JPS6320828B2 - - 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 is an amino or acylamino group;
R ² represents a hydrogen atom or a carboxyl protecting group. ] and its salts. 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 [ ] and a salt thereof having 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 1,4-dihydro-4-oxonaphthyridine derivatives and salts thereof represented by the general formula [] 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. In the compound of general formula [] and its salt,
Examples of the acylamino group for R ¹ include C _1-4 acylamino groups such as acetylamino, propionylamino, and butyrylamino. Also,
As the carboxyl protecting group for ^R2 , 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. 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, in the compound of the present invention, isomers (for example, optical isomers, geometric isomers, tautomers, etc.)
If present, the present invention includes all isomers thereof and extends to all crystal forms and hydrates. Next, a method for producing the compound of the present invention will be explained. Methods for producing the compound of the present invention include methods known per se, and representative production methods will be explained in detail below. The compound of the present invention can be produced, for example, according to the following production route. [In the formula, R ³ represents a halogen atom, R ^2a represents a carboxyl protecting group similar to R ² , and R ¹ and R ₂ have the same meanings as described above.] As the halogen atom in R ³ , fluorine ,
Examples include chlorine, bromine, and iodine atoms. 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
For example, aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol dimethyl ether, and dithyl cellosolve; halogenated hydrocarbons such as methylene chloride, chloroform, and 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 13
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, 2,4-difluoroaniline is used in equal moles or more than equimolar amount to the compound of general formula [] or the compound or salt thereof of general formula []. , usually 0 to 100°C, preferably 10
~60℃, usually 20 minutes to 30 hours, preferably 1
Allow to react for ~5 hours. Alternatively, a compound of general formula [] or a compound of 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.
carried out at 20-160°C, preferably 100-150°C,
The reaction time is usually 5 minutes to 30 hours, preferably
It takes 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. A salt or a compound of the general formula [] or a salt thereof, the formula

〔Effect of the invention〕

Next, the antibacterial activity and acute toxicity of representative compounds of the present invention will be shown. 1 Antibacterial activity Test method Japanese Society of Chemotherapy Standard Method [CHEMOTHERAPY Vol. 29 No. 1 No. 76-79
(1981)], a bacterial suspension cultured at 37°C for 20 hours in Heart Infusion broth (manufactured by Eiken Chemical Co., Ltd.) was cultured in Heart Infusion agar medium containing a drug. (manufactured by Eiken Chemical Co., Ltd.)
After culturing at 37°C for 20 hours, the presence or absence of bacterial growth was observed, and the minimum concentration at which bacterial growth was inhibited was defined as the MIC (μg/ml). however,
The amount of inoculated bacteria was 10 ⁴ cells/plate (10 ⁶ 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

〔Example〕

Next, the present invention will be explained by giving reference examples and examples. 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 is 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, 5 ml of 5% aqueous sodium bicarbonate solution and 50 ml of saturated brine, 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
If purified with eluent: toluene), the melting point is 64-65℃.
23.5 g of 2,6-dichloro-5-fluoronicotinoyl acetic acid ethyl ester having the following properties are obtained. IR (KBr) cm ^-1 ; ν _C=O 1650, 1630, 1620 NMR (CDClC 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. The obtained residue was subjected to column chromatography (Wako silica gel C-200, eluent: chloroform).
2-(2,
6-dichloro-5-fluoronicotinoyl)-
9.0 g of 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-difluoro 9.0 g of phenylamino)acrylic acid ethyl ester in N,
Dissolve in 90 ml of N-dimethylformamide, add 3.6 g of sodium hydrogen carbonate, and react at 120°C for 20 minutes. Then, the solvent is distilled off under reduced pressure, and the resulting residue is dissolved in 50 ml of chloroform. Mix this reaction solution with 30ml of water and saturated saline.
After sequentially washing with 30 ml, dry with 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-, which had a melting point of 220-222°C.
Fluoro-1-(2,4-difluorophenyl)
-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester
Obtain 7.0g. 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
-0.50 g of oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester in 5 ml of chloroform.
0.20 g of 3-acetylaminopyrrolidine and 0.15 g of triethylamine are added thereto, and the mixture is 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; Chloroform: Ethanol = 30:1
(volume ratio)], 7-(3-acetylamino-1-pyrrolidinyl)-6-fluoro-1-(2,4-difluorophenyl)-1,4- exhibits a melting point of 233-235℃ dihydro-4-oxo-
0.50 g of 1,8-naphthyridine-3-carboxylic acid ethyl ester is obtained. IR (KBr) cm ^-1 ; ν _C=O 1725, 1700 Example 2 7-(3-acetylamino-1-pyrrolidinyl)
-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8
-Naphthyridine-3-carboxylic acid ethyl ester
Dissolve 0.25 g in 2.5 ml of 6N-hydrochloric acid, and add 2.5 g under reflux.
Allow time to react. 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.
If the precipitated crystals are taken, washed with 2 ml of water, and dried, 7-(3-amino-1-pyrrolidinyl)-6
-Fluoro-1-(2,4-difluorophenyl)
0.18 g of -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid is obtained. NMR (TFA- _d1 ); 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 = 11Hz), 9.16 ( 1H, s) Example 3 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 Example 4 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, 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 ; ν _C=O 1730 Example 5 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, which exhibits a temperature of 260°C.
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 1.82-2.42 (m) 2.27 (s) (5H), 3.12-4.30 (5H, m), 6.92-8.17 ( 8H, m), 8.79 (1H, s)

Claims (1)

[Claims] 1. General formula [In the formula, R ¹ is an amino or acylamino group;
R ² represents a hydrogen atom or a carboxyl protecting group. ] A 1,4-dihydro-4-oxonaphthyridine derivative and a salt thereof.