JP2621204B2 - Antibacterial compound - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a novel quinolone carboxylic acid compound 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. Most of these commercially available and developed products have a piperazinyl group at the 7-position, but quinolone carboxylic acid compounds having a condensed piperazinyl group at the 7-position are also new compounds different from these commercial products. Research has been done, and several patent applications have been filed. These patent applications include:
For example, JP-A-61-205258, JP-A-59-204193, JP-A-59-2041
94, 59-222494, 60-23381 and 60-23382. The rings condensed with the piperazinyl ring at the 7-position of the quinolone carboxylic acid compounds specifically disclosed in these patent applications are all saturated rings. On the other hand, a quinolone compound having a heterocyclic group in which an unsaturated ring is fused at the 7-position is disclosed in JP-A-60-166681.

[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 as strong as against Gram-negative bacteria. Further, further improvement in oral absorbability or bioavailability (bioavailability) when administered orally to animals or humans 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. Improved antibacterial activity against staphylococci such as methicillin / cephem-resistant Staphylococcus aureus and Staphylococcus epidermidis, and Gram-positive bacteria such as streptococci and streptococci, which are highly resistant to third-generation cephem strains, and side effects (particularly central There is a demand for an antibacterial agent having less).

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

[Means for Solving the Problems] The present inventors have conducted intensive studies to obtain a quinolone compound having better antibacterial activity, and as a result, 5,6,
7,8-tetrahydroimidazo [1,2-a] pyrazine-7-
A quinolone compound having a specific condensed heterocyclic group called an yl group was successfully created, and among the compounds having a specific condensed heterocyclic group at the 7-position, the quinolone compounds of the present invention having a specific group at the 1-position in particular Compounds or salts thereof, surprisingly, have been found to exhibit significantly better antibacterial activity not only against gram-negative bacteria but also against gram-positive bacteria as compared to conventionally specifically known quinolone compounds. It was completed.

That is, the present invention provides a compound represented by the general formula [I]: (Wherein X represents a halogen and R represents a carboxyl group which may be esterified) or a salt thereof, a production method thereof, and an antibacterial agent containing them as an active ingredient.

In the compound represented by the general formula [I], the ester portion of the esterified carboxyl group represented by R includes, for example, an optionally substituted lower alkyl, lower alkenyl, aryl, heterocyclic group and silyl group. No. Further, specific examples thereof include methyl ethyl, ethyl ester, 6-propyl ester, benzyl ester, 4-nitrobenzyl ester, phenyl ester, pivaloyloxymethyl ester, and acetoxymethyl ester.

The halogen represented by X includes fluorine, chlorine, bromine and iodine.

Among the compounds of the present invention, compounds wherein X is fluorine or chlorine and R is a carboxyl group are preferred. Particularly, a compound in which X is fluorine and R is a carboxyl group is an embodiment showing excellent antibacterial action.

The target compound of the present invention represented by the general formula [I] is represented by the general formula [II]: (Wherein Y represents a reactive leaving group, X and R are as defined above) or a salt thereof, and a general formula [III] By condensing the compound represented by the formula (1) and, if necessary, hydrolyzing it. Examples of the reactive leaving group in the formula [II] include a halogen atom (eg, fluorine, chlorine), an arylsulfonyl (eg, benzenesulfonyl, p-tolylsulfonyl), an arylsulfinyl (eg, benzenesulfinyl), a lower alkylsulfonyl ( For example, methanesulfonyl), arylsulfonyloxy (for example, benzenesulfonyloxy), lower alkylsulfonyloxy (for example,
Methanesulfonyloxy) and the like.

This reaction is carried out using alcohols such as ethanol, ethers such as dioxane, tetrahydrofuran and 1,2-dimethoxyethane, aromatic hydrocarbons such as benzene, toluene and xylene, acetonitrile, dimethylformamide, dimethylacetamide and dimethylsulfoxide. The reaction is carried out in an inert solvent at 10 to 200 ° C., preferably 50 to 150 ° C., for 30 minutes to 24 hours, usually 1 to 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, R can be converted to a carboxyl group after the condensation reaction, if desired, by a commonly known method, for example, hydrolysis with an acid or alkali.

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, alkali metal or alkaline earth metal salts at the carboxyl group, for example, salts of sodium, potassium, magnesium and the like can be mentioned.

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

As a salt of the starting compound represented by the general formula [II],
For the compound represented by the general formula [I], the salts as described above are applied as they are.

The other starting compound [III] is also described in, for example, Journal Chemical Research Synops 1984, p. 28,
(J. Chem. Research (S), 1984, 28) or a method similar thereto.

Furthermore, 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
It is preferable to administer 100100 mg / kg in 2 to 3 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] The in vitro antibacterial activity of the compound of Example 1 which is a representative compound of the present invention described below was examined together with the in vitro antibacterial activities of commercially available norfloxacin and ofloxacin. The results are shown in Table I. The in vitro antibacterial activity is
The minimum inhibitory concentration (MIC) was expressed in μg / ml by the following method.

Measurement method The MIC value of the test compound was determined using the agar dilution method.
ethod). That is, 1.0 ml of a sequentially diluted aqueous solution of the test compound is poured into a petri dish (petri dish),
Next is Trypticase s
oy 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. 1 at 37 ° C
After 8 hours of incubation (incubation), the lowest concentration of the test compound that completely inhibits the growth of the test bacteria is determined by the minimum inhibitory concentration (MI
C: minimal inhibitory concentration).

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 norfloxacin and ofloxacin. 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 examples and examples, but these are merely examples and do not limit the present invention in any way.

In the following Reference Examples and Examples, NMR spectra were measured using XL-tetramethylsilane as an internal or external standard.
It was measured with a 100A (100MHz), EM360 (60MHz) type spectrometer, and all δ values were shown in ppm. The numerical values shown in parentheses in the mixed solvents are the volume mixing ratios of the respective solvents. The symbols in Reference Examples and Examples have the following meanings.

s: Cyglet dd: Double doublet m: Multiplet J: Coupling constant Example 1 1-Syllopropyl-6,8-difluoro-7- (5,6,7,8
-Tetrahydroimidazo [1,2-a] pyrazin-7-yl) -1,4-dihydro-4-oxo-quinoline-3-carboxylic acid 1-sillopropyl-6,7,8-trifluoro-1,4- 1.0 g of dihydro-4-oxo-quinoline-3-carboxylic acid (obtained according to JP-A-61-1682) and 5,6,7,8-tetrahydroimidazo [1,2-a] pyrazine {Journal Chemical Research Synops> 1984, p. 28, (J. Che
m.Research (S), 1984, 28) obtained 1.73g
Is dissolved in 100 ml of tetrahydrofuran and refluxed for 2 hours. The solvent was distilled off under reduced pressure, 20 ml of methanol was added to the residue, and the crystals were collected by filtration and recrystallized from a mixed solvent of methanol and chloroform to give 1-cyclopropyl-6,8-difluoro-7- (5,6 , 7,8-tetrahydroimidazo [1,2-
a) Pyrazin-7-yl) -1,4-dihydro-4-oxo-quinoline-3-carboxylic acid 850 mg are obtained.

Melting point 283-285 ° C Elemental analysis C ₁₉ H ₁₆ F ₂ N ₄ O ₃・ 0.8H ₂ O Calculated: C, 56.94; H, 4.43; N, 13.98 Found: C, 56.82; H, 4.22; N, 13.68 NMR spectrum (CDCl ₃ -CD ₃ OD) δ: 1.2-1.4 (4H, m),
3.75-4.3 (7H, m), 6.95-7.2 (2H, m), 7.96 (1H, dd, J
= 12Hz, 2Hz), 8.81 (1H, s)

Claims (5)

(57) [Claims] 1. A compound of the general formula [I] (Wherein X represents a halogen and R represents a carboxyl group which may be esterified) or a salt thereof. 2. The method according to claim 1, wherein X is a fluorine atom.
Item. 3. A compound of the general formula [II] (Wherein X represents a halogen, R represents a carboxyl group which may be esterified and Y represents a reactive leaving group) or a salt thereof, and a general formula [III] Wherein the compound represented by the general formula [I] is condensed and, if necessary, hydrolyzed. Wherein X and R are as defined above, or a salt thereof. 4. A compound of the formula [I] (Wherein X represents a halogen and R represents a carboxyl group which may be esterified) or a salt thereof, which is an antibacterial agent. 5. The method according to claim 4, wherein X is a fluorine atom.
The antibacterial agent according to Item.