GB2191776A

GB2191776A - 6-Fluoro-1,4-dihydro-4-oxonaphthyridines

Info

Publication number: GB2191776A
Application number: GB08716897A
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: 1987-07-17
Publication date: 1987-12-23
Anticipated expiration: 2007-07-17
Also published as: CH673458A5; FR2614620A1; GB8510297D0; NL187314C; HUT38634A; DK165877B; IL75021A; HU194226B; FI80453C; RO95509B; DD238795A5; NO162238C; DE3514076C2; IT8548002A0; ES8700256A1; JPS6320828B2; FR2563521B1; SE8804586L; ES542584A0; SE463102B

Abstract

Novel compounds of the formula I <IMAGE> wherein R<1> is H or a carboxyl protecting group, R<2> is substituted or unsubstituted aryl and R<3> is halogen or substituted or unsubstituted cyclic amino, and salts thereof, are antibacterial agents.

Description

GB 2 191776 A 1

SPECIFICATION

1,4-dihydro-4-oxonaphthyridine derivatives and salts thereof, process for producing the same and antibacte rial agents comprising the same 5 Description

This invention relates to a novel 1,4-dihydro-4-oxonaphthyridine derivative having a substituted or unsubsti tuted 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. 10 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-(1pipera-zinyi)-3-quinolinecarboxylic acid (norfloxacin) orthe like, as a substitute for the conventional synthetic 15 antibacterial agents. These compounds have excellent antibacterial activities against various Gramnegative 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 20 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-4oxonaphthyridine derivative and a salt thereof having excellent properties, for example, strong antibacterial activities against Gram-positive and Gram negative bacteria, particularly against anti biotic-resistant bacteria, and giving high concentrations in blood when administered orally or parenterally, and being high in safety. 25 Another object of this invention is to provide a process for producing a novel 1,4-dihydro-4 oxonaphthyridine derivative and a salt thereof. 1 A further object of this invention is to provide an antibacterial agent which Is useful for the treatment of infections of bacteria or the like and which comprises a novel 1,4- dihydro-4-oxonaphthyridine derivative or a saitthereof. 30 According to this invention, there is provided a 1,4-dihydro-4- oxonaphthyridine derivative represented by the general formula:

0 F - 1 35 COOR - r1 tNZ R 3 -12 40 R wherein R' represents a hydrogen atom or a carboxyl-protecting group, R 2 represents a substituted or unsubstituted aryl group, and R 3 represents a halogen atom or a substituted or unsubstituted cyclic amino group, and a salt thereof. 45 Further, this invention provides a process for producing a 1,4-dihydro-4oxonaphthyridine derivative represented by the general formula [11 or a salt thereof, and also an antibacterial agent comprising the 1,4-dihydro-4-oxonaphthyridine derivative represented by the general formula [11 or a salt thereof.

This invention will be explained in detail below.

In the compound represented by the general formula [11 or a salt thereof, the carboxyl-protecting group for 50 R' 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. 55 Among these carboxyi-protecting groups, the preferred protecting groups include, for example, carboxyl protecting groups described in Japanese Patent Application Kokai (Laid- Open) No. 80,665184.

The aryl group for R 2 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 60 Cl-Cloalkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyi, heptyl, octyl and the like; hydroxyl group; alkoxy groups, for example, straight of branched chain Cl-Cloalkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n- butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy and the like; cyano group; amino group; acylamino groups, for example, Cl-C4acylarnino groups such as formylamino, acetylamino, propionylamino, butyrylami- 65 2 GB 2 191776 A 2 no and the like; and trihalogenalkyl groups, for example, trihalogeno-Cl- C4-alkyl groups such as trifluoromethyl, trichloromethyl and the like.

Moreover, the halogen atom for R 3 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 -pyrroliclinyl, 5 piperidino, 1 -piperaziny], 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 Cl-C4alkyl groups such as methyl, ethyl, n- propyi, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl; amino group; aminoalkyl groups, for example, amino-Cl-C4a]kyl groups such as aminomethyl, 2-aminoethyl, 3-aminopropyl and the like; hydroxyalkyl groups, for example, hydroxy-Cl- 10 C4alkyl groups such as hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl and the like; hydroxyl group; aikenyl groups, for example, C2-C4alkenyl groups such as vinyl, allyl and the like; acyl groups, for example, Cl-C4acyl groups such as formy], acetyl, propiony], butyryl and the like; aikylamino groups, for example, Cl C4alkylamino groups such as methylamino, ethylamino, n-propylamino, isopropylamino and the like; dialkylamino groups, for example, di-Cl-C4alkyiamino groups such as dimethylamino, diethylamino, di-n- 15 propylamino, methylethylamino and the like; cyano group; oxo group; aralkylamino groups, for example, ar-Cl-C4alkylamino groups such as benzylamino, phenethylamino and the like; acylamino groups, for example, Cl-C4acylarnino groups such as acetylamino, propionylamino, butrylamino and the like; alkoxycar bonyl groups, for example, Cl-C4alkoxycarbonyl groups such as methoxycarbony], ethoxycarbonyi, n propoxycarbonyl, isopropoxycarbonyl and the like; and N-acyl-N-alkylamino groups, for example, Wacyl-N- 20 aikylamino groups wherein the nitrogen of the above-mentioned alkylamino group is substituted by a Cl-C4acyl group such as acetyl, propionyl, butyryl or the like.

Among the compounds represented by the general formula [11, those wherein R' represents a fluorine substituted phenyl group and R' represents a substituted or unsubstituted 1-pyrrolidinyl or 1-piperazinyl group are preferred, and those wherein R' is a 2,4-difluorophenyl group and R 3 is a 3-amino-l-pyrrolidinyl 25 group are more preferable.

The salt of the compound represented by the general formula [11 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 30 acid and the like; salts with sulfonic acids such as methane-sulfonic acid, p-toluenesulfonic acid, naphthalene sulfonic 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, clibenzylamine, N-benzyi-p-phenethylamine, 1-ephenamine, N,N-dibenzyiethylenediamine, triethylamine, trimethylamine, 35 tributylamine, pyridine, N,N-dimethyianiline, N-methylpiperidine, Nmethyimorpholine, diethylamine, dicyc lohexylamine and the like.

Ifthe compound represented by the general formula [11 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. 40 Antibacterial activities and acute toxicities are illustrated with reference to typical compounds of this invention.

1. ANTIBACTERIAL ACTIVITY Testmethod 45 According to the standard method of Japan Society of Chemotherapy [CHEMOTHERAPY, 29(1), 76-79 (198M, a bacteria solution obtained by culturing in Heart Infusion broth (manufactured by Eiken Kagaku) at 370C 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 ofthe bacteria was observed, to determine the minimum concentration at which the growth of the bacteria was inhibited as MIC (1Lg/mi). The amount of the inoculated bacteria was 104 50 cells/plate (106 cells/m]). The MIC values ofthe following test compounds areas shown in Table 1.

Symbols used in Table 1 have the following meanings:

11: penicillinase-producing bacteria.

2: cephalosporinase-producing bacteria, 55 3: inoculation size: 108 cells/m], Me: methyl group, Et: ethyl group, n-Pr: n-propyl group, i-Pr: isopropyl group 60 0) CA) CA) C> Table 1

F COOH it 110 110 r, R 3 N N 3 MeN, CN- CN II0 1 R -----CN R 2 Compound 1 2 3 4 Compound NO _ Bacteria No.

St. aureus FDA209P 0.1:50. 0 5 50. 0 5 0.1 St. epidermidis I1D866 0.1 o.os 50.05 0.1 St. aureus F-1371 0.1:50.05:50. 0 5 0.1 E. coli NIIIJ:50.05 0.39 0.1 550.05 E. coli TK-111:50.05 0.2 50.05 50.05 E. coli GN54822 50.05 0.1 50.05 50.05 Ps. aeruginosa S-68 0.39 6.25 1.56 1.56 Aci. anitratus A-6 0.2 0.2 50.05 0.1 Ps. aeruginosa IF03445 3.13 12.5 3.13 3.13 ps. aeruginosa GN9182 0.39 3.13 0.78 0.78 Cont 1 d (n 0 (n W W M m ul 0 ul 0 Table 1 (ContId) F F Me HO-D- HO---; 1 IIO-()-.. - F F-gi F-gi HN N- 110 r---\ 1 ---- \ i-prN CH 2=CII "CN - HN N- n-PrN N- 1 CH N N 2 6 7 9 10 0.2 50.05 0.2 0.2 0.2 0.2 0.393 0.13 0.78 0.2 0.2 0.2 0.2:0.05 0.39 0.2 0.2 0.2 50.0 5:50. 0 5 50.05 0. 0 5 0.05 0.05 50.05 50.05 50.05 50. 0 5 0.05 0.05 50.05:0.05 so. 05 0.05 0.05 50.65 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 j.13 Cont 1 d - 4h W Table 1 (Cont d) F F F F F F N CH 2=CH HCl.II 2 N\C 112 MelIN,,'C MelIN 1 N- N N- CH 21 1 N- 11 12 13 14 15 o.2 50.05 50.05 0.2 0.2 0.39:50. 0 5 0.1 0.2 0.2 0.2 0.05 0.1 0.1 0.2 0.39;50.05 0.05 0.05 50.05 0.1 0.05 0.05 0.05 50.05 0.1 0.05 50.05 0.05 50. 0 5 6.25 0.2 0.2 0.78 1.56 0.2 50.05 50.05 0.1 0.1 G) 12.5 0.2 0.2 1.56 1.56 3.13 0.1 0.1 0.39' 0.39 > P0 6 GB 2 191776 A 6 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 mglkg or more.

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

The compound of this invention can be produced, for example, according to the following production route: 5 0 0 F COOR la F COOR la 10 R 3a N Cl 3b N Cl R [IV] or a salt thereof 15 0- 0 F COOR la F COOR la 20 2 N N Cl NH-R 2 R 3a Cl NH-R R 3 25 [Ill] or a salt thereof [V] or a salt thereof 0 COOR 0 COOR 30 F -9 F - N N ICN &N R 3a 12 R 3b 12 35 R R lIal or a salt thereof [Ibl or a salt thereof 40 wherein R representsthe same carboxy-protecting group as in W; R represents the same halogen atom as in R 3; R 1b represents the same substituted or unsubstituted cyclic amino group as in R'; and R' and R 2 have the same meanings as defined above.

The salts of the compounds represented by the general formulae []a], [1b], [1111, [IV] and [V] include the same salts as those of the compounds represented by the general formula [11. 45 (i) The compound represented by the general formula [lill 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 [111 or the compound represented by the general formula [WI or a salt thereof with an acetal such as N,N-d iethylformamidod i methyl acetal, N,NdimethyiformamidodiethylacetaI or the like and then with an amine represented by the general formula, R 2 -NH2 (R2 has the same meaning as defined above). 50 The solvent to be used in the above reactions maybe 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,N-dimethylformamide, N,N-dimethylacetamide and the like; sulfoxides such as dimethyisuifoxide and the like; etc. and these 55 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 compound represented by the general formula [111 or the compound represented by the general formula [IVI or a salt thereof. The reactions are usually conducted at Wto 1 OWC, preferably at Wto WC, 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 60 [111 or the compound represented by the general formula [IVI or a salt thereof. The reaction is usually conducted at Wto 1 OWC, preferably 1 O'to WC, 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 [111 or the compound represented by the general formula [IVI or a salt thereof with ethyl orthoformate or methyl orthoformate in the presence of acetic anhydride, and then with an amine reoresented by the general formula, 65 7 GB 2 191 776 A 7 R 2 -NH2 or a saitthereof to obtain the compound represented bythe general formula [1111 or a saitthereof orthe compound represented by the general formula [V] or a saitthereof respectively.

(H) The compound represented bythe general formula [lal or a salt thereof orthe compound represented by the general formula [Ibl or a saitthereof is, respectively, obtained by subjecting the compound represented by the general formula [1111 or a saitthereof orthe compound represented bythe general formula [V] or a salt 5 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-dimethylformarnide, N,N- dimethylacetamide and the like; ethers such as dioxane, anisole, diethylene glycol dimethyl ether and the like; suffoxides such as dimethyisuifoxide and the like; etc. These solvents may be used alone or in admixture of two or more. The base includes, for 10 example, sodium hydrogen-carbonate, potassium carbonate, potassium tertbutoxide, 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 [1111 or [V] or a salt thereof. The reaction is usually conducted at 200 to 160'C, preferably at 1 00'C 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 [IVI or a salt thereof, the compound represented by the 15 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 [111, the compound represented by the general formula [1111 or a salt thereof, or the compound represented by the general formula []a] or a salt thereof with a cyclic amine represented by the general formula, R 3b -H or a salt thereof (wherein R 3b has the same meaning as above. 20 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-dimethylformarnide, N,N-dimethyiacetamide and the like; sulfoxides such as dimethyisuifoxide and the like; alcohols such as 25 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 [111, the compound represented by the general formula [1111 or a salt thereof, or the compound represented by the general formula [lal or a salt thereof. If the amount of the cyclic amine used is about 1 to 1.3 moles, it is 30 sufficient that an acid-binding agent is used in an amount of 1 mole per mole of the compound represented by the general formula [111, the compound represented by the general formula [1111 or a salt thereof, or the compound represented by the general formula [fa] or a salt thereof. The acid-binding agent includes organic or inorganic bases such as triethylamine, 1,8-diazabicyclo[5,4,Olundec-7- ene (DBU), potassium tert-butoxide, potassium carbonate, sodium carbonate, sodium hydride and the like. 35 The salt of R 3b -H includes the same as the salts atthe basic group of the compound represented by the general formula [11.

The reaction is usually conducted at O'to 150'C, preferably at 50'to 1 00'C, and usually for 5 minutes to 30 hours, preferably 30 minutes to 3 hours.

The compound represented by the general formula []a], [Ibl, [1111 or [V], wherein R' represents a 40 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 00 to 1 00'C, preferably at 20'C to 1 00'C for 5 minutes to 50 hours, preferably 5 minutes to 4 hours.

Further, the compound represented by the general formula [lal, [Ibl, [1111 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 45 reaction or esterification known per se. If the compound represented by the general formula [fa], [fill, [iV] or [V] or a salt thereof has an active group (for example, hydroxyl group, amino group orthe 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 50 such as column chromatography, recrystallization, extraction and the like.

The compound represented by the general formula [1] or a salt thereof, wherein R 3 represents a halogen atom (corresponding to the compound represented by the general formula [fa]), is also useful as an intermediate for obtaining a compound wherein R 3 represents a substituted or unsubstituted cyclic amino group (corresponding to the compound represented by the general formula [ibl). 55 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 maybe usually administered orally or parenterally (for example, by injection, 60 drip, administration to rectum) to an adult in an amount of 0.1 to 100 mglkg/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, 65 8 GB 2 191776 A 8 n-Pr: n-propyl group, i-Pr: isopropyl group, Ac: acetyl group, allyl group, :ethylene group.

Referential Example 1 5 In 210 m] 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,-dimethy[formarnide were added to the resulting solution. The resulting mixture was reacted at 7WC 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 mi of tetrahydrofuran. In 110 mi of tetrahydrofuran was dissolved 25.1 g of diethyl ethoxymagnesium malonate, and the solution was cooled to 10 -400to -30'C. Into this solution was dropped a tetrahydrofuran solution of 2,6-dichloro-5-fluoronicotinoyl chloride which had previously been prepared at the same temperature over 30 minutes. This mixed solution was stirred atthe 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 mi of chloroform and 100 mi of water. The pH was adjusted to 1 with 6 N 15 hydrochloric acid. The organic layer was separated, washed successively with 50 mi of water, 50 mi of 5% aqueous sodium hydrogencarbonate solution and 50 m] of saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and to the oily product obtained were added 50 mi of water and 0.15 g of p-toluenesulfonic acid, after which the resulting mixture was subjected to reaction with vigorous stirring at 1 OOOC for 2 hours. The reaction 20 mixture was extracted with 100 m] of chloroform. The organic layer was washed with 50 mi 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 chromatogra phy (WAKO SILICA GEL C-200, eluant: toluene) to obtain 23.5 g of ethyl (2, 6-dichloro-5-fluoronicotinoyi)- acetate having a melting point of 64-65'C. 25 IR (KBr) cm-l: vc=o 1650,1630,1620 NIVIR (CDC]3) 3 values:

1.25 (1.29H, t, J=71-1z), 1.33 (1.71 H, t, J=71-1z), 4.07 (1.14H, s), 4.28 (2H, q, J=71-1z), 5.82 30 (0.43H, s), 7.80 (1 H, d, J =7Hz), 12.62 (0.43H, s) Referential Example 2 In 40 mi of benzene was dissolved 8.8 g of ethyl (2,6-dichloro-5- fluoronicotinoyi)acetate, and 4.5 g of N,N-dimethyiformamidodimethylacetaI was added thereto, after which the resulting mixture was subjected to 35 reaction at 700C 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 9 of ethyl 2-(2,6dichloro-5-fluoronicotinoyi)-3-(2,4- difluorophenylamino) acrylate having a melting point of 138-139'C. 40 IR (KBr) cm-l: vc=o 1690 NIVIR (C13C13) 8 values:

1.08 (3H,t, J=71-1z), 4.10 (2H, q, J=71-1z), 6.77-7.40 (4H, m), 8.50 (1 H, d, J = 13Hz), 45 12.70 (1 H, cl, J = 1 3Hz) In a similar manner, the compounds shown in Table 2 were obtained.

9 GB 2 191776 A 9 Table 2

0 COOE- 5 cira cl N Cl C, 1' NH 1 10 R 2 Commound Phvsical pronertiens 15 R 2 Me!tinq IR (KBr) c_m point ( C) v C=O- 87-89 1690 20 110-11a 1710, 1680 25 92-93 1710, 1680 30 135-137 1720(sh), 1690- 35 F 78-80 1690 40 oily 1705, 1680(sh) 45 F 1.54-155 1720(sh),1685 so 50 F F 100-101 1700(sh), 1685 123-125 1710, 1680 55 Cont'd W GB 2 191776 A 10 Table 2 (CcDn-;'-'d) 0 145-146 1705, 1680 5 B r 147-149 1685 10 e e Oilv 1695 is Ome 119-121 1700 20 Oilv 1700 25 183-186 1685,16-10 kc 30 $ 136-138 1705,1680 CF3.

Me 35 114-116 1680 F 137.5-139 1725(sh), 1680 40 F VMe F 92-95 1705 45 Ome 0 125-126 1700(sh), 1660 so Me Me 91-92 1705, 1690 55 0Me Note: The neat method was used in place of the KBr method.

11 GB 2 191 776 A 11 Referential Example 3 (1) In 55 mi of chloroform were dissolved 5.5 g of ethyl (2,6-dichloro-5- fluoronicotinoyi)acetate, 2.37 g of N-methylpiperazine and 2.37 g of triethylamine, and the resulting solution was subjected to reaction at Wto 65C for 2 hours. The reaction mixture was washed with 30 mi of water, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue obtained was 5 purified by a column chromatography (WAKO SILICA GEL C-200, eluant: chloroform) to obtain 5.4 g of oily ethyl [2-ch lo ro-541 uoro-6-(4-m ethyl- 1 -pi perazi nyl) nicoti noyll acetate.

IR (Neat) cm-': ve=o 1750,1695 NMR (CDC[3) 3 values: 10 1.25 (31-1, t. J=7Hz), 2.32 (31-1, s), 2.12-2.70 (41-1, m), 3.55-3.96 (4H, m), 4.03 (21-1, s), 4.20 (21-1, q, J=71-1z), 7.78 (1 H, d, J = 131-14 In a similar manner, the compound shown in Table 3 was obtained. 15 T. a b 1 -- 3 0 20 COOEt- C il 25 R 3 30 (2) In 22.5 m] of benzene was dissolved 4.5 g of ethyl [2-chloro-5-fluoro- 6-(4-methyi-l-piperazinyi)- nicoti noyl]acetate, and 1.87 9 of N,N-di methylform am idodi methyl aceta 1 was added to the resulting solution, 45 after which the resulting mixture was subjected to reaction at 7WC 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, euant:

chloroform:ethanol = 100: 1 (by volume)]. The crystalline substance obtained was washed with 10 mi of 50 diethyl ether to obtain 5.0 g of ethyl 2-[2-chloro-5-fluoro-6-(4-methy]-1piperazinyi)nicotinoyll-3-(4-methoxy-2- methyl ph enyla m i no)acry] ate having a melting point of 141-142'C.

]R (KBr) cm-l: vc=o 1710(sh), 1695 NIVIR (CDC13) 8 values: 55 1.08 (31-1, t. J=7Hz), 2.32 (31-1, s), 2.40 (31-1, s), 2.23-2.68 (41-1, m), 3.47-3.83 (41-1, m), 3.75 (31-1, s), 4.07 (21-1, q, J =7Hz), 6.65-7.25 (31-1, m), 7.20 (1 H, d, J=13Hz), 8.48 (1 H, d, J=1 31-14, 12.82 (1 H, d, J=131-14 60 In a similar manner, the compounds shown in Table 4 were obtained.

Commound Physical Properties 3 Melting!R (KBr) cm -1:

R OC) point C=0 AcN N- 67-71 1730 12 GB 2 191776 A 12 Table 4

0 F 0OEt 3 N 1 CH R NH 1 10 R2 is Compound Physical Properties 15 R2 R 3 Melting paint 1RJ) (OC) cm-l: vc=o 2 20 Me oily 1720 (sh), 1715 25 F 2 0 oily 1735, 30 1700 F 2 35 Oily 1695 0Me 40 1 1685, 45 161-164 1670 NHAc so 50 2 CO F Oily 1720 (sh), 1715 55 0Me - Cont'd 60 13 GB 2 191 776 A 13 Table 4 (Cont'd) MeN 1705 (sh), N- 132-136 e 1685 0Me 10 Me 2 1720 (sh), ACN N- Oilv is 1700 0Me Note:M: KBr 20 2: neat Example 1

In 90 mi of N,N-climethylformarnide was dissolved 9.0 g of ethyl 2-(2,6dichloro-5-fluoronicotinoyi)-3-(2,4- 25 difl uorophenyla m ino)acry] ate, 3.6 g of sodium hydrogencarbonate was added to the resulting solution, after which the resulting mixture was subjected to reaction at 12WC for 20 minutes. Then, the solvent was removed by distillation under reduced pressure, and the residue obtained was dissolved in 50 mi of chloroform. The resulting solution was washed successively with 30 mi of water and 30 mi of saturated aqueous sodium chloride solution, and then dried overanhydrous magnesium sulfate. The solvent was removed by distillation 30 under reduced pressure, and the crystalline substance obtained was washed with 30 mi of diethyl ether to obtain 7.0 g of ethyl 7-chloro-6-fluoro-l-(2,4-difluorophenyi)-1,4dihydro-4-oxo-1,8-naphthyridine -3carboxylate having a melting point of 220-222'C.

IR (KBr) cm-l: vc=o 1730,1690 35 NIVIR (C13C13) 8 values:

1.36 (31-1, t, J=71-1z), 4.30 (21-1, q, J=71-1z), 6.80-7.60 (31-1, m), 8.27 (1 H, d, J=71-1z), 8.42 (1 H, s) In a similar manner, the compounds shown in Table 5 were obtained. 40 14 GB 2 191776 A 14 Table 5

0 F:)::::(lTyCIOF-I- 5 cl i R 10 Commound Physical Properties 15 2 Melting paint IR(KBr) R CC) cm-1: v C=0 20 1730, 222-224 1685 25 0 1730, 30 F 231-232 1705 35 239-241 1685 40 1735, 45 205-208 1685 W 0 244-246 1720, --" F 1680 55 F - Cont'd W GB 2 191776 A 15 Table 5 (Cont'd) F 1730, 207-209-5 1690 F 10 F F is 210-214 1735 (sh), 15 1705 20 0 207-208 1730, 9 1680 25 F 181-186 1730, 30 1685 35 0 204-205 1730, 1685 40 Br 0 1735, 45 216-218 1695 so Me 50 196-198 1735, 55 1685 0Me - Cont'd 60 16 GB 2 191776 A 16 Table 5 (Con.L--'d) ome 1730, 5 156-160 1690 10 is 0 1730, 15 231-236 1685 W 20 0 27o-273 1730, 1690 25 NRAc 0 199-201 1730, 30 1680 W 3 35 Me 0 1735, 199-202 1685 40 F Me 45 0 1730, c 208-211 1695 F so 50 F 0 1740, 142-144-1 1695 55 0Me Cont'd 60 17 GB 2 191776 A 17 Table 5 (Cont'd) 0Me 1730, 163-165 1695 Me 10 -me 0 160-162 1735, 15 1 1690 0Me 20 Example 2 (1) In 35 mi of chloroform was dissolved 3.5 9 of ethyl 7-chloro-6-fluorol-(2,4-difluorophenyi)-1,4-dihydro-4oxo-1,8-n aphthyridi ne-3-ca rboxyl ate, and 1.5 g of N-acetylpiperazine and 1.6 g of triethylamine were then added to the resulting solution, after which the resulting mixture was subjected to reaction at MC for 1 hour. 25 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-acetyi-l-piperazinyi)-6-fluoro-l-(2,4difluorophenyl)-1,4-dihydro-4-oxo -l,8- naphthyridine-3-carboxylate having a melting point of 207-209'C.

30 IR (KBr) cm-l: vc=o 1730,1695 NMR (CDC13) 8 values:

1.38 (3H, t, J=7H4, 2.05 (31-1, s), 3.53 (81-1, bs), 4.30 (21-1, q, J =7Hz), 6.80-7.75 (31-1, m), 8.00 (1 H, cl, J = 1 3Hz), 8.30 (1.H, s) 35 In a similar manner, the compounds shown in Table 6 were obtained.

18 GB 2 191776 A 18 Table 6

0 F COOEt R MA, "M 5 1 R2 Commound Physical Promerti 10 Lies 2 3 melting point IR(KBr) (OC) 1 cm-i: VC=0 15 216-218 1730, 1690 (sh) 20 Ac 1730, 155-156 25 i690 30 1730, MeN N- 217-218 1-695 35 Me,,. 1730, HN N- 144-146 1690 40 Me 45 HN N- 143 1730 Me \ so 1725 HN N- 198-202 1690 Me 55 ContId 19 GB 2 191776 A 19 Table 6 (Cont'd) 1730, 5 220-222 1-695 10 Ac 253-255 1730, is 1690 is 203-205 1-730, 20 1700 25 Ac 211-213 1735 F 30 F 17251 IS j-- 206 1690 35 Me 193-194 1730, 40 0 1700 F 45 Ac.Nr--i - 244-246 1725, 1690 so W F Ac 1725, 0 Me 186-187 1690 (sh)_ 55 F GB 2 191776 A 20 Table 6 (Cont-'d) Me 0 1720, 5 HN N- 155-157 1685 F Me,,. 1730, 153-154 1700 Me Me 153-155 1730, 20 1695 1730 (sh), N- 166-168 1690 4.0 Me 1730, 35 E W1 N202-204 2 1690 1725 (sh), AcN\- 230-231 1695 F 45 FF 1720 (sh), 193-194 1680, 50 1675 55 0 Me 207 1725, 1695 1 60 Cont'd - -I 21 GB 2 191 776 A 21 Table 6 (Cont'd) 0 Ac 254 1730, 1 1-690 cl 10 1730, 60 Mel-- 208 1690 1 15 br Ac 246-247 1730, 20 1690 25 0 Me 167-169 1730, 1695 30 Me Ac 206-207.5 1730, 35 1690 40 0 163-165 1735, ON - 1700' 45 0Me 15 Me 174-176 1730, 50 1690 55 1735, E t.,N -181 \_JT 180 1695 60 ContIcl 22 GB 2 191776 A 22 Table 6 (Contld) 0 C_\ 1730, n-PrN N- 171-172.5 1685 Me 1730, p r.N 208-5-210 1690 is 1730, 20 HC-\-N N- 200-202 1-690 162-163 1725, 1690 30 1735, 35 AcN N- 197-199 1690 f 0Me Me 136-138 1725, 40 1685 45 0 Ac 270-272 1730, W 1690 W 55 0 245-249 1730, 1695 NHAc 60 - Cont,d 23 GB 2 191776 A 23 6 Table 0 (Con'L-'d) ACNI-i 249-252 1730, 5 1695 to 3 10 Me 0 263-2641 1730 15 0 0Me 1730, 20 Me-NT 166-169 1685 1-730, AcN '11 222.5-223.5 30 1690 1730, 35 0 MeN 165-168 1685 Ome 40 1730, ti ACC 215-219 1695 45 so Ome 1725, 50 0 Me 170-171 1690 55 Me 1725, 0 AcN N169-172 1690 tLM e 60 24 GB 2 191776 A 24 (2) In 25 mi of 6 N hydrochloric acid was dissolved 2.5 g of ethyl 7-(4acetyi-l.piperazinyi)-6-fluoro-l-(2,4difluorophenyi)-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 mi of water, and then dried to obtain 1.8 9 of 5 6-fluoro-l -(2,4-difluorophenyi)-1,4-dihydro-4-oxo-7-(1-piperazinyi)-1,8naphthyridine-3 -carboxylic acid.

NMR (TFA-dl) 8 values:

3.30-4.50 (81-1, m), 7.00-7.85 (31-1, m), 8.33 (1 H, d, J = 1 3Hz), 9.21 (1 H, s) 10 In a similar manner, the compounds shown in Table 7 were obtained.

GB 2 191 776 A 25 Table 7

0 F c 0 0 H1 5 R xu 1 2 R 10. 10 Commound Physical Properties R 2 R 3 Melting paint i-R(KBr) 15 (OC) cm VC=0 20 HN 252.5-254.5 1730 25 0 MeHN-C-N- >280 1720(sh) 30 35 H.1 279-280 1725(sh) - q,--j 40 234-236 1720 45 F so 222-224 1725 50 55 0 >280 1720 "" F F 60 Cont'd 26 GB 2 191776 A 26 Table 7 (ContId) 0 5 MeNH-\,-/N- 254-258 1725 10 F 2057207 1730 15 F 225-227 1725 20 25 >280 1725 30 cl 0 273-277 1720 35 40 0 245-246 1725 45 Me 0 >280 1725 so W 56 0 >280 1730, W H 1710 - Cont'd 27 GB 2 191 776 A 27 Table 7 (Contld) 1725, 5 0 Me- 232-236 1710, 1690 NHAc is QO HN- >280 1725 15 W 3 0 --Me 230-232 1730 20 25 Note: The nujol method was used in place of the KBr method.

Example 3 (1) In 5 m[ of chloroform was dissolved 0.50 g of ethyl 7-chloro-6-fluoro- l-(2,4-difluorophenyi)-1,4-dihydro-4oxo-1,8-naphthyridine-3-carboxylate, and to the resulting solution were added 0.20 g of 3-acetyl aminopyrrolidine and 0.15 g of triethylamine, after which the resulting mixture was subjected to reaction at 600C 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 g of ethyl 7-(3-acetylamino-lpyrrolidinyi)-6-fluoro-l-(2,4-difluorophenyi)-1,4- 35 dihyd ro-4-oxo-1,8-na phthyridi ne-3-ca rboxyl ate having a melting point of 233-235'C.

IR (KBr) cm-l: vc=o 1725,1700 NIVIR (CIDC13) 8 values:

1.32(31-1, t, J =7Hz), 1.77-2.27 (m) 40 2.08 (S) 3.12-3.74(41-1, m), 4.02-4.74 (m) (31-1) 4.29(q, J=7Hz 6.75-7.60(4H,m), 7.93(1H,d,J=8Hz), 8.24(1 H, s) 45 In a similar manner, the compounds shown in Table 8 were obtained.

28 GB 2 191776 A 28 Table 8

0 0OEt 5 R2 10 Compound Physical Properties 2 3 Melting point IR(KBr) 15 R R (OC) cm- 1: Vc=o 0 g O'"DN - 231-233 1730, 20 1700 F 25 Me2N 1730, \N156 1690 30 AcHN 1725, 35 203-205 1690 40 1725, MeAbc- 201-202 1695 45 so 0 F Me 2 N 165 1730, so 1690 F MeN 55 1730 A 196-197 N 1695 60 Cont'd 29 GB 2 191776 A 29 Table 8 (Cort'd) F AcHN 5 0 241-244 1725, F 1700 F 10 0 153-155 1735 is Ome HO 185-187 1730, 20 1690 25 (2) In 2.5 mi of 6 N hydrochloric acid was dissolved 0.25 g of ethyl 7-(3acetylamino-l-pyrrolidinyi)-6-fluoro1-(2,4-difluorophenyi)-1,4-dihydro-4oxo-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 30 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 2 m] of water and then dried to obtain 0.18 9 of 7-(3-amino-l-pyrrolidinyi)-6-fluoro-l-(2,4-difluorophenyi)-1,4-dihydro-4oxo -l,8-naphthyridine-3-carboxylic acid.

35 NIVIR (TFA-dl) 8 values:

2.25-2.85 (2H, m), 3.37-4.69 (5H, m), 6.93-7.81 (3H, m), 8.22 (1 H, cl, J = 11 Hz), 9.16 (1 H, s) In a similar manner, the compounds shown in Table 9 were obtained. 40 GB 2 191776 A 30 Table 9

0 F COOH 5 R 33 CN N 12 10 R Compound Physical properties is 2 3 Me!ting IR (KBr) R R paint - 1 v (OC) cm c=o 20 0 2 tN- 260-263 172'0 25 F me-HN 30 tN- 259-261 1720 (sh) 35 0 275-278 1720 (sh) 40 F F H N 45 CO F 2 tN278-280 1720 50 31 GB 2 191776 A 31 Example 4 (1) In 20 mi of chloroform were dissolved 2.09 of ethyl 2,6-dichloro-5- fluoronicotinoylacetate, 0,969 of 3-acetylaminopyrrolidine and 0.8 g of triethylamine and the resulting solution was subjected to reaction at 60Q to WC for 2 hours. The reaction mixture was washed with 30 mi of water, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue thus 5 obtained was purified by a column chromatography [WAKO SILICA GEL C-200, eluant: benzene: ethyl acetate = 1: 1 (by volurnefl to obtain 1.8 g of oily ethyl [2-chloro-5-fluoro-6- (3-acetylamino-1 -pyrrolidinyi)nicotinoyl] acetate.

IR (Neat) cm-': vc=o 1740,1650 10 NIVIR (CDC13) 8 values:

1.28 (31-1, t, J=7Hz), 1.97 (31-1, s), 1.90-2.62 (21-1, m), 4.02 (21-1, s), 4.15 (21-1, q, J =7Hz), 3.50-4.70 (51-1, m), 7.06 (1 H, cl, J=6Hz), 7.57 (1 H, cl, J= 131-14 15 (2)In 10 mi of benzene was dissolved 0.7 g of ethyl 2-chloro-5-fluoro-6- (3-acetylamino-l- pyrrolidinyl)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 70C for 2 hours. To the reaction mixture was added 0.243 g of 2,4-difluoroaniline, and the resulting mixture was 20 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 volumefl, and the oily product thus obtained was triturated with diisopropyl ether to obtain 0.25 g of ethyl 2-[2-chloro-5- fluoro-6-(acetylamino-1 pyrrolidinyl)nicotinoyll-3-(2,4-difluorophenylamino)acrylate having a melting point of 82-85C. 25 IR (KBr) cm-': T=0 1695 (sh), 1660 NIVIR (C13C13) 8 values:

1.25 (31-1, t, J=7Hz), 2.07 (31-1, s), 1.90-2.30 (21-1, m), 4.19 (21-1, q, J=71-1z), 30 3.60-4.70 (51-1, m), 6.49 (1 H, cl, J=6Hz), 6.80-7.50 (41-1, m), 8.53 (1 H, d, J = 1 3Hz), 12.46 (1 H, cl, J = 1 3Hz) (3) In 3 mi of N,N-dimethylformamide was dissolved 0.2 g of ethyl 2-[2chloro-5-fluoro-6-(acetylamino-lpyrrolidinyl)nicotinoyll-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 12TC for 1 hour.

Subsequently, the solvent was removed by distillation under reduced pressure, and the residue thus obtained was dissolved in 10 mi of chloroform. The resulting solution was washed successively with 10 mi of water and 10 mi of saturated aqueous sodium chloride solution, and thereafter dried over anhydrous magnesium 40 sulfate. The solvent was removed by distillation under reduced pressure, and the crystalline substance thus obtained was washed with 5 m] of diethyl etherto obtain 0.13 g of ethyl 7- (3-acetylamino-l-pyrrolidinyl)-6fluoro-l-(2,4-difluorophenyi)-1,4-dihydro-4-oxo-1,8-naphthyridine-3carboxyl ate having a melting point of 233-2350C.

In a similar manner, ethyl 7-(3-acetylamino-l-pyrrolidinyi)-6-fluoro-l-(4fluorophenyi)-1,4-dihydro-4-o xo- 45 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 mi of 6 N hydrochloric acid was suspended 0.50 g of ethyl 7- chloro-6-fluoro-l-(2,4-difluorophenyl) 50 1,4-dihydro-4-oxo-1,8naphthyridine-3-carboxylate, and the suspension was heated under ref lux for 3 hours. Then, the reaction mixture was diluted with 50 mi of water and extracted with three 50-mi portions of chloroform. The combined extracts were washed with 100 mi 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 mi of diethyl ether to obtain 0.40 9 55 of 7-chloro-6-fluoro-l-(2,4-difluorophenyi)-1,4-dihydro-4-oxo-1,8naphthyridine -3-carboxylic acid having a melting point of 244-248T.

IR (KBO cm-': 'C=0 1720 NMR W6-DIVISO) 8 values: 60 7.26-8.56 (31-1, m), 8.86 (1 H, cl, J =7Hz), 9.18 (1 H, s) (2) In 3 mi of dimethyisuifoxide was suspended 0.30 g of 7-chloro-6- fluoro-l-(2,4-difluorophenyl)-1,4dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, and then 0.25 g of Nmethylpiperazine was added to the 65 32 GB 2 191776 A 32 resulting suspension, after which the resulting suspension was subjected to reaction at 600C for 30 minutes.

Then, the solvent was removed by distillation under reduced pressure, and to the residue thus obtained was added 30 m] 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 mi of water to obtain 0.24 g of 6-fluoro-l-(2,4-difluorophenyi)-1, 4-dihydro-7-(4-methyl-l-piperazinyl)-4- 5 oxo-1,8-naphthyridine-3-carboxylic acid having a melting point of 2082090C.

IR (KBr) cm-l: vC=0 1730 NMR (TFA-dj) 8 values:

3.30 (31-1, s), 3.45-5.25 (8H, m), 10 7.12-8.10 (31-1, m), 8.49 (1 H, d, J=13Hz), 9.38 (1 H, s) Example 6

In 50 mi of N,N-dimethylformarnide was dissolved 5.0 g of ethyl 2-[2chloro-5-fluoro-6-(4-methyl-lpiperazinyi)nicotinoyl]-3-(4-methoxy-2-methylphenylamino)acrylate, then 1. 03 g of sodium hydrogencarbon ate was added to the resulting solution, and the resulting mixture was subjected to reaction at 112WC for 3 hours. Then, the solvent was removed by distillation under reduced pressure, and the residue thus obtained was dissolved in 50 mI of chloroform. The resulting solution was washed successively with 30 mi of saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was 20 removed by distillation under reduced pressure, and the crystalline substance obtained was washed with 30 mi of diethyl ether to obtain 2.38 g of ethyl 6-fluoro-1,4-dihydro-l-(4methoxy-2-methylphenyi)-7-(4-methyl-lpiperazinyi)-4-oxo-1,8-naphthyridine-3-carboxylate having a melting point of 144-145'C.

IR (KBO cm-': vC=0 1690 25 NMR (C13C13) 8 values:

1.33 (3H, t, J =7Hz), 1.95 (31-1, s), 2.20 (31-1, s), 2.05-2.62 (41-1, m), 3.32-3.63 (41-1, m), 3.82 (31-1, s), 4.32 (21-1, q, J=71-1z), 6.60-7.15 (31-1, m), 30 8.02 (1 H, d, J = 1 3Hz), 8.23 (1 H, s) In a similar manner, the compounds shown in Table 10 were obtained.

33 GB 2 191776 A 33 Table 10

0 COOEt R 33 N NY 5 12 R 10 Compound Physical properties 15 3 Melting IR (KBr) R R point -1 (OC) cm C=0 20 1725, MeN N- 199-202 6 \--i - 1685 F 25 168-171 1735, 1720 F 30 &- Ome 11 174-175 1730, 35 1695 amorphous 1725, 40 NE1Ac 1690 ---, 186-189 1725, 45 0Me 1690 so 50 1.1 Me 166-168 1730, 0Me 1695 55 Me 1725, AcN N- 169-172 e 1690 Ome 60 34 GB 2191776 A 34 Example 7

In 5 mi of 47% hydrobromic acid was dissolved 2.0 g of ethyl 6-fluoro-1,4dihydro-l-(4-methyl-2- methyl phenyl)-7-(4-methyM -piperazi nyl)-4-oxo-1,8-na phthyridine-3-ca rboxylate, and the resulting solution was subjected to reaction at 1200 to 125'C 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 5 collected byfiltration and washed with 10 mi of water to obtain 1.8 9 of 6-fluoro-1,4-dihydro-l-(4-hydroxy-2- methyl phenyl)-7-(4-methyi-l -pi perazinyi)-4-oxo-1,8-na phthyridi ne-3- ca rboxyl ic acid having a melting point of >2801C.

IR (KBr) cm-l: 'C=0 1725,1700 (sh) 10 NIVIR (TFA-dl) &values: 2.08 (31-1, s), 3.12 (31-1, s), 2.88-5.12 (81-1, m), 6.93-7.62 (31-1, m), 9.25 (1 H, s), 9.43 (1 H, cl, J = 131-14 In a similar manner, the compounds shown in Table 11 were obtained. 15 GB 2 191776 A 35 Table 11

0 F COOH 5 3 T ? T R N N 1 2 R 10 Commound Physical properties Melting R 2 R 3 point IR (Kj:)j. 15 (OC) cm- 1: v. C=0 CN- 143-146 1725, 20 OH 1710 25 HIZ N- >280 1710 MeN N- >280 1710 EtN N- >280 1730 35 n-PrN N- >280 1725 40 i-PrN N- >280 1715 45 1720, so HO N N- 200-205 50 1705 AIN N- >280 1725 55 Cont'd - 36 GB 2 191776 A 36 -Lable 11 (C ont 1 d) 245-250 1-125, 5 MeN N (decomp.) 700 (sh) OH 10 H 1725, CY >280 1690 15 OH 1725, HN N220-224 1710 20 F 1730, MeN N- >280 1710 (sh) 25 F >-)80 1730 30 OH 35 HN N- >255 1725 F 40 MeN N- 251-252 1720 OH 45 OH 1725 (sh), >280 1700 so Me so 1730.1 Me 228-230 1700 (sh) 55 OH Me HN N- 275 1720 60 cc \-i OH 37 GB 2 191776 A 37 Example 8

In 10 m] of 47% hydrobromic acid was dissolved 0.40 g of ethyl 6-fluoro-1, 4-dihydro-l-(4-methoxyphenyi)-7(1-pyrrolidinyi)-4-oxo-1,8-naphthyridine-3-carboxylate, and the resulting solution was subjected to reaction at 12Wto 125'C 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 5 washed with 4 mi of water to obtain 0.30 g of 6-fluoro-1,4-dihydro-1 -(4- hydroxyphenyi)-7-(1 -pyrrolidinyl)-4 oxo-1,8-naphthyridine-3-carboxylic acid having a melting point of 263265T.

IR (KBr) cm-l: 'C=0 1725,1705 NMR (TFAA1) 8 values: 10 1.54-2.40 (4H, m), 3.14-4.14 (41-1, m), 6.95-7.69 (41-1, m), 8.09 (1 H, d, J = 1 2Hz), 9.14 (1 H, s) In a similar manner, the following compound was obtained:

is 6-Fluoro-1,4-dihydro-1 -(4-hydroxyphenyi)-7-(3-hydroxy-1 -pyrrolidinyi)-4- oxo-1,8-naphthyridine-3- carboxylic acid.

Melting point: 180-18WC IR (KBr) cm-l: 'C=0 1725,1705 20 Example 9

To 0.1 g of ethyl 7-(4-acetylA -piperazinyl)-6-fluoro-1 -(4-fluorophenyi)1,4-dihydro-4-oxo-1,8-naphthyridine3-carboxylate were added 2 mi of 1 N aqueous sodium hydroxide solution and 2 mi of ethanol, and the resulting solution was subjected to reaction at 4Wto 50T for 10 minutes. Subsequently, acetic acid was added 25 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 mi of water and 5 mi 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 mi of diethyl ether to obtain 0.08 g of 7-(4-acetyl-l-piperazinyi)-6- fluoro-1 -(4-fluorophenyi)-1,4-dihydro-4oxo-1,8-naphthyridine-3-carboxylic acid having a melting point of >280'C.

IR (KBr) cm-l: 'C=0 1730 NIVIR (d6-DMSO) 8 values:

2.05 (31-1, s), 3.57 (8H, bs), 35 7.13-7.80 (41-1, m), 8.13 (1 H, d, J = 13Hz), 8.70 (1 H, s) In a similar manner, the compounds shown in Table 12 were obtained.

38 GB 2 191776 A 38 Table 12

0 F COOH N:rN INST 5 R3 19 R- 10 Commound Physical properties 2 3 Me 1 t_ in g IR (KBr) 15 R R point - 1 v - PC) cm C=0 MeN N- 277-280 1720 282-290 1725, 25 1700 (sh) Me 30 HN N- 268-270 1725 Me HN N- 283-285 1720 Me 40 Me HN N- 267-270 1730 45 Me so 50 H01\-N N- 138-139 1690 F >280 1730, 55 0 N1700 (sh) 60 MeN N- >280 1720 F 39 GB 2 191776 A 39 Table 12 (Cont'd) F 208-209 1730 5 F Me 10 HN N- >280 1720 Me 15 MeN N- 210-211 1735 20 Me MeN N- 225-226 1720 25 30 I^IN N- 219-220 1730 1730, 35 MeN N- 283284 1700 (sh) cl MeN /---\ IN- 277-280 1730, 40 1700 (sh) Br 45 271-274 1725 so Me so 250-252 1725 0Me 55 GB 2 191776 A 40 Example 10

To 0.10 g of ethyl 6-fluoro-l-(4-fluorophenyi)-1,4-dihydro-7-(3-hydroxy-lpyrrolidinyi)-4-oxol,8- naphthyridine-3-carboxylate were added 2 mi of 1 N aqueous sodium hydroxide solution and 2 mi of ethanol, and the resulting mixture was subjected to reaction at 400 to 500C 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 5-mi portions of chloroform. The combined extracts were washed successively with 5 mi of water and 5 mi 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 mi of diethyl etherto obtain 0.08 g of 6-fluoro-l-(4-fluorophenyi)- 1,4-dihydro-7-(3-hydroxy-lpyrrolidinyi)-4-oxo-1,8-naphthyridine-3-carboxylic acid having a melting point of >2800C. 10 IR (KBr) cm-l: 'C=0 1730 NIVIR (d6-DMSO) 8 values:

1.92-2.52 (21-1, m), 3.22-5.00 (51-1, m), is 6.97-7.60 (41-1, m), 8.01 (1 H, d, J = 11 Hz), 15 9.00 (1 H, s) In a similar manner, the compounds shown in Table 13 were obtained.

Table 13

20 F COOH 3 XN 25 R N 1 2 R Compound Physical properties 30 2 3 Melting IR (KBr) R R paint cm - 1: v C=0 35 ( OC) Me 2 N bN- 264-265 1725 40 F 45 227 1725 so so Example 11

In 2.5 mi of conc. hydrochloric acid was dissolved 0.25 g of 6-fluoro-1,4dihydro-l-(4-hydroxy-2- methyl phenyi)-4-oxo-7-(1-piperazinyi)-1,8-naphthyridine-3-carboxylic acid, and then 20 m] of ethanol was added to the resulting solution, after which the resulting mixture was stirred at room temperature for 15 55 minutes. The crystals thus deposited were collected by filtration and washed with 5 mi of ethanol to obtain 0.2 g of the hydrochloric acid salt of 6-fluoro-1,4-dihydro-l-(4-hydroxy-2methylphenyi)-4-oxo-7-(1-piperazinyi)- 1,8-naphthyridine-3-carboxylic acid having a melting point of >280'C.

60]R (KBr) cm-l: 'C=0 1725 (sh), 1705 60 In a similar manner, the compounds shown in Table 14 were obtained.

41 GB 2 191776 A 41 Table 111

0 F COOH Hydrochloric 5 acid salt of R 3 jN R- io 10 Commound Physical properties 2 3 Melting IR (KBr) R R point -1 VC= 15 (OC) cm 0 MeN N- 283 1730 20 FIN N- 275-278 1720 25 F F F 249-252 30 (decomp.) 1730 F 35 >280 1710 OH 40 is MeN N- 280-282 1730 45 F 1720 (sh), HN N- 279-283 1705 50 OH F 1720 (sh), MeN N- 266-269 1700 55 OH Me 60 282 1730 OH 1 65 42 GB2191776A 42 Example 12

In 20 mi of conc. hydrochloric acid was dissolved 2.0 g of 7-(3-amino-lpyrrolidinyi)-6-fluoro-l-(2,4difluorophenyi)-1,4-dihydro-4-oxo-1,8naphthyridine-3-carboxylic acid, then 200 m[ 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 mi of ethanol to obtain 1.4 g of the hydrochloric 5 acid salt of 7-(3-amino-l-pyrrolidinyl)-6-fluoro-l-(2,4-difluorophenyi)-1, 4-dihydro-4-oxo -l,8-naphthyridine-3- carboxylic acid having a melting point of 247-250'C (decomp.) IR (KBr) cm-l: 'C=0 1730 10 Example 13 (1) In 2.5 mi of chloroform were dissolved 0.5 g of ethyl 2-(2,6-dichioro5-fiuoronicotinoyl)-3-(2,4- difluorophenylamino)acrylate, 0.143 g of N-methylpiperazine and 0.145 g of triethylamine, and the resulting solution was under refluxfor15 hours. Then, the reaction mixture was washed successively with 3 mi of water and 3 mi of saturated aqueous sodium chloride solution and then dried over anhydrous magnesium 15 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-methyil-piperazinyl)nicotinoyll-3-(2,4- difluorophenylamino)acrylate.

20 IR (Neat) cm-': 'C=0 1735,1700 NIVIR (C13C13) 3 values:

1.13 (3H, t, J=7H4, 2.36 (3H, s), 2.55 (4H, t, J=5H4, 3.70 (41-1, t, J=5Hz), 4.15 (21-1, q, J=71-1z), 6.77-7.90 (4H, m), 25 8.51 (1 H, d, J=131-1z), 12.50 (1 H, cl, J=113Hz) (2)By treating 0.2 g of ethyl 2-[2-chloro-5-fluoro-6-(4-methyi-l- piperazinyi)nicotinoyll-3-(2,4difluorophenylamino)acrylate in the same manner as in Examples 6 and 9,0. 12 g of 6-fluoro-1-(2,4 difluorophenyi)-1,4-dihydro-7-(4-methyi-l-piperazinyi)-4-oxo-1,8naphthyridi ne-3-carboxylic acid having a 30 melting point of 208-2O9oC was obtained.

Example 14

To 0.3 9 of ethyl 7-(4-ethoxycarbonyi-2-methyi-l-piperazinyi)-6-fluoro-l(2,4-difluorophenyi)-1,4-dihydro-4- oxo-1,8-naphthyridine-3-carboxylate were added 5 mi of 1 N aqueous sodium hydroxide solution and 5 mi of 35 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 9 of 6-fluoro-l-(2,4- difluorophenyi)-1,4-dihydro-7-(2-methyi-lpiperazinyi)-4-oxo-1,8-naphthyridine-3-carboxylic acid having a melting point of 230-239'C 40 iR (KBr) cm-l: 'C=0 1730 NIVIR (TFA-dl) 8 values:

1.50 (31-1, s), 3.20-5.15 (71-1, m), 7.00-7.90 (3H, m), 8.35 (1 H, cl, J=13Hz), 9.20 (1 H, s) 45 Example 15

In 20 mi of ethanol was suspended 1.0 g of dihydrochloric acid salt of 3aminopyrrolidine, 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-difluorphenyi)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate was added to the solution at WC so over 15 minutes, and the resulting mixture was subjected to reaction at the same temperature for 3 hours.

After the completion ofthe reaction,30 m] of waterwas added to the reaction mixture, and the crystals thus deposited were collected byfiltration andwashedwith 4mi of water. The crystalline substance thus obtained was suspended in 13 m[ 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 55 filtration and washed with two 2-mi portions of water to obtain 1.97 g of hydrochloric acid salt of 7-(3-amino-1 -pyrrolidinyi)-6-fluoro-1 -(2,4-difluorophenyi)-1,4-dihydro4-oxo-1,8-naphthyridine-3-carboxylic acid.

IR (KBr) cm-': 'C=0 1730 60 Example 16

In 75 mi of ethanol and 75 m[ of water was suspended 10.0 g of 7-(3-aminol-pyrrolidinyi)-6-fiuoro-l-(2,4difluorophenyi)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid. To the resulting suspension was added 5.2 9 of p-toluenesulfonic acid monohydrate at 400C, and the resulting mixture was stirred at the same 65 43 GB 2 191 776 A 43 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 mi of ethanol and 5 mi of water to obtain 12.8 g of the p-toluenesulfonic acid monohydrate salt of 7-(3amino-l-pyrrolidinyi)-6-fluoro-l-(2,4difluorophenyi)-1,4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid having a melting point of 258-2600C.

5 IR (KBr) cm-l: 'C=0 1735 NMR (DIVISO-d6) 8 values:

1.82-2.42 (m) (51-1) 3 ' 12-4.30 (5H, m), 2.27(s) 6.92-8.17 (8H, M), 8.79 (1 H, s) 10 In a similar manner, the following compound was obtained:

Oxalic acid salt of 7-(3-amino-l-pyrrolidinyl)-6-fluoro-l-(2,4difluorophenyi)-1,4-dihydro-4-oxo -1,8naphthyridine-3-carboxylic acid is Melting point (OC): 250-253 IR (KBO cm-l: 'C=0 1730 Example 17

To the solution of 1.6 g of methanesulfonic acid and 25 mi of acetic acid was added 5.00 g of 20 7-(3-amino-1 -pyrrolidinyi)-6-fluoro-l-(2,4-difluorophenyl)-1,4-dihydro-4oxo-1,8-naphthy ridine-3-carboxylic acid, after which the resulting suspension was stirred at room temperature to form a solution. To the solution was added 100 mi of ethanol at 400 to 450C 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-mi portions of ethanol to obtain 3.12 g of methanesulfonic acid salt of 7-(3-amino-lpyrrolidinyl)-6-fluoro-l-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8naphthyr idine-3-carboxylic acid having a melting point of >3000C.

IR (KBr) cm-l: 'C=0 1735 30 In a similar manner, the following compound was obtained:

Sulfuric acid salt of 7-(3-amino-l-pyrrolidinyi)-6-fluoro-1 -(2,4difluorophenyi)-1,4-dihydro-4-oxo-1,8- naphthyridine-3-carboxylic acidMelting point ('C): 220-230 35 IR (KBr) cm-l: T=0 1735 Preparation Example 1 With 50 g of 6-fluoro-l -(2,4-difluorophenyi)-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 19 of magnesium stearate, 40 and the blend was compressed into 1,000 flat-type tablets.

Preparation Example 2 With 100 g of 6-fluoro-l -(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 1,00 capsules were filled with the resulting blend to 45 obtain capsules.

Preparation Example 3 With 50 g of7-(3-amino-l-pyrrolidinyi)-1-(2,4-difluorophenyi)-6-fluoro-1, 4-dihydro-4-o xo-1,8-naphthyridine- 3-carboxylic acid were blended 49 g of crystalline cellulose, 50 g of corn starch and 1 g of magnesium stearate, 50 and the blend was compressed into 1,000 flat-type tablets.

Preparation Example 4 With 200 g of7-(3-amino-l-pyrrolidinyi)-1-(2,4-difluorophenyi)-6-fluoro-1, 4-dihydro-4-o xo-1,8- naphthyridine-3-carboxylic acid was blended 50 g of corn starch, and 1, 000 capsules were filled with the 55 resulting blend to obtain capsules.

Claims

1. A 1,4-dihydro-4-oxonaphthyridine derivative represented by the formula, or a salt thereof: 60 44 GB 2 191776 A 44 0 F 1 COOR XN N 5 3 t R 1 2 R wherein R' represents a hydrogen atom or a carboxyl-protecting group, R 2 represents a substituted or 10 unsubstituted aryl group, and R' represents a halogen atom or a substituted or unsubstituted cyclic amino group.

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

3. A 1,4-dihydro-4-oxonaphthyridine derivative or a salt thereof according to Claim 2, wherein R 3 15 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 R 2 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 20 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 R 3 represents a 1-pyrrolidinyi, piperidino, 1-piperazinyl or morpholino group which may be substituted by at least one substituent selected from the group consisting of alky], amino, aminoalkyl, hydroxyalkyl, hydroxyl, alkenyl, acy], alkylamino, dialkylamino, cyano, oxo, aralkyiamino, acylamino, alkoxycarbonyl and N-acyl-N- 25 alkylamino groups.

6. A 1,4-dihydro-4-oxonaphthyridine derivative or a salt thereof according to Claim 5, wherein R 3 represents a 1-pyrrolidinyi, piperidino, 1-piperazinyl, or morpholino group which may be substituted by at least one substituent selected from the group consisting of alkyl, amino, hydroxyalky], hydroxy], alkenyl, acyl, alkylamino, dialkylamino, acylamino, alkoxycarbonyl and N-acy]-N- alkylamino groups. 30

7. A 1,4-dihydro-4-oxonaphthyridine derivative or a salt thereof according to Claim 5, wherein R 2 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 R 2 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 R 3 35 represents a 1-pyrroliclinyl group which maybe substituted by at least one substitutuent selected from the group consisting of amino, hydroxyl, alkylamino, dialkylamino, acylamino and N-acy]-N-alkylamino groups.

10. A 1,4-dihydro-4-oxonaphthyridine derivative or a salt thereof according to Claim 9, wherein R 2 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 40 group, an acylamino group and a trihalogenoalkyl group.

11. A 1,4-dihydro-4-oxonaphthyridine derivative or a salt thereof according to Claim 10, wherein R 3 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 R 2 represents a phenyl group substituted by at least one halogen atom. 45

13. A 1,4-dihydro-4-oxonaphthyridine derivative or a salt thereof according to Claim 12, wherein R 2 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-l-pyrrolidinyl group.

15. A 1,4-dihydro-4-oxonaphthylidine derivative or a salt thereof according to Claim 14, wherein R 2 50 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.

16. A 1,4-dihydro-4-oxonaphthyridine derivative or a salt thereof according to Claim 15, wherein R 2 represents a phenyl group substituted by at least one halogen atom. 55

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 R' represents a 1-piperazinyl group which maybe substituted by at least one substituent selected from the group consisting of alkyl, hydroxyialky], alkenyl, acyl and alkoxycarbonyl groups. 60

19. A 1,4-dihydro-4-oxonaphthyridine derivative or a salt thereof according to Claim 18, wherein R 2 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.

20. A 1,4-dihydro-4-oxonaphthyridine derivative or a salt thereof according to Claim 19, wherein R 3 65 GB 2 191 776 A 45 represents a 1-piperazinyl group.

21. A 1,4-dihydro-4-oxonaphthyridine derivative or a salt thereof according to Claim 20, wherein R' 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 R 2 represents a 4-fluorophenyl or 2,4-difluorophenyl group. 5

23. A7-Chloro-l-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8naphthyridin e-3-carboxylic acid or a saitthereof.

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

25. 1-(2,4-Difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1, 8-naph thyridine-3-carboxylic acid 10 or a salt thereof.

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

27. A process for producing a 1,4-dihydro-4-oxo-naphthyridine derivative represented by the formula, ora saitthereof:

F COOR N NN 20 R 33) 1 12 R 25 wherein R' represents a hydrogen atom or a carboxyl-protecting group, R 2 represents a substituted or unsubstituted aryl group, and R' 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:

0 COOR la 30 N Cl 2 35 R 3P NHR wherein Wa represents a carboxyl-protecting group, and R' and R' 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 R' represents a substituted or unsubstituted phenyl group. 40

29. A process according to Claim 28, wherein R 3 represents a 1- pyrrolldinyl group which maybe substituted by at least one substituent selected from the group consisting of amino, hydroxyl, alkylamino, acylamino and N-acyl-N-alkylarnino groups.

30. A process according to Claim 29, wherein R 3 represents a 1pyrrolidinyl group substituted by an amino or acylamino group. 45

31. A process according to Claim 30, wherein R 2 represents a phenyl group substituted by at least one halogen atom.

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

33. A process according to Claim 28, wherein R 3 represents a 1piperazinyl group which maybe substituted by at least one substituent selected from the group consisting of alkyl, hydroxylalkyl, alkeny], acyl 50 and alkoxycarbonyl groups.

34. A process according to Claim 33, wherein R 3 represented a 1piperazinyl group.

35. A process according to Claim 34, wherein R 2 represents a phenyl group substituted by at least one halogen atom.

36. A process according to Claim 35, wherein R 2 represents a 4-fl uoro phenyl or 2,4-dif luo roph enyl g rou p. 55

37. A process according,to Claim 27, wherein the ring closure reaction is conducted at a temperature of 200 to 160T.

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

60 46 GB 2 191776 A 46 0 F COOR 5 /11"1 N N b 12 R wherein R' represents a hydrogen atom or a carboxyl-protecting group, R 2 represents a substituted or 10 unsubstituted aryl group, and R 3b represents a substituted or unsubstituted cyclic amino group, characterized by reacting the compound represented by the formula, or a salt thereof:

0 is F COOR N N -a 20 R 2 R wherein R represents a halogen atom, and R' and R2 have the same meanings as defined above, with a compound represented by the formula, or a salt thereof: 25 R 3b-11 wherein R 3b has the same meaning as defined above.

39. A process according to Claim 38, wherein R2 represents a substituted orunsubstituted phenyl group. 30

40. A process according to Claim 39, wherein R 3b 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-acyi-N-alkylamino groups.

41. A process according to Claim 40, wherein R 3b represents a 1pyrrolidinyl group substituted by an amino or acylamino group. 35

42. A process according to Claim 41, wherein R 2 represents a phenyl group substituted by at least one halogen atom.

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

44. A process according to Claim 39, wherein R 3b represents a 1piperazinyl group which may be substituted by at least substituent selected from the group consisting of alkyl, hydroxylalkyl, alkenyl, acyl and 40 alkoxycarbonyl groups.

45. A process according to Claim 44, wherein R 3b represents a 1piperazinyl group.

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

47. A process according to Claim 46, wherein R 2 represents a 4fluorophenyl or2,4-difluorophenyl group. 45

48. A process according to Claim 37, wherein the reaction is conducted at a temperature ofOoto 11500C.

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

so so F COOR 55:NN 55 3 1 R 12 R wherein R' represents a hydrogen atom or a carboxyi-protecting group, R 2 represents a substituted or 60 unsubstituted ary] group, and R' represents a halogen atom or a substituted or unsubstituted cyclic amino group.

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

51. A process for producing the derivative as claimed in claim land substantially as described in anyone 65 47 GB 2 191776 A 47 of the specific examples hereinbefore setforth.

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

Printed for Her Majesty's Stationery Office by Croydon Printing Company (UK) Ltd, 11187, D89911685.

Published by The Patent Office, 25 Southampton Buildings, London WC2A IlAY, from which copies may be obtained.

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