JPH0516429B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention discloses novel 1, which exhibits extremely excellent antibacterial activity.
This invention relates to 8-naphthyridine derivatives, esters thereof and salts thereof. More specifically, the compound of the present invention has the following general formula: (In _the formula _, means an atom or lower alkyl group, R ₃ , R ₄
and R ₅ are the same or different and mean a hydrogen atom or a halogen atom, and n means an integer 4. However, when R ₁ is an amino group, mono- or di-lower alkylamino group, R ₂ is a lower alkyl group. ) 1,8-naphthyridine derivatives, esters thereof and salts thereof. In this specification, a halogen atom and fluorine, chlorine, bromine or iodine are meant, and a lower alkyl group means an alkyl group having 1 to 3 carbon atoms. Further, the cyclic amine represented by the formula [] below means azetidine, pyrrolidine or piperidine. 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,
Salts with inorganic acids such as phosphoric acid, or metal salts of compounds such as sodium, potassium, zinc, silver, etc.
Alternatively, it is a salt with an organic base. 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. Since the compound of the present invention has an asymmetric carbon atom in the substituent at the 7-position, it can exist as optical isomers. Therefore, these optical isomers are included in the compounds of the present invention. Furthermore, certain compounds of the invention may have two asymmetric carbon atoms in their 7-position substituent and therefore may exist as different stereoisomers (cis, trans). . These stereoisomers are also included in the compounds of the present invention. The method for producing the compound of the present invention will be explained below. The compound of the present invention has the following general formula: (In the formula, Z means a functional group that can be substituted with the cyclic amine derivative described below, and X, R ₃ , R ₄ and R ₅ are the same as above.) or an ester thereof (preferably a lower alkyl ester) and the following general formula (In the formula, R ₁ , R ₂ and n are the same as above.) It can be produced by reacting a cyclic amine derivative represented by the following formula and isolating the product by a conventional method. The reactive functional group represented by Z in formula [] is
Examples include halogen atom, arylsulfonyl, arylsulfinyl, lower alkylsulfonyl, lower alkoxy, lower alkylthio, lower alkylsulfinyl, arylsulfonyloxy, and lower alkylsulfonyloxy. In this reaction, the starting compound [ ] or its ester and [ 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 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. ] 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 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 Examples 1 and 2 or a method analogous thereto. Raw material compound [] is Reference Example 3
It can be produced by the method described in and 4 or a method analogous thereto. When the compound of the present invention obtained by the above method is an ester, it 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, 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, by the above method using a compound [] having a cis or trans configuration,
It is also possible to produce compounds of the 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 [] exhibits extremely excellent antibacterial activity and is therefore valuable as an antibacterial agent. The compound [ ] or its salt 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, and the like. 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 []. It is a useful compound from a pharmaceutical standpoint because it can exert its effects. Next, data regarding the antibacterial activity of the compounds of the present invention are listed below.

【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 used as a bulk powder, it is usually administered in a prepared form together with a pharmaceutical carrier. Specific examples thereof include tablets, capsules, granules, fine granules, powders, syrups, injections, and the like. 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-chloro-6-fluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-
1,8-Naphthyridine-3-carboxylic acid ethyl ester (1) 60 g of 2,6-dichloro-5-fluoronicotinonitrile, a known compound, is heated in concentrated sulfuric acid at 65-75°C for 1 hour. Add water and further increase to 100-110℃
Heating for 2 hours gives 59.8 g of 2,6-dichloro-5-fluoronicotinic acid. mp155−156
℃. (2) Treat 45.2g of this compound with thionyl chloride,
47.5 g of 2,6-dichloro-5-fluoronicotinic acid chloride are obtained as an oil. (3) 47.5 g of this compound is reacted with diethyl ethoxymagnesium malonate in anhydrous ether to obtain diethyl 2,6-dichloro-5-fluoronicotinoylmalonate as an oil. Add water and a catalytic amount of p-toluenesulfonic acid to this and heat at 140°C for 2 hours to obtain 46 g of ethyl 2,6-dichloro-5-fluoronicotinoyl acetate.
get. mp69−70℃. (4) Treat 40 g of this compound with ethyl orthoformate and acetic anhydride to obtain 2-(2,6-dichloro-5-
42 g of ethyl fluoronicotinoyl)-3-ethoxyacrylate are obtained as an oil. (5) Dissolve 6.0 g of this compound in ethanol, react with 4-fluoroaniline at room temperature, and react with 2-fluoroaniline.
7.0 g of ethyl (2,6-dichloro-5-fluoronicotinoyl)-3-(4-fluorophenylamino)acrylate is obtained. mp111−112℃. (6) 6.0 g of this compound was reacted with potassium t-butoxide in anhydrous dioxane to produce 7-chloro-
6-Fluoro-1-(4-fluorophenyl)-
5.1 g of ethyl 1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate are obtained.
mp227−228℃. Reference Example 2 According to the method of Reference Example 1, the following compound is obtained. (1) Ethyl 7-chloro-6-fluoro-1-(2-fluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate, mp212-213°C. (2) 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4
-Ethyl-oxo-1,8-naphthyridine-3-carboxylate, mp212-213°C. (3) 7-chloro-1-(3,4-difluorophenyl)-6-fluoro-1,4-dihydro-4
-Ethyl-oxo-1,8-naphthyridine-3-carboxylate, mp246-247°C. (4) 7-chloro-1-(4-chlorophenyl)-6
-Fluoro-1,4-dihydro-4-oxo-
Ethyl 1,8-naphthyridine-3-carboxylate, mp 197-198°C. (5) 7-chloro-6-fluoro-1-phenyl-
Ethyl 1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate, mp221-
222℃. (6) Ethyl 7-chloro-6-fluoro-1-(3-fluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate, mp242-243°C. Reference example 3 3-acetylamino-4-methylpyrrolidine-
By reacting 3-amino-1-benzyl-4-methylpyrrolidine (see JP-A-55-22699) with acetic anhydride, 3-acetylamino-1-benzyl-4-
Methylpyrrolidine is obtained as an oil. IR spectrum: 3300, 1650cm ^-1 . Catalytic reduction of this compound in the presence of 5% palladium on carbon gives 3-acetylamino-4-methylpyrrolidine as an oil. In addition, the 3-acetylamino-1-benzyl-4-methylpyrrolidine obtained above was separated and purified by silica gel column chromatography to obtain trans-3-acetylamino-1-benzyl-4-methylpyrrolidine (mp62-63 °C) and cis-3-acetylamino-1-benzyl-4-methylpyrrolidine (mp96-97 °C). These compounds were catalytically reduced in the presence of 5% palladium-carbon to give the corresponding trans-3-acetylamino-4-methylpyrrolidine and cis-3-acetylamino-4-methylpyrrolidine as oils. get as. Reference example 4 3-acetylamino-3-methylpyrrolidine 1
-benzyl-3-pyrrolidone (J.Org.Chem.,
30, 740 (1965)) with methylmagnesium bromide to form 1-benzyl-3-hydroxy-
3-Methylpyrrolidine is obtained as an oil. b.
p.106℃/0.5mmHg. This compound was treated with a mixed solution of acetonitrile and concentrated sulfuric acid under ice cooling, and
-acetylamino-1-benzyl-3-methylpyrrolidine is obtained. mp105−106℃. This is catalytically reduced in the presence of 5% palladium on carbon to give 3-acetylamino-3-methylpyrrolidine as an oil. Example 1 7-(3-amino-3-methyl-1-pyrrolidinyl)-6-fluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-1,8-
Naphthyridine-3-carboxylic acid (1) ethyl 7-chloro-6-fluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate 900 mg, A mixture of 630 mg of 3-acetylamino-3-methylpyrrolidine, 1 ml of triethylamino, and 15 ml of acetonitrile is stirred at room temperature for 1 hour. The reaction solution is concentrated to dryness under reduced pressure, and the residue is separated and purified by silica gel column chromatography. The resulting crude crystals were recrystallized from ethyl acetate-diisopropyl ether to give 7-(3-acetylamino-3-methyl-1-pyrrolidinyl).
-6-fluoro-1-(4-fluorophenyl)
1.05 g of ethyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate is obtained. mp141−143℃. (2) Dissolve 610 mg of the above ester in 6 ml of 20% hydrochloric acid,
Heat to reflux for 4 hours. After the activated carbon treatment, add 20 ml of water to the reaction solution. Filter the precipitated crystals,
After washing with water and drying, 7-(3-amino-3-methyl-1-pyrrolidinyl)-6-fluoro-1-
(4-fluorophenyl)-1,4-dihydro-
420 mg of 4-oxo-1,8-naphthyridine-3-carboxylic hydrochloride are obtained. mp300℃ or more. (3) Dissolve 370 mg of the above hydrochloride in a 1N aqueous sodium hydroxide solution and neutralize with a 10% acetic acid aqueous solution. The precipitated crystals were collected by filtration, washed with water and dried to give 7-(3
-amino-3-methyl-1-pyrrolidinyl)-
6-Fluoro-1-(4-fluorophenyl)-
230 mg of 1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid are obtained. m.
p.273−277℃ (decomposition). The compound of Example 2 is obtained in the same manner as in Example 1. Example 2 (1) 7-(3-acetylamino-3-methyl-1
-pyrrolidinyl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-
Ethyl 4-oxo-1,8-naphthyridine-3-carboxylate, mp239-241℃ (2) 7-(3-amino-3-methyl-1-pyrrolidinyl)-1-(2,4-difluorophenyl)
-6-Fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid methanesulfonate, mp 300°C or higher. Example 3 7-(3-amino-4-methyl-1-pyrrolidinyl)-6-fluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-1,8-
Naphthyridine-3-carboxylic acid hydrochloride (1) Ethyl 7-chloro-6-fluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate 1.28 g and 800 mg of 3-acetylamino-4-methylpyrrolidine were reacted in the same manner as in Example 1-(1) to obtain 7-(3-acetylamino-4-methyl-1-pyrrolidinyl)-6-fluoro- 1
1.05 g of ethyl -(4-fluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate is obtained. Chloroform-
Recrystallize from ethyl acetate. mp251-252℃ This compound is a stereoisomer (cis type,
trans type). (2) 850 mg of the above ester was reacted in the same manner as in Example 1-(2), and 7-(3-amino-4-methyl-1-pyrrolidinyl)-6-fluoro-1-(4
-fluorophenyl)-1,4-dihydro-4
720 mg of -oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride are obtained. mp300℃ or higher (decomposition). The compound of Example 4 is obtained in the same manner as in Example 3. Example 4 (1) 7-(trans-3-acetylamino-4-
Methyl-1-pyrrolidinyl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-
Ethyl dihydro-4-oxo-1,8-naphthyridine-3-carboxylate, mp246-248℃ (2) 7-(trans-3-amino-4-methyl-
1-pyrrolidinyl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic hydrochloride, mp232-238°C Example 5 7-(3-aminomethyl-1-pyrrolidinyl)-
6-Fluoro-1-(4-fluorophenyl)-
1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic hydrochloride (1) 7-chloro-6-fluoro-1-(4-fluorophenyl)-1,4-dihydro-4 A mixture of 800 mg of ethyl -oxo-1,8-naphthyridine-3-carboxylate, 470 mg of 3-acetylaminomethylpyrrolidine, 370 mg of sodium bicarbonate, and 25 ml of acetonitrile is heated under reflux for 1 hour.
After the reaction solution was concentrated to dryness under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. Separate the organic layer
Dry after washing with water. Chloroform is distilled off, and the residue is separated and purified by silica gel column chromatography. The resulting crude crystals were recrystallized from ethyl acetate to give 7-(3-acetylaminomethyl-1
500 mg of ethyl pyrrolidinyl)-6-fluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate are obtained. mp219−220℃. (2) Dissolve 400 mg of the above ester in 6 ml of 20% hydrochloric acid,
Heat to reflux for 4 hours. After concentrating the reaction solution to dryness under reduced pressure, ethanol was added and the crystals were collected by filtration.
7-(3-aminomethyl-1-pyrrolidinyl)-
6-Fluoro-1-(4-fluorophenyl)-
300 mg of 1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic hydrochloride are obtained.
Recrystallize from ethanol. mp223−225℃. Example 6 7-(3-aminomethyl-1-pyrrolidinyl)-
1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic hydrochloride (1) 7-chloro-1-(2, 4-difluorophenyl)-6-fluoro-1,4-dihydro-4
1.2 g of ethyl -oxo-1,8-naphthyridine-3-carboxylate and 660 mg of 3-acetylaminomethylpyrrolidine were reacted in the same manner as in Example 5-(1).
-pyrrolidinyl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-
800 mg of ethyl 4-oxo-1,8-naphthyridine-3-carboxylate are obtained. Recrystallize from ethanol. mp130−131℃. (2) 400 mg of the above ester was reacted in the same manner as in Example 5-(2), and 7-(3-aminomethyl-1-pyrrolidinyl)-1-(2,4-difluorophenyl)-6-fluoro- 1,4-dihydro-4-
300 mg of oxo-1,8-naphthyridine-3-carboxylic hydrochloride are obtained. Recrystallize from water-ethanol. mp297−300℃ or higher. The compound of Example 7 is obtained in the same manner as in Example 6. Example 7 (1) 7-(3-acetylaminomethyl-1-pyrrolidinyl)-1-(3,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-
Ethyl oxo-1,8-naphthyridine-3-carboxylate, mp 131-132°C. (2) 7-(3-aminomethyl-1-pyrrolidinyl)
-1-(3,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,
8-naphthyridine-3-carboxylic hydrochloride,
mp280−283℃.

Claims (1)

[Claims] 1. General formula (In _the formula _, means an atom or lower alkyl group, R ₃ , R ₄
and R ₅ are the same or different and mean a hydrogen atom or a halogen atom, and n means an integer 4. However, when R ₁ is an amino group, mono- or di-lower alkylamino group, R ₂ is a lower alkyl group. ) 1,8-naphthyridine derivatives, esters thereof and salts thereof.