JPH0725747B2 - Quinolonecarboxylic acid derivative - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel optically active quinolonecarboxylic acid derivative having excellent antibacterial activity or a salt thereof, and an antibacterial agent containing the same as an active ingredient.

[Conventional technology]

Conventionally, synthetic antibacterial agents such as nalidixic acid and pyromidic acid are known as therapeutic agents for infectious diseases caused by Gram-negative bacteria. However, they have a drawback that they are less effective against intractable diseases such as Pseudomonas aeruginosa infection. On the other hand, antibacterial agents with strong antibacterial activity such as norfloxacin and ofloxacin have been developed and used clinically.

[Problems to be Solved by the Invention]

However, in order for the synthetic antibacterial agent to effectively act in the living body, it is necessary to have strong antibacterial activity and good utilization rate. However, the above-mentioned conventional synthetic antibacterial agents have poor absorption and bioavailability. It had the drawback of being low.

[Means for Solving the Problems]

In this situation, the present inventor synthesized a number of quinoline derivatives and studied their antibacterial activity and absorption into the living body, and found that the following formula (A) (In the formula, R ₁ is a lower alkyl group, R ₂ is a hydrogen atom or a lower alkyl group, R ₃ is a hydrogen atom or a halogen atom, and R ₄ and R ₅ together may contain another hetero atom, and It forms a 5- to 6-membered ring which may have a substituent, provided that R ₁
Is a methyl group, R ₂ and R ₃ are hydrogen atoms, and Has been found to have excellent antibacterial activity and absorbability, and a patent application (Japanese Patent Application No. Hei 1-189214) has been filed. Furthermore, they have found that the optically active quinolonecarboxylic acid derivative represented by the general formula (I) described later and its salt have particularly excellent antibacterial activity, and completed the present invention.

That is, the present invention provides the following general formula (I): The present invention provides an optically active quinolonecarboxylic acid derivative or a salt thereof and an antibacterial agent containing the same as an active ingredient.

The compound (I) of the present invention is produced, for example, by the following method.

(In the formula, R represents a lower alkyl group and X represents a halogen atom.) That is, the compound (II) is halogenated to give a compound (II
I) and the optically active 3-aminopyrrolidine (I
Compound (V) is obtained by reacting V) and then dehydrohalogenated and hydrolyzed to produce Compound (I) of the present invention or a salt thereof.

The raw material compound (II) is produced, for example, by the method described in West German Patent DB 3,522,406.

To produce (III) from compound (II), 1 to 5 mol of a halogenating agent is used with respect to 1 mol of (II), and the reaction is performed in a solvent at room temperature or under reduction for 1 to 20 hours. Here, as the halogenating agent, thionyl chloride, thionyl bromide, phosphorus oxychloride, phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, etc. are used, and as the solvent, methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroketane, trichloroethane, etc. are used. After completion of the reaction, the reaction product is concentrated and the residue is purified by silica gel column chromatography or the like to obtain (III).

In order to produce (V) from compound (III), 1 mol of (III) is added to 1 to 3 parts of optically active 3-aminopyrrolidine (IV).
Using 5 mol, the reaction is carried out by heating in a solvent such as dimethyl sulfoxide or acetonitrile at room temperature to 100 ° C. for 1 to 15 hours. After completion of the reaction, the reaction product is poured into cold water, neutralized with an acid and then extracted with a solvent such as chloroform, and then the solvent is distilled off, or the reaction product is concentrated and purified by silica gel column chromatography or the like. For example, the compound (V) is obtained.

To produce the compounds (V) to (I), 2 to 4 mol of alkali is used with respect to 1 mol of (V), and the mixture is heated and reacted in a solvent such as ethanol for 5 to 60 hours. Here, sodium hydroxide and potassium hydroxide are preferable as Lucari. After completion of the reaction, the compound (I) of the present invention can be obtained almost purely by neutralizing with an acid and collecting the formed precipitate by filtration. In addition, a pure product of (I) can be obtained by recrystallization from a suitable solvent.

The compound (I) of the present invention thus obtained can be further converted, if necessary, into a salt of an alkali metal, an inorganic acid, an organic acid or the like by a conventional method. For example, as the alkali metal salt, lithium salt, sodium salt, potassium salt, etc .; as the inorganic acid salt, hydrochloride, sulfate, nitrate, hydrobromide,
Phosphate, etc .; as organic acid salts, acetate, fumarate,
Examples thereof include maleate, lactate, tartrate, citrate, malate, oxalate, methanesulfonate, benzenesulfonate and the like.

When the compound (I) thus obtained is used as an antibacterial agent, the dose varies depending on the patient's weight, age, sex, administration method, physical condition, medical condition, etc. A suitable dose is 200 to 800 mg, and 5 to 40 mg per day for parenteral administration.

The compound (I) of the present invention can be prepared by a conventional method for tablets, granules,
It can be made into various forms of antibacterial agents such as powders, capsules, suspensions, injections and suppositories.

To produce a solid preparation, an excipient and, if necessary, a binder, a disintegrating agent, a lubricant, a coloring agent, a flavoring agent, a bulking agent, a coating agent, a sugar-coated tablet and the like are added to Compound (I). After that, it is preferable to prepare tablets, granules, powders, capsules, suppositories and the like by a conventional method. When preparing an injection, the compound (I)
Is previously dissolved and dispersed in an aqueous carrier such as distilled water for injection,
It may be emulsified or made into powder for injection and dissolved at the time of use. The injection method includes intravenous administration,
Intraarterial administration, portal vein administration, intraperitoneal administration, intramuscular administration, subcutaneous administration are included.

〔Example〕

Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto.

Reference Example 1 1- (1-chloroprop-2-yl) -6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester: 6,7-difluoro-1,4-dihydro 1- (1-hydroxyprop-2-yl) -4-oxoquinoline-3-carboxylic acid ethyl ester 4.45 g (14.3 mmol) and thionyl chloride 5.10 g (42.9 mmol) were dissolved in chloroform 130 ml and heated under reflux. Allow to react for 1 hour. After cooling, the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (chloroform: methanol = 100: 1), and recrystallized from ethanol to give 1- (1-chloroprop-
3.53 g of 2-yl) -6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester was obtained as colorless needle crystals.

mp 184-158 ° C ¹ H-NMR (CDCl ₃ ) δppm 1.42 (3H, t, J = 7.1Hz) 1.77 (3H, d, J = 6.8Hz) 3.86 (2H, d, J = 5.7Hz) 4.41 (2H, q, J = 7.1Hz) 4.6 to 5.1 (1H, m) 7.37 (1H, d, d, J = 11.6Hz, 6.1Hz) 8.34 (1H, d, d, J = 10.3Hz, 9.0Hz) 8.56 (1H, s) Reference Example 2 (3S) -7- (3-aminopyrrolidinyl) -1- (1-
Chloroprop-2-yl) -6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester: 6,7-difluoro-1,4-dihydro-1- (1-chloroprop-2- Yl) -4-oxoquinoline-3-carboxylic acid ethyl ester 660 mg (2 mmol) and (3S)-(−)-
4-Aminopyrrolidine (414 mg, 4.8 mmol) is dissolved in acetonitrile (40 ml) and heated under reflux for 4 hours. After the reaction,
The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (chloroform: methanol: aqueous ammonia = 300: 6: 1), and (3S) -7- (3-aminopyrrolidinyl) -1. -(1-chloroprop-2-yl)
-6-Fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester as pale yellow crystals 46
5 mg was obtained.

mp 149-152 ℃ ¹ H-NMR (CDCl ₃ ) δppm 1.39 (3H, t, J = 7.0Hz) 1.70 (disappeared at 2H, s, D ₂ O) 1.74 (3H, d, J = 7.0Hz) 3.1 to 3.9 (7H, m ) 4.37 (2H, q, J = 7.0Hz) 4.6 to 5.1 (1H, m) 6.32 (1H, d, J = 7.0Hz) 7.96 (1H, d, J = 14.5Hz) 8.42 (1H, s) Example 1 (3S) -7- (3-aminopyrrolidinyl) -6-fluoro-1,4-dihydro-4-oxo-1- (prop-1-
En-2-yl) -quinoline-3-carboxylic acid: (3S) -7- (3-aminopyrrolidinyl) -6-fluoro-1,4-dihydro-4-oxoquinoline obtained in Reference Example 2. -3-carboxylic acid ethyl ester 753 mg (1.9 mmo
l) dissolved in 50 ml of ethanol and crushed potassium hydroxide 3
20 mg (5.7 mmol) is added, and the mixture is reacted under heating under reflux for 26 hours. After cooling, the mixture was neutralized to pH 7-8 with 1N hydrochloric acid, and the formed precipitate was collected by filtration, washed with water, air-dried and then dried under reduced pressure, (3S)-
7- (3-aminopyrrolidinyl) -6-fluoro-1,4
-Dihydro-4-oxo-1- (prop-1-ene-2
597 mg of -yl) -quinoline-3-carboxylic acid was obtained as light brown crystals.

mp 249-255 ℃ ¹ H-NMR (d ₆ -DMSO) δppm 1.6-2.2 (2H, m) 2.23 (3H, s) 3.0-4.4 (3H, br) 3.2-3.8 (5H, m) 5.51 (1H, s) 5.71 ( 1H, s) 6.43 (1H, d, J = 7.7Hz) 7.79 (1H, d, J = 14.3Hz) 8.51 (1H, s) Test Example 1 Antibacterial test Based on the Japan Chemotherapy Society MIC measurement method Table 1 The following conditions were measured for the bacteria shown in. As a control, ofloxacin and the compound (A) of Japanese Patent Application No. 1-189214 were used. The results are shown in Table 1.

Medium used Bacteria Mueller hinton Medium Specimen dilution 25% Dimethyl sulfoxide to 1000 mcg / ml, and then diluted with sterile purified water to 100 mcg-0.006 mcg
And After that, dilute 10 times with the medium to make a plate.

Inoculum of 10 ⁶ / ml is 1 ese Culture condition 37 ℃ 48hr Judgment 24th hour From Table 1, when compared with ofloxacin, the compound (I) of the present invention shows almost the same effect on Gram-negative bacteria but a strong antibacterial effect against Gram-positive bacteria and methicillin-resistant Staphylococcus. You can see that. Further, it showed a generally strong antibacterial effect as compared with the compound (A).

〔The invention's effect〕

Since the compound (I) of the present invention has high antibacterial activity, good absorption and high bioavailability, an antibacterial agent containing this compound as an active ingredient is useful for preventing and treating infectious diseases in mammals including humans.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Taedo Nogata 2-517-1 Iiyamamanmachi, Funabashi City, Chiba Prefecture (72) Inventor Tadayuki Kuraishi 1656-3 Kashiwai Town, Chiba City Chiba Prefecture Yachiyodai Park Heights B-2- 104 (56) References JP-A-62-185085 (JP, A) JP-A-2-290870 (JP, A)

Claims (2)

[Claims] 1. The following general formula (I): An optically active quinolonecarboxylic acid derivative represented by or a salt thereof. 2. An antibacterial agent containing the optically active quinolonecarboxylic acid derivative or its salt according to claim 1 as an active ingredient.