JPS60112790A - Pyridylnaphthyridine derivative - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I (R1 is fluoroethyl, or cyclopropyl). EXAMPLE:6-Fluoro-1-( 2-fluoroethyl )-7-( 4-pyridyl )-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid. USE:An antibacterial agent against Gram-positive and Gram-negative bacteria, and glucose-nonfermenting bacteria, and a food antiseptic. PREPARATION:A compound shown by the formula I wherein R1 is fluoroethyl group is obtained by fluoroethylating a compound shown by the formula II (R2 is H, or lower alkyl) at 1-position, followed by hydrolysis. A compound shown by the formula I wherein R1 is cyclopropyl group is obtained by subjecting a pyridine derivative shown by the formula III (Y is lower alkyl) to ring closure in the presence of a basic catalyst to be used for Dieckmann reaction, followed by dehydrogenation and hydrolysis.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel pyridylnaphthyridine derivative represented by the following general formula (1 (in the formula, R1 means a fluoroethyl group or a cyclopropyl group)) and a salt thereof.

Examples of the salt of the compound represented by general formula (1) include salts with inorganic or organic acids such as hydrochloric acid, sulfuric acid, and methanesulfonic acid, or sodium salts and potassium salts of the compound represented by formula [l]. Can be mentioned.

The compound [1] of the present invention and its salts are suitable for Durham-positive bacteria such as Staphylococcus aureus and Gram-negative bacteria such as Escherichia coli.

It has extremely strong antibacterial activity against non-glucose-fermenting bacteria, including Pseudomonas aeruginosa, and is used not only as a medicine but also as a veterinary drug and a fish disease drug.

Used in various forms as a food preservative.

The compound [I] of the present invention and its salts are produced, for example, by the following method.

The compound of the present invention [I] in which It+ is a fluoroethyl group (
In the formula, R2 means a hydrogen atom or a lower alkyl group. ) Fluoroethylate the 1st position of the compound represented by
Alternatively, after hydroxyethylation, the hydroxy moiety is substituted with a fluorine atom, and when an ester is obtained, the compound of formula [1] can be produced by further hydrolyzing this.

As the fluoroethylating agent, known ones are used.

Specific examples include halogenated fluoroethyl esters such as fluoroethyl iodide and fluoroethyl esters such as fluoroethyl 1""-toluenesulfonic acid. This fluoroethylation reaction is carried out in a conventional manner, that is, by allowing the fluoroethylating agent to act under heating in a solvent that does not participate in the reaction. The solvent that does not participate in the reaction may be either non-aqueous or water-containing. For example, ethanol.

Examples include dioxane, dimethylformamide, dimethyl sulfoxide, water, and the like. During this reaction, the reaction is further promoted by adding an acid acceptor, for example, a base such as alkali carbonate, caustic alkali, alkali metal alcoholade, sodium hydride, triethylamine, benzyltrimethylammonium hydroxide, and the like.

The hydrolysis reaction that takes place when an ester is obtained is
This can be carried out by bringing the ester body into contact with water at 20 to 150°C. It is generally carried out in the presence of an acid or base to accelerate the reaction. Examples of the acid include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and phosphoric acid, and organic acids such as acetic acid, oxalic acid, and toluenesulfonic acid. Examples of the base include hydroxides such as sodium hydroxide and norium hydroxide, carbonates such as sodium carbonate and lium carbonate, and sodium acetate.

The pyridine visiting conductor represented by the compound [I] of the present invention in which R1 is a cyclopropyl group (in the formula, Y is the same or different and means lower alkyl) was prepared according to Diekmann (Diekmann).
ckmann) reaction in the presence of a basic catalyst commonly used in the reaction to produce a compound represented by the following general formula (wherein, Y is the same as above), and then this compound (
It can be produced by dehydrogenating IVI and further hydrolyzing it.

When producing the compound CIVI, the starting compound (1
) in a solvent in the presence of a base catalyst such as metallic sodium, sodium hydride, sodium ethylate, or potassium t-butyralate, resulting in intramolecular ring closure, to obtain the compound [■]. At this time, the reaction can be more effectively achieved by adding a catalytic amount of lower alcohols such as methanol, ethanol, and butanol.

Aromatic hydrocarbons such as benzene and toluene, and ethers such as dioxane, tetrahydrofuran, 1,2-dimethoxyethane and diethylene glycol dimethyl ether are suitable as reaction solvents. The heating temperature is not particularly limited, but a temperature of 60 to 180°C is usually preferred.Compound (IV) can also be represented by the following general formula (wherein, Y is the same as above) Compound ([V) is dehydrated. In order to dissolve the compound [■],
Inert solvents (e.g. benzene, toluene, xylene).

Ethyl acetate, dioxane, t-butyl alcohol.

dimethylformamide, ethanol, etc.), 2,3-
Dichloro-5,6-dicyano-1,4-benzoi/7C
DDQ'), tetrachloro-1,4 benzoquinone (chloranil), tetracyanoethylene, palladium-carbon,
A general dehydrogenating agent such as N-bromosuccinimide (NBS), manganese dioxide, or gelene dioxide may be reacted by heating for a short time at room temperature or near the boiling point of the solvent used, or compound (IV) or benzene directly above its melting point.

Toluene, dioxane, ethanol, n-hexano.

Simply heating in an inert solvent such as carbon tetrachloride, dimethylformamide, or diphenyl ether is sufficient.

The ester thus obtained can be converted into hydrolyzed water m1 of the compound H) of the present invention by a conventional method.

The compound (1) of the present invention can also be produced by the following method. That is, the following general formula (wherein, R
+ is the same as above. ) The ester of the compound [1] of the present invention is produced by subjecting the amine group at the 6-position of the lower alkyl ester of the compound represented by the above formula to a Schiemann reaction in which the amine group at the 6-position is converted into a diazonium salt by a conventional method. ,
This can then be hydrolyzed by a conventional method to produce the compound (1) of the present invention.

Furthermore, in addition to the above-mentioned synthesis methods, the compounds of the present invention can also be produced by appropriately combining the above-mentioned unit reactions depending on the purpose.

The raw material compounds [■] and (lit) are produced by the method described in the reference examples or a method similar thereto, and the ester of the raw material compound (V) is produced by the method described in the reference example, or by a method similar thereto.
It can be produced by a method similar to the method disclosed in No. 5 or the method for producing compound [1] of the present invention.

The compound of the present invention produced in this manner is isolated and purified according to conventional methods. Salt form depending on isolation and purification conditions,
Although it is obtained in the form of a free carboxylic acid or a free amine, these can be mutually converted depending on the purpose to produce the compound of the present invention in the desired form.

The thus obtained compound []] and its salt are both new compounds and exhibit extremely excellent antibacterial activity, so they are valuable as antibacterial agents. Compound [1] can be used not only as a medicine for humans and animals, but also as a medicine for fish diseases, a preservative for pesticides and foods, and the like.

Next, data regarding the antibacterial activity of the compounds of the present invention are listed below.

(Left below) ” S, a,: Staphylococcus aureus A3
0774S, p,: Streptococcus pyogenes
65AE, c,: Escherichia coli P-5101
P, a,: Pseudomonas aeruginosa A12*2
Experimental conditions Minimum inhibitory concentration (MIC)
y.

It was carried out according to the method (revised draft) described in Vol. 29, No. 1, p. 76 (1981), and the results are shown in the table above.

Next, the present invention will be explained in more detail by referring to Reference Examples and Examples.

Reference Example 1 47p of 6-(4-pyridyl)-1,2-dihydro-2-oxopyridine-3-carbonitrile was nitrated with concentrated sulfuric acid and fuming nitric acid to produce 5-nitro-6-(4-pyridyl).
-1,2-dihydro-2-oxonicotinic acid (melting point 30
0°C or higher) 35y was obtained, which was heated in 8°C sulfuric acid to decarboxylate it to give 5-nitro-6-(4-pyridyl)-1.
, 2-dihydro-2-oxopyridine (melting point 239-2
40°C) to obtain 18fi'. It is then chlorinated by heating with phosphorus oxychloride to form 2-chloro-5-nitro-6-(4
-pyridyl)pyridine (melting point 137-”138°C) 18
Obtain ゜87. This was reacted with ammonia in ethanol to obtain 15.3y of 2-amino-5-nitro-6-(4-pyridyl)pyridine (ta point 300°C or higher). 15.3 g of this amine compound was acetylated with acetic anhydride to give 2-acetylamino-5-nitro-6-(4-pyridyl)pyridine (tΔI point 285-289°C) 16.
Get 9 points. The 2-acetylamino compound is catalytically reduced in a hydrogen stream using Raney nickel as a catalyst, and the catalyst is separated. Without taking out the reaction product, 42% tetrafluoroboric acid and sodium hyponitrite were reacted to form a diazonium salt, and then heated in xylene to perform a diman reaction to form 6-acetylamino-3. -Fluoro-2-(4-
pyridyl) pyridine (melting point 254-256℃) 9.1y
get.

The substance was hydrolyzed with hydrochloric acid to produce 6-amino-3-fluoro-2-(4-pyridyl)pyridine (melting point 189-190).
°C) and condensed ethoxymethylene malonic acid diethyl ester to this 7.3y to obtain N-1:3-fluoro-2-(4-pyridyl)-6-pyridylcoamino methylene malonic acid diethyl ester (melting point 140 -141°'
C) Obtain 11.517. This was then ring-closed by heating to give 6-fluoro-7-(4-pyridyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester (melting point 280-285'C) 7 ．．
2 f! get.

Example 1 (1) 6-fluoro-7-(4-pyridyl)-1,4-
A mixture of dihydro-4-oxy-1,8-naphthymedino-3-carboxylic acid ethyl ester 2.0y and dimethylformamide 2o,=f was stirred at 60 to 70°C, and 6
Add 255+++ g of sodium water and heat and stir for 30 minutes. After adding p-)luenesulfonic acid 2-fluoroethyl ester 14y and stirring with heating for 1.5 hours, dimethylformamide was distilled off. Water was added to the residue, extracted with chloroform, chloroform was distilled off under reduced pressure, and then chromatographed on a silica gel column (eluent: chloroform) to obtain 6-fluoro-1-(2-fluoroethyl)- 7-(4-pyridyl)-1,4-dihydro-
4-oxy-1°8-naphthyridine-3-carboxylic acid ethyl ester 115y is obtained. Melting point 200-201℃:
Recrystallization solvent, acetic acid ethyl ester.

(2) 6-fluoro-1-(2-fluoroethyl)-7
-(4-pyridyl)-1,4-dihydro-4-oxo-
A mixture of i,s-naphthyridine-3-carboxylic acid ethyl ester 11y and a 2°-IN aqueous solution of sodium hydroxide is heated and stirred at 75-80'C for 20 minutes.

After cooling, acetic acid was added to adjust the pH to 6.5 to 7.0.
The precipitated crystals were taken as M'' and washed with water. Recrystallized from ethanol to give 6-fluoro-1-(2-fluoroethyl).
370 ml of -7-(4-pyridyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid are obtained. Melting point 270-272°CO Reference Example 2 5-nitro-6-(4-pyridyl)-1,2-dihydro-2-oxonicotinic acid 20f! 20 nM of phosphorus oxychloride is added to the mixture, and the mixture is heated under reflux for 2 hours while stirring.

After phosphorus oxychloride was distilled off under reduced pressure, chloroform and ethanol were added, and the mixture was further heated under reflux for 1 hour.

The solvent was distilled off under reduced pressure, ice water was added to the residue, the pH was adjusted to 0 with an aqueous solution of 10% sodium hydroxide, and the mixture was extracted with chloroform. Chloroform was distilled off, and the residue was 3-(N
-Cyclopropyl)aminopropionic acid ethyl ester (2.4 gI) and ethanol were added, and the mixture was heated under reflux for 1.5 hours while stirring. After the solvent was distilled off, it was treated with a 7 silica gel column (eluent: chloroform) to obtain 2-[N-
2.02% of cyclopropyl-N-(2-ethoxycarbonylethyl)amine]-5-nitro-6-(4-HJ yl)nicotinic acid ethyl ester is obtained. Melting point 106-
107'C: Recrystallization solvent, in7°robyl ether.

Reference example 3 2-[N-cyclopropyl-N-(2-ethoxycarbonylethyl)amine2-5-nitro6-(4-hy+)
sil) Nicotinic acid ethyl ester 2.259. ! : A mixture of 230 rne of anhydrous t-butyl alcohol was stirred at room temperature, and 920 rng of potassium t-butyralate was slowly added thereto. After 10 minutes, add acetic acid to pH 6.5-7.
, 0, and the precipitated crystals are collected. Wash with water and alcohol to remove 1-cyclonitrol-6-nitro-7.
-(4-pyridyl)-1,2,3,4-tetrahydro-
4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester 162 is obtained. Melting point 195-198°C: recrystallization solvent, ethanol.

Reference example 4 1-ncroglovir-6-nitro-7-(4-pyridyl)-1,'2,3.4-tetrahydro-4-oxo-1
,8-naphthyridine-3-carboxylic acid ethyl ester 3
．． A mixture of 5y, dioxane 1801ne, and chloranil 342 is heated to reflux for 15 minutes while stirring.

The solvent is distilled off under reduced pressure, and the residue is added with an aqueous solution of IJ (IN hydroxide) and extracted with chloroform. Chloroform was distilled off under reduced pressure to obtain 1-cyclopropyl-6-nitro-7-(4-pyridyl)-1,! -dihydro 4-oxo 1,8-naphthyridine-3-carboxylic acid ethyl ester 3. Get Oy. Melting point 200-201°C: recrystallization solvent, acetic acid ethyl ester.

Reference Example 5 1-Cyclopropyl-6-nitro-7-(4-pyridyl)'-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester 1.85 g1.
A mixture of 40 me of acetic acid and 100 me of palladium on carbon is catalytically reduced under a hydrogen stream. When the theoretical amount of hydrogen has been absorbed, the precipitated crystals are collected and 25 rnl of 42-tetrafluoroboric acid is added thereto to remove insoluble materials. This solution is cooled with water, and a solution of 500 mg of sodium nitrite in water (3me) is added thereto at 0-3°C and stirred for 10 minutes.

Add 25me of cold ethanol and 9'Ome of cold ether and take 1 portion of the precipitated crystals. After thoroughly drying, toluene 70
suspend in ME and heat and stir at 100-110°C for 1 hour.

Toluene was distilled off under reduced pressure, IN aqueous sodium hydroxide solution was added to the residue, and the mixture was extracted with chloroform. Chloroform was distilled off, ethyl acetate was added to the residue, one crystal was collected,
1-cycloprobyl-6-fluoro-7-(4-pyridyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester 700~ is obtained. Melting point 209-211°C: recrystallization solvent, acetic acid ethyl ester.

Example 2 1-Nclobrovir-6-fluoro7-(4-pyridyl)-1,4-dihydro-4-oxo-1°8-naphthyridine-3-carboxylic acid ethyl ester acid was added to pH
6 to 7, and then extracted with chloroform. Chloroform was distilled off under reduced pressure to give 350 to 1-cycloprobyl-6-fluoro-7-(4-pyridyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid.
get. Melting point 300'C or higher: Recrystallization solvent, chloroform-ethanol 0 Patent applicant Dainippon Pharmaceutical Co., Ltd. Agent Patent attorney Yu Tsuboi 4th Department

Claims (1)

[Claims] In the formula C, R+Id means a fluoroethyl group or a cyclopropyl group. ) Pyridylnaphthyridine derivatives and salts thereof.