JPH0373549B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention discloses novel 1, which exhibits extremely excellent antibacterial activity.
8-Naphthyridine derivatives. More specifically, the compound of the present invention has the following general formula: (R in the formula means a hydrogen atom or a lower alkyl group.) A 1,8-naphthyridine derivative, an ester thereof, or a salt thereof. Among the compounds of the present invention, preferred compounds are those in which R in formula [] is a hydrogen atom or a methyl group, and particularly preferred are compounds in which R is a hydrogen atom. Salts of the compounds of the present invention include acetic acid, lactic acid, succinic acid, methanesulfonic acid, maleic acid, malonic acid,
Salts with organic acids such as gluconic acid, amino acids such as aspartic acid and glutamic acid, or inorganic acids such as hydrochloric acid and phosphoric acid, or metal salts such as sodium, potassium, zinc and silver of the compound of formula [], or organic bases. It is salt. The ester of the compound of formula [] is a lower alkyl ester such as methyl ester or ethyl ester of the compound [], or a known ester that is easily eliminated by hydrolysis or in vivo to form the compound []. Esters such as pivaloyloxymethyl ester, ethoxycarbonyloxyethyl ester, 5-indanyl ester, phthalidyl ester, etc. are meant. Compounds of the invention may also exist as hydrates. Therefore, such forms are naturally included in the compounds of the present invention. Next, the method for producing the compound of the present invention will be explained below. (1) The compound of the present invention has the following general formula: (In the formula, X means a functional group that can be substituted with the piperazine [ ] described below.) A carboxylic acid represented by or an ester thereof (preferably a lower alkyl ester) and the following general formula (In the formula, R is the same as above.) It can be produced by reacting piperazines represented by the following and isolating the product by a conventional method. The reactive functional group represented by X in formula [] is
Arylsulfonyl, lower alkylsulfonyl,
Examples include halogen atom, lower alkoxy, lower alkylthio, lower alkylsulfinyl, arylsulfonyloxy, and lower alkylsulfonyloxy. In this reaction, the raw material compound [] or its ester and [] are mixed in an inert solvent such as ethanol, acetonitrile, dioxane, dimethylformamide, toluene, or xylene at 20 to 180°C, preferably 50 to 150°C. 120 minutes, usually
This can be carried out by mixing and stirring for 20 to 60 minutes.
The amount of the starting compound [] to be used relative to the starting compound [] or its ester is equivalent to or slightly in excess. Depending on the type of functional group of Compound [] may be used in excess to serve as an acid acceptor. Furthermore, when piperazine is used as a starting compound, one of its N atoms may be protected with acetyl, benzyloxycarbonyl, etc., and the protecting group may be removed by a conventional method after the reaction is completed. The raw material compound [] or its ester can be produced by the method described in Reference Example 1 or a method analogous thereto. (2) The ester form of the compound [] of the present invention can also be expressed by the following general formula: (In the formula, Y is the same or different and means a lower alkyl group, and R is the same as above.) The pyridine derivative represented by formula (In the formula, R and Y are the same as above.) It can be produced by producing a compound represented by the following and then dehydrogenating this compound []. When producing the compound [], the starting compound [] is subjected to a heating reaction in a solvent in the presence of a base catalyst such as sodium metal, sodium hydride, sodium ethylate, potassium t-butylate,
Compound [ ] is obtained by intramolecular ring closure. At this time, the reaction can be more effectively achieved by adding a catalytic amount of lower alcohols such as methanol, ethanol, and t-butanol. benzene,
Aromatic hydrocarbons such as toluene, dioxane, tetrahydrofuran, 1,2-dimethoxyethane,
Ethers such as 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. Note that the compound [ ] is also represented by the following general formula. (R and Y in the formula are the same as above.) To dehydrogenate compound [], compound []
2,3-dichloro-5,6-dicyano-1,4-benzoquinone ( DDQ), tetrachloro-1,4-benzoquinone (chloranil), tetracyanoethylene, palladium-on-carbon, N-bromosuccinimide (NBS), manganese dioxide or gelene dioxide at room temperature or at room temperature. The reaction may be carried out by heating for a short time near the boiling point of the solvent, or the compound [] may be directly heated above its melting point, or benzene, toluene,
Simply heating in an inert solvent such as dioxane, ethanol, n-hexane, carbon tetrachloride, dimethylformamide, or diphenyl ether is sufficient. The raw material compound [] used in this reaction is used in a form in which the N atom at position 4 of the piperazine moiety is protected with acetyl, benzyloxycarbonyl, etc., as in the case of method (1) above, and after the completion of this reaction, The protecting group may be removed by conventional methods. The raw material compound [] can be produced by the method described in Reference Example 2 or a method similar thereto. Incidentally, the compound (ester form) obtained by the above method can be converted into a compound of formula [] by hydrolyzing the ester moiety by a conventional method. Furthermore, if necessary, the compound of formula [] can be esterified by a conventional method to lead to an ester of the compound of formula []. The compound of the present invention produced in this manner is isolated and purified according to conventional methods. Depending on the isolation and purification conditions, the compounds of the present invention can be obtained in the form of salts, free carboxylic acids, or free amino acids, but these can be mutually converted depending on the purpose to produce the compound of the present invention in the desired form. Ru. The compound thus obtained, its ester, and its salt are all new compounds. In particular, compounds [], especially compounds in which R is a hydrogen atom, exhibit extremely excellent antibacterial activity even in living organisms and are weakly toxic, so they are valuable as antibacterial agents. The compound [] can be used not only as a medicine for humans and animals, but also as a medicine for fish diseases, an agricultural chemical, a food preservative, etc. Also,
Of course, the ester form of compound [] is valuable as a raw material for the synthesis of compound [], but in addition, this compound can easily be converted into compound [] in vivo.
When converted into , it can exhibit the same effects as compound [ ], so it is a useful compound from a pharmaceutical standpoint. Next, regarding the antibacterial activity of the main compounds of the present invention,
The following data is listed.

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【table】

【table】

[Table] When the compound of the present invention is used as an antibacterial agent in humans, the dosage varies depending on age, body weight, symptoms, administration route, number of administrations, etc.
It is recommended to administer 5g in one or several divided doses. The route of administration may be either oral or parenteral. Although the compound of the present invention may be administered as a bulk powder, it is usually administered in a prepared form together with a pharmaceutical carrier. Specific examples include tablets, capsules, granules,
Examples include fine granules, powders, syrups, and injections. These formulations are prepared according to conventional methods. Oral preparation carriers include starch, mannitrate,
Substances commonly used in the pharmaceutical field, such as crystalline cellulose and CMC Na, and which do not react with the compound of the present invention are used. Examples of the carrier for injection include carriers commonly used in the field of injections such as water, physiological saline, glycol solution, and infusion preparations. Next, the method for synthesizing the compound of the present invention will be explained in more detail by giving examples and reference examples. Example 1 1-Cyclopropyl-6-fluoro-7-(1
-Piperazinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid synthesis method (1) 1-cyclopropyl-7-(p-tolylsulfonyl)-6-fluoro-1, A mixture of 860 mg of ethyl 4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate, 516 mg of anhydrous piperazine and 30 ml of acetonitrile is heated under reflux for 1 hour. The solvent was distilled off under reduced pressure to obtain an oily product of 1-cyclopropyl-6-fluoro-
7-(1-piperazinyl)-1,4-dihydro-
Ethyl 4-oxo-1,8-naphthyridine-3-carboxylate was dissolved in 10 ml of 20% hydrochloric acid and heated under reflux for 3 hours. The solvent was distilled off under reduced pressure, ethanol was added to the residue, and the resulting crude crystals were recrystallized from a mixed solvent of water and ethanol to give 1-cyclopropyl-6-fluoro-7-(1-piperazinyl)-1, 4-dihydro-4-oxo-1,8
-naphthyridine-3-carboxylic acid hydrochloride 604
Get mg. mp280-294℃ (decomposition) (2) Ethyl 1-cyclopropyl-7-(p-tolylsulfonyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate 860 mg A mixture of 768 mg of 1-acetylpiperazine, 606 mg of triethylamine and 20 ml of dimethylformamide is heated and stirred at 120-130°C for 3 hours. The solvent was distilled off under reduced pressure, and the resulting crude crystals were recrystallized from a mixed solvent of ethanol and isopropyl ether.
683 mg of ethyl (4-acetyl-1-piperazinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate are obtained. 480mg of this stuff
and 8 ml of 20% hydrochloric acid was heated under reflux for 7 hours. The solvent was distilled off under reduced pressure, ethanol was added to the residue, and after cooling, the obtained crystals were recrystallized from a mixed solvent of water and ethanol to obtain 1-cyclopropyl-6.
-fluoro-7-(1-piperazinyl)-1,4
300 mg of hydrochloride of -dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid are obtained. m.
p.280-294℃ (decomposition) Example 2 1-cyclopropyl-7-(p-tolylsulfonyl)-6-fluoro-1,4-dihydro-4
A mixture of 860 mg of ethyl -oxo-1,8-naphthyridine-3-carboxylate, 600 mg of 1-methylpiperazine, and 30 ml of acetonitrile is heated under reflux for 1 hour. The solvent was distilled off under reduced pressure, and the resulting crude crystals were recrystallized from a mixed solvent of ethyl acetate and isopropyl ether to give 1-cyclopropyl-
7-(4-methyl-1-piperazinyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-
Ethyl naphthyridine-3-carboxylate is obtained. Suspend this in 10ml of 1N sodium hydroxide,
Heat for 1.5 hours on a boiling water bath. After cooling, neutralize with 10% acetic acid solution and extract with chloroform. After drying the chloroform layer over anhydrous sodium sulfate, the chloroform was distilled off, and the resulting crystals were recrystallized from a mixed solvent of chloroform and ethanol to give 1-cyclopropyl-7-(4-methyl-1-piperazinyl)-6-fluoro- 1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid
You get 519mg. mp246-248℃ Reference Example 1 7- used as the starting material in Examples 1 and 2
Synthesis method of ethyl (p-tolylsulfonyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (1) Known compound 2,6-dichloro -32.5g of 5-fluoronicotinonitrile, 400ml of ethanol
In the medium, 23.2 g of p-thiocresol and potassium salt of p-thiocresol obtained from 12.2 g of potassium hydroxide were reacted at room temperature, mp124-125℃.
2-chloro-6-(p-toluylthio)-5-
42.4 g of fluoronicotinonitrile are obtained. (2) Add 36g of this compound to dry dimethyl sulfoxide.
Dissolve in 180 ml, add 22.2 g of anhydrous potassium fluoride, and heat and stir at 130-135°C for 1 hour. The solvent was distilled off under reduced pressure, water was added to the residue, and the resulting crude crystals were recrystallized from ethanol.
30 g of 2,5-difluoro-6-(p-tolylthio)nicotinonitrile at 121°C are obtained. (3) 4 g of this compound was reacted with dry hydrogen chloride in absolute ethanol, and 2,5-difluoro-6-
3 g of ethyl (p-toluylthio)nicotinate is obtained. (4) Repeat the above reaction, dissolve 25 g of ethyl 2,5-difluoro-6-(p-tolylthio)nicotinate obtained in 400 ml of dimethylformamide, and add 25.4 g of ethyl N-cyclopropylaminopropionate and carbonate. 14g sodium hydrogen
and stir at 100 to 110°C for 10 hours.
The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with toluene. After washing the toluene layer with dilute hydrochloric acid and then with water, the toluene layer is dried over anhydrous sodium sulfate. Toluene was distilled off under reduced pressure to obtain 32 g of ethyl 6-(p-toluylthio)-2-[N-cyclopropyl-N-(2-ethoxycarbonylethyl)amino]-5-fluoronicotinate as a viscous liquid. . (5) Dissolve 3.2 g of this compound in 50 ml of dry toluene and add 0.32 g of 65% sodium hydride at room temperature.
g and stir the mixture for 10 minutes. Add a catalytic amount of absolute ethanol and stir for an additional 2 hours. After heating at 50 to 60°C for 1 hour, water is added and neutralized with a 10% acetic acid aqueous solution. The organic layer is separated, dried over anhydrous sodium sulfate, and then toluene is distilled off under reduced pressure. The resulting crude crystals were recrystallized from a mixed solvent of n-hexane and isopropyl ether to give 7-(p-toluylthio)-1-cyclopropyl-6-fluoro-1,
2,3,4-tetrahydro-4-oxo-1,
Ethyl 8-naphthyridine-3-carboxylate 2.5
get g. (6) Dissolve 2.0g of this compound in 50ml of toluene,
Add 1.25 g of 2,3-dichloro-5-,6-dicyano-p-benzoquinone to this, and
Then, heat and stir at 50-60°C for 1 hour.
After cooling, the precipitated crystals are collected by filtration, dissolved in chloroform, washed successively with 1N sodium hydroxide and water, and the chloroform layer is dried over anhydrous sodium sulfate. Chloroform was distilled off, and the resulting crude crystals were recrystallized from a mixed solvent of ethanol and isopropyl ether to give 7-(p
-toluylthio)-1-cyclopropyl-6-
Fluoro-1,4-dihydro-4-oxo-
Ethyl 1,8-naphthyridine-3-carboxylate
Obtain 1.7g. (7) Dissolve 1.59 g of this compound and 1.90 g of m-chloroperbenzoic acid (80%) in 50 ml of chloroform,
Heat at reflux for 30 minutes. After cooling, add 2N sodium carbonate,
Wash sequentially with water, and dry the chloroform layer with anhydrous sodium sulfate. Chloroform was distilled off, and the resulting crude crystals were recrystallized from ethyl acetate to give 7-(p-tolylsulfonyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4- at mp216-218°C. 1.55 g of ethyl oxo-1,8-naphthyridine-3-carboxylate are obtained. Example 3 6-(4-acetyl-1-piperazinyl)-2-
4.5 g of ethyl [N-cyclopropyl-N-(2-ethoxycarbonylethyl)amino]-5-fluoronicotinate was dissolved in 100 ml of dry toluene, and 406 mg of 65% sodium hydroxide was added at room temperature.
Stir the mixture for 10 minutes. Add a catalytic amount of absolute ethanol and stir for an additional 2 hours. After cooling, add water and neutralize with 10% acetic acid aqueous solution. The organic layer is dispersed and dried over anhydrous sodium sulfate. 7 obtained
Isolating ethyl -(4-acetyl-1-piperazinyl)-1-cyclopropyl-6-fluoro-1,2,3,4-tetrahydro-4-oxo-1,8-naphthyridine-3-carboxylate. 2,3-dichloro-5-,6-
Add 2.27 g of dicyano-p-benzoquinone, and heat and stir at room temperature for 2 hours, then at 50-60°C for 30 minutes. After cooling, the crystals that can be precipitated are collected by filtration, dissolved in chloroform, washed successively with 1N sodium hydroxide and water, and the chloroform layer is dried over anhydrous sodium sulfate. Chloroform was distilled off, and the resulting crude crystals were recrystallized from a mixed solvent of ethanol and isopropyl ether to give 7-(4-acetyl-1-piperazinyl)-1-cyclopropyl-
6-Fluoro-1,4-dihydro-4-oxo-
Ethyl 1,8-naphthyridine-3-carboxylate
Obtain 3.3g. This product was prepared in the same manner as in Example 1 (2).
% hydrochloric acid, isolated and purified to give 1-cyclopropyl-6-fluoro-7-(1-piperazinyl)-1,4-dihydro-4-oxo-1,8-
Naphthyridine-3-carboxylic hydrochloride is obtained. Reference example 2 6- described in Japanese Patent Application Publication No. 1983-72981
6.6 g of ethyl (4-acetyl-1-piperazinyl)-2-chloro-5-fluoronicotinate and 18.84 g of ethyl 2-cyclopropylaminopropionate.
The mixture is heated and stirred at 130-140°C for 4 hours. Dilute with 200 ml of toluene, wash sequentially with 5% hydrochloric acid and water, and separate the organic layer. After drying the organic layer over anhydrous sodium sulfate, the toluene was distilled off and the viscous liquid
-(4-acetyl-1-piperazinyl)-2-[N
4.05 g of ethyl -cyclopropyl-N-(2-ethoxycarbonylethyl)amino]-5-fluoronicotinate is obtained.

Claims (1)

[Claims] 1. General formula (R in the formula means a hydrogen atom or a lower alkyl group.) A 1,8-naphthyridine derivative, an ester thereof, or a salt thereof. 2 7-(1-piperazinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid or a salt thereof according to claim 1 .