JPS58174367A - Quinoline derivative and its preparation - Google Patents

Abstract

NEW MATERIAL:A quinoline derivative shown by the formula I (R is H or lower alkyl) or its salt. EXAMPLE:1-Ethyl-5-amino-6, 8- difluoro-7-( 1-piperazinyl )-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid. USE:An antibacterial agent. Having powerful antibacterial activity of wide range against various kinds of resistant bacteria such as Gram-positive or Gram-negative bacteria, ampicillin resistant bacteria, etc., good absorption characteristics by oral administration, capable of keeping high blood concentration for a long time, having good transmigration properties to the organs, exhibiting improved remedying effect especially on infections diseases in a urinary tract or nephritis. PROCESS:A 1,4-dihydroquinoline derivative(new substance) shown by the formula IIis reacted with a piperazine compound shown by the formula III in a proper solvent at 100-200 deg.C to give easily a compound shown by the formula I .

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel quinoline derivative and a method for producing the same, and more particularly to a quinoline derivative represented by the general formula (wherein P represents a hydrogen atom or a lower T-alkyl group) and a method for producing the same.

Compound (I) of the present invention is a new compound and is a useful pharmaceutical compound as an antibacterial agent because it has excellent antibacterial activity.

Conventional compounds (I) of the present invention and compounds similar in structure and having antibacterial activity include 1-ethyl-6-fluoro-2methyl-4-oxo-1゜4-dihydroquinoline-3-carboxylic acid. (Unexamined Japanese Patent Publication No. 55-100365),
1-ethyl-6,8-difluoro-7-methyl-4-oxo-1,4-dihydroquinoline-3-carvone w (JP-A-56-53656), 1-ethyl-6-fluoro-7-( 1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carvone # (Japanese Patent Publication No. 55-341
No. 44) are known.

The present inventors have conducted various studies to find a compound that is more excellent as an antibacterial agent than the above-mentioned known compounds, and have found that the quinoline derivative (I) represented by the above-mentioned general formula (I) is strong against various bacteria and We have completed the present invention by discovering that it has a wide range of antibacterial activity, is well absorbed upon oral administration, maintains a high blood concentration for a long time, and has good transferability to organs.

The compound of the present invention is represented by general formula (I).

Examples include compounds in which R is a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms, such as a thyl group, an ethyl group, a propyl group, or a butyl group. Among these, compounds with lower tL are 1-ethyl-5-amino, No. 6.8
-difluoro-7-(1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or 1-
Ethyl-5-ymino-6゜8-difluoro-7-(4-
Methylpiperazin-1-yl)-4-oxo-1,4-
Dihydroquinoline-3-carboxylic acid is mentioned.

According to the present invention, compound (I) is produced by reacting a 1,4-dihydroquinoline derivative represented by the formula with a piperazine compound represented by - (wherein R has the same meaning as above). be able to.

The reaction between compound ([[) and compound ([)] can be easily carried out in an appropriate solvent. As a solvent.

For example, pyridine, dioxane, ethylene glycol, 3
-Methoxybutanol, diethylene glycol, dimethylformamide, etc. can be suitably used. This reaction is preferably carried out at 100 to 200°C.

The thus obtained compound (■) of the present invention has excellent anti-inhibitory activity against Durham-positive and -negative bacteria such as Staphylococcus aureus, K. pneumoniae, K. proteus, M. aeruginosa, Shigella enterica, and Salmonella enterica. .

It also has excellent antibacterial activity against various resistant bacteria such as anopicillin-resistant bacteria, nalidix-resistant bacteria, oxolinic acid-resistant bacteria, and gentamicin-resistant bacteria. Therefore, the compound (I) of the present invention is useful as an antibacterial agent for mammals including poultry and humans, as well as against bacterial infections caused by Durum-positive bacteria and Gram-negative bacteria. In particular, the compound (I) of the present invention has the advantage of being well absorbed after oral administration and maintaining a high blood concentration for a long period of time, and has the advantage of not being easily transferred to organs such as the kidneys, lungs, and liver. Excellent,
It also has the advantage of exhibiting excellent therapeutic effects against urinary tract infections and nephritis because of its good transferability to the kidneys.

When compound (I) of the present invention is used for pharmaceutical purposes.

It can be used both in free form and in the form of pharmaceutically acceptable salts. Examples of pharmacologically acceptable salts include non-toxic metal salts such as sodium salts, calcium salts, magnesium salts; dimethylamine salts and benzylamine salts.

Non-toxic organic amine salts such as dicyclohexylamine salts and triethylamine salts; basic amino acid salts such as lysine salts and arginine salts;
Examples include mineral acid salts such as phosphates and sulfates; organic acid salts such as oxalates, acetates, methanesulfonates, and )7 leenesulfo/acids.

Compound (I) of the present invention can be administered either orally or parenterally. 13. As a dosage form. For example, tablets
Examples include solid preparations such as pills and capsules, and liquid preparations such as &Ni, suspensions, and emulsions.

Furthermore, when administering parenterally, it can also be used as an injection or as a 1/2-half solution.

Moreover, the compound (1) of the present invention can also be used in combination with a suitable pharmaceutical excipient. As an excipient & lies.

For example, gelatin, lactose, glucose, salt, and starch.

Examples include magnesium stearate, talc, and vegetable oil.

Note that the raw material compound ([) of the present invention is also a new compound and can be produced, for example, by the method shown in the following reaction formula.

(IV) (I (■) (■) (X) (O) (in the above formula
FlF and R2 represent a lower T alkyl group.

X represents a halogen atom. ) That is, 9 The raw material compound (seal) of the present invention is obtained by preparing (1) compound (IV) in the presence of a metal powder (for example, iron powder) at a concentration of 50 to 1
Compound (V) by treatment with acid (e.g. vinegar #I) at 30t
and (2) the compound (■) and the compound (■) in a solvent (
For example, a condensation reaction is carried out at 90 to 150 t'' in ethanol) to form a compound (Vl), and (3) the compound (■) is converted into a solvent (for example, 15 to 300 t'' in diphenyl ether '1).
An intramolecular ring-closing reaction is performed at t to form a compound (■), and (4) the compound (■) is dissolved in a solvent (for example, dimethylformamide).
React with IJum at 10~50υ...
After forming the sodium salt of the compound (■), the sodium salt and the compound (■) are reacted in a solvent (e.g., dimethylformamide) at 177M humidity to 100°C to form the compound (X), and (6) the compound (X) is obtained. Compound (X) is mixed with a solvent (e.g.

Vinegar i! ! &) in the presence of a catalyst (e.g. palladium on carbon) at ￥ temperature to 100'C to form the compound (X[)
(6) Then, the compound (X[) can be produced by hydrolyzing the compound (X[) with an aqueous alkali metal hydroxide solution (eg, aqueous sodium hydroxide) in a solvent (eg, dioxane).

Experimental Example 1 (Antibacterial activity) Minimum emission level 11 of the following sample compound (compound was dissolved in 0.2N sodium hydroxide and diluted with sterile distilled water)
If15111 stop concentration (M,■,C)cμri/lj)
on) was determined by the plate dilution method (cultivated at 37°C, determined after 20 hours) using an agar medium. The results are shown in Table 1 below.

(Compound of the present invention) (The same applies hereinafter) (1) 1-ethyl-5-difluoro-6,8-difluoro-
7-(1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (2) 1-ethyl-5-amino-6,8-difluoro-
7-(4-Methylbiperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid Table 1 (Antibacterial activity) The antibacterial activity against each oak resistant soybean was measured in the same manner as in Experimental Example 1. did. The results are shown in Tables 2 to 4 below.

@Table 2 (Antibacterial activity against anopicillin-resistant bacteria) Table 3 (Antibacterial activity against gentaficin-resistant bacteria) Table 4 (Antibacterial activity against nalidixic acid-resistant bacteria) Example 3 (Therapeutic effect on experimental infections in mice) Various tests Tryptosoya broth (Tryptosoya,
brother) and 37′? :, cultured for 18 hours.

1. Suspend a certain amount of bacterial cells in 5-dimucin solution. The suspension was inoculated into the abdominal cavity of 41dY male mice (1 group; 10 mice, 2 days old; 20 days old). One hour after inoculation, a 0.5 tinicol suspension of the compound of the present invention (1) was poured into a cup! Completed. One week after administration, the mice were observed for survival, and the dose 1 (ED6o) required for the survival of 509 g of mice was determined from the survival rate. The results are shown in Table 5 below.

@Table 5* (Lo5.) When mice are inoculated with bacteria, the amount of bacteria required to kill 50 mice within 7 days after inoculation (number of meters).

Experimental Example 4 (Blood concentration and body distribution of test compound in mice)
) using a probe (dose: 100 9/V)
a) I did. After a certain period of time, blood was collected from the animals by decapitation, and the blood was allowed to stand to separate the serum. Concentrations of compounds in serum were determined by bioassay (b41'oassay). Organs (lungs, liver, and kidneys) were collected from mice that were sacrificed at the age of 1 year. After washing each organ with physiological saline, 1/15 MIJ acid buffer of 4x was added, homogenized using a glass homogenizer, and centrifuged. minIll (10,O
OOrpm, 15 min) The shite supernatant was collected. Compound concentration in the supernatant was determined by bioassay. These results are shown below @Table 6 ~ Table 6 (Concentration in the helmet) (*) Control compound (same below) 21-ethyl-6-fluoro-7-(1-piperazinyl)
-4-Oxo-1,4-dihydroquinoline-3-carboxylic acid (compound described in Japanese Patent Publication No. 55-34144) Table 7 (It! Concentration in the viscera) Table 8 (Concentration in the liver) Table s9 ( (concentration in the kidney) Experimental Example 5 (Therapeutic effect on experimental route infection in mice) - +1dY male mice (4 withdrawals) whose water supply was restricted at night were treated with bentoparbital sodium (5019/I!f"l) by intraperitoneal injection. Escherichia coli (2004) was anesthetized and placed in the exposed bladder.
Suspension of 0.05-1/(10' CFU/mouse)
was inoculated.

The abdominal incision was closed with suture rivets, and the external urethra was self-closed for approximately 3 hours to stop urination. Mice were further housed with water restriction for 24 hours. The test compound was continuously administered orally once a day for 7 days starting 24 hours after the bacterial inoculation. On the day after the final administration of the test compound, the dorsum was removed from the mouse and homogenized. The homogenized product was diluted 10 times, and the diluted solution was diluted with 1011
The flesh was inoculated onto a DHL agar plate medium containing 9/d streptomycin and cultured to establish the number of flaccid flesh. A bacterial count of 10"cpu/kidney or less was determined to be effective, and an effective dose of 501! (ICD50) was calculated from the effectiveness rate at the dose.

The results are shown in the table below.

Table 10 [Synthesis of raw material compound (!
Heat to 05-110"C and add iron powder 13,4 to this solution.
7 is added at this pressure and the mixture is brought to reflux. After the reaction solution has finished refluxing, the solution is cooled.6 The reaction solution is poured into ice water 3E, and insoluble matter is filtered off. Add the insoluble matter to chloroform and filter off the material insoluble in chloroform. After drying the filtrate, the solvent is distilled off under reduced pressure.

By purifying the residue with silica gel chromatography (solvent: chloroform), 2,4-difluoro-
3-chloro-5-nitroanili 75.6F is obtained.

NMR (cDc et al.) at M, P, 90-92 - 3.98 ('broad 8m 2H), 7.43
(7, IH,, r-8L5.J-+7Hz) (212,
4-difluoro-3-chloro-5-nitro gamma 735
．． 4F, ethoxymethylene diethyl malonate 36.72
While stirring the mixture of ethanol and asy at 120'C, ethanol in the mixture is distilled off. The mixture was left to stand for 1 hour at the same temperature, and then the ethanol was distilled off at the same temperature under reduced pressure. Cool the reaction mixture and add isopropyl ether to the mixture.

The precipitated crystals were collected by filtration and recrystallized from inpropatool to give [N-(2,4-difluoro-3-chloro-5
-nitrophenyl)7minomethylene]malonic acid diethyl ester 5B, 3p is obtained as yellow flakes.

M-p, 128-13l2 8-130tN also) ♂: 1.36 (t, 3H, J-7Hz), 1-39 (t,
3H, J=7Hz) 4-30(q, 2H,:r-7az
), 4-35(q, 2E1., T=7Hz) 7.95(
t, lH,:f = 8Hz), 8-36(d, IH-J
-13&)11-21 (tl, lH, J-13Hz
) (at C5-(2,4-difluoro-3-chloro-5-nitrophenyl)aminomethylene comalonic acid diethyl ester 30.3 F and diphenyl ether 500
Stir the mixture with w7 at 250-255t for 30 minutes.

After the mixture has cooled, 500 ml of GCn-hexane is added to the mixture. The precipitated crystals are collected by filtration, washed with methanol, and dried to obtain 5-nitro-6,8-difluoro-7-chloro-4-hydroxyquinoline-3-carboxylic acid ethyl ester 18.6F.

M, p, 28Qp or more NMI ((OF3CO2D) t: 1.57 (t,
3H, J-7Hz), 4.75(q +2H+J-7H
z) 9.56 (Japanese, IH) 14) 5-nitro-6,8-difluoro-7-chloro-
11.55F of 4-hydroxyquinoline-3-carboxylic acid ethyl ester was suspended in 100d of dimethylformamide, and 60.51 sodium hydride was added to the suspension.
Add 1 at room temperature. Stir the mixture for 1 hour (5-nitro-6,8-difluoro-
The sodium salt of 7-chloro-4-hydroxyquinoline-3-carboxylic acid ethyl ester is formed). Add 10.9F of ethyl iodide to the mixture and bring the mixture to 55~
Stir at 6o'c for 20 hours. The mixture was concentrated under reduced pressure to remove the solvent. Add water to the S tube and collect the precipitated crystals by filtration. After dissolving the crystals in chloroform, the crystals were purified by silica gel chromatography (solvent: chloroform) to obtain 1-ethyl-5-nitro-6,8-difluoro-
7-chloro-4-oxo-], 4-dihydroquinol/-
9.5 p of 3-carboxylic acid ethyl ester are obtained.

M-p, 192-195111″ (recrystallized from ethanol, colorless needle crystals) NMFi(d6-Dyso)j: ]-30(t, 3H, r-7Hz), 1.54(t, 3
Ti, J-7Hz) 4.26(q, 2H,, T-7Hz
), 4.2-4.75 (m, 2H) 8-77 (s, IH
) C5) 1-ethyl-5-nitro-6,8-difluoro-
7-chloro-4-oxo-1,4-dihydroquino 17
No 3-carboxylic acid ethyl ester 9.5 F, 51
A mixture of g palladium, 1 y of carbon, and 300 d of acetic acid is subjected to a catalytic reduction reaction. After the reaction is completed, the catalyst is filtered off.

The filtrate is concentrated under reduced pressure to remove the solvent. Add Improper Tool to the residue and filter the precipitated crystals. By recrystallizing the crystals from ethanol, 1-ethyl-5-γmino-6,8-difluoro-7-10rho-4-oxo-1,
7.7y of 4-dihydroquinoline-3-carboxylic acid ethyl ester was obtained.

y, p, 210-212, NMB (CF3CO2D) coni 1.56 (t, 3H, y='/Hz), 1-73 (d,
t, 3H, J=m7Hzt, r-1Hz) 4-70(t
, 2H, J=7Hz), 4.66-5-15(, 2H)
9.10(s, IH') (6) 1-ethyl-5-7 minnow 6.8-difluoro-
7-chloro-4-oxo-1,4-dihydroquinol-4-
3-carboxylic acid ethyl ester 9.51 to dioxane 5
00d, and add 2.0% sodium hydroxide to the suspension.
Add 9F-containing water 2504 at room temperature and stir for 1.5 hours. The mixture was neutralized with 10% hydrochloric acid, and the mixture was
Stir for some time. Filter the precipitated crystals.

Dry after washing with water. By recrystallizing the crystals from a mixture of dimethylformamide and ethanol.

1-ethyl-5-,7 minnow 6,8-difluoro-7-
Chloro-4-oxo-1,4-dihydroquinoline-3-
Carvone m 8-21 is obtained.

M-p-298-300t (decomposition) NMR (CF3CO2D) J: 1.5-2-0 (rn, 3H), 4-6-5.1
5(m, 2H)9-16(s, 1a) [Synthesis of target compound (II)] 1-ethyl-5-7minor 6.8-difluoro-7-chloro-4-oxo-1,4-dihydroquinoline A mixture of 5.2 F of -3-carboxylic acid, 7.4 F of piperazine, and 18 F of 3-methoxybutanol is stirred at 140 to 150 t for 5 hours. The reaction mixture is concentrated under reduced pressure and the solvent is distilled off. Residue Add 150ml of a 30ml aqueous solution of acetic acid to the mixture, and filter out insoluble materials.The filtrate is concentrated under reduced pressure to remove the solvent.

Filter the precipitated crystals and wash with ethanol. Crystal water 20
Suspended to 0d.

The pH of the suspension was adjusted to pH 7.5 to 8.5 with T ammonia water.
shall be. 1-ethyl-5-amino-
6,8-difluoro-7-(1-piperazinyl)-4-
Oxo-1,4-dihydroquinoline-3-carboxylic acid 1
．． 955F is obtained as pale yellow needles.

M-p-262-265℃ (decomposition) vass (m/e): 352 (M'') NMR (CF
3CO2D) j: 1-73 (t, 3H9, r=7Hz) e 3-
4 4.3 (rn * 8H) 4-5-5-2 (+n
, 2H), 9.12 (a, IH') Example 2 1-ethyl-5-amino-6,8-difluoro-7-lyrow-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 1-1p+ N-methylpiperazine 1.82P
and 3.5w1l of 3-methoxybutanol.
Stir at 50-160°C for 6 hours. The mixture is concentrated under reduced pressure to remove the solvent. A 30 ml acetic acid aqueous solution is added to the residue, and insoluble matter is filtered off. The filtrate was placed under reduced pressure to remove the solvent. Add ethanol to the residue and filter the precipitated crystals. The crystals are suspended in water, and a 10% aqueous sodium hydroxide solution is added to the suspension to dissolve insoluble matter. The liquid properties of this solution were made neutral with 1091 hydrochloric acid, and the precipitated crystals were collected by filtration. By recrystallizing the crystals from ethanol, 1-ethyl-5-ymino-6,8-dichloro-7-(4-methylpiperazin-1-yl)-4-year-old xo-1,4-dihydroquinoline- 0.5y of 3-carboxylic acid is obtained as yellow needles.

M-1), 247-249℃ (angle I?1%) Mas
s (m/e) 2 366 (M+)NMR(O
DCfi3) J:

Claims (1)

[Scope of Claims] 1. A quinoline derivative represented by the general formula (wherein R represents a hydrogen atom or a lower alkyl group) or a pharmacologically acceptable salt thereof. 2. The compound is 1-ethyl-5-amino-6,8-difluoro-7-(1-piperazinyl)-4-oxo-1,4
-dihydroquinoline-3-carboxylic acid or a pharmacologically acceptable salt thereof. 3. The compound is 1-ethyl-5-amino-6,8-difluoro-7-(4-methylpiperazin-1-yl)-4-
The compound according to claim 1, which is oxo-1,4-dihydroquinol-7-3-carboxylic acid or a pharmacologically acceptable salt thereof. 4. A 1,4-dihydroquinoline derivative represented by the formula is reacted with a piperazine compound represented by the general formula (wherein R represents a hydrogen atom or a lower T-alkyl group), and if necessary, the product is A method for producing a quinoline derivative or a pharmacologically acceptable vine salt thereof as shown in the patent (wherein R has the same meaning as above), characterized in that the quinoline derivative is converted into a pharmacologically acceptable vine salt.