JPH03190883A - New quinolinecarboxylic acid derivative and antibacterial agent containing the same compound as active component - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R is lower alkyl). EXAMPLE:9,1-(Methylimino)methano-7-fluoro-8-[4-(2-oxopropyl)-1-piperaz inyl]-5- oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylic acid. USE:An antibacterial agent having low toxicity and excellent activity especially against Gram-positive bacteria. PREPARATION:The objective compound can be produced by reacting a compound of formula II with 1,3-dichloroacetone, reacting the product with an inorganic acid to obtain a compound of formula III, reacting the compound with methylamine, reacting the reaction product with a lower alkyl iodide of formula RI, reacting the resultant compound of formula IV with a di(lower alkyl) malonate sodium, heating the product in the presence of a condensation agent, heating the obtained new compound of formula V in concentrated sulfuric acid, reacting with piperazine and finally reacting the obtained compound of formula VI with a compound of formula VII (X is halogen).

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a novel quinoline carboxylic acid derivative and an antibacterial agent containing the compound as an active ingredient.

More specifically, a quinoline carboxylic acid derivative represented by the following formula (I) (wherein R represents a lower alkyl group).

(2) An antibacterial agent containing a quinoline carboxylic acid derivative represented by the following formula (1) (wherein R represents a lower alkyl group) as an active ingredient.

The present invention relates to a novel quinoline carboxylic acid derivative represented by the formula (wherein R represents a lower alkyl group) and an antibacterial agent containing the compound as an active ingredient.

[Conventional technology]

Since the discovery of nalidixic acid as a synthetic antibacterial agent, various quinoline carboxylic acid derivatives have been investigated with the aim of improving antibacterial activity, and fused tetracyclic compounds have also been investigated. That is, European Patent Publication No. 286089 describes 9,1-epoxymethano-5H-thiazolo [3,2
-a] A fused tetracyclic compound having a quinoline skeleton, such as the following compound X, is disclosed.

Compound

An object of the present invention is to provide a novel fused tetracyclic compound having excellent antibacterial activity and an antibacterial agent containing the same.

(Means for Solving the Problems) As a result of various studies, the present inventors have developed a novel 9,1-(methylimino)methano-5H-thiazolo [3,2-al quinoline skeleton represented by the following formula (I)]. The present invention was completed by successfully synthesizing a fused four-ring compound having the following properties, and confirming that the compound has excellent antibacterial activity, particularly against Durham-positive bacteria, and has low toxicity. .

The compounds of the present invention also include pharmaceutically acceptable salts of the compound represented by formula (1).

Compound (I) of the present invention is produced by the following method (wherein R
represents a lower alkyl group. ) (II) (III) (Vr) (■) (X) (In the formula, R is as described above, and X represents a halogen atom.) That is, the known compound (II) (European Patent Publication No. 2)
86089) with 1,3-dichloroacetone in an organic solvent such as chloroform, methylene chloride or a lower alcohol to obtain 3-chloro-N-(2,3,4-1-lifluorophenyl)dithiocarbamic acid. 2-oxopropyl ester (III) is obtained.

Then compound (III) was mixed with methanol, ethanol,
4-chloromethyl=3-(2,3,4-trifluorophenyl)=2 (3H)-1,3-thiazolethione by reacting with an inorganic acid such as hydrogen chloride or sulfuric acid in a solvent such as ethyl acetate. (IV) is obtained.

Next, compound (IV) and methylamine are reacted in an organic solvent such as N,N-dimethylformamide or acetonitrile to produce 5-methyl-6°7-difluoro-IH,4H.
-thiazolo[3°4-a]quinoxaline-1-thione (
V) is obtained (1).

Next, N,N-dimethylformamide, acetonitrile,
Compound (V) and lower alkyl iodide are reacted in a polar organic solvent such as ethanol to form a 1-lower alkylthioquinoxalino[12-c]deazolium iosito derivative (V
l) is obtained.

Next, in an organic solvent such as tetrahydrofuran or dioxane, the compound (Vl) is reacted with storium malonic acid di-lower alkyl ester prepared from sulfur hydride and sulfur hydride (5-methyl -6,7difluoroIH,4H-thiazolo[3,4a
] Quinoxalin-1-ylidene) malonic acid di-lower alkyl ester derivative (■) is obtained.

Compound (■) can be obtained by reacting compound (V) with phosgene or trichloromethyl chloroformate in an inert solvent such as toluene or benzene, and then reacting this product with malonic acid dichloride in a polar solvent such as acetonitrile. It can also be produced by reacting a lower alkyl ester in the presence of a tertiary amine such as triethylamine.

Next, by heating the compound (■) with a condensing agent such as polyphosphoric acid or polyphosphoric acid ethyl ester, a new fused tetracyclic compound having a 9.1-(methylimino)methano-5H-thiazolo[3,2-mycoquinoline skeleton] is produced. Lower alkyl esters (■) can be produced. The reaction temperature is usually 80°C to 130°C, preferably 85°C to 100°C, and the reaction time is 3 to 15 hours.

9. Next, compound (■) was heated in concentrated sulfuric acid.
1-(Methylimino)methano-5H-deazolo[3,2
-Mycoquinoline-4-carboxylic acid derivative (IX) can be produced. The reaction temperature is 50°C to 130°C, preferably 60°C to 100°C, and the reaction time is usually 5 hours to 22 hours.

Note that the above compound (■) can also be hydrolyzed to obtain compound (IX) without isolation.

Subsequently, in a polar organic solvent such as dimethyl sulfoxide or N,N-dimethylformamide, an equimolar amount or an excess amount of piperazine or an acid addition salt thereof relative to compound (IX) is added to compound (IX) as an acid scavenger. 9.1-(Methylimino)methano-7-fluoro-8-(1-piperazinyl)-5-oxo-5H-deazolo[3,2-a-coquinoline-4carboxylic acid (X) You can.

As the acid scavenger, tertiary amines such as triethylamine, inorganic bases such as sodium carbonate and potassium carbonate, or piperazine can be used. When excess piperazine is used as an acid scavenger, the reaction is usually carried out using 3 to 7 moles of piperazine per 1 mole of compound (■).

When using a tertiary amine or an inorganic base as an acid scavenger, usually 1 to 1.5 mol of piperazine or its acid salt and 2 to 6 mol of the acid scavenger are used per 1 mol of compound (■). Carry out the reaction.

Finally, compound (X) and compound (
The compound (I) of the present invention can be produced by reacting an equimolar amount to an excess amount of a halomethylcarbonyl compound, such as bromoacetone, with respect to X) in the presence of an acid scavenger.

As the acid scavenger, inorganic bases such as sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, etc., or tertiary amines such as triethylamine can be used. The reaction temperature is 10°C to 80°C, preferably 5°C to around room temperature, and the reaction time is usually 2 hours to 30 hours.

The compound N) of the present invention produced by the above method is purified to single i1 by conventional purification means, such as silica gel column chromatography or recrystallization.

The compound (■) of the present invention exhibits excellent antibacterial activity as described below, has low toxicity, and is useful as an antibacterial agent.

Compound N) of the invention is administered to humans as an antibacterial agent orally or parenterally, eg by injection.

Dosage forms for oral administration include solid preparations such as tablets, granules, powders, fine granules, and hard capsules, as well as liquid preparations such as syrups and soft capsules. Such preparations are manufactured by conventional methods, and tablets, granules, powders, and fine granules are prepared by adding the compound (1) of the present invention and conventional pharmaceutical additives such as lactose, starch, crystalline cellulose, magnesium stearate, and talc. Hard capsules are produced by appropriately filling capsules with the above-mentioned fine granules and powders.

In addition, syrups are prepared by dissolving or suspending the compound (I) of the present invention in an aqueous solution containing white sugar, carboxymethylcellulose, etc., and soft capsules are prepared by dissolving or suspending the compound (I) of the present invention in an aqueous solution containing white sugar, carboxymethylcellulose, etc., and soft capsules are prepared by dissolving or suspending the compound (I) of the present invention in an aqueous solution containing white sugar, carboxymethyl cellulose, etc. It is manufactured by dissolving or suspending the compound (I) of the invention and filling it into soft capsules.

Injections are produced by dissolving or emulsifying the compound (I) of the present invention in physiological saline or a lipid excipient such as vegetable oil, oily emulsion, or glycol, and aseptically sealing the solution in an ampoule or vial.

The dosage of the antibacterial agent of the present invention varies depending on the patient's age, weight, symptoms, etc., but in general, compound (1) is
．． 5-30 mg/kg body weight/day, preferably 2-20
mg/kg body weight/day, administered once a day or divided into 2 to 4 times a day.

〔Effect of the invention〕

Compound (I) of the present invention has excellent antibacterial activity, particularly against Durham-positive bacteria (see Test Example 1 below), and also has strong antibacterial activity against clinically derived resistant Staphylococcus aureus (see below). (See Test Example 2).

1 2 Furthermore, when the compound (1) of the present invention was tested using experimental animals infected with Staphylococcus aureus, it was confirmed that it exhibited excellent infection treatment effects (see Test Example 3 below).

On the other hand, the toxicity of the compound (1) of the present invention is low.

For example, even when the compound of Example 1 was orally administered to mice at a rate of 2000 mg/kg, no mortality was observed (see Test Example 4 below).

Therefore, the compound (1) of the present invention can be an excellent prophylactic and therapeutic agent for various infectious diseases, particularly those caused by Durum-positive bacteria.

The present invention will be explained below with reference to test examples.

[Test Example 1] Antibacterial activity (minimum inhibitory concentration: MTC) 1
, test compound/compound of Example 1...9.1-(methylimino)methano-7-fluoro-8-(4-(2-oxopropyl)-1piperazinyl]-5-oxo-5H-thiazolo[ 3,2
-a] Quinoline-4-carboxylic acid/known compound X...9,1-epoxymethano-7-fluoro-8-(4-methyl-1-piperazinyl)-5-
Oxo-5H-thiazolo[3,2-a]quinoline-4-
Carboxylic acid/hydrochloride 2, the compound of Test Method Example 1 was added to 0. It was dissolved in IN aqueous sodium hydroxide solution to prepare a 5000 μg/ml solution. Known compound X was dissolved in sterile purified water to prepare a 5000 μg/ml solution.

Next, each of the above solutions was diluted with sterile purified water to prepare a standard solution having a concentration of 1000 μg/ml of each test compound. After that, the method specified by the Japanese Society of Chemotherapy (Chemo
therapy.

29.76-79 (1981), TOKYO).

3. Test results Shown in Table 1.

5 16 [Test Example 2] Minimum inhibitory concentration for clinically isolated methicillin-resistant Staphylococcus aureus: 1, test compound Same as in Test Example 1.

2. The compound of Test Method Example 1 was 0. The compound was dissolved in an aqueous IN sodium hydroxide solution, and the known compound Next, each of the above solutions was diluted with sterile purified water to prepare a standard solution having a concentration of 1000 pg/ml of each test compound. After that,
The method specified by the Japanese Society of Chemotherapy (Che-mothera)
py, 29.76-79 (1981), TOKYO), the minimum inhibitory concentration (MIC) for 54 clinically isolated methicillin-resistant Staphylococcus aureus strains was measured, and tests were conducted on these resistant strains. Compound MIC range (MICr,, nga)
, the minimum concentration that inhibits the growth of 50% of the strains (MI[;5
0 ) and the lowest concentration that inhibits the growth of 90% of the strains (
MIC9o) 3, the test results are shown in Table 2.

Table 2 I asked for

(Test Example 3) Therapeutic effect 1 on systemic infection caused by Staphylococcus aureus, test compound Same as in Test Example 1.

2. Test bacteria and inoculum amount Staphylococcus aureus (S, aureus)
s) IID 803, 2. 3 x 1
0'CFU/mouse 3, test method The test bacteria were incubated at 37°C for 18 hours in trypto soya broth (manufactured by Nissui Pharmaceutical Co., Ltd.), and then cultured in PBS (Du
lbeccosphosphate buffer-e
d 5aline) and an equal volume of 10% (W/V)
Mucjn[BAcTOMIICIN BACTE
RIOLOGICAL (Difc.

A bacterial solution was prepared. 0.5 ml of this bacterial solution was inoculated intraperitoneally into male ddY mice (5 weeks old, weight 25-28 g, 5 mice in - group) to infect them. Immediately after infection, the compound of Example 1 suspended in a 0.5% (W/V) sodium carboxymethyl cellulose aqueous solution or the known compound X dissolved in sterile purified water was orally administered. One week later, the number of surviving mice was determined by the Weft method to obtain a 50% effective dose 4, and the test results are shown in Table 3.

Table 3 [Test Example 4] Acute Toxicity Test 1, Test Method 9.1-(Methylimino)methano-7-fluoro-8-
(4-(2-oxopropyl)-1piperazinyl)-5
-oxo-5H-deazolo[3,2-a]quinoline-4
-carboxylic acid (compound of Example 1) at 0, 5'* (
W/V) Suspended in sodium carboxymethyl cellulose aqueous solution, this suspension was administered at a rate of 2000 mg/Kg to ddY male mice (5 weeks old, body weight 20-25 g, 5 mice in - group) that had been fasted for 18 hours. Administered orally. then 1
The number of deaths in the mice was observed up to the first week, but no deaths were observed.

9 〔Example〕 The present invention will be explained below with reference to Examples.

9.1-(Methylimino)methano-7-fluoro-8-
(4-(2-oxopropyl)-1piperazinyl)-5
-oxo-5H-thiazolo[3,2-a]quinoline-4
- Synthesis of carboxylic acid [compound in which R is a methyl group in formula (1)]: The title compound was synthesized through the following 9 steps.

First step N-(2,3,4-1-lifluorophenyl)dithiocarbamic acid 3-chloro-2-oxopropyl ester [
Compound of formula (III)] 1,3-dichloroacetone 2
．． Add 0g to 100ml of methylene chloride and add 2 while stirring.
At ~5°C, N-(2,3,4-trifluorophenyl)
50 g of triethylammonium dithiocarbamate (see European Patent Publication No. 286089) was added.

The mixture was then stirred for 60 minutes and washed with 3O N hydrochloric acid and then with water. After drying the organic layer over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was crystallized from a mixed solvent of hexane-acetic acid ether to obtain 4.2 g of the title compound.

Mass spectrum (m/e) + 313 (M "")
Second step 4-chloromethyl-3-(2,3,4-trifluorophenyl)-2(3H)-thiazolethione [formula (IV)
Compound]: 4.0 g of N-(2,3,4,-1-lifluorophenyl)dithiocarbamic acid 3-chloro-2-oxopropyl ester was added to 15 ml of 30% hydrogen chloride methanol solution and heated under reflux for 3 hours. .

The solvent was then distilled off under reduced pressure, cold water was added to the residue, and the mixture was extracted with chloroform. The extract was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from cyclohexane to obtain 2.6 g of the title compound as pale yellow crystals.

Melting point, 127-130°C NMR (CDCIa) δ: 4.1 (I
H, d, J-13Hz), 4.2 (u+, d, J-13
H2), 6. a(u+,s), 7.2(28,
m).

I R (Hr) 1lma. cm-': 307
2,151B, 1504.13141280.1102 Elemental analysis value (as C+oHa NS2 F3 CI)
Calculated value (%) C, 40, 61, H, 1, 70, N, 4
．． 74 Analysis value (%) C, 40, 59, H, 1, 80,
N, 4.71 Third step 5-methyl-6,7-difluoro-IH4H-thiazolo[3,4-a]quinoxaline 1-thione [compound of formula (V)] 4-chloromethyl-3-(2, 2.5 g of 3,4-trifluorophenyl)-2(3H)-thiazolethione was dissolved in 25 ml of acetonitrile, and 3.3 g of a 40% methanol solution of methylamine was added thereto, followed by stirring at 50° C. for 16 hours.

The reaction mixture was dried under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The extract was washed with brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The resulting residue was recrystallized from a mixed solvent of cyclohexane-ethyl acetate to obtain 2.0 g of the title compound as pale yellow crystals.

Melting point: 165-167°C NMR (CDCl3) δ: 3.0 (3H, d,
J-2,5)IZ), 4.0 (2H,d, J-IHz)
, 6.4 (IH, t, J-IHz), 6.9 (IHc
lt, J=llHz, J-9,5Hz>, 9.3(I
H, ddd, J-2, 5H2J・5l-1z, J-9,
5Hz).

I R(KBr) u,,Xcm-': 1502,
1492,1306.12901032゜Elemental analysis value (as C++H6N2S2F2) Calculated value (%) C,48,87; l-1,2,98,
N, 10.36 analysis value (%) C, 49,04, H, 2
,96,N,10.41 4th step 5-methyl-6,7-difluoro-1-methylthio-4
H-quinoxalino[1,2-c]thiazolium iosito [compound in which R is a methyl group in formula (Vl)] 5-methyl-6,7-difluoro-IH.

0.4 g of 4H-thiazolo[3,4-a]quinoxaline-3 1-thione and 0.4 g of methyl iodide were mixed with N,N
-Dissolved in 3 ml of dimethylformamide and left in the dark at room temperature for 40 hours. The precipitate was collected by filtration and washed successively with acetonitrile and ether to give the title compound 0.0 as yellow crystals.
5g was obtained.

NMR(DMSQ-d6) δ: 3.0(3
H, d, J-4,0Hz) 3.1 (3N, s), 4.4
(28, s), 7.3 (IHdt J-8Hz9.5H
z), 7.9 (LH, ddd, J-2Hz J-5H
zJ"9.5Hz), 8.0 (ILs) 5th step (5-methyl-6,7-difluoro-IH4H-thiazolo[3,4-a]quinoxaline 1-ylidene) malonic acid diethyl ester (formula (■ ) in which R is an ethyl group] oily sodium hydride (content rate approximately 60 w/w 9
6) Suspend 54 mg in 3 ml of tetrahydrofuran,
02 g of diethyl malonate was added dropwise at 0° C. and stirred for 20 minutes. Next, 0.5 g of 5-methyl-67difluoro1-methylthio-4H-quinoxa4lino[1,2-c cothiazolium iodide was added at 10°C, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was dried under reduced pressure, cold water was added, insoluble materials were collected by filtration, washed with water,
After drying, it was recrystallized from a mixed solvent of hexane-ethyl acetate to obtain 0.34 g of the title compound as yellow crystals. Melting point 146-148°C NMR (CDCh) δ: 1.2 (6H, t, J-
7Hz), 3.1(3)1゜d, J-4,5Hz)
, 3.9 (4H, q, J・7H7), 4.0 (2H
,s).

8.5 (IH, t, J-IHz), 6.8 (IH, d
t, J-8Hz, J-9Hz), 7.3 (I
H, ddd, J-2flz, J-5Hz, J-91-1
z).

IR(KBr)ull, cm-':1700,1
642,1508,1426゜1294.1188.1
082゜Elemental analysis value (as C+aH+aN204 S F2)
: Calculated value (IC, 54, 54; H, 4, 58; N, 7.
07 analysis value (96) C, 54, 45, l-1, 4, B
1. N, 8.89 Step 6 9.1-(Methylimino)methano-7,8-difluoro-5-oxo-5H-thiazolo[3°2-a coquinoson-4-carboxylic acid ethyl ester [R in formula (■)]
is an ethyl group compound) A mixture of 1.2 g of diethyl malonic acid (5-methyl-6,7-difluoro-IH4H-thiazolo[3,4-a]quinoxaline-1-ylidene) and 10 g of polyphosphoric acid was heated at 100'C. Stirred for 5 hours. Cold water was added to the reaction mixture, and the mixture was extracted with chloroform. The extract was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of chloroform-ethanol to obtain 0.6 g of the title compound as pale yellow crystals.

Melting point: Decomposition near 285°C NMR (DMSO-c16) 6 1.3 (3+1.
t, J-71-IZ), 3.2 (3H, d, J-5,
5Hz), 4.3(2)1. q, J-71-1z),
4.5(2)1. d, J-11-1z), 7.3(1
)1. s), 7.4 (IH, dd.

J-7.5Hz, J-10.5Hz).

IR(KBr)b,,xcl-':3060,170
8,1574.14961478 1456 1050 05 analysis value (as C16HI2N2035 F2)・
Calculated value (%) C, 54,85; H, 3,45; N 8
．． 00 Analysis value (%) C, 54,65, l (3,59・
N 7.97 Step 7 9.1-(Methylimino)methano-7,8-difluoro-5-oxo-5H-thiazolo[32-a]quinoline-
4-Carboxylic acid [compound of formula (IX)] 9.1-(methylimino)methano-78-difluoro-
5-oxo-5H-thiazolo[3,2-a]quinoline-
4-carboxylic acid ethyl ester 1.6g 1l: concentrated sulfuric acid 1
8ml of the mixture was added and stirred at 85°C for 6 hours. Wood chips were added, and the resulting precipitate was collected by filtration and washed with water to obtain 125 g of a crude product, which was recrystallized from a mixed solvent of dimethyl sulfoxide and ethanol to obtain 1.0 g of the title compound.

Decomposed near the melting point of 262°C NMR (IIMSO-d6) δ: 3.2 (3H, d
, J-8Hz), 4.6 (2Hs), 7.5(1)1
．． s), 7.6 (1M, dd, J-7Hz, J-9H
z) 15.6 (III, bS) 7 IR (to Br) νIIaX cm-' +169[1
,1552,1506,14801472,1456,
1404 Elemental analysis value (as C14H1l N203S F2)
: Calculated value (%) J52.17. )1.2.50. N,
8.69 Analysis value (%) C, 52,07; H, 2,77
;N, 8.47 8th step 9.1. -(methylimino)methano-7-fluoro-8
-(1-piperazinyl)-5-oxo5H-thiazolo[
3,2-a]quinoline-4carboxylic acid [compound of formula (X)] 9.1-(methylimino)methano-7,8difluoro-
5-oxo-5H-thiazolo[3,2-a]quinoline-
4-carboxylic acid 0.9g and piperazine hexahydrate 1
Add 83g to 25+nl of dimethyl sulfoxide at 80°C.
The mixture was stirred for 25 hours. The deposited precipitate was collected by filtration and washed successively with water and ethanol. This was recrystallized from dimethyl sulfoxide to obtain 1.1 g of the title compound as orange crystals.

Decomposes around melting point = 255°C 8 NMR (DMSO-d6 + C20) δ:
2.8(3)1. S), 2.8-2.9 (4H, m
), 3.3-3.4 (4H, m), 4.4 (211, s
).

7.5 (1)1. S), 7.6 (IH, d, J-
13H2) I R (KBr) vlI, 1. cm-
'+1699.1fi12,14894466゜Elemental analysis value (as Cl8H17N403S F・1/2H20)
Calculated value (%) C, 54,40; H, 4,57; N, 1
4.10 Analysis value (%) C, 54,52; H, 4,47
,N, 14.04 9th step 9.1-(methylimino)methano-7-fluoro-8-
(4-(2-oxopropyl)-1piperazinyl)-5
-oxo-5H-thiazolo[3,2-a]quinoline-4
-Carboxylic acid [compound in which R is a methyl group in formula (I)] 9.1-(methylimino)methano-7-fluoro-8
-(1-piperazinyl)-5-oxo-5H-thiazolo[3,2-a]quinoline 4-carboxylic acid 05g, potassium hydrogen carbonate 014g and N,N-dimethylformamide 3
The suspension was suspended in 0 ml of water, and 0.22 g of bromoacetone was added thereto. After the dropwise addition, the mixture was further stirred at room temperature for 10 hours, and then the solvent was distilled off under reduced pressure. The obtained residue was diluted with 80 ml of chloroform.
After washing with water and saline in sequence, it was dried over anhydrous sulfur and sulfur.

The solvent was distilled off under reduced pressure, and the resulting residue was dissolved in chloroform-
The title compound o, 1s was recrystallized from a mixed solvent of ethanol.
I got g.

Decomposes near the melting point of 242°C NMR (CDCl5) 62.2 (3H, s),
2.6-2.7 (4)1. m) 2.8 (:01.s)
, 3.3(2H,s), 3.5~3.6(41(,
m) 4.3 (2N, s), 7.0 (IH, s), 7
．． 8 (IH, d, J-12, 58Z), 15.5 (
IH,s) I R(KBr)u,, cm-'+1716.17
00,1488.1468 elemental analysis value (C2+H2+N
404S F) Calculated value (%) C,,5B,75
．． )1,4.7fi,N,12.61 Analysis value (%) C
, 5B, 48. H, 4,77, N, 12.59 Toru Ikuyoshi Manufacture of tablets 9.1-(Methylimino)methano-7-fluoro-8-(4-(2-oxopropyl) )-1-Piperazinyl]-5-oxo-5H-thiazolo[32-a]quinoline-4-carboxylic acid (compound of Example 1) 100 mg tablets were obtained.

[fi] Hiroyoshi Amount Main ingredient (compound of Example 1) 100 parts by weight Corn starch 46 parts by weight Microcrystalline cellulose 98 parts by weight Hydroxypropyl cellulose 2 parts by weight Magnesium stearate
4 parts by weight [Operation] The herbal medicine, corn starch and microcrystalline cellulose were mixed, and hydroxypropyl cellulose dissolved in 50 parts by weight of water was added thereto and thoroughly kneaded. This kneaded product was passed through a sieve and granulated into granules and dried. Magnesium stearate was mixed with the resulting granules and the mixture was compressed into 250 mg tablets.

2

Claims (2)

[Claims] (1) Below formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・(I) (In the formula, R represents a lower alkyl group.) A quinoline carboxylic acid derivative represented by (2) The quinoline carboxylic acid derivative represented by the following formula (I) ▲Mathematical formulas, chemical formulas, tables, etc.▼・・・(I) (In the formula, R represents a lower alkyl group) is used as an active ingredient. antibacterial agent.