JPH0723369B2 - Pyridonecarboxylic acid derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial application] The present invention relates to a compound having extremely strong antibacterial activity and excellent pharmacokinetics.

[Prior Art] Various studies have been conducted so far on compounds having antibacterial properties, and are disclosed in JP-A-59-67269 and JP-A-60.
In Japanese Patent No. -214773, a wide range of compounds belonging to pyridonecarboxylic acid derivatives as substances having antibacterial properties are described in the claims. And, as a preferred compound, the formula: In which X is N, CH or CF, Y is fluorine, R ₁ is ethyl, 2-fluoroethyl, cyclopropyl.

However, among the basic substituents Z having a great influence on antibacterial activity and physicochemical properties, those having a pyrrolidine group as the most preferable one are described in Example 11 of JP-A-59-67279 (code name CI of compound). -934) and JP-A-60-21477
No. 3, Examples 43-47 (compound of Example 44 is PD-117558,
(See the 26th ICAAC abstract) (In the formula, R ₂ and R ₃ are hydrogen or lower alkyl). However, CI-934 has insufficient antibacterial activity against Gram-negative bacteria, and PD-117558 has insufficient antibacterial activity against Pseudomonas aeruginosa, so it cannot be said to be satisfactory yet.

[Object of the Invention] The present invention has excellent antibacterial activity against anaerobic bacteria as well as aerobic bacteria, and has high solubility in water.
An object is to provide a compound having excellent intestinal absorbability and metabolic stability.

[Means for Achieving the Object] In the pyridonecarboxylic acid derivative, the present inventor A compound having a group represented by the following formula, in which at least one of Rb and Rc is a lower alkyl group, particularly by the combination of this substituent and the type of 1-position substituent and the type of 8-position atom, It has been found that the levorotatory optically active substance is a compound that has both a strong antibacterial action and good water solubility, and was able to achieve the object of the present invention.

[Structure of the Invention] The present invention has the general formula (In the formulae, Ra and Rb are each hydrogen or lower alkyl, Rc is lower alkyl, and Rb is Ra or Rc.
And a methylene chain represented by (CH ₂ ) n (n is 2 to 5) may be formed. Rd is ethyl, 2-fluoroethyl, vinyl,
Meaning isopropyl, isopropenyl, cyclopropyl, monofluorophenyl or difluorophenyl. Q is CH, CF, C-Cl or N) and salts thereof.

Here, the lower alkyl group has 1 to 6 carbon atoms,
Methyl and ethyl are particularly suitable. Rb and Rc form a methylene chain having 2 to 5 carbon atoms and Ra
Those which form a methylene chain having 2 to 4 carbon atoms with Rb are also preferable. Rd is preferably ethyl, cyclopropyl or 2,4-difluorophenyl, and Q is preferably CH, CF, C-Cl or N.

Examples of the salt of the compound of the present invention include salts with inorganic or organic acids such as hydrochloric acid, sulfuric acid and methanesulfonic acid, or alkali metal salts or alkaline earth metal salts such as sodium salts and calcium salts of carboxylic acids. To be done. Furthermore, the compound of the present invention may exist as a hydrate.

The compounds of the present invention can be synthesized by the methods exemplified below. That is, the general formula [II]: (Wherein Rd and Q are the same as above, Xs means a substituent capable of nucleophilic substitution with an amine, such as halogen, methanesulfonyl group, etc.), and a compound represented by the general formula [III]: (In the formula, Ra, Rb and Rc are the same as above), and can be produced by reacting a pyrrolidine derivative.

This reaction is performed using acetonitrile, tetrahydrofuran (TH
F), ethanol, chloroform, dimethylsulfoxide (DMSO), dimethylformamide (DMF), pyridine, picoline, it is good to carry out at a temperature of about 20 ° C to about 150 ° C in the presence of a non-reactive solvent such as water.

The pyrrolidine derivative represented by the general formula [III] is synthesized, for example, by the following method.

That is, 1-benzyl-4-carboxy-2- of the known compound
Treating pyrrolidone with thionyl chloride to the acid chloride,
Further, it is reacted with Meldrum's acid and then decarboxylated to give 4-acetyl derivative. The ketone part of the acetyl group was converted to oxime with hydroxylamine and catalytically reduced with Raney nickel to give 4- (1-aminoethyl) -1-benzyl-2-
Get pyrrolidone. This is treated with 2- [tertiary butoxycarbonyloxyimino] -2-phenylacetonitrile (hereinafter Bo
abbreviated as c-ON) and tertiary butoxycarbonylation (Boc
This compound is separated into two stereoisomers by high performance liquid chromatography (HPLC) or fractional recrystallization. One of them is treated with trifluoroacetic acid (TFA) to remove B
turn into oc. The obtained primary amino compound is reacted with an acid chloride of N-paratoluenesulfonylproline and then optically resolved by column chromatography. The resulting optically active compound is treated with a base to remove tosylproline, the amide of the pyrrolidine ring is reduced with lithium aluminum hydride, and the primary amine moiety is Boc-protected to protect it and then deprotected with palladium-carbon or the like. Optically active 3-benzylated
Obtain (1-tertiary butoxycarbonylamino) ethylprolidine.

In the production method of the present invention described above, in the general formula [II
The amino group of the pyrrolidine derivative represented by [I] may be protected so as to be substantially inert to the reaction. Examples of such a protecting group include an acyl group such as formyl, acetyl and trifluoroacetyl; an alkoxycarbonyl group having 2 to 6 carbon atoms such as ethoxycarbonyl and tertiary butoxycarbonyl (Boc): benzyloxycarbonyl,
Aryloxycarbonyl such as p-methoxybenzyloxycarbonyl and phenoxycarbonyl: silyl group such as trimethylsilyl: trityl, tetrahydropyranyl, vinyloxycarbonyl, o-nitrophenylsulfenyl, diphenylphosphinyl, p-toluenesulfonyl and benzyl Groups are exemplified. These protective groups can be removed by a known method such as acid or base hydrolysis after the reaction, if desired.

Next, reference examples and examples will be described, but the present invention is not limited thereto.

Reference Example 1: 4-Acetyl-1-benzyl-2-pyrrolidone (1) To 10 g of thionyl chloride and 30 ml of dioxane was added to 4.4 g of 1-benzyl-4-carboxy-2-pyrrolidone, and the mixture was heated with stirring at 90 to 100 ° C for 30 minutes. After that, the solvent and excess thionyl chloride are distilled off under reduced pressure to obtain a residue of acid chloride.

2.5 g of magnesium ethoxide and 3.5 g of ethyl malonate are added to 40 ml of anhydrous ether, and the mixture is refluxed for 1 hour and a half. The resulting solution of ether of acid chloride is added dropwise while stirring under ice cooling. After the dropwise addition, the mixture is refluxed for 1 hour, added with excess dilute sulfuric acid to make it weakly acidic under ice cooling, extracted with ether, and dried.

After distilling off the solvent, 10 ml of acetic acid, 45 ml of water and 1 ml of concentrated sulfuric acid are added to the residue and the mixture is refluxed for 5 hours, and then the solvent is distilled off under reduced pressure. The residue was dissolved in chloroform, washed successively with 10% hydrochloric acid and saturated sodium hydrogen carbonate and dried, and the solvent was evaporated to give 3.3 g of the above compound (1) as an oil.

NMR (CDCl ₃ ) δppm: 2.2 (3H, s) 2.66 (2H, d, J = 7.2Hz), 3.0 to 3.6 (3H, m) 4.32,4.52 (each 1H, d, J = 14Hz, AB-q) , 7.29 (5H, s) Reference Example 2: 1-benzyl-4- (1-hydroxyiminoethyl)
-2-Pyrrolidone (2) To 3,3 g of the compound (1) and 2.5 g of hydroxylamine hydrochloride are added 15 ml of pyridine, and the mixture is heated at 90 ° C for 5 hours. After adding water to acidify the hydrochloric acid, the mixture is extracted with dichloromethane. Dichloromethane was distilled off, and the obtained residue was subjected to column chromatography on 30 g of silica gel and eluted with methanol-chloroform (1:20) to obtain 2.6 g of the above compound (2) as a powder.

NMR (CDCl ₃ ) δppm: 1.8 (3H, s) 2.62 (2H, d, J = 7.2Hz), 2.9 to 3.6 (3H, m) 4.44 (2H, s), 7.28 (5H, s) Reference Example 3: 4- (1-Aminoethyl) -1-benzyl-2-pyrrolidone (3) 69.3 g of the oxime derivative (2), 20 ml of Raney nickel and 700 ml of methanol are mixed and shaken under a hydrogen stream for 8 hours. The catalyst was filtered off and the methanol was distilled off under reduced pressure to give a pale yellow oil (3)
I got 64g. ¹ H-NMR (CDCl ₃ ) δppm: 0.09 (3H, d, J = 7Hz), 1.06 (3H, d, J = 7Hz), 1.96 (3H, s), 2.0 to 2.6 (3H, m), 2.6 to 3.5 (3H, m), 4.42 (2H, s), 7.28 (5H, s) Reference Example 4 1-benzyl-4- (1-tertiary butoxycarbonylaminoethyl) -2-pyrrolidone (4B) Amino form (3) Dissolve 64.0 g in 600 ml of tetrahydrofuran, add 72.2 g of Boc-ON, and stir for 70 minutes. Evaporate the solvent,
The residue is dissolved in ethyl acetate 1. After washing with 0.2N sodium hydroxide solution and saturated saline solution, the organic layer is dried with mirabilite.
The solvent is distilled off and n-hexane is added to the residue to solidify. After filtration, it was washed with petroleum ether to obtain 67.0 g of powder.

Recrystallization from ether gave 23.7g of isomer 4A, melting point 138 ° C.
Was obtained as colorless needles. The mother liquor was repeatedly recrystallized from ether to obtain 12.9 g of isomer 4B as colorless prism crystals having a melting point of 139 to 141 ° C. 4A and 4B show a single peak on HPLC.

Column: Nucleosyl 50-5 20 × 250 mm Solvent: Ethyl acetate-THF (95: 5), Flow rate: 5 ml / min Retention time: 4A 46.5 min 4B 52.5 min ¹ H-NMR (CDCl ₃ ) δppm: 4A 1.06 (3H, d, J = 7Hz), 1.42 (9H, s) 2.2 to 2.7 (2H, m), 2.9 to 3.5 (2H, m), 3.5 to 3.9 (1H, m), 4.3 to 4.5 (1H, m), 4.46 (2H, AB-q, J = 16Hz), 7.35 (5H, m) 4B 1.09 (3H, d, J = 7Hz), 1.42 (9H, s) 2.1 to 2.6 (2H, m), 2.8 to 3.4 (2H , m), 3.4 to 3.8 (1H, m), 4.1 to 4.4 (1H, m), 4.48 (2H, AB-q, J = 16Hz), 7.37 (5H, m) Reference Example 5: 4- (1- Aminoethyl) -1-benzyl-2-pyrrolidone (5B) 8.0 g of Boc form (4B) was added to 50 ml of trifluoroacetic acid under ice cooling, followed by stirring at room temperature for 1 hour. Trifluoroacetic acid is distilled off under reduced pressure. To the residue is added 50 ml of water and neutralized with NaHCO ₃ . After extraction with chloroform and drying over Na ₂ SO _{4, the} solvent was distilled off to obtain 5.5 g of a colorless oil (5B). ¹ H-NMR (CDCl ₃ ) δppm: 1.05 (3H, d, J = 7Hz), 1.24 (2H, s), 2.0 to 2.6 (3H, m), 2.6 to 3.0 (1H, m), 3.0 to 3.5 ( 2H, m), 4.45 (2H, s), 7.28 (5H, s) Reference Example 6: (-)-1-benzyl-4- [1-((S) -1-p-toluenesulfonylprolylamino) Ethyl] -2-pyrrolidone (6b) (S) -Np-toluenesulfonylproline (2.5 g), thionyl chloride (2.1 ml) and benzene (20 ml) are mixed and heated under reflux for 5 hours. Benzene was distilled off, benzene was added to the residue, and the distillation was repeated (three times) to obtain acid chloride as an oil.

3.55 g of 4-aminoethyl derivative (5B) and 1.1 ml of pyridine are dissolved in 15 ml of dichloromethane, and the above acid chloride is dissolved in 15 ml of dichloromethane and added dropwise thereto while stirring at room temperature. After 24 hours, the reaction solution was washed with 2N hydrochloric acid, water, 2N sodium hydroxide, and water in this order, dried over sodium sulfate, and the solvent was distilled off to obtain a yellow oily substance. This is 1: 1 on silica gel TLC (ethyl acetate-methanol 95: 5).
It was confirmed to be a mixture (Rf 0.29 and Rf 0.26) of the above, so it was applied to a column of 100 g of silica gel and ethyl acetate-
Each isomer obtained by elution with methanol (95: 5) was recrystallized from ethyl acetate-n-hexane. Isomer 6a 870 mg,
Melting point 96-98 ° C TLC Rf = 0.29, [α] _D -91.3 ° (c = 0.515, chloroform) Isomer 6b 820 mg, melting point 126-132 ° C TLC Rf = 0.26 [α] _D -136.0 ° (c = 0.350, Chloroform) ¹ H-NMR (CDCl ₃ ) δppm: 6a 1.19 (3H, d, J = 7Hz), 1.4 to 1.8 (3H, m) 1.8 to 2.2 (2H, m), 2.44 (3H, m), 2.28 to 2.8 (2H, m), 3.0 to 3.4 (3H, m), 3.4 to 3.7 (1H, m), 3.9 to 4.2 (2H, m), 4.50 (2H, AB-q, J = 16Hz), 6.88 (1H , d, J = 8Hz) 7.28 (5H, s), 7.44 (2H, d, J = 7Hz), 7.70 (2H, d, J = 7Hz) 6b 1.15 (3H, d, J = 7Hz), 1.4 to 1.9 (4H, m) 2.0 to 2.8 (3H, m), 2.45 (3H, s), 3.0 to 3.4 (2H, m), 3.4 to 3.8 (2H, m), 4.45 (2H, AB-q, J = 16Hz ), 6.88 (1H, d, J = 8Hz) 7.39 (5H, s), 7.44 (2H, d, J = 7Hz), 7.69 (2H, d, J = 7Hz) Reference Example 7: (-)-4- (1-aminoethyl) -1-benzyl-
2-Pyrrolidone (7b) 1.08 g of isomer (6b), 10 ml of 15% sodium hydroxide and 30 ml of ethanol are mixed and heated under reflux for 3 days. Concentrate ethanol, extract with chloroform, dry with Glauber's salt, evaporate the solvent and remove 480 m.
g of a colorless oil (7b) was obtained.

[Α] _D -4.6 ° (c = 2.0, chloroform) Isomer (6a) 1.0 g, 5% sodium hydroxide 10 ml, ethanol 30 ml were mixed and reacted in the same manner as above to give colorless oil (7a).
430 mg was obtained.

[Α] _D + 4.4 ° (c = 2.0, chloroform) ¹ H-NMR (CDCl ₃ ) δppm: 7a, 7b 1.05 (3H, d, J = 7Hz), 1.24 (2H, s) 2.0 to 2.6 (3H , m), 2.6 to 3.0 (1H, m) 3.0 to 3.5 (2H, m), 4.45 (2H, s), 7.28 (5H, s) Reference Example 8: (-)-1-benzyl-4- (1 -Tertiary butoxycarbonylaminoethyl) -2-pyrrolidone (8b) (+) amino compound (7a) 345mg was dissolved in THF 30ml and B
Add oc-ON 389mg and let stand for 3 days. The solvent is distilled off under reduced pressure and the residue is dissolved in 50 ml of ethyl acetate. After washing with 0.5N sodium hydroxide and water and drying with sodium sulfate, the solvent is distilled off. Attached to a column of 30 g of silica gel and chloroform-methanol (98:
Elution with 2) gave 340 mg of colorless crystals (8a). Melting point 129-
130 ° C [α] _D + 31.9 ° (c = 0.295, chloroform) Dissolve 406 mg of (-) amino compound (7b) in 20 ml of THF and add B to this.
Add 530 mg of oc-ON and stir for 24 hours. After the THF was distilled off, the same treatment as above was performed to obtain 410 mg of colorless crystals (8b) having a melting point of 129-131 ° C.

[Α] _D −32.5 ° (c = 0.30, chloroform) ¹ H-NMR was in agreement with 4B.

Reference Example 9: 480 mg of (-)-1-benzyl-3- (1-tertiary butoxycarbonylaminoethyl) pyrrolidine (9b) (-) amino compound (7b) was dissolved in 30 ml of THF, and LiAlH ₄ 500 mg was dissolved therein. After adding, the mixture is heated under reflux for 2 hours. 2 ml of water was added dropwise under ice cooling, and the insoluble material was filtered off. Boc-ON 540mg in the filtrate
And stir for 12 hours. The solvent was distilled off and the residue was ethyl acetate
Dissolve in 50 ml, wash with 0.5 N sodium hydroxide and water, and dry with Glauber's salt. It was subjected to column chromatography on 30 g of silica gel and eluted with ethyl acetate-benzene (2: 1) to obtain 480 mg of a colorless oil (9b).

[Α] _D −9.80 ° (c = 2.0, chloroform) ¹ H-NMR (CDCl ₃ ) δppm: 1.10 (3H, d, J = 7Hz) 1.44 (9H, s), 1.6 to 3.0 (m, 2H) 3.60 (2H, AB-q, J = 16Hz), 7.30 (5H, s) Reference Example 10: (-)-3- (1-tertiary butoxycarbonylaminoethyl) pyrrolidine (10b) 1-benzyl (9b) 460 mg to 5% Pd-C (water content 52.5%) 800
Using 20 mg of ethanol as a catalyst, irradiation with a tungsten lamp in 20 ml of ethanol under a flow of hydrogen at 4 atmospheres and shaking for 4 hours are performed.

The catalyst was filtered off and the filtrate was concentrated to dryness to give 320 mg of a colorless oil (10
b) got. Part of it solidifies if left unattended.

Example 1: (-)-7- [3- (1-Aminoethyl) -1-pyrrolidinyl] -1-ethyl-6,8-difluoro-1,4-dihydro-
4-oxoquinoline-3-carboxylic acid Obtained by catalytic reduction of 1.04 g of benzyl derivative (9b) (-)
-3- (1-tertiary butoxycarbonylaminoethyl) pyrrolidine (10b) and 1-ethyl-6,7,8-trifluoro-
1,4-dihydro-4-oxoquinoline-3-carboxylic acid 800 mg
2 in 20 ml acetonitrile with 2 ml triethylamine
Heat to reflux for hours. The crystals precipitated by concentration are collected by filtration and washed with ether. This is added to 20 ml of TFA and stirred for 20 minutes. When TFA is distilled off and 150 ml of water is added, crystals are precipitated. Concentrated hydrochloric acid is added to this to make a solution, which is then extracted with chloroform. Water layer
Concentrate to 100 ml, adjust to pH 12 with 15% sodium hydroxide solution under water cooling and adjust to pH 7.20 with hydrochloric acid. Extract with chloroform, dry with sodium sulfate, and evaporate the solvent. Recrystallize the residue from ethanol,
608 mg of colorless crystals having a melting point of 218 ° C. were obtained.

[Α] _D- 221.0 ° (c = 0.428, 0.1N hydrochloric acid) Elemental analysis value Calculated as C ₁₈ H ₂₁ F ₂ N ₃ O ₃ · 1 / 2H ₂ O C 57.75 H 5.92 N 11.22 Analytical value C 58.13 H 5.90 N 11.14 ¹ H-NMR (NaOD): 1.12 (3H, d, J = 7Hz), 1.44 (3H, t, J = 7Hz) 1.4 to 1.7 (1H, m) 1.9 to 2.2 (2H, m), 2.7 to 2.9 (1H, m) 3.4 to 4.0 (4H, m), 4.3 to 4.6 (2H, m) 7.72 (1H dd.J = 2Hz, 15Hz), 8.32 (1H, S) Example 2: (-)-7 -[3- (1-Aminoethyl) -1-pyrrolidinyl] -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid Pyrrolidine derivative (10b) obtained by catalytic reduction of benzyl (9b) 1.10g and 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 750mg Is heated to reflux with 20 ml of acetonitrile together with 2 ml of triethylamine for 4 hours to precipitate crystals. After cooling, the crystals were collected by filtration to obtain 1.07 g of yellow needle crystals having a melting point of 233-236 ° C.
1.04 g of this is added to 20 ml of TFA and stirred for 20 minutes. After removing TFA and adding 150 ml of water, the pH was adjusted to 1 with 2N sodium hydroxide solution under ice cooling.
Set to 2. Adjust to pH 7.20 with hydrochloric acid and extract with chloroform.
The organic layer is dried over sodium sulfate and the solvent is distilled off. The residue was recrystallized from ethanol-ammonia water to obtain 660 mg of colorless needle crystals with a melting point of 217-229 ° C.

[Α] _D −250.0 ° (c = 0.495, 0.1N hydrochloric acid) Elemental analysis value C ₁₉ H ₂₁ F ₂ N ₃ O ₃ Calculated value C 60.47 H 5.61 N 11.13 Analytical value C 60.37 H 5.69 N 11.11 ¹ H-NMR (NaOD): 1.12 (3H, d, J = 7Hz), 1.0 to 1.3 (4H, m), 1.4 to 1.7 (1H, m), 1.9 to 2.2 (2H, m), 2.7 to 2.9 (1H, m) , 3.4 to 3.9 (2H, m), 3.9 to 4.0 (1H, m), 7.65 (1H, dd J = 15Hz, 2Hz), 8.47 (1H, s) Example 3: 7- [3- (1-amino Ethyl) -1-pyrrolidinyl]
-1- (2,4-difluorophenyl) -6-fluoro-1,4-dihydro-4-oxo-1.8-naphthyridine-3-carboxylic acid 7-Chloro-1- (2,4-difluorophenyl) -1,4-dihydro-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid 200 mg in acetonitrile 50 ml and 3- [1- Add 250 mg of tertiary butoxycarbonylaminoethyl] pyrrolidine and reflux for 1.5 hours. After cooling, the solvent is distilled off under reduced pressure, 5 ml of ethanol is added to the residue for crystallization, which is collected by filtration and washed with ether. Trifluoroacetic acid (5 ml) was added to the obtained crude crystals, and the mixture was stirred at room temperature for 10 minutes to remove Boc, the solvent was distilled off under reduced pressure, and 1N sodium hydroxide (10 ml) was added to the residue to dissolve it.
Neutralize with N hydrochloric acid and collect the precipitated crystals by filtration. The crude crystals were recrystallized from concentrated ammonia-ethanol to obtain 70 mg of the title compound having a melting point of 213 to 214 ° C.

Elemental analysis value Calculated as C ₂₁ H ₁₉ F ₃ N ₄ O ₃ 1 / 2H ₂ O: C 60.86 H 6.32 N 10.14 Analytical value: C 60.65 H 5.99 N 10.07 ¹ H-NMR (NaOD): 1.04 (3H, d J = 7Hz), 1.35 to 1.6 (1H, m), 1.8 to 2.1 (1H, m), 1.70 (1H, m), 3.0 to 4.0 (4H, m), 7.25 (2H, m) 7.45 (1H, m) m), 7.90 (1H, d, J = 12Hz), 8.34 (1H, s) Example 4: 7- [3- (1-aminoethyl) -1-pyrrolidinyl]
-8-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (racemic form) Debenzylated product obtained by reducing 270 mg of 1-benzyl-3- (1-tertiary butoxycarbonylaminoethyl) -pyrrolidine in 40 ml of ethanol using 5 mg of Pd-C 500 mg as a catalyst and 8-chloro-1-cyclopropyl -6,7-Difluoro-1,4-dihydroquinoline-3-carboxylic acid 150mg, triethylamine 1m
l and 20 ml of acetonitrile are mixed and heated under reflux for 12 hours.

After cooling, acetonitrile is concentrated under reduced pressure and the precipitated crystals are collected by filtration and dissolved in 10 ml of TFA. After stirring for 30 minutes, concentrate under reduced pressure. Add 20 ml of water to the residue and adjust to pH 12 with 2N sodium hydroxide solution.
Adjust the pH to 7.2. After extraction with chloroform and drying with sodium sulfate, the solvent was distilled off, and the residue was recrystallized from aqueous ethanol ammonia to obtain 55 mg of pale yellow crystals having a melting point of 131 ° C.

Elemental analysis value Calculated as C ₁₉ H ₂₁ FClN ₃ O ₃・ 3 / 4H ₂ O: C 56.02 H 5.77 N 10.32 Analysis value: C 56.19 H 5.18 N 10.35 ¹ H-NMR δ (DMSO-d ₆ ): 1.09 ( 3H, d J = 7Hz), 0.8 to 1.3 (4H, m), 1.4 to 1.8 (1H, m), 1.8 to 2.2 (2H, m), 2.6 to 2.9 (1H, m), 3.2 to 4.0 (4H, m) m), 4.1 to 4.5 (1H, m), 7.88 (1H, d J = 15Hz), 8.87 (1H, s) Example 5: (−)-7- [3- (1-aminoethyl) -1- Pyrrolidinyl] -8-chloro-1-cyclopropyl-6-fluoro-
4-oxo-1,4-dihydroquinoline-3-carboxylic acid A debenzylated product obtained by reducing 410 mg of 1-benzyl-3- (1-tertiary butoxycarbonylaminoethyl) pyrrolidine (9b) in 50 ml of ethanol using 1.0 g of 5% Pd-C as a catalyst;
8-Chloro-1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (150 mg), triethylamine (1 ml) and acetonitrile (30 ml) are mixed and heated under reflux for 12 hours. Acetonitrile is distilled off under reduced pressure and the residue is dissolved in chloroform. After washing with 10% citric acid and water and drying the organic layer with sodium sulfate, the solvent is distilled off. To the residue is added 20 ml of water, adjusted to pH 11 with 1N sodium hydroxide, and adjusted to pH 7.25 with hydrochloric acid. After extraction with chloroform and drying over Na ₂ SO _{4, the} solvent is distilled off. Recrystallization from ethanol gave 118 mg of colorless crystalline powder having a melting point of 198-200 ° C.

[Α] _D -163.7 ° (c = 0.430, 0.1N hydrochloric acid) Elemental analysis value C ₁₉ H ₂₁ ClFN ₃ O ₃・ 1 / 2H ₂ O Calculated value C 56.65 H 5.50 N 10.43 Analytical value C 56.58 H 5.59 N 10.41 ¹ H-NMR (NaOD): 0.08 to 1.10 (2H, m), 1.16 (3H, d, J = 7Hz), 1.1 to 1.35 (2H, m) 1.5 to 1.9 (1H, m), 2.0 to 2.3 (2H , m), 2.8 to 3.0 (1H, m), 3.4 to 3.7 (4H, m) 3.7 to 4.0 (1H, m), 4.2 to 4.4 (1H, m) 7.82 (1H, d, J = 15Hz), 8.61 (1H, s) [Effect of the invention] According to the present invention, by introducing a lower alkyl group into at least one of the substituents Rb or Rc in [I], water solubility while maintaining strong antibacterial activity is achieved. And a compound having excellent intestinal absorbability and metabolic stability can be obtained. That is, the compound of the present invention is expected to exhibit favorable pharmacokinetics and has low toxicity, and can be expected to be highly useful as a pharmaceutical.

Accordingly, the compounds of the present invention can be widely used as antibacterial agents in the form of oral, parenteral and topical administration, eg to humans and other mammals. That is, it is suitable for the treatment of various infectious diseases such as respiratory system, urinary system, intestinal tract, etc., and in addition to bronchitis, nephritis, cystitis, prostatitis, urethritis, etc. Particularly excellent effects can be expected.

The dose is 50 mg to 2 g per day for an adult, usually 100 to 6
Oral administration of 00 mg may be carried out in 1 to 3 divided doses. It can also be administered parenterally, for example 50 per adult
It can also be used externally as a suppository, an ointment, a cream, an eye drop, etc., by injecting ˜150 mg intravenously.

As the preparation, tablets, capsules, powders, granules, syrups, injections and the like can be produced by appropriately using excipients, disintegrating agents, solubilizing agents, stabilizers and the like. For example, 100 mg of the compound of the present invention, 23 mg of corn starch, C
MC • Na2 2.5 mg, hydroxypropyl cellulose 3 mg, and magnesium stearate 1.5 mg can be mixed to form a capsule.

The compounds of the present invention are less toxic, for example the compound of Example 1.
When 200 mg was intravenously injected into 5 mice, none of them died, and LD ₅₀ is considered to be 200 mg or more.

Next, the antibacterial activity (MIC μ
g / ml).

Claims (6)

[Claims] 1. A general formula (In the formulae, Ra and Rb are each hydrogen or lower alkyl, Rc is lower alkyl, and Rb is Ra or Rc.
And a methylene chain represented by (CH ₂ ) n (n is 2 to 5) may be formed. Rd is ethyl, 2-fluoroethyl, vinyl,
Meaning isopropyl, isopropenyl, cyclopropyl, monofluorophenyl or difluorophenyl. Q is CH, CF, C-Cl or N) and its salts 2. In the general formula [I], Ra is hydrogen or methyl, Rb is hydrogen or methyl, Rc is methyl or ethyl, Rd is ethyl or cyclopropyl, 4-fluorophenyl, 2,4-difluorophenyl, Q. The compound according to claim 1, wherein is CH or N. 3. The compound according to claim 1, wherein in the general formula [I], Ra and Rb are hydrogen, Rc is methyl or ethyl, Rd is ethyl or cyclopropyl, and Q is CF. 4. The compound according to claim 1, wherein the compound represented by the general formula [I] is an optically active substance. 5. The compound according to claim 4, wherein the optically active substance is levorotatory. 6. A general formula (In the formulae, Ra and Rb are each hydrogen or lower alkyl, Rc is lower alkyl, and Rb is Ra or Rc.
And a methylene chain represented by (CH ₂ ) n (n is 2 to 5) may be formed. Rd is ethyl, 2-fluoroethyl, vinyl,
Meaning isopropyl, isopropenyl, cyclopropyl, monofluorophenyl or difluorophenyl. Q is CH, CF, C-Cl or N), and an infectious disease therapeutic agent containing a compound represented by