GB2158825A

GB2158825A - Naphthyridines

Info

Publication number: GB2158825A
Application number: GB08510297A
Authority: GB
Inventors: Hirokazu Narita; Yoshinori Konishi; Jun Nitta; Hideyoshi Nagaki; Isao Kitayama; Yoriko Kobayashi; Mikako Shinagawa; Yasuo Watanabe; Akira Yotsuji; Shinzaburo Minami; Isamu Saikawa
Original assignee: Toyama Chemical Co Ltd
Current assignee: Toyama Chemical Co Ltd
Priority date: 1984-04-26
Filing date: 1985-04-23
Publication date: 1985-11-20
Also published as: SE501412C2; AT389698B; FR2563521B1; DE3514076C2; ES8700256A1; NL9100648A; NO162238B; EG17339A; LU85871A1; DE3546658C2; ES8706673A1; GB2191776A; NZ211895A; RO91871B; AR241911A1; NL187314C; ID21142A; ES551538A0; FI851637L; AU612993B2

Abstract

Compounds of the general formula <IMAGE> (R<1> = H or protecting group; R<2> = unsubstituted or substituted aryl group; R<3> = halogen atom or unsubstituted or substituted cyclic amino group) and their salts are antibacterial agents.

Description

SPECIFICATION 1.4-dihydro-4-oxonaphthyridine derivatives and salts thereof, process for producing the same and antibacterial agents comprising the same This invention relates to a novel 1,4-dihydro-4-oxonaphthyridine derivative having a substituted or unsubstituted aryl group at the 1-position and a halogen atom or a substituted or unsubstituted cyclic amino group at the 7-position and a salt thereof, a process for producing the same and an antibacterial agent comprising the same.

Nalidixic acid, piromidic acid, pipemidic acid and the like have heretofore been widely used as synthetic antibacterial agents. However, none of these agents are satisfactory in therapeutic effects on the infections of Ps. aeruginosa and a Gram-positive bacteria which are refractory diseases. Therefore, various pyridone carboxylic acid type compounds are being developed, for example, 1-ethyi-6-fluoro-1,4-dihydro-4-oxo-7-(1- piperazinyl)-3-quinolinecarboxylic acid (norfloxacin) or the like, as a substitute for the conventional synthetic antibacterial agents. These compounds have excellent antibacterial activities against various Gram-negative bacteria including Ps. aeruginosa, but are unsatisfactory in antibacterial activities against Gram-positive bacteria.Therefore, the development of a synthetic antibacterial agent having a broad antibacterial spectrum has been desired which agent is effective on not only Gram-negative bacteria but also Gram-positive bacteria.

Under these circumstances, the present inventors have, as a result of extensive research, found that a novel 1,4-dihydro-4-oxonaphthyridine derivative and a salt thereof can solve the aforementioned problems.

An object of this invention is to provide a novel 1 ,4-dihydro-4-oxonaphthyridine derivative and a salt thereof having excellent properties, for example, strong antibacterial activities against Gram-positive and Gram-negative bacteria, particularly against antibiotic-resistant bacteria, and giving high concentrations in blood when administered orally or parenterally, and being high in safety.

Another object of this invention is to provide a process for producing a novel 1 ,4-dihydro-4oxonaphthyridine derivative and a salt thereof.

A further object of this invention is to provide an antibacterial agent which is usefui for the treatment of infections of bacteria or the like and which comprises a novel 1 ,4-dihydro-4-oxonaphthyridine derivative or a salt thereof.

According to this invention, there is provided a 1,4-dihydro-4-oxonaphthyridine derivative represented by the general formula:

wherein R1 represents a hydrogen atom or a carboxyl-protecting group, R2 represents a substituted or unsubstituted aryl group, and R3 represents a halogen atom or a substituted or unsubstituted cyclic amino group, and a salt thereof.

Further, this invention provides a process for producing a 1,4-dihydro-4-oxonaphthyridine derivative represented by the general formula [I] or a salt thereof, and also an antibacterial agent comprising the 1 ,4-dihydro-4-oxonaphthyridine derivative represented by the general formula [I] or a salt thereof.

This invention will be explained in detail below.

In the compound represented by the general formula [I] or a salt thereof, the carboxyl-protecting group for R1 includes, for example, ester-forming groups which may be removed by catalytic reduction, chemical reduction or other treatments under mild conditions; ester-forming groups which may be easily removed in a living body; organic silyl-containing groups, organic phosphorus-containing groups and organic tin-containing groups which may be easily removed by treatment with water or an alcohol; and other various well-known ester forming groups.

Among these carboxyl-protecting groups, the preferred protecting groups include, for example, carboxyl-protecting groups described in Japanese Patent Application Kokai (Laid-Open) No. 80,665/84.

The aryl group for R2 includes, for example, phenyl, naphthyl and the like. The aryl group may be substituted by one or more substituents selected from the group consisting of halogen atoms, for example, fluorine, chlorine, bromine, iodine and the like; alkyl groups, for example, straight or branched chain C1-Cl0alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl and the like; hydroxyl groups; alkoxy groups, for example, straight or branched chain C1-C10alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, secbutoxy, tert-butoxy, pentyloxy, hexyloxy, heptyloxy, oxtyloxy and the like; cyano group; amino group; acylamino groups, for example, C1-C4acylamino groups such as formylamino, acetylamino, propionylamino, butyrylamino and the like; and trihalogenoalkyl groups, for example, trihalogeno-Cl-C4-alkyl groups such as trifluoromethyl, trichloromethyl and the like.

Moreover, the halogen atom for R3 includes, for example, fluorine, chlorine and bromine. The cyclic amino group for R3 have at least one nitrogen atom and may have additionally one or more oxygen atoms as the hetero atoms forming the ring, and includes 5-or 6-membered cyclic amino groups such as 1-pyrrolidinyl, piperidino, 1-piperazinyl, morpholino and the like.The aforementioned cyclic amino groups may be substituted by one or more substituents selected from the group consisting of alkyl groups, for example, straight or branched chain C1-C4alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl; amino group; aminoalkyl groups, for example, amino-C1-C4alkyl groups such as aminomethyl, 2-aminoethyl, 3-aminopropyl and the like; hydroxyalkyl groups, for example, hydroxy-C1 C4alkyl groups such as hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl and the like; hydroxyl group; alkenyl groups, for example, C2-C4alkenyl groups such as vinyl, allyl and the like; acyl groups, for example, Cl-C4acyl groups such as formyl, acetyl, propionyl, butyryl and the like; alkylamino groups, for example, C1-C4alkylamino groups such as methylamino, ethylamino, n-propylamino, isopropylamino and the like; dialkylamino groups, for example, di-C1-C4alkylamino groups such as dimethylamino, diethylamino, di-n-propylamino, methylethylamino and the like; cyano group; oxo group; aralkylamino groups, for example, ar-C1-C4alkylamino groups such as benzylamino, phenethylamino and the like; acylamino groups, for example, C1-C4acylamino groups such as acetylamino, propionylamino, butyrylamino and the like; alkoxycarbonyl groups, for example, C1-C4alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and the like; and N-acyl-N-alkylamino groups, for example, N-acyl-N-alkylamino groups wherein the nitrogen atom of the above-mentioned alkylamino group is substituted by a C1-C4acyl group such as acetyl, propionyl, butyryl or the like.

Among the compounds represented by the general formula [I], those wherein R2 represents a fluorine-substituted phenyl group and R3 represents a substituted or unsubstituted 1-pyrrolidinyl or 1-piperazinyl group are preferred, and those wherein R2 is a 2,4-difluorophenyl group and R3 is a 3-amino-1-pyrrolidinyl group are more preferable.

The salt of the compound represented by the general formula [I] includes conventional salts at basic groups such as an amino group and the like, and at acidic groups such as a carboxyl group and the like. The salts at the basic groups include, for example, salts with mineral acids such as hydrochloric acid, sulfuric acid and the like; salts with organic carboxylic acids such as oxalic acid, formic acid, trichloroacetic acid, trifluoroacetic acid and the like; salts with sulfonic acids such as methane-sulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid and the like.The salts at the acidic groups include, for example, salts with alkali metals such as sodium, potassium and the like; salts with alkaline earth metals such as calcium, magnesium and the like; ammonium salts; and salts with nitrogen-containing organic bases such as procaine, dibenzylamine, N-benzyl-ss-phenethylamine, 1-ephenamine, N,N-dibenzylethylenediamine, triethylamine, trimethylamine, tributylamine, pyridine, N,N-dimethyl-aniline, N-methylpiperidine, Nmethylmorpholine, diethylamine, dicyclohexylamine and the like.

If the compound represented by the general formula [I] and a salt thereof have isomers (for example, optical isomers, geometrical isomers, tautomers and the like), this invention includes all of the isomers, crystal forms and hydrates thereof.

Antibacterial activities and acutetoxicities are illustrated with reference to typical compounds of this invention.

1. ANTIBACTERIAL ACTIVITY Test method According to the standard method of Japan Society of Chemotherapy [CHEMOTHERAPY, 29(1), 76-79(1981)],a bacteria solution obtained by culturing in Heart Infusion broth (manufactured by Eiken Kagaku) at 37"C for 20 hours was inoculated onto a Heart Infusion agar containing a drug and cultured at 37"C for 20 hours, after which the growth of the bacteria was observed, to determine the minimum concentration at which the growth of the bacteria was inhibited as MIC (g/ml). The amount of the inoculated bacteria was 104 cells/plate (106 cells/ml). The MIC values of the following test compounds are as shown in Table 1.

Symbols used in Table 1 have the following meanings: *1: penicillinase-producing bacteria, *2: cephalosporinase-producing bacteria, *3: inoculation size: 108 cells/ml, Me: methyl group, Et: ethyl group, n-Pr: n-propyl group, i-Pr: isopropyl group TABLE 1

Compound No. 1 2 3 4 Bacteria St. aureus FDA209P 0.1 '0.05 #0.05 0.1 St. epidermidis ID866 0.1 0.05 #0.05 0.1 St. aureus F-137*1 0.1 #0.05 ='0.05 0.1 E. coli NIHJ ='0.05 0.39 0.1 #0.05 E. coli TK-111 ='0.05 0.2 ='0.05 ='0.05 E. coli GN5482*2 #0.05 0.1 #0.05 #0.05 Ps. aeruginosa S-68 0.39 6.25 1.56 1.56 Aci. anitratus A-6 0.2 0.2 #0.05 0.1 Ps. aeruginosa IFO3445 3.13 12.5 3.13 3.13 Ps. aeruginosa GN918*2 0.39 3.13 0.78 0.78 TABLE 1 (cont'd)

5 6 7 8 9 10 0.2 ='0.05 0.2 0.2 0.2 0.2 0.39*3 0.1*3 0.78 0.2 0.2 0.2 0.2 ='0.05 0.39 0.2 0.2 0.2 ='0.05 ='0.05 ='0.05 '0.05 #0.05 ='0.05 #0.05 ='0.05 #0.05 #0.05 ='0.05 ='0.05 #0.05 #0.05 ='0.05 #0.05 ='0.05 #005 ='0.05 0.39 1.56 1.56 3.13 3.13 3.13 0.2 0.1 0.2 0.2 0.78 0.2 0.78 3.13 1.56 12.5 6.25 3.13 0.39 0.78 0.78 3.13 1.56 3.13 TABLE 1 (Cont'd)

11 12 13 14 15 0.2 #0.05 ='0.05 0.2 0.2 0.39 #0.05 0.1 0.2 0.2 0.2 =0.05 0.1 0.1 0.2 0.39 =0.05 =0.05 #0.05 ~0.05 0.1 #0.05 #0.05 = < 0.05 #0.05 ='0.05 0.1 =0.05 #0.05 #0.05 #0.05 6.25 0.2 0.2 0.78 1.56 0.2 #0.05 #0.05 0.1 0.1 12.5 0.2 0.2 1.56 1.56 3.13 0.1 0.1 0.39 0.39 2. ACUTE TOXICITY The LD50 values obtained by intravenously administering the test compounds of No. 5, 6 and 12 as mentioned above to mice (ICR strain, male, body weight: 18-24 g) were 200 mg/kg or more.

The process for producing the compound of this invention will be explained below.

The compound of this invention can be reproduced, for example, according to the following production route:

[Ia] or a salt thereof [Ib] or a salt thereof wherein R1a represents the same carboxy-protecting group as in R1; R3a represents the same halogen atom as in R3; R3b represents the same substituted or unsubstituted cyclic amino group as in R3; and R1 and R2 have the same meanings as defined above.

The salts of the compounds represented by the general formulae [la], [Ib], [III], [IV] and [V] include the same salts as those of the compounds represented by the general formula [I].

(i) The compound represented by the general formula [III] or a salt thereof or the compound represented by the general formula [V] or a salt thereof is, respectively, obtained by reacting the compound represented by the general formula [II] or the compound represented by the general formula [IV] or a salt thereof with an acetal such as N,N-diethylformamidodimethylacetal, N,N-dimethylformamidodiethylacetal or the like and then with an amine represented by the general formula, R2-NH2 (R2 has the same meaning as defined above).

The solvent to be used in the above reactions may be any solvent inert to the reactions and includes, though not critical, aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol dimethyl ether and the like; halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane and the like; amines such as N,Ndimethylformamide, N,N-dimethylacetamide and the like; sulfoxides such as dimethylsulfoxide and the like; etc. and these solvents may be used alone or in admixture of two or more. The amount of the acetal used is preferably 1 mole or more, particularly about 1.0-1.3 moles, per mole of the compound represented by the general formula [II] or the compound represented by the general formula [IV] or a salt thereof.The reactions are usually conducted at 0 ro 100 C, preferably at 50 to 80"C, and usually for 20 minutes to 50 hours, preferably 1 to 3 hours. And the amine is used in an amount of 1 mole or more per mole of the compound represented by the general formula [II] or the compound represented by the general formula [IV] or a salt thereof. The reaction is usually conducted at 0 to 100 C, preferably 10 to 60"C, and usually for 20 minutes to 30 hours, preferably 1 to 5 hours.

As an alternative method, it is possible to react the compound represented by the general formula [II] or the compound represented by the general formula [IV] or a salt thereof with ethyl orthoformate or methyl orthoformate in the presence of acetic anhydride, and then with an amine represented by the general formula, R2-NH2 or a salt thereof to obtain the compound represented by the general formula [III] or a salt thereof or the compound represented by the general formula [V] or a salt thereof, respectively.

(ii) The compound represented by the general formula [la] or a salt thereof or the compound represented by the general formula [Ib] or a salt thereof is, respectively, obtained by subjecting the compound represented by the general formula [III] or a salt thereof or the compound represented by the general formula [V] or a salt thereof to ring closure reaction (preferably with heating) in the presence or absence of a base.

The solvent to be used in this reaction may be any solvent inert to the reaction and includes, though not critical, for example, amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; ethers such as dioxane, anisole, diethylene glycol dimethyl ether and the like; sulfoxides such as dimethylsulfoxide and the like; etc. These solvents may be used alone or in admixture of two or more. The base includes, for example, sodium hydrogencarbonate, potassium carbonate, potassium tert-butoxide, sodium hydride and the like. The amount of the base to be used is preferably 0.5 to 5 moles per mole of the compounds represented by the general formula [III] or [V] or a salt thereof.The reaction is usually conducted at 20 to 1600C, preferably at 100" to 150"C, and usually for 5 minutes to 30 hours, preferably 5 minutes to 1 hour.

(iii) The compound represented by the general formula [IV] or a salt thereof, the compound represented by the general formula [V] or a salt thereof, or the compound represented by the general formula [Ib] or a salt thereof is, respectively, obtained by reacting the compound represented by the general formula [II], the compound represented by the general formula [III] or a salt thereof, or the compound represented by the general formula [la] or a salt thereof with a cyclic amine represented by the general formula, R3bH or a salt thereof (wherein R3b has the same meaning as above).

The solvent to be used in the reaction may be any solvent inert to the reaction and includes, though not critical, aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and the like; halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane and the like; amides such as N,N-di-methylformamide, N,N-dimethylacetamide and the like; sulfoxides such as dimethylsulfoxide and the like; alcohols such as methanol, ethanol and the like; nitriles such as acetonitrile and the like; etc., and these solvents may be used alone or in admixture of two or more.The amount of the cyclic amine or a salt thereof to be used is preferably an excess, more preferably 2 to 5 moles per mole of the compound represented by the general formula [II], the compound represented by the general formula [III] or a salt thereof, or the compound represented by the general formula [la] our a salt thereof. If the amount of the cyclic amine used is about 1 to 1.3 moles, it is sufficient that an acid-binding agent is used in an amount of 1 mole per mole of the compound represented by the general formula [II], the compound represented by the general formula [III] or a salt thereof, or the compound represented by the general formula [la] or a salt thereof. The acid-binding agent includes organic or inorganic bases such as triethylamine, 1 ,8-diazabicyclo[5,4,0]undec-7-ene (DBU), potassium tertbutoxide, potassium carbonate, sodium carbonate, sodium hydride and the like.

The salt of R3b-H includes the same as the salts at the basic group of the compound represented by the general formula [I].

The reaction is usually conducted at 0 to 150 C, preferably at 500 to 100"C, and usually for 5 minutes to 30 hours, preferably 30 minutes to 3 hours.

The compound represented by the general formula [la], [Ib], [III] or [V], wherein Rl represents a carboxyl-protecting group, or a salt thereof can, if desired, be converted to the corresponding free carboxylic acid by hydrolyzing the same in the presence of a conventional acid or alkali, which is used in hydrolysis, usually at 0 to 100 C, preferably at 20 to 100 C for 5 minutes to 50 hours, preferably 5 minutes to 4 hours.

Further, the compound represented by the general formula [la], [Ib], [III] or [V] or a salt thereof can, if desired, be converted to a salt or an ester of the corresponding compound by subjecting the same to salt-forming reaction oresterification known peruse. If the compound represented by the general formula [la], [III], [IV] or [V] or a salt thereof has an active group (for example, hydroxyl group, amino group or the like) at other positions than the reaction sites, it is possible to previously protect the active group by the conventional method and remove the protecting group after completion of the reaction.

The compound thus obtained may be subjected to as conventional isolation and purification procedures such as column chromatography, recrystallization, extraction and the like.

The compound represented by the general formula [I] or a salt thereof, wherein R3 represents a halogen atom (corresponding to the compound represented by the general formula [la]), is also useful as an intermediate for obtaining a compound wherein R3 represents a substituted or unsubstituted cyclic amino group (corresponding to the compound represented by the general formula [lb]).

When the compound of this invention is used as a drug or medicine, it is appropriately combined with carriers which are used in conventional pharmaceutical preparations, and is prepared into tablets, capsules, powders, syrups, granules, suppositories, ointments, injections and the like in a conventional manner. The administration routes, dosage and number of administrations can be appropriately varied depending upon the symptoms of patients, and it may be usually administered orally or parenterally (for example, by injection, drip, administration to rectum) to an adult in an amount of 0.1 to 100 mg/kg/day in one to several portions.

This invention will be explained below referring to Referential Examples, Examples and Preparation Examples.

Symbols used in Referential Examples and Examples have the following meanings: Me: methyl group, Et: ethyl group, n-Pr: n-propyl group, i-Pr: isopropyl group, Ac: acetyl group, ~: allyl group, ethylene group.

Referential Example 1 In 210 ml of chloroform was dissolved 21 g of 2,6-dichloro-5-fluoronicotinic acid, and 23.8 g of thionyl chloride and 0.1 g of N,N-dimethylformamide were added to the resulting solution. The resulting mixture was reacted at 70"C for 2 hours. The solvent and the excessive thionyl chloride were removed by distillation under reduced pressure, and the residue thus obtained was dissolved in 21 ml oftetrahydrofuran. In 11 Om I of tetrahydrofuran was dissolved 25.1 g of diethyl ethoxymagnesium malonate, and the solution was cooled to -40 to -300C. Into this solution was dropped a tetrahydrofuran solution of 2,6-dichloro-5-fluoronicotinoyi chloride which had previously been prepared at the same temperature over 30 minutes.This mixed solution was stirred at the same temperature for 1 hour, and then the temperature of the solution was gradually raised to room temperature. The solvent was removed by distillation under reduced pressure, and to the residue thus obtained were added 200 ml of chloroform and 100 ml of water. The pH was adjusted to 1 with 6 N hydrochloric acid. The organic layer ways separated, washed successively with 50 ml of water, 50 ml of 5% aqueous sodium hydrogencarbonate solution and 50 ml of saturated aqueous sodium chloride solution, and dried over an hydrous magnesium sulfate.The solvent was removed by distillation under reduced pressure, and to the oily product obtained were added 50 ml of water and 0.15 g of p-toluenesulfonic acid, after which the resulting mixture was subjected to reaction with vigorous stirring at 100"C for 2 hours. The reaction mixture was extracted with 100 ml of chloroform. The organic layer was washed with 50 ml of saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, after which the solvent was removed by distillation under reduced pressure. The residue obtained was purified by a column chromatography (WAKO SILICA GEL C-200, eluant: toluene) to obtain 23.5 g of ethyl (2,6-dichloro-5fluoronicotinoyl)acetate having a melting point of 64-65"C.

IR (KBr) cm~1: vc=o 1650,1630,1620 NMR (CDCL3) values: 1.25 (1.29H, t, J=7Hz), 1.33 (1.71 H,t, J=Hz), 4.07 (1.14H, s), 4.28 (2H, q, J=7Hz), 5.82 (0.43H, s), 7.80 (1H, d, J=7Hz), 12.62 (0.43H, s) Referential Example 2 In 40 ml of benzene was dissolved 8.8 g of ethyl (2,6-dichloro-5-fluoronicotinoyl)acetate, and 4.5 g of N,N-dimethylformamidodimethylacetal was added thereto, after which the resulting mixture was subjected to reaction at 70"C for 1.5 hours. Then, 4.1 g of 2,4-difluoroaniline was added to the reaction mixture and the resulting mixture was subjected to reaction at room temperature for 4 hours. The solvent was removed by distillation under reduced pressure. The residue obtained was purified by a column chromatography (WAKO SILICA GEL C-200, eluant: chloroform) to obtain 9.0 g of ethyl 2-(2,6-dichloro-5-fluoronicotinoyl)-3-(2,4- difluorophenylamino)-acrylate having a melting point of 138-139"C.

IR (KBr) cm-l: vc=o 1690 NMR (CDC13) 8 values: 1.08 (3H, t, J=7Hz),4.10 (2H, q, J=7Hz), 6.77-7.40 (4H, m), 8.50 (1H, d, J=13Hz),12.70 (1H, d, J=13Hz) In a similar manner, the compounds shown in Table 2 were obtained.

TABLE 2

Compound Physical properties R2 Melting IR(KBrJ cm point PC) vc=o A K) 87-89 1690 110-114 1710,1680 92-93 1710,1680 /"y F 135-137 1720(sh), 1690 78-80 1690 F'F Oily 1705, 1680(sh) * 154-155 1720(sh), 1685 100-101 1700(sh), 1685 F 123-125 1710,1680 Cl 145-146 145-146 1705,1680 Br 147-149 1685 Oily 1695* OMe ~OMe 119-121 1700 Oily 1700* 183-186 183-186 1685,1670 NHAc 136-138 1705,1680 3 Table 2 (Cont'd)

114-116 1680 F OMe 137.5-139 1725(sh),1680 101 F 92-95 1705 Me tOMe 125-126 1700(sh), 1660 Me tMe 91-92 1705,1690 OMe Note: The neat method was used in place of the KBr method.

Referential Example 3 (1) In 55 ml of chloroform were dissolved 5.5 g of ethyl (2,6-dichloro-5-fluoronicotinoyl)acetate, 2.37 g of N-methylpiperazine and 2.37 g of triethylamine, and the resulting solution was subjected to reaction at 60 to 65 C for 2 hours. The reaction mixture was washed with 30 ml of water, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue obtained was purified by a column chromatography (WAKO SILICA GEL C-200, eluant: chloroform) to obtain 5.4 g of oily ethyl [2-chloro-541 uoro-6-(4-methyl-1-piperazinyl)nicotinoyl]acetate.

IR (Neat) cm-': vc=o 1750, 1695 NMR (CDCI3) 8 values: 1.25 (3H, t, J =7Hz), 2.32 (3H, s), 2.12-2.70 (4H, m), 3.55-3.96 (4H, m), 4.03 (2H, s), 4.20 (2H, q, J=7Hz), 7.78 (1H, d,J=13Hz) In a similar manner, the compound shown in Table 3 was obtained.

TABLE 3

Compound Physical Properties R3 Melting IR rKBrJ cm1: point f C) vc=o AcN N- 67-71 1730 (2) In 22.5 ml of benzene was dissolved 4.5 g of ethyl [2-chloro-5-fluoro-6-(4-methyl-1- piperazinyl)nicotinoyl]acetate, and 1.87 g of N,N-dimethylformamidodimethylacetal was added to the resulting solution, after which the resulting mixture was subjected to reaction at 70 C for 2 hours. To the reaction mixture was added 1.8 g of 4-methoxy-2-methylaniline, and the resulting mixture was subjected to reaction at room temperature for 4 hours.Then, the solvent was removed by distillation under reduced pressure, and the residue thus obtained was purified by a column chromatography [WAKO SILICA GEL C-200, eluant: chloroform: ethanol = 100:1 (by volume)]. The crystalline substance obtained was washed with 10 ml of diethyl etherto obtain 5.0 g of ethyl 2-[2-chloro-5-fluoro-6-(4-methyi-1-piperazinyl)nicotinoyi]- 3-(4-methoxy-2-methylphenylamino)acrylate having a melting point of 141-142"C.

IR (KBr) cm-1: vc=O 1710(sh), 1695 NMR (CDCI3) 3 values: 1.08 (3H, t, J =7Hz), 2.32 (3H, s), 2.40 (3H, s), 2.23-2.68 (4H, m), 3.47-3.83 (4H, m), 3.75 (3H, s), 4.07 (2H, q, J=7Hz), 6.65-7.25 (3H, m), 7.20 H, H, d, J=13Hz), 8.48 H, H, d, J=13Hz), 12.82 (1H, d, J=13Hz) In a similar manner, the compounds shown in Table 4 were obtained.

TABLE 4

Compound Physical Properties R2 Ra Melting point it(*) PC) cm-C: vc=o Oily 1720(sh), 1715 1715 "2 0 Oily 1735, p 1700 F Oily *21695 OMe I *1 t 161-164 1685, 1670 NHAc *2 o ,. Oily 1720 (sh), p 1715 OMe *1 o MeN N 132-136 1705 (sh), tMe \J 1685 OMe In *2 | Me *2 AcN N- Oily 1720(sh), Note: *1:KBr OMe *2: Neat Example 1 In 90 ml of N,N-dimethylformamide was dissolved 9.0 g of ethyl 2-(2,6-dichloro-5-fluoronicotinoyl)-3-(2,4 difluorophenylamino)acrylate, 3.6 g of sodium hydrogencarbonate was added to the resulting solution, after which the resulting mixture was subjected to reaction at 120"C for 20 minutes. Then, the solvent was removed by distillation under reduced pressure, and the residue obtained was dissolved in 50 ml of chloroform. The resulting solution was washed successively with 30 ml of water and 30 ml of saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the crystalline substance obtained was washed with 30 ml of diethyl ether to obtain 7*0 g of ethyl 7-chloro-6-fluoro-l -(2,4-difl uorophenyl)-l ,4-dihydro-4-oxo-l ,8- naphthyridine-3-carboxylate having a melting point of 220-222"C.

IR (KBr) cm-1: vc=o 1730, 1690 NMR (CDCl3) 3 values: 1.36(3H, t, J=7Hz), 4.30(2H, q, J=7Hz), 6.80-7.60(3H, m), 8.27(1 H, d, J=7Hz), 8.42(1 H, s) In a similar manner, the compounds shown in Table 5 were obtained.

TABLE 5

Compound Physical Properties R2 Melting point lR(KBr) PCI cm1:vc-o 222-224 1730, 1685 231-232 1730, F 1705 tX 239-241 1685 239-241 1685 F 205-208 1735, 1685 rOl 244-246 1720, F 1680 F F' 207-209.5 1730, F 1 690 FI F 210-214 1735(sh 1705 4 < F Q F 207-208 1730, 1680 F 181-186 1730, 1685 ci 204-205 1730, 1685 Br 1 216-218 1735, 1695 196-198 1735, OMe 1685 OMe 156-160 1730, 1690 9 231-236 1730, 1685 CN 270-273 1730, 1690 NHne 199-201 1730, 1680 cF Me 199-202 1735, 1685 OMe F 208-211 1730, 208-211 1730, F 1695 Table 5 (Cont'd)

Compound Physical Properties R2 Melting point lR(KBr) fC) cm-'::vc=o 0F 142-144 1740, 0 142-144 1740, 1695 OMeJVOMe 0 163-165 1730, r 1695 Me wts Me 160-162 1735, 1690 OMe Example 2 (1) In 35 ml of chloroform was dissolved 3.5 g of ethyl 7-chloro-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro- 4-oxo-1 ,8-naphthyridine-3-carboxylate, and 1.5 g of N-acetylpiperazine and 1.6 9 of triethylamine were then added to the resulting solution, after which the resulting mixture was subjected to reaction at 60"C for 1 hour.

Then, the solvent was removed by distillation under reduced pressure, and the residue obtained was purified by a column chromatography [WAKO SILICA GEL C-200, eluant: chloroform : ethanol = 30:1 (by volume)] to obtain 3.5 g of ethyl 7-(4-acetyl-1-piperazinyl)-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-l ,8- naphthyridine-3-carboxylate having a melting point of 207-209"C.

IR (KBr) cm-1: vc=o 1730,1695 NMR (CDC13) 3values: 1.38(3H, t, J =7Hz), 2.05(3H, s), 3.53(8H, bs), 4.30(2H, q, J=7Hz), 6.80-7.75(3H, m), 8.00(1 H, d, J= 13Hz), 8.30(1 H, s) In a similar manner, the compounds shown in Table 6 were obtained.

TABLE 6

Compound Physical Properties R2 R3 Melting point lR(KBr) {' C) cm-': vc=o Q AcNT - 216-218 1730, 1690 (sh) I Ac ss r4eN{p- 155-156 1730, at 1690 rm MeN N- 217-218 1730, LJ 1695 MeX NN N- 144-146 1730, 1690 Me HN N- 143 1730 Me 198-202 1725, 1690 Me m\ Ncj 220-222 1730, 1695 tI AcN9- 253-255 1730, 1690 Table 6 (Cont'd)

Compound Physical Properties Ra R3 Melting point lR(KBr) ("C) cm 1:vc=o In 05q 203-205 1730, our F 1700 j AcNC > - 211-213 1735 206 1725, k .. 206 1725, 1690 0 Me InN 193-194 1730, MeN ctOi- 244-246 1725, 1690 F Ac 0 MeN1 N- 186-187 1725, 1690 (soh) F 155-157 1720, Hd J 1685 F M Ma)7 153-154 1730, Eler3- 1700 Me MeP- 153-155 1730, 1695 In 7--NuN- N- 166-168 1730 (sh), 1690 Me Me .. EtO2CNs N- 202-204 1730, 'U 1690 1690 AcMf 230-231 1695 P 1695 FF 1720 (sh), g t 193-194 1680, 1675 ss MeN34- 207 1725, 1695 ci g C1 AcrgN- 254 1730, cm 1690 A 208 1730, bur 1690 In Acm,N 246-247 1730, 1690 ss Me- 167-169 1730, Me 1695 AcNN- 206-207.5 1730, 1690 Table 6 (Cont'd)

Compound Physical Properties R2 R3 Melting point lR(KBr) I"Cl cm-': vc=o X C N- 163-165 1735, ONe 1700 In MeEtr- 174-176 1730, 1690 r 180-181 1735, 1695 r\ 171-172.5 1730, once 1685 1685 ' i-Pr- 208.5-210 1730, 1690 In 200-202 1730, HO'VNr- 200-202 1730, 1690 In 162-163 1725, 1690 In 197-199 1735, Acm/ 1690 1690 1 OMe 1685 1685 t) Act 270-272 1730, CN 245-249 1690 245-249 1730, W 245-249 1730, NNAc 1695 0 Ac- 249-252 1730, CF3Me 1695 CF 1 695 3 > Me ? .. 263-264 1730 In f OMe MeNX X N- 166-169 16835 1685 AcN- z N 222.5-223.5 1730, 1690 In 165-168 1730, ONe 1685 OMe AcNN- 215-219 1730, 1695 ONe o Me 170-171 1725, Me 1690 Me In r- 169-172 1725, e 1690 1690 (2) In 25 ml of 6 N hydrochloric acid was dissolved 2.5 g of ethyl 7-(4-acetyl-1-piperazinyl)-6-fluoro-1-(2,4- difluorophenyl)-1 ,4-dihydro-4-oxo-1 ,8-naphthyridine-3-carboxylate, and the resulting solution was heated under reflux for 2 hours. Then, the reaction mixture was cooled to room temperature, and the pH thereof was adjusted to 12 with 1 N aqueous sodium hydroxide solution and then to 6.5 with acetic acid. The crystals thus deposited were collected by filtration, washed with 30 ml of water, and then dried to obtain 1.8 g of 6-fluoro-1 -(2,4-difluorophenyl)-1 ,4-dihydro-4-oxo-7-(1 -piperazinyl)-1 ,8-na phthyridine-3-carboxylic acid.

NMR (TFA-d,) 3 values: 3.30-4.50(8H, m), 7.00-7.85(3H, m), 8.33(1 H, d, J=13Hz), 9.21(1 H, s) In a similar manner, the compounds shown in Table 7 were obtained.

TABLE 7

Compound Physical Properties R2 R3 Melting point IRRKBr) PC) cm-t: vc=o lA HN yN- 252.5-254.5 1730 1 x MeNN- > 280 }720 (sh) F 279-280 1725 (sh) 234-236 1720 222-224 1725 \F > 280 1720 F Q(F MeNH4N- 254-258 1725 In 205-207 1730 "NUFJ FfF of n 225-227 1725 > 280 1725 C1 273-277 1720 Br 245-246 1725 Me > 280 " 1725 cN lf .. > 280 1730, MN2 1710 NH2 Table 7 (Cont'd)

Compound Physical Properties R2 R3 Melting point lR(KBr) f C) cm1:vc=o ($ In 232-236 1725, NNAc 1710, 1690 In HNu N- > 280 1725 CF3 230-232 1730 Note: * The nujol method was used in place of the KBr method.

Example 3 (1) In 5 ml of chloroform was dissolved 0.50 9 of ethyl 7-chloro-6-fluoro-1 -(2,4-difluorophenyl)-1 ,4-dihydro- 4-oxo-1 ,8-naphthyridine-3-carboxylate, and to the resulting solution were added 0.20 9 of 3-acetylaminopyrrolidine and 0.15 9 of triethylamine, after which the resulting mixture was subjected to reaction at 60 C for 1 hour. Then, the solvent was removed by distillation under reduced pressure, and the residue obtained was purified by a column chromatography [WAKO SILICA GEL C-200, eluant: chloroform:ethanol = 30:1 (by volume) to obtain 0.5 9 of ethyl 7-(3-acetylamino-1 -pyrrolidinyl)-S4luoro-1 -(2,4-difluorophenyl) 1 ,4-dihydro-4-oxo-1 ,8-naphthyridine-3-carboxylate having a melting point of 233-235 C.

IR (KBr) cm-1: vc=o 1725,1700 NMR (CDC13) â values: 1.32(3H,t, J=7Hz), 1.77-2.27(m)} (5H), 2.08 (5) 3.12-3.74 (4H, m), 4.02-4.74 (m) t))(3H), 4.29 (q, J=7Hz) 6.75-7.60 (4H. m). 7.93 (1H. d. J=8Hzi.

8.24(1 H, s) In a similar manner, the compounds shown in Table 8 were obtained.

TABLE 8

Compound Physical Properties R2 Ra Melting point IR{KBR) 1 cm1:v-0 f) NO 231-233 1730, Y 1700 1700 Me 2N 156 Hz 156 1730, 1690 AcHN t 203-205 1725, 1690 MeN Ac - 201-202 1725, 1695 0F Ne2N 165 1730, C - 165 1730, F P 1690 Table 8 (Cont'd)

R2 R3 Melting point IR(KBR) CC) cm vc=o MeN 1e MCNAlc 196-197 1730, 1695 0F AcNN F 241-244 1725, |Js > 241-244 1725, FF 1700 X G- -153-155 1735 OMe HO NO 185-187 1730, 1690 (2) In 2.5 ml of 6 N hydrochloric acid was dissolved 0.25 g of ethyl 7-(3-acetylamino-1-pyrrolidinyl)-6-fluoro 1-(2,4-difluorophenyl)-1 ,4-dihydro-4-oxo-1 ,8-naphthyridine-3-carboxylate, and the resulting solution was heated under reflux for 2 hours. Then, the reaction mixture was cooled to room temperature, and the pH thereof was adjusted to 12 and 1 N aqueous sodium hydroxide solution and then to 6.5 with acetic acid.The crystals thus deposited were collected by filtration, washed with 2 ml of water and then dried to obtain 0.18 9 of 7-(3-amino-1 -pyrrolidinyl )-6-fluoro-1 -(2,4-difluorophenyl)-1 ,4-dihydro-4-oxo-1 ,8-naphthyridine-3- carboxylic acid.

NMR (TFA-d,) å values: 2.25-2.85 (2H, m), 3.37-4.69(5H, m), 6.93-7.81 (3H, m), 8.22 (1 H, d, J= 11 Hz), 9.16 (1H, s) In a similar manner, the compounds shown in Table 9 were obtained.

TABLE 9

Example 4

Compound Physical properties R2 Ra Melting point lR(KBR) JS cm1:v=0 F XCN 260-263 1720 MeHN XCN- 259-261 1720(sh) 275-278 1720(sh) FFF N2N 278-280 1720 F (1) In 20 ml of chloroform were dissolved 2.0 g of ethyl 2,6-dichloro-5-fluoronicotinoylacetate, 0.96 9 of 3-acetylaminopyrrolidine and 0.8 9 of triethylamine and the resulting solution was subjected to reaction at 60 to 65"C for 2 hours. The reaction mixture was washed with 30 ml of water, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue thus obtained was purified by a column chromatography [WAKO SILICA GEL C-200, eluant: benzene: ethyl acetate = 1 : 1 (by volume)] to obtain 1.8 g of oily ethyl [2-chloro-5-fluoro-6-(3-acetylamino-1-pyrrolidinyl)- nicotinoyl] acetate.

IR (Neat) cm-1: vc=o 1740,1650 NMR (CDCI3) 8 values: 1.28 (3H, t, J=7Hz), 1.97 (3H, s), 1.90-2.62 (2H, m), 4.02 (2H, s), 4.15 (2H, q, J=7Hz), 3.50-4.70 (5H, m), 7.06 (1H, d, J=6Hz), 7.57 (1H, d, J=13Hz) (2) In 10 ml of benzene was dissolved 0.7 g of ethyl 2-chloro-5-fluoro-6-(3-acetylamino-1pyrrolidinyl)nicotinoyl-acetate, and to the resulting solution was added 0.235 g of N,Ndimethylformamidodimethylacetal, after which the resulting mixture was subjected to reaction at 70"C for 2 hours To the reaction mixture was added 0.243 g of 2,4-difluoroaniline, and the resulting mixture was subjected to reaction at room temperature for 8 hours.Subsequently, the solvent was removed by distillation under reduced pressure, and the residue thus obtained was purified by a column chromatography [WAKO SILICA GEL C-200, eluant: benzene: ethyl acetate = 1:1 (by volume)], and the oily product thus obtained was triturated with diisopropyl ether to obtain 0.25 g of ethyl 2-[2-chloro-5-fluoro-6-(3-acetylamino- 1-pyrrolidinyl)nicotinoyl]-3-(2,4-difluorophenylamino)acrylate having a melting point of 82-85"C.

IR (KBr) cm.-': vc=o 1695 (sh), 1660 NMR (CDCl3) 8values: 1.25 (3H, t, J=7Hz), 2.07 (3H, s), 1.90-2.30 (2H, m), 4.19 (2H, q, J=7Hz), 3.60-4.70 (5H, m), 6.49 (1H, d, J=6Hz), 6.80-7.50 (4H, m), 8.53 (1H, d, J=13Hz), 12.46 (1H, d, J=13Hz) (3) In 3 ml of N,N-dimethylformamide was dissolved 0.2 g of ethyl 2-[2-chloro-5-fluoro-6-(3-acetylamino-1 pyrrolidinyl)nicotinoyl]-3-(2,4-difluorophenylamino)acrylate, and to the resulting solution was added 0.04 g of sodium hydrogencarbonate, after which the resulting mixture was subjected to reaction at 120"C for 1 hour.Subsequently, the solvent was removed by distillation under reduced pressure, and the residue thus obtained was dissolved in 10 ml of chloroform. The resulting solution was washed successively with 10 ml of water and 10 ml of saturated aqueous sodium chloride solution, and thereafter dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the crystalline substance thus obtained was washed with 5 ml of diethyl ether to obtain 0.13 g of ethyl 7-(3-acetylamino-1 pyrrolidinyl)-6-fluoro-1 -(2,4-dif luorophenyl)-1,4-di hydro-4-oxo-l ,8-naphthyridine-3-carboxylate having a melting point of 233-235 C.

In a similar manner, ethyl 7-(3-acetylamino-1 -pyrrolidinyl)-6-fluoro-l -(4-fluorophenyl)-l ,4-dihydro-4-oxo- 1,8-naphthyridine-3-carboxylate was obtained. The physical properties of this product were identical with those obtained in Example 3-(1).

Example 5 (1) In 15 ml of 6 N hydrochloric acid was suspended 0.50 g of ethyl 7-chloro-6-fluoro-1 -(2,4-difluorophenyl) 1 ,4-dihydro-4-oxo-1 ,8-naphthyridine-3-carboxylate, and the suspension was heated under reflux for 3 hours.

Then, the reaction mixture was diluted with 50 ml of water and extracted with three 50-ml portions of chloroform. The combined extracts were washed with 100 ml of saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the crystalline substance thus obtained was washed with 15 ml of diethyl ether to obtain 0.40 g of 7-chloro-6-fluoro-1 -(2,4-difluorophenyl)-1 ,4-dihydro-4-oxo-l ,8-naphthyridine-3-carboxylic acid having a melting point of 244-248"C.

IR (KBr) cm-': vc=O 1720 NMR (d6-DMSO) ô values: 7.26-8.56 (3H, m), 8.86 (1 H, d, J =7Hz), 9.18 (1H,s) (2) In 3 ml of dimethylsulfoxide was suspended 0.30 g of 7-chloro-6-fluoro-1 -(2,4-difluorophenyl)-1 ,4dihydro-4-oxo-1 ,8-naphthyridine-3-carboxylic acid, and then 0.25 g of N-methylpiperazine was added to the resulting suspension, after which the resulting suspension was subjected to reaction at 60 C for 30 minutes.

Then, the solvent was removed by distillation under reduced pressure, and to the residue thus obtained was added 30 ml of water. The pH of the resulting mixture was adjusted to 12 with 10% aqueous sodium hydroxide solution, then to 7 with acetic acid. The crystalline substance deposited was collected by filtration and washed with 5 ml of water to obtain 0.24 g of 64luoro-1 -(2,4-difluorophenyl)-1 ,4-dihydro-7-(4-methyl-1 - piperazinyl)-4-oxo-1 ,8-naphthyridine-3-carboxylic acid having a melting point of 208-209"C.

IR (KBr) cm-1: vc=o 1730 NMR (TFA-d,) 5values: 3.30 (3H, s), 3.45-5.25 (8H, m), 7.12-8.10 (3H, m), 8.49 (1H, d, J=13Hz), 9.38 (1 H, s) Example 6 In 50 ml of N,N-dimethylformamidewas dissolved 5.0 g of ethyl 2-[2-chloro-5-fluoro-6-(4-methyl-1 piperazinyl)nicotinoyl]-3-(4-methoxy-2-methylphenylamino)-acrylate, then 1.03 g of sodium hydrogencar bonate was added to the resulting solution, and the resulting mixture was subjected to reaction at 120"C for 3 hours. Then, the solvent was removed by distillation under reduced pressure, and the residue thus obtained was dissolved in 50 ml of chloroform.The resulting solution was washed successively with 30 ml of water and 30 ml of saturated aqueous sodium chloride solution, and then dried over an hydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the crystalline substance obtained was washed with 30 ml of diethyl etherto obtain 2.38 9 of ethyl 6-fluoro-1,4-dihydro-1-(4-methoxy- 2-methylpheny[)-7-(4-methyl-1 -piperazinyl )-4-oxo-1,8-naphthyridine-3-carboxylate having a melting point of 144-145 C.

IR (KBr) cm-1: vc=o 1730, 1690 NMR (CDCl3) 8 valuers: 1.33 (3H,t,J=7Hz), 1.95 (3H,s), 2.20 (3H, s), 2.05-2.62 (4H, m), 3.32-3.63 (4H, m), 3.82 (3H, s), 4.32 (2H, q, J=7Hz), 6.60-7.15 (3H, m), 8.02 (1H, d, J=13Hz), 8.23(1 H, s) In a similar manner, the compounds shown in Table 10 were obtained.

TABLE 10

Compound Physical properties R2 R3 Me Iting point lR(KBR) ("C) cm7:i;c=o MeN N- 199-202 1725, F 1685 F 168-171 1735, F 1720 174-175 1730, ONe 1695 4 .- amorphous 1725, NEXAC 1690 o 186-189 1725, F 1690 OMe ssls .. 166-168 1730, Me 1695 OMe Ne AcM N- 169-172 1725, 1690 OMe Example 7 In 5 ml of 47% hydrobromic acid was dissolved 2.0 g of ethyl 6-fluoro-1,4-dihydro-1-(4-methoxy-2- methylphenyl)-7-(4-methyl-1 -piperazinyl)-4-oxo-1 ,8-naphthyridine-3-carboxylate, and the resulting solution was subjected to reaction at '120"C to 1 250C for 2 hours. The pH of the reaction mixture was adjusted to 13 with 10% aqueous sodium hydroxide solution, then to 6.5 with acetic acid. The crystals thus deposited were collected by filtration and washed with 10 ml of water to obtain 1.8 g of 6-fluoro-1,4-dihydro-1-(4-hydroxy-2- methylphenyl)-7-(4-methyl-1 -piperazinyl)-4-oxo-1 ,8-naphthyridine-3-carboxylic acid having a melting point of > 280 C.

IR (KBr cm-l: vc=o 1725,1700 (sh) NMR (TFA-d) 8 values: 2.08 (3H, s), 3.12 (3H, s), 2.88-5.12 (8H, m), 6.93-7.62 (3H, m), 9.25 (1 H, s), 9.43 (1H, d,J=13Hz) In a similar manner, the compounds shown in Table 11 were obtained.

TABLE 11

Compound Physical properties R2 R3 Melting point IRIKBrJ PC) cm-':vc,o o C N- 143-146 1725, ON 1710 In NM N- > 280 1710 MeN N- > 280 1710 'U In FtN N- > 280 1730 \J n-PrN N- > 280 1725 i-PrN N- > 280 1715 In HO ~ N N- 200-205 1720, 1705 /\ Nr 13~ > 280 1725 'U In ( MeN N- 245-250 1725, \ ' (decomp.) ON oH /i/ > 280 1725, 1690 In oH NM N- 220-224 1725, 'U F In MeN N- > 280 1730, u 1710(sh) > 280 1730 ON In " N- > 255 1725 V F In ( t F MeN 3 N- 251-252 1720 oN ON t > 280 1725 (sh), 1700 Me Ne 228-230 1730, ON my 1700 (sh) e/ Me HN N- 275 1720 ON Example 8 In 10 ml of 47% hydrobromic acid was dissolved 0.40 g of ethyl 6-fluoro-1,4-dihydro-1 -(4-methoxyphenyl)- 7-(1-pyrrolidinyl)-4-oxo-1,8-naphthyridine-3-carboxylate, and the resulting solution was subjected to reaction at120 to 1250Cfor2 hours. The pH of the reaction mixture was adjusted to 13 with 10% aqueous sodium hydroxide solution, then to 6.5 with acetic acid. The crystals thus deposited were collected by filtration and washed with 4 ml of water to obtain 0.30 g of 64luoro-1 ,4-dihydro-1 -(4-hydroxyphenyl)-7-(1 - pyrrolidinyl)-4-oxo-1 ,8-naphthyridine-3-carboxylic acid having a melting point of 263-265 C.

IR (KBr) cm-': vc=o 1725, 1705 NMR (TFA-d) values: 1.54-2.40 (4H, m), 3.14-4.14 (4H, m), 6.95-7.69 (4H, m), 8.09 (1H, d,J=12Hz), 9.14 (1H,s) In a similar manner, the following compound was obtained: 6-Fluoro-1 ,4-dihydro-1 -(4-hydroxyphenyl)-7-(3-hydroxy-1 -pyrrolidinyl)-4-oxo-1 ,8-naphthyridine-3- carboxylic acid Melting point: 180-183"C IR (KBr) cam~':: vc=o 1725,1705 Example 9 To 0.1 g of ethyl 7-(4-acetyl-1 -piperazinyl )-6-fluoro-1 -(4-fluorophenyl)-1 ,4-dihydro-4-oxo-1 ,8- naphthyridine-3-carboxylate were added 2 ml of 1 N aqueous sodium hydroxide solution and 2 ml of ethanol, and the resulting solution was subjected to reaction at 40" to 50"C for 10 minutes. Subsequently, acetic acid was added to the reaction mixture to adjust the pH thereof to 6.5. Then, the mixture was extracted with two 5-mI portions of chloroform. The combined extracts were washed successively with 5 ml of water and 5 ml of saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate.

The solvent was removed by distillation under reduced pressure, and the crystalline substance thus obtained was washed with 2 ml of diethyl etherto obtain 0.08 g of 7-(4-acetyl-1-piperazinyl)-6-fluoro-1-(4 fluorophenyl)-1 ,4-dihydro-4-oxo-1 ,8-naphthyridine-3-carboxylic acid having a melting point of > 280 C.

IR (KBr) cm-'; vc=O 1730 NMR (d6-DMSO) â values: 2.05 (3H, s), 3.57 (8H, bs), 7.13-7.80 (4H, m),8.13 (1H, d,J=13Hz), 8.70 (1 H, s) In a similar manner, the compounds shown in Table 12 were obtained.

TABLE 12

Compound Physical properties R2 Ra Melting point IR (KBR) ,' CJ cm-': vc=o In MeN N- 277-280 1720 'U 282-290 1725, F 1700 (sh) Me NM N- 268-270 1725 'U Me s eN N- 283-285 1720 , Me Me NMThN 267-270 1730 y Me IOvN N- 138-139 F 'U 1690 In > 280 1730, 1700 (sh) F F MeN N- > 280 1720 F 'U 208-209 1730 Me N- 208-209 1730 Me > 280 1720 Me 1735 NeMM- 210-211 1735 Me 225-226 1720 U /7 " N- 219-220 1730 'U MeN N- 283-284 1730, MeN im 1700 (sh) m\ O MeN N- 277-280 1730, Br 'U 1700 (sh) 271-274 1725 Me (81 " 250-252 1725 OMe Example 10 To 0.10 g of ethyl 641 uoro-1 -(4-fluorophenyl)-1 ,4-dihydro-7-(3-hydroxy-1 -pyrrolidinyl )-4-oxo-1 ,8- naphthyridine-3-carboxylate were added 2 ml of 1 N aqueous sodium hydroxide solution and 2 ml of ethanol, and the resulting mixture was subjected to reaction at 40 to 50for 10 minutes. Subsequently, acetic acid was added to the reaction mixture to adjust the pH thereof to 6.5. Then, the mixture was extracted with two 5-ml portions of chloroform. The combined extracts were washed successively with 5 ml of water and 5 ml of saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate.

The solvent was removed by distillation under reduced pressure, and the crystalline substance thus obtained was washed with 2 ml of diethyl etherto obtain 0.08 g of 6-fluoro-1 -(4-fluorophenyl)-1,4-dihydro-7-(3- hydroxy-1-pyrrolidinyl)-4-oxo-1 ,8-naphthyridine-3-carboxylic acid having a melting point of > 280 C.

IR (KBr) cm-1: vc=O 1730 NMR (d6-DMSO å values: 1.92-2.52 (2H, m), 3.22-5.00 (5H, m), 6.97-7.60 (4H, m), 8.01(1 H, d, J=1 1Hz), 9.00 (1 H, s) In a similar manner, the compounds shown in Table 13 were obtained.

TABLE 13

Compound Physical properties R2 Ra Melting point IR (KBr) C cm-': vc=o Me2N 264-265 1725 J o F F Example 71 In 2.5 ml of conc. hydrochloric acid was dissolved 0.25 g of 6-fluoro-1,4-dihydro-1-(4-hydroxy-2 methylphenyl)-4-oxo-7-(1 -piperazinyl)-1 ,8-naphthyridine-3-carboxylic acid, and then 20 ml of ethanol was added to the resulting solution, after which the resulting mixture was stirred at room temperature for 15 minutes. The crystals thus deposited were collected by filtration and washed with 5 ml of ethanol to obtain 0.2 g of the hydrochloric acid salt of 6-fluoro-1 ,4-dihydro-1-(4-hydroxy-2-methylphenyl )-4-oxo-7-( 1 - piperazinyl)-1 ,8-naphthyridine-3-carboxylic acid having a melting point of > 280 C.

IR (KBr) cm-1: vc=o 1725 (sh), 1705 In a similar manner, the compounds shown in Table 14 were obtained.

TABLE 14 Hydrochloric acid salt of

Compound Physical properties R2 Ra Melting point IR (KBr) CC1 cm-':vc=o F MeN\JN- 283 1730 F NeNff- 283 1730 0 In NM F u 275-278 1720 F 249-252 1730 F (decamp,) ( ., > 280 1710 ON In MeN N- 280-282 1730 'U In o MN N- 279-283 1720 (sh), 'U ON 1705 F 1720 (sh), t F MeN N- 266-269 1700 ON Ne " 282 1730 ON Example 12 In 20 ml of conc. hydrochloric acid was dissolved 2.0 g of 7-(3-amino-1-pyrrolidinyl)-6-fluoro-1-(2,4- difluorophenyl)-1 ,4-dihydro-4-oxo-1 ,8-naphthyridine-3-carboxylic acid, then 200 ml of ethanol was added to the resulting solution at room temperature, and the resulting solution was stirred for 15 minutes.The crystals thus deposited were collected by filtration and washed with 40 ml of ethanol to obtain 1.4 g of the hydrochloric acid salt of 7-(3-amino-1 -pyrrolidinyl)-6-fluoro-l -(2,4-difluorophenyl)-1 ,4-dihydro-4-oxo-1 ,8- naphthyridine-3-carboxylic acid having a melting point of 247-2505C (decomp.).

IR (KBr) cm-1: vc=o 1730 Example 13 (1) In 2.5 ml of chloroform were dissolved 0.5 g of ethyl 2-(2,6-dichloro-5-fluoronicotinoyl)-3-(2,4- difluorophenylamino)acrylate, 0.143 g of N-methylpiperazine and 0.145 g of triethylamine, and the resulting solution was heated under reflux for 3.5 hours. Then, the reaction mixture was washed successively with 3 ml of water and 3 ml of saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate.The solvent was removed by distillation under reduced pressure, and the residue thus obtained was purified by a column chromatography [WAKO SILICA GEL C-200, eluant: chloroform : ethanol = 50:1 (by volume)] to obtain 0.294 g of oily ethyl 2-[2-chloro-5-fluoro-6-(4-methyl-1-piperazinyl)nicotinoyl]- 3-(2,4-difluorophenylamino)acrylate.

IR (Neat) cm-1: vc=O 1735,1700 NMR (CDCl3) 5 values: 1.13 (3H, t, J=7Hz), 2.36 (3H, s), 2.55 (4H, t, J=5Hz), 3.70 (4H, t, J=5Hz), 4.15 (2H, q, J=7Hz), 6.77-7.90 (4H, m), 8.51 (1H,d,J=13Hz),12.50(1H,d,J=13Hz) (2) By treating 0.2 g of ethyl 2-[2-chloro-5-fluoro-6-(4-methyl-1-piperazinyl)nicotinoyl]-3-(2,4- difluorophenylamino)acrylate in the same manner as in Examples 6 and 9,0.12 g of 6-fluoro-1-(2,4- difluorophenyl)-l ,4-dihydro-7-(4-methyl-l-piperazinyl)-4- ,8-naphthyridine-3-carboxylic acid having a melting point of 208-209 C was obtained.

Example 14 To 0.3 g of ethyl 7-(4-ethoxycarbonyl-2-methyl-1 -piperazinyl)-6-fluoro-1 -(2,4-difluorophenyl)-1 ,4-dihydro- 4-oxo-1 ,8-naphthyridine-3-carboxylate were added 5 ml of 1 N aqueous sodium hydroxide solution and 5 ml of ethanol, and the resulting mixture was subjected to reaction at 900C for 2 hours. Then, acetic acid was added to the reaction mixture to adjust the pH thereof to 6.5. The crystals thus deposited were collected by filtration, washed with water and then dried to obtain 0.2 g of 6-fluoro-1 -(2,4-difluorophenyl)-1 ,4-dihydro-7 (2-methyl-1 -piperazinyl)-4-oxo-1 ,8-naphthyridine-3-carboxylic acid having a melting point of 230-239 C.

IR (KBr) cm-1: vc=o 1730 NMR (TFA-d, 8values: 1.50 (3H, s), 3.20-5.15 (7H, m), 7.00-7.90 (3H, m), 8.35 (1H, d, J=13Hz), 9.20 (1H,s) Example 15 In 20 ml of ethanol was suspended 1.0 g of dihydrochloric acid salt of 3-aminopyrrolidine, and 2.06 g of triethylamine was added to the resulting suspension to form a solution. Then, 2.0 g of ethyl 7-chloro-6-fluoro-1 -(2,4-difluorphenyl)-1 ,4-dihydro-4-oxo-1 ,8-naphthyridine-3-carboxylate was added to the solution at 30"C over 15 minutes, and the resulting mixture was subjected to reaction at the same temperature for 3 hours.After the completion of the reaction, 30 ml of water was added to the reaction mixture, and the crystals thus deposited were collected by filtration and washed with 4 ml of water. The crystalline substance thus obtained was suspended in 13 ml of 6 N hydrochloric acid, and the resulting suspension was heated under reflux for 2 hours. Subsequently, the reaction mixture was cooled, and the crystals thus deposited were collected by filtration and washed with two 2-ml portions of water to obtain 1.97 g of hydrochloric acid salt of 7-(3-amino-1 -pyrrolidinyl)-64luoro-1 -(2,4-difluorophenyl )-1 ,4-dihydro-4-oxo- 1 ,8-naphthyridine-3-carboxylic acid.

IR (KBr) cm-l: vc=o 1730 Example 16 In 75 ml of ethanol and 75 ml of water was suspended 10.0 g of 7-(3-amino-1 -pyrrolidinyl)-6-fluoro-1 -(2,4 difluorophenyl)-1 ,4-dihydro-4-oxo-1 ,8-naphthyridine-3-carboxylic acid. To the resulting suspension was added 5.2 g of p-toluenesulfonic acid monohydrate at 40eC, and the resulting mixture was stirred at the same temperature for 30 minutes.Subsequently, the reaction mixture was cooled to 15 C, and the crystals thus deposited were collected by filtration and washed with a mixed solvent of 5 ml of ethanol and 5 ml of water to obtain 12.8 g of the p-toluenesulfonic acid monohydrate salt of 7-(3-amino-1 -pyrrolidinyl)-6-fluoro-1 -(2,4- difluorophenyl)-1 ,4-dihydro-4-oxo-1 ,8-naphthyridine-3-carboxylic acid having a melting point of 258-2605C.

IR (KBr) cm-1: vc=o 1735 NMR (DMSO-d6) 3values: 1.82-2.42 (m) (5H), 3.12-4.30 (5H, m), 2.27 1 (5) 6.92-8.17 (8H, m), 8.79 (1H, s) In a similar manner, the following compound was obtained: Oxalic acid salt of 7-(3-amino-1 -pyrrolidinyl)-64luoro-1 -(2,4-difluorophenyl)-1 ,4-dihydro-4-oxo-1 ,8- naphthyridine-3-carboxylic acid Melting point ("C): 250-253 IR (KBr) cm-1:: vc=o 1730 Example 17 To the solution of 1.6 g of methanesulfonic acid and 25 ml of acetic acid was added 5.00 g of 7-(3-amino-1 -pyrrolidinyl)-6-fluoro-1 -(2,4-difluorophenyl)-1 ,4-dihydro-4-oxo-1 ,8-naphthyridine-3-carboxylic acid, after which the resulting suspension was stirred at room temperature to form a solution. To the solution was added 100 ml of ethanol at 40 to 45"C over 30 minutes. Subsequently, the reaction mixture was cooled to room temperature, and stirred for 30 minutes.The crystals thus deposited were collected by filtration and washed with three 20-ml portions of ethanol to obtain 3.12 g of methanesulfonic acid salt of 7-(3-amino-1 -pyrrolidinyl)-6-fluoro-1 -(2,4-difluorophenyl )-1 ,4-dihydro-4-oxo-1 ,8-naphthyridine-3-carboxylic acid having a melting point of > 300 C.

IR (KBr) cm-1: vc=o 1735 In a similar manner, the following compound was obtained: Sulfuric acid salt of 7-(3-amino-1 -pyrrolidinyl)-64luoro-1 -(2,4-difluorophenyl)-1 ,4-dihydro-4-oxo-1 ,8- naphthyridine-3-carboxylic acid Melting point (aC): 220-230 IR (KBr) cm-1: vc=o 1735 Preparation Example 1 With 50 g of 64luoro-1 -(2,4-difluorophenyl )-1 ,4-dihydro-4-oxo-7-(1 -piperazinyl)-1 ,8-naphthyridine-3- carboxylic acid were blended 49 g of crystalline cellulose, 50 g of corn starch and 1 g of magnesium stearate, and the blend was compressed into 1,000 flat-type tablets.

Preparation Example 2 With 100 g of 6-fluoro-1 -(2,4-difluorophenyl)-1 ,4-dihydro-4-oxo-7-(1-piperazinyl)-1 ,8-naphthyridine-3- carboxylic acid was blended 50 g of corn starch, and 1,000 capsules were filled with the resulting blend to obtain capsules.

Preparation Example 3 With 50 g of 7-(3-amino-1 -pyrrolidinyl)-1 -(2,4-difluorophenyl)-64luoro-1 ,4-dihydro-4-oxo-1 ,8- naphthyridine-3-carboxylic acid were blended 49 g of crystalline cellulose, 50 g of corn starch and 1 g of magnesium stearate, and the blend was compressed into 1,000 flat-type tablets.

Preparation Example 4 With 100 g of 7-(3-amino-1 -pyrrolidinyl)-1 -(2,4-difluorophenyl)-6-fluoro-l ,4-dihydro-4-oxo-l ,8- naphthyridine-3-carboxylic acid was blended 50 g of corn starch, and 1,000 capsules were filled with the resulting blend to obtain capsules.

Claims

1. A 1 ,4-dihydro-4-oxonaphthyridine derivative represented by the formula, or a salt thereof:

wherein R1 represents a hydrogen atom or a carboxyl-protecting group, R2 represents a substituted or unsubstituted aryl group, and R3 represents a halogen atom or a substituted or unsubsituted cyclic amino group.

2. A 1 ,4-dihydro-4-oxonaphthyridine derivative or a salt thereof according to Claim 1, wherein R2 represents a substituted or unsubstituted phenyl group.

3. A 1 ,4-dihydro-4-oxonaphthyridine derivative or a salt thereof according to Claim 2, wherein R3 represents a substituted or unsubstituted cyclic amino group selected from the group consisting of 1-pyrrolidinyl, piperidino, 1-piperazinyl and morpholino group.

4. A 1,4-dihydro-4-oxonaphthyridine derivative or a salt thereof according to Claim 3, wherein R2 represents a phenyl group which may be substituted by at least one substituent selected from the group consisting of a halogen atom, an alkyl group, a hydroxyl group, an alkoxy group, a cyano group, an amino group, an acylamino group and a trihalogenoalkyl group.

5. A 1 ,4-dihydro-4-oxonaphthyridine derivative or a salt thereof according to Claim 4, wherein R3 represents a 1-pyrrolidinyl, piperidino, 1-piperazinyl or morpholino group which may be substituted by at least one substituent selected from the group consisting of alkyl, amino, aminoalkyl, hydroxyalkyl, hydroxyl, alkenyl, acyl, alkylamino, dialkylamino, cyano, oxo, aralkylamino, acylamino, alkoxycarbonyl and N-acyl-Nalkylamino groups.

6. A 1 ,4-dihydro-4-oxonaphthyridine derivative or a salt thereof according to Claim 5, wherein R3 represents a 1-pyrrolidinyl, piperidino, 1-piperazinyl, or morpholino group which may be substituted by at least one substituent selected from the group consisting of alkyl, amino, hydroxyalkyl, hydroxyl, alkenyl, acyl, alkylamino, dialkylamino, acylamino, alkoxycarbonyl and N-acyl-N-alkylamino groups.

7. A 1 ,4-dihydro-4-oxonaphthyridine derivative or a salt thereof according to Claim 6, wherein R2 represents a phenyl group substituted by at least one halogen atom.

8. A 1 ,4-dihydro-4-oxonaphthyridine derivative or a salt thereof according to Claim 7, wherein R2 represents a 4-fluorophenyl or 2,4-difluorophenyl group.

9. A 1 ,4-dihydro-4-oxonaphthyridine derivative or a salt thereof according to Claim 2, wherein R3 represents a 1-pyrrolidinyl group which may be substituted by at least one substituent selected from the group consisting of amino, hydroxyl, alkylamino, dialkylamino, acylamino and N-acyl-N-alkylamino groups.

10. A 1 ,4-dihydro-4-oxonaphthyridine derivative or a salt thereof according to Claim 9, wherein R2 represents a phenyl group which may be substituted by at least one substituent selected from the group consisting of a halogen atom, an alkyl group, a hydroxyl group, an alkoxy group, a cyano group, an amino group, an acylamino group and a tri-halogenoalkyl group.

11. A 1,4-dihydro-4-oxonaphthyridine derivative or a salt thereof according to Claim 10, wherein R3 represents a 1-pyrrolidinyl group substituted by an amino or acylamino group.

12. A 1 ,4-dihydro-4-oxonaphthyridine derivative or a salt thereof according to Claim 11, wherein R2 represents a phenyl group substituted by at least one halogen atom.

13. A 1 ,4-dihydro-4-oxonaphthyridine derivative or a salt thereof according to Claim 12, wherein R2 represents a 4-fluorophenyl or 2,4-difluorophenyl group.

14. A 1 ,4-dihydro-4-oxonaphthyridine derivative or a salt thereof according to Claim 2, wherein R3 represents a 3-amino-1-pyrrolidinyl group.

15. A 1 ,4-dihydro-4-oxonaphthylidine derivative or a salt thereof according to Claim 14, wherein R2 represents a phenyl group which may be substituted by at least one substituentselected from the group consisting of a halogen atom, an alkyl group, a hydroxyl group, an alkoxy group, a cyano group, an amino group, an acylamino group and a trihalogenoalkyl group.

16. A 1,4-dihydro-4-oxonaphthylidine derivative or a salt thereof according to Claim 15, wherein R2 represents a phenyl group substituted by at least one halogen atom.

17. A 1 ,4-dihydro-4-oxonaphthyridine derivative or a salt thereof according to Claim 16, wherein R2 represents a 4-fluorophenyl or 2,4-difluorophenyl group.

18. A 1 ,4-dihydro-4-oxonaphthyridine derivative or a salt thereof according to Claim 2, wherein R3 represents a 1-piperazinyl group which may be substituted by at least one substituent selected from the group consisting of alkyl, hydroxylalkyl, alkenyl, acyl and alkoxycarbonyl groups.

19. A 1 ,4-dihydro-4-oxonaphthyridine derivative or a salt thereof according to Claim 18, wherein R2 represents a phenyl group which may be substituted by at least one substituent seleted from the group consisting of a halogen atom, an alkyl group, a hydroxyl group, an alkoxy group, a cyano group, an amino group, an acylamino group and a trihalogenoalkyl group.

20. A 1 ,4-dihydro-4-oxonaphthyridine derivative or a salt thereof according to Claim 19, wherein R3 represents a 1-piperazinyl group.

21. A 1 ,4-dihydro-4-oxonaphthyridine derivative or a salt thereof according to Claim 20, wherein R2 represents a phenyl group substituted by at least one halogen atom.

22. A 1 ,4-dihydro-4-oxonaphthyridine derivative or a salt thereof according to Claim 16, wherein R2 represents a 4-fluorophenyl or 2,4-difluorophenyl group.

23. 7-Chloro-1 -(2,4-difl uorophenyl)-6-fl uoro-1 ,4-dihydro-4-oxo-1 ,8-naphthyridine-3-carboxylic acid or a salt thereof.

24. 7-(3-Amino-1-pyrrolidinyl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1 ,8-naphthyridine-3- carboxylic acid our a salt thereof.

25. 1 -(2,4-Difl uorophenyl )-6-fluoro-1 ,4-dihydro-4-oxo-7-(1 -piperazinyl)-1 ,8-naphthyridine-3-carboxyl ic acid ora saltthereof.

26. 7-(3-Amino-1-pyrrolidinyl)-6-fluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-1 ,8-naphthyridine-3- carboxylic acid or a salt thereof.

27. A process for producing a 1 ,4-dihydro-4-oxo-naphthyridine derivative represented by the formula, or a salt thereof

wherein R1 represents a hydrogen atom or a carboxyl-protecting group, R2 represents a substituted or unsubstituted aryl group, and R3 represents a halogen atom or a substituted or unsubstituted cyclic amino group, characterized by subjecting the compound represented by the formula, or a salt thereof:

wherein Ra represents a carboxyl-protecting group, and R2 and R3 have the same meanings as defined above to ring closure reaction, and then, if desired, removing the carboxyl-protecting group.

28. A process according to Claim 27, wherein R2 represents a substituted or unsubstituted phenyl group.

29. A process according to Claim 28, wherein R3 represents a 1-pyrrolidinyl group which may be substituted by at least one substituent selected from the group consisting of amino, hydroxyl, alkylamino, acylamino and N-acyl-N-alkylamino groups.

30. A process according to Claim 29, wherein R3 represents a 1-pyrrolidinyl group substituted by an amino or acylamino group.

31. A process according to Claim 30, wherein R2 represents a phenyl group substituted by at least one halogen atom.

32. A process according to Claim 31, wherein R2 represents a 4-fluorophenyl or 2,4-difluorophenyl group.

33. A process according to Claim 28, wherein R3 represents a 1 -piperazinyl group which may be substituted by at least one substituent selected from the group consisting of alkyl, hydroxylalkyl, alkenyl, acyl and alkoxycarbonyl groups.

34. A process according to Claim 33, wherein R3 represents a 1-piperazinyl group.

35. A process according to Claim 34, wherein R2 represents a phenyl group substituted by at least one halogen atom.

36. A process according to Claim 35, wherein R2 represents a 4-fluorophenyl or 2,4-difluorophenyl group.

37. A process according to Claim 27, wherein the ring closure reaction is conducted at a temperature of 20"to160"C.

38. A process for producing a 1 ,4-dihydro-4-oxo-naphthyridine derivative represented by the formula, or a salt thereof:

wherein R1 represents a hydrogen atom or a carboxyl-protecting group, R2 represents a substituted or unsubstituted aryl group, and R3b represents a substituted or unsubstituted cyclic amino group, characterized by reacting the compound represented by the formula, or a salt thereof:

wherein R3a represents a halogen atom, and R1 and R2 have the same meanings as defined above, with a compound represented by the formula, or a salt thereof: R3b - H wherein R3b has the same meaning as defined above.

39. A process according to Claim 38, wherein R2 represents a substituted or unsubstituted phenyl group.

40. A process according to Claim 39, wherein R3b represents a 1-pyrrolidinyl group which may be substituted by at least one substituent selected from the group consisting of amino, hydroxyl, alkylamino, dialkylamino, acylamino and N-acyl-N-alkylamino groups.

41. A process according to Claim 40, wherein R3b represents a 1-pyrrolidinyl group substituted by an amino or acylamino group.

42. A process according to Claim 41, wherein R2 represents a phenyl group substituted by at least one halogen atom.

43. A process according to Claim 42, wherein R2 represents a 4-fluorophenyl or 2,4-difluorophenyl group.

44. A process according to Claim 39, wherein R3b represents a 1-piperazinyl group which may be substituted by at least substituent selected from the group consisting of alkyl, hydroxylalkyl, alkenyl, acyl and alkoxycarbonyl groups.

45. A process according to Claim 44, wherein R3b represents a 1-piperazinyl group.

46. A process according to Claim 45, wherein R2 represents a phenyl group substituted by at least one halogen atom.

47. A process according to Claim 46, wherein R2 represents a 4-fluorophenyl or 2,4-difluorophenyl group.

48. A process according to Claim 37, wherein the reaction is conducted at a temperature of 0 to 1 500C.

49. An antibaceterial agent comprising a 1,4-dihydro-4-oxonaphthyridine derivative represented by the formula or a salt thereof:

wherein R1 represents a hydrogen atom or a carboxyl-protecting group, R2 represents a substituted or unsubstituted aryl group, and R3 represents a halogen atom or a substituted or unsubstituted cyclic amino group.

50. A 1,4-dihydro-4-oxonaphthyridine derivative as claimed in claim 1 and substantially as described in any one of the specific examples hereinbefore set forth.

51. A process for producing the derivative as claimed in claim 1 and substantially as described in any one of the specific examples hereinbefore set forth.

52. Each and every novel embodiment herein set forth taken separately or in combination.