JPS6237006B2 - - 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 an optionally substituted cyclic amino group. ] The present invention relates to an antibacterial agent containing a 1,4-dihydro-4-oxonaphthyridine derivative or 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. It is an object of the present invention to provide an antibacterial agent containing a novel compound represented by the general formula [] or a salt thereof, which has excellent properties such as high compatibility. [Prior art] Conventionally, nalidixic acid, pyromidic acid, pipemidic acid, etc. have been widely used as synthetic antibacterial agents, but none of them have been shown to be effective in treating intractable diseases such as Pseudomonas aeruginosa infection and Gram-positive bacterial infection. was not satisfactory. For this reason, various pyridonecarboxylic acid compounds, such as 1-ethyl-6
-Fluoro-1,4-dihydro-4-oxo-7
-(1-Piperazinyl)-3-quinolinecarboxylic acid (norfloxacin) is being developed as an alternative to conventional synthetic antibacterial agents, but these compounds are effective against various Gram-negative bacteria including Pseudomonas aeruginosa. However, its antibacterial activity against Gram-positive bacteria was still not sufficient. [Problems to be Solved by the Invention] Therefore, it has been desired to develop a synthetic antibacterial agent that has a broad antibacterial spectrum and is effective against not only Gram-negative bacteria but also Gram-positive bacteria. [Means for Solving the Problems] Under these circumstances, the present inventors conducted intensive research and found that a 1,4-dihydro-4-oxonaphthyridine derivative represented by the general formula [] or a salt thereof The inventors have discovered that an antibacterial agent containing the above can achieve the above object, and have completed the present invention. The present invention will be explained in detail below. In the compound represented by the general formula [],
The cyclic amino group of R ¹ may further contain one or more oxygen atoms in addition to one or more nitrogen atoms as heteroatoms forming the ring, such as 1-pyrrolidinyl, piperidino, Examples include 5- or 6-membered cyclic amino groups such as 1-piperazinyl and morpholino. 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 such as 3-aminopropyl
C _1-4 alkyl group; hydroxyalkyl group, such as hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, etc.
C _1-4 alkyl group; hydroxyl group; alkenyl group, e.g. C _2-4 alkenyl group such as vinyl, allyl; acyl group, e.g. C _1-4 acyl group such as formyl, acetyl, propionyl, butyryl; alkylamino groups, e.g. _C1-4 alkylamino groups such as methylamino, ethylamino, n-propylamino, isopropylamino; dialkylamino groups, e.g. dimethylamino,
Di-C _1-4 alkylamino groups such as diethylamino, di-n-propylamino, and methylethylamino; cyano groups; oxo groups; aralkylamino groups, such as al-C _1-4 alkyl such as benzylamino and phenethylamino Amino group; acylamino group, for example, C _1-4 acylamino group such as acetylamino, propionylamino, butyrylamino; alkoxycarbonyl group, for example,
methoxycarbonyl, ethoxycarbonyl, n-
C _1-4 alkoxycarbonyl groups such as propoxycarbonyl and isopropoxycarbonyl; N-acyl-N-alkylamino groups, for example, when the nitrogen atom of the same alkylamino group as above is an acyl group,
For example, it may be substituted with one or more substituents selected from N-acyl-N-alkylamino groups substituted with _C1-4 acyl groups such as acetyl, propionyl, and butyryl. 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 carboxyl groups. Examples of salts in basic groups 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; salts with sulfonic acids such as methanesulfonic acid, p-toluenesulfonic acid, and naphthalenesulfonic acid; Examples of salts with acidic groups 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-phenethylamine, 1-ephenamine, N/N-dibenzylethylenediamine, triethylamine, trimethylamine, tributylamine, pyridine , N.N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine and other nitrogen-containing organic bases. 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. Next, a method for producing the compound of general formula [] and its salt will be explained. Methods for producing the compound of general formula [] and its salts include methods known per se, and representative production methods will be explained in detail below. The compound of general formula [] and its salt can be produced, for example, according to the following production route. [In the formula, R ^1a represents a halogen atom, R ² represents a hydrogen atom or a carboxyl protecting group, R ^2a represents a carboxyl protecting group, and R ¹ has the same meaning as described above. ] As the halogen atom in R ^1a , fluorine,
Chlorine, bromine, and iodine atoms are also R ² and R ^2a
As the carboxyl protecting group in
Examples include the carboxyl protecting groups described in No. Examples of the salts of the compounds of the general formulas [], [], [] and [] include the same salts as those listed as the salts of the compounds of the general formula []. (i) A compound of the general formula [] or a salt thereof, or a compound of the general formula [] or a salt thereof, is a compound of the general formula [] or a compound of the general formula [] or a salt thereof, respectively, and N/N-dimethylformamide. After reacting acetals such as dimethyl acetal or N.N-dimethylformamide diethyl acetal, 2.
It is obtained by reacting 4-difluoroaniline. 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 xylene; dioxane, tetrahydrofuran, anisole, diethylene glycol dimethyl ether, and dimethyl cellosolve. Ethers such as; halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane;
Amides such as N-dimethylformamide and N/N-dimethylacetamide; sulfoxides such as dimethyl sulfoxide;
Two or more of these solvents may be used in combination. The amount of acetals to be used is at least equimolar to the compound of general formula [] or the compound of general formula [] or its salt, especially about 1.0 to 1.3
Double molar ratio is preferred. This reaction is usually carried out at 0 to 100℃.
Preferably, it is carried out at 50-80°C, and the reaction time is
Usually 20 minutes to 50 hours, preferably 1 to 3 hours. Then, in order to react with 2,4-difluoroaniline, the amine is used in an equimolar amount or more than the equimolar amount based on the compound of the general formula [] or the compound of the general formula [] or a salt thereof, and the temperature is usually 0 to 100°C. , preferably at 10-60℃, usually 20
The reaction is allowed to proceed for minutes to 30 hours, preferably for 1 to 5 hours. Alternatively, a compound of the general formula [] or a compound of the general formula [] or a salt thereof may be reacted with ethyl orthoformate or methyl orthoformate in acetic anhydride, and then reacted with 2,4-difluoroaniline. can lead to a compound of the general formula [] or a salt thereof, or a compound of the general formula [] or a salt thereof, respectively. (ii) A compound of general formula [] or a salt thereof or a compound of general formula [] or a salt thereof is a compound of general formula [] or a salt thereof, or a compound of general formula [] or a salt thereof, respectively, in the presence of a base. Alternatively, it can be obtained by subjecting it to a ring-closing reaction (preferably under heating) in its absence. The solvent used in this reaction is not particularly limited as long as it is inert to the reaction, but examples include N・N-dimethylformamide, N・N-
Examples include amides such as dimethylacetamide; ethers such as dioxane, anisole, diethylene glycol dimethyl ether, and dimethyl cellosolve; and sulfoxides such as dimethyl sulfoxide. Two or more of these solvents may be used as a mixture. Examples of bases include sodium hydrogen carbonate, potassium carbonate,
Potassium tert-butoxy, sodium hydride, etc. are used, and the amount used is preferably 0.5 to 5 times the mole of the compound of general formula [] or [] or a salt thereof.
The reaction is carried out at 20 to 160°C, preferably 100 to 150°C, and the reaction time is usually 5 minutes to 30 hours, preferably 5 minutes to 1 hour. (iii) A compound of general formula [] or a salt thereof, a compound of general formula [] or a salt thereof, or a compound of general formula [] or a salt thereof are a compound of general formula [], a compound of general formula [] or its salt, respectively. It can be obtained by reacting a salt or a compound of the general formula [] or a salt thereof with an amine represented by the formula R ¹ -H (R ¹ has the same meaning as described above). 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 xylene; dioxane, tetrahydrofuran, anisole, and diethylene glycol diethyl ether. Ethers; halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane; N/N-dimethylformamide, N/N
-Amides such as dimethylacetamide; Sulfoxides such as dimethyl sulfoxide; Alcohols such as methanol and ethanol; Nitriles such as acetonitrile;
Two or more of these solvents may be used in combination. The amount of cyclic amines to be used is preferably an excess amount, particularly 2 to 5 times the molar amount, relative to the compound of general formula [], the compound of general formula [] or its salt, or the compound of general formula [] or its salt, When the amount used is about 1 to 1.3 times the mole, the deoxidizing agent is used in an equimolar amount relative to the compound of general formula [], the compound of general formula [] or its salt, or the compound of general formula [] or its salt. You can use . As a deoxidizing agent, triethylamine, 1,8-diazabicyclo-[5,4,
0]-undec-7-ene (DBU), potassium tert-butoxy, potassium carbonate, sodium carbonate, sodium hydride, and other inorganic or organic bases. This reaction is usually carried out at 0 to 150°C.
Preferably, the reaction is carried out at 50 to 100°C, and the reaction time is usually 5 minutes to 30 hours, preferably 30 minutes to 3 hours.
It's time. In addition, compounds of the general formula [], [], [] or [] in which the carboxyl group is protected with a carboxyl protecting group, or salts thereof, can be treated in the presence of an ordinary acid or alkali used in a hydrolysis reaction. The corresponding compounds can be converted to free carboxylic acids by hydrolysis, usually at 0 to 100°C, preferably at 20 to 100°C, for 5 minutes to 50 hours, preferably 5 minutes to 4 hours. Furthermore, the general formula [], [],
The compound [ ] or [ ] or a salt thereof can be subjected to a salt-forming reaction or an esterification reaction, which are known per se, to form a salt or ester of the corresponding compound, respectively, as desired. It should be noted that the compound of the general formula [], [], [] or [] or a salt thereof has an active group (e.g. hydroxyl group,
(such as an amino group), protect the active group in advance using a conventional method, and after the reaction is complete,
The protecting group may be removed. The compound obtained as described above may be subjected to conventional isolation and purification operations such as column chromatography, recrystallization, and extraction. Next, the antibacterial activity and acute toxicity of representative compounds of general formula [] or salts thereof, which are the active ingredients of the antibacterial agent of the present invention, will be shown. 1 Antibacterial activity test method Bacterial solution cultured at 37°C for 20 hours in Heart Infusion broth (manufactured by Eiken Chemical Co., Ltd.) according to the Japanese Society of Chemotherapy standard method [CHEMOTHERAPY Vol. 29, No. 1, pp. 76-79 (1981)] was inoculated into Heart Infusion agar medium (manufactured by Eiken Kagaku Co., Ltd.) containing the drug, and after culturing at 37℃ for 20 hours, the presence or absence of bacterial growth was observed. (μg/ml). However, the amount of inoculated bacteria is 10 ⁴ cells/plate (10 ⁶ cells/ml)
And so. 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 *1 Data for inoculated bacteria amount of ¹⁰⁸ cells/ml

[Table] 2 Acute toxicity test Test compounds 1 and 2 above in mice (ICR
system, 〓, body weight 18-24 g) in intravenous administration
The LD ₅₀ value was 200 mg/Kg or more. The antibacterial agent of the present invention can be prepared by preparing the compound of the general formula [] or a salt thereof into tablets, capsules,
Powders, syrups, granules, suppositories, ointments,
Prepare into 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.) 0.1-100 depending on target administration
The dose may be administered in doses of mg/Kg/day in one to several doses. Examples Next, the present invention will be explained by giving reference examples, examples, and formulation examples. Note that the symbols used in Reference Examples and Examples have the following meanings. Me: methyl group, Et: ethyl group, Ac: acetyl group,

[Formula]; Allyl group reference example 2,6-dichloro-5-fluoronicotinic acid 21
Dissolve g in 210 ml of chloroform, add 23.8 g of thionyl chloride and N.N-dimethylformamide.
Add 0.1 g 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 ml of tetrahydrofuran. 25.1 g of diethyl ethoxymagnesium malonate prepared from 2.67 g of magnesium is dissolved in 110 ml of tetrahydrofuran and cooled to -40 to -30°C. To this solution, the previously prepared tetrahydrofuran solution of 2,6-dichloro-5-fluoronicotinic acid chloride was added dropwise at the same temperature over 30 minutes. After stirring this mixed solution at the same temperature for 1 hour,
Gradually warm up to room temperature. The solvent was distilled off under reduced pressure, and 200 ml of chloroform and water were added to the resulting residue.
Add 100ml and adjust the pH to 1 with 6N hydrochloric acid. The organic layer is separated, washed sequentially with 50 ml of water, 50 ml of 5% aqueous sodium bicarbonate solution and 50 ml of saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting oil was added with 50 ml of water and p
- Add 0.15 g of toluenesulfonic acid, react with vigorous stirring at 100°C for 2 hours, and then extract with 100 ml of chloroform. Add 50 ml of saturated saline solution to the organic layer.
After washing with
200, eluent: toluene), the melting point is 64.
23.5 g of 2,6-dichloro-5-fluoronicotinoyl acetic acid ethyl ester are obtained, exhibiting a temperature of ~65°C. IR (KBr) cm ^-1 ; ν _C=0 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 (1) 8.8 g of 2,6-dichloro-5-fluoronicotinoyl acetic acid ethyl ester is dissolved in 40 ml of benzene, 4.5 g of N.N-dimethylformamide dimethyl acetal is added, and the mixture is reacted at 70°C for 1.5 hours. Next, 4.1 g of 2,4-difluoroaniline was added to this reaction solution, and the mixture was reacted at room temperature for 4 hours, and then the solvent was distilled off under reduced pressure. When the obtained residue was purified by column chromatography (Wako silica gel C-200, eluent: chloroform), 2-
9.0 g of (2,6-dichloro-5-fluoronicotinoyl)-3-(2,4-difluorophenylamino)acrylic acid ethyl ester is obtained. IR (KBr) cm ^-1 : ν _C=O 1690 NMR (CDCl ₃ ); δ value 1.08 (3H, t, J=7Hz), 4.10 (2H, q,
J=7Hz), 6.77-7.40 (4H, m), 8.50 (1H,
d, J = 13Hz), 12.70 (1H, d, J = 13Hz) (2) 2-(2,6-dichloro-5-fluoronicotinoyl)-3-(2,4-difluorophenylamino)acrylic acid Dissolve 9.0 g of ethyl ester in 90 ml of N-N-dimethylformamide, add 3.6 g of sodium hydrogen carbonate, and heat to 120°C.
Incubate for 20 minutes. Then, the solvent is distilled off under reduced pressure, and the resulting residue is dissolved in 50 ml of chloroform. This reaction solution is washed successively with 30 ml of water and 30 ml of saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting crystalline material was washed with 30 ml of diethyl ether to give 7-chloro-
6-Fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1.
7.0 g of 8-naphthyridine-3-carboxylic acid ethyl ester are obtained. IR (KBr) cm ^-1 ; ν _C=O 1730, 1690 NMR (CDCl ₃ ); δ value 1.36 (3H, t, J=7Hz), 4.30 (2H, q,
J=7Hz), 6.80-7.60 (3H, m), 8.27
(1H, d, J = 7Hz), 8.42 (1H, s) (3) 7-chloro-6-fluoro-1-(2.4-
difluorophenyl)-1,4-dihydro-4
-3.5 g of oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester in 35 ml of chloroform.
Dissolved in N-acetylpiperazine.
Add 1.5 g and 1.6 g of triethylamine,
React at 60°C for 1 hour. Then, the solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography [Wako silica gel C-200, eluent: chloroform:ethanol = 30:1 (volume ratio)] to give a melting point of 207. 7 indicating ~209℃
-(4-acetyl-1-piperazinyl)-6-fluoro-1-(2,4-difluorophenyl)-
1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester 3.5
get g. IR (KBr) cm ^-1 ; ν _C=O 1730, 1695 NMR (CDCl ₃ ); δ value 1.38 (3H, t, J=7Hz), 2,05 (3H,
s), 3.53 (8H, bs), 4.30 (2H, q, J=
7Hz), 6.80-7.75 (3H, m), 8.0 (1H,
d, J=13Hz), 8.30 (1H, s) In the same manner, the compounds shown in Table 2 below were obtained.

【table】

[Table] (4) 7-(4-acetyl-1-piperazinyl)-6
-Fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8
2.5 g of naphthyridine-3-carboxylic acid ethyl ester is dissolved in 25 ml of 6N hydrochloric acid and reacted under reflux for 2 hours. Then, the reaction solution was cooled to room temperature and adjusted to pH 12 with 1N aqueous sodium hydroxide solution.
After adjusting to PH6.5 with acetic acid. If the precipitated crystals are collected, washed with 30 ml of water, and dried, 6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-
1.8 g of oxo-7-(1-piperazinyl)-1,8-naphthyridine-3-carboxylic acid are obtained. NMR (TFA-d ₁ ); δ value 3.30-4.50 (8H, m), 7.0-7.85 (3H,
m), 8.33 (1H, d, J = 13Hz), 9.21
(1H, s), Compounds shown in Table 3 below were obtained in the same manner.

[Table] Example 2 (1) 7-chloro-6-fluoro-1-(2.4-
difluorophenyl)-1,4-dihydro-4
0.50 g of -oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester is suspended in 15 ml of 6N hydrochloric acid and heated under reflux for 3 hours. Next, the reaction solution was diluted with 50 ml of water, extracted three times with 50 ml of chloroform each time, and the combined extracts were added with 100 ml of saturated saline.
After washing with water, dry with anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting crystalline substance is washed with 15 ml of diethyl ether to give 7-chloro-6-fluoro-1-(2,4-difluorophenyl), which has a melting point of 244-248°C. -1・4
0.40 g of -dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid is obtained. IR (KBr) cm ^-1 ; ν _C=O 1720 NMR (d ₆ -DMSO); δ value 7.26-8.56 (3H, m), 8.86 (1H, d, J=
7Hz), 9.18 (1H, s) (2) 7-chloro-6-fluoro-1-(2.4-
difluorophenyl)-1,4-dihydro-4
-0.30 g of oxo-1,8-naphthyridine-3-carboxylic acid was suspended in 3 ml of dimethyl sulfoxide, and 0.25 g of N-methylpiperazine was added.
Incubate at 60°C for 30 minutes. Then, the solvent was distilled off under reduced pressure, and 30 ml of water was added to the resulting residue.
After adjusting the pH to 12 with a 10% aqueous sodium hydroxide solution, the pH is further adjusted to 7 with acetic acid. If you take the precipitated crystalline substance and wash it with 5 ml of water, the melting point
6-fluoro-1-(2.4
-difluorophenyl)-1,4-dihydro-
7-(4-methyl-1-piperazinyl)-4-oxo-1,8-naphthyridine-3-carboxylic acid
Obtain 0.24g. IR (KBr) cm ^-1 ; ν _C=O 1730 NMR (TFA-d ₁ ); δ value 3.30 (3H, s), 3.45-5.25 (8H, m), 7.12
~8.10 (3H, m), 8.49 (1H, d, J=13
Hz), 9.38 (1H, s) Example 3 (1) 5.5 g of 2,6-dichloro-5-fluoronicotinoyl acetic acid ethyl ester, 2.37 g of N-methylpiperazine and 2.37 g of triethylamine were dissolved in 55 ml of chloroform, Incubate for 2 hours at ~65°C. After washing the reaction solution with 30 ml of water,
Dry with 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
5.4 g of ethyl nicotinoyl acetate (piperazinyl) are obtained. IR (neat) cm ^-1 ; ν _C=O 1750, 1695 NMR (CDCl ₃ ); δ value 1.25 (3H, t, J=7Hz), 2.32 (3H,
s), 2.12-2.70 (4H, m), 3.55-3.96
(4H, m), 4.03 (2H, s), 4.20 (2H, q,
J=7Hz), 7.78 (1H, d, J=13Hz) Similarly, the compounds shown in Table 4 below were obtained.

[Table] (2) Dissolve 0.7 g of ethyl 2-chloro-5-fluoro-6-(4-methyl-1-piperazinyl) nicotinoyl acetate in 8 ml of benzene,
Add 0.267 g of N.N-dimethylformamide dimethyl acetal and react at 70°C for 3 hours. Add 2,4-difluoroaniline to this reaction solution.
Add 0.262g and react at room temperature for 4 hours.
Then, the solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography [Wako silica gel C-200, eluent: chloroform:ethanol = 60:1 (volume ratio)] to obtain oily 2
-[2-chloro-5-fluoro-6-(4-methyl-1-piperazinyl)nicotinoyl]-3-
0.52 g of (2,4-difluorophenylamino)acrylic acid ethyl ester is obtained. IR (neat) cm ^-1 ; ν _C=O 1735, 1700 (3) 2-[2-chloro-5-fluoro-6-(4-
Methyl-1-piperazinyl)nicotinoyl]-
After dissolving 0.5 g of 3-(2,4-difluorophenylamino)acrylic acid ethyl ester in 5.0 ml of N.N-dimethylformamide, 0.104 g of sodium bicarbonate is added and the mixture is reacted at 120°C for 3 hours. Then, the solvent is distilled off under reduced pressure, and the resulting residue is dissolved in 50 ml of chloroform. Add this solution to 30 ml of water and 30 ml of saturated saline.
After successively washing with water, drying with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting crystalline material was washed with 5 ml of diethyl ether to give 6-fluoro-1.
4-dihydro-1-(2,4-difluorophenyl)-7-(4-methyl-1-piperazinyl)
0.19 g of -4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester is obtained. IR (KBr) cm ^-1 ; ν _C=O 1735, 1720 Example 4 7-(4-methyl-1-piperazinyl)-6-fluoro-1-(2,4-difluorophenyl)-
0.2 g of 1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester
Add 4 ml of 1N aqueous sodium hydroxide solution and 4 ml of ethanol, and react at 40 to 50°C for 10 minutes. Next, acetic acid was added to the reaction solution to adjust the pH to 6.5, followed by extraction twice with 10 ml of chloroform each.
The combined extracts are washed successively with 10 ml of water and 10 ml of saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting crystalline material was washed with 4 ml of diethyl ether, with a melting point of 208.
7-(4-methyl-1-piperazinyl)-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1.
0.15 g of 8-naphthyridine-3-carboxylic acid is obtained. IR (KBr) cm ^-1 ; ν _C=O 1730 In the same manner, the compounds shown in Table 5 below were obtained.

【table】

[Table] Example 5 7-(3-amino-1-pyrrolidinyl)-6-fluoro-1-(2,4-difluorophenyl)-
After dissolving 2.0 g of 1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid in 20 ml of concentrated hydrochloric acid, 200 ml of ethanol was added at room temperature.
Stir for a minute. Remove the precipitated crystals and add 40ml of ethanol.
If washed with
-(3-amino-1-pyrrolidinyl)-6-fluoro-1-(2,4-difluorophenyl)-1,4
1.4 g of hydrochloride of -dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid are obtained. IR (KBr) cm ^-1 ; ν _C=O 1730 Similarly, the compounds shown in Table 6 below were obtained.

[Table] Example 6 (1) 2-(2,6-dichloro-5-fluoronicotinoyl)-3-(2,4-difluorophenylamino)acrylic acid ethyl ester 0.5 g, N
- 0.143 g of methylpiperazine and 0.145 g of triethylamine are dissolved in 2.5 ml of chloroform and heated under reflux for 3.5 hours. Then, the reaction solution was washed successively with 3 ml of water and 3 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,
Eluent: Chloroform:ethanol = 50:1
(volume ratio)], oily 2-[2-chloro-5-fluoro-6-(4-methyl-1-
piperazinyl) nicotinoyl]-3-(2,4-
0.294 g of difluorophenylamino)acrylic acid ethyl ester is obtained. IR (neat) cm ^-1 : ν _C=O 1735, 1700 NMR (CDCl ₃ ); δ value 1.13 (3H, t, J=7Hz), 2.36 (3H,
s), 2.55 (4H, t, J=5Hz), 3.70
(4H, t, J = 5Hz), 4.15 (2H, q, J =
7Hz), 6.77-7.90 (4H, m), 8.51 (1H,
d, J=13Hz), 12.50 (1H, d, J=13
Hz) (2) 2-[2-chloro-5-fluoro-6-(4-
Methyl-1-piperazinyl)nicotinoyl]-
Example 1-
If reacted and treated in the same manner as (2), the melting point will be 208 ~
6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-7-(4
-methyl-1-piperazinyl)-4-oxo-
1,8-naphthyridine-3-carboxylic acid 0.12g
get. Example 7 7-(4-ethoxycarbonyl-2-methyl-
1-piperazinyl)-6-fluoro-1-(2.4
-difluorophenyl)-1,4-dihydro-4
- Oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester 0.3 g - Add 5 ml of 1N aqueous sodium hydroxide solution and 5 ml of ethanol, and heat at 90℃ for 2 hours.
Allow time to react. Next, acetic acid was added to the reaction solution to adjust the pH.
Adjust to 6.5. After removing the precipitated crystals and washing with water,
6-Fluoro-1-(2,4-difluorophenyl)-1,4 with a melting point of 230-239°C when dried
-dihydro-7-(2-methyl-1-piperazinyl)-4-oxo-1,8-naphthyridine-3-
Obtain 0.2 g of carboxylic acid. IR (KBr) cm ^-1 ; ν _C=O 1730 NMR (TFA-d ₁ ); δ value 1.50 (3H, s), 3.20-5.15 (7H, m), 7.0-
7.90 (3H, m), 8.35 (1H, d, J = 13Hz) 9.2
(1H, s) Example 8 7-(3-acetylamino-1-pyrrolidinyl)-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1.
0.25 g of 8-naphthyridine-3-carboxylic acid ethyl ester is dissolved in 2.5 ml of 6N hydrochloric acid and reacted under reflux for 2 hours. Then, the reaction solution was cooled to room temperature, adjusted to pH 12 with a 1N aqueous sodium hydroxide solution, and then adjusted to pH 6.5 by adding acetic acid. The precipitated crystals are collected, washed with 2 ml of water, and dried to give 7-(3-amino-1-pyrrolidinyl)-6-fluoro-1-(2,4-difluorophenyl)-1,4-. dihydro-4-oxo-1.
0.18 g of 8-naphthyridine-3-carboxylic acid is obtained. NMR (TFA-d ₁ ); δ value 2.25-2.85 (2H, m), 3.37-4.69 (5H, m),
6.93-7.81 (3H, m), 8.22 (1H, d, J=11
Hz), 9.16 (1H, s) Example 9 1.0 g of 3-aminopyrrolidine dihydrochloride was suspended in 20 ml of ethanol, and 2.06 g of triethylamine was added.
Add and dissolve. Then, to this, 7-chloro-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8
-Naphthyridine-3-carboxylic acid ethyl ester
2.0g was added over 15 minutes at 30°C and reacted at the same temperature for 3 hours. After the reaction is complete, add 30ml of water to the reaction solution.
was added, and the precipitated crystals were collected and washed with 4 ml of water. The obtained crystalline substance was suspended in 13 ml of 6N hydrochloric acid,
React under reflux for 2 hours. Then, after cooling the reaction solution, the precipitated crystals were collected and washed twice with 2 ml of water each to give 7-(3-amino-1-pyrrolidinyl)-
6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-
1.97 g of naphthyridine-3-carboxylic acid hydrochloride are obtained. IR (KBr) cm ^-1 ; νC=O1730 Example 10 7-(3-amino-1-pyrrolidinyl)-6-fluoro-1-(2,4-difluorophenyl)-
Add 10.0 g of 1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid to 75 ml of ethanol.
and suspend in 75 ml of water. To this was added 5.2 g of p-toluenesulfonic acid monohydrate at 40°C, and the mixture was stirred at the same temperature for 30 minutes. Then, after cooling the reaction solution to 15°C, the precipitated crystals are collected and washed with a mixed solvent of 5 ml of ethanol and 5 ml of water, resulting in a melting point of 258~
7-(3-amino-1-pyrrolidinyl)-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1.
12.8 g of p-toluenesulfonate monohydrate of 8-naphthyridine-3-carboxylic acid is obtained. IR (KBr) cm ^-1 ; ν _C=O 1735 NMR (DMSO−d ₆ ); δ value

[Formula] 3.12-4.30 (5H, m), 6.92-8.17 (8H, m)
8.79 (1H, s) Formulation example 1 6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-7-(1
-piperazinyl)-1,8-naphthyridine-3-
50g carboxylic acid, 49g crystalline cellulose, 50g cornstarch and 1g magnesium stearate
are mixed and compressed into 1000 flat tablets to obtain tablets. Formulation example 2 6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-7-(1
-piperazinyl)-1,8-naphthyridine-3-
100 g of carboxylic acid and 50 g of cornstarch are mixed and filled into 1000 capsules to obtain capsules.

Claims (1)

[Claims] 1. General formula [In the formula, R ¹ represents an optionally substituted cyclic amino group. ] An antibacterial agent containing a 1,4-dihydro-4-oxonaphthyridine derivative or a salt thereof.