JPH0892241A - 5-hydrazinoquinolonecarboxylic acid derivative and antibacterial agent containing the same as active ingredient - Google Patents

Abstract

PURPOSE: To obtain a new compound having excellent antibacterial activity against gram-negative bacteria and gram-positive bacteria including methicillin- resistant Staphylococcus aureus, having excellent internal activity, and useful for preventing and treating various infectious diseases as an antibacterial agent. CONSTITUTION: A compound of formula I (R<1> is amino, hydroxyl, etc.; R<2> is H, halogen, etc.; n is 1-3; but when n is 1, there is not a case wherein R<1> and R<2> are simultaneously amino and H, respectively), e.g. (3RS)-7-[3-(N-t- butoxycarbonyl-N-methylamino)-1-pyrrolidinyl]-1-cyclopropyl-6,8-difluo ro-5- hydrazino-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. The compound is obtained e.g. by reacting a compound of formula II (X is halogen: Z is H, benzyl, etc.) with hydrazine in the presence of a basic catalyst in a solvent, and further, if necessary, hydrolyzing the reaction product. The reaction is performed at 0-150 deg.C in the flow of nitrogen gas.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel 5-hydrazinoquinolonecarboxylic acid derivative having excellent antibacterial activity against Gram-positive bacteria including Gram-negative bacteria and resistant bacteria, and an antibacterial agent containing the same. Regarding

[0002]

2. Description of the Related Art Conventionally, the problems to be solved by the invention
Synthetic antibacterial agents such as nalidixic acid and pyromidic acid are known as therapeutic agents for infectious diseases, but these have a problem that they are less effective against intractable diseases such as Pseudomonas aeruginosa infection.
Therefore, as a solution to such a problem, quinolonecarboxylic acid derivatives in which the 6-position is substituted with a fluorine atom, such as norfloxacin, ofloxacin, ciproxacin and spafloxacin, have been developed. Since these have a strong antibacterial action against Gram-negative bacteria, they are widely used in clinical practice. However, conventional synthetic antibacterial agents have a problem that they have poor pharmacokinetics and have a low antibacterial action against Gram-positive bacteria, particularly resistant bacteria such as methicillin-resistant Staphylococcus aureus.

Further, the 5-hydrazinoquinolonecarboxylic acid derivative described in WO94 / 10163 has an antibacterial activity against Gram-negative bacteria and Gram-positive bacteria in vitro, but in vivo.
In the above, there is a problem that the antibacterial activity is greatly reduced due to the poor pharmacokinetics.

Therefore, the present invention solves the above-mentioned problems and has excellent pharmacokinetics, and not only in vitro but also in
A 5-hydrazinoquinolone carboxylic acid derivative having excellent antibacterial activity against Gram-negative and Gram-positive bacteria in vivo as well as excellent antibacterial activity against resistant bacteria and an antibacterial agent containing the same The purpose is to provide.

[0005]

Under such circumstances, the present inventor synthesized a large number of quinolonecarboxylic acid derivatives and examined their antibacterial activity and pharmacokinetics. 5-hydrazinoquinolone carboxylic acid derivative has excellent pharmacokinetics,
In comparison with known quinolone carboxylic acid derivatives, the antibacterial activity against Gram-negative bacteria such as Pseudomonas aeruginosa and Gram-positive bacteria including resistant bacteria such as methicillin-resistant Staphylococcus aureus as well as o. The present invention has been completed by finding that it is remarkably excellent.

That is, the present invention provides the following general formula (1);

[0007]

[Chemical 3]

[In the formula, R ¹ represents an amino group, a hydroxyl group or a lower alkoxy group which may have a substituent; R ² represents a hydrogen atom, a halogen atom or a lower group which may have a substituent. Represents an alkyl group; n represents an integer of 1 to 3. However, when n = 1, R ¹ does not simultaneously represent an amino group and R ² does not represent a hydrogen atom].
A hydrazinoquinolonecarboxylic acid derivative is provided.

The present invention also provides an antibacterial agent containing the 5-hydrazinoquinolonecarboxylic acid derivative (1) as an active ingredient.

The meaning of R ¹ in the general formula (1) is as described above, but more specifically is as follows. Examples of the substituent of the amino group which may have a substituent include a lower alkyl group, an acyl group, a lower alkoxycarbonyl group, a benzyloxycarbonyl group and an aralkyl group. Here, as the lower alkyl group, a linear or branched alkyl group having 1 to 5 carbon atoms, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, t-butyl group, pentyl Group, isopentyl group and the like; as the acyl group, formyl group, acetyl group, propionyl group, isobutyryl group, bivaloyl group, benzoyl group, phenacyl group, trifluoroacetyl group and the like;
Examples of the lower alkoxycarbonyl group include methoxycarbonyl group, ethoxycarbonyl group, butoxycarbonyl group, pentyloxycarbonyl group and the like; aralkyl groups include benzyl group, phenylethyl group, methylbenzyl group, methoxybenzyl group, Examples thereof include a naphthylmethyl group. The amino group which may have a substituent may have one or two of these substituents.

As the lower alkoxy group, a linear or branched alkoxy group having 1 to 5 carbon atoms, for example, methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, s- Examples thereof include butoxy group, t-butoxy group, pentyloxy group, isopentyloxy group, neopentyloxy group, t-pentyloxy group and the like.

As R ¹ , an amino group which may have a substituent and a hydroxyl group are preferable, and an amino group which may have a lower alkyl group and / or a lower alkoxycarbonyl group and a hydroxyl group are preferable. Further, an amino group which may further have a lower alkyl group is preferable.

The meaning of R ² in the general formula (1) is as described above, but more specifically is as follows. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. As the lower alkyl group, a linear or branched alkyl group having 1 to 5 carbon atoms, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, t-butyl group, pentyl group, isopentyl group. A group etc. can be mentioned. Further, the substituent in the lower alkyl group which may have a substituent is represented by a halogen atom, an amino group, a lower alkylamino group [-NHR ³ (R ³ represents the above lower alkyl group). Group], lower dialkylamino group [-
Group represented by N (R ⁴ ) ₂ (R ⁴ represents the above lower alkyl group)], hydroxyl group, lower alkoxy group, mercapto group, lower alkylthio group and the like.

R ² is preferably a hydrogen atom or a halogen atom.

In the general formula (1), n represents an integer of 1 to 3, preferably 1 or 2, and particularly preferably 1.

5-hydrazinoki represented by the general formula (1)
Examples of the noronecarboxylic acid derivative include R in the formula.¹Is a substituent
Represents an amino group or a hydroxyl group which may have
Then R ²Represents a hydrogen atom or a halogen atom, and n is 1 or
Is preferably 2. More preferably,
Examples thereof include compounds represented by the following formula (2).

[0017]

[Chemical 4]

The 5-hydrazinoquinolonecarboxylic acid derivative of the present invention also includes an ester which can be easily removed by hydrolysis or in vivo to give a compound represented by the general formula (1). Examples of the ester include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t
Lower alkyl ester such as butyl ester, choline ester, dimethylaminoethyl ester, aminoethyl ester such as piperidinoethyl ester, acetoxymethyl ester, vivaloyloxymethyl ester,
Examples thereof include ethoxycarbonyloxyethyl ester.

The 5-hydrazinoquinolonecarboxylic acid derivative of the present invention also includes salts of 5-hydrazinoquinolonecarboxylic acid. Examples of the salt include salts with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid and phosphoric acid, acetic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, citric acid, malic acid, oxalic acid and methanesulfonic acid. , Salts with organic acids such as benzenesulfonic acid and p-toluenesulfonic acid, salts with acidic amino acids such as aspartic acid and glutamic acid, metal salts such as sodium, potassium, calcium, magnesium, zinc and silver, dimethylamine, triethylamine , Salts with organic bases such as diethanolamine, benzylamine, lysine,
Examples thereof include salts with basic amino acids such as arginine.

The 5-hydrazinoquinolonecarboxylic acid derivative of the present invention includes those present as hydrates.
Further, those having an asymmetric carbon atom are also included, and when they can exist as an optically active substance, they are also included. Furthermore,
Those having a plurality of asymmetric carbon atoms are also included, and when they can exist as different stereoisomers, those stereoisomers are also included.

The 5-hydrazinoquinolonecarboxylic acid derivative represented by the general formula (1) of the present invention can be produced, for example, by reacting the compound (3) with hydrazine according to the following reaction formula.

[0022]

[Chemical 5]

(In the formula, X represents a halogen atom, Z represents a hydrogen atom, a lower alkyl group, a benzyl group or the like,
R ¹ , R ² and n are the same as above)

The reaction of the compound (3) with hydrazine (including a hydrate and a salt of an inorganic acid or an organic acid) is carried out in a solvent in the presence of a base, preferably in a nitrogen stream. The amount of compound (3) and hydrazine used is 1 to 20 mol of hydrazine, preferably 1 to 1 mol, relative to 1 mol of compound (3).
It is 0 mol. Examples of the solvent used in this reaction include methanol, ethanol, isopropanol, ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, benzene, toluene, xylene, acetonitrile, pyridine, dimethylformamide, dimethylsulfoxide, hexamethylphosphoric trioxide. Mention may be made of amides or N-methylpyrrolidone and mixtures of two or more thereof. Examples of the base include hydroxides such as sodium hydroxide and potassium hydroxide, carbonates such as sodium carbonate and potassium carbonate, bicarbonates such as sodium bicarbonate, triethylamine, 1,8-diazabicyclo [5.4.0]. Examples thereof include organic bases such as undecene-7 (DBU). The reaction temperature is usually -20 to 2
The temperature is 00 ° C, preferably 0 to 150 ° C.

After the reaction is completed, the formed precipitate is collected by an appropriate means such as filtration, evaporation of the solvent or extraction, and thereafter,
The 5-hydrazinoquinolonecarboxylic acid derivative represented by the general formula (1 ′) can be obtained by purification by a purification means such as recrystallization. In the general formula (1 '), when Z is other than a hydrogen atom, the compound (1) of the present invention can be obtained by hydrolysis according to a conventional method. The compound represented by the formula (3), which is a raw material, can be obtained by, for example, Chem. Pharm. Bull., 38, 2390 (199) in addition to the synthesis examples described below.
0), European Patent Publication Nos. 391169, 221.
No. 463, No. 342649, No. 242789,
German Patent Publication Nos. 37191193 and 390636.
5, JP-A-61-243077, JP-A-62-46.
It can be manufactured by the methods described in JP-A-9, WO94 / 10163, or the like, or methods equivalent thereto. In that case, if possible, a group that does not participate in the reaction may be used in a protected form, and the protecting group may be removed after completion of the reaction.

The 5-hydrazinoquinolonecarboxylic acid derivative of the present invention thus obtained has excellent antibacterial activity and pharmacokinetics and is useful as an antibacterial agent.

The antibacterial agent of the present invention comprises a 5-hydrazinoquinolonecarboxylic acid derivative represented by the general formula (1) as an active ingredient. This active ingredient may be used alone or in other pharmaceutically acceptable forms. It can be configured with a pharmaceutical carrier. The antibacterial agent of the present invention can be orally or parenterally administered to humans or animals, and tablets, granules, powders, capsules, suspensions, injections, ointments, eye drops, suppositories. A desired dosage form such as a drug can be prepared.

In the case of making a solid preparation among these, as a pharmaceutically acceptable pharmaceutical carrier, an excipient such as starch, lactose, sucrose, glucose, crystalline cellulose, syrup,
Gum arabic, tragacanth, gelatin, carboxymethyl cellulose and other binders, carboxymethyl cellulose calcium, starch, calcium carbonate and other disintegrants, magnesium stearate, talc and other lubricants, colorants, menthol and other flavoring agents, and extenders. , Coating agents, sugar coating agents such as sucrose, etc.

When making an ointment, fat as a base,
Lanolin, petrolatum, paraffin, glycols, higher alcohols, water, emulsifiers, suspending agents and the like can be used, and preservatives, antioxidants and the like can be added.

In the case of producing eye drops, sterile purified water or the like can be used as a solvent, and stabilizers, solubilizers, emulsifiers, buffers, isotonic agents, preservatives and the like can be added.

In the case of an injection, a stabilizer,
Preservatives, emulsifiers and the like can be added, and powders for injection can be made into injections prepared just before use. The injection can be administered intravenously, intraarterially, intraportally, intraperitoneally, intramuscularly, or subcutaneously.

The dose of the antibacterial agent of the present invention depends on the body weight of the patient,
Depending on age, sex, administration method, physical condition, medical condition, etc.,
As a 5-hydrazinoquinolone carboxylic acid derivative represented by the general formula (1), in the case of an adult usually, it is orally administered once daily.
0 to 1000 mg is suitable, and 1 to 1 day by parenteral administration
500 mg is suitable.

[0033]

EXAMPLES The present invention will be described in more detail with reference to Examples, Reference Examples and Test Examples, but the present invention is not limited to these. The following reference example is a synthesis example of compound (3).

Reference Example 1 (3RS) -7- [3- (Nt-butoxycarbonyl-N-methylamino) -1-pyrrolidinyl] -1-cyclopropyl-5,6,8-trifluoro-1, Synthesis of 4-dihydro-4-oxoquinoline-3-carboxylic acid: 1
-Cyclopropyl-5,6,7,8-tetrafluoro-
Boron fluoride chelate of 1,4-dihydro-4-oxoquinoline-3-carboxylic acid 1.00 g (2.87 mmol)
Was suspended in 50 ml of ethanol, and (3RS) -3- (N-
0.57 g (2.87 mmol) of t-butoxycarbonyl-N-methylamino) pyrrolidine and 0.58 g (5.74 mmol) of triethylamine were added, and the mixture was stirred at room temperature for 3 hours. Then, the precipitated crystals were collected by filtration, and 1N was added to the crystals.
An aqueous sodium hydroxide solution was added, and the mixture was stirred at 90 ° C for 10 minutes. After cooling, it was neutralized with 50% acetic acid, and the precipitated crystals were collected by filtration, washed with water and dried to obtain 1.21 g of the title compound.
The physicochemical properties of this compound are as follows.

¹ H-NMR (δ ppm) (CDCl ₃ ):
1.00 to 1.50 (4H, m), 1.48 (9H,
s), 1.90 to 2.30 (2H, m), 2.86 (3
H, s), 3.60 to 4.10 (6H, m), 8.70.
(1H, s).

Reference Example 2 1-Cyclopropyl-5,6,8-trifluoro-7-
Synthesis of (4-hydroxy-1-piperidino) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid: 1-
Cyclopropyl-5,6,7,8-tetrafluoro-
A mixture of 1.00 g (3.32 mmol) of 1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 0.40 g (3.96 mmol) of 4-hydroxypiperidine and 20 ml of pyridine was heated at 80 to 90 ° C for 2 hours. Heated and stirred. Then, the solvent was distilled off under reduced pressure, water was added to the residue, the mixture was extracted with a mixed solution of chloroform / methanol, the organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was washed with hot ethanol and dried to give 0.42 g of the title compound as pale yellow needle crystals. The physicochemical properties of this compound are as follows.

M. p. : 293-295 ° C (decomp.) IR (KBr method): 3482, 1712, 1636 cm
^{-1 1 H-NMR (δppm)} (DMSO-d 6): 1.1
4 to 1.15 (4H, m), 1.50 to 1.58 (2
H, m), 1.86 to 1.90 (2H, m), 3.21
~ 3.26 (2H, m), 3.52 to 3.55 (2H,
m), 3.70 to 3.75 (1H, m), 4.08 to
4.12 (1H, m), 4.72 (1H, d, J = 4H
z), 8.62 (1H, s).

Example 1 (3RS) -7- [3- (Nt-butoxycarbonyl-N-methylamino) -1-pyrrolidinyl] -1-cyclopropyl-6,8-difluoro-5-hydrazino-
Production of 1,4-dihydro-4-oxoquinoline-3-carboxylic acid (Compound No. 1-1): (3RS) -7- [3
-(Nt-butoxycarbonyl-N-methylamino)
-1-Pyrrolidinyl] -1-cyclopropyl-5,6
A mixture of 481 mg (1.00 mmol) of 8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 501 mg (10.00 mmol) of hydrazine monohydrate, 20 ml of acetonitrile and 10 ml of ethanol was heated for 8 hours. Refluxed. After cooling, the solvent was distilled off under reduced pressure, water was added to the residue, the mixture was extracted with a chloroform / methanol mixture, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was recrystallized from acetonitrile, 200 mg of the title compound (Compound No. 1-1) was obtained. The physicochemical properties of this compound are as follows.

Yellow brown powdery crystal ¹ H-NMR (δ ppm) (DMSO-d ₆ ): 0.9
5 to 1.30 (4H, m), 1.50 (9H, s),
1.80 to 2.30 (2H, m), 2.88 (3H,
s), 3.60 to 4.20 (6H, m), 4.80 (1
H, br), 8.58 (1H, s), 9.52 (1H,
br), 14.64 (1H, br).

Examples 2 to 7 According to Example 1, compounds Nos. 1-2 to 1-7 were produced.

Example 2 (3S) -7- [3- (Nt-butoxycarbonyl-
N-methylamino) -1-pyrrolidinyl] -1-cyclopropyl-6,8-difluoro-5-hydrazino-1,
4-Dihydro-4-oxoquinoline-3-carboxylic acid (Compound No. 1-2): The physicochemical properties of this compound are as follows.

Brown yellow powdery crystal ¹ H-NMR (δ ppm) (DMSO-d ₆ ): 0.9
5 to 1.30 (4H, m), 1.50 (9H, s),
1.90 to 2.25 (2H, m), 2.85 (3H,
s), 3.60 to 4.15 (5H, m), 4.60 to
5.00 (1H, m), 8.64 (1H, s).

Example 3 (3R) -7- [3- (Nt-butoxycarbonyl-
N-methylamino) -1-pyrrolidinyl] -1-cyclopropyl-6,8-difluoro-5-hydrazino-1,
4-Dihydro-4-oxoquinoline-3-carboxylic acid (Compound No. 1-3): The physicochemical properties of this compound are as follows.

Brown-yellow powdery crystal ¹ H-NMR (δ ppm) (DMSO-d ₆ ): 0.9
5 to 1.30 (4H, m), 1.50 (9H, s),
1.90 to 2.25 (2H, m), 2.85 (3H,
s), 3.60 to 4.15 (5H, m), 4.60 to
5.00 (1H, m), 8.64 (1H, s).

Example 4 (3RS) -1-Cyclopropyl-7- (3-N-ethylamino-1-pyrrolidinyl) -6,8-difluoro-
5-hydrazino-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (Compound No. 1-4): The physicochemical properties of this compound are as follows.

Green-brown powdery crystals (recrystallized from dimethyl sulfoxide) m. p. : 205-210 ° C (decomp.) IR (KBr method): 3392, 1558, 1540 cm
^{-1 1 H-NMR (δppm)} (DMSO-d 6): 1.0
2 to 1.09 (7H, m), 1.72 to 1.77 (1
H, m), 2.02 to 2.05 (1H, m), 2.54
Up to 2.64 (2H, m), 2.80 to 2.92 (1H,
m), 3.40 to 3.80 (4H, m), 4.25 to
4.27 (1H, m), 8.38 (1H, s), 9.0
6 (1H, br).

Example 5 cis-7- (3-Amino-4-fluoro-1-pyrrolidinyl) -1-cyclopropyl-6,8-difluoro-
5-hydrazino-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (Compound No. 1-5): The physicochemical properties of this compound are as follows.

Pale yellowish green powdery crystal (recrystallized from dimethyl sulfoxide / water mixture) m. p. : 280 to 284 ° C (decomp.) IR (KBr method): 3357, 1711, 1635 cm
^{-1 1 H-NMR (δppm)} (DMSO-d 6): 0.9
6 to 1.20 (4H, m), 3.50 to 4.33 (6
H, m), 5.00 (1H, dt, J = 55, 3H
z), 8.64 (1H, s), 9.53 (1H, s),
14.50 (1H, br).

Example 6 (3RS) -1-Cyclopropyl-6,8-difluoro-5-hydrazino-7- (3-hydroxy-1-pyrrolidinyl) -1,4-dihydro-4-oxoquinoline-3
-Carboxylic acid (Compound No. 1-6): The physicochemical properties of this compound are as follows.

Yellow powdery crystal (recrystallized from chloroform / ethanol mixture) m. p. : 281-283 ° C. (decomp.) IR (KBr method): 3340, 1699, 1623, 1
^{519cm -1 1 H-NMR (δppm} ) (DMSO-d 6): 0.9
9-1.14 (4H, m), 1.86-1.96 (2
H, m), 3.40 to 3.43 (1H, m), 3.62
~ 3.67 (1H, m), 3.85-3.94 (2H,
m), 4.01 to 4.05 (1H, m), 4.37 (1
H, brs), 4.97 (1H, d, J = 2Hz),
8.50 (1H, s), 9.27 (1H, d, J = 3H
z).

Example 7 1-Cyclopropyl-6,8-difluoro-5-hydrazino-7- (4-hydroxy-1-piperidino) -1,
4-Dihydro-4-oxoquinoline-3-carboxylic acid (Compound No. 1-7): The physicochemical properties of this compound are as follows.

Yellow powdery crystals (dimethyl sulfoxide /
Recrystallized from ethanol mixture) m. p. : 230-232 ° C (decomp.) IR (KBr method): 3431, 1711, 1624, 1
^{522cm -1 1 H-NMR (δppm} ) (DMSO-d 6): 1.0
5 to 1.14 (4H, m), 1.49 to 1.57 (2
H, m), 1.84 to 1.88 (2H, m), 3.20.
Up to 3.25 (2H, m), 3.47 to 3.51 (2H,
m), 3.68 to 3.72 (1H, m), 4.05
4.09 (1H, m), 4.69 (1H, brs),
8.54 (1H, s), 9.35 (1H, d, J = 2H
z).

Example 8 (3RS) -1-Cyclopropyl-6,8-difluoro-5-hydrazino-7- (3-N-methylamino-1-)
Preparation of Pyrrolidinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid (Compound No. 1-8): (3
RS) -7- [3- (Nt-butoxycarbonyl-N
-Methylamino) -1-pyrrolidinyl] -1-cyclopropyl-6,8-difluoro-5-hydrazino-1,4
-Dihydro-4-oxoquinoline-3-carboxylic acid 20
0 mg (0.41 mmol) was suspended in 3 ml of acetic acid, 5 drops of 30% hydrobromic acid acetic acid solution was added, and the mixture was stirred at room temperature for 1 hr. Ether was added to the reaction mixture, the deposited precipitate was collected by filtration, the obtained precipitate was dissolved in methanol, triethylamine was added to neutralize the solvent, and the solvent was evaporated under reduced pressure. Chloroform was added to the residue, the crystals were collected by filtration, washed with a small amount of chloroform, dried, and recrystallized from ethanol to obtain 50 mg of the title compound (Compound No. 1-8). The physicochemical properties of this compound are as follows.

Yellow-brown powdery crystals m. p. : 220-229 ° C (decomp.) IR (KBr method): 3421, 1636, 1559, 1
^{540cm -1 1 H-NMR (δppm} ) (DMSO-d 6): 1.0
1-1.12 (4H, m), 1.75-1.79 (1
H, m), 2.01 to 2.04 (1H, m), 2.32
(3H, s), 3.35 to 3.45 (1H, m), 3.
42-3.45 (1H, m), 3.66-3.81 (3
H, m), 4.01 to 4.05 (1H, m), 8.50.
(1H, s), 9.27 (1H, d, J = 2Hz).

Examples 9 to 10 According to Example 8, compounds Nos. 1-9 to 1-10 were produced.

Example 9 (3S) -1-Cyclopropyl-6,8-difluoro-
5-hydrazino-7- (3-N-methylamino-1-pyrrolidinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid (Compound No. 1-9): The physicochemical properties of this compound are: It is as follows.

Yellow-brown powdery crystals m. p. 184 to 188 ° C (decomp.) IR (KBr method): 3422, 1637, 1442 cm
^{-1 1 H-NMR (δppm)} (DMSO-d 6): 1.0
4 to 1.17 (4H, m), 1.77 to 1.80 (1
H, m), 2.03 to 2.06 (1H, m), 2.35.
(3H, s), 3.20 to 3.30 (1H, m), 3.
45-3.47 (1H, m), 3.68-3.81 (3
H, m), 4.02 to 4.05 (1H, m), 8.50.
(1H, s), 9.28 (1H, d, J = 2Hz).

Example 10 (3R) -1-Cyclopropyl-6,8-difluoro-
5-hydrazino-7- (3-N-methylamino-1-pyrrolidinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid (Compound No. 1-10): The physicochemical properties of this compound are It is as follows.

Yellow-brown powdery crystals m. p. : 180 to 184 ° C (decomp.) IR (KBr method): 3422, 1637, 1448 cm
^{-1 1 H-NMR (δppm)} (DMSO-d 6): 1.0
4 to 1.16 (4H, m), 1.93 to 1.96 (1
H, m), 2.14 to 2.18 (1H, m), 2.49
(3H, s), 3.53 to 4.04 (6H, m), 8.
52 (1H, s), 9.31 (1H, d, J = 2H
z).

Example 11 (Tablet) 100 g of 5-hydrazinoquinolonecarboxylic acid derivative (Compound No. 1-8), lactose, crystalline cellulose and magnesium stearate were mixed and tableted with a tableting machine to give a total of 10 tablets.
00 tablets were obtained.

Example 12 (Capsule) 100 g of 5-hydrazinoquinolonecarboxylic acid derivative (Compound No. 1-8), lactose and magnesium stearate were mixed and filled in a capsule by an automatic filling machine to obtain 1000
One capsule was obtained.

Example 13 (Injection) 10 g of 5-hydrazinoquinolonecarboxylic acid derivative (Compound No. 1-8) was dissolved in distilled water for injection to make 100 parts in total.
Make up to 0 ml and filter aseptically. This was aseptically sealed at a rate of 1 ampoule 5 ml to obtain an injection.

Example 14 (Ointment) 10 g of 5-hydrazinoquinolonecarboxylic acid derivative (Compound No. 1-8), cetanol, white petrolatum, sodium edetate, glyceryl monostearate, polyoxyethylene cetyl ether and water were kneaded. Combined ointment 100
0 g was obtained.

Example 15 (ophthalmic solution) 0.3 g of 5-hydrazinoquinolonecarboxylic acid derivative (Compound No. 1-8) was dissolved in sterilized purified water, and sodium chloride, benzalkonium chloride and sodium edetate were added, The pH was adjusted to 6 with hydrochloric acid, and the total amount was adjusted to 100 ml with sterile purified water to obtain an eye drop.

Test Example 1 (Antibacterial Test) The antibacterial property of the 5-hydrazinoquinolonecarboxylic acid derivative of the present invention against the bacteria shown in Table 1 was tested according to the MIC measurement method of the Japan Chemotherapy Society under the following conditions. As a control, it is described in WO94 / 10163 (3
S) -7- (3-Amino-1-pyrrolidinyl) -1-cyclopropyl-6,8-difluoro-5-hydrazino-
1,4-dihydro-4-oxoquinoline-3-carboxylic acid (Compound A) was used. The results are shown in Table 1.

(Test conditions) Medium used: Bacteria Mueller hinton Medium. Specimen dilution: 1000% with 25% dimethylsulfoxide
g / ml, and then diluted with sterile purified water to 100 times
~ 0.006 μg / ml, and then 10
It was diluted twice and made into a flat plate. Inoculum: 10 ⁶ / ml 1 ase. Culture conditions: 37 ° C. for 48 hours. Judgment: 24th hour.

[0067]

[Table 1]

Test Example 2 (Infection test) Using a mouse E. coli systemic infection model, measurement was carried out under the following conditions. The same compound A as in Test Example 1 was used as a control drug. Table 2 shows the results.

Experimental animals: ICR male mice 4 weeks old 1
A group of 5 animals was used. Animals weighed 23 ± 2 g. Preparation of sample solution: Used by dissolving in sterile purified water. Preparation of inoculum: Escherichia coli
The cryopreserved bacterial solution of O-1 was inoculated into tryptic soy broth and cultured at 37 ° C. for 16 hours. The bacterial solution was collected by centrifugation, washed with physiological saline, and then suspended in the same solution to obtain a predetermined bacterial amount, and 10% (W / V) mucin was added.
Equal amount was added to the bacterial biological (Difco). Creation and treatment of infection model: 0.5 inoculum for mice
The drug was intraperitoneally administered (2.6 × 10 ⁶ CFU / mouse) to establish infection, and immediately thereafter, the drug was orally administered once as a single dose. The life and death of mice up to 6 days after infection was observed to determine the drug efficacy.

[0070]

[Table 2]

[0071]

INDUSTRIAL APPLICABILITY The 5-hydrazinoquinolonecarboxylic acid derivative (1) of the present invention is effective against Gram-negative bacteria such as Pseudomonas aeruginosa and Gram-positive bacteria including resistant bacteria such as methicillin-resistant Staphylococcus aureus. It has excellent antibacterial activity and excellent pharmacokinetics. Therefore, the 5-hydrazinoquinolonecarboxylic acid derivative of the present invention and the antibacterial agent containing the same as the active ingredient are clinically useful for the prevention and treatment of various infectious diseases.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Kazuki Maebashi 5-9-13-502 Moto Okubo, Narashino City, Chiba Prefecture (72) Inventor Kenmitsu Asaoka 1-17-1-1306 Karabe, Narita City, Chiba Prefecture (72) Inventor Hideaki Matsuda 2-29-8 Higashi Abiko, Abiko City, Chiba Prefecture (72) Inventor Tadayuki Kuraishi 2-5-4 Kasumi, Narashino City, Chiba Prefecture

Claims (3)

[Claims] 1. The following general formula (1): [In the formula, R ¹ represents an amino group, a hydroxyl group or a lower alkoxy group which may have a substituent; R ² represents a hydrogen atom, a halogen atom or a lower alkyl group which may have a substituent. Shown: n is an integer of 1 to 3. However,
When n = 1, R ¹ does not represent an amino group and R ² does not represent a hydrogen atom at the same time.] A 5-hydrazinoquinolonecarboxylic acid derivative. 2. The following formula (2); A 5-hydrazinoquinolonecarboxylic acid derivative represented by: 3. An antibacterial agent comprising the 5-hydrazinoquinolonecarboxylic acid derivative according to claim 1 or 2 as an active ingredient.