JPH0794452B2 - Novel pyridonecarboxylic acid derivative, its ester and its salt - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel pyridonecarboxylic acid derivative useful as an antibacterial agent, its ester and its salt.

2. Description of the Related Art Since it was revealed that nalidixic acid is useful as an antibacterial agent, various pyridonecarboxylic acid compounds have been synthesized and their usefulness as an antibacterial agent has been investigated. For example, JP-A-62-187459 discloses a pyridonecarboxylic acid derivative having a structure similar to that of the compound of the present invention,
It is pointed out that the pyridonecarboxylic acid disclosed herein does not always have sufficient photostability in an aqueous solution.

OBJECT OF THE INVENTION The present invention provides a pyridonecarboxylic acid derivative having a further enhanced antibacterial activity than conventional compounds and excellent light stability in an aqueous solution.

Structure of the Invention The compound of the present invention has the following formula (I): And pyridonecarboxylic acid derivatives, lower alkyl esters thereof and salts thereof.

In the present specification, examples of the halogen atom include fluorine, chlorine or bromine. Examples of the lower alkyl group include methyl, ethyl, propyl, butyl, isobutyl, t-butyl, pentyl, neopentyl and the like.

The salt of the compound of the present invention includes salts with inorganic acids such as hydrochloric acid and phosphoric acid; salts with organic acids such as acetic acid, lactic acid, oxalic acid, succinic acid, methanesulfonic acid, maleic acid, malonic acid and gluconic acid; Salts with acidic amino acids such as aspartic acid and glutamic acid; or metal salts of the compound of formula (I) such as sodium, potassium, calcium, magnesium, zinc and silver; organic bases such as dimethylamine, triethylamine, dicyclohexylamine and benzylamine And a salt with a basic amino acid such as lysine and arginine.

Examples of the lower alkyl ester of the compound of formula (I) include methyl ester, ethyl ester, propyl ester, butyl ester, pentyl ester and the like.

The compounds of the present invention may also exist as hydrates. Therefore, such forms are naturally included in the compound of the present invention.

Furthermore, since the compound of the present invention has a plurality of asymmetric carbon atoms, it exists as a stereoisomer, and these stereoisomers are also included in the compound of the present invention.

Next, a method for producing the compound of the present invention will be described.

The compound of the present invention has the following general formula (II) (In the formula, X means a halogen atom, Y means an amino group or a protected amino group, and R means a hydrogen atom or a lower alkyl group.) It can be produced by reacting the compound represented by and isolating the product by a conventional method.

This reaction is carried out in an inert solvent at 10 to 180 ° C, preferably 20 to 130 ° C.
In, the starting compounds (II) and (III) may be stirred for 10 minutes to 24 hours, preferably 30 minutes to 3 hours.

Examples of the solvent include dimethylformamide, ethanol, methanol, acetonitrile, water, chloroform,
Pyridine and the like can be mentioned. You may use these solvent individually or in mixture.

This reaction is generally carried out in the presence of an acid acceptor using the starting compound (III) in an equivalent amount to a slight excess of the starting compound (II). It may also be used as an acid acceptor.

Examples of the acid acceptor include organic bases such as triethylamine, dimethylaniline, N, N-diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-undecene (DBU) and pyridine, sodium hydroxide and potassium hydroxide. And the like, carbonates such as sodium carbonate and potassium carbonate, bicarbonates such as sodium bicarbonate and potassium bicarbonate, and the like.

The starting compounds (II) and / or (III) used in this reaction may be used, if necessary, in a form in which amino groups not involved in the reaction are protected, and the protecting groups may be removed by a conventional method after the reaction. . The protecting group may be any as long as it can be removed without destroying the structure of the compound of the present invention formed by the reaction, such as peptide, amino sugar,
A protecting group usually used as a protecting group in the field of chemistry of nucleic acids or β-lactam compounds is used. Preferred protecting groups include, for example, easily hydrolyzable groups such as acetyl, trifluoroacetyl, ethoxycarboyl,
Alternatively, an easily hydrogenolytic group such as a benzyl group may be mentioned as an example.

The starting compound (II) can be produced by the method described in Reference Examples 2, 3 and 5 or a method analogous thereto.

When the compound of the present invention thus obtained is a lower alkyl ester, it can be converted to the compound of formula (I) by hydrolyzing the ester portion by a conventional method.

The compound of the present invention thus produced is isolated and purified by a conventional method. Depending on the isolation and purification conditions, it can be obtained in the form of a salt or a free form, which are mutually converted depending on the purpose to produce the desired form of the compound of the present invention.

The stereoisomers of the compound of the present invention can be separated from each other by a conventional method such as fractional crystallization and chromatographic separation. A starting compound having a specific configuration may be used to produce the compound of the present invention having a corresponding specific configuration by the above method.

EFFECTS OF THE INVENTION The compound (I) thus obtained, its lower alkyl ester and its salt are all novel compounds, and since they show extremely excellent antibacterial activity, they are valuable as antibacterial agents. The compound (I) or a salt thereof can be used not only as a drug for humans and animals but also as a fish disease drug, an agricultural chemical, a preservative for foods, and the like. The ester form of compound (I) is valuable as a raw material for the synthesis of compound (I).

Next, the antibacterial activity and other properties of the compound of the present invention will be described in comparison with the following compounds.

The compound of the present invention: 5-amino-1-cyclopropyl-6-fluoro-7-
(Cis-3,5-Dimethyl-1-piperazinyl) -1,4-di
Hydro-4-oxoquinoline-3-carboxylic acid (Example
1 compound). Compound A: 1-Cyclopropyl-6-fluoro-7- (1-pipera
Dinyl) -1,4-dihydro-4-oxoquinoline-3-
Carboxylic acid (ciprofloxacin). Compound B: 5-amino-1-cyclopropyl-6,8-difluoro-
7- (1-Piperazinyl) -1,4-dihydro-4-oxy
Soquinoline-3-carboxylic acid (JP-A-62-187459)
Report). Test Example 1 (In vitro antibacterial activity) The minimum inhibitory concentration (MIC: μg / ml) was defined as Chemotherapy,29
According to the method described in (1), 76 (1981), Mueller
Measured by agar plate dilution method using Hinton medium
It was The results are shown in Table 1.

Test Example 2 (protective effect against infection) European Patent Publication No. 31
It was measured according to the method described in No. 2085. The results are shown in Table 2.

Test Example 3 (anti-mycoplasma activity) The anti-mycoplasma activity was measured according to the method described in European Patent Publication No. 312085. The results are shown in Table 3.

Test Example 4 (anti-chlamydia activity) The anti-chlamydia activity was measured according to the method described in European Patent Publication No. 312085. The results are shown in Table 4.

Test Example 5 (Acute Toxicity) The oral toxicity of the compound of the present invention to male Std-ddY mice was examined by a conventional method, and the LD ₅₀ value (mg / kg) was calculated by the Behrens-Kelber method. As a result, the oral toxicity (LD ₅₀ :> 2,000 mg / kg) of the compound of the present invention was extremely low.

Test Example 6 (urinary excretion) Oral administration of a suspension of the compound of the present invention to mice (5 mg / kg)
And collect urine for 24 hours after administration. The compound concentration in urine was quantified by a bioassay using Escherichia coli kp as an indicator bacterium, and a recovery rate of 8.33% was obtained.

Test Example 7 (Light stability in aqueous solution) Each compound is dissolved in 0.1N hydrochloric acid or 0.1N sodium hydroxide aqueous solution to prepare a 0.05 mg / ml test solution.

Put each sample solution in a 10 ml colorless volumetric flask and irradiate with light under fluorescent lamp (6000 lux) at 20 ° C. for 100 hours. The compound content in the solution at the start of the experiment and after 100 hours was calculated by comparison of peak heights with the standard solution using high performance liquid chromatography.

The results are shown in Table 5. The numbers in the table represent the residual rate (%) when the initial value is 100.

The compounds of the present invention show excellent antibacterial activity and broad antibacterial spectrum in in vitro tests.

In addition, the compound of the present invention exhibits an excellent protective effect against systemic infections of various bacteria in animals, and also shows good safety in general toxicity tests in animals.

Furthermore, the compound of the present invention has excellent properties not only in urinary excretion but also in light stability in an aqueous solution.

Therefore, the compound of the present invention is a compound useful as an antibacterial agent for injection as well as an oral antibacterial agent.

When the compound of the present invention is used as an antibacterial agent in humans, it is recommended to administer 5 mg to 5 g per day in one to several doses, although the dose varies depending on age, body weight, symptoms, administration route, etc. To be done.

While the compound of the present invention may be administered as the bulk powder, it is usually administered in the form prepared together with a carrier for formulation. Specific examples thereof include tablets, liquids, pscels, granules, fine granules, powders, syrups, injections, ointments and the like. These preparations are prepared according to a conventional method. As the oral pharmaceutical carrier, substances commonly used in the pharmaceutical field such as starch, mannitol, crystalline cellulose, CMC Na, water and ethanol and which do not react with the compound of the present invention are used.
Examples of carriers for injection include carriers commonly used in the field of injectables such as water, physiological saline, glucose solutions, and infusions.

Further, the above-mentioned solutions and ointments can also be used in otolaryngology and ophthalmology treatment.

EXAMPLES Next, the production method of the compound of the present invention will be explained more specifically with reference to Reference Examples and Examples.

Reference Example 1 Ethyl 3-cyclopropylamino-2- (2,3,4,6-tetrafluorobenzoyl) acrylate: (1) Known compound 2,3,4,6-tetrafluorobenzoic acid 38.
Treatment of 8 g with thionyl chloride gives 36 g of oily 2,3,4,6-tetrafluorobenzoic acid chloride. bp87-89 ° C (3
6mmHg). (2) 36 g of the above compound is reacted with sodium diethyl malonate in anhydrous toluene to obtain diethyl 2,3,4,6-tetrafluorobenzoylmalonate as an oil. To this, add water and a catalytic amount of p-toluenesulfonic acid, and add 2.5
After heating under reflux for 2 hours, 28.4 g of oily ethyl 2,3,4,6-tetrafluorobenzoyl acetate is obtained. bp103-104 ℃ (3mm
Hg). (3) 28.4 g of the above compound was treated with ethyl orthoformate and acetic anhydride to give ethyl 3-ethoxy-2- (2,3,4,6-tetrafluorobenzoyl) acrylate, and then this compound was cyclopropylamine. Process with 3
Get 2.8g.

mp107-108 ° C. Reference Example 2 Ethyl 1-cyclopropyl-5,6,7-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate: 3-cyclopropylamino-2- (2,3,4,6 15% of a mixture of 33 g of ethyl tetrafluorobenzoyl) acrylate, 8.85 g of potassium fluoride and 100 ml of dimethylformamide.
After stirring at 0 to 160 ° C for 2 hours, the mixture is allowed to cool to room temperature. 300 ml of water is added to the reaction solution and the crystals are collected by filtration. Chloroform and water are added to the crystals, and the aqueous layer is made alkaline with saturated aqueous sodium carbonate. The chloroform layer is separated, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The residue was applied to column chromatograph and the desired product (mp 220-221 ° C,
2.0g) was obtained. In addition, 1-cyclopropyl-5,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3
-Ethyl carboxylate (mp 211-212 ° C, 27g) was also separated.

Reference Example 3 Ethyl 5-benzylamino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate: 1-cyclopropyl-5,6,7-trifluoro- Ethyl 1,4-dihydro-4-oxoquinoline-3-carboxylate 2.57
A mixture of g, 1.8 ml of benzylamine and 180 ml of trichlene is heated under reflux for 3 hours and 40 minutes. After adding water and 10% hydrochloric acid to the reaction solution to make the aqueous layer acidic, the trichlene layer is separated and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was separated and purified by silica gel column chromatography to obtain the desired product.
I get 2.78g. mp144-145 ° C. Reference Example 4 Ethyl 2- (N-acetyl-2-benzylamino-3,4,6-trifluorobenzoyl) -3-cyclopropylaminoacrylate: (1) 2,3,4,6-tetrafluorobenzoic acid A mixture of 19.4 g, dioxane 20 ml and benzylamine 35.3 ml is heated to reflux for 3 hours. The reaction mixture is concentrated to dryness under reduced pressure, water is added to the residue, the pH is adjusted to 3 with hydrochloric acid, and the mixture is extracted with ethyl acetate. After the extract is dried, it is treated with activated carbon and concentrated. Ether and n-hexane were added to the residue and the crystals were collected by filtration to obtain 20.2 g of 2-benzylamino-3,4,6-trifluorobenzoic acid.

mp140-141 ° C. (2) A mixture of 21.7 g of the above compound, 16.8 ml of acetic anhydride and 200 ml of chloroform is heated under reflux for 9 hours. The reaction solution is pH 9
Extract with ~ 10 aqueous sodium hydroxide. The extract is adjusted to pH 3-4 with hydrochloric acid and then extracted with ethyl acetate. The extract was dried, concentrated under reduced pressure, isopropyl ether was added to the residue, and the crystals were collected by filtration to obtain 17.6 g of 2- (N-acetylbenzylamino) -3,4,6-trifluorobenzoic acid.

mp150-153 ° C. (3) A mixture of 1.6 g of the above compound, 0.99 ml of triethylamine and 10 ml of toluene is ice-cooled, and 3 ml of a toluene solution of 0.62 ml of ethyl chlorocarbonate is added dropwise thereto over 10 minutes. After stirring for 1 hour, the precipitate is filtered off (reaction solution A). To a toluene solution of 1.67 ml of diethyl malonate, 780 mg of 92% sodium ethoxide was added, and the mixture was stirred at room temperature for 1 hour. After distilling off the produced ethanol, the Hanno station A was added dropwise thereto at room temperature and stirred for 2 hours. The reaction solution was extracted with a sodium hydroxide aqueous solution having a pH of 10 to 11, and the extract was adjusted to pH 3 to 4 with hydrochloric acid,
Extract with ethyl acetate. The extract was dried and then concentrated to dryness under reduced pressure, and the residue was purified by silica gel coromatography (extract: chloroform) and diethyl 2- (N-acetylbenzylamino) -3,4,6-trifluorobenzoylmalonate. Get 2.3 g. 10 ml of water and 480 mg of p-toluenesulfonic acid monohydrate are added to this and heated under reflux for 1 hour. After cooling, extract with ethyl acetate, dry the extract and concentrate under reduced pressure to give 2
1.9 g of ethyl-(N-acetylbenzylamino) -3,4,6-trifluorobenzoyl acetate are obtained.

(4) A mixture of 1 g of the above compound, 0.6 ml of acetic anhydride and 0.64 ml of ethyl orthoformate is heated under reflux for 1.5 hours. The reaction mixture was concentrated to dryness under reduced pressure, the residue was dissolved in isopropyl ether, and 0.2 ml of cyclopropylamine was added under ice cooling to add 1
Stir for hours. 10 ml of n-hexane was added to the reaction solution, and the precipitated crystals were collected by filtration to obtain 933 mg of the desired product. mp119 ~ 12
1 ° C. Reference Example 5 5-benzylamino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid: (1) 2- (N-acetyl-2-benzylamino- 3,4,
Ethyl 6-trifluorobenzoyl) -3-cyclopropylaminoacrylate 26.3 g of tetrahydrofuran 150 ml
Then, 7.1 g of potassium t-butoxide is added little by little under ice cooling and stirred for 30 minutes. After stirring at room temperature for 1.5 hours, ice water was added, the pH was adjusted to 4-5 with hydrochloric acid, and the mixture was extracted with chloroform. The extract was dried and then concentrated to dryness under reduced pressure, ether was added to the residue, and the crystals were collected by filtration to give 5- (N-acetylbenzylamino) -1-cyclopropyl-6,7-difluoro-1,4.
21.4 g of ethyl dihydro-4-oxoquinoline-3-carboxylate are obtained. mp147-150 ° C. (2) 4.4 g of the above compound in concentrated sulfuric acid-glacial acetic acid-water (1: 8:
Add 20 ml of the mixture of 6) and heat to reflux for 6 hours. After cooling, water is added to the reaction solution, crystals are collected by filtration, and washed successively with water and ethanol. Recrystallization from chloroform-ethanol gives 3.0 g of the desired product as pale yellow needle crystals. mp214 ~ 2
16 ° C. Example 1 5-amino-1-cyclopropyl-6-fluoro-7-
(Cis-3,5-Dimethyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid: (1) 5-benzylamino-1-cyclopropyl-6 obtained in Reference Example 5 A mixture of 1.0 g of 7,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 1.08 g of cis-2,6-dimethylpiperazine and 10 ml of pyridine is heated under reflux for 4 hours. The solvent was distilled off under reduced pressure and ethanol was added to the residue.
Add 15 ml, heat and stir at 80 ° C., and then cool with ice. The precipitated crystals were collected by filtration and recrystallized from chloroform-ethanol,
5-benzylamino-1-cyclopropyl-6-fluoro-7- (cis-3,5-dimethyl-1-piperazinyl)
1.13 g of -1,4-dihydro-4-oxoquinoline-3-carboxylic acid are obtained. mp184-186 ° C. (2) Dissolve 1.0 g of the above compound in 20 ml of glacial acetic acid and add 5
% 0.1% palladium-carbon is added and catalytic reduction is performed at room temperature. After absorbing the theoretical amount of hydrogen, the catalyst is filtered off and the solvent is distilled off under reduced pressure. The residue is dissolved in 15 ml of water, adjusted to pH 8-9 with 28% aqueous ammonia and cooled with ice. The crystals are collected by filtration and washed with water to obtain 0.75 g of the desired product.

mp253-254 ° C. (3) The above compound is dissolved in a 1N sodium hydroxide aqueous solution, and 10% hydrochloric acid is added thereto to make it acidic. The precipitated crystals are filtered off and washed with water and ethanol to obtain the desired hydrochloride. mp 300 ° C or higher. Example 2 5-amino-1-cyclopropyl-6-fluoro-7-
(Cis-3,5-dimethyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylate ethyl: (1) 5-benzylamino-1-cyclopropyl-obtained in Reference Example 3 Ethyl 6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate and cis-2,6-dimethylpiperazine were treated in the same manner as in Example 1 (1) to give 5-benzylamino. Ethyl -1-cyclopropyl-6-fluoro-7- (cis-3,5-dimethyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylate is obtained.

(2) The above compound (1.48 g) is dissolved in ethanol (20 ml), 5% palladium-carbon (0.1 g) is added thereto, and catalytic reduction is carried out at 50 ° C. After absorbing the theoretical amount of hydrogen, the catalyst was filtered off,
The solvent is distilled off under reduced pressure. The residue is recrystallized from ethyl acetate to obtain 1.13 g of the desired product.

m.p.194-196 ° C.

 ─────────────────────────────────────────────────── ─── Continuation of front page (72) Inventor Junichi Matsumoto 3-15-2, Shikanodai-higashi, Ikoma-shi, Nara (72) Inventor Shin-ichi Nakamura 1-12-20 Tsukawaki, Takatsuki-shi, Osaka (56) References Special Kai 62-187459 (JP, A) JP 61-243077 (JP, A) JP 62-469 (JP, A) JP 62-215572 (JP, A)

Claims (2)

[Claims] 1. The following formula The pyridonecarboxylic acid derivative represented by, lower alkyl esters thereof and salts thereof. 2. A pyridonecarboxylic acid derivative is 5-amino-
1-cyclopropyl-6-fluoro-7- (cis-3,5
-Dimethyl-1-piperazinyl) -1,4-dihydro-4
-Oxoquinoline-3-carboxylic acid (1)
The described compound.