JPH03193786A - New quinolinecarboxylic acid derivative, its production and intermediate thereof - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [group of formula II is group of formula III (R<1> is H, OH or lower alkyl; R<2> is H or lower alkyl) or formula IV (R<3> is H, Oh or amino); X is H or F]. EXAMPLE:7,8-Difluoro-2-methyl-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]quinoli ne-4- carboxylic acid. USE:An antibacterial agent having low side effect. PREPARATION:The objective compound can be produced by reacting a compound of formula V (R is H or lower alkyl) with a cycloamine of formula VI and, when the group R contains lower alkyl, removing the lower alkyl.

Description

Detailed Description of the Invention [Field of Industrial Application] The present invention relates to a novel quinolone carboxylic acid derivative, and more particularly, to a fused pentacyclic quinolone carboxylic acid derivative having excellent antibacterial activity, a method for producing the same, and a method for producing the same. This invention relates to novel intermediates useful for producing compounds.

[Prior Art] Since the discovery of nalidixic acid as a synthetic antibacterial agent, various quinolone carboxylic acid derivatives have been synthesized with the aim of improving antibacterial activity, expanding the antibacterial spectrum, and reducing side effects.
Many patent applications have been filed.

Among these studies, norfloxacin (Japanese Patent Application Laid-open No. 141286/1983) and enoxacin (Japanese Patent Application Laid-Open No. 1983-141286)
No. 5-83785), ofloxacin (JP-A No. 57-4
No. 6986), ciprofloxacin (Japanese Unexamined Patent Publication No. 58-74
No. 667), etc., have been developed and are currently in widespread clinical use.

[Problems to be Solved by the Invention] As mentioned above, several antibacterial agents based on quinolone carboxylic acid derivatives have been provided, but in the field of synthetic antibacterial agents, many people are not satisfied with the effects of existing compounds. It is important to develop new compounds with the aim of improving antibacterial activity, expanding the antibacterial spectrum, and reducing side effects.

Therefore, there has been a need to provide new quinolone carboxylic acid derivatives and advantageous methods for producing them.

[Means for Solving the Problems] The present inventors have continued intensive research to produce a novel quinolone carboxylic acid derivative having excellent antibacterial activity, and as a result, a novel compound represented by formula (I) below has a strong It was found to have antibacterial activity and broad antibacterial spectrum.

We have also discovered an advantageous method for producing compound (I) and an intermediate that can be used in this method.

The present invention was completed based on the above findings,
Its purpose is to represent the general formula (1) or a lower alkyl group, R2 represents a hydrogen atom or a lower alkyl group, R3 represents a hydrogen atom, a hydroxyl group, or an amine group), and X represents a hydrogen atom or a fluorine atom] The present invention provides a quinolonecarboxylic acid derivative represented by: and a salt thereof.

Another object of the present invention is to provide a method for producing the above compound.

Still another object of the present invention is to provide an intermediate useful for the synthesis of the above compound, represented by the following formula (II) (wherein, X is a hydrogen atom or a fluorine atom, and R is a hydrogen atom or a lower alkyl group). The present invention provides a compound represented by:

Aminopyrrolidine group, 3-hydroxypyrrolidino group, 1
-piperazinyl group, 3-methyl-1-piperazinyl group,
4-methyl-1-piperazinyl group or 4-ethyl-1
-piperazinyl group and the like. Also, compound (I)
Salts include addition salts with inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid; acetic acid, propionic acid, tartaric acid, citric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, methanesulfonic acid, glutamic acid, and aspartic acid. addition salts with organic acids such as; metal salts such as sodium salts, potassium salts, and calcium salts at carboxyl groups; addition salts with basic amino acids such as lysine and arginine, and known non-toxic amines.

The quinolone carboxylic acid derivative (I) of the present invention can be obtained by converting a compound represented by formula (II) into a compound represented by formula (m), for example, according to the following reaction formula.
It is produced by reacting a cyclic amine represented by ) and removing the lower alkyl group from the reaction product if R has a lower alkyl group.

For this purpose, compound (IV) is heated at a temperature of 80 to 90''C for 2 to 3 hours in a solvent such as a water-ethanol mixture containing 10 to 30% hydrochloric acid. Good.

Compound (II''), which is a starting material, is a new compound, and can be prepared, for example, according to the reaction formula shown below.

(Ro represents a lower alkyl group) The reaction between the compound (11) and the cyclic amine (m) is carried out in a solvent such as pyridine, dimethylsulfoxide, dimethylformamide, etc., in the presence of a base such as triethylamine as necessary, to react with 1 equivalent of the compound. This is carried out by reacting 1 to 5 equivalents of cyclic amine ([1) with (II).

This reaction is carried out by heating at 40-120°C for 1-24 hours.

When the compound obtained by the above reaction is an ester represented by formula (IV), in order to obtain compound (I), the lower alkyl group is further hydrolyzed αω (where Ro and X have the meanings described above). (Y represents a nitro group or a halogen atom such as chlorine, bromine, iodine, etc.) In the above reaction, 1 to 5 equivalents of thiadiazole compound (Vl) is added to about 1 equivalent of compound (V). It is carried out by refluxing for about 0.5 to 5 hours in an inert atmosphere such as argon gas in the presence of an alkali hydride and 1 to 5 equivalents of a copper halide catalyst, and removing the ester group of the product if necessary. . Compound (V) and thiadiazole compound (VI), which are raw materials, are both known compounds (JP-A-60-72885, JP-A-60-16947).
No. 5 and USP No. 3,497,597),
It is preferable to use a thiadiazole compound (Vl) in which Y is a nitro group. In addition, examples of the alkali hydride used in this reaction include sodium hydride, potassium hydride, lithium hydride, etc.
Moreover, iodized steel is preferably used as the copper halide catalyst.

To remove the ester group present in the product (Ila) and obtain compound (II b'), compound (IIa) is
It may be heated at a temperature of 80 to 90° C. for 2 to 3 hours in a solvent such as a water-ethanol mixture containing 0 to 30% hydrochloric acid.

The compound (I) of the present invention obtained as described above is purified, if necessary, by known means including recrystallization, column chromatography, and the like. Furthermore, if desired, it can be converted into a pharmaceutically acceptable salt thereof, such as an addition salt with the above-mentioned inorganic or organic acids, a metal salt, a basic amino acid, a non-toxic amine, etc., by a conventional method. can.

The compound of the present invention obtained as described above has excellent antibacterial activity as described later, and is low in toxicity, so it can be advantageously used as an antibacterial agent.

In order to use the compound of the present invention as an antibacterial agent, an effective amount of compound (I) may be administered as it is or in the form of a formulation with a known carrier.

As the administration method, either oral or parenteral administration methods can be used, and the above-mentioned formulation can also be performed according to these administration methods. For example, dosage forms for oral administration include solid preparations such as tablets, capsules, granules, and powders, and liquid preparations such as syrups and soft capsules. For example, solid carriers such as lactose, starch, cellulose and its derivatives, magnesium stearate, and talc are used depending on the product.For the production of liquid preparations, purified water, aqueous sugar solutions, and aqueous solutions of glycerin sugar are used. Carriers and oily carriers such as vegetable oils, oily emulsions and sugars are utilized. In addition, parenteral dosage forms include injections, external preparations, half-open preparations, etc., and these can also be easily prepared using known carriers.

The dosage of the compound (I) of the present invention varies depending on the route of administration, the age, body weight, symptoms, etc. of the recipient, but in general, in the case of oral administration, the dose of the compound (I) per adult is 0.0 per day.
The amount may be about 3 to 1.8 g, preferably about 0.12 to 1.2 g, and may be administered in 2 to 4 doses.

[Effects of the Invention] The compounds of the present invention exhibit excellent antibacterial activity and a broad antibacterial spectrum, as shown in the test examples below. Therefore, the compounds of the present invention are useful as prophylactic and therapeutic agents for infectious diseases caused by various microorganisms.

[Examples] Next, the present invention will be explained in more detail by referring to reference examples, working examples, and test examples, but the present invention is not limited to these examples in any way.

Reference example 1゜2-Methyl-5-nitro-1,3,4-thiadiazole: A mixture of 5.0 g of 2-amino-5-methyl-1,3,4-thiadiazole and 13.5 g of sodium nitrite, It was gradually added to a mixture of 7.2 ml of sulfuric acid and 60 ml of water at -5°C, stirred at the same temperature for 1.5 hours, and then further heated to room temperature for 1 hour.
Stir for hours. The resulting solution was added to 300 ml of an aqueous solution of 60 g of sodium nitrite and 27 g of sodium hydrogen carbonate at 60°C, stirred at the same temperature for 15 minutes, and then extracted with chloroform. After drying with magnesium sulfate, the solvent was distilled off. The resulting residue was subjected to silica gel column chromatography (Merck, Art.

7734.30g), and the crude product obtained from the chloroform eluate was further subjected to silica gel column chromatography (Art, manufactured by Merck & Co., Ltd., 9385.25g=
), and 0.83 g of 2-methyl-5-nitro-1°3.4-thiadiazole was obtained from the toluene eluate.

'H-NMR (90MHz, CDCl3)
δppa+: 2, 92 (3H,s, Ar-CH
3) MS: 145 (M”) Elemental analysis value [as C3H3N30°S (145,14)]: Calculated value C24,83, H2,08,N 2B,95 Analysis value C24,8?, H2,00,N 28.78 Example 1 7.8-difluoro-2-methyl-5-oxo-5H-
1,3,4-thiadiazolo[3,2-a]quinoline-4
-Carboxylic acid ethyl ester (compound 071) 2.4.5- Trifluorobenzoylacetic acid ethyl ester 984 mg, 50% sodium hydride 192 mg
, 1.52 g of iodized steel and 696 mg of 2-methyl-5-nitro-1,3,4-thiadiazole were added to 100 mg of anhydrous dioxane, and the mixture was heated under reflux for 3 hours under a stream of argon gas. Aqueous 5% acetic acid was added cold to adjust the pH to 4, and the solvent was distilled off. Chloroform is added to the resulting residue, insoluble matter is filtered off, and the solvent is distilled off. The residue was subjected to silica gel column chromatography (Merck, Art, 773).
4.60 g) and n-hexane-chloroform (1
: 1) From the elution part, 7,8-difluoro-2-methyl-5-oxo-5H-1,3,4-thiadiazolo[3,
2-alquinoline-4-carboxylic acid ethyl ester 62
Get 4 mg. This was recrystallized from chloroform to obtain a purified product.

'H-NMR (90MHz, CDC13) δppm
:1.47 (38,t, J=7.0Hz)2.72
(IH, s) 4.48 (2H, q, J=1.0Hz>7.97~
8.38 (2)1. a+) MS: 325 (
MHJ Example 2゜7.8-difluoro-2-methyl-5-oxo-5H-
1,3,4-thiadiazolo[3,2-a]quinoline-4
-Carboxylic acid (compound 072) nia, 8-difluoro-2-methyl-5-oxo-5H-
1,3,4-thiadiazolo[3°2-a]quinoline-4
4 ml of ethanol and 4 ml of 18% hydrochloric acid were added to 273 mg of -carboxylic acid ethyl ester, and the mixture was heated under reflux for 1.5 hours. After cold welding, the precipitated crystals were collected by filtration and washed with water and cold ethanol to give 7,8-difluoro-2-methyl-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]quinoline. 230 mg of -4-carboxylic acid was obtained.

'H-NMR (90MHz, CDC13) δP
f)l: 2.81 (38, s) 8.23-8.41 (2H, m) 14.87 (18, brs) MS: 297 (MH”) Example 3゜7.8.9-tri Fluoro-2-methyl-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]quinoline-4-carboxylic acid ethyl ester (compound 064): 2.3,4.5-tetrafluorobenzoyl Acetic acid ethyl ester 1.06g, 50% sodium hydride 19
2mg of copper iodide, 1.52g of 2-methyl-5-nitro-1,3,4-thiadiazole and 1.16g of 2-methyl-5-nitro-1,3,4-thiadiazole were added to 100ml of anhydrous dioxane, and the mixture was heated under an argon gas stream for 3 hours.
Heat to reflux for an hour. Aqueous 5% acetic acid was added cold to adjust the pH to 4, and the solvent was distilled off. Chloroform is added to the resulting residue, insoluble matter is filtered off, and the solvent is distilled off. The residue was subjected to silica gel column chromatography (Merck, Art,
7,8.9-trifluoro-2-methyl-5-oxo-5H-1,3,4 was obtained from the fraction eluted with l'l-hexane-chloroform (1:1).
-thiadiazolo[3° 605 mg of 2-a-coquinoline-4-carboxylic acid ethyl ester are obtained. This was recrystallized from chloroform to obtain a purified product.

'H-NMR(90MH2,CDCl3)δp
pm: 1.47 (3H, t, J near, 0H2)2
．． 75 (3H, s) 4.49 (2H, q, J=7.0Hz) 8.19
(IH, ddd, J=10.2, 7.9°2.3NZ
) MS: 343 (MH”> Example 4゜7.8.9-)-lifluoro-2-methyl-5-oxo-5H-1,3,4-thiadiazolo[3,2-mycoquinoline-4-carboxylic acid (Compound 065) Nia, 8,9-trifluoro-2-methyl-5-oxo-
To 457 mg of 5H-1,3,4-thiadiazolo[3,2-mycoquinoline-4-carboxylic acid ethyl ester] were added 8 ml of ethanol and 8 ml of 18% hydrochloric acid, and the mixture was heated under reflux for 2 hours. After cold welding, the precipitated crystals were collected by filtration, washed with water and cold ethanol, and 7,8.9-trifluoro-2-methyl-
5-oxo-5H-1,3,4-thiadiazole [3,
410 mg of 2-mycoquinoline-4-carboxylic acid are obtained.

'H-NMR (400MHz, CDC1a)
δppm: 2.84 (3H, s) 8.22 (18, ddd, J=10.0.7.8°2.2Hz) 14.65 (LH, s) MS: 315 (MH”) Example 5゜7-fluoro-2-methyl-5-oxo-8-(1-piperazinyl)-5H-1゜3.4-thiadiazolo[3,
2-a coquinoline-4-carboxylic acid (compound 073) p
Let's call it H7. The precipitate was collected by filtration, washed with water, cold ethanol, and chloroform, and 7-fluoro-2-methyl-5-oxo-8-(1-piperazinyl)-5H-1,
66 mg of 3,4-thiadiazolo[3,2-mycoquinoline-4-carboxylic acid are obtained.

' H-NMR (90MH2, CDC13-CD3
0D) δI) PI: 2.86 (3H, s) 3.09-3.16 (4H, m) 3.28-3.47 (4H, m) 8.54-9.49 (2H, shoe) MS: 363 (MH+) 7.8-difluoro-2-methyl-5-oxo-5H-
1,3,4-thiadiazolo[3゜2-mycoquinoline-4
- carboxylic acid eomg and anhydrous piperazine 86mg,
After heating under reflux in 2 ml of pyridine for 3 hours and distilling off the solvent, a small amount of water was added to the shallow pickles, and Example 6゜7-fluoro-2-methyl-8-(3-methyl-1- piperazinyl)-5-oxo-5H-1,3,4-thiadiazolo[3°2-mycoquinoline-4-carboxylic acid (Compound 074): 7,8-difluoro-2-methyl-5-oxo-5H-
1,3,4-thiadiazolo[3゜2-mycoquinoline-4
-60 mg of carboxylic acid and 100 mg of 2-methylpiperazine
mg was heated under reflux in 2 ml of pyridine for 22 hours, the solvent was distilled off, a small amount of water was added to the residue, and the mixture was diluted with 5% acetic acid water.
Let's call it H7. The precipitate was collected by filtration, washed with water, cold ethanol, and chloroform, respectively, to give 7-fluoro-2-methyl-8-(3-methyl-1-piperazinyl)-5=oxo-5H-1,3,4- 78 mg of thiadiazolo[3°2-mycoquinoline-4-carboxylic acid are obtained.

' H-NMR (90MH2, CDC13-CD3
0D) δppm: 1.21 (3H, d, J=6.8Hz) 2.86
(3H, s) 2.96-3.22 (3H, m) 3.52-3.80 (48, l) 7.72-8.10 (2H, @> MS+37 7 (mu (Hl) Example 7°(3-amino-1-pyrrolidinyl)-7-fluoro-2-methyl-5-oxo-5H-1,3,4-thiadiazolo[3,2-mycoquinoline-4-carboxylic acid (compound 07
5) Nia, 8-difluoro-2-methyl-5-oxo-5H-
1,3,4-thiadiazolo[3゜2-a coquinoline-4
- 60 mg of carboxylic acid, 159 mg of 3-aminopyrrolidine dihydrochloride, and 253 mg of triethylamine were heated under reflux in 2 ml of acetonitrile for 18 hours, the solvent was distilled off, a small amount of water was added to the residue, and 5% acetic acid solution was added. pH at
Set it to 7.

The precipitate was collected by filtration, washed with water, cold ethanol, and chloroform, and (3-amino-1-pyrrolidinyl)-7
-Fluoro-2-methyl-5-oxo-5)(-1,3
, 77 mg of 4-thiadiazolo[3,2-mycoquinoline-4-carboxylic acid are obtained.

' H-NMR (90MHz, CF3CO0D
) δppm: 2.21-2.52 (28, l) 2.73 (3H, s) 3.50-4.30 (7H, ■) 7.32-7.96 (2H, a) MS: 363 (MH”) Example 8゜7.9-difluoro-2-methyl-5-oxo-8-(
1-piperazinyl)-5H-1,3,4-thiadiazolo[3,2-mycoquinoline-4-carboxylic acid (compound 06
8) Nia, 8,9-trifluoro-2-methyl-5-oxo-
70 mg of 5H-1,3,4-thiadiazolo[3,2-mycoquinoline-4-carboxylic acid and 96 m of anhydrous piperazine
After heating under reflux in 2 ml of pyridine for 5 hours and distilling off the solvent, a small amount of water was added to the residue, and the pH was adjusted with 5% acetic acid.
Set it to 7. The precipitate was collected by filtration, washed with water, cold ethanol, and chloroform, and 7,9-difluoro-2-methyl-5-oxo-8-(l-piperazinyl)-5H-
1,3,4-thiadiazole [3,2-mycoquinoline-
55 mg of 4-carboxylic acid are obtained.

'H-NMR (90MHz, CDCl5-CD
30D) δρpm= 2.85 (3H, s) 2.98~3.11 (4L m) 3.32~3.56 (4H, proverb) 7.89~s, o 5 (IH, s+) MS:
381 (MH') Example 9゜7.9-difluoro-2-methyl-8-(3-methyl-
1-piperazinyl)-5-oxo-5H-1,3,4-
Thiadiazolo[3,2-mycoquinoline-4-carboxylic acid (compound 069) nia, 8.9-1-lifluoro-2-methyl-5-oxo-5H-1,3,4-thiadiazolo[3,2-a] 70 mg of quinoline-4-carboxylic acid and 111 mg of 2-methylpiperazine were heated under reflux in 2 ml of pyridine for 3 hours, the solvent was distilled off, and a small amount of water was added to the residue to give a 5%
Adjust the pH to 7 with aqueous acetic acid. The precipitate was collected by filtration, washed with water, cold ethanol, and chloroform, respectively, to give 7,9-difluoro-2-methyl-8-(3-methyl-1-piperazinyl)-5-oxo-5H-1,3, 4- Thiadiazolo [
83 mg of 3,2-a]quinoline-4-carboxylic acid are obtained.

'H-NMR<400MHz, CD013-C
D30D) δppm: 1, 16 (3H, d, J=6.4Hz) 2.84
(3H, s) 3.03~3.10 (3H, m) 3.35~3.38 (2H, ■) 3.46~3.49 (2H, m) 7.95 (LH, dd, J =11.7,2.0Hz
) MS: 395 (MH”) Example 10°(3-amino-1-pyrrolidinyl)-7°9-difluoro-2-methyl-5-oxo-5H-1,3,4-thiadiazolo[3°2- a] Quinoline-4-carboxylic acid (compound 070) nia, 8,9-trifluoro-2-methyl-5-oxo-
70 mg of 5H-1,3,4-thiadiazolo[3,2-alquinoline-4-carboxylic acid, 177 mg of 3-aminopyrrolidine dihydrochloride, and 372 mg of triethylamine.
After heating under reflux in 2 ml of acetonitrile for 3.5 hours and distilling off the solvent, a small amount of water is added to the residue, and the pH is adjusted to 7 with 5% aqueous acetic acid.

The precipitate was collected by filtration, washed with water, cold ethanol, and chloroform, and (3-amino-1-pyrrolidinyl)-7
,9-difluoro-2-methyl-5-oxo-5H-1
,3,4-thiadiazolo[3,2-a]quinoline-4-
86 mg of carvone M are obtained.

' H-NMR (90MHz, CF3CO0D
) δppa+ : 2.19-2.50 (2H, m) 2.73 (:lH, s) 3.80 (2H, s) 3.85-4.32 (5)! , a+)7.87 (
If(,dd, J=13.9.1.3H2)MS:
381 (MH+) Example 11゜7.9-difluoro-2-methyl-5-oxo-8-(
1-pyrrolidinyl)-5H-1,3,4-thiadiazolo[3,2-a]quinoline-4-carboxylic acid (compound 06
6) Ni, 8.9-trifluoro-2-methyl-5-oxo-5H-1,3,4-thiadiazolo[3,2-al quinoline-4-carboxylic acid 63 mg and pyrrolidine 71 mg
was heated under reflux in 2 ml of pyridine for 1 hour, the solvent was distilled off, a small amount of water was added to the residue, and the pH was adjusted to 7 with 5% acetic acid.
shall be. The precipitate was collected by filtration, washed with water, cold ethanol, and chloroform, and 7.9-difluoro-2-methyl-5-oxo-8-(1-pyrrolidinyl)-5H
-1,3,4-thiadiazolo[3,2-alquinoline-
74 mg of 4-carboxylic acid are obtained.

'H-NMR (90MHz, CDCl3)δ
PI)l: 1.90-2.06 (4H, m) 2.78 (3H, s) 3.68-3.91 (4H, honor) 7.84 (IH, dd, J=14.0. 1.9Hz
)15.40 (IH,s) MS: 366 (MH+) Example 12゜7.9-difluoro-2-methyl-8-(4-methyl-
1-piperazinyl)-5-oxo-5H-1,3,4-
Thiadiazolo[3,2-a]quinoline-4-carboxylic acid (compound 062) Ni,8,9-trifluoro-2-methyl-5-oxo-5H-1,3,4-thiadiazolo[3,2-a ] 70 mg of quinoline-4-carboxylic acid and 111 mg of 1-methylpiperazine were heated under reflux in 2 ml of pyridine for 5 hours, the solvent was distilled off, and a small amount of water was added to the residue to give a 5%
Adjust the pH to 7 with acetic acid water. The precipitate was collected by filtration, washed with water, cold ethanol, and chloroform, respectively, to give 7,9-difluoro-2-methyl-8-(4-methyl-1-piperazinyl)-5-oxo-5H-1,3, 71 mg of 4-thiadiazolo[3,2-a]quinoline-4-carboxylic acid are obtained.

'HN M R (90MH2, CDCl3) δpp
a+: 2.38 (3H, s) 2.54-2.64 (4H) 2.80 (3H, s) 3.44-3.62 (4H, I) 7.92 (LH, dd, J =11.8.2.
1Hz) MS: 395 (MH+) Example 13゜7.9-difluoro-2-methyl-8-(4-ethyl-
1-piperazinyl)-5-oxo-5H-1,3,4-
Thiadiazolo[3,2-a)quinoline-4-carboxylic acid (compound 067) nia,8.9-)-lifluoro-2-methyl-5-oxo-5H-1,3,4-thiadiazolo[3,2- a] 70 mg of quinoline-4-carboxylic acid and 127 mg of 1-ethylpiperazine were heated under reflux in 2 ml of pyridine for 5 hours, the solvent was distilled off, and a small amount of water was added to the residue to give a 5%
Adjust the pH to 7 with aqueous acetic acid. The precipitate was collected by filtration, washed with water, cold ethanol, and chloroform, respectively, to give 7,9-difluoro-2-methyl-8-(4-ethyl-1-piperazinyl)-5-oxo-5H-1,3, 76 mg of 4-thiadiazolo[3,2-a]quinoline-4-carboxylic acid are obtained.

'H-NMR(90MH2,CDCl3)δp
p-21,15 (38,t, J=6.5Hz)2.
40~2.69 (6H,■) 2.81 (38,s) 3.34~3.76 (48,i+) 7.92 (IH, dd, J=11.7.2.3Hz
) MS: 409 (MH”) Example 14゜7-fluoro-2-methyl-8-(3-hydroxy-1
-pyrrolidinyl)-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]quinoline-4-carboxylic acid (
Compound 076) Nia, 8-difluoro-2-methyl-5-oxo-5H-
1,3,4-thiadiazolo[3°2-a]quinoline-4
-35 mg of carboxylic acid and 3-hydroxypyrrolidine 1
After heating and refluxing 27 mg in 1.5 ml of pyridine for 3 hours and distilling off the solvent, a small amount of water was added to the residue to give a 5%
Adjust the pH to 4 with aqueous acetic acid. The precipitate was collected by filtration, washed with water, cold ethanol, and chloroform, respectively, to give 7-fluoro-2-methyl-8-(3-hydroxy-1-pyrrolidinyl)-5-oxo-5H-1,3,4- Chia Jiazoro [
40 mg of 3,2-a]quinoline-4-carboxylic acid are obtained.

'H-NMR (90MHz, DMSO-da
) δppm: 1.84 to 2.16 (2H, m) 2.78 (3H, S) 3.44 to 3.88 (48, ■) 4.28 to 4.52 (18, Maro) 5, 10 (IH,brd, J=3.6Hz,)7,
12 (IH, d, J=7.9Hz)7.75 (I
H, d, J=14.1Hz) 15.93 (IL b
rs) MS: 364 (MH+) Test Example The antibacterial activity of typical compounds of the present invention was tested below. Antibacterial action was determined using the standard method of the Japanese Society of Chemotherapy (Journal of the Japanese Society of Chemotherapy, 29(1), 76-79 (1981).
), the minimum inhibitory concentration (MIC) was measured and investigated using the agar plate dilution method. That is, a bacterial suspension cultured at 37°C for 18 hours using susceptibility assay broth is diluted to 10'CFU/m1 with the same medium. This was inoculated onto a drug-containing agar medium for susceptibility measurement using a microplanter, and cultured at 37°C for 18 hours.
was measured. The results are shown in Table 1.

(Margin below)

Claims (4)

[Claims] (1) General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (I)
There are chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (where R^1 is a hydrogen atom, hydroxyl group, or lower alkyl group, R^2 is a hydrogen atom or lower alkyl group, R^ 3 represents a hydrogen atom, a hydroxyl group, or an amino group), and X represents a hydrogen atom or a fluorine atom] A quinolone carboxylic acid derivative or a salt thereof. (2) In general formula (I), ▲ includes mathematical formulas, chemical formulas, tables, etc. ▼ is pyrrolidino group, 3-aminopyrrolidino group, 3-hydroxypyrrolidino group, 1-piperazinyl group, 3-methyl-1-piperazinyl The quinolone carboxylic acid derivative or salt thereof according to claim 1, which is a 4-methyl-1-piperazinyl group or a 4-ethyl-1-piperazinyl group. (3) General formula (II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (II) (In the formula, R represents a hydrogen atom or a lower alkyl group, and X represents a hydrogen atom or a fluorine atom) and formula (III) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (III) [In the formula, ▲ there are mathematical formulas, chemical formulas, tables, etc. ▼ is ▲
There are chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (where R^1 is a hydrogen atom, hydroxyl group, or lower alkyl group, R^2 is a hydrogen atom or lower alkyl group, R^ 3 represents a hydrogen atom, a hydroxyl group, or an amino group) and a cyclic amine represented by the formula (I), and if a lower alkyl group exists in R, this is removed. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (I) (In the formula, ▲There are mathematical formulas, chemical formulas, tables, etc.▼ and X have the same meanings as above) Production of quinolone carboxylic acid derivatives or their salts Law. (4) Formula (II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (II) (In the formula, X represents a hydrogen atom or a fluorine atom, and R represents a hydrogen atom or a lower alkyl group).