JPS61152682A - Pyridonecarboxylic acid derivative, its ester and salt - Google Patents

Abstract

NEW MATERIAL:A compound of formula I [X is N, C-H, C-F; Y is halogen; R1 is heterocyclic group which may be substituted; R2 is formulas II or III (R3, R4 are H, lower alkyl; R5 is H, hydroxy, amino; n is 3-5)]. EXAMPLE:7-(3-Amino-1-pyrrolidinyl)-6-fluoro-1-(2-thienyl)-1,4--dihydro -4-oxo-1,8-na pthtylidine-3-carboxylic acid. USE:Antibacterial. It can be used as a medicine for fish diseases, an agricultural chemical or a food preservative. PREPARATION:The reaction of a carboxylic acid of formula IV (Z is a functional group which may be substituted with a cyclic amine derivative) or its ester with a cyclic amine derivative of the formula: R2-H is carried out in an inert solvent such as ethanol at 20-150 deg.C to give the compound of formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel pyrido/carbo7alls conductors, esters thereof, and salts thereof, which exhibit excellent antibacterial activity.

More specifically, the compound of the present invention has the following general formula (wherein X
means a nitrogen atom, C-H or C-F, Y means a halogen atom, RI means a polycyclic group which may have a substituent, Rz is represented by the following formula group, where R3 and R4 mean a hydrogen atom or a lower alkyl group, and RS is a hydrogen atom, a hydroxy group,
It means an amine 7 group, a mono- or di-lower alkyl amine 7 group, an amino-lower alkyl group, or a mono- or di-lower alkyl amine/lower alkyl group, and n means an integer of 3, 4 or 5. ) pyrido/carboxylic acid derivatives, their esters, and their salts.

In this specification, halogen atom means fluorine.

It means chlorine, bromine or iodine, and lower alkyl means an alkyl group having 1 to 3 carbon atoms.

Further, examples of the compound ring include pyrrole, furano, thiophene, thiazole, inthiazole, oxazole, inoxazole, pyrazole, imidazole, pyridino, and pyridazine.

Examples include pyrazino and pyrimidine.

Salts of the compounds of the present invention include acetic acid, lactic acid, and succinic acid.

Salts with organic acids such as meta-7 sulfo/acid, maleic acid, malonic acid, gluconic acid, etc., salts with amino acids such as asparagino a, glutamic acid, or salts with non-a acids such as hydrochloric acid, phosphoric acid, or the formula [ metal salts such as sodium, potassium, zinc, aI, etc., or salts with organic bases.

The ester of the compound of formula [■] refers to a lower alkyl ester such as methyl ester or ethyl ester of compound [I], or an ester that is easily eliminated by hydrolysis or in vivo to become compound [1]. Known esters such as pivaloyloxymethyl ester, ethoxycarbonyloxyethyl ester, aminoethyl esters such as dimethylaminoethyl ester and 1-piperidinylethyl ester, 5-i/danyl ester, phthalidyl ester, etc. means.

Compounds of the invention may also exist as hydrates. Therefore, such forms are naturally included in the compounds of the present invention.

The compounds of the present invention include those having an asymmetric carbon atom in the substituent R2 at the 7-position, and these may exist as optically active forms. Therefore, these optically active forms may be included in the compounds of the present invention. Included.

Furthermore, some of the compounds of the present invention may have two asymmetric carbon atoms in the substituent R2 at the 7-position and therefore may exist as different stereoisomers (cis form, trans form). These stereoisomeric forms are also encompassed by 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 is a carboxylic acid or its ester ( Preferably lower alkyl ester) is reacted with a cycloamide/derivative represented by the following general formula % [111] (wherein R3 is the same as above), and the product is isolated by a conventional method. can be manufactured.

The reactive functional group represented by Z in formula [11] includes halogen atom, arylsulfonyl, arylsulfinyl,
Examples include lower alkylsulfonyl, lower alkyl-1'/, lower alkylthio, lower alkylsulfinyl, arylsulfonyloxy, and lower alkylsulfonyloxy7.

This reaction uses ethanol, acetonitrile, dioxane,
In an inert solvent such as dimethylformamide, toluene, xylene, 10-180°C, preferably 20-150°C
In, the raw material compound [11] or its ester and [
111] for 5 to 120 minutes, usually 20 to 60 minutes.

The amount of raw material compound [111] used relative to raw material compound [■] or its ester is not equivalent - it is excessive.
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 of the reaction, so in such cases it is common to use an acid acceptor.
The raw material compound [rf1] may be used in excess to serve as an acid acceptor.

Further, the starting compound [111] used in this reaction may be used in a protected form with cetyl or the like, and after the completion of the reaction, the protecting group may be removed by a conventional method.

The starting compound [■] or its ester can be produced by the method described in Reference Examples 1 and 2 or a method analogous thereto. The raw material compound [■] can be produced by the method described in Reference Examples 3, right 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 to the compound of formula [I] by hydrolyzing the ester moiety by a conventional method.

Furthermore, if necessary, the compound of formula [I] can be esterified by a conventional method to lead to an ester of the compound of formula CI].

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 salt form,
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.

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, it is also possible to produce the compounds of the present invention having the cis-type or trans-type configuration, respectively, by using the compound [1111 having the cis-type or trans-type configuration, and by the above method.

Optically active forms of the compounds of the present invention can be separated by applying known methods.

The compound thus obtained [! ], its esters and its salts are all new compounds. In particular, compound [1] and its salts exhibit extremely excellent antibacterial activity and are therefore valuable as antibacterial agents.

Compound [I] or a salt thereof can be used not only as a medicine for humans and animals, but also as a medicine for fish diseases, a preservative for 1L food, and the like. In addition, the ester form of compound [I] is of course valuable as a raw material for the synthesis of compound [1], but if this compound is easily converted into compound [1] in vivo, the compound [■ ] It is a compound that can be used as an antibacterial agent because it can exhibit the same effect as that of antibacterial agents.

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

c) Anti-Δ effect in vitro” “Experimental conditions Minimum inhibitory concentration (MIC: 8 g/ml) is Che
The results are shown in the table above.

“The compound of Example 1-■ is irradiated with alpha rays (the same applies hereinafter).

When the compound of the present invention is used as an antibacterial agent in humans, the dosage depends on age, body weight, symptoms and route of administration.

Although it varies depending on the number of administrations, etc., it is recommended to administer 5 to 5 g per day 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 Ω powder, it is usually administered in a prepared form together with a pharmaceutical carrier. Specific examples include tablets, capsules, and granules.

Examples include fine granules, powders, syrups, and injections. Follow the usual methods for these preparations! l is made. As a carrier for oral preparations, starch/mannitol is used.

Substances commonly used in the pharmaceutical field, such as crystalline cellulose and CMCNa, and which do not react with the compound of the present invention are used. Examples of carriers for injection include carriers commonly used in the field of injections, such as water, physiological saline, gluten solution, and infusion solutions.

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-(2-chenyl)-1
,4-dihydro-4-oxo-1,8-naphthyridine-
Ethyl 3-carboxylate: (厘) Known compound, 60 g of 2,6-dichloro-5-fluoronicotinoyluryl was dissolved in concentrated sulfuric acid at 65-75°C for 1
Heat for an hour. Add water and further 100~2I at 0℃
I! Heated for 7 hours to produce 2,6-dichloro-5-fluorodiphthyl! Obtain 59.8 g. m, l), 155
~156°C ■ 45.2 g of this compound was treated with thionyl chloride to produce 47.2 g of 2,6-dichloro-5-fluora nicotinic acid chloride. El is obtained as oil.

(3) 47.5 g of this compound was reacted with diethyl ethoxymagnesium malonate in anhydrous ether, and 2
．． Diethyl 6-dichloro-5-fluoronicothimeylmalonate is obtained as an oil compound. Touch this with water' [ff
1 of p-toluenesulfo/acid was added and heated at 140°C for 2 hours to give 2,6-dichloro-5-7k.

48 g of ethyl nicotinoyl acetate are obtained.

m, 9. 69-70°C (4) 12 g of this compound was treated with ethyl orthoformate and anhydrous 4-acetic acid to give 2-(2,8-dichloro-5-
ethyl fluoronicotinoyl)-3-ethoxyacrylate, and then this compound was diluted with 2
- React the stannic chloride complex salt of aminothiophene hydrochloride with triethylamine/2~(2゜6-dichloro-5-
Fluoronicotinoyl)-3-(2-chenylamino)
15 g of ethyl acrylate are obtained. m, p, 11
4°C +5) 15 g of this compound were reacted with potassium t-butoxide in anhydrous dioxane to give 7-chloro-6-fluoro-1-C2-chenyl)-1,4-dihydro-4.
9.5 g of -oxo-1,8-naphthyridine-3-carbo/II ethyl are obtained.

m, 9.　193~195℃ Reference example 2 The following compound is produced according to the method of Reference Example 1.

(1) Ethyl 7-chloro-6-fluoro-1-(2-thiazolyl)-1,4-dihydro-4-oxo-1,8-naphthyridi-7-3-carboxylate m, I), 182
~184℃ ■ 7-chloro-6-fluoro-1-(3-methyl-5
-inthiazolyl)-1,4-dihydro-4-oxo-
1,8-naphthyridi/-3-carbo/ll! II Ethyl m, P, 179-180℃ (3) 7-chloro-
6-Fluoro-1-(3-ynoxasilyl)-1,4
-dihydro-4-okine-l, 8-naphthyldi/-3=
Power Rubo 7m Ethyl m, 9. 21 (1-212°C (4) 7-chloro-6-fluoro-1-(5-methyl-
Ethyl 3-ynoxasilyl)-1,4-dihydro-4-oxo-1,8-naphthyridi/-3-carboxylate
m, p, 188-168°C 07-chloro-6-fluoro-1-(5-ynoxasilyl)-1,4-dihydro-4-oxo-1,8-naphthyridi/-3-carboxylic acid ethyl m, p, 147-148°C (6) 7-chloro-1-(μ5-dimethyl-4-ynoxasilyl)-6-fluoro-1,4-dihydro-4-
Oxo-1,8-naphthyridine-3-1 ethyl carboxylate m, P, 248-250℃■ 7-chloro-6-fluoro-1-(3-pyridyl)-1,4-dihydro-4-oxo-1 , 8-naphthyridi/-3-carbo/II ethyl m, p, 208-208°C (8) 7-chloro-6-fluoro-1-(4-pyridyl)-1,4-dihydro-4-oxo-1 , 8-naphthyridi/-3-carbo/ethyl acid m, p, 252-253°C (9) 7-chloro-6-fluoro-1-(4-ynoxasilyl)-1,4-dihydro-4-oxo -1,8-
Ethyl naphthyrid/-3-carboxylate m, 9. 187
~189°C 017-chloro-6-fluoro-1-(3-methyl-5
-inoxasilyl)-1,4-dihydro-4-oxo-1,8-naphthyridi/-3-carboxylic acid ethyl m
, p, 182-183°C Reference Example 3 3-acetylamino-4-methylpyrrolidi/: 3-7 minnow 1-be/gi-4-methylpyrrolidi/
-22899) with acetic anhydride to obtain 3-acetylamino-1-benzyl-4-methylvirolidi/ as an oil. IR spectrum: 3300.185
0c*-', this compound is catalytically reduced in the presence of 5% palladium on carbon to give 3-acetylamino-4-methylviridi/ as an oil.

Reference Example 4 3-acetylamino-3-methylpyrrolidine=1-benzyl-3-pyrrolidone [J, Org, Chem.

30, 740 (19Ei5)] with methylmagnesium bromide to obtain ■-benozyl-3-hydroxy-3-methylpyrrolidine as an oil.

b, f), 108°C/0.5ms Hg - This compound was treated with a mixed solution of acetonitrile and concentrated sulfuric acid under water cooling to form 3-acetylamino-1-benzyl-3-
methylpyrrolidi/ is obtained. m, 9. 105-100
℃. 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-!-pyrrolidinyl)-6-fluoro-1-(2-chenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid and its hydrochloric acid Salt: (I) Ethyl 7-chloro-6-fluoro-1-(2-chenyl)-1,4-dihydro-4-okine-1,8-naphthyridine-3-carboxylate 500 m, 3-acetylaminopyrrolidine 240 m , sodium hydrogen carbonate 240m
g+ A mixture of 4 parts and 1 part of acetonitrile is stirred at room temperature for 1 hour. The reaction mixture was evaporated to dryness under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. Separate the layer, dry it, and then distill off the chloroform. The resulting crude crystals were recrystallized from ethanol to give 7-(3-acetylamine 7-
1-pyrroli7dinyl)-6-fluoro-1-(2-thenyl)-1,4-dihydro-4-oxo-1,8-naphthyridi/-3-irbo/i! l! Ethyl 560- is obtained.

m, p, 231°C (2) A mixture of 560 ml of the above ester and 41 ml of 20% hydrochloric acid is heated under reflux for 5 hours. After cooling, take 4 crystals, wash them with ethanol, dry them, and... -(3-amino-1-pyrrolidinyl)-6-fluoro-1-(2-chenyl)-1,
4-dihydro-4-okine-1゜8-naphthyldi/-3
- Obtain 400 mg of carboxylic hydrochloride. Recrystallize from water-ethanol.

m, p, 293-295°C (decomposition) (3) Suspend 400 ml of the above hydrochloride in IQ ml of water and neutralize with 10% aqueous ammonia. The precipitated crystals are collected by filtration, dried,
7-(3-Amino-1-pyrrolidinyl)-6-fluoro-1-(2-chenyl)-1,4-dihydro-4-oxo-1,8-naphthyridi/-3-carbo7 f1330
■ Get.

m, p, 288-291°C (decomposition) The following procedures were carried out in the same manner as in Example 1 to obtain compounds of Examples 2 to 2.

Example 2 (1) 7-(3-acetylamino-3-methyl-1-
ethyl pyrrolidinyl)-6-fluoro-1-(2-thenyl)-1,4-dihydro-4-okyne-1゜8-naphthyridi/-3-carboxylate m, p, 243~
244℃ ■ 7-(3-amino-3-methyl-1-pyrrolidinyl)-6-fluoro-1-(2-chenyl)-1,4-dihydro-4-oxo-1,8-naphthyridi/-3- Carbo/hydrochloride m, I), 215-218°C Example 3 (dish) 7-(3-acetylami7-4-methyl-1-pyrrolidinyl)-6-fluoro-1-(2-chenyl)
-1,4-dihydro a-4-okyne-1,8-naphthyridi/-3-carboxylic acid ethyl m, 9. 236-237°C ■ 7-(3-amino-4-methyl-1-pyrrolidinyl)-6-fluoro-1-(2-chenyl)-1,4-dihydro-4-oxo-1,8-naphthyridinyl /-3-
carbo/hydrochloride m, 9. 296-297°C (decomposition) Example 4 (117-(3-acetylaminomethyl-1-pyrrolidinyl)-6-fluoro-1-(2-chenyl)-1,4
-dihydro-4-oxo-1,8-naphthyridine-3-
Ethyl carboxylate m, 9. 99-100℃ ■ 7-(3-Aminomethyl-1-pyrrolidinyl)-6
-Fluoro-1-(2-chenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic hydrochloride m, 9. 237-240°C Example 5 (1) 7-(3-7 cetylami-7-1-pyrrolidinyl)
-6-fluoro-1-(2-thiazolyl)-1,4-dihydro-4-oxo-1,8-naphthyridi/-3-carbo7r! li ethyl m, p, 253-255°C ■ 7-(3-amino-1-pyrrolidinyl)-6-fluoro-1-(2-thiazolyl)-1,4-dihydro-4
-oxo-1,8-naphthyridi/-3-carbo/hydrochloride m, 9. 28 [3-288°C (decomposition), Example 6 (117-(3-acetylamino-1-pyrrolidinyl)
-8-fluoro-1-(3-ynoxasilyl)-1,
4-dihydro-4-okine-1,8-naphthyldi/-3
-ethyl carboxylate m, 9. 219-220℃ ■ 7-(3-amino-1-pyrrolidinyl)-6-fluoro-1-(3-ynoxacylyl)-1,4-dihydro-4-okine-1,8-su7tyridi/-3 -carboxylic hydrochloride m, P, >300'C Example 7 (117-(3-7cetylamino-1-pyrrolidinyl)
-6-yluorol-1-(4-ynoxacylyl)-1,
4-9hydro-4-oxo-1,8-naphthyridi7-3
-Ethyl carboxylate m, p-187-188°C ■ 7-(3-amino-1-pyrrolidinyl)-6-fluoro-1-(4-ynoxasilyl)-1,4-dihydro-4-oxo-1 ,8-naphthyldi/-3-carbo/
Hydrochloric acid salt m, P, >300'C Example 8 (11'?-(3-7cetylamino l-pyrrolidinyl)-6-fluoro-1-(5-ynoxacylyl)-
Ethyl 1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate m, p, violet 97°C ■ 7-(3-amino-1-pyrrolidinyl)-6-fluoro-1-(5- (inoxacylyl)-1,4-dihydro-4-okyne-1,8-naphthyridine-3-carboxylic hydrochloride m, 9. 236-238°C Example 8 (Otori) 7-(3-acetylaminomethyl-lysinyl)
-8-fluorol'-1-(3-ynoxacylyl)-1
．． 4-dihydro a-4-okine'1.8-su7 chiridi 7
-3-carbo/methyl m. p. 230℃ ■ 7-(3-Aminomethyl-1-pyrrolidinyl)-6
-Fluoro-1-(3-ynoxacylyl)-1.4-
Dihydro-4-okine-1. 8-naphthyridi7-3-carboxylic acid hydrochloride m. P. > 300°C Example 10 (1) 7-(3-acetylamino-1-pyrrolidinyl)
-1-(3,5-dimethyl-4-ynoxasilyl)-
6-Fluoro-1,4-dihydro-4-oxo-1.8
Ethyl naphthyridine-3-carboxylate m. 9.
243-245°C (217-(3-amino-1-pyrrolidinyl)-1-(3,5-dimethyl-4-ynoxasilyl) = 6-fluoro-1,4-dihydro-4-oxo-1,8 -Naphthyridine-3-carbo7F!! Hydrochloride (317-(3-ami/-1-pyrrolidinyl)-1-(
3,5-dimethyl-4-ynoxasilyl)-6-fluoro-1,4-dihydro0-4-okyne-1,8-naphthyridi/-3-carbo/acid m, p, 264”C (decomposition) Implementation Example: 1 (1) 7-(3-acetylamino-1-pyrrolidinyl)
-6-FluoC'-1-(3-methyl-5-monoxazolyl)-1,4-dihydro-4=oxo-1,8-
Ethyl naphthyridi/-3-carboxylate m, P,
244-245°C (2) 7-(3-amino-1-pyrrolidinyl)-6-fluoro-1-(3-methyl-5-ynoxasilyl)-1,4-dihydro-4-oxo-1
゜8-naphthyridi/-3-carbo/hydrochloride m, p,
294-296°C (decomposition) Example 12 6-fluoro-7-(1-piperazinyl)-1-(2-
Thiazolyl)-1,4-dihydro-4-oxo-1,8
-Naphthyridine-3-carboxylic acid and its hydrochloride: (1) 7-rioa-6-7tkta-1-(2-thiazolyl)-1,4-dihydro-4-oxo-1,8-na7
Ethyl tyridine-3-carboxylate soo sg and 220 μl of 4-acetylpiperazine were reacted in the same manner as in Example 1-(1) to obtain 7-(4-acetyl-1-piperazinyl)-6-fluoro-1- (2-thiazolyl)-1,4-
Dihydro-4-oxo-1,8-7 naphthyridine-3
-550 ml of carbo/l911 ethyl are obtained. Recrystallize from ethyl acetate.

m, 9. 202-203° C. (1) A mixture of the above ester 500 and 10% hydrochloric acid 8-1 is heated under reflux for 4 hours. After cooling, 4 crystals precipitated were collected and dried to give 6-fluoro0-7-(1-piperazinyl)-
1-(2-thiazolyl)-1,4-dihydro-4-okine-1,8-naphthyridine-3-carbo/hydrochloride 40
Get 3 ■.

(3) Suspend 380 u of the above hydrochloride in water lO 1,
Neutralize with IN sodium hydroxide. The precipitated crystals are collected by filtration, washed with water, and then dried. Recrystallized from dimethylformamide to give 6-fluoro-7-(1-piperazinyl)-1-
(2-thiazolyl)-1,4-dihydro-4-oxo-
1,8-naphthyridine-3-carvone 19II 284g
get. m, p, 269-271'C (decomposition) Compounds of Examples 13-14 were obtained in the same manner as in Example 12.

Example 13 (117-(4-acetyl-1-piperazinyl)-6-
Fluo-0-1-(3-pyridyl)-1,4-dihydro-
Ethyl 4-oxygen-1,8-naphthyridine-3-carboxylate m, 9. 218-219℃ ■ 6-Fluoro-
7-(1-piperazinyl)-1-(3-pyridyl)-1
,4-dihydro-4-oxo-1,8-naphthyridine-
3-carboxylic hydrochloride m, p, 298-299
°C (decomposition) Example 14 (1) 7-(4-acetyl-1-piperazinyl)-6
-Fluoro-1-(5-ynoxacylyl)-1,4-
:) Ethyl hydro-4-oxo-8-naphthyridine-3-carboxylate m, 9. 225-227℃ ■ 6-Fluoro-1-(5-ynoxacylyl)-7
-(1-piperazinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboheptadhydrochloride
m, P, 294-297°C (decomposition) Example 15 6-fluoro-7-(4-methyl-1-piperazinyl)
-1-(2-chenyl)-1,4-dihydro-4-okine-1,8-naphthyridine-3-carbo/acid: (dish) 7-chloro-6-7ruol-1-(2-chenyl)- 500 μl of ethyl 1,4-dihydro-4-oxo-1,8-naphthyridi/-3-carboxylate and 90 μl of 4-methylpiperazine were reacted in the same manner as in Example 1-(11) to give 6-fluoro- 7-(4-methyl-1-piperazinyl)-1-(2-chenyl)-1,4-dihydro-
500 ml of ethyl 4-oxo 1,8-naphthyridine-3-carbo7ate is obtained. Recrystallize from ethanol.
m, p, 193-194℃ ■The above ester 450
A mixture of sputum and 0.5N sodium hydroxide at 90-1
Heat and stir at 00°C for 30 minutes.

After 6 hours, the mixture was neutralized with IN acetic acid and extracted with chloroform.

Separate the intermediate layer, wash with water and dry. Chloroform was distilled off, and the resulting crude crystals were recrystallized from chloroform-ethanol to give 6-fluoro-7-(4-methyl-1-piperazinyl)-1-(2-chenyl)-1,4-dihydro-
4-okine-1,8-naphthyldi/-3-carvoneff
Get 1370q.

m, p, 242-243°C Compounds of Examples 16-20 were obtained in the same manner as in Example 5 below.

Example 16 (1) 6-fluoro-7-(4-methyl-1-piperazinyl)-1-(2-thiazolyl)-1,4-dihydro-
4-oxo-1,8-naphthyridi-1-3-carbo7i1
Z Chill m, I), 115-118℃ (2)
6-Fluoro-7-(4-methyl-1-pibe...radinyl)-1-(2-thiazolyl)-1,4-dihydro-4
-oxo-1,8-naphthyridi/-3-carboxylic acid
m, 9. 274-275°C (decomposition) Example 17 (dish) 6-Fluoro-1-(3-methyl-5-inchazolyl)-7-(4-methyl-1-piperazinyl)-
1,4-dihydro-4-oxi7-1,8-naphthyridi/
-3-Ethyl carboxylate m, 9. 118-119°C (2) 6-fluoro-1-(3-methyl-5-inchazolyl)-7-(4-methyl-1-piperazinyl)-
1,4-dihydro-4-okyne-1,8-naphthyridine-3-carbo/acid m, 9. 275-277°C (decomposition) Example 18 (1) 6-fluoro-1-(5-methyl-3-ynoxacylyl)-7-(4-methyl-1-piperazinyl)
-1,4-dihydro-4-okine-1゜8-naphthyridi/-3-carboxylic acid ethyl m, p, 154~
155℃ ■ 6-Fluoro-1-(5-methyl-3-ynoxasilyl)-7-(4-methyl-1-piperazinyl)-1
,4-dihydro-4-oxygen-1゜8-naphthyridine-
3-carboxylic acid m, p, 228-230°C (decomposition) Example 19 tl) 1-(3,5-dimethyl-4-ynoxacylyl)-6-fluoro0-7-(4-methyl-1- ethyl piperazinyl)-1,4-dihydro-4-oxo-1,8-naphthyridi/-3-carboxylate m, p, 208°C (2) 1-(3,5-dimethyl-4-ynoxasilyl)- 6-Fluoro-7-(4-methyl-1-piperazinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carbo/acid m, P, 2111-22
0°C (decomposition) Example 20 (凰) 6-Fluoro-7-(4-methyl-1-piperazinyl)-1-(4-pyridyl)-1,4-dihydro-
Ethyl 4-oxo-1,8-naphthyridine-3-carboxylate m, p, 203-204℃ ■ 6-Fluoro-7-(4-methyl-1-piperazinyl)-1-(4-
pyridyl)-1,4-dihydro-4-oxo-1,8-
naphthyridine-3-carbonam, p, 29
0-292°C Example 21 6-fluoro-7-(1-piperazinyl)-1-(2-
chenyl)-1,4-dihydro0-4-okine-1.8-
naphthyridi/-3-carboxylic acid = (1) 7-chloro-
6-FluoC1-1-(2-chenyl)-1,4-dihyde cI-4-ox 7-1.8-naphthyridine-3-carboxylic acid ethyl 5QQl@, % water piperazine y490mg,
1. Stir a mixture of 51 acetonitrile at room temperature for 1 hour. 1. Condense the reaction mixture to dryness under reduced pressure, add water to the residue,
Extract with chloroform. Separate the layer a, dry it, and then distill off the chloroform. The resulting crude crystals were recrystallized from ethyl acetate to give 6-fluoro-7-(1-piperazinyl)-
Ethyl 1-(2-chenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate 500
Obtain 5g. rn, I), 187-188℃
(2) A mixture of the above ester 402 and 0.5N sodium hydroxide 31 is heated and stirred at 90 to 100°C for 30 minutes.

Neutralize with IN acetic acid at room temperature. After 6 days, the precipitated crystals are taken out, washed with water, and then dried. The crude crystals were recrystallized from chloroform-ethanol to give 6-fluoro-7-(1-piperazinyl)-1-(2-chenyl)-1,4-dihydro-4
-oxo-1,8-naphthyridine-3-carbo/acid 30
Get 0 bucks.

m, p, 222-223°C Compounds of Examples 22-23 are obtained in the same manner as in the case of the side stone.

Example 22 (I) 6-Fluoro-1-(3-ynoxasilyl)-
Ethyl 7-(1-piperazinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate
m, 9. 209-21G'C-〇-fluoro1-
(3-ynoxacylyl)-7-(1-piperazinyl)
-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carbo/acid m, 9. 249~250"C
(Decomposition) Example 23 (1) 6-Fluoro-1-(5-methyl-3-ynoxasilyl)-7-(1-piperazinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine -3-Ethyl carboxylate m, p, 170~+71'C ■ 6-Fluoro-1-(5-methyl-3-ynoxacylyl)-7~(l-piperazinyl) = 1.4-dihydro-4- Oxo-1,8-naphthyldi/-3-carbo/
acid m, I), 248-249°C (decomposition) Example 24 6-Fluoro-7-(l-pyrrolidinyl)-1-(2-
Thiazolyl)-1,4-dihydro-4-oxo-1,8
-Naphthyridi/-3-carboxylic acid: (1) 7-chloro-
Ethyl 6-fluoro-1-(2-thiazolyl)-1,4-dihydro-4-okyne-1,8-naphthyridine-3-carboxylate 500 ml.

pirolisif 250. , acetonitrile 51 is stirred at room temperature for 1 hour. The precipitated crystals were collected by filtration and recrystallized from ethyl acetate to give 6-fluora-7-(l-pyrrolidinyl)-1-(2-thiazolyl)-1,4-dihydro-
Ethyl 4-oxo-1,8-naphthyridi/-3-carbo7ate 500. get.

m, 9. 205-206°C (2) The above ester 388■ was treated in the same manner as in Example 2l-(2) to obtain 6-fluoro-7-(l-pyrrolidinyl)-1-(2-thiazolyl)-1,4- dihydro-4
-oxo-1,8-naphthyridine-3-carvone f13
Get 40m. Recrystallize from dimethylformamide ethanol. m, p, >300'C or less Compounds of Examples 25 to 27 are obtained in the same manner as in Example 24.

Example 25 (Otori) 6-fluoro-1-(3-pyridyl)-7-(
ethyl 1-pyrrolidinyl)-1,4-dihydro-4-okyne-1,8-naphthyridi/-3-carbo7ate m,
9. 251-252℃ ■ 6-Fluoro-1-(3-
pyridyl)-7-(1-pyrrolidinyl)-1,4-dihydro-4-oxo-1,8-naphthyridi/-3-carboxylic acid m, 9. 295-297°C (decomposition) Example 26 (Otori) 6-Fluoro-1-(4-pyridyl)-7-(
l-pyrrolidinyl)-1,4-dihydro-4-oxo-
Ethyl 1,8-naphthyridine-3-carboxylate m,
p, 248-249℃ ■ 6-Fluoro-1-(4
-pyridyl)-7-(1-pyrrolidinyl)-1,4-dihydro-4-oxo-1,8-naphthyridi/-3-carboxylic acid m, p, > 300°C Example 27 0) 6-fluoro- Ethyl 1-(5-methyl-3-ynoxasilyl)-7-(1-pyrrolidinyl)-1,4-dihydro-4-oxo-1,8-naphthyridi/-3-carboxylate m, p, 200~ 201'C (2) 6-Fluoro-1-(5-methyl-3-ynoxasilyl)-7-(1-pyrrolidinyl)=1,4-dihydro-4-oxo-1,8-naphthyridine-3- carboxylic acid

Claims (1)

[Claims] General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, X means a nitrogen atom, C-H or C-F,
Y means a halogen atom, R_1 means a heterocyclic group that may have a substituent, and R_2 is a group represented by the following formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ Numerical formulas, chemical formulas , tables, etc. ▼ , where R_3 and R_4 mean a hydrogen atom or a lower alkyl group, and R_5 is a hydrogen atom, a hydroxy group, an amino group, a mono- or di-lower alkylamino group, an amino-lower alkyl group, or a mono- or di-lower alkylamino lower alkyl group, where n is an integer of 3 or 4.
Or it means 5. ) Pyridonecarboxylic acid derivatives, esters thereof and salts thereof.