JPH0811749B2 - Novel quinoline derivative and its salt - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial field of application] [In the formula, R ¹ represents a hydrogen atom or a carboxy protecting group; R ² represents a halogen atom, a cyano group, a hydroxyl group, an amino group,
Lower alkyl, lower alkenyl, cycloalkyl optionally substituted with one or more groups selected from alkyl group, alkoxy group, aryl group, cycloalkyl group, acylamino group, acyloxy group, lower alkenyl group and trihalogenoalkyl group. Or an aryl group; (R ⁴ has two carboxyl groups, and further has an alkyl group which may have one or more substituents selected from a halogen atom, an alkyl group, an aryl group and a mono- or di-alkylamino group. n n R ⁵ are the same or different,
A lower alkyl group; R ⁶ represents a hydrogen atom or a lower alkyl group; n represents 0, 1, 2, 3 or 4. ) Represents a group represented by. ] The present invention relates to a novel quinoline derivative and a salt thereof.

The object of the present invention is to identify Gram-positive and Gram-negative bacteria,
In particular, the compound of the general formula [I] has a strong antibacterial action against antibiotic-resistant bacteria and has excellent properties such as high blood concentration obtained by oral or parenteral administration and high safety. It is to provide a novel compound represented.

[Prior Art] Conventionally, norfloxacin and the like have been widely used as a quinoline-based synthetic antibacterial agent, but the antibacterial spectrum and absorption are still insufficient, and the safety is not satisfactory.

[Problems to be Solved by the Invention] It is desired to develop a synthetic antibacterial agent which is effective against Gram-negative bacteria and Gram-positive bacteria, has a broad antibacterial spectrum, is highly absorbable, and is highly safe. It was

[Means for Solving the Problems] Under these circumstances, the present inventors have conducted diligent research and as a result, found that the quinoline derivative represented by the general formula [I] and its salt achieve the above-mentioned object. The present invention has been completed and the present invention has been completed.

In the present specification, unless otherwise specified, examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom;
For example, a C _1-10 alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyloctyl and the like; examples of the lower alkyl group include the above-mentioned alkyl groups. Among these groups, a C _1-5 alkyl group; a lower alkenyl group is, for example, a C _2-5 alkenyl group such as vinyl, allyl, 1-propenyl, 1-butenyl; a cycloalkyl is, for example, cyclopropyl, cyclobutyl, _C3-6 cycloalkyl group such as cyclopentyl; aryl group such as phenyl and naphthyl; alkoxy group such as -O-alkyl group (wherein the alkyl group represents the above _C1-10 alkyl group). ); As an alkoxycarbonyl group, for example, —CO—O-alkyl (The alkyl group, the above C
_1-10 alkyl group is shown. ); The acylamino group, for example, formylamino, acetylamino, propionylamino, C _{1 to 4} acylamino group such butyrylamino; The acyloxy group, e.g., formyloxy, acetyloxy, propionyloxy, _{C. 1 to} such butyryloxy ₄ acyloxy groups; examples of trihalogenoalkyl groups include trihalogeno C _1-4 alkyl groups such as trifluoromethyl and trichloromethyl; examples of mono- or di-alkylamino groups include
For example, a group such as a mono- or di-C _1-5 alkylamino group such as methylamino, ethylamino, propylamino, dimethylamino, diethylamino and the like is meant.

 The present invention will be described in detail below.

In the compound of the general formula [I] and salts thereof, the carboxy protecting group for R ¹ is, for example, an ester-forming group that is eliminated by treatment under catalytic reduction, chemical reduction or other mild conditions, or in vivo And an ester-forming group such as an organic silyl group, an organic phosphorus group or an organic tin group, which is easily eliminated by treatment with water or alcohol. Of these protecting groups, suitable protecting groups include, for example, the carboxy protecting group described in JP-A-59-80806.

Further, each group of R ² is a halogen atom; a cyano group; a carboxyl group; a hydroxyl group; an amino group; an alkyl group; an alkoxy group; an alkoxylcarbonyl group; an aryl group;
Cycloalkyl group; acylamino group; acyloxy group;
Lower alkenyl group; may be substituted with one or more substituents selected from trihalogenoalkyl groups and the like.

Also, R ³ is the formula, (Wherein R ⁵ , R ⁶ and n have the same meanings as described above), and the alkyl group having two carboxyl groups of R ⁴ is, for example, 1,2-dicarboxyethyl, 1,3-dicarboxy-n-propyl, 1,3-dicarboxy-2-propyl, 1,4-dicarboxy-n-
And dicarboxy-C _1-5 alkyl groups such as butyl. And the alkyl moiety in these R ⁴ is
It may be substituted with one or more substituents selected from halogen atom; alkyl group; hydroxyl group; amino group; alkoxy group; aryl group; mono- or di-alkylamino group and the like.

Examples of the salt of the compound of the general formula [I] include salts of commonly known basic groups such as amino groups or acidic groups such as hydroxyl or carboxyl groups. Examples of the salt in the basic group include salts with mineral acids such as hydrochloric acid and sulfuric acid; salts with organic carboxylic acids such as formic acid, citric acid, trichloroacetic acid and trifluoroacetic acid; methanesulfonic acid, benzenesulfonic acid, p A salt with a sulfonic acid such as toluenesulfonic acid, mesitylenesulfonic acid or naphthalenesulfonic acid; and a salt in an acidic group, for example, a salt with an alkali metal such as sodium or potassium; an alkaline earth such as calcium or magnesium. Salts with similar metals; ammonium salts; trimethylamine, triethylamine, tributylamine, pyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-
Benzyl-β-phenethylamine, 1-ephenamine,
Examples thereof include salts with N-containing organic bases such as N, N'-dibenzylethylenediamine.

Further, in the compound of the general formula [I] and a salt thereof,
When isomers exist (eg, optical isomers, geometric isomers, tautomers, and the like), the present invention includes all such isomers and extends to all crystalline forms and hydrates. It is.

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

As a method for producing the compound of the present invention, a method known per se can be mentioned. For example, it can be produced by the following production route.

[Wherein R ¹ , R ² and R ³ have the same meanings as described above, (R ⁵ , R ⁶ and n have the same meanings as described above.)
X represents a fluorine atom or a chlorine atom. Examples of the salts of the compounds of the general formulas [II], [III] and [IV] include the same salts as described for the compound of the general formula [I].

(1) Production Method 1 The compound of general formula [I] or a salt thereof can be obtained by subjecting the compound of general formula [II] or a salt thereof to an alkylation reaction in the presence or absence of a base.

The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include aromatic hydrocarbons such as benzene and toluene; dioxane, tetrahydrofuran, anisole, diethylene glycol dimethyl ether, dimethyl. Ethers such as cellosolve; halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane; amides such as N, N-dimethylformamide, N, N-dimethylacetamide; sulfoxides such as dimethyl sulfoxide; methanol, ethanol, propanol , Alcohols such as isopropanol and butanol, etc., and two or more kinds of these solvents may be mixed.

The alkylating agent used in this reaction includes saturated aliphatic dicarboxylic acids having a leaving group and salts thereof, such as halogen atom, methanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy, and toluenesulfonyloxy. C _3-7 saturated aliphatic dicarboxylic acids such as malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, and their salts or unsaturated fats substituted with a leaving group such as alkanesulfonyloxy or arenesulfonyloxy groups. Group dicarboxylic acids and salts thereof, for example, C _3-7 unsaturated aliphatic dicarboxylic acids such as maleic acid, fumaric acid, pentenedioic acid, hexenedioic acid and heptenedioic acid. These alkylating agents may be substituted with the same substituents as mentioned for R ⁴ .

Moreover, as the salt of these alkylating agents, the same salts as described in the general formula [I] can be mentioned.

Examples of the base used in this reaction include, for example,
Inorganic bases such as alkali hydroxide, alkali hydrogen carbonate, alkali carbonate; and pyridine, triethylamine, 1,8
And organic bases such as diazabicyclo [5.4.0] -7-undecene.

The amount of the alkylating agent used is equimolar or more, preferably 1 to 5 times the molar amount of the compound of the general formula [II] or a salt thereof.

The amount of the base used is equimolar or more to the compound of the general formula [II] or a salt thereof.

This reaction is carried out at 0 ° C to the boiling point of the solvent used, preferably at 50 to 100 ° C, usually for 30 minutes to 50 hours, preferably,
It may be carried out for 3 to 20 hours.

(2) Process 2 The compound of the general formula [I] or a salt thereof can be prepared by reacting the compound of the general formula [III] or a salt thereof with the general formula [I] in the presence of a base.
It can be obtained by reacting a compound of V] or a salt thereof.

The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction, and specific examples thereof include the same solvents as those described in the production method 1. To be

Examples of the base used in this reaction include the same inorganic bases and organic bases as those described in Process 1.

The amount of the compound of the general formula [IV] or its salt used is equimolar or more to the compound of the general formula [III] or its salt,
It is preferably 1.0 to 1.3 times mol.

The amount of the base used is preferably equimolar or more to the compound of the general formula [III] or a salt thereof.

This reaction is usually 0 to 150 ° C, preferably 50 to 100 ° C,
It may be carried out for 5 minutes to 30 hours, preferably 30 minutes to 3 hours.

The starting compound (general formula [I
When the compound of [I], [III], [IV] or a salt thereof or an alkylating agent) has an active group such as a hydroxyl group, an amino group or a carboxyl group in addition to the reaction site, the active group is previously prepared according to a conventional method. It can be protected and the protecting group can be eliminated after the reaction is completed.

The compound of the general formula [I] of the present invention or a salt thereof obtained as described above can be isolated by a conventional method.

When the compound of the present invention is used as a medicine, a carrier usually used for formulation is appropriately used, and a tablet is prepared according to a conventional method.
Adjust to capsules, powders, syrups, granules, suppositories, ointments, injections, etc. In addition, the administration method, dose, and frequency of administration can be appropriately selected according to the symptoms of the patient, and usually for adults, it is oral or parenteral (eg, injection, infusion, administration to the rectal site, etc.). Depending on the administration, 0.1 to 100 mg / kg / day may be divided into 1 to several times for administration.

[Effect of the invention] Test compound A 7- [4- (1,2-dicarboxyethyl) -1-piperazinyl] -1- (2,4-difluorophenyl) -6-
Fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid Test compound B 1-Cyclopropyl-7- [4- (1,2-dicarboxyethyl) -1-piperazinyl] -6-fluoro-1 ,Four
-Dihydro-4-oxo-3-quinolinecarboxylic acid Test compound C 7- [3- (1,2-dicarboxyethyl) amino-1
-Pyrrolidinyl] -1- (2,4-difluorophenyl)
-6-Fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid 1. Antibacterial activity Test method Japanese Society of Chemotherapy Standard Method [Chemothera
py) Vol. 29, No. 1, pp. 76-79 (1981)], 3 with Peptone broth (manufactured by Eiken Chemical Co., Ltd.)
After culturing at 7 ℃ for 20 hours, inoculate the bacterial solution into Heart Infusion agar medium (Eiken Chemical Co., Ltd.) containing the drug, and after culturing at 37 ℃ for 20 hours, check for the growth of bacteria. The MIC (μg / ml) was defined as the minimum concentration at which the growth of bacteria was inhibited. However, the inoculum is 10 ⁴ /
Plates (10 ⁶ pieces / ml) were prepared. The results are shown in Table-1.

2. Solubility Test compound A (24 mg) was added to 3 ml of pH 7 phosphate buffer at 25 ° C, and the mixture was stirred and uniformly dissolved. (≧ 8 mg / ml) On the other hand, norfloxacin 10 mg was added to 20 ml of pH 7 phosphate buffer at 25 ° C. and stirred, but it was not uniformly dissolved. (<
0.5 mg / ml) 3. Acute toxicity The LD ₅₀ value of the test compound A when administered intravenously to mice (ICR strain, male, body weight 18 to 24 g) was 2 g / Kg or more.

From the above results, it can be understood that the compound of the present invention is a useful compound having an excellent antibacterial action, an excellent solubility, and a high safety.

EXAMPLES Next, the present invention will be described with reference to examples, but the present invention is not limited thereto. The symbols used in the examples have the following meanings.

Me; methyl group, Et; ethyl group Example 1 1- (2,4-difluorophenyl) -6-fluoro-
7- (1-Piperazinyl) -1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester 1.00 g, maleic acid dimethyl ester 1.67 g and triethylamine 1.17 g were dissolved in ethanol 20 ml and heated under reflux for 9 hours. React. After completion of the reaction, the solvent is distilled off under reduced pressure, and 30 ml of chloroform and 20 ml of water are added to the obtained residue. Then, the organic layer is separated, washed successively with water and saturated saline, and then dried over anhydrous magnesium sulfate. The obtained residue was purified by column chromatography [Kieselgel 60, Art 7734 (manufactured by Mekru); toluene: ethyl acetate = 1: 1 (volume ratio)] to give 1- (2.4-
Difluorophenyl) -7- [4- (1,2-dimethoxycarbonylethyl) -1-piperazinyl] -6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester 720 mg (yield 54.0 %).

Melting point; 155 to 157 ° C (recrystallization solvent; ethyl acetate-diisopropyl ether mixed solvent) IR (KBr) cm-1; νco 1730 NMR (CDCl ₃ ) δ value; 1.36 (3H, t, J = 7Hz), 2.30 to 3.40 (1
0H, m), 3.50 to 4.03 (7H, m), 4.34 (2H, q, J = 7Hz), 6.12
(1H, d, J = 7Hz), 6.80 to 7.70 (3H, m), 7.93 (1H, d, J, =
13Hz), 8.27 (1H, s) Similarly, the compounds in Table-2 are obtained.

Example 2 1- (2.4-difluorophenyl) -7- [4- (1,2
-Dimethoxycarbonylethyl) -1-piperazinyl]
6-Fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester 500 mg was added to ethanol 5 ml.
And 1N-sodium hydroxide aqueous solution (5 ml), and the mixture is reacted at room temperature for 10 hours. After completion of the reaction, 5 ml of water was added, pH was adjusted to 5.0 with acetic acid, and the precipitated crystals were collected by filtration to give 7-
360 mg of [4- (1,2-dicarboxyethyl) -1-piperazinyl] -1- (2,4-difluorophenyl) -6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid Yield 79.8%).

Melting point; 254 to 256 ° C. (recrystallization solvent; ethanol-water mixed solvent) IR (KBr) cm-1; νco 1730 NMR (CF ₃ COOD) δ value; 3.27 to 4.58 (10H, m), 4.58 to 5.00
(1H, m), 6.83 (1H, d, J = 6Hz), 7.02 ~ 8.00 (3H, m), 8.
40 (1H, d, J = 13Hz), 9.23 (1H, s) In the same manner, the compounds in Table-3 are obtained.

 ─────────────────────────────────────────────────── ─── Continuation of front page (72) Inventor Yasuo Watanabe 2-4-9 Nishida district town, Toyama city, Toyama prefecture (72) Inventor Ken Tai 3-17-30, Awashima town, Toyama city, Toyama prefecture (72) Inventor Yu Kawai 7-52 Oizumi Naka-cho, Toyama City, Toyama Prefecture Judgment Panel Judgment Head Judge Tokio Hashioka Judge Kazuko Miyamoto Judge Keiko Ogawa (56) Reference JP 59-157068 (JP, A) JP 59-170070 (JP, A) JP-A-55-47658 (JP, A) JP-A-54-66686 (JP, A)

Claims (1)

[Claims] 1. A general formula [In the formula, R ¹ represents a hydrogen atom or a carboxy protecting group; R ² represents a halogen atom, a cyano group, a hydroxyl group, an amino group,
Lower alkyl, lower alkenyl, cycloalkyl optionally substituted with one or more groups selected from alkyl group, alkoxy group, aryl group, cycloalkyl group, acylamino group, acyloxy group, lower alkenyl group and trihalogenoalkyl group. Or an aryl group; R ³ is a formula, (R ⁴ has two carboxyl groups, and further has an alkyl group which may have one or more substituents selected from a halogen atom, an alkyl group, an aryl group and a mono- or di-alkylamino group. n n R ⁵ are the same or different,
A lower alkyl group; R ⁶ represents a hydrogen atom or a lower alkyl group; n represents 0, 1, 2, 3 or 4. ) Represents a group represented by. ] The quinoline derivative represented by these, and its salt.