JPS61218585A - Novel quinoline carboxylic acid derivative and fungicide containing the same as active ingredient - Google Patents

Abstract

NEW MATERIAL:1-Cyclopropyl-6,8-difluoro-1,4-dihydro-7-(3-hydroxypyrro-lidin- 1-yl)-4-oxoquinoline-3-carboxylic acid o formula I and its salt. USE:It is used as a remedy for a variety of infectious diseases, because it has strong antibacterial activity. It shows strong proliferation inhibition against both gram-positive and gram-negative bacteria. PREPARATION:The reaction between 6,7,8-trifluoroquinoline carboxylic acid derivative of formula II and 3-hydroxypyrrolidine of formula III is carried out in a solvent such as methanol in the presence of an acid acceptor such as triethylamine at room temperature to 150 deg.C to give a compound of formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel quinolinecarboxylic acid derivative and an antibacterial agent containing the compound as an active ingredient.

More specifically, 1-cyclopropyl-
8,8-difluoro-1,4-dihydro-1-(3-hydroxypyrrolidin-1-yl)-4-oxoquinoline-3-carvone #(1) and its pharmaceutically acceptable salt, and the compound This invention relates to an antibacterial agent containing as an active ingredient.

Conventionally, there have been a large number of compounds with antibacterial activity.
4-dihydro-4-oxoquinoline-3-carboxylic acid derivatives are known, but there are also derivatives that have a cyclopropyl group at the 1-position, a pyrrolidinyl group at the 7-position, and fluoro groups at the 6- and 8-positions. This is one of them.

That is, JP-A-59-212471 discloses a compound represented by the following formula (hereinafter referred to as comparative compound A).

Comparative Compound A The present inventors focused on Comparative Compound A, and in order to find an antibacterial agent superior to Comparative Compound A, they attempted to change the structure of N and examined the correlation between the structure and antibacterial activity.

The present inventors have discovered that l-cyclopropyl-6 represented by the following formula
,8-difluoro-1,4-dihydro-7-(3-hydroxypyrrolidin-1-yl)-4-oxoquinoline-
The present invention was completed after synthesizing 3-carboxylic acid (I) and finding that it exhibits a strong antibacterial effect.

The compound of the present invention encapsulates a quinolinecarboxylic acid derivative having a hydroxypyropyridinyl group represented by formula CI) and a pharmaceutically acceptable salt thereof.

Here, the pharmaceutically acceptable salts of the compound of formula (I) include salts at its carboxyl group, for example,
Preferred examples include sodium salts, potassium salts, and calcium salts.

Compound (I) of the present invention corresponds to a compound obtained by converting the 7-position pyrrolidinyl group of Comparative Compound A to a 3-hydroxypyrrolidinyl group.

However, compared to Comparative Compound A, Compound (I) of the present invention has
Its antibacterial activity is excellent and it is acceptable as an antibacterial agent (see test section below).

The compound (I) of the present invention is as shown by the following formula: <6°7.8
−) Lifluoroquinoline carboxylic acid derivative (■) and 3
- Produced by reacting with hydroxypyrrolidine (III).

The reaction between compound C (■) and compound (III) is preferably carried out in the presence of an acid scavenger using a reaction solvent.

Preferred solvents include methanol, ethanol, acetone, tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide, and acid scavengers include triethylamine, pyridine, quinoline, and sodium bicarbonate.

Examples include potassium bicarbonate.

Usually, 1.0 mol of compound (n) is used.
0 to 1.5 molar amounts of compound (m) and 1.0 to 3.0
A molar amount of acid scavenger is used. Note that an excess of compound (m) may be used as the acid scavenger.

The reaction temperature is room temperature to 150° C. The reaction is completed in 30 minutes to 5 hours.

Compound CI) produced as described above is isolated and purified by conventional purification means, such as recrystallization.

If necessary, the above-mentioned pharmaceutically acceptable salts can be prepared by treatment with a corresponding base according to a conventional method.

Compound (I) of the present invention or a pharmaceutically acceptable salt thereof is used as an antibacterial agent and is preferably administered orally to humans. The dosage form for oral administration includes compound CI) or a salt thereof, corn starch, lactose, magnesium stearate, microcrystalline cellulose, kaolin,
It can be mixed with commonly used non-toxic pharmaceutically acceptable additives such as calcium carbonate and talc, and made into the form of tablets, granules, fine granules, powders, syrups, etc., or the above-mentioned fine granules. Capsules prepared by appropriately filling capsules with agents or powders are preferably used.

The dosage varies depending on the age, weight, symptoms, etc. of the patient, but is generally 71 to 50 mg/kg for compound CI).
Body weight/day is preferably in the range of 5 to 30 g/kg body weight per day, and is preferably administered in divided doses 2 to 4 times a day.

11 Rikkyu 1 It was found that the compound CI) of the present invention exhibited a strong antibacterial effect and was superior to the above-mentioned comparative compound A as an antibacterial agent. That is, as shown in Test Example 1 below, compound CI) of the present invention exhibits strong growth inhibition activity against both Durum-positive bacteria and Durum-negative bacteria, and its activity is superior to that of Comparative Compound A. ing. Furthermore, as shown in Test Example 2 below, the antibacterial activity of Compound (I) of the present invention is superior to that of Comparative Compound A in infected animal experiments.

In addition, the acute toxicity (LD50, ms/kg) of the compound (1) of the present invention when administered orally to mice was 4000.
mg/kg or more, and the compound CI of the present invention can be said to have low toxicity (see Test Example 3).

The above facts indicate that the compound of the present invention is more useful than the known comparative compound A as a therapeutic agent for various infectious diseases.

The results of pharmacological tests demonstrating the usefulness of the compounds of the present invention are shown below.

[Test Example 1] Minimum inhibitory concentration (arc) 1, test compound (1) 1-cyclopropyl-6,8-difluoro-1,
4-dihydro-7-(3-hydroxypyrrolidine-1-
yl)-4-oxoquinoline-3-carboxylic acid (compound of Example 1) (2) 1-cyclopropyl-8,8-difluoro-1,
4-dihydro-4-oxo-7-(1-pyrrolidinyl)
Quinoline-3-carboxylic acid (comparative compound A) 2 and test method Each of the test compounds was dissolved in a sterilized 0, IN potassium hydroxide aqueous solution (concentration 5000 g/lQ).

Dilute this with sterile purified water until the concentration of the test compound is xoo
A standard solution of o, g/d was prepared. After that, use the method specified by the Japanese Society of Chemotherapy (Chemotherapy 29).
, 7f1-79 (1981), TOKYO) I went there.

3. Results The test results are shown in Table 1.

[Test Example 2] Infection prevention effect (Eu2O) 1. Test compound Same as in Test Example 1.

2. Test materials and methods (1) Bacterial strain used O Staphylococcus aureus (S.

aureus) IID 803 0 Esierichia coli (E, cali) KO-140
Seutomonas aeruginosa (P.

aeruginosa) E-2 (2) Animals Used Male ddY mice (4 weeks old, weight 18-20 g) were preliminarily bred and then fasted overnight before use.

(3) Preparation of specimen Each test compound was suspended in a 0.5% (W/V) sodium carboxymethyl cellulose aqueous solution.

(4) Test method The strain used was incubated in trypto soya broth (manufactured by Nissui Pharmaceutical Co., Ltd.) at 37°C for 16 to 18 hours, and then incubated in PBS (
Dulbecca's phosphate buffe
diluted with 10% (W/V) H
ucin (BACTOM(101% BACT
ERIOI, 0GICAL (manufactured by Difco)] in equal amounts. This bacterial solution was injected intraperitoneally into a group of 5 mice.
5- inoculated. The specimen was orally administered 1 hour after infection. From then on, the mice were observed daily for survival and death, and the 50% effective dose (Eu5O value) was calculated by the Wail method based on the number of survivors after one week.

3. Results The test results are shown in Table 2.

Table 2 [Test Example 3] Acute toxicity test (LD5G) 1, test compound Compound 2 of Example 1, test method ddY male mice (body weight 20-25 g, 10 mice per group)
Each test compound was suspended in a 0.5% (W/V) sodium carboxymethylcellulose aqueous solution and administered orally, and the number of deaths up to 2 weeks after administration was observed.

3. Results No deaths were observed in the test compound administration group at 4000 mg/kg, and the LD50 value was 4000 mg/kg or higher.

From the following results, it is clear that the compound of the present invention can serve as an effective and highly safe antibacterial agent.

Example 1 Quinquinoline-3-carboxylic 1-cyclopropyl-[1,7,8-)refluoro-1
, 4-dihydro-4-oxoquinoline-3-carboxylic acid (synthesized according to the method described in JP-A-59-212474) 4.5 g of 3-hydroxyvirolidiy
(manufactured by Aldrich Chemical Go) 4.
Add 15g of dimethyl sulfoxide, 100~
The mixture was heated and stirred at 105°C for 1 hour.

The reaction solution was cooled to room temperature, poured into ice water, and neutralized (pH 7) with 50% acetic acid.The precipitate was collected by filtration and washed with water.

This was recrystallized from ethanol/dimethylformamide to obtain the title compound 3.88 as pale, poor-colored needle-like crystals.

Melting point: Starts to turn brown around 270℃, 280~2
It decomposes at 87°C and turns dark brown.

Elemental analysis value (as CI7H18F2N204): Calculated value (%) C, 5B, 50:H, 4, 72:N, 8.
05 actual measurement value (%) C, 5B, 2Q;)! , 4.6Q
:N, 8.0G Example 2 Manufacture of tablets [Formulation] Main drug (compound of Example 1) 250g Cornstarch 46〃Microcrystalline cellulose
100 //Suarin Magnesium 47/00g [Procedure] Water was added to the main ingredient, corn starch, and microcrystalline cellulose and kneaded. After passing this mixture through a sieve and granulating it into single granules and drying, the resulting granules were mixed with magnesium stearate and compressed into 4,001 g tablets.
Tablets containing 0 mg were obtained.

Example 3 Production of granules [Formulation] Crude drug (compound of Example 1) 250g lactose
2357/Corn starch
109 /1 Hydroxypropylcellulose 6/! 00g [Operation] The herbal medicine, lactose and cornstarch were mixed, and hydroxypropylcellulose dissolved in 12G of water was added thereto and thoroughly kneaded. This composite was passed through a 20-mesh sieve, granulated, dried, and then sized to obtain granules.

Example 4 Manufacture of capsules [Formulation] Main drug (vl Example 1 (F) compound) 250g Corn starch 5 Q // Milk Jl
35 tt Stearin Magnesium 5//50g [Operation] Thoroughly mix each of the above ingredients and add 35111w of this mixed bundle.
Fill capsules with 250 g of crude drug in each capsule.
Capsules containing mg were obtained.

Claims (2)

[Claims] (1) 1-cyclopropyl-6,8-difluoro-1,
4-dihydro-7-(3-hydroxypyrrolidine-1-
yl)-4-oxoquinoline-3-carboxylic acid and its pharmaceutically acceptable salts. (2) 1-cyclopropyl-6,8-difluoro-1,
4-dihydro-7-(3-hydroxypyrrolidine-1-
An antibacterial agent containing as an active ingredient 4-oxoquinoline-3-carboxylic acid and a pharmaceutically acceptable salt thereof.