JP2666320B2 - Antibacterial compound - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a novel quinolocarboxylic acid compound or a salt thereof having improved antibacterial activity, a method for producing the same, and an antibacterial agent containing the novel compound as an active ingredient.

[Prior Art] Quinolonecarboxylic acid-based antibacterial agents have been developed from nalidixic acid to pyrimidic acid and pipemidic acid. These are clinically used as effective therapeutic agents for urinary tract infections against Gram-negative bacteria. In recent years, norfloxacin, enoxacin and ofloxacin, which have been developed, are currently widely used clinically as new quinolone antibacterial agents. Of these commercial products and developed products, those having a piperazinyl group at the 7-position are predominant. As a new system of compounds different from these commercially available products, some patent applications have been made for quinolone carboxylic acid compounds having a group having a crosslinked structure at the 7-position such as a piperazine ring or a fused heterocyclic group.

A group of derivatives having a bicyclo [4,3,0] nonan-4-yl group at the 7-position is one of them, and patent applications of such derivatives include JP-A-59-204194 and JP-A-60-166681. . These are (Hereinafter abbreviated as Comparative Compound A). Further, JP-A-59-137481, 59-204193, 60-
Related compounds are also disclosed in 23381, 60-23382, 62-174077 and 61-205258.

[Problems to be Solved by the Invention] Norfloxacin and enoxacin exhibit remarkable antibacterial activity against Gram-negative bacteria including Pseudomonas aeruginosa, but their activity against Gram-positive bacteria is not so strong as against Gram-negative bacteria. Further, when administered orally to animals or humans, further improvement in oral absorption or bioavailability (bioavailability) is desired. Ofloxacin is considered to be an antibacterial agent in which these problems have been improved to some extent, but it is not always satisfactory in terms of antibacterial activity.

An object of the present invention is to provide a quinolone carboxylic acid compound having a new structure with improved antibacterial activity as compared with such conventional quinolone compounds.

[Means for Solving the Problems] The present inventors have conducted intensive studies in order to obtain a quinolone carboxylic acid compound having better antibacterial activity. As a result, a cyclopropyl group at 1, a fluoro group at 6,8 position, The compound having a specific group of 1,4-diazabicyclo [4,3,0] nonan-4-yl group at the 7-position is surprisingly more gram than the quinolone-based compound having a similar structure which is conventionally specifically known. It has been found that it exerts excellent antibacterial activity not only on negative bacteria but also on gram-positive bacteria, and it also shows that it exhibits excellent antibacterial activity, especially when compared to comparative compounds with the most similar structure. After further investigation, the present invention has been completed.

That is, the present invention provides a compound of the formula [I] (Hereinafter abbreviated as compound [I]) or a salt thereof, a production method thereof, and an antibacterial agent containing them.

Among the optical isomers of the compound [I] of the present invention, the 6S form of the 1,4-diazabicyclo [4,3,0] nonan-4-yl group of the substituent at the 7-position of quinoline is particularly excellent in antibacterial activity. .

The compound of the present invention represented by the formula [I] or a salt thereof is represented by the general formula [II] (Wherein R represents a carboxyl group which may be esterified, and Y represents a reactive leaving group) or a salt thereof (hereinafter abbreviated as compound [II]) and formula [III] Ie, 6 (S) -1,4-diazabicyclo [4,3,0] nonane, 6 (S) -1,4-diazabicyclo [4,3,0] nonane or 6 (R, S) -Obtained by condensing diazabicyclo [4,3,0] nonane and, if necessary, hydrolyzing. Examples of the ester portion of the esterified carboxyl group in the compounds represented by the formulas [I] and [II] include an optionally substituted lower alkyl, alkenyl, aryl, heterocyclic group and silyl group. Further, specific examples thereof include methyl ester, ethyl ester, propyl ester, benzyl ester, 4-nitrobenzyl ester, phenyl ester, pivaloyloxymethyl ester, acetoxymethyl ester and the like. Examples of the reactive leaving group include a halogen atom (eg, fluorine, chlorine), arylsulfonyl (eg, benzenesulfonyl, p-tolylsulfonyl), arylsulfinyl (eg, benzenesulfinyl), lower alkylsulfonyl (eg, methanesulfonyl) ), Arylsulfonyloxy (eg, benzenesulfonyloxy), lower alkylsulfonyloxy (eg, methanesulfonyloxy) and the like.

The present invention relates to alcohols such as ethanol, ethers such as dioxane, tetrahydrofuran and 1,2-dimethoxyethane, aromatic hydrocarbons such as benzene, toluene and xylene, acetonitrile, dimethylformamide, dimethylacetamide, dimethylsulfoxide, N −
In an inert solvent such as methylpyrrolidone at 10 to 200 ° C, preferably 50 to 150 ° C, for 30 minutes to 24 hours, usually 1 hour.
Perform for ~ 5 hours.

This reaction is generally carried out in the presence of a deoxidizing agent using the starting compound [III] in an equivalent amount or a slight excess with respect to the starting compound [II]. Examples of the deoxidizing agent include hydroxides such as sodium hydroxide and potassium hydroxide, sodium carbonate,
Examples thereof include carbonates such as potassium carbonate, bicarbonates such as sodium hydrogencarbonate, and organic bases such as triethylamine, pyridine and picoline. Note that pyridine, picoline, triethylamine or the like may be used in excess to combine the role of a deoxidizing agent with the role of a solvent. Alternatively, the starting compound [II
I] may be used in excess to also serve as a deoxidizing agent.

Further, when R is an esterified carboxyl group, after this condensation reaction, if necessary, a group represented by R or the like can be converted into a carboxyl group by a generally well-known method, for example, hydrolysis with an acid or alkali. it can.

Next, the compound represented by the formula [I] can be converted into a salt thereof according to a conventional method, if desired. As the salt of the present invention, commonly used non-toxic salts are suitable, for example,
Salts with inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid, and salts of organic acids such as methanesulfonic acid, lactic acid, citric acid, tartaric acid and the like can be mentioned. Further, an alkali metal or alkaline earth metal salt at the 3-position carboxyl group, for example, sodium, potassium,
Salts such as calcium and magnesium are included.

[I] or a salt thereof thus obtained can be obtained by a method known per se, for example, concentration, liquid conversion, phase transfer, solvent extraction,
It can be isolated and purified by lyophilization, crystallization, recrystallization, chromatography and the like.

The starting compound represented by the formula [II] can be produced, for example, according to the method described in JP-A-61-1682 or a method similar thereto.

The other starting compound represented by the formula [III], that is, 6 (S) -1,4-diazabicyclo [4,3,0] nonane, 6 (R) -1,4-diazabidiclo [4,3,0] Nonane and 6 (R, S) -1,4-diazabicyclo [4,3,0] nonane are described in The Journal of Organic Chemistry, Vol. 25, pp. 2108 (1960), 33, 2379 (1968), JP-A-59-20419.
3, a known substance disclosed in JP-A-60-166681 and the like.

When the compound [I] of the present invention or a physiologically acceptable salt thereof is used as an antibacterial agent for humans, the dose varies depending on age, body weight, symptoms, administration route, administration frequency, and the like. 0.5 to 500 mg / kg per day, preferably 5 to 10
0 mg / kg is preferably administered in divided doses two to three times a day. The administration route may be oral or parenteral.

The compounds of the present invention may be in bulk, but are usually administered in a form prepared with a pharmaceutical carrier. Specific examples thereof include tablets, capsules, granules, fine granules, powders, syrups, and injections. These preparations are prepared according to a conventional method. As the pharmaceutical carrier for oral use, substances commonly used in the pharmaceutical field such as starch, mannitol, crystalline cellulose, sodium carboxymethylcellulose and the like are used. As the carrier for injection, distilled water, physiological saline, glucose solution, infusion agent and the like are used.

[Effects of the Invention] Examples 1, 2, and 3, which are representative compounds of the present invention described below.
The in vitro antibacterial activity of the compound (1) was examined together with the in vitro antibacterial activity of commercially available ofloxacin and the comparative compound A. The results are shown in Table I.

The in vitro antimicrobial activity was represented by the minimum inhibitory concentration (MIC) in μg / ml according to the following method.

Measurement method The MIC value of the test compound was determined using the agar dilution method.
hod). That is, 1.0 ml of an aqueous solution of a test compound which has been sequentially diluted is poured into a petri dish, and then trypticase soy agar (Trypticase soy agar) is added.
agar) Pour 9.0 ml and mix. The suspension of the test bacteria (about 10 ⁸ CFU / ml) is spread on the mixed agar plate.

After culturing (incubation) at 37 ° C for 18 hours, the minimum concentration of the test compound that completely inhibits the growth of the test bacterium is defined as the minimum inhibitory concentration (MIC).

As can be seen from the minimum inhibitory concentrations shown in Table I, the compounds of the present invention show stronger antibacterial activity not only against Gram-negative bacteria but also against Gram-positive bacteria as compared with commercially available ofloxacin and Comparative compound A. Therefore, the compound of the present invention is useful as a therapeutic agent for diseases such as animals and fish including humans caused by various pathogenic bacteria, and can also be used as a preservative for agricultural chemicals, foods, or a disinfectant for surgical instruments.

[Examples] Hereinafter, the present invention will be described in more detail with reference to examples, but these are merely examples and do not limit the present invention in any way.

In the following examples, NMR spectra were obtained using XL-100A (10%) using tetramethylsilane as an internal or external reference.
0MHz), EM360 (60MHz), EM390 (90MHz) or T ₆₀ (60M
Hz) spectrometer, and all δ values are shown in ppm. In the mixed solvents, the numerical values shown in parentheses are the volume mixing ratios of the respective solvents. The symbols in the examples have the following meanings.

s: singlet dd: double doublet m: multiplet J: coupling constant Example 1 (-)-1-cyclopropyl-6,8-difluoro-7-
[(6S) -1,4-diazabicyclo [4,3,0] nonane-4-
Yl] -1,4-dihydro-4-oxo-quinoline-3-
Carboxylic acid 1.0 g of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (obtained according to JP-A-61-1682) and 1.0 g of (6S ) -1,4-
1.1 g of diazabicyclo [4,3,0] nonane and 7 ml of pyridine
And then reflux for 1.5 hours. The solvent is distilled off under reduced pressure,
15 ml of ethanol was added to the residue, and the crystals were collected by filtration and recrystallized from a mixed solvent of ethanol and chloroform (-).
-1-cyclopropyl-6,8-difluoro-7-[(6
S) 830 mg of 1,4-diazabicyclo [4,3,0] nonan-4-yl] -1,4-dihydro-4-oxo-quinoline-3-carboxylic acid are obtained.

Melting point 212-214 ° C ▲ [α] ^{24 °} _D ▼ = -54.1 ° (c = 1.06, 1 / 10N NaOH) Elemental analysis Calculated as C ₂₀ H ₂₁ N ₃ O ₃ F ₂ Calculated: C, 61.69; H, 5.44 ; N, 10.79 Found: C, 61.41; H, 5.48 ; N, 10.58 NMR spectrum _{(CDCl 3) δ: 1.1-2.6 (} 12H, m), 2.95-
3.8 (4H, m), 3.8-4.3 (2H, m), 7.83 (1H, dd, J = 2Hz and 1
2Hz), 8.73 (1H, s) Example 2 (±) -1-cyclopropyl-6,8-difluoro-7-
[(6R, S) -1,4-diazabicyclo [4,3,0] nonane-4
-Yl] -1,4-dihydro-4-oxo-quinoline-3
-Carboxylic acid 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid 0.4 g and (6R, S) -1,4-diazabicyclo [4, 3,0] Nonane 0.45g
Are dissolved in 6 ml of pyridine and heated at 100 ° C. for 2 hours. The solvent was distilled off under reduced pressure, and 10 ml of ethanol was added to the residue.
Filter the crystals. Recrystallization from a mixed solvent of ethanol and chloroform gives (±) -1-cyclopropyl-6,8-
0.4 g of difluoro-7-[(6R, S) -1,4-diazabicyclo [4,3,0] nonan-4-yl] -1,4-dihydro-4-oxo-quinoline-3-carboxylic acid was obtained. Can be

Mp 224-225 ° Elemental analysis _{C 20 H 21 N 3 O 3} F 2 Calculated: C, 61.69; H, 5.44 ; N, 10.79 Found: C, 61.52; H, 5.37 ; N, 10.71 Example 3 ( +)-1-cyclopropyl-6,8-difluoro-7-
[(6R) -1,4-diazabicyclo [4,3,0] nonane-4-
Yl] -1,4-dihydro-4-oxo-quinoline-3-
Carboxylic acid 0.5 g of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid and (6R) -1,4-diazabicyclo [4,3,0 0.47 g of nonane is dissolved in 7 ml of pyridine and heated at 90 ° C. for 2 hours. The solvent is distilled off under reduced pressure, ethanol is added to the residue, and the crystals are collected by filtration. After washing with ethanol and ethyl ether and drying, (+)-1-cyclopropyl-6,8-difluoro-7-[(6R) -1,4-diazabicyclo [4,3,0] nonan-4-yl]- 0.41 g of 1,4-dihydro-4-oxo-quinoline-3-carboxylic acid is obtained.

Melting point 214-216 ゜ ▲ [α] ¹⁷ _D ▼ = + 39.8 ゜ (c = 0.80, 1 / 10N NaOH) Elemental analysis Calculated as C ₂₀ H ₂₁ N ₃ O ₃ F ₂ Calculated: C, 61.69; H, 5.44 ; N, 10.79 Found: C, 61.65; H, 5.44; N, 10.67

Claims (6)

(57) [Claims] (1) General formula (Wherein R represents a carboxyl group which may be esterified) or a salt thereof. 2. The general formula (Wherein R represents a carboxyl group which may be esterified, and Y represents a reactive leaving group) or a salt thereof, and a compound represented by the general formula: 3. The method for producing a quinolone compound or a salt thereof according to claim 1, wherein the compound is condensed with a compound represented by the formula (1) and hydrolyzed if necessary. 3. The method of claim 1, wherein the quinolone compound is 1-cyclopropyl-6,
2. The compound according to claim 1, which is 8-difluoro-7-[(6S) -1,4-diazabicyclo [4,3,0] nonan-4-yl] -1,4-dihydro-4-oxoquinoline-3-carboxylic acid. Or a salt thereof. 4. The method of claim 1, wherein the quinolone compound is 1-cyclopropyl-6,
Claims being 8-difluoro-7-[(6R, S) -1,4-diazabicyclo [4,3,0] nonan-4-yl] -1,4-dihydro-4-oxoquinoline-3-carboxylic acid. Item 4. The quinolone compound or a salt thereof according to item 1. 5. The method of claim 1, wherein the quinolone compound is 1-cyclopropyl-6,
2. The compound according to claim 1, which is 8-difluoro-7-[(6R) -1,4-diazabicyclo [4,3,0] nonan-4-yl] -1,4-dihydro-4-oxoquinoline-3-carboxylic acid. Or a salt thereof. 6. An antibacterial agent comprising the quinolone compound according to claim 1 or a salt thereof.