JPH0154345B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention describes the general formula () useful as an antibacterial agent. (In the formula, R ¹ represents hydrogen or fluorine, X represents carbon or nitrogen, and Y represents an alkali metal. n
indicates 0 or 1, but when X is carbon, it indicates 1,
indicates 0 when is nitrogen. n' indicates 0 or 1. )
The present invention relates to a pyridonecarboxylic acid derivative or a salt thereof. The present inventors have previously demonstrated that quinoline or 1,8-naphthyridine carboxylic acid derivatives having fluorine at the 6th or 6th and 8th positions and piperacine or its derivatives at the 7th position are antibacterial agents that are strong against Gram-positive and negative bacteria. 141286/1986, 47658/1982). However, since these compounds are generally near neutral and poorly soluble in water, they are mainly used as oral preparations. However, in the case of oral administration, it is difficult to achieve complete absorption even with innovative formulations, and it is also difficult to obtain high blood concentrations, which poses problems in terms of bioavailability. Furthermore, the fact that these compounds generally have relatively high intravenous toxicity is one of the reasons why it is difficult to administer them intravenously. The present inventors synthesized various derivatives of these compounds and examined their water solubility and intravenous toxicity, and found that the N-methanesulfonate or its derivatives had excellent properties. For example, 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)quinoline-3-carboxylic acid (hereinafter referred to as compound A)
compared to its N-methanesulfonic acid sodium salt [sodium 1-(3-carboxy-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-quinolyl)piperazine-4-methanesulfonate] salt (hereinafter referred to as compound B) and disodium salt (hereinafter referred to as compound C)] are highly water-soluble.
Furthermore, when comparing the intravenous toxicity, Compounds B and C are less toxic than Compound A (2.3 times in terms of molar ratio,
2.9 times), and was safer.

[Table] On the other hand, as shown in Test Example 1, the antibacterial activity of Compound B was almost equivalent to that of Compound A on a molar basis (however, the table shows it in μg/ml). A compound represented by the general formula () is a compound represented by the general formula () (wherein R ¹ , n and n' have the same meanings as above) and formalin are represented by the general formula () HSO ₃ Y () (wherein Y has the same meanings as above) In the presence of the compound, in an inert solvent, at room temperature ~
Either by reacting in a temperature range of 100°C, or by reacting a compound represented by the general formula () with a compound represented by the general formula () HO-CH ₂ SO ₃ Y () (wherein, Y has the same meaning as above). compound in an inert solvent at room temperature to 100°C.
It can be produced by reacting at a temperature range of .degree. Water or a water-soluble organic solvent such as alcohols, ethers, etc. as an inert solvent;
A mixed solvent with The compound represented by the general formula () can be converted into its salt by a conventional method. Examples of the salt include salts of inorganic bases such as sodium and potassium, and salts of organic bases such as amines. The compound of the present invention has strong antibacterial activity against Gram-positive and -negative bacteria, and is useful as an antibacterial agent in the treatment of various infectious diseases. It is formulated and administered not only as an injection, but also as an oral drug, suppository, etc. Examples of the present invention will be shown below, but the present invention is not limited thereto. Example 1 5.5 g of acidic sodium sulfite was dissolved in 40 ml of water, and 4.5 g of 37% formalin was added dropwise while stirring. 75
After heating and stirring at °C for 30 minutes, the mixture was cooled to room temperature.
1-ethyl-6-fluoro-1,4 while stirring
16.0 g of -dihydro-4-oxo-7-(1-piperazinyl)quinoline-3-carboxylic acid was added.
After heating and stirring at 75°C for 0.5 to 3 hours, 50 to 100 ml of ethanol was added to the resulting transparent plate and cooled on ice.
The precipitated crystals were collected and washed with ethanol. The obtained crystals were recrystallized from a mixed solvent of water and ethanol to give a white to yellowish-white crystalline powder with 20.7
g (yield: 88%) of 1-(3-carboxy-1-
Ethyl-6-fluoro-1,4-dihydro-4-
Oxo-7-quinolyl)piperazine-4-methanesulfonic acid sodium salt was obtained. Gradually decomposes from around the melting point of 260℃. Elemental analysis value (as C ₁₇ H ₁₉ FN ₃ NaO ₆ S・2H ₂ O) C H N Calculated value (%) 43.31 4.92 8.91 Actual value (%) 43.37 4.94 8.88 Example 2 Add 16.5 g of acidic sodium sulfite to 50 ml of water While stirring, 13.5 g of 37% formalin was added dropwise. 75
After stirring at °C for 30 minutes, the mixture was cooled to room temperature. 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl) with stirring.
48g of quinoline-3-carboxylic acid, 6g of caustic soda
An aqueous solution of g and 150 ml of water was added thereto, and the mixture was stirred at 75°C for 1 hour. After cooling, 300 ml of ethanol was added, and the precipitated crystals were collected and washed with ethanol. Recrystallized from a mixed solvent of water and ethanol, 68.0g as colorless powder
(Yield: 92%) of 1-(3-carboxy-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-quinolyl)piperazine-4-methanesulfonic acid disodium salt was obtained. . Melting point over 300℃. Elemental analysis value (as C ₁₇ H ₁₈ FN ₃ Na ₂ O ₆ S・2H ₂ O) C H N Calculated value (%) 41.38 4.49 8.52 Actual value (%) 41.50 4.58 8.62 Example 3 Add 2.8 g of acidic sodium sulfite to water The mixture was dissolved to 100 ml, and 2.4 g of 37% formalin was added dropwise while stirring. 75
After stirring at °C for 30 minutes, the mixture was cooled to room temperature. While stirring, add 1-ethyl-6,8-difluoro-1,
9.0 g of 4-dihydro-4-oxo-7-(1-piperazinyl)quinoline-3-carboxylic acid monohydrate,
Next, an aqueous solution of 1.1 g of caustic soda and 10 ml of water was added, followed by stirring at 75° C. for 1 hour. Ethanol after cooling
500 ml was added, and the precipitated crystals were collected and washed with ethanol. Recrystallized from a mixed solvent of water and ethanol, 11.2g (yield: 81%) of 1-(3-
Carboxy-1-ethyl-6,8-difluoro-
1,4-dihydro-4-oxo-7-quinolyl)
Piperazine-4-methanesulfonic acid disodium salt was obtained. Melting point over 300℃. Elemental analysis value (as C ₁₇ H ₁₇ F ₂ N ₃ Na ₂ O ₆ S・4H ₂ O) C H N Calculated value (%) 37.30 4.60 7.68 Actual value (%) 37.44 4.14 7.93 Example 4 1-ethyl-6 -Fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8
To an aqueous solution of 320 mg of -naphthyridine-3-carboxylic acid, 44 mg of caustic soda and 1 ml of water was added 167 mg of hydroxymethanesulfonic acid sodium salt monohydrate with stirring, and the mixture was stirred at 75°C for 1 hour. After cooling, 5 ml of ethanol was added, and the precipitated crystals were collected and washed with ethanol. 477 is recrystallized from a mixed solvent of water and ethanol as a colorless to yellowish white powder.
mg (yield: 92%) of 1-ethyl-6-fluoro-
1,4-dihydro-4-oxo-7-(4-sulfomethyl-1-piperazinyl)-1,8-naphthyridine-3-carboxylic acid disodium salt was obtained.
Melting point over 300℃. Elemental analysis value (as C ₁₆ H ₁₇ FN ₄ Na ₂ O ₆ S・3.5H ₂ O) C H N Calculated value (%) 36.86 4.64 10.74 Actual value (%) 36.58 4.29 10.70 Example 5 7-[4-( p-aminobenzyl)-1-piperazinyl]-1-ethyl-6-fluoro-1,4-
Dihydro-4-oxoquinoline-3-carboxylic acid
An aqueous solution of 1.6 g of caustic soda and 10 ml of water was added with stirring into a mixture of 17.0 g of sodium sulfite, 4.4 g of acidic sodium sulfite, 3.7 g of 37% formalin, and 30 ml of water.
After stirring at 75℃ for 1 hour, add ethanol 150℃ after cooling.
ml was added, and the precipitated crystals were collected and washed with ethanol. Recrystallized from a mixed solvent of water and ethanol,
20.4 g (yield: 80%) of 7-[4
-(p-sulfomethylaminobenzyl)-1-piperazinyl]-1-ethyl-6-fluoro-1,4
-dihydro-4-oxoquinoline-3-carboxylic acid disodium salt was obtained. Melting point over 300℃. Elemental analysis value (as C ₂₄ H ₂₅ FN ₄ Na ₂ O ₆ S・4H ₂ O) C H N Calculated value (%) 45.42 5.24 8.83 Actual value (%) 45.53 5.04 8.92 Example 6 7-[4-(p -aminobenzyl)-1-piperazinyl]-1-ethyl-6,8-difluoro-1,
1.1 g of caustic soda and 5 ml of an aqueous solution were added to a mixture of 11.1 g of 4-dihydro-4-oxoquinoline-3-carboxylic acid, 4.1 g of hydroxymethanesulfonic acid sodium salt monohydrate powder and 70 ml of water with stirring. After stirring at 80-90°C for 2 hours, 200 ml of ethanol was added after cooling, and the precipitated crystals were collected and washed with ethanol. Recrystallized from a mixed solvent of water and ethanol, yielding 11.4 g as a colorless powder (yield: 68
%) of 7-[4-(p-sulfomethylaminobenzyl)-1-piperazinyl]-1-ethyl-6,8-
Difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid disodium salt was obtained. Melting point over 300℃. Elemental analysis value (as C ₂₄ H ₂₄ F ₂ N ₄ Na ₂ O ₆ S・5H ₂ O) C H N Calculated value (%) 42.99 5.11 8.35 Actual value (%) 43.14 5.01 8.55 Test example 1 Designated by the Japanese Society of Chemotherapy Antibacterial tests were conducted according to the method of . The results are shown in the table below.

【table】

[Table] Reference Example 1: Compound A [1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-
piperazinyl)quinoline-3-carboxylic acid] Example 1: Compound B [1-(3-carboxy-4-
Oxo-7-quinolyl)piperazine-4-methanesulfonic acid sodium salt] Example 2: Compound C [1-(3-carboxy-4-
Oxo-7-quinolyl)piperazine-4-methanesulfonic acid disodium salt] Reference example 2: 1-ethyl-6,8-difluoro-
1,4-dihydro-4-oxo-7-(1-piperazinyl)quinoline-3-carboxylic acid Reference example 3: 1-ethyl-1,4-dihydro-6-
Fluoro-7-(1-piperazinyl)4-oxo-1,8-naphthyridine-3-carboxylic acid Reference example 4: 1-ethyl-7-[4-(p-aminobenzyl)-1-piperazinyl]1,4 -dihydro-6-fluoro-4-oxoquinoline-3-
Carboxylic acid reference example 5: 7-[4-(p-aminobenzyl)-1
-piperazinyl]-1-ethyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

Claims (1)

[Claims] 1. General formula (In the formula, R ¹ represents hydrogen or fluorine, X represents carbon or nitrogen, and Y represents an alkali metal. n represents 0 or 1, but when X is carbon, it represents 1,
When X is nitrogen, it indicates 0. n' indicates 0 or 1. ) A pyridonecarboxylic acid derivative or a salt thereof. 2 1-(3-carboxy-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-quinolyl)piperazine-4-methanesulfonic acid sodium salt according to claim 1 Compound. 3 1-(3-carboxy-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-quinolyl)piperazine-4-methanesulfonic acid disodium salt according to claim 1 compound. 4 1-(3-carboxy-1-ethyl-6,8
-difluoro-1,4-dihydro-4-oxo-
The compound according to claim 1, which is 7-quinolyl)piperazine-4-methanesulfonic acid disodium salt. 5 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(4-sulfomethyl-1-
The compound according to claim 1, which is the disodium salt of (piperazinyl)-1,8-naphthyridine-3-carboxylic acid. 6 7-[4-(p-sulfomethylaminobenzyl)-1-piperazinyl]-1-ethyl-6-fluoro-1,4-dihydro-4-oxoquinoline-
The compound according to claim 1, which is a 3-carboxylic acid disodium salt. 7 7-[4-(p-sulfomethylaminobenzyl)-1-piperazinyl]-1-ethyl-6,8-
The compound according to claim 1, which is difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid disodium salt.