxo-1゜8-su7 tilisin-3-carboxylic acid ethyl ester λ1? get.

IR(KBr)Crn-';I'C-01730,1
In the same manner as No. 690, the compounds shown in Table 4 were obtained.

Table -4 (continued) Table -4 (continued) Table -4 (continued) Table -4 (continued) Table -4 (continued) Table -4 (continued) Table -4 (continued) Table -4 (continued) Table - 4 (continued) (4) 7-(4-acetyl-1-piperazinyl)-6-
Fluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester 2.0? was dissolved in 25 mj of 6N hydrochloric acid and reacted under reflux for 2 hours. Then, the reaction solution was cooled to room temperature and diluted with 1N aqueous sodium hydroxide solution.
After adjusting fA to H12, the pH was further adjusted to 6.5 with acetic acid. If the precipitated crystals are collected, washed with 3Qml of water, and dried, 6-fluoro-
1-(4-fluorophenyl)-1,4-dihydro-4
-Oquine-7-(1-piperazinyl)-1,8-su7tyridine-3-carboxylic acid 1.4? get.

IR(KBr)crrl-'; Wc-0172
5- In the same manner, the compounds shown in Table 5 below were obtained.

Margin Table -5 Table -5 (Continued) Table -5 (Continued) Table -5 (Continued) Example 2 m z, s-diprolow 5-fluoronicotinoyl acetic acid ethyl ester 5.5P% N-methylbiperazine 23
7? and triethylamine 2.37? was dissolved in 55 ml of chloroform and reacted at 60-65°C for 2 hours. The reaction solution was washed with 301 L of water and then 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° eluent; chloroform) to obtain oily 2-chloro-5-fluoro-6-(4-methyl -1-piperazinyl) nicotinoyl acetic acid ethyl ester 5.4)'t- is obtained.

Engineering R (=-t1m-': Mc-o 175
0/1695 NMR (C1) CI, l; δ value 1.25 (3H,t, J-7Hz).

λ32(3)(, sl.

λ12~Z70 (4H, ml.

3.55-3.96 (4H, m).

4.0312H, sl.

4.20 (2H, q, J-7Hz l.

7.7811H, d, J-13t (same as zl,
The compounds shown in Table 6 below were obtained.

J, :I, Lower thread 1.1 Table 6 (2) 2-chloro-5-fluoro-6-(4-methyl-
1-piperazinyl) nicotinoyl acetic acid ethyl ester 4
．． Dissolve 215 ml of 5Pi benzene, add 1.87 F of N,N-dimethylformamide dimethyl acetal, and react at 70°C for 2 hours. 1.8 P of 4-methoxy-2-methylaniline is added to this reaction solution, and the mixture is reacted at room temperature for 4 hours. Then, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to column chromatography [Wako Silica Gel C-200, eluent: chloroform:ethanol = 1
00:1 (capacitance)] and washing the obtained crystalline substance with 10 ml of diethyl ether gives a contact point of 141~
2-[2-chloro-5-fluoro-6- showing 142°C
(4-methyl-1-piperazinyl)nicotinoyl]-3
-(4-methoxy-2-methylphenylamino)acrylic acid ethyl ester 5.0? Get it.

IR(KBr)cm-': vc,,o 1710
(sh), 1695NMR (CDCI, ): δ value 1.08 (3H, t, J-7Hz) tλ32 (3
H, sl.

λ40 (3H, 8), Z23~z68 (4H, m
l.

3.47-3.83 (4H, m), 3.75 (3
H,s)+4.07 (2H,q, J-7Hz)
, 6.65-7.25 (3H, ml.

7.20 (IH, d, J-13Hz l.

8.48 (IH, d, J-13Hz l.

1182 (IH, d, J-13Hz l) Compounds shown in Table 7 were obtained in the same manner.

Table 7 H t *IHKBr *2; neat +3) 2-(2-chloro-5-fluoro-6-(4-methyl-1-piperazinyl)nicotinoyl]-3-(4-
Methoxy-2-methylphenylamino)acrylic acid ethyl ester 5,0% N.

After dissolving in 50 d of N-dimethylformamide, 1.035' of sodium hydrogen carbonate is added and the mixture is reacted at 120°C for 3 hours. Then, the solvent was distilled off under reduced pressure, and the resulting residue was dissolved in 50 d of chloroform. This solution is washed with 30 d of water and 30.7 L of saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting crystalline substance was dissolved in diethyl ether 3
6-Fluoro-1,4-dihydro-1-(4-methoxy-2-
2.38P of methylphenyl)-7-(4-methyl-1-piperazinyl)-4-oxo-1,8-su7tyridine-3-carboxylic acid ethyl ester is obtained.

IR(KBr)m-'; vc=o 1730.1
69ONMR (CDCI, r: δ value 1.33 (3H, t, J-7Hz), 1.95
(3H, s l.

120 (3H, s)t ZO5~242 (4H,
ml.

3.32-3.63 (4H, m), 3.82 (3
H,s).

4.32 (2H,q, J-7Hz l, 6.60
~7.15 [3H, ml.

8.02 (IH, d, J -13Hz), 8.
23 (IH,s) In the same manner as in 1, the compounds shown in Table 8 were obtained.

L) Bottom margin table -8 Table -8 (continued) Example 3 6-fluoro-1,4-dihydro-1-+4-methoxy-2-methylphenyl)-7-(4-methyl-1-piperazinyl)- 4-oxo-1,8-naphthyridine-3-
Carboxylic acid ethyl ester zoy 47% hydrobromic acid 5
Dissolve m1VC and react at 120-125°C for 2 hours. Then, an aqueous solution of IJ was added to the reaction solution to adjust the pH to +13 and +4, and then acetic acid was added to adjust the pH to 6.5Kv4. After washing, 6-fluoro-1°4-dihydro-1-(4-hydroxy-2
-methylphenyl)-7-+4-methyl-1-piperazinyl)-4-okino 1,8-cathyridine-3-carboxylic acid 1.8? get.

IR(KBr)crn-': C-01725.
1700 (ah) NMR (TFA-d, ): δ value ZO8 (3H, sl.

3.12 (3H, sl.

λ88~5.12 (8H, m).

6.93-7.62 (3H, ml.

9.43 (IH, d, J-13Hz l.

9.25 (IH, 3) In the same manner, the compounds shown in Table 9 below were obtained.

Quantum table -9 Table -9 (rL9.) Table -9 (continued) Table -9 (continued) Example 4 7-(4-a7,000-1-piperazinyl)-6-fluoro-1=(4-fluoro Phenyl l-1゜4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester 0.1PKIN-sodium hydroxide.
Add 1 ml of aqueous solution and 2 at of ethanol,
React for 10 minutes at 0-50°C. Next, acetic acid was added to the reaction solution to adjust the p) to 16.5, and then chloroform was added to
Extract twice with ml each.

The combined extracts are gradually washed with 5 ml of water and 5 ml of saturated saline, and then dried over anhydrous macanenium sulfate. The solvent was distilled off under reduced pressure, and the resulting crystalline substance was washed with 1 ml of diethyl ether, giving a melting point of 280"C[h
7-(4-acetyl-1-piperazinyl)-6-
0.085' of fluoro-1-(4-fluorophenyl l-1,4-dihydro-4-oxo-1,8-cathyridine-3-carboxylic acid is obtained.

IR(KBrJm-'; νc,, (+173O
NMR (tun-L) Ms (11, δ Iro 1 [2,05 (
3H,s).

3.5718H, bs).

7.13-7.80 +4) (,rnl.

8.13 +1) I, d, J-13H=, l.

8.70 (IH, l!) In the same way, next! A compound shown in -10 was obtained.

Table-10! -10+ continued) Table 10 (continued) Example 5 6-fluoro-1,4-dihydro-1-+4-hydroxy-2-methylphenyl)-4-oxo-7-(1-piperazinyl)-1,8 After dissolving 0.257 of -naphthyridine-3-carboxylic acid in 2.5 ml of concentrated hydrochloric acid, ethanol, x2Qm/ was added at room temperature and stirred for 15 minutes. If the precipitated crystals are collected and washed with 5 tzl of ethanol, 6-fluoro-1,4-dihydro-1-(4-hydroxy-2-methylphenyl)-4-, which has a melting point of 280°C or higher, is obtained.
Oxo-7-(l-piperazinyl l-1,8-naphthyridine-3-carboxylic acid IiL acid L10.25' to obtain IR(KBr)cWl-': I'C-0172
5 (sh), 1705, table-11 of Tsuki
The compound shown in was obtained.

Table-11

Claims (1)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^1 is a hydrogen atom or a carboxyl protecting group, R^2 is an optionally substituted aryl group, R^3
each represents a halogen atom or an optionally substituted cyclic amino group. However, this excludes the case where R^1 is a hydrogen atom and R^2 is a 2,4-difluorophenyl group. ] An antibacterial agent containing a 1,4-dihydro-4-oxonaphthyridine derivative or a salt thereof.