JPH0568477B2 - - 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:

^A 1,8 ^- naphthyridine derivative or its It is an ester or its salt. 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, aspartic acid,
Salts with amino acids such as glutamic acid, or hydrochloric acid,
These are salts with inorganic acids such as phosphoric acid, metal salts such as sodium, potassium, zinc, silver, etc. of the compound of formula [], or salts with organic bases. The ester of the compound of formula [] is a lower alkyl ester such as methyl ester or ethyl ester of the compound [], or a compound [] that is easily eliminated by hydrolysis or in vivo.
Known esters such as pivaloyloxymethyl ester, ethoxycarbonyloxyethyl ester, aminoethyl esters such as dimethylaminoethyl ester and 1-piperidinylethyl ester, 5-indanyl ester, phthalidyl ester etc. Compounds of the invention may also exist as hydrates. Therefore, such forms are naturally included in the compounds of the present invention. The compound of the present invention has an asymmetric carbon atom on its pyrrolidine ring and therefore can exist as optical isomers. Therefore, these optical isomers are included in the compounds of the present invention. Furthermore, certain of the compounds of the present invention may have two asymmetric carbon atoms on their pyrrolidine ring, thus giving rise to different stereoisomers (cis, cis,
trans form). These stereoisomers are also included in the compounds of the present invention. Among the compounds of the present invention, preferred compounds are as follows. 7-(3-amino-4-methyl-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,
4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid 7-(3-amino-3-methyl-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,
4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid 7-(4-methyl-3-methylamino-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro- 4-oxo-1,8-naphthyridine-3-carboxylic acid, esters thereof and salts thereof. 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:

[Chemical formula] (In the formula, Z means a functional group that can be substituted with the pyrrolidine derivative described below.) A carboxylic acid or its ester (preferably a lower alkyl ester) represented by the following general formula

Reacting a pyrrolidine derivative represented by [formula, R ¹ and R ² are the same as above],
The product can be produced by isolating it by conventional methods. Examples of the reactive functional group represented by Z in formula [] include arylsulfonyl, lower alkylsulfonyl, halogen atom, lower alkoxy, lower alkylthio, lower alkylsulfinyl, arylsulfonyloxy, and lower alkylsulfonyloxy. This reaction consists of ethanol, acetonitrile, dioxane, dimethylformamide, toluene,
In an inert solvent such as xylene at 20-180°C, preferably 50-150°C, the raw material compound []
Or the ester and [] for 5 to 120 minutes,
This can usually be carried out by mixing and stirring for 20 to 60 minutes. Raw material compound [] of raw material compound []
Alternatively, the amount used is equivalent to or slightly in excess of the ester. Depending on the type of Z functional group in the raw material compound [] or its ester, an acid such as hydrochloric acid may be produced as a by-product as a result of the reaction, so in such cases it is common to use an acid acceptor.
The raw material compound [] may be used in excess to serve as an acid acceptor. In addition, the raw material compounds used in this reaction []
If possible, the R ¹ NH- portion may be used in a protected form with acetyl or the like, and after the reaction is completed, the protecting group may be removed by a conventional method. 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:

[Chemical formula] (In the formula, Y is the same or different and means a lower alkyl group, and R ¹ and R ² are the same as above.) A pyridine derivative represented by Heated in the presence of the following general formula

It can be produced by producing a compound represented by the following formula (wherein R ¹ , R ² and Y are the same as above) and then dehydrogenating this compound [ ]. When producing the compound [], the raw material compound [] is mixed with sodium metal, sodium hydride, sodium ethylate, potassium t, etc. in a solvent.
The compound [] is obtained by carrying out a heating reaction in the presence of a base catalyst such as -butyrate to cause 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. Aromatic hydrocarbons such as benzene, toluene, dioxane, tetrahydrofuran, 1,2
-dimethoxyethane, diethylene glycol
Ethers such as 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.

[Chemical formula] To dehydrogenate the compound [], add an inert solvent (e.g. benzene, toluene, xylene, ethyl acetate, dioxane, t
-butyl alcohol, dimethylformamide,
2,3-dichloro-5,
Common materials such as 6-dicyano-1,4-benzoquinone (DDQ), tetrachloro-1,4-benzoquinone (chloranil), tetracyanoethylene, palladium-carbon, N-bromosuccinimide (NBS), manganese dioxide or gelene dioxide The dehydrogenating agent may be reacted by heating for a short time at room temperature or near the boiling point of the solvent used, or the compound [] may be directly heated above its melting point, or the compound [] may be directly heated to a temperature above its melting point, or benzene, toluene, dioxane, ethanol, n- Simply heating in an inert solvent such as hexane, carbon tetrachloride, dimethylformamide, diphenyl ether, etc. is sufficient. As in the case of method (1) above, the raw material compound [] used in this reaction is used in a form where the R ¹ NH- part of its pyrrolidine moiety is protected with an acetyl group, etc., if possible, and after the completion of this reaction. , the protecting group may be removed by a conventional method. The raw material compound [] can be produced by the method described in Reference Example 2 or a method similar thereto. The compound (ester form) obtained by the above method [(1) or (2)] 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 way is
Isolated and purified according to conventional methods. Depending on the isolation and purification conditions, it can be obtained in the form of a salt, a free carboxylic acid, or a free amine, but these can be mutually converted depending on the purpose to produce the compound of the present invention in the desired form. Ru. Stereoisomers (cis, trans) of the compounds of the invention can be separated from each other by conventional methods, such as fractional crystallization, chromatographic separation, and the like. In addition, using a compound [] having a cis-type or trans-type configuration, the above method
According to (1), it is also possible to produce compounds of the present invention having cis and trans configurations, respectively. Optical isomers of the compounds of the present invention can be separated by applying known methods. The compound thus obtained, its ester, and its salt are all new compounds.
In particular, compound [] shows extremely excellent antibacterial activity and is valuable as an antibacterial agent.
The compound [ ] or its salt can be used not only as a human and veterinary medicine, but also as a fish disease medicine, agricultural chemicals,
It can also be used as a food preservative. In addition, the ester form of compound [] is of course valuable as a raw material for the synthesis of compound [], but if this compound is easily converted into compound [] in the living body, it is necessary to use an ester form equivalent to compound []. Because it can be effective,
It is also a useful compound from a pharmaceutical standpoint. Next, data regarding the antibacterial activity of the compound produced in Example 1 (3) among the compounds of the present invention is listed below.

【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, glucose solution, and infusion preparations. Next, the method for producing the compound of the present invention will be explained in more detail with reference to Examples and Reference Examples. Reference example 1 7-(p-tolylsulfonyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4
-Ethyl oxo-1,8-nafritidine-3-carboxylate (1) Known compound 32.5 g of 2,6-dichloro-5-fluoronicotinonitrile in 400 ml of ethanol,
23.2g of p-thiocresol and potassium hydroxide
The potassium salt of p-thiocresol obtained from 12.2 g is reacted at room temperature to obtain 42.4 g of 2-chloro-6-(p-toluylthio)-5-fluoronicotinonitrile with a mp of 124 to 125°C. (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 crystallized from ethanol.
30 g of 2,5-difluoro-6-(p-tolylthio)nicotinonitrile are obtained at ~121°C. (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 mixture of n-hexane and isopropyl ether to give 7-(p-toluylthio) at mp 124-125°C.
-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,
To this, 2,3-dichloro-5,6-dicyano-
Add 1.25 g of p-benzoquinone, and heat and stir at room temperature for 2 hours, then at 50-60°C for 1 hour. After cooling, the precipitated crystals were taken, dissolved in chloroform, washed sequentially with 1N sodium hydroxide and water,
Dry the chloroform layer with anhydrous sodium sulfate. Chloroform was distilled off, and the resulting crude crystals were recrystallized from a mixture of ethanol and isopropyl ether to give 7-(p-toluylthio)-1-cyclopropyl-6-fluoro-1,4-dihydro- 1.7 g of ethyl 4-oxo-1,8-naphthyridine-3-carboxylate is obtained. (7) Dissolve 1.59 g of this compound and 1.90 g of m-chloroperbenzoic acid (80%) in 50 ml of chloroform,
Heat to reflux for 30 minutes. After cooling, the mixture is washed successively with 2N sodium carbonate and water, and the chloroform layer is dried over 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. Oxo-1,8
-Ethyl naphthyridine-3-carboxylate 1.55g
get. Example 1 7-(3-amino-4-methyl-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-
1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic hydrochloride (1) 7-(p-tolylsulfonyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-
4.3 g of ethyl 4-oxo-1,8-naphthyridine-3-carboxylate, 3-acetylamino-4
- A mixture of 1.85 g of methylpyrrolidine (mixture of cis and trans isomers), 1.26 g of sodium bicarbonate, and 60 ml of acetonitrile is heated under reflux for 1 hour. Concentrate to dryness under reduced pressure, add water to the residue, and extract with chloroform. The organic layer is washed with dilute hydrochloric acid and water, and then dried over anhydrous sodium sulfate. The solvent is distilled off and the residue is subjected to silica gel chromatography to obtain the following three components. (a) Stereoisomer A 1.1g (b) A small amount of a mixture of stereoisomer A and stereoisomer B 2.9g (c) Stereoisomer B 0.1g Components (a) and (c) were each dissolved in ethanol. Recrystallized from isopropyl ether to give 7-(3-acetylamino-4-methyl-1-pyrrolidinyl)
-1-cyclopropyl-6-fluoro-1,4-
Dihydro-4-oxo-1,8-naphthyridine-
Stereoisomer A of ethyl 3-carboxylate (mp280-
282.5°C) and stereoisomer B (mp 209-210°C). (2) A mixture of 0.97 g of stereoisomer A of the above ester and 10 ml of 20% hydrochloric acid is heated under reflux for 3 hours. Concentrate to dryness under reduced pressure, add ethanol, and collect the precipitated crystals. Recrystallization from water-ethanol yields the carboxylic hydrochloride salt corresponding to stereoisomer A, namely 7-(3-amino-4-methyl-1-
pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,
8-Naphthyridine-3-carboxylic acid hydrochloride
Obtain 0.57g. mp234−238℃ (decomposition). (3) 2.9 g of component (B) obtained in (1) was treated in the same manner as in (2), and 7-(3-amino-4-methyl-1-pyrrolidinyl)-1-cyclopropyl-6- Fluoro-1,4-dihydro-4-oxo-1,8
-naphthyridine-3-carboxylic acid hydrochloride 2.02
get g. mp270−278℃ (decomposed). This substance is
It was confirmed by high performance liquid chromatography analysis that it contained 6% and 94% of carboxylic hydrochloride salts corresponding to stereoisomers A and B, respectively. Example 2 The following compound was obtained by the same reaction treatment as in Example 1. 2(a) 7-(3-amino-3-methyl-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-
Naphthyridine-3-carboxylic acid; (hydrochloride,
5/4 hydrate) mp285-287°C (decomposition). 2(b) 7-(4-amino-3-methylamino-1
-pyrrolidinyl)-1-cyclopropyl-6-
Fluoro-1,4-dihydro-4-oxo-
1,8-naphthyridine-3-carboxylic acid; mixture of isomers A and B (hydrochloride, 5/4 hydrate)
mp258−277℃ (decomposition). Reference example 2 6-(3-acetylamino-4-methyl-1-
pyrrolidinyl)-2-[N-cyclopropyl-N
-(2-ethoxycarbonylethyl)amino]-
Ethyl 5-fluoronicotinate 6-(p-toluylthio) obtained in Reference Example 1(4)
-2-[N-cyclopropyl-N-(2-ethoxycarbonylethyl)amino]-5-ethyl fluoronicotinate is oxidized using m-chloroperbenzoic acid to obtain 6-(p-tolylsulfonyl) −
6-(3-acetylamino- 4-methyl-1-pyrrolidinyl)
Ethyl -2-[N-cyclopropyl-N-(2-ethoxycarbonylethyl)amino]-5-fluoronicotinate is obtained. Example 3 7-(3-amino-4-methyl-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-
1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic hydrochloride 6-(3-acetylamino-4-methyl-1-
pyrrolidinyl)-2-[N-cyclopropyl-N-
Reference Example 1 Using ethyl (2-ethoxycarbonylethylamino)-5-fluoronicotinate as a raw material
By reacting according to the method described in 7.
Ethyl -(3-acetylamino-4-methyl-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate is obtained. This was hydrolyzed in the same manner as in Example 1 (2) and (3), and 7-
(3-amino-4-methyl-1-pyrrolidinyl)-
1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3
- Obtain the carboxylic hydrochloride. Example 4 7-(3-amino-4-methyl-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-
1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester 7-(3-amino-4-methyl-1-pyrrolidinyl)-1-cyclo obtained in Example 1(3) Propyl
6-Fluoro-1,4-dihydro-4-oxo-
1,8-naphthyridine-3-carboxylic hydrochloride
Suspend 6.6 g in absolute ethanol, add 7 g of concentrated sulfuric acid, and heat under reflux for 1 hour while stirring. After distilling off about 20 ml of ethanol, add 20 ml of absolute ethanol and heat to reflux again. After repeating this operation three times, the mixture was heated under reflux for 15 hours while stirring. Ethanol is distilled off under reduced pressure, and chloroform and 20% aqueous sodium hydroxide solution are added to the residue to adjust the pH to 9 or higher. The organic layer was separated, chloroform was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate to give 7-
(3-amino-4-methyl-1-pyrrolidinyl)-
1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3
-4.3 g of carboxylic acid ethyl ester are obtained. m.
p.148−150.5℃.

Claims (1)

[Claims] 1 Represented by the general formula: (wherein, R ¹ means a hydrogen atom or a lower alkyl group, and R ² means a lower alkyl group bonded to the 3- or 4-position) A 1,8-naphthyridine derivative, an ester thereof, or a salt thereof. 2 7-(3-amino-4-methyl-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-
The compound according to claim 1, which is 1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, or its ester or salt thereof.