DD238795A5 - PROCESS FOR PREPARING A 1,4-DIHYDRO-4-OXONAPHTHYRIDINE DERIVATIVES - Google Patents

Abstract

The invention relates to novel 1,4-dihydro-4-oxonaphthyridine derivatives which carry a substituted or unsubstituted aryl group in the 1-position and have a halogen atom or a substituted or unsubstituted cyclic amino group in the 7-position. There are also described salts of these compounds, as well as processes for the preparation of the compounds and antibacterial agents containing the novel compounds.

Description

Field of application of the invention

The invention relates to novel 1,4-dihydro-4-oxonaphthyridine derivatives having a substituted or unsubstituted aryl group in the 1-position and a halogen atom or a substituted or unsubstituted, cyclic amino group in the 7-position. The invention further relates to the salts of these compounds, processes for the preparation of the compounds and antibacterial agents containing the novel compounds.

Characteristic of the known solutions

Nalidixic acid, piromidic acid, pipemidic acid and the like are known, widely used synthetic anti-bacterial agents. However, none of these known agents are satisfactory in therapeutic effects in the treatment of infections by Ps.aeruginosa and Gram-positive bacteria, i. in refractory diseases. Therefore, various pyridone-carboxylic acid type compounds have been developed, e.g. 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl) -3-quinolinecarboxylic acid (norfloxacin), with the aim of replacing the conventional synthetic antibacterial agents create. These compounds have excellent antibacterial activities against various Gram-negative bacteria including Ps. Aeruginosa. However, they are unsatisfactory in their antibacterial activity against gram-positive bacteria. The development of synthetic antibacterial agents with a broad antibacterial spectrum is therefore highly desirable. A suitable agent should be effective not only against Gram-negative bacteria but also against Gram-positive bacteria.

As a result of extensive research, it has been found by the inventors that novel 1,4-dihydro-4-oxo-naphthyridine derivatives and salts thereof can solve the above-mentioned problems.

Object of the invention

Object of the present invention is thus the creation of new 1,4-dihydro-4-oxonaphthyridin derivatives and salts thereof with excellent properties, eg. B. a strong antibacterial activity against gram-positive and gram-negative bacteria, especially against antibiotic-resistant bacteria. The new agents should also achieve high concentrations in the blood when administered orally or parenterally and be of high safety.

It is a further object of the invention to provide a process for the preparation of novel 1,4-dihydro-4-oxonaphthyridine derivatives and

To create salts of the same.

Finally, it is an object of the present invention to provide an antibacterial agent which is useful for the treatment of bacterial infections or the like and which is a novel 1,4-dihydro-4-oxonaphthyridine derivative or a salt

of the same.

Explanation of the essence of the invention According to the invention, novel 1,4-dihydro-4-oxonaphthyridine derivatives of the following general formula are provided:

• COOR ¹ (I)

wherein R ^{1 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 the salts

the same.

The invention further provides a process for the preparation of a 1 ^ -Dihydro ^ -oxonaphthyridine derivative of the general A formula (I) or a salt thereof, and also an antibacterial agent which comprises the 1,4-dihydro-4-

oxonaphthyridine derivative of the general formula (I) or a salt thereof.

The invention will be explained in detail below. In the compound represented by the general formula (I) or a salt thereof, R ^{1 is included} Carboxyl protecting group, for example, ester-forming groups which can be removed by catalytic reduction,

by chemical reduction or by other treatments under mild conditions; ester-forming groups that can be easily removed in the living body; organic, silyl-containing groups, organic, phosphorus-containing groups and organic, tin-containing groups which can be easily removed by treatment with water or an alcohol; such as

various other known ester-forming groups.

Among these carboxyl-protecting groups, the preferred protecting groups include, for example, carboxyl-protecting groups such as

they are described in the JA-OS 80665/84.

As the aryl group for R ² , for example, phenyl, naphthyl and the like. In question. The aryl group may be substituted by

one or more substituents selected from halogen atoms, e.g. Fluorine, chlorine, bromine, iodine and the like; Alkyl groups, e.g. B.

straight or branched chain C 1-6 alkyl groups such as methyl, ethyl, n-propyl, isopropyl, η-butyl, isobutyl, sec-butyl, tert-butyl pentyl, hexyl, heptyl, octyl and the like; Hydroxyl groups, alkoxy groups, e.g. B. straight-chain or branched Ci-io-

Alkoxy groups, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, Hexyloxy, heptyloxy, octyloxy and the like; Cyanogmppe; amino group; Acylamino groups, eg. B. C ^ -Acylamino groups, such as Formylamino, acetylamino, propionylamino, butyrylamino and the like; and trihaloalkyl groups, e.g. Trihalogen-C, ^ -

alkyl groups such as trifluoromethyl, trichloromethyl and the like.

Suitable halogen atoms for R ³ are, for example, fluorine, chlorine and bromine. The cyclic amino group for R ³ has

at least one nitrogen atom and may additionally have one or more oxygen atoms as heteroatoms, which the

Form ring. For example, 5-membered or 6-membered cyclic amino groups, such as 1-pyrrolidinyl, piperidino, 1, are included. Piperazinyl, morpholino and the like. The above-mentioned cyclic amino groups may be substituted by a

or more substituents selected from alkyl groups, e.g. B. straight-chain or branched-chain C ^ alkyl groups, such as

-5- 233 795

Methyl, ethyl, n-propyl, isopropyl, η-butyl, isobutyl, sec-butyl and tert-butyl; amino group; Aminoalkyl groups, e.g. Amino-C 1-8 alkyl groups such as aminomethyl, 2-aminoethyl, 3-aminopropyl and the like; Hydroxyalkyl groups, ζ. Β. Hydroxy-C 1-4 alkyl groups such as hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl and the like; hydroxyl group; Alkenyl groups, ζ. Β. C ₂ - alkenyl groups such as vinyl, allyl and the like; Acyl groups, ζ. C 1-4 acyl groups such as formyl, acetyl, propionyl, butyryl and the like; Alkylamino groups, ζ. C 1-5 alkylamino groups such as methylamino, ethylamino, n-propylamino, isopropylamino and the like; Dialkylamino such. Di-C 1-4 -alkylamino groups such as dimethylamine, diethylamino, di-n-propylamino, methylethylamino and the like; cyano group; oxo group; Aralkylamino groups, eg. B. Ar-C ₁ ^ -alkylamino groups such as benzylamino, phenethylamino and the like; Acylamino groups, ζ. C 1-8 acylamino groups such as acetylamino, propionylamino, butyrylamino and the like; Alkoxycarbonyl groups, ζ. B. C 1-4 alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and the like; and N-acyl-N-alkylamino groups, ζ. N-acyl-N-alkylamino groups in which the nitrogen atom of the above-mentioned alkylamino group is substituted by a C 1-8 acyl group such as acetyl, propionyl, butyryl or the like.

Among the compounds according to the general formula (I), preferred are those in which R ^{2 is} a fluorine-substituted phenyl group and R ^{3 is} a substituted or unsubstituted 1-pyrrolidinyl or 1-piperazinyl group. Those compounds in which R "is a 2,4-difluorophenyl group and R" is a 3-amino-1-pyrrolidinyl group are particularly preferred.

The salts of the compounds of the general formula (i) include conventional salts of the basic groups such as an amino group or the like, as well as salts of the acidic groups such as a carboxyl group and the like. The salts of the basic groups include e.g. 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 msthansulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid and the like. The salts of the acidic groups include, for. 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, dibsnzylamine, N-benzyl-O-phenethylamine, 1-eph.enamine, Ν, Ν-dibenzylethylenediamine, triethylamine, trimethylamine, tributylamine, pyridine, Ν, Ν-dimethylaniline, N-methylpiperidine , N-methylmorpholine, diethylamine, dicyclohexylamine and the like.

When the compound represented by the general formula (I) or a salt thereof has isomers (e.g., optical isomers, geometric isomers, tautomers and the like), these isomers are also included in the present invention. Furthermore, the invention encompasses all crystal forms and hydrates of the compounds according to the invention. In the following, antibacterial activity and acute toxicity will be explained with reference to typical compounds of the present invention

 1. Antibacterial activity

test method

According to the standard method of the Japan Society of Chemotherapy [Chemotherapy, 29 (1), 76-79 (1981)], a bacterial solution obtained by culturing in cardiac infusion broth (manufactured by Eiken Kagaku) for 20 hours at 37 ^° C., a cardiac infusion agar vaccinated, which contains a drug. The whole is cultured at 37 ° C for 20 h. Subsequently, the growth state of the bacteria is examined. In this way, the minimum concentration is determined at which the growth of the bacteria is inhibited. This value is given as MIC (/ xg / ml). The amount of inoculated bacteria is 10 ⁴ cells / plate (10 ⁶ cells / ml). Table 1 gives the MIC values for each of the identified test compounds. The symbols used in Table 1 have the following meanings: * 1: penicillase-producing bacteria * 2: cephalosporinase-producing bacteria * 3: inoculation amount: 10 ⁸ cells / ml Me: methyl group Et: ethyl group

n-Pr: n-propyl group i-Pr: isopropyl group.

Table 1

I ² R ² F ^H0 \ Pj - HO-Zo) HO-Zo) 4 R ³ MeN ^ Ji O- O- 0.1 ^ ~~~~ ^^ ~ ^ _ ^ Connection ^^ - ^ <_ No. Bacteria ^ "^ - ^^^ 1 2 3 0.1 St. aureus FDA209P 0.1 5.20 5.20 0.1 St. epidermidis IID866 0.1 ^ 12:05 5.20 5.20 St. aureus F-137 * ¹ 0.1 $ 0.05 5.20 5.20 E. coli NIHJ 5.20 12:39 0.1 5.20 E. coli TK-111 5.20 0.2 5.20 1:56 E. coli GN5482 * ² 5.20 0.1 5.20 0.1 Ps. Aeruginosa S-68 12:39 6.25 1:56 3.13 Aci. Anitratus A-6 0.2 0.2 5.20 0.78 Ps. Aeruginosa IFO3445 3.13 12.5 3.13 Ps. Aeruginosa GN918 * ² 12:39 3.13 0.70

ι ι Q I O CM (N CN ιη ιη ιη cn (N rn rn 1 0 0 ο O O ο ο ο t-l O Co) Z (N Οι ο ο ο cn cn rn T X S I • Η X Vl Vl Vl ο υ-υ I as H 0 CN X pm Ό I C CO cn (N CN CN ιη ιη ιη rn · "* in vo (Ο) ο O O ο ο ο • -ι O CN in ο ο ο τη VO _ ( T I Vl Vl Vl Q 0 K S I I CO <Ν CN ιη ιη m m CN (Ο) , ζ. O O O ο ο ο .H O in J P ο ο ο CN m O S ο ' Vl Vl V * r | S • rts ο β) Σ I CD V \ 00 σι Φ [O] CN Γ "· η ιη ιη ιη vo CN VO 00 H H ν O O ο O ο ο in O in Φ ι ο ο ο .H O 03 Cm Vl Vl Vl Cm i ιη * ιη VO ο H ο ιη ιη ιη VO m co • ο ο ο in • I ^ J ο O ο • • • • O • • Vl Vl ο ο ο m O I Vl   Vl Vl Cm η Cu I σ> in CN η (N ιη ιη ιη cn CN 00 cn [Oj O ο O ο ο ο cn O m ο ο ο O O O ι Vl Vl Vl Cm

Ο ι J. a A • I f " in CM CM (N in in in VO i CM O VO ro \ / ε / \ P as " rh O O O O O O in O in O / W O a a O O O _ _ rh / / CM υ-υ Il Vl VI Vl I / 2 Z CN a Il (N. H a a rh -S U U CN (N in XTi in ca O KD ro τ a r | O O O O O O CM in O O O O O O rh IO Vl Vl Vl  Ρ Ή O cn A in O »- 'T ro in O rh rh in σ r-i > elle_ T rh O O O in O in O in O CM vi CM O μ- « as eu Vl O O O UJ O EH VI Vl vi Vj I in in in in O ToI O O O in in in O rh f λ O O O O O O Vl (N O Vl Vl Vl O O O O Vl Vl Vl Vj I CM ro l ^ o) (N ro CN σ " O rh • -λ O O O ro "-H <H in ro cn O O O (N

2. Acute toxicity

The LD ₅₀ values are determined by administering the above-mentioned test compounds Nos. 5, 6 and 12 intravenously to mice (ICR strain, male, body weight: 18 to 24 g). The LD ₅₀ values are 20 mg / kg or more.

The process for preparing the compounds according to the invention is explained in more detail below.

The compounds according to the invention can be obtained, for example, by the following route of preparation:

COOR

.3b

COOR

la

[IV] or a salt thereof

/ ^ N ^ vci ^ NH-R

R ^- "R"

[III] or a salt thereof [V] or a salt thereof

COOR

COOR

R ^3b R ' ^R R'

[la] or a salt thereof Hb] or a salt thereof

R ^{1a is} the same carboxyl protecting group as R ¹ ; R ^{3a represents} the same halogen atom as R ³ ; R ^{3b represents} the same substituted or unsubstituted cyclic amino group as R ³ ; and R ¹ and R ² have the meaning given above.

The salts of the compounds according to the general formulas (I a), (I b), (III), (IV) and (V) comprise the same salts as have been explained above in connection with the compounds of general formula (I) ,

(i) The compound of the general formula (III) or a salt thereof or the compound of the general formula (V) or a salt thereof is obtained by reacting the compound of the general formula (II) or the compound of the general formula (II) or reacting the compound of the general formula (IV) or a salt thereof with an acetal, such as N, N-diethylformamidodimethylacetal, Ν, Ν-dimethylformamidodiethylacetal or the like, and then with an amine of the general formula R ² -NH ₂ (where R is ^{2 has} the above meaning).

The solvent used in the above reactions may be any solvent inert in the reactions. Suitable solvents include, without being critical to the success of the reaction, 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, Ν, Ν-dimethylacetamide and the like; Sulfoxides such as dimethyl sulfoxide and the like, etc. These solvents may be used each alone or as a mixture of two or more. The amount of the acetal used is preferably 1 mole or more, more preferably about 1.0 to 1.3 moles, per mole of the compound of the general formula (II) or the compound of the general formula (IV) or a salt thereof. The reactions are generally carried out at 0 to 100 ⁰ C, preferably 50 to 8O ⁰ C, and indeed generally for 20 minutes to 50 hours, preferably 1 to 3 hours. The amine is used in an amount of 1 mole or more per mole of the compound of the general formula (II) or the compound of the general formula (IV) or a salt thereof. The reaction is generally carried out at 0 to 100 ^° C., preferably at 10 to 60 ^° C. The reaction time is generally 20 minutes to 30 hours, preferably 1 to 5 hours. As an alternative method, the compound of the general formula (II) or the compound of the general formula (IV) or a salt thereof may be reacted with ethyl-o-formate or methyl-o-formate in the presence of acetic anhydride and then with an amine of the general formula Formula R ² -NH ₂ or a salt thereof to obtain the compound of the general formula (IM) or a salt thereof or the compound of the general formula (V) or a salt thereof.

(ii) The compound of the general formula (Ia) or a salt thereof or the compound of the general formula (Ib) or a salt thereof is obtained by reacting the compound of the general formula (III) or a salt thereof or the compound of the general formula (V) or a salt thereof is subjected to ring-closing reaction (preferably with heating) in the presence or absence of a base.

The solvent used in this reaction may be any solvent inert in the reaction. Suitable solvents include, without being critical to the success of the reaction, for example, amides such as Ν, Ν-dimethylformamide, N, N-dimethylacetamide and the like; Ethers such as dioxane, anisole, diethylene glycol dimethyl ether and the like; Sulfoxides such as dimethyl sulfoxide and the like; etc. These solvents may be used each 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 / mole of the compounds of the general formula (III) or (V) or a salt thereof , The reaction is usually carried out at 20 to 160 ⁰ C, preferably at 100 to 15O ⁰ C. The reaction time is usually 5 minutes to 30 hours, preferably 5 minutes to 1 hour. (iii) The compound of the general formula (IV) or a salt thereof, the compound of the general formula (V) or a salt thereof or the compound of the general formula (Ib) or a salt thereof are obtained by reacting the compound the general formula (II), the compound of the general formula (II) or a salt thereof or the compound of the general formula (Ia) or a salt thereof with a cyclic amine of the general formula R ^3b -H or a Reacting salt thereof, wherein R ^{3b has} the meaning given above.

In this reaction, any, inert for the reaction solvent can be used. Suitable solvents include, without being critical, aromatic hydrocarbons such as benzo, 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 Ν, Ν-dimethylformamide, Ν, ιΜ-dimethylacetamide and the like; Sulfoxides such as dimethyl sulfoxide and the like; Alcohols such as methanol, ethanol and the like; Nitriles such as acetonitrile and the like, etc. These solvents may be used alone or as a mixture of two or more. The cyclic amine or a salt thereof is preferably used in excess, more preferably in an amount of 2 to 5 moles / mole of the compound of the general formula (II), the compound of the general formula (III) or a salt thereof or the compound the general formula (Ia) or a salt thereof. If the amount of the cyclic amine used is about 1 to 1.3 mol, it is sufficient that an acid-binding agent in an amount of 1 mol / mol of the compound of the general formula (II), the compound of the general formula (III) or a salt thereof or the compound of the general formula (Ia) or a salt thereof. Suitable acid-binding agents include organic or inorganic bases such as triethylamine, 1,8-diazabicyclo [5,4,0] undec-7-ene (DBU), potassium t-butoxide, potassium carbonate, sodium carbonate, sodium hydride and the like.

Suitable salts of the compound R ^3b -H are the same salts as the salts of the basic group of the compound of the general formula (I).

The reaction is generally carried out at 0 to 150 ⁰ C, preferably at 50 to 100 ° C. The reaction time is usually 5 minutes to 30 hours, preferably 30 minutes at 3 hours.

The compound according to the general formula (Ia), (Ib), (III) or (V) wherein R ^{1 is} a carboxyl-protecting group, or a salt thereof may, if desired, be converted into the corresponding free carboxylic acid, by hydrolyzing the compound in the presence of an acid or base conventionally used for hydrolysis purposes. The hydrolysis is in general Beio to 100 ° C, preferably at 20 to 100 ⁰ C, during 5 min to 50 h, preferably 5 min to 4 h, performed. Further, the compound of the general formula (Ia), (Ib), (III) or (V) or a salt thereof may, if desired, be converted to a salt or an ester of the corresponding compound by reacting the compound as it is known Salt formation reaction or esterification reaction subjects. When the compound represented by the general formula (I a), (III), (IV) or (V) or a salt thereof has an active group (e.g., a hydroxyl group, amino group or the like) in positions other than Having reaction sites, it is possible to protect the active group before the reaction in a conventional manner and to remove the protective group after completion of the reaction. The compound thus obtained may be isolated and purified in a conventional manner, e.g. By column chromatography, recrystallization, extraction and the like.

The compound of the general formula (I) or a salt thereof in which R ^{3 is} a halogen atom (corresponding to the compound of the general formula [Ia]) also provides a useful intermediate to obtain compounds in which R ^{3 represents} a substituted or unsubstituted cyclic amino group (corresponding to the compound of general formula [Ib]).

When using the compound of the invention as a drug or medicament, the compound is conveniently combined with carrier materials as used in conventional pharmaceutical preparations. The composition is conventionally processed into tablets, capsules, powders, syrups, granules, suppositories, ointments, injections and the like. The routes of administration, dosages and the number of administrations may be varied as appropriate, according to the symptoms of the patients. Generally, the agent is administered orally or parenterally (eg, as an injection, drip, by rectal administration). Administration to an adult is in an amount of 0.1 to 100 mg / kg / day in one or more portions.

The invention will be explained below with reference to examples, examples and preparation examples. The symbols used in the Reference Examples and Examples have the following meanings:

Me: methyl group; Et: ethyl group; n-Pr: n-propyl group; i-Pr; isopropyl; Ac: acetyl group; , gf ^ ** - ^ ^ allyl group;

^^ - v ^ - ': ethylene group.

Reference Example 1

In 210 ml of chloroform, 21 g of 2,6-dichloro-5-fluoronicotinic acid are dissolved. 23.8 g of thionyl chloride and 0.1 g of Ν, Ν-dimethylformamide are added to the resulting solution. The resulting mixture is reacted at 70 ° C for 2 h. The solvent and excess thionyl chloride are removed by distillation under reduced pressure. The residue obtained is dissolved in 21 ml of tetrahydrofuran. In 110 ml of tetrahydrofuran is dissolved 25.1 g of diethylethoxy-magnesium malonate and the solution is cooled to -40 to -30 ° C from. In this solution is added dropwise at the same temperature for 30 min, a previously prepared tetrahydrofuran solution of 2,6-dichloro-5-fluornicotinoylchlorid. This mixed solution is stirred for 1 h at the same temperature. Subsequently, the temperature of the solution is gradually raised to room temperature. The solvent is removed by distillation under reduced pressure. 200 ml of chloroform and 100 ml of water are added to the residue obtained. The pH is adjusted to 1 with 6 N hydrochloric acid. The organic layer is separated, washed successively with 50 ml of water, 50 ml of 5% aqueous sodium bicarbonate solution and 50 ml of saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure. To the obtained oily product are added 50 ml of water and 0.15 g of p-toluenesulfonic acid. Subsequently, the resulting mixture is reacted at 100 ^° C. for ² hours with vigorous stirring. The reaction mixture is extracted with 100 ml of chloroform. The organic layer is washed with 50 ml of saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Subsequently, the solvent is removed by distillation under reduced pressure. The residue obtained is purified by column chromatography (Wako Silica Gel C-200; eluent: toluene). This gives 23.5 g of ethyl (2,6-dichloro-5-fluoronicotinoyl) -acetate, mp. 64 to 65 ° C.

IR (KBr) cm ^-1 : y _{c = o} 1 650, 1 630, 1 620

NMR (CDCl ₃ ) 5: 1.25 (1.29H, t, J = 7Hz), 1.33 (1.71H, t, J = 7Hz), 4.07 (1.14H, s), 4 , 28 (2H, q, J = 7Hz), 5.82 (0.43H, s), 7.80 (1H, d, J = 7Hz), 12.52 (0.43H, s).

Bezugsbeispiai2

In 40m! ! Benzene lös * iy to 8.3 g Ht - -aceiat (2,5-dichloro-5-fluoronicotinoyl) is 4.5 g Ν, Ν-DiiTiethylformarriidcdimethylscetal to and then sets the resultant mixture for 1.5 hours at 70 ⁰ C. around. Then, 4.1 g of 2,4-difluoroaniline are added to the reaction mixture, and the resulting mixture is reacted at room temperature for 4 hours. The solvent is removed by distillation under reduced pressure. The residue obtained is purified by column chromatography (Wako Silica Gel C-200; eluent: chloroform). This gives 9.0 g of ethyl 2- (2,6-dichloro-5-fluoronicotinoyl) -3- (2,4-difluorophenylamino) acrylate, m.p. 138-139 ° C

IR (KBr) Cm " ¹ : v _c = _o 1 690

NMR (CDCl ₃ ) 5: 1.08 (3H, t, J = 7Hz), 4.10 (2H, q, J = 7Hz), 6.77-7.40 (4H, m), 8.50 ( 1 H, d, J = 13Hz), 12.70 (1H, J = 13Hz). In a similar manner, the compounds shown in Table 2 are obtained.

table

COOEt

Connection Physical Properties

R "mp ( ⁰ C)

IR (KBr) cm " ¹ :

C = O

87-89 1690

O ν

110-114 1710, 1630

92-93 1710, 1680

135-137 1720 (Sch), 1690

78-80 1690

oil in 1705, 1680 (Sch)

F ι F [O

154-155 1720 (Sch), 1685

100-101 1700 (Sch), 1685

Cl

123-125 1710, 1680

Table 2 (cont.)

br

145-1461705, 1680

147-1491685

OMe

oily 1695

OMe

119-1211700

oily 1700

NHAc

183-1861685, 1670

136-1381705, 1680

me

114-1161680

O V

OMe

137.5-139 1725 (Sch), L680

92-951705

[O νMe

OMe

125-1261700), 1660

O VOMe

me

91-921705, 1690

Note: Instead of the KBr pellet, the pure substance is examined.

Reference Example 3

(1) In 55 ml of chloroform is dissolved 5.5 g of ethyl (2,6-dichloro-5-fluoronicotinoyl) acetate, 2,37g of N-methylpiperazine and 2,37g of triethylamine and sets the resulting solution for 2 hours at 60 to 65 ⁰ C um. The reaction mixture is washed with 30 ml of water and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure, and the residue obtained is purified by column chromatography (Wako Silica Gel C-200, eluent: chloroform).

cleaned. This gives 5.4 g of oily ethyl [2-chloro-5-fluoro-6- (4-methyl-1-piperazinyl) nicotinoyl] acetate.

IR (in) cm " ¹ : i> _{c = o} 1750.1695

NMR (CDCl ₃ ) 5: 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, H = 13Hz)

 In a similar manner, the compounds listed in Table 3 are obtained.

Table 3

COOEt

connection Physical Properties IR (KBr) cm " ¹ : ^V C = O R ³ Mp ~ (° C) 1730 / \ AcN N- \ t 67-71

(2) In 22.5 ml of benzene, 4.5 g of ethyl [2-chloro-5-fluoro-6- (4-methyl-1-piperazinyl) -nicotinoyl] -acetate are dissolved. To the resulting solution is added 1.87 g Ν, Ν-Dimethylformamido dimethyl acetal and then sets the resultant mixture to 2h at 7O ⁰ C. The reaction mixture is admixed with 1.8 g of 4-methoxy-2-methylaniline and the resulting mixture is reacted at room temperature for 4 h. Then, the solvent is removed by distillation under reduced pressure, and the obtained residue is purified by column chromatography (Wako Silica Gel C-200; eluent: chloroform-ethanol = 100/1 [by volume]). The resulting crystalline substance is washed with 10 ml of diethyl ether; 5.0 g of ethyl 2- [2-chloro-5-fluoro-6- (4-methyl-1-piperazinyl) -nicotinoyl] -3- (4-methoxy-2-methylphenylamino) -acrylate, m.p. 141 are obtained

IR (KBr) Cm- ¹ IVc = O 1 710 (Sch), 1 695

NMR (CDCl ₃ ) 5: 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 (1H, d, J = 13Hz), 8.48 (1H, d, J = 13Hz), 12.82 ( 1 H, d, J = 13Hz). Similarly, the compounds listed in Table 4 are obtained.

Table 4

, 3- ^ N

connection

Physical Properties

M.p. ( ⁰ C) cm

MeN N-

oil bottle * 2

1720 (Sch), 1715

oily1735, 1700

OMe

oily * 2

1695

NHAc

161-164 * 1

1685, 1670

OMe

oily * 2

1720 (Sch), 1715

233

Table 4 (cont.)

MeN N- 132-136 *1 1705 (Sch), * 2 1720 (Sch), \ / 1685 1700 Y ^ Me OMe I ^ Me / - \ AcN N- oily (ρΤ \ / OMe

* 2: pure

example 1

9.0 g of ethyl 2- (2,6-dichloro-5-fluoronicotinoyl) -3- (2,4-difluorophenylamino) acrylate are dissolved in 90 ml of N, N-dimethylformamide, giving 3.6 g of sodium bicarbonate to the resulting Solution and then the resulting mixture for 20min at 12O ⁰ C to. Then, the solvent is removed by distillation under reduced pressure, and the residue obtained is dissolved in 50 ml of chloroform. The resulting solution is washed successively with 30 ml of water and 30 ml of saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure and the resulting crystalline substance is washed with 30 ml of diethyl ether. This gives 7.0 g of ethyl 7-chloro-6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate, m.p. 220-222 ° C , IR (KBr) Cm " ¹ : y _{c = 0} 1 730, 1690.

NMR (CDCl ₃ ) 5: 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). Similarly, the compounds shown in Table 5 are obtained.

Physical property sn

fp

( ⁰ C)

IR (KBr) cm " ¹ : ^V C = O

222-224 1730, 1635

231-2321730, 1705

239-2411685

205-2081735, 1685

Table 5 (cont.)

244-246

1720, 1680

207-209.5

1730, 1690

210-214

1735 {.Sch), 1705

207-208

1730, 1680

Cl

181-186

1730, 1685

br

204-205

1730, 1685

me

216-218

1735, 1695

OMe

196-198

"1733, 1685

Table 5 (cont.)

OMe

156-160

1730, 1690

CN

231-236

1730, 1685

NHAc

270-273

1730, 1690

CF.

199-201

1730, 1680

me

199-202

1735, 1685

208-211

1730, 1695

OMe

142-144

1740, 1695

Table 5 (cont.)

I _x OMe Ψ Me 163-165 1730, 1695 (of OMe 160-162 1735, 1690

Step Example! 2

(1) In 35m! Chloroform is dissolved in 3.5 g of ethyl-7-chicr-6-fluoro-1- {2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,3-n3-phthyridine-3.

carboxylate, adds 1.5 g of N-acetylpiperazine and 1.6 g of triethylamine to the resulting solution and then sets the resulting

Mixture for 1 h at 60 ° C to. Then the solvent is removed by distillation under reduced pressure and the resulting Residue was purified by column chromatography (Wako Silica Gel C-200; eluent: chloroform-ethanol = 30/1 [VoI]). 3.5 g of ethyl 7- (4-acetyl-1-piperazinyl) -6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oyo-1,8-naphthyridine-3 are obtained carboxylate,

Mp 207 to 209 ⁰ C.

IR (KBr) Cm- ¹ : y _{c = o} 1730,1695 NMR (CDCl ₃ ) 5: 1.38 (3H, t, J = 7Hz), 2.05 (3H, s), 3.53 (8H, bs), 4.30 (2H, q, J = 7 Hz), 6.80-7.75 (3H, m), 8.00 (1H, d, J = 13Hz), 8.30

(1H, s). Similarly, the compounds listed in Table 6 are obtained.

table

COOEt

connection

Physical Properties

fp

( ⁰ C)

IR (KBr)

Ac

rv 216-218

1730, 1690 (Sfch)

Ac

155-156

1730, 1690

MeN N-S /

217-213

1730, 1695

Me HN N-144-146

1730, 1690

Me HN

143

1730

Me HN

198-202

1725, 1690

Table 6 (cont.)

O ^ -N N-

220-222

1730, 1695

Acr / N-

253-255

1730, 1690

r ~ \

203-205

1730, 1700

AcN N-

211-213

1735

206

1725.1690

MeN N-

193-194

1730, 1700

AcN \ -

244-246

1725, 1690

Ac

Ir

MeNK N-

186-187

1725, 1690 (Sch)

Table 6 (cont.)

HN N-

155-157

1720, 1685

MeN _x η

153-154

1730, 1700

me

153-155

1730, 1695

N-

166-168

1730 (Sch), 1690

Oi N-

202-204

1730, 1690

230-231

1725 (Sch), i 1695

193-194

1720 (Sch),

1680,

1675

f Cl

MeN

N-

207

1725, 1695

-24- 233 795

Table 6 (cont.)

Cl

Ac

254

1730, 1690

Γ ~ \

to k

208

1730, 1590

AcN N-

246-247

1730, 1690

me

MeN \ -

167-169

1730, 1695

TO N

206-207.5

1730, 1690

OMe

163-165

1735, 1700

174-176

1730, 1690

180-181

1735, 1695

Table 6 (cont.)

OMe n-PrN ' ρ- 171-172.5 1730, 1685 η 203.5-210 1730, 1690 η ΗΟ ^ Χ / Ν Ν- N / 200-202 1730, 1590 η ^ - N N- 162-163 1725, 1690 η ACN ^ Ji 197-199 1735, 1690 JL ^ OMe (ο; MeN yN- 136-138 1725, 1685 (s) CN AcN N- 270-272 1730, 1690 NHAc η 245-249 1730, 1695

Table 6 (cont.)

O CF.

Ac

N JH-

249-252

1730, 1695

2S3-2S4

1730

/ -λ

MeN N-

166-169

1730, 1635

AcN

222.5-223.5

1730, 1690

MeN N-

165-168

1730, 1685

Aclf N-

215-219

1730, 1695

OMe

Meli il-

170-171

1725, 1690

iMe

AcN N-

169-172

1725, 1690

-27- 233 795

(2) Dissolve 2.5 g of ethyl 7- (4-acetyl-1-piperazinyl) -6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo in 25 ml of 6N hydrochloric acid. 1,8-naphthyridine-3-carboxylate and the resulting solution refluxed for 2 hours. Then, the reaction mixture is cooled to room temperature and its pH is adjusted to 6.5 with 1 N aqueous sodium hydroxide solution and then to 6.5 with acetic acid. The deposited crystals are collected by filtration, washed with 30 ml of water and then dried. 1.8 g of 6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-7- (1-piperazinyl) -1,8-naphthyridine-3-carboxylic acid are obtained. NMR (TFA-d,) δ: 3.30-4.50 (8H, m), 7.00-7.85 (3H, m), 8.33 (1H, d, J = 13Hz), 9 , 21 (1 H, s). The compounds listed in Table 7 are obtained in a similar manner.

Table 7

COOH

connection

Physical Properties

Mp.

HH N-

252.5-254.5

IR (KBr) era " ¹ : v _{c = 0}

1730

multipath

> 280

1720

279-280

1725

234-236

1720

222-224

1725

> 280

1720

Table 7 (cont.)

O T

br

O Me

CN

NH.

MeNH

254-258

205-207

225-227

> 280

273-277

245-246

> 280

> 280

1725 1730

1725

17251720

1725

1725

1730, 1710

Table 7 (cont.)

NHAc Meii k- 232-236 1725, 1710, 1690 CF ₃ / ~ \ > 2S0 1725 φ * F Il 230-232 1730

Comment:

* Instead of the KBr process, the Nujol

drive used.

Example 3

(1) In 5 ml of chloroform is dissolved 0.50 g of ethyl 7-chloro-6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate , The resulting solution is mixed with 0.20 g of 3-Acetylaminopyrrolidin and 0.15 g of triethylamine and then the resulting mixture for 1 h at 60 ⁰ C to. Then, the solvent is removed by distillation under reduced pressure, and the resulting residue is purified by column chromatography (Wako Silica Gel C-200; eluent: chloroform-ethanol = 30/1 [vol.]). 0.5 g of ethyl 7- (3-acetylamino-1-pyrrolidinyl) -6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-one is obtained. carboxylate, mp. 233-235 ⁰ C.

IR (KBr) cm ^-1 : v _c = _o 1 725, 1 700 NMR (CDCl ₃ ) 5: 1.32 (3H, t, J = 7Hz), 1.77-2.27 (m) 2.08 (s) (5H), 3,12-3,74 (4H, m), 4,02 ^ 1,74 (m) 4,29 (q, J = 7Hz), (3H), 6,75-7 60

(4H, m), 7.93 (1H, d, J = 8Hz), 8.24 (1H, s)

 In a similar manner, the compounds listed in Table 8 are obtained.

Table 8

OOEt

connection i η R ³ "Λ Me ₂ N ^ - Ph3 ^r 3ical3 Eiganschaftan IR (ICBr) cm: νQ ₌ Q 2 η HO ACHN Mp: ( ⁰ C) 1730, 1700 n Ac 231-233 1730, 1690 156 1725, 1690 203-205 1725, 1695 201-202

-31- 233 795

Table 8 (cont.)

F Me ₂ N _x N- 165 1730, 1690 η i MeN 195-197 1730, 1695 s ^ ^F ACHN ^ Z ¹ I i - ώ * i ι 1725, 1700 OMe 153-155 1735 η 185-187 1730, 1690

(2) In 2.5 ml of 6N hydrochloric acid are dissolved 0.25 g of ethyl 7- (3-acetylamino-1-pyrrolidinyl) -6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro ^ -oxo -i ^ -naphthyridine-S-carboxylate and the resulting solution refluxed for 2 h. Then, the reaction mixture is cooled to room temperature and its pH is adjusted to 6.5 with 1 N aqueous sodium hydroxide solution and then to 6.5 with acetic acid. The deposited crystals are collected by filtration, washed with 2 ml of water and then dried. This gives 0.18 g 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,) 5: 2.25-2.85 (2H, m), 3.37 ^ 1.69 (5H, m), 6.93-7.81 (3H, m), 8, 22 (1 H, d, J = 11 Hz), 9.16 (1 H, s). In a similar manner, the compounds listed in Table 9 are obtained.

-32- 233 795

Table 9 o

F I COOH

connection R ² R ³ \ N- M Physical Properties IR (K3r) cm ^-1 : ^V C = O Γ F H ₂ N Ί ^ - Fd. ( ⁰ C) 1720 Il multipath 260-263 1720 F 259-261 1720 ] 275-278 1720 278-280

Example 4

(1) In 20 ml of chloroform is dissolved 2.0 g of ethyl ^ e-dichloro-ö-fluoronicotinoylacetate, 0.96 g 3-acetylamino-pyrrolidine and 0.8 g of triethylamine, and sets the resulting solution for 2 hours at ⁰ to 65 C at 60th The reaction mixture is washed with 30 ml of water and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure, and the residue thus obtained is purified by column chromatography (Wako Silica Gel C-200; eluent: benzene-ethyl acetate = 1/1 [vol.]). 1.8 g of oily ethyl [2-chloro-5-fluoro-6- (3-acetylamino) -1-pyrrolidinyl) -nicotinoyl] acetate are obtained.

IR (in) cm " ¹ : y _{c = 0} 1 740, 1 650

NMR (CDCl ₃ ) δ: 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 is dissolved 0.7 g of ethyl 2-chloro-5-fluoro-6- (3-acetylamino-1-pyrrolidinyl) nicotinoyl, the resulting solution with 0.235g Ν, Ν-dimethylformamido-dimethyl acetate and Then the resulting mixture for 2h at 7O ⁰ C to. To the reaction mixture is added 0.243 g of 2,4-difluoroaniline and the resulting mixture is allowed to react at room temperature for 8 hours. The solvent is then removed by distillation under reduced pressure, and the residue thus obtained is purified by column chromatography (Wako Silica Gel C-200, eluent: benzene-ethyl acetate = 1/1

233

[Vol.]). The resulting oily product is triturated with diisopropyl ether to give O, 25g of ethyl 2- [2-chloro-5-fluoro-6- (3

acetylamino-1-pyrrolidinyl) -nicotinoyl] acrylate -3- (2,4-difluorophenylamino) Fp.82 to 85 ⁰ C. IR (KBr) cm ^"1: i> _{c = o} 1695 (sh), 1 660

NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 7Hz), 2.07 (3H, s), 1.90-2.30 (2H, m), 4.19 (2H, q, J = 7 Hz), 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 is dissolved 0.2 g of ethyl 2- [2-chloro-5-fluoro-6- (3-acetylamino-1-pyrrolidinyl) -nicotinoyl] -3- (2,4- difluorophenylamino) acrylate, the resulting solution is mixed with 0.04 g of sodium bicarbonate and finally the resulting mixture for 1 h at 12O ⁰ C to. Subsequently, the solvent is removed by distillation under reduced pressure and the residue thus obtained is dissolved in 10 ml of chloroform. The resulting solution is washed successively with 10 ml of water and 10 ml of saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure and the resulting crystalline substance is washed with 5 ml of diethyl ether. There are obtained O, 13 g of ethyl 7- (3-acetylamino-1-pyrrolidinyl) -6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphyl; yrid; n-3-carboxy!, mp 233-235 "C.

In similar white, ethyl 7- (3-acetylamino-1-pyrrolidinyl) -6-fluoro-1- (4-fluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate is obtained , The physical properties of this product are identical to those of the product obtained in Example 3 (1).

Example 5

(1) 0.15 g of ethyl 7-chloro-6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3 are suspended in 15 ml of 6N hydrochloric acid. carboxylate and heated the suspension for 3h under reflux. Then the reaction mixture is diluted with 50 ml of water and extracted with three 50 ml portions of chloroform. The unified extracts are washed with 100 ml of saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is removed by Dosti! ' c LiOTi υπίΰί "by" ii ^ dcr * 2rTi Drijc! ' or. ΐί 2γγίϊ and diG dnb "i ^ηί " Γ * ο 't ^ ro kri ^' ci ν τ ° Su b ^ * ^ π ζ ρί it 15 r ^ i Di ^ ic '! other q εν / 3 sch cn One obtains 0.40q T-chloro-S-fluoro-II-di-difluorophenyl-1-dihydro-oxo-S-naphthyridine-S-carboxylic acid, m.p.244-248 ° C. IR (KBr) cm ^"1: f _'c = _o 1720 NMR Id ₆ -DMSO) δ: 7.26 to 8.56 (3H, m), 8.86 (1H" d, J = 7Hz), 9.18 (1H, s).

(2) In 3 ml of dimethyl sulfoxide is suspended 0.30 g of 7-chloro-6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridin-3-carboxylic acid, added the resulting suspension with 0.25 g of N-methylpiperazine and then reacts the resulting suspension at 60 ° C for 30min. Subsequently, the solvent is removed by distillation under reduced pressure and the residue thus obtained is mixed with 30 ml of water. The pH of the resulting mixture is adjusted to 12 with 10% aqueous sodium hydroxide solution and then to 7 with acetic acid. The deposited crystalline substance is collected by filtration and washed with 5 ml of water. 0.24 g of 6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-7- (4-methyl-1-piperazinyl) -4-oxo-1,8-naphthyridine-3-carboxylic acid are obtained , Mp 208-209 ⁰ C.

NMR (TFA-Cl ₁ ) δ: 3.30 (3H, s), 3.45-5.25 (8H, m), 7.12-8.10 (3H, m), 8.49 (IH, d, J = 13 Hz), 9.38 (1H, s).

Example 6

5.0 g of ethyl 2- [2-chloro-5-fluoro-6- (4-methyl-1-piperazinyl) -nicotinoyl] -3- (4-methoxy-2-methylphenylamino ) acrylate, the resulting solution is mixed with 1.03 g of sodium bicarbonate and the resulting mixture is reacted at 120 ⁰ C for 3 h. Then, the solvent is removed by distillation under reduced pressure, and the residue thus obtained is dissolved in 50 ml of chloroform. The resulting solution is 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 is removed by distillation under reduced pressure and the resulting crystalline substance is washed with 30 ml of diethyl ether. This gives 2.38 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, mp. 144-145 ° C.

NMR (CDCl ₃ ) δ: 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 (1H, s). In a similar manner, the compounds listed in Table 10 are obtained.

COOEt

Connection Physical Properties

TR (X3r) cm " ¹ : ^v C = 0

/ - \

MeN N- /

199-202

1725,

1685

168-171

1735, 1720

OMe

174-175

1730,

1695

NHAc

amorphous

1725, 1690

OMe

186-189

1725, 1690

me

OMe

166-168

1730, 1695

me

OMe

/ - \

AcN N-

N /

169-172

1725, 1690

Example 7

2.0 ml of ethyl 6-fluoro-1,4-dihydro-1- (4-methoxy-2-methylphenyl) -7- (4-methyl-1-piperazinyl) -4-oxo are dissolved in 5 ml of 47% hydrobromic acid -1,8-naphthyridine-3-carboxylate, and sets the resulting solution for 2 hours at 120 to 125 ⁰ C in order. The pH of the reaction mixture is adjusted to 13 with 10% aqueous sodium hydroxide solution and then to 6.5 with acetic acid. The deposited crystals are collected by filtration and washed with 10 ml of water. 1.8 g of 6-fluoro-1,4-dihydro-1- (4-hydroxy-2-methylphenyl) -7- (4-methyl-1-piperazinyl 1-4-OXO-1,8-naphthyridine-3 carboxylic acid, mp> 280 ° C. IR (KBr) Cm " ¹ : v _{c = o} 1 725, 1 700 (Sch)

NMR (TFA-d,) δ: 2.08 (3H, s), 3.12 (3H, s), 2.88-5.12 (8H, m), 6.93-7.62 (3H, m), 9.25 (1H, s), 9.43 (1H, d, J = 13Hz). In a similar manner, the compounds listed in Table 11 are obtained.

COOH

physical

Mp ( ⁰ C)

cm

" ¹

C = 0

C-

143-146

1725, 1710

> 280

1710

MeN N-

> 280

1710

EtN N

> 280

1730

n-PrN N-

> 280

1725

i-PrN N-

> 280

1715

HO - N

200-205

1720, 1705

> 280

1725

-36- 233 795

Table 11 (cont.)

OH

MeN N-

245-250 (Zers.)

1725, 1700 (Sch)

OH

> 230

1725, 1690

OH

HN N-

220-224

1725, 1710

Man-

> 280

1730, 1710 (Sch)

OH

> 280

1730

HN N-

> 255

1725

OH

MeN N-

251-252

1720

OH

O Me

> 280

• 1725 (Sch), 1700

me

OH

228-230

1730, 1700 (Sch)

Table 11 (cont.)

275

1720

Example 8

In 10 ml of 47% hydrobromic acid are 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 for 2 h at 120 to 125 ⁰ C to. The pH of the reaction mixture is adjusted to 13 with 10% aqueous sodium hydroxide solution and to 6.5 with acetic acid. The precipitated crystals are collected by filtration and washed with 4 m water. This gives 0.30 g of SF!: Jor-1,4-d: hydro-1- (4-hydroxyphenyl) -7- (1-pyrrolidinyl) -4-oxo-1,8-naphthyridine-3-carboxylic acid, m.p. 263 to 265''C.

IR (KBr) Cm " ¹ : j; _{c = 0} 1 725, 1 705

NMR (TFA-di) S: 1.54-2.40 (4H, m), 3.14-4.14 (4H, m), 6.35-7.69 (4H, m), 8.09 (1H, d, J = 12Hz), 9.14 (1H, s).

Similarly, the following compound is obtained:

6-fluoro-i-dihydro-i-i'-hydroxyphenyl P ^ -is-hydroxy-i-pyrrolidinyO - ^ - oxo-1-s-rthyrothyridine-S-carboxylic acid, m.p.

183-C.

ΪΓΪ (KBr) cm " ¹ : i> _{c = o} 1 725, 1 705

Example 9

To 0.1 g of ethyl 7- (4-acety! -1-piperazinyl) -6-fluoro-1- (4-fluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3 carboxylate is added 2 ml of 1N aqueous sodium hydroxide solution and 2 ml of ethanol. The resulting solution is reacted at 40 to 5O ⁰ C 10min

 Then, acetic acid is added to the reaction mixture to adjust its pH to 6.5. Then the mixture is extracted with two 5 ml portions of chloroform. The combined extracts are 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 is removed by distillation under reduced pressure and the resulting crystalline substance is washed with 2 ml of diethyl ether. 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, m.p. > 280 ° C

IR (KBr) Cm " ¹ : v _{c = 0} 1 730

NMR (d ₆ -DMSO) δ: 2.05 (3H, s), 3.57 (8H, bs), 7.13-7.80 (4H, m), 8.13 (1H, d, J = 13Hz), 8.70 (1H, s)

 In a similar manner, the compounds listed in Table 12 are obtained.

Table 12

COOH

connection R ² R ³ Physical Properties IR (KBr) cm: C = O (O) MeN N- Mp ( ⁰ C) 1720 277-280

Table 12 (cont.)

282-290

1725, 1700 (Sch)

me

HN N-

268-270

1725

Me.

HN N-Me '

283-285

1720

HN N-

267-270

1730

HO A ^ N N /

138-139

1690

O N-

> 280

1730, 1700 (Sch)

MeN N-

> 280

1720

O "Y

208-209

1730

Me, HN N-

> 280

1720

MeN N-

210-211

1735

-39- 233 795

Table 12 (cont.)

me

MeN N-

225-226

1720

219-220

1730

MeN

283-284

1730, 1700 (Sch)

277-230

1730, 17Q0 (Sch)

271-274

1725

250-252

1725

Example 10

To 0.10 g of ethyl-e-fluoro-i-iA-fluorophenyl-1-dihydro-T-hydroxy-1-pyrrolidinyl-1-oxo-1-naphthyridine-S-carboxylate is added 2 mL of 1N aqueous sodium hydroxide solution and 2 mL of ethanol. The resulting mixture is reacted at 40 to 50 ⁰ C 10min

 Then, acetic acid is added to the reaction mixture to adjust its pH to 6.5. Then the mixture is extracted with two 5 ml portions of chloroform. The combined extracts are 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 is removed by distillation under reduced pressure and the resulting crystalline substance is washed with 2 ml of diethyl ether. 0.08 g of G-fluoro-1-fluoro-1-fluoro-1-hydroxy-1-pyrrolidinyl-1-oxo-1-naphthyridine-S-carboxylic acid, mp> 280 ° C. is obtained

IR (KBr) Cm " ¹ : y _{c = o} 1 730

NMR Id ₆ -DMSO) δ: 1.92-2.52 (2H, m), 3.22-5.00 (5H, m), 6.97-7.60 (4H, m), 8.01 (1H, d, J = 11 Hz), 9.00 (1H, s)

 In a similar manner, the compounds listed in Table 13 are obtained.

connection R ² R ³ Me ₀ N Physical Properties IR (KBr) cm " ¹ : ^V C = O F η Fo. ( ⁰ C) 1725 F 264-255 1725 227

Step Example! 11

In 2.5 ml conc. Hydrochloric acid is dissolved in 0.25 g of 6-fluoro-1,4-dihydro-1- (4-hydroxy-2-methylphenyl) -4-oxo-7- (1-piperazinyl) -i ^ -naphthyridine-S-carboxylic acid, added then the resulting solution with 20 ml of ethanol and finally the resulting mixture is stirred for 15 min at room temperature. The deposited crystals are collected by filtration and washed with 5 ml

Washed ethanol. 0.2 g of 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, m.p.> 280 ° C. IR (KBr) cm ^-1 : v _{c = o} 1 725 (Sch), 1 705. Similarly, the compounds listed in Table 14 are obtained.

table

Hydrogen chloride salt of

CCX) H

connection R ² R ³ Physical Properties IR (KBr) cm " ¹ : ^V C = O Φ) F MeN N- / Mp ( ⁰ C) 1730 283

Table 14 (cont.)

HN N-

275-278

249-252 (Zers.)

1720

1730

> 280

230-232

279-283

1710 1730

1720 (Sch) 1705

MeN N-

266-269

282

1720 (Sch) 1700

1730

Example 12

In 20ml conc. Hydrochloric acid is dissolved in 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. The resulting solution is then added at room temperature with 200 ml of ethanol and the resulting solution stirred for 15 min. The deposited crystals are collected by filtration and washed with 40 ml of ethanol. There are obtained 1.4 g hydrochloric acid salt of 7- (3-amino-1-pyrrolidinyl) -6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro ^ -oxo-1-naphthyridine-S-carboxylic acid , Mp. 247 to 250 ⁰ C (Zers.)

IR (KBr) cm " ¹ : v _{c = o} 1 730.;

Example 13

(1) In 2.5 ml of chloroform are 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 , The resulting solution is heated at reflux for 3.5 h. Then, the reaction mixture is 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 is removed by distillation under reduced pressure, and the resulting residue is purified by column chromatography (Wako Silica Gel C-200; eluent: chloroform-ethanol = 50/1 [vol.]). This gives 0.294 g of oily ethyl 2- [2-chloro-5-fluoro-6- (4-methyl-1-piperazinyl) nicotinoyl] -3- (2,4-difluorophenylamino) acrylate.

IR (in) cm " ¹ : v _{c = o} 1 735, 1 700

NMR (CDCl ₃ ) δ: 1.13 (3H, t, J = 7Hz), 2.36 (3H, s),

2.55 (4H, t, J = 5 Hz), 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 according to Examples 6 and 9 give 0.12 g of 6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-7- (4-methyl-1-piperazinyl) -4-oxo-1,8-naphthyridine -3-carboxylic acid, mp. 208-209 ⁰ C.

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 are added 5 ml of 1 N aqueous sodium hydroxide solution and 5 ml of ethanol. The resulting mixture is reacted at 90 ^° C. for 2 hours. Then, acetic acid is added to the reaction mixture to adjust the pH to 6.5. The deposited crystals are collected by filtration, washed with water and then dried. This gives 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, mp. 230-239 ⁰ C.

IR (KBr) cm ^-1 : v _{c = o} 1 730 NMR (TFA- (J ₁ ) δ: 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, 1.0 g of the hydrochloric acid salt of 3-aminopyrrolidine is suspended, and the resulting suspension is mixed with 2.06 g of triethylamine to form a solution. Then, 2.0 g of ethyl 7-chloro-6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyl chloride in 3-carboxy-I during 15 min at 30 ^C C was added to the solution. The resulting mixture is reacted at the same temperature for 3 hours. After completion of the reaction, 30 ml of water are added to the reaction mixture. The deposited crystals are collected by filtration and washed with 4 ml of water. The resulting crystalline substance is suspended in 30 ml of 6N hydrochloric acid and the resulting suspension is refluxed for 2 hours. Subsequently, the reaction mixture is cooled. The crystals deposited in this way are collected by filtration and washed with two 2 ml portions of water. This gives 1.97 g of the hydrochloric 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. IR (KBr) cm " ¹ : *> _{c = 0} 1730.

Example IS

in 75 ml of ethanol and 75 ml of water is suspended 10,0g7- (3-amino-1-pyrrolidinyl) -6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1, 8-naphthyrif! in-3-c3rbonsäure. 5.2 g of p-toluenesulfonic acid monohydrate are added to the resulting suspension at 40 ° C. and the resulting mixture is stirred for 30 minutes at the same temperature. Subsequently, the reaction mixture is cooled to 15 ° C. The deposited crystals are collected by filtration and washed with a mixed solvent of 5 ml of ethanol and 5 ml of water. This gives 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, m.p. 258 to 26O ⁰ C. IR (KBr) cm-:. v _c = _o 1735 NMR _(DMSO-d6) δ: 1.82 to 2.42 (m), (5H ), 3.12 ^ 1.30 (5H, m), 2.27 (s)

6.92-8.17 (8H, m), 8.79 (1H, s).

Similarly, the following compound is obtained:

Oxalic 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, m.p. 250 to 253 ⁰ C

IR (KBr) CrTT ¹ : v _{c = 0} 1 730.

Example 17

To a solution of 1.6 g of methanesulfonic acid and 25 ml of acetic acid are 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 and then the resulting suspension is stirred at room temperature to form a solution. The solution is mixed for 30 min at 40 to 45 ⁰ C with 100 ml of ethanol. Subsequently, the reaction mixture is cooled to room temperature and stirred for 30 min. The resulting crystals are collected by filtration and washed with three 20 ml portions of ethanol. 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, m.p.> 300 ° C.

IR (KBr) Cm " ¹ : v _{c = o} 1 735.

Similarly, the following compound is obtained:

Sulfuric 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, mp. 220 to 230 ⁰ C.

IR (KBr) cm " ¹ : y _{c = o} 1 735.

Preparation example 1

With 50 g 6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-7- (1-piperazinyl) -1,8-naphthyridine-3-carboxylic acid, 49 g of crystalline cellulose, 50 g of corn starch and 1 g of magnesium stearate are obtained mixed. The mixture is processed by pressing into 1 000 tablets of the flat type.

Preparation Example 2

50 g of corn starch are mixed with 100 g of 6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-7- (1-piperazinyl) -1,8-naphthyridine-3-carboxylic acid. The resulting mixture is used to fill 1000 capsules. In this way one obtains the agent in capsule form.

Preparation example 3

With 50 g of 7- (3-amino-1-pyrrolidinyl) -1- (2,4-difluorophenyl) -6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid 49g become crystalline Cellulose, 50g cornstarch and 1 g magnesium stearate. The mixture is processed by pressing into 1000 flat type tablets.

Preparation Example 4

With 100 g of 7- (3-amino-1-pyrrolidinyl) -1- (2,4-difluorophenyl) -6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 50 g of corn starch mixed. The resulting mixture is used to fill 1 000 capsules, the agent being obtained in capsule form.

Claims (61)

claims: A process for producing a 1,4-dihydro-4-oxonaphthyridine derivative according to the following formula or a set thereof wherein R ^{1 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, marked by (A) The ring closure reaction of a compound of the following formula or a salt thereof wherein R ^{1a is} a carboxyl-protecting group and R ² and R ³ are as defined above or (B) reacting a compound of the following general formula or a salt thereof wherein R ^{3a represents} a halogen atom and R ¹ and R ^{2 have} the abovementioned meaning, with a compound of the following formula or a salt thereof R ^3b -H wherein R ^{3b represents} a substituted or unsubstituted cyclic amino group, followed by deprotecting or protecting the carboxyl group after step (A) or (B), or converting the product into a salt.
2. A method according to item 1, characterized in that a compound of the following formula or a salt thereof wherein R ^1a , R ² and R ^{3 have} the meaning according to point 1, subjected to a ring closure reaction and then optionally removed the protective group or protects the carboxyl group or converts the product into a salt. 3. The method according to item 2, characterized in that R ^{2 is} a substituted or unsubstituted phenyl group. 4. The method according to item 3, characterized in that R ^{3 is} a substituted or unsubstituted cyclic amino group selected from 1-pyrrolidinyl, piperidino, 1-piperazinyl and Morpholino groups. 5. The method according to item 4, characterized in that R ^{2 represents} a phenyl group which may be substituted by at least one substituent selected from a halogen atom, an alkyl group, a hydroxyl group, an alkoxy group, a cyano group, an amino group, an acylamino group and a trihaloalkyl group. 6. The method according to item 5, characterized in that R ^{3 represents} a 1-pyrrolidinyl, piperidino, 1-piperazinyl or Morpholino group which may be substituted by at least one substituent selected from alkyl, amino, Aminoalkyl, hydroxyalkyl, hydroxyl, alkenyl, acyl, alkylamino, dialkylamino, cyano, oxo, aralkylamino, acylamino, alkoxycarbonyl and N-acyl-N-alkylamino groups. 7. The method according to item 6, characterized in that R ^{3 represents} a 1-pyrrolidinyl, piperidino, 1-piperazinyl or Morpholino group which may be substituted by at least one substituent selected from alkyl, amino, Hydroxyalkyl, hydroxyl, alkenyl, acyl, alkylamino, dialkylamino, acylamino, alkoxycarbonyl and N-acyl-N-alkylamino groups. 8. The method according to item 7, characterized in that R ^{2 represents} a phenyl group which is substituted by at least one halogen atom. 9. The method according to item 8, characterized in that R ^{2 is} a 4-fluorophenyl group. 10. The method according to item 8, characterized in that R ^{2 is} a 2,4-difluorophenyl group. 11. The method according to item 3, characterized in that R ^{3 is} a 1-pyrrolidinyl group which may be substituted by at least one substituent selected from amino, hydroxyl, alkylamino, dialkylamino, acylamino and N-acyl N-alkylamino. 12. The method according to item 11, characterized in that 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 Triha log enalky! Group. 13. The method according to item 12, characterized in that R ^{3 is} a 1-Pyrrolidiny! Group which is substituted by an amino or acylamino group. 14. The method according to item 13, characterized in that R ^{2 represents} a phenyl group which is substituted by at least one halogen atom. 15. The method according to item 14, characterized in that R ^{2 represents a} 4-fluorophenyl group. 16. The method according to item 14, characterized in that R ^{2 is} a 2,4-difluorophenyl group. 17. The method according to item 3, characterized in that R ^{3 is} a 3-amino-i-pyrrolidinyl group. 18. The method according to item 17, characterized in that 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, a Acylamino group and a trihaloalkyl group. 19. The method according to item 18, characterized in that R ^{2 represents} a phenyl group which is substituted by at least one halogen atom. 20. The method according to item 19, characterized in that R ^{2 is} a 4-fluorophenyl group. 21. The method according to item 19, characterized in that R ^{2 is} a 2,4-difluorophenyl group. 22. The method according to item 3, characterized in that R ^{3 is} a 1-piperazinyl group which may be substituted by at least one substituent selected from alkyl, hydroxyalkyl, alkenyl, acyl and alkoxycarbonyl groups. 23. The method according to item 22, characterized in that 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 trihaloalkyl group. 24. The method according to item 23, characterized in that R ^{3 is} a 1-Piperazinylgruppe. 25. The method according to item 24, characterized in that R ^{2 is} a phenyl group which is substituted by at least one halogen atom. 26. The method according to item 25, characterized in that R ^{2 is} a 4-fluorophenyl group. 27. The method according to item 25, characterized in that R ^{2 represents} a 2,4-difluorophenyl group. 28. The method according to item 2, characterized in that the product is 7-chloro-1- (2,4-difluorophenyl) -6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridin-3 carboxylic acid or a salt thereof. 29. The method according to item 2, characterized in that the product is 7- (3-amino-1-pyrrolidinyl) -1 - (2,4-difluorophenyl) -6-fluoro-M-dihydro ^ -oxo-i ^ - naphthyridine-S-carboxylic acid or a salt thereof. 30. The method according to item 2, characterized in that the product is 1- (2,4-difluorophenyl) -6-fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl) -1,8- naphthyridine-3-carboxylic acid or a salt thereof. i 31. The method according to item 2, characterized in that the product is 7- (3-amino-1-pyrrolidinyl) -6-fluoro-1- (4-fluorophenyl) -1,4-dihydro-4-oxo-1, 8-maphthyridine-3-carboxylic acid or a salt thereof. : 32. The method according to any one of items 2 to 31, characterized in that the ring closure reaction is carried out at a temperature of 20 to 160 ⁰ C. 33. The method according to item 1, characterized in that a compound of the following formula or a salt thereof wherein R ', R ² and R ^{3a have} the meaning according to point 1, with a compound of the following formula or a salt thereof ^: R ^3b -H wherein R ^{3b has} the meaning according to item 1, and then optionally removes the protective group or protects the carboxyl group or converts the product into a salt. 34. The method according to item 33, characterized in that R ^{2 represents} a substituted or unsubstituted phenyl group. 35. The method according to item 34, characterized in that R ^{3b is} a substituted or unsubstituted cyclic amino group selected from 1-pyrrolidinyl, piperidino, 1-piperazinyl and Morpholino groups. 36. The method according to item 35, characterized in that R ^{2 is} a phenyl group which may be substituted by at least one substituent selected from the group consisting of halogen, alkyl, hydroxyl, alkoxy, cyano, amino, acyl, and trihaloalkyl. 37. The method according to item 36, characterized in that R ^{3b represents} a 1-pyrrolidinyl, piperidino, 1-piperazinyl or morpholino group which may be substituted by at least one substituent selected from alkyl, amino, aminoalkyl , Hydroxyalkyl, hydroxyl, alkenyl, acyl, alkylamino, dialkylamino, cyano, oxo, aralkylamino, acylamino, alkoxycarbonyl and N-acyl-N-alkylamino groups. 38. The method according to item 37, characterized in that R ^{3b is} a 1-pyrrolidinyl, piperidino, 1-piperazinyl or morpholino group which may be substituted by at least one substituent selected from alkylamino, hydroxyalkyl, Hydroxyl, alkenyl, acyl, alkylamino, dialkylamino, acylamino, alkoxycarbonyl and N-acyl-N-alkylamino groups. 39. The method according to item 33, characterized in that R ^{2 is} a phenyl group which is substituted by at least one halogen atom. 40. The method according to item 33, characterized in that R ^{2 stands} for a 4-Fiucrphsnylgruppa. 41. The method according to item 39, characterized in that R ^{2 stands} for a 2,4-difluorophenyl group. 42. The method according to item 34, characterized in that R ^{3d is} a 1-pyrrolidinyl group which may be substituted by at least one substituent selected from amino, hydroxyl, alkylamino, dialkylamino, acylamino and N-acyl N-alkylamino. 43. The method according to item 42, characterized in that 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 Acy laminogruppe and a Trihalogenalky! group. 44. The method according to item 43, characterized in that R ^{3b represents} a 1-pyrrolidinyl group which is substituted by an amino or acylamino group. 45. The method according to item 44, characterized in that R ^{2 is} a phenyl group which is substituted by at least one halogen atom. 46. The method according to item 45, characterized in that R ^{2 stands} for a 4-Ruorphenylgruppe. 47. The method according to item 45, characterized in that R ^{2 stands} for a 2,4-difluorophenyl group. 48. The method according to item 34, characterized in that R ^{3b is} a 3-amino-1-pyrrolidinylgruppe. 49. The method according to item 48, characterized in that 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 trihaloalkyl group. 50. The method according to item 49, characterized in that R ^{2 is} a phenyl group which is substituted by at least one halogen atom. 51. The method according to item 50, characterized in that R ^{2 is} a 4-fluorophenyl group. 52. The method according to item 50, characterized in that R ^{2 stands} for a 2,4-difluorophenyl group. 53. The method according to item 34, characterized in that R ^{3b is} a 1-piperazinyl group which may be substituted by at least one substituent selected from alkyl, hydroxyalkyl, alkenyl, acyl and alkoxycarbonyl groups. 54. The method according to item 53, characterized in that 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 trihaloalkyl group. 55. The method according to item 54, characterized in that R ^{3b is} a 1-piperazinyl group. 56. The method according to item 55, characterized in that R ^{2 represents} a phenyl group which is substituted by at least one halogen atom. 57. The method according to item 56, characterized in that R ^{2 is} a 4-fluorophenyl group. 58. The method according to item 56, characterized in that R ^{2 stands} for a 2,4-difluorophenyl group. 59. The method according to item 33, characterized in that the product is 7- (3-amino-1-pyrrolidinyl) -1 - (2,4-difluorophenyl) -e-fluoro-i ^ -dihydro ^ -oxo-i ^ -naphthyridine-S-carboxylic acid or a salt thereof. 60. The method according to item 33, characterized in that the product is 1- (2,4-difluorophenyl) -6-fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl) -1,8- naphthyridine-3-carboxylic acid or a salt thereof. 61. The method according to item 33, characterized in that the product is 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. 62. The method according to any one of points 33 to 61, characterized in that the reaction is carried out at a temperature of 0 to 150 ^C C.