JP2640967B2 - Quinolonecarboxylic acid derivatives and salts thereof - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a novel quinolone carboxylic acid derivative having excellent antibacterial activity and a salt thereof.

BACKGROUND ART Quinoline derivatives having an alkylthio group at the 7-position are described in, for example, JP-A-48-23784 and JP-A-54-112877.

However, the antibacterial activity of the compounds described in these documents is weak as described later.

An object of the present invention is to provide a novel quinolone carboxylic acid derivative having excellent antibacterial activity and a salt thereof.

The present invention provides a compound represented by the following general formula (I) (Wherein, Y represents a hydrogen atom or an amino group, and R represents an amino lower alkyl group or a group represented by the following formula (a).

Here, R ₁ represents a hydrogen atom or a lower alkyl group, W represents an oxygen atom or a methylene group, n is an integer of 1 to 3, m is an integer of 0 to 2, p is an integer of 0 or 1, and the sum of n and m is 2 or 3.

However, when W is an oxygen atom, m is an integer 2. ) And a salt thereof.

Here, the lower alkyl group has 1 to 1 carbon atoms.
5, preferably a linear or branched one composed of 1 to 3, and examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl. Ethyl, isobutyl, n-butyl are preferred.

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

 Further, the compound of the present invention may exist as a hydrate.

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

(1) The compound of the present invention has the following general formula (II) (Wherein L represents a halogen atom, Y represents the same as described above) and a compound represented by the following general formula (III) R-SH (III) (wherein, R is the same as described above) Can be produced by reacting a compound represented by the following formula in the presence of a base.

This reaction is carried out in an inert solvent at 0 to 150 ° C., preferably at 50 ° C.
The reaction can be carried out by stirring the starting compounds (II) and (III) at 100 ° C. in the presence of a base for 15 minutes to 24 hours, preferably 1 to 3 hours.

Examples of the solvent include alcohols such as methanol and ethanol, acetonitrile, dimethylformamide, water, chloroform and the like. These solvents may be used alone or as a mixture.

Examples of the base include an organic base such as triethylamine and an inorganic base such as potassium carbonate.

The amino group present in the structure of the starting compounds (II) and (III) may be protected with a protecting group such as a trityl group, if possible, and after the reaction is completed, the protecting group may be removed by a conventional method.

The starting compound (II) is produced by the method described in Reference Examples below or a method analogous thereto.

(2) The compound of the present invention also has the following general formula (IV) (Wherein, Y represents the same as defined above) and a compound represented by the general formula (V) RL (V) (where L is a halogen atom and R is the same as defined above) The compound can be produced by reacting with a compound represented by the formula: in the presence of a base.

This reaction is carried out in an inert solvent at 0 to 150 ° C, preferably at 50 ° C.
The reaction can be carried out by stirring the starting compounds (IV) and (V) at 100 ° C. in the presence of a base for 30 minutes to 24 hours, preferably 1 to 5 hours.

The same solvent and base as those described in the above-mentioned production method (1) are used. The amino group present in the structures of the starting compounds (IV) and (V) may be used in a protected form, if possible, and the protective group may be removed by a conventional method after completion of the reaction.

The starting compound (IV) can be produced by reacting the starting compound (II) described in the production method (1) with hydrogen sulfide in the presence of a base. It is convenient to manufacture.

The compound of the present invention thus produced is isolated and purified according to a conventional method. Depending on the conditions of isolation and purification, the compound can be obtained in the form of a salt or in a free form. However, these compounds are mutually converted according to these purposes to produce a desired compound of the present invention.

Effects of the Invention The novel compound (I) of the present invention and a salt thereof thus obtained each show excellent antibacterial activity and are valuable as antibacterial agents. Compound (I) or a salt thereof is used not only for human and veterinary medicine, but also for fish disease drugs, pesticides,
It can also be used as a food preservative.

Next, the antibacterial activity of the compound of the present invention is shown below in comparison with the compound (compound A) described in Example 1 of JP-A-48-23784 mentioned at the beginning.

When the compound of the present invention is used as an antibacterial agent for humans, the dosage varies depending on age, body weight, symptoms, administration route, etc., but it is recommended to administer 5 mg to 5 g per day in one or several divided doses. Is done. The administration route may be oral or parenteral.

The compound of the present invention may be administered as it is, but usually,
It is administered in the form of a prepared preparation together with a sawmill carrier.
Specific examples of the preparation include tablets, liquids, capsules, granules, fine granules, powders, syrups, injections, ointments and the like. 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, CMC Na, water and ethanol and which do not react with the compound of the present invention are used. Injectable carriers include carriers commonly used in the field of injectables, such as water, physiological saline, glucose solutions, and fluid solutions.

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

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

Reference Example 1 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-
Dihydro-4-oxoquinoline-3-carboxylic acid (1) A mixture of 25 g of the known compound ethyl pentafluorobenzoyl acetate [J. Org. Chem., 35 , 930 (1970)], 20 g of ethyl orthoformate, and 23 g of acetic anhydride was added to 2 parts. After heating and refluxing for hours,
The reaction mixture is concentrated to dryness under reduced pressure. The residue is dissolved in diethyl ether and reacted with 5.1 g of cyclopropylamine at room temperature to obtain 28 g of ethyl 3-cyclopropylamino-2- (pentafluorobenzoyl) acrylate.

mp 89 ° C (2) Dissolve 28 g of this compound in anhydrous tetrahydrofuran and react with 3.85 g of 60% sodium hydride at room temperature to give 1-cyclopropyl-5,6,7,8-tetrafluoro-
18.4 g of ethyl 1,4-dihydro-4-oxoquinoline-3-carboxylate are obtained.

mp 170-171 ° C. (3) A mixture of 10 g of this compound, 60 ml of glacial acetic acid, 50 ml of water and 7 ml of concentrated sulfuric acid is hydrolyzed by heating to reflux for 30 minutes to obtain 8.7 g of the desired product.

mp 181 ° -182 ° C. (recrystallized from chloroform) Reference Example 25 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (1) It consists of 28.2 g of ethyl 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate, 9.8 ml of benzylamine, 23.6 g of anhydrous potassium carbonate, and 140 ml of acetonitrile. Mix 100
Heating at ~ 110 ° C for 1 hour to give 5-benzylamino-1-
21.4 g of ethyl cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate are obtained.

mp 134-135 ° C (recrystallized from ethanol) (2) 20 g of this compound is treated with 100 ml of acetic acid and 150 ml of ethanol.
And hydrolyzed in the presence of 0.5 g of 5% palladium-carbon to give 5-amino-1-cyclopropyl-6,7,8-
Trifluoro-1,4-dihydro-4-oxoquinoline-
14.1% of ethyl 3-carboxylate are obtained.

mp 236-237 ° C (recrystallized from chloroform-ethanol) (3) 12.6 g of this compound, 80 ml of acetic acid, 50 ml of water, 9 concentrated sulfuric acid
The mixture consisting of ml was heated at 100-110 ° C for 40 minutes to hydrolyze to obtain 11.1 g of the desired product.

mp 294-295 ° C (recrystallized from chloroform-ethanol) Reference Example 3 1-Cyclopropyl-6,8-difluoro-1,4-dihydro-7-mercapto-4-oxoquinoline-3-carboxylic acid (1) 1 -Cyclopropyl-6,7,8-trifluoro-
A mixture of 1.6 g of ethyl 1,4-dihydro-4-oxoquinoline-3-carboxylate, 0.8 g of 70% sodium hydrosulfide powder and 20 ml of ethanol is stirred at 60-70 ° C. for 3 hours. After cooling with ice, the precipitated crystals are collected by filtration and washed with ethanol. After dissolving the crystals in 20 ml of water and treating with activated carbon,
Acidify with acetic acid. The precipitated crystals are collected by filtration and washed successively with water and ethanol to give 1.32 g of the desired ethyl ester as colorless needles.

mp 180-182 ° C (2) A mixture of 1.32 g of this compound, 8 ml of acetic acid, 6 ml of water and 1 ml of concentrated sulfuric acid is stirred at 105 ° C for 30 minutes. After cooling,
The reaction solution is poured into ice water (100 ml), and the precipitated crystals are collected by filtration. Washing sequentially with water and ethanol gives 1.1 g of the desired product (carboxylic acid) as pale yellow crystals.

mp 225-227 ° C Reference Example 4 5-Amino-1-cyclopropyl-6,8-difluoro-
1,4-dihydro-7-mercapto-4-oxoquinoline-3-carboxylic acid (1) 5-amino-1-cyclopropyl-6,7,8-trifluoro-1 obtained in Reference Example 2 (2) , 4-Dihydro-4-
A mixture of 3.26 g of ethyl oxoquinoline-3-carboxylate, 1.6 g of 70% sodium hydrosulfide powder and 50 ml of ethanol is stirred at 50-60 ° C. for 1.5 hours. The reaction solution is concentrated to dryness under reduced pressure, water is added to the residue, the mixture is adjusted to pH 5 with acetic acid, and cooled with ice. The precipitated crystals are collected by filtration, washed successively with water and ethanol, and then recrystallized from chloroform-ethanol to obtain 2.89 g of the desired ethyl ester.

mp 187-189 ° C (2) 2.0 g of this mixture, 8 ml of acetic acid, 6 ml of water and concentrated sulfuric acid
The mixture consisting of 1 ml is stirred at 105 ° C. for 30 minutes. The reaction solution is cooled on ice, and the precipitated crystals are collected by filtration. Washing with water and ethanol in that order gives 1.79 g of the desired product (carboxylic acid) as yellow crystals.

mp 300 or more Example 1 7-[(2-aminoethyl) thio] -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 1-cyclopropyl-6 3.0 g of 7,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid
-1.63 g of aminoethanethiol, 4.4 ml of triethylamine
And a mixture of 60 ml of acetonitrile are heated to reflux for 2 hours. After cooling, the crystals are collected by filtration and washed with water. 10
Dissolve in aqueous sodium hydroxide solution, treat with activated carbon, and neutralize with 10% aqueous acetic acid solution. The precipitated crystals are collected by filtration, washed sequentially with water and ethanol, and then dried to obtain the desired product 3.
0 g are obtained as colorless needles.

mp 270-274 ° C (decomposition) Example 2 5-Amino-7-[(2-aminoethyl) thio] -1-
Cyclopropyl-6,8-difluoro-1,4-dihydro-4
-Oxoquinoline-3-carboxylic acid 5-amino-1-cyclopropyl-6, obtained in Reference Example 2
7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 2.0 g, 2-aminoethanethiol 1.
55 g, triethylamine 5.6 ml and acetonitrile 50 ml
Is heated to reflux for 1 hour. After cooling, the crystals are collected by filtration and washed with water. The crystals are dissolved in a 10% aqueous acetic acid solution, treated with activated carbon, and then neutralized with a 10% aqueous sodium hydroxide solution. The precipitated crystals are collected by filtration, washed sequentially with water and ethanol, and dried to obtain 1.2 g of the desired product as yellow needles.

mp 215-219 ° C (decomposition) Example 3 5-Amino-1-cyclopropyl-6,8-difluoro-
1,4-dihydro-7-[(2-morpholinyl) methylthio] -4-oxoquinoline-3-carboxylic acid 5-amino-1-cyclopropyl-6, obtained in Reference Example 4
8-difluoro-1,4-dihydro-7-mercapto-4-
A mixture of 3.12 g of oxoquinoline-3-carboxylic acid, 2.7 g of 2-chloromethylmorpholine, 8.5 ml of triethylamine and 30 ml of acetonitrile is heated under reflux for 6 hours. The reaction solution is concentrated to dryness under reduced pressure, water is added to the residue, and the mixture is adjusted to pH 5 with acetic acid. Extract with chloroform, dry the extract, and concentrate under reduced pressure. The residue was recrystallized from chloroform-ethanol to give 1.25 g of the desired product as yellow needles.

mp 231-232 ° C Example 4 5-Amino-1-cyclopropyl-6,8-difluoro-
1,4-dihydro-4-oxo-7-[(3-pyrrolidinyl) thio] quinoline-3-carboxylate hydrochloride (1) 5-amino-1-cyclopropyl-6,8- obtained in Reference Example 4 After stirring a mixture of 1.56 g of difluoro-1,4-dihydro-7-mercapto-4-oxoquinoline-3-carboxylic acid, 1.38 g of anhydrous potassium carbonate and 50 ml of acetonitrile at 80 ° C. for 15 minutes, 3-methanesulfonyloxy- 3.06 g of 1-tritylpyrrolidine is added, and the mixture is refluxed for 8 hours. After cooling on ice, the precipitated crystals are collected by filtration. The crystals are suspended in water, neutralized with a 10% aqueous acetic acid solution, and the crystals are collected by filtration. This is dissolved in chloroform and purified by column chromatography. Recrystallization from chloroform gave 5-
Amino-1-cyclopropyl-6,8-difluoro-1,4-
1.56 g of dihydro-4-oxo-7-[(1-trityl-3-pyrrolidinyl) thio] quinoline-3-carboxylic acid are obtained.

mp 233-234 ° C (2) 0.9 g of the above compound and 5 ml of 20% hydrochloric acid were added at 105 ° C for 1.5 hours.
Stir for hours. After cooling on ice, the precipitated crystals are filtered off. The filtrate is concentrated to dryness under reduced pressure, and 5% hydrochloric acid is added to the residue and dissolved by heating. After treatment with activated carbon, the mixture is cooled on ice, and the precipitated crystals are collected by filtration and washed with ether to give 0.35 g of the desired product as yellow needles.

mp 275-278 ° C (decomposition) Example 5 5-amino-7-[(2-amino-1-methylethyl)
Thio] -1-cyclopropyl-6,8-difluoro-1,4-
Dihydro-4-oxoquinoline-3-carboxylic acid (1) By using 1-phthalimido-2-methanesulfonyloxypropane, 5-amino-1-cyclopropyl-6 was obtained in the same manner as in Example 4 (1). , 8-Difluoro-1,4-dihydro-4-oxo-7-[(2-phthalimido-1-methylethyl (thio) quinoline-3-carboxylic acid is obtained.

227 ° -229 ° C. (2) A mixture of 0.8 g of the above compound, 1.2 ml of hydrazine hydrate and 30 ml of methanol is heated to reflux for 3 hours.
The reaction solution is concentrated to dryness under reduced pressure, and a 5% acetic acid aqueous solution is added to the residue. After treatment with activated carbon, neutralize with 28% aqueous ammonia and cool with ice. The precipitated crystals are collected by filtration, washed successively with water and ethanol, and dried to obtain 0.35 g of the desired product.

mp 201 to 202 ° C. Examples 6 to 14 The corresponding compounds are reacted and treated in the same manner as in Examples 4 and 5 to obtain the following compounds.

Continued on the front page (51) Int.Cl. ⁶ Identification code Agency reference number FI Technical display A61K 31/535 A61K 31/535 (72) Inventor Shinichi Nakamura 1-1-12-20 Tsukawaki, Takatsuki-shi, Osaka ( 56) References JP-A-48-23784 (JP, A) JP-A-54-112877 (JP, A) JP-A-60-260573 (JP, A) JP-A-60-260577 (JP, A)

Claims (1)

(57) [Claims] (1) General formula (Wherein, Y represents a hydrogen atom or an amino group, and R represents an amino lower alkyl group or a group represented by the following formula. Here, R ₁ represents a hydrogen atom or a lower alkyl group, W represents an oxygen atom or a methylene group, n is an integer of 1 to 3, m is an integer of 0 to 2, p is an integer of 0 or 1, and the sum of n and m is 2 or 3. However, when W is an oxygen atom, m is an integer 2. A quinolone carboxylic acid derivative represented by the formula: and a salt thereof.