JPS6130675B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention has the following formula [] useful as an antibacterial agent. Novel 1-vinyl-6-fluoro-
This invention relates to 1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-3-carboxylic acid and salts thereof. Here, specific examples of the salt include salts with inorganic or organic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, tartaric acid, and methanesulfonic acid, and sodium salts and potassium salts of carboxylic acids. The present invention provides 1-vinyl-6-fluoro-1.8
This invention was completed based on the finding that -naphthyridine derivatives have a significantly enhanced antibacterial effect over a wider range than corresponding compounds that do not have a fluorine atom at the 6-position. The compound of the present invention [] and its salt can be prepared by (1) a method in which a 1,8-naphthyridine derivative having a functional group at the 7-position is reacted with an amine (7-position amino substitution method), (2) the same method as in the reference example described below. method, i.e. 1.
A method of subjecting diazonium fluoroborate at the 6-position of an 8-naphthyridine derivative to a Schiemann reaction to fluorinate the 6-position (6-position fluorination method);
and (3) a method similar to the method disclosed in JP-A-50-106974, that is, heating a 1,8-naphthyridine derivative having a substituent at the 1-position that can be converted into a vinyl group such as a 2-halogenoethyl group. Although it can be produced by a processing method (1-position vinylation method), the production method using the above-mentioned 1-position vinylation method will be explained in more detail as a representative example. The compound of the present invention [] has the general formula [] (In the formula, R ₁ is a hydrogen atom or a protective group, R ₂ is a hydrogen atom or a lower alkyl group, and X and Y are different from each other, such as a hydrogen atom, a halogen atom,
It means a lower alkoxy group, a benzyloxy group, an alcoholic hydroxyl group or a derivative thereof, or a group that can form a tertiary or quaternary amine with the remainder, and either X or Y is always a hydrogen atom. ) can be obtained by simply heating or heating in the presence of a catalyst such as an acidic substance, an acid anhydride, or a base, and then subjecting it to a hydrolysis reaction if desired. As a catalyst, in addition to ordinary acids such as hydrochloric acid, sulfuric acid, polyphosphoric acid, phosphoric anhydride, formic acid, acetic acid, toluenesulfonic acid, and acidic potassium sulfate, Lewis acids such as thionyl chloride, phosphorus oxychloride, boron trifluoride, and zinc chloride can be used. acids, caustic alkalis, alkali carbonates, metal hydrides such as sodium hydride, alkali metal alcoholates such as sodium ethylate, sodium methylate, potassium butoxide, pyridine,
Examples include collidine, benzyltrimethylammonium hydroxyside, acetic anhydride, phthalic anhydride, silver oxide, iodine, butyllithium, and the like. Heating conditions are usually selected within the range of 50 to 270°C. Although this reaction proceeds without a solvent, it is preferably carried out in the following solvent. That is, it is carried out in a solvent such as water, alcohol, acetic acid, dimethylformamide, dimethylsulfoxide, ether, benzene, dioxane, tetrahydrofuran, pyridine, or the like. In addition, the hydrolysis reaction carried out as desired is
This is carried out to remove the protecting group or ester residue in the reaction product to obtain the desired product. Such hydrolysis reaction is described, for example, in JP-A-50-108276.
It can be carried out according to the disclosure of the specification of the present invention. In general formula [], specific examples of the protecting group represented by R ₁ include acid residues such as acetyl, trifluoroacetyl, benzoyl, formyl, benzyloxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, p- Examples include groups that can be easily eliminated by hydrolysis, such as aryl or lower alkylsulfonyl groups such as toluenesulfonyl and methanesulfonyl, arylthio groups such as o-nitrophenylthio, vinyl groups, and 1-propenyl groups. In addition, the derivatives of alcoholic hydroxyl groups in the general formula [] include acyloxy groups such as acetyloxy, benzoyloxy, and ethoxycarbonyloxy, aryl or lower alkylsulfonyloxy groups, S-aryl or S-lower alkyldithiocarbonyloxy groups, etc. means. Furthermore, specific examples of groups that can form tertiary or quaternary amines with the remainder include -N( _CH3 ) ₂ , -N
( _C2H5 ) _{2 ,}

[Formula] -N(CH ₃ ) ₃ I, -N(C ₂ H ₅ ) ₃ OH,

Examples include [Formula]. The desired product [ ] can be obtained in the form of a salt, an ester, a free carboxylic acid, or a free amine depending on the selection of raw materials and reaction conditions, and these can be converted into each other. The antibacterial activity of the compound of the present invention thus obtained is shown below in comparison with a known corresponding compound unsubstituted at the 6-position.

[Table] The numbers in the table indicate the minimum inhibitory concentration (MIC; μg/ml) of the test compound against each test bacterium. The minimum inhibitory concentration was determined by serially diluting the test compound (0.01-100 μg/ml) in 5 ml of gravy broth (PH 7.0).
Next, 100 to 1000 live bacteria were inoculated, and after culturing at 37°C for 48 hours, judgment was made. Furthermore, the compound of the present invention [] has excellent antibacterial activity in animal experiments. For example, the therapeutic effect (ED ₅₀ ) of Compound A on mice systemically infected with Pseudomonas aeruginosa No. 12 (ddY strain, male) was approximately 3 mg/Kg when administered orally. Furthermore, the therapeutic effect (ED ₅₀ ) of the compound A of the present invention on mice (female) with ascending renal infection caused by Pseudomonas aeruginosa No. 12 was determined by oral administration. It was 0.56mg/Kg. The compound [ ] of the present invention and its salts have strong antibacterial activity, especially against Gram-negative bacteria including Pseudomonas aeruginosa, and can be applied in various forms not only as medicine but also as veterinary medicine, fish disease medicine, and food preservative. . Next, the present invention will be explained in more detail by referring to Reference Examples and Examples. Reference example N- to 2,6-dichloro-3-nitropyridine
Reacting ethoxycarbonylpiperazine, 6
-chloro-2-(4-ethoxycarbonyl-1-
6-Amino-2-(4-ethoxycarbonyl-1- piperazinyl)-3-nitropyridine (mp 132-134°C), and then treated with acetic anhydride in acetic acid to react with 6-acetylamino-2-nitropyridine.
(4-ethoxycarbonyl-1-piperazinyl)-
3-nitropyridine (mp168-169℃) was obtained,
This was subjected to catalytic reduction in acetic acid using 5% palladium on carbon as a catalyst to give 3-amino-6acetylamino-2-(4-ethoxycarbonyl-1-piperazinyl)pyridine. The 3-amino derivative obtained here was mixed with ethanol at 42% without purification.
Dissolve in a mixed solution consisting of hydroborofluoric acid (HBF ₄ ), and add an ethanol solution of isoamyl nitrite at below 0° C. while stirring. After 20 minutes, ether was added, and the precipitated crystals were collected by filtration and washed with a methanol-ether mixture and then with chloroform to give 6-acetylamino-2-(4-ethoxycarbonyl-1-piperazinyl)-3-pyridinediazonium fluoroborate. (Decomposition point 117-117.5℃) is obtained. This diazonium salt is suspended in toluene, heated gradually with stirring, and stirred for 30 minutes at a bath temperature of 120°C. Toluene was distilled off under reduced pressure, the residue was made alkaline by adding 10% aqueous sodium carbonate solution, then extracted with chloroform, and the extract was dried over potassium carbonate. The solvent is distilled off and the crystalline residue is recrystallized from ethyl acetate to obtain 6-acetylamino-2-(4-ethoxycarbonyl-1-piperazinyl)-3-fluoropyridine (mp 132-133°C). This 3-fluoro derivative was hydrolyzed with a 15% hydrochloric acid-methanol (1:2 V/V) mixture to obtain 6-amino-2-(4-ethoxycarbonyl-1-piperazinyl)-3-fluoropyridine. Diethyl ethoxymethylene malonate 130-140
Diethyl N-[2-(4
-ethoxycarbonyl-1-piperazinyl)-3
-fluoro-6-pyridinyl] aminomethylene malonate (mp 144-145°C), which was ring-closed by heating to 7-(4-ethoxycarbonyl-
1-piperazinyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3
-Carboxylic acid ethyl ester (mp279-281
℃) is obtained. 7-(4-ethoxycarbonyl-1-piperazinyl)-6-fluoro-1,4-dihydro-4-
10.5 g of oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester, dimethylformamide
A mixture consisting of 100 ml and 7.4 g of potassium carbonate
Heat to 100°C for 15 minutes. Then 10.1 g of ethylene bromohydrin in dimethylformamide (10 ml)
After adding the solution and reacting by heating at 100° C. for 45 minutes with stirring, the precipitated inorganic substances were filtered off, and the filtrate was concentrated to dryness under reduced pressure. Add 80 ml of water to the residue and collect the crystals by filtration. The obtained crystals were recrystallized from ethanol to give 10.2 g of 7-(4-ethoxycarbonyl-1).
-piperazinyl)-6-fluoro-1-(2-hydroxyethyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester. Melting point 215-217℃. 4.6 g of the above hydroxyethyl derivative is dissolved in 50 ml of chloroform, 5.0 g of thionyl chloride is added thereto, and the mixture is heated under reflux for 30 minutes. After cooling, water
Add 30 ml and neutralize with saturated aqueous sodium bicarbonate solution. The chloroform layer was separated, washed with water, dried with Glauber's salt, and then the solvent was distilled off. The residue was subjected to silica gel column chromatography using chloroform as a solvent, and the crystals obtained from the main fraction were recrystallized from ethyl acetate to yield 4.7 g of 1-(2-chloroethyl)-7-(4-ethoxycarbonyl). -1-piperazinyl)-6-fluoro-1,4-dihydro-4
-Oxo-1,8 naphthyridine-3-carboxylic acid ethyl ester is obtained. Melting point 143-144℃. Chloroethyl derivatives obtained in Examples and Reference Examples
2.27 g was dissolved in 15 ml of ethanol under heating, and a solution of 0.84 g of potassium hydroxide in ethanol (15 ml) was added thereto under stirring, followed by heating under reflux for 2 hours. The precipitated crystals are collected by filtration and washed with ethanol. The obtained crystals were heated and dissolved in 20 ml of water, and 10% acetic acid was added.
Adjust the pH to 4-5. Collect the precipitated crystals by filtration, wash with water,
Recrystallize from ethanol-chloroform mixture
1.74 g of 7-(4-ethoxycarbonyl-1-piperazinyl)-6-fluoro-1,4-dihydro-4-oxo-1-vinyl-1,8-naphthyridine-3-carboxylic acid are obtained. Melting point 246-248℃. 7-(4-ethoxycarbonyl-1-piperazinyl)-6-fluoro-1,4-dihydro-4-
Oxo-1-vinyl-1,8-naphthyridine-3
- Add 30 ml of 5% aqueous sodium hydroxide solution to 1.5 g of carboxylic acid, and heat under reflux for 5 hours while stirring. After cooling, acetic acid was added to adjust the pH to 7, and the precipitated crystals were collected by filtration. The obtained crystals were heated and dissolved in 10% acetic acid, the pH was adjusted to 9 by adding aqueous ammonia, the precipitated crystals were collected by filtration, and 0.98 g of 6-fluoro-1,4-dihydro-4-oxo-7-(1 -piperazinyl)-1-vinyl-1,8-naphthyridine-3-carboxylic acid is obtained. Melting point 256-260℃ (decomposition).

Claims (1)

[Claims] 1 1-vinyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,
8-Naphthyridine-3-carboxylic acid and its salts.