JPH03218383A - Optically active quinolinecarboxylic acid derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula [R<1> is lower alkyl; R<2> is H, lower alkyl or (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl; R<3> is H or lower alkyl]. EXAMPLE:S-(-)-6-fluoro-1-methyl-7-(4-methyl-1-piperazinyl)-4-oxo-4 H-[1,3]thiazeto[3,2-a]-3-carboxylic acid. USE:An antibacterial agent against Gram-positive bacteria, Gram-negative bacteria, etc. It has low toxicity and is useful as a therapeutic agent for infectious diseases such as systemic infection, urinary infection and biliary infection. PREPARATION:The exemplified compound can be produced e.g. by subjecting a solution of racemic 6-fluoro-1-methyl-7-(4-methyl-1-piperazinyl)-4-oxo-4 H-[1,3]thiazeto[3,2-a]-3-carboxylic acid to high performance liquid chromatography and purifying the eluted fraction.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to optically active quinoline carboxylic acid derivatives that have antibacterial activity and are useful as therapeutic agents for various infectious diseases. More specifically, the present invention relates to an optically active quinoline carboxylic acid derivative represented by the following general formula [I] and a pharmacologically acceptable salt thereof.

0 In the formula, R1 represents lower alkyl, R2 represents hydrogen, lower alkyl, or (5-methyl-2-oxo1,3-dioxolen-4-yl)methyl, and R3 represents hydrogen or lower alkyl.

[Conventional technology]

Currently, nalidixic acid, biromidic acid, pipemic acid, enoxacin, ofloxacin, and the like are widely used as synthetic antibacterial agents for treating infections caused by Durham-negative bacteria. However, these cases have been increasing in recent years, and they are not satisfactory in the treatment of chronic Pseudomonas aeruginosa infections and Durham-positive bacterial infections, which are intractable diseases. In order to solve this problem, various compounds have been synthesized and numerous patent applications have been filed.

The present inventors have also synthesized various compounds, discovered quinoline carboxylic acid having excellent antibacterial activity, and have already filed a patent application (Japanese Patent Application No. 62-281550, etc.).

Among the compounds disclosed in such patent publications, the compounds in which the 1st position is substituted have an asymmetric carbon in the 1st position in their structure, and the usual production method produces a racemic form ((±) form, specific optical rotation [ α][lO°).

[Problem to be solved by the invention]

An object of the present invention is to provide a synthetic antibacterial agent that has better pharmacological action than existing antibacterial agents and is less toxic.

[Means to solve the problem]

The gist of the present invention lies in the structure itself of the compound represented by the general formula CI).

The optically active substance according to the present invention is a new compound that has not been described in any literature, and, as described later, has far superior antibacterial activity and extremely low toxicity compared to the existing (±) form. It is.

The alkyl in the general formula [I] is preferably a straight or branched alkyl having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, lobutyl, isobutyl, sebutyl, etc. I can do it.

The compound of the present invention can be obtained by optically resolving a racemate produced by the method described in the above-mentioned patent publication by a known method. For example, it can be separated into two optically active substances by a fractional crystallization method, a physical separation method such as chromatography, or a combination thereof.

When the compound of the present invention is administered as a medicament, the compound of the present invention may be administered as is or in a pharmaceutically acceptable non-toxic and inert carrier, for example, from 0.1 to 99.5%, preferably from 0.5 to 99.5%. It is administered to animals, including humans, as a pharmaceutical composition containing 90%.

As carriers, one or more solid, semisolid, or liquid diluents, fillers, and other formulation auxiliaries are used.

Preferably, the pharmaceutical composition is administered in dosage unit form. The pharmaceutical composition of the present invention can be administered orally, intracellularly, locally (transdermally, etc.), or rectally. Of course, it is administered in a dosage form suitable for these administration methods. For example, oral administration is particularly preferred.

It is desirable to adjust the dose as a therapeutic agent for infectious diseases, taking into account the patient's condition such as age and weight, the route of administration, the nature and severity of the disease, etc. As for the amount of ingredients, per day, in the case of oral administration, 50
~1000 mg/human, preferably 100-30
A range of 0 mg/person is common. In some cases,
A dose less than this may be sufficient, or a larger dose may be required. It is also desirable to administer the drug in divided doses 2 to 3 times a day.

〔Example〕

The present invention will be explained in more detail below with reference to Examples and Test Examples.

Example I S-(-)-6-fluoro-1-methyl-7-(4
-methyl-1-biverazinyl)-4-oxo4N-[
1. 3] Thiazet [3. 2-a] 3-Canolebonic acid 6-fluoro-1-methyl-7-(4-methyl-1-piverazinyl)-4-oxo 4H-[1. 3] Thiazet [3. Racemic form of 2-a-3-carboxylic acid 132
．． 7 mg was dissolved in an aqueous solution of methanesulfonic acid, subjected to high performance liquid chromatography (HPLC), and fractionated.

(2) The conditions for PLc are as follows.

Column: YMC SH363-5 120AAM O
DS 3x250 mm mobile phase; water: methanol-4:
1. Copper sulfate (pentahydrate > 3mM) - phenylalanine [3mM] containing flow rate. , concentrated under reduced pressure, and made weakly alkaline by adding an aqueous solution of sodium bicarbonate.Then, the precipitate was collected by filtration and washed with an aqueous solution of sodium bicarbonate.Additionally, methanol, chloroform:methanol (5
: Extraction was performed in the order of mixed solvent 1). This extract was mixed with the previous washing solution, and the aqueous layer was divided into chloroform; methanol-5:
1 of a mixed solvent, and the organic layer was washed with saturated brine.

The aqueous layer was extracted with the same mixed solvent. The extract was dried over sodium sulfate and concentrated under reduced pressure. Next, 5% hydrochloric acid was added to the residue, and the resulting precipitate was washed with 5% hydrochloric acid, ethanol, and ether in this order, and dried under reduced pressure. Then, in addition to a sodium bicarbonate aqueous solution, extraction was performed with a mixed solvent of chloroform:methanol-5:1. The extract was washed with saturated brine, dried with sodium sulfate, and the solvent was distilled off under reduced pressure.

Finally, the residue was recrystallized from ethanol to obtain 81. 4m
Crystals of g were obtained.

X-ray analysis revealed that this product was in the S- (-) form.

The fraction eluted later was also subjected to the same post-treatment to obtain R-
(+) Obtained a body.

The retention time in HPLC and other physicochemical properties are as follows.

HPLC conditions: Column゜YMC8M302 S-5 120A OD
S46X150mm Mobile phase: Same as preparative RS Flow rate = 1.0 companies/min Detection: 350 nm (+) body: Retention time 6.81 minutes Melting point 234-235℃ (decomposition) [α] Ro 3168.78 (c = 0.801 chloroform: methanol - 5 = 1) (-) form: retention time 5.51 minutes melting point 234-235°C [α] ε' - 171.76 (c = 0.765 chloroform; methanol = 5: 1 ) Example 2 S-(-)-6-fluoro-1-methyl-7-(1-piverazinyl)-4-oxyv-41{-[1,3-cothiazeto[3. Similarly to 2-a]-3-carboxylic acid, 6-fluoro-1-methyl-7-(1-piperazinyl)-4-oxo-4H-[1,3-cothiazeto[3. 2-a] Two types of optically active forms were obtained from the racemic form of 3-carboxylic acid.

R- (+) form: melting point 300°C [α]P 125.81 (c=1.011 0M
F>S-(-) body: melting point 280-285℃Ca]V
-119. 20 (c=1.005 0MP)
Example 3 S-(1)-6-fur-1-methyl-7-[4
-(5-methyl-2oxo-1,3-dioxolene-4
-yl)methyl-1-piverazinyl]-4-oxo4
8-[1. 3] Thiazet [3. 2-a]3-carboxylic acid 6-fluoro-1-methyl-7-[4i5-methyl-
2-oxo1,3-dioxolen-4-yl)methyl-1-piperazinylco-4-oxo4H-[1.3]
Thiacet [3. Two types of optically active forms were obtained in the same manner from the racemic form of 2-a]-3 carboxylic acid.

R-(10) form: Melting point 140°C [α]P 86. 85 (c=1.004 0
MF) S- (-) form: melting point 139-141°C [α]P
-90.81 (c=1.013 0MF) Test Examples The results of pharmacological tests showing the usefulness of representative examples of the compounds of the present invention are shown below.

Test method 1. Minimum inhibitory concentration (MIC) measurement test method: MIC was measured by the agar plate dilution method according to the Japanese Society of Chemotherapy standard method (see Journal of the Japanese Society of Chemotherapy 29(1) 76-79 (1981)). That is, using the susceptibility measurement broth, a bacterial suspension cultured at 37°C for 18 hours was diluted with the same medium to 10 6 CFII/1. This was inoculated onto a drug-containing agar medium for susceptibility measurement using a microplanter.
After culturing at ℃ for 18 hours, MIC was measured. A racemate was used as a control drug. The results are shown in Table 1. The S-1(-) form of the compound of the present invention exhibited extremely strong antibacterial activity against Pseudomonas aeruginosa, as well as Durum-positive and Durum-negative bacteria.

Table 1 Bacterial strain ■S, aureus Smith ■E, faecalis ATCC 29212■M
．． Iuteus ATCC 9341MIC (μg/m
l! ) Inventive product Control 0.025 0.05 01 0.39 078 1.56 ■B. coli K[:-14 ≦0
．． 00625 0.025■B. coli Kp
≦0.00625 0,02
5■S,marcasceneslPO3736
0.1 0.2 ■P, aeruginosa
IPO 3445 0.2
0.39■P, cepacia ATCC 2
5416 0. 025 0. 05■^
, faacalis 1 (PCAR)
6.25 The present invention in Table 25 represents the compound of Example 1, and the control represents the racemic form of the compound of Example 1.

MIC (μg/1) Strain Inventive product Control ■S, a
ureus Smith 0. 05
0. 05■B, faecal is ATCC
29212 0. 39 0. 78■M,
Iuteus 8TCC 9341
0.39 0.39 ■ B, coli
KC-14 ≦0.00625 0,0
125 ■ [i. coli Kp ≦0,
00625 0,0125 ■S, marcescen
es IFD 3736 0.025 0.0
5 ■ P, aeruginosa IFO 3445
0.05 0.10■P,c
epacia eight TCC 25416
0,20 0,39■A,faecal
is 1 (PCAR) >100 >10
The present invention in Table 0 represents the compound of Example 2, and the control represents the racemic compound of Example 2.

The compound of Example 3 is a prodrug and exhibits activity only after being metabolized into the active substance in vivo.
n vitro activity was not measured.

2. Test method for therapeutic effect on mouse infection Escherichia coli (B. coli KC-14) and P. aeruginosa (P. aeruginosa B-2) were suspended in 5% mucin, and 0.5% of the suspension was injected into ddY male mice ( The mice were inoculated intraperitoneally to 20 g (weight 20 g, 4 weeks old, 10 animals per group).

The amount of inoculated bacteria is 5.0 for E. coli. I x 10'CFLl/mouse, Pseudomonas aeruginosa 7.5 x 10'CFU/mouse.

The drug was orally administered once 2 hours after bacterial inoculation, and BDso was determined based on the survival rate after 1 week (Probit).
Required by law. A racemate was used as a control drug. The results are shown in Table 2.

The compound of the present invention showed a strong therapeutic effect on murine infections.

Table 2 12 Compounds (Example numbers) Example 1 Racemic product of Example 1 Example 2 Racemic product of Example 2 Example 3 Racemic product of Example 3 “N.T.” [Effects of the invention] The above As is clear from the results, the compound of the present invention has excellent antibacterial activity against both Durham-positive and Durham-negative bacteria, as well as Pseudomonas aeruginosa, at a much lower dose than existing antibacterial agents. It also showed high efficacy in the treatment of infectious diseases.It also has very low toxicity.

The compound of the present invention has excellent properties not found in existing pharmaceuticals.
67 0 607 N. T, Shin≦0. 00625 N, T, * 0 802 KC-14 E D so O. 288 0. 664N. T. "B, col i l VIrc ≦0. 00625 0, 025 0. 012 Represents not tested.

effective and has low toxicity. Therefore, it can be safely used in mammals, including humans, as a therapeutic agent for systemic infections or local infections such as urinary tract infections or biliary tract infections.

Claims (1)

[Claims] (1) An optically active quinoline carboxylic acid derivative represented by the following general formula [I] and a pharmacologically acceptable salt thereof. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [I] In the formula, R^1 is lower alkyl, R^2 is hydrogen, lower alkyl, or (5-methyl-2-oxo-1,3-dioxolene-4 -yl)methyl, R^3 represents hydrogen or lower alkyl.