CH673458A5 - - Google Patents

Description

DESCRIPTION

The present invention relates to new 1,4-di-hydro-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 and their salts as well Process for producing the same and an antibacterial agent containing the same.

Nalidixic acid, piromidic acid, pipemidic acid and the like have been widely used as synthetic antibacterial agents. However, none of these agents has a satisfactory therapeutic effect on infections with Ps. Aeruginosa and with gram-positive bacteria, which are persistent diseases. Therefore, various compounds of the pyridonecarboxylic acid type have been developed to replace the conventional synthetic antibacterial agents, e.g. 1-ethyl-6-fluoro-1,4-dihydro -4-oxo -7- (l-piperazinyl) -3-quinolinecarboxylic acid (norfloxacin) or the like. These compounds have excellent antibacterial activity against various gram-negative bacteria, including Ps. Aeruginosa, but have unsatisfactory antibacterial activity against gram-positive bacteria. Therefore, there has been a desire to develop a synthetic antibacterial agent with a wide antibacterial spectrum, which agent should be effective not only against gram-negative bacteria but also against gram-positive bacteria.

Under these circumstances, as a result of extensive research, it was found that new 1,4-dihydro-4-oxonaphthyridine derivatives and their salts are able to solve the above problems.

The object of the present invention is to provide new 1,4-di-hydro-4-oxonaphthyridine derivatives and their salts which have excellent properties, e.g. have strong antibacterial activity against gram-positive and gram-negative bacteria, in particular against antibiotic-resistant bacteria, and, when administered orally or parenterally, give high concentrations in the blood and are also highly harmless.

Another object of the invention is to provide a process for the preparation of the new 1,4-dihydro-4-oxonaphthyridine derivatives and their salts.

Another object of the invention is to provide an antibacterial agent which is useful for the treatment of infections with bacteria or the like and which contains at least one new 1,4-dihydro-4-oxo-naphthyridine derivative or a salt thereof.

The invention thus relates to 1,4-dihydro-4-oxonaphthyridine derivatives of the general formula:

'■ W) w

R

R

wherein R1 is hydrogen or a carboxyl protecting group, R2 is a substituted or unsubstituted aryl group

5 673 458

and R3 represents a halogen atom or a substituted or unsubstituted cyclic amino group, and their salts.

The invention further relates to processes for the preparation of 1,4-dihydro-4-oxonaphthyridine derivatives of the general formula I or their salts and also to an antibacterial agent which comprises at least one 1,4-dihydro-4-oxonaphthyridine derivative of the general formula I or a salt thereof.

The invention is explained in more detail below.

The carboxyl protecting groups represented by R1 in the compounds of general formula I and their salts include e.g. ester-forming groups which can be removed by catalytic reduction, chemical reduction or 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, and various other well-known ester-forming groups.

The preferred protecting groups among these carboxyl protecting groups include e.g. Carboxyl protecting groups described in Japanese Patent Application Laid-Open (Kokai) No. 25 80 665/84.

The aryl groups represented by R2 include e.g. Phenyl, naphthyl and the like. The aryl group may be substituted by one or more substituents selected from halogen atoms, e.g. Fluorine, chlorine, bromine, 30 iodine and the like; Alkyl groups, e.g. unbranched or branched alkyl groups having 1 to 10 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl and the like; Hydroxyl groups; Alkoxy groups, e.g. unbranched or branched alkoxy groups with 1 to 10 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, N-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, heptyloxy, Octyloxy and the like; Cyano groups; Amino groups; Acylamino groups, e.g. Acyl-40 amino groups having 1 to 4 carbon atoms such as formyl-amino, acetylamino, propionylamino, butyrylamino and the like; and trihaloalkyl groups, e.g. Trihaloalkyl groups of 1 to 4 carbon atoms such as trifluoromethyl, trichloromethyl and the like.

45 Furthermore, the halogen atoms represented by R3 include e.g. Fluorine, chlorine and bromine. The cyclic amino groups represented by R3 have at least one nitrogen atom and can additionally contain one or more oxygen atoms as ring-forming heteroatoms; 5-or 6-membered cyclic amino groups such as 1-pyrrolidinyl, piperidino, 1-piperazinyl, morpholino and the like are heard. The cyclic amino groups mentioned above may be substituted by one or more substituents selected from alkyl groups, e.g. unbranched 55 or branched alkyl groups having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl; Amino groups; Aminoalkyl groups, e.g. Aminoalkyl groups having 1 to 4 carbon atoms such as aminomethyl, 2-aminoethyl, 3-aminopro-60 pyl and the like; Hydroxyalkyl groups, e.g. Hydroxyalkyl groups having 1 to 4 carbon atoms such as hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl and the like; Hydroxyl groups; Alkenyl groups, e.g. Alkenyl groups of 2 to 4 carbon atoms such as vinyl, allyl and the like; Acyl groups, e.g. Acyl groups having 1 to 4 carbon atoms such as formyl, acetyl, propionyl, butyryl and the like; Alkylamino groups, e.g. Alkylamino groups with 1 to 4 carbon atoms, such as methylamino, ethylami-

673 458 6

no, n-propylamino, isopropylamino and the like; Dial ammonium salts; and salts with nitrogenous organic

kylamino groups, e.g. Dialkylamino groups with 1 to 4 bases each, such as procaine, dibenzylamine, N-benzyl-b-phe-

Carbon atoms in the alkyl radicals, such as dimethylamino, nylethylamine, a-ephenamine, N, N-dibenzylethylenediamine,

Diethylamino, di-n-propylamino, methylethylamino and triethylamine, trimethylamine, tributylamine, pyridine, N, N-

the like; Cyano groups; Oxo groups; Aralkylamino-5 dimethylaniline, N-methylpiperidine, N-methylmorpholine, groups, e.g. Aralkylamino groups with 1 to 4 carbon diethylamine, dicyclohexylamine and the like.

atoms in the alkyl radical, such as benzylamino, phenylethylamino When the compounds of the general formula I and the like; Acylamino groups, e.g. Acylaminogrup - their salts have isomers (e.g. optical isomers, geometric

pen with 1 to 4 carbon atoms, such as acetylamino, proisomers, tautomers and the like), the invention is intended

pionylamino, butyrylamino and the like; Alkoxycarbo->> all isomers, crystal forms and hydrates thereof-

nyl groups, e.g. Alkoxycarbonyl groups with 1 to 4 carbons.

Oxygen atoms in the alkoxy radical, such as methoxycarbonyl, eth- The antibacterial activity and the acute toxicity are

oxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and the like in relation to typical compounds according to the invention; and N-acyl-N-alkylamino groups, e.g. explained.

N-acyl-N-alkylamino groups in which the nitrogen atom 15 1- Antibacterial activity of the above-mentioned alkylamino group by an acyl test method:

grappe with 1 to 4 carbon atoms, such as acetyl, propio- according to the standard method of the Japan Society of Che-

nyl, butyryl or the like is substituted. motherapy [CHEMOTHERAPY 29 (1), 76-79 (1981)]

Of the compounds of the general formula I, a bacterial solution is preferred which, by cultivation in heart infusion, prefers those in which R2 denotes a fluorine-substituted Phe-20 bread (manufactured by Eiken Kagaku) at 37 C during 20 nyl group and R3 receives a substituted or unsubstituted hour was vaccinated on a heart infusion agar, which means tuated 1-pyrrolidinyl or 1-piperazinyl group, containing an active ingredient and at 37 ° C. for 20 hours and those in which R2 had grown a 2,4-difluorophenyl group, after which the Bacterial growth is observed and R3 means a 3-amino-1-pyrrolidinyl group, was observed to the minimum concentration at which this is particularly preferred. 25 growth of the bacteria was inhibited as MIC (ng / ml) to determine the salts of the compounds of the general formula. The amount of bacteria inoculated included conventional salts of basic groups, such as 104 cells / plate (106 cells / ml). The MIC values of the amino group and the like, and on acidic groups, following test compounds are shown in Table 1, such as a carboxyl group and the like. The salts on The symbols used in Table 1 have the following basic group belong e.g. Salts with mineral acids, 30 meanings:

such as hydrochloric acid, sulfuric acid and the like; Salts with organic carboxylic acids such as oxalic acid, formic acid, tri- * 1: penicillinase-producing bacteria chloroacetic acid, trifluoroacetic acid and the like; Salts * 2: cephalosporinase-producing bacteria with sulfonic acids, such as methanesulfonic acid, p-toluenesulfonic * 3: inoculation amount: 108 cells / ml acid, naphthalenesulfonic acid and the like. The 35 Me: methyl group zen on the acidic group include e.g. Salts with alkame et: ethyl group such as sodium, potassium and the like; Salts with earth n-Pr: n-propyl group alkali metals such as calcium, magnesium and the like; i-Pr: isopropyl group

Table 1

fyyVC00H

r3 N N R2

R2

HO-H ^

HO— (Ö)

F

R3

MeiT ^ ß-

O

0

1

indung

Bakt he ien

1

2nd

3rd

4th

St. aureus FDA209P

0.1

<0.05

<0.05

0.1

St. epidermidis IXD8 66

• O; 1

^ 0.05

SUN, 05

0.1

St. aureus F-137 * ^

0.1

<0.05

m o o

VI

0.1

E. coli NIHJ

<0.05

0.39

0.1

IA

O

O Ln

E. coli TK-111

<0.05

0.2

in o o VI

in o o

VI

E. coli GN5482 * 2

<0.05

0.1

SUN, 05

SUN, 05

Ps. Aeruginosa S-68

0.39

6.25

1.56

1.56

Aci. anitratus A-6

0.2

0.2

SUN, 05

0.1

Ps. Aeruginosa IF03445

3.13

12.5

3.13

3.13

Ps. Aeruginosa GN918 * 2

0.39

3.13

0.78

0.78

7

Table 1 (continued)

673 458

F — 1 (0 ^ -

F- <ö £

^ Me

F- <Ö> -

H0— (S) ~

HO—

/ - \ HN N-

CN-

HN N -

n-PrN N-

/ - \ i-PrN N-

CH. = CH

2 1 / -x

CH2N) N-

5

6

7

8th

9

10th

0.2

<0.05

0.2

0.2

0.2

0.2

0.39 * 3

0.1 * 3

0.78

0.2

0.2

0.2.

0.2

SUN, 05

0.39

0.2

0.2

0.2

<0.05

<0.05

<0.05

£ 0.05

SUN, 05

SUN, 05

SUN, 05

<0.05

<0.05

SUN, 05

<0.05

SUN, 05

• <0.05

<0.05

<0.0 5

SUN, 05

SUN, 05

SUN, 05

0.39

1.56

1.56

3.13

3.13

3.13

0.2

0.1

0 j 2 •

0.2

0.78

0.2

0.78

• 3.13

1.56

12.5

6.25

3.13

0.39

0.78

0.78

3.13

1.56

3.13

'- <° £

- F ^ °> -

F- ^ Ö ^ -

CH, = CH

2 1 ^

CH2N \ _yN ~

HCl-H-N

T>

H "N

O-

•

MeHN

T>

11

12

13

14

15

0.2

SUN, 05

SUN, 05

0.2

0.2

0.39

SUN, 05

0.1 •

0.2

0.2

0.2.

SUN, 05

0.1

0.1

0.2 •

0.39

<0.05 '

SUN, 05

SUN, 05

SUN, 05

0.1

SUN, 05

SUN, 05

SUN, 05

SUN, 05

0.1

SUN, 05

SUN, 05

SUN, 05

SUN, 05

6.25

0.2

0.2

0.78

1.56

0.2

<0.05

<0.05

0.1

0.1

12.5

0.2

0.2

1.56

1.56

3.13

0.1

0.1

0.39.

0.39

2. Acute toxicity

The LD50 values obtained by intravenous administration 65 The methods for producing the compounds of the present invention of the above-mentioned test compounds Nos. 5, 6 and 12 are explained below.

Mice (ICR strain, male, body weight: 18 to 24 g) The compounds according to the invention can e.g. after obtained were 200 mg / kg or more. the following production scheme:

673 458

8th

-by'

la

R

, 3b

COOR

la

R

COOR

la

(IV) or a salt thereof

I o

, 1a

Cl NH-R2

COOR

N ^ Cl \ NH-R

R - R

(III) or a salt thereof (V) or a salt thereof

COOR

COOR

(Ia) or a salt thereof

(Ib) or a salt thereof

30th

wherein RIa represents the same carboxyl protecting group as can be represented by R1; R3a represents the same halogen atom as can be represented by R3; R3b represents the same substituted or unsubstituted cyclic amino group as can be represented by R3; and R1 and R2 have the above meanings.

The salts of the compounds of the general formulas Ia, Ib, III, IV and V comprise the same salts as those of the compounds of the general formula I.

(i) The compounds of general formula III or their salts or the compounds of general formula V or their salts are obtained by combining a compound of general formula II or a compound of general formula IV or a salt thereof with an acetal , such as N, N-diethylformamidodimethylacetal, N, N-dimethylformamidodiethylacetal or the like, and then with an amine of the general formula R2-NH2, wherein R2 has the above meaning.

Any of the solvents which are inert to the reactions may be used in the above reactions, for example, although not critical, aromatic hydrocarbons such as benzene, toluene, xylene and the like; Ethers such as dioxane, tetrahydrofuran, anisole, di-ethylene glycol dimethyl ether and the like; halogenated hydrocarbons such as methylene chloride, chloroform, di-chloroethane and the like; Amines such as N, N-dimethylformamide, N, N-dimethylacetamide and the like; Sulfoxides such as dimethyl sulfoxide and the like; etc., and these solvents can be used alone or as mixtures of two or more of them. The amount of the acetal used is preferably 1 mol or more, in particular approximately 1.0 to 1.3 mol, per mol of the compound of the general formula II or the compound of the general formula IV or a salt thereof. The reactions are usually carried out at 0 to 100 ° C, preferably at 50 to 80 ° C, and usually for 20 minutes to 50 hours, preferably for 1 to 3 hours. The amine is used in an amount of 1 mole or more per mole of the compound

40

45

of general formula II or the compound of general formula IV or a salt thereof. The reaction is usually carried out at 0 to 100 ° C, preferably 10 to 60 ° C, and usually 20 minutes to 30 hours for 35, preferably 1 to 5 hours.

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

(ii) The compounds of general formula Ia or their salts or the compounds of general formula Ib or their salts are obtained by using a compound of general formula III or a salt thereof or a compound of general formula V or a salt thereof in the presence or absence of a base undergoes a ring closure reaction (preferably with heating).

Any solvent inert to the reaction can be used in this reaction, for example, although not critical, amides such as N, N-dimethylformamide, N, N-dimethylacetamide and the like; Ethers such as dioxane, anisole, diethylene glycol dimethyl ether and the like; Sulfoxides such as dimethyl sulfoxide and the like; etc. These solutions can be used alone or as a mixture of two or more of them. The bases include e.g. Sodium hydrogen carbonate, potassium carbonate, potassium tert-butoxide, sodium hydride and the like. The amount of the base to be used is preferably 0.5 to 5 moles per mole of the compounds of the For-65 mei III or V or their salts. The reaction is usually carried out at 20 to 160 ° C, preferably at 100 to 150 ° C, and usually for 5 minutes to 30 hours, preferably 5 minutes to 1 hour.

9

673 458

(iii) The compounds of general formula IV or their salts or the compounds of general formula V or their salts or the compounds of general formula Ib or their salts are obtained by using a compound of general formula II, a compound of general Formula III or a salt thereof or a compound of the general formula Ia or a salt thereof with a cyclic amine of the general formula R3b-H or a salt thereof, in which R3b has the meaning given above.

Substantial solvents which are inert to the reaction may be used in the reaction, for example, although not critical, aromatic hydrocarbons such as benzene, toluene, xylene and the like; Ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol cold diethyl ether and the like; halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane and the like; Amides such as N, N-dimethylformamide, N, N-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., and these solvents can be used alone or as mixtures of two or more of them. The amount of the cyclic amine or a salt thereof to be used is preferably an excess, particularly 2 to 5 moles, per mole 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 from that. When the amount of the cyclic amine used is about 1 to 1.3 moles, it suffices that an acid-binding agent is used in an amount of 1 mole per mole of the compound of the general formula II, the compound of the general formula III or a salt thereof or the compound of general formula Ia or a salt thereof is used. Acid-binding agents include organic or inorganic bases, such as tri-ethylamine, 1,8-diazabicyclo- [5,4,0] -undec-7-ene (DBU), potassium tert-butoxide, potassium carbonate, sodium carbonate , Sodium hydride and the like.

The salts of the compound of the formula R3b-H comprise the same salts on the basic group as were mentioned in connection with the compound of the general formula I.

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

The compounds of the general formulas Ia, Ib, III or V, in which R1 denotes a carboxyl protecting group, or their salts can, if desired, be converted into the corresponding free carboxylic acid by reacting them in the presence of a conventional acid or a conventional alkali which are required for the hydrolysis be used, hydrolyzed, usually at 0 to 100 ° C, preferably at 20 to 100 ° C, for 5 minutes to 50 hours, preferably 5 minutes to 4 hours. Furthermore, the compounds of the general formulas Ia, Ib, III or V or their salts can, if desired, be converted into a salt or an ester of the corresponding compound by subjecting them to a salt formation reaction or esterification known per se. If the compounds of the general formulas Ia, III, IV or V or their salts have an active group (for example a hydroxyl group, an amino group or the like) in positions other than the reaction sites, it is possible to protect the active groups beforehand using conventional methods and remove the protecting group after the reaction is completed.

The compounds thus obtained can be conventional

Isolation and purification processes such as column chromatography, recrystallization, extraction and the like are subjected.

The compounds of general formula I or their 5 salts in which R3 represents a halogen atom (corresponding to the compounds of general formula Ia) are also useful as intermediates for the preparation of compounds in which R3 represents a substituted or unsubstituted cyclic amino group (corresponding to the 10 compounds of the general formula Ib).

If the compounds according to the invention are used as an active ingredient or medicament, they can be combined in a suitable manner with carriers which are used in conventional pharmaceutical preparations and in a conventional manner to give tablets, capsules, powders, syrups, granules, suppositories, ointments , Injection solutions and the like are processed. The mode of administration, the dosage and the number of administrations can be appropriately varied according to the symptoms of the patients, and they can usually be in an amount of 0.1 to 100 mg / kg and day in one or more servings administered orally or parenterally (e.g. by injection, drip infusion or administration into the rectum) to adults. 25 The invention is explained below with reference to reference examples, examples and production examples.

The symbols used in the reference examples and examples have the following meanings: Me: methyl group 30 n-Pr: n-propyl group Ac: acetyl group: ethylene group Et: ethyl group i-Pr: isopropyl group 35: allyl group

Reference Example 1 21 g of 2,6-dichloro-5-fluoronicotinic acid was dissolved in 210 ml of chloroform, and 23.8 g of thionyl chloride and 0.1 g of 40 N, N-dimethylformamide were added to the resulting solution. The resulting mixture was reacted at 70 ° C for 2 hours. The solvent and the excess thionyl chloride were removed by distillation under reduced pressure, and the residue thus obtained was dissolved in 21 ml of tetrahydrofuran. 25.1 g of diethylethoxymagnesium malonate was dissolved in 110 ml of tetrahydrofuran and the solution was cooled to -40 to -30 ° C. A tetrahydrofuran solution of 2,6-dichloro-5-fluoronicotinoyl chloride was added dropwise to this solution, which solution had previously been prepared at the same temperature for 30 minutes. This mixed solution was stirred at the same temperature for one hour, and then the temperature of the solution was gradually raised to room temperature. The solvent 55 was removed by distillation under reduced pressure, and 200 ml of chloroform and 100 ml of water were added to the residue thus obtained. The pH was adjusted to 1 with 6 normal hydrochloric acid. The organic layer was separated, washed successively with 50 ml of 60 water, 50 ml of 5% aqueous sodium hydrogen carbonate solution and 50 ml of saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and to the obtained oily product, 50 ml of water and 0.15 g of p-toluenesulfonic acid were added, and the resulting mixture was subjected to the reaction with vigorous stirring at 100 ° C for 2 hours has been. The reaction mixture was with

673 458

10th

100 ml of chloroform extracted. The organic layer was added dimethylacetal, whereupon the resulting mixture, containing 50 ml of saturated aqueous sodium chloride solution, was stirred at 70 ° C. for 1.5 hours and dried over anhydrous magnesium sulfate. Then 4.1 g of 2,4-difluoroaniline were added, after which the solvent was added by distillation under reduced reaction mixture, and the resulting pressure was removed. The residue obtained was mixed and reacted at room temperature for 4 hours by column chromatography (WAKO SILICA GEL ion. The solvent was purified by Destilla-C-200, eluent: toluene), giving 23.5 g of eth removed under reduced pressure. The yl- (2,6-dichloro-5-fluoronicotinoyl) acetate obtained with a melt residue was purified by column chromatography (WAKO point from 64 to 65 ° C. SILICA GEL C-200, eluent: chloroform) was purified.

IR (KBr), cm vc = 0 1650.1630.1620 10 nigt, with 9.0 g of ethyl 2- (2,6-dichloro -5-fluoronicotinoyl) -3-

NMR (CDC13), 5 values: (2,4-difluorophenylamino) acrylate with a melting point

1.25 (1.29H, t, J = 7 Hz), 1.33 (1.71H, t, J = 7 Hz), 4.07 from 138 to 139 ° C.

(1.14H, s), 4.28 (2H, q, J = 7 Hz), 5.82 (0.43H, s), 7.80 (IH, IR (KBr), cm "1: uc = 0 1690

d, J = 7 Hz), 12.62 (0.43H, s) NMR (CDC13), 5 values:

15 1.08 (3H, t, J = 7 Hz), 4.10 (2H, q, J = 7 Hz), 6.77-7.40 Reference Example 2 (4H, m), 8.50 (1H, d , J = 13 Hz), 12.70 (1H, d, J = 13 Hz)

8.8 g of ethyl (2,6-dichloro-5-fluoronicotinoyl) acetate were similarly dissolved in 40 ml of benzene as shown in Table 2, and 4.5 g of N, N-dimethylformamido compounds were obtained.

Table 2 O

connection

Physical Properties

R2

Melting point (° C)

IR (KBr), cm

VC = 0

è

87-89

1690

(§.

F

110-114

1710, 1680

92-93

1710, 1680

& '

135-137

1720 (Sch), 1690.

F

. 78-80

1690

r & '

Celi?

1705, 1680 (Sch) *

w

154-155.

1720 (Sch), 1685

AyF

M

F

100-101

1700 (Sch), 1685

é

Cl

123-125

1710, 1680

u

Table 2 (port setting)

673 458

Footnote: * The pure substance was used instead of a KBr tablet.

(0)

145-146

1705, 1680

Br

ê)

147-149

1685

Me

(a)

Oily

1695 *

OMe

./k^OMe

119-121

1700

&

Oily

1700 *

CN

Q

183-186

1685, 1670

NHAc

136-138

1705, 1680

. cf3

£ oTMe

114-116

1680

1

F

(0r ° m

137.5-139

1725 (Sch), 1680

F

92-95

1705

OMe

(oroMe

125-126

1700 (Sch), 1660

Me

(° T "e

91-92

1705, 1690

OMe

Reference Example 3 (1) 5.5 g of ethyl (2,6-dichloro-5-fluoronicotinoyl) acetate, 2.37 g of N-methylpiperazine and 2.37 g of triethylamine were dissolved in 55 ml of chloroform and the resulting solution became subjected to the reaction at 60 to 65 ° C for 2 hours. The reaction mixture was washed with 30 ml of water and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue obtained was purified by column chromatography (WAKO SILICA

GEL C-200, eluent: chloroform), giving 60 5.4 g of oily ethyl] - [2-chloro-5-fluoro-6- (4-methyl-1-piperazi-nyl) nicotinoyl] acetate .

IR (neat), cm-: uc = 0 1750, 1695 NMR (CDC13) S values:

1.25 (3H, t, J = 7 Hz), 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 = 7 Hz), 7.78 (IH, d, J = 13 Hz)

The compound shown in Table 3 was obtained in a similar manner:

673 458 12

Table 3

0

connection

Physical Properties

R3

• melting point (° C)

IR (KBr), cm 1i VC = 0

Act /

67-71

1730

(2) 4.5 g of ethyl [2-chloro-5-fluoro -6- (4-methyl-1-piperazi- crystalline substance obtained was mixed with 10 ml of diethyl ether nyl) nicotinoyl] acetate in 22.5 ml Dissolved benzene, and washed, whereby 5.0 g of ethyl 2- [2-chloro-5-fluoro -6- (4-me-

1.87 g of N, N-dimethylformamidodimethylacetal were converted to thyl -l-piperazinyl) -nicotinoyl] -3- (4-methoxy -2-methylphe-

added to the resulting solution, whereupon the resulting 25-nylamino) acrylate having a melting point of 141 to the mixture was obtained at 70 ° C. for 2 hours under-142 ° C.

was thrown. 1.8 g IR (KBr), cm-1: uc = 0.1710 (Sch), 1695 were added to the reaction mixture

4-Methoxy -2-methylaniline added, and the resulting NMR (CDC13), S values:

The mixture was mixed at room temperature for 4 hours, the Re- 1.08 (3H, t, J = 7 Hz), 2.32 (3H, s), 2.40 (3H, s),

action subjected. Then the solvent was replaced by 30 2.23-2.68 (4H, m), 3.47-3.83 (4H, m), 3.75 (3H, s), 4.07 (2H,

Distillation removed under reduced pressure, and so q, J = 7 Hz), 6.65-7.25 (3H, m), 7.20 (1H, d, J = 13 Hz), 8.48

residue obtained was determined by column chromatography (1H, d, J = 13 Hz), 12.82 (IH, d, J = 13 Hz)

(WAKO SILICA GEL C-200, eluent: chloro- In a similar manner, the form: ethanol given in table 4 in a volume ratio of 100: 1) were cleaned. The connections get:

35

'Table 4

[x £ c

NH

connection

Physical Properties

R2

R3

Melting point f ° C)

IR (*),

cm-1: vc = 0

è

MeN ^ / N-

Oily

* 2

1720 (Sch), 1715

¥

F

If

Oily

* 2

1735, 1700

13 673 458

Table k (port setting)

él

OMe

It

Oily

* 2

1695

IO)

NHAc fr

161-164

*1

1685, 1670

OMe

11

Oily

* 2

1720 (Sch), 1715

OMe

Met / N- \ /

132-136

*1

1705 (Sch) 5 1685

OMe

Act / N-

Oily

* 2

1720 (Sch), 1700

Footnote: * 1: KBr

* 2: Pure substance

example 1

9.0 g of ethyl 2- (2,6-dichloro-5-fluoronicotinoyI) -3- (2,4-di-fluorophenylamino) acrylate were dissolved in 90 ml of N, N-dimethylformamide, and 3.6 g of sodium hydrogen carbonate was added to the resulting solution, after which the resulting mixture was subjected to the reaction at 120 ° C for 20 minutes. Then the solvent was removed by distillation under reduced pressure, and the residue obtained was dissolved in 50 ml of chloroform. The resulting solution was washed successively with 30 ml of water and 30 ml of saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the crystalline substance obtained was washed with 30 ml of diethyl ether, whereby 7.0 g of ethyl 7-chloro-6-fluoro-l- (2,4-difluorophenyl) -1, 4 dihydro -4-oxo -1,8-naphthyridine -3-carboxylate with a melting point of 220 to 222 ° C were obtained.

IR (KBr), cm-1: uc = o 1730, 1690

NMR (CDCI3), S values:

1.36 (3H, t, J = 7 Hz), 4.30 (2H, q, J = 7 Hz), 6.80-7.60 (3H, m), 8.27 (1H, d, J = 7 Hz), 8.42 (1H, s)

The compounds shown in Table 5 were obtained in a similar manner:

673 458

14

Table 5

0

connection

Physical Properties

R2

Melting point

C? C)

IR (KBr), cm: VC = 0

è

.222-224

1730, 1685

Co)

F

231-232

1730, 1705

239-241

1685

&

205-208

1735, 1685

F

244-246

1720, 1680

A9J

F

207-209.5

1730, 1690

w

210-214

1735 (Sch), 1705

4c

F

207-208

1730, 1680

15

Table 5 (port setting)

Ti

X

Br

Me

OMe

OMe

181-186

204-205

216-218

196-198

156-160

1730, 1685

1730, 1685

1735, 1695

1735, 1685

1730, 1690

CN

231-236

1730, 1685

(3rd

NHAc

270-273

1730, 1690

CF.

199-201

1730, 1680

Me

199-202

1735, 1685

iMe

208-211

1730, 1695

673 458

16

Table 5 (port setting)

142-144

1740, 1695

OMe

i ^ OMe

cor

1730,

163-165

1695

Me

¥

160-162

1735, 1690

OMe

Example 2

(1) 3.5 g of ethyl 7-chloro-6-fluoro-l- (2,4-difluorophenyl) -1,4-dihydro -4-oxo -1,8-naphthyridine -3-carboxylate were added in 35 ml Chloroform dissolved, 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 the reaction at 60 ° C for one hour. The solvent was then removed by distillation under reduced pressure and the residue obtained was purified by column chromatography (WAKO SILICA GEL C-200, eluent: chloroform: ethanol in a volume ratio of 30: 1), giving 3.5 g of ethyl 7- (4 -acetyl -1-piperazinyl) -6-fluoro -l- (2,4-difluorophenyl) -l, 4-dihydro -4-oxo -1,8-naphthyridine -3-carboxylate with a melting point of 207 to 209 ° C. were obtained.

30 IR (KBr), cm- ': uc = 0 1730, 1695 NMR (CDClj), 5 values:

1.38 (3H, t, J = 7 Hz), 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 = 13 Hz), 8.30 (1H, s)

35 The compounds shown in Table 6 were obtained in a similar manner:

Table 6 O

connection

Physical Properties

R2

R3

Melting point (° C)

IR (KBr), cm-1: vc = 0

AcN \ j- \ /

216-218

1730,

1690 (Sch).

$

Ac

MeN- (N- \ /

155-156

1730, 1690

H

Mei / N-

217-218

1730, 1695

17th

Table 6 (continued)

ti

Mv.

HN ^ N-

144-146

1730, 1690

II

Me

- \ HN N-

143

1730

n

Me

HN N-Me

198-202

1725, 1690

(O)

F

/ ~ \ HO- N-

220-222

1730, 1695

II

/ \ AcN ^

253-255

1730, 1690

II

/ \

203-205

1730, 1700

èk

F

/ \ AcI ^

211-213

1735

ty n

206

1725, 1690

F

/ ~ \ Mel ^ ^ N-

193-194

1730, 1700

II

AcN ^ 3-

244-246

1725, 1690

<& '

F

Ac

MeN- ^ N-

186-187

1725,

1690 (Sch)

673 458 18

Table 6 (continued)

¥

F

Mv ^.

HN N- \ /

155-157

1720, 1685

ti

MeN ^

153-154

1730, 1700

II

- - ^ - Me r <

Meï ^ ^ N-

153-155

1730, 1695

II

/ \

N- \ /

166-168

1730 (Sch), 1690

II

Me r ~ \

EtO-CN N- \ /

202-204

1730, 1690

j ° r '

F

A ~ \

Acl ^ ^ T-

230-231

1725 (Sch), 1695

'ìèr'

M

193-194

1720 (Seh),

1680,

1675

(°)

Cl

/ \ MeN ^ Y ~

207

1725, 1695

4th

Cl r ~ \

AcN Jl-

254

1730, 1690

(O)

Br

/ \ MeN ^

208

1730, 1690

ti

/ ~ A

Ac ^ ^ N-

246-247

1730, 1690

19 673 458

Table 6 (continued)

Me

/ \ MeN k-

167-169

1730, 1695

II

r ~ \

Acl ^ ^ N-

206-207.5

1730, 1690

OMe

O-

163-165

1735, 1700

II

/ ~ A

Me ^ fl-

174-176

1730, 1690

II

180-181

1735, 1695

t ° i

OMe r ~ \

n-PrN ^ / N-

171-172.5

1730, 1685

II

/ \ i-Prt ^ ^ 1-

208.5-210

/

1730, 1690

II

/ ~ \

HO '^ N N- \ /

200-202

1730, 1690

II

^ A ~ \

162-163

1725, 1690

II

/ \ AcN ^ JX-

197-199

1735, 1690

OMe

/ \ MeN ^ ^ N-

136-138

1725, 1685

673 458 20

Table 6 (continued)

1 1

/ ~ \

Acl ^

270-272

1730, 1690

CN

é

n

245-249

1730, 1695

NHAc

>

O

0

1

249-252

1730, 1695

CF3

l ^ me

loj

H

263-264

1730

F

loMe cor

/ ~ A Met ^ JS-

166-169

1730, 1685

F

f (

r ~ \

AcN

222.5-223.5

1730, 1690

¥

/ \ Meî ^ ^ N-

165-168

1730, 1685

OMe

II

>

O

0

1

215-219

1730, 1695

/ V / OMe

/

Mei ^ ^ 1-

170-171

1725, 1690

Me

/ ~ A

ACN N-

V_ /

169-172

1725, 1690

OMe

65

(2) 2.5 g of ethyl 7- (4-acetyl -1-piperazinyl) -6-fluoro-l- (2,4- and the resulting solution became difluorophenyl) -1,4-dihydro for 2 hours 4-oxo -1,8-naphthyridine heated to reflux. Then the reaction mixture was on

-3-carboxylate was dissolved in 25 ml of 6 normal hydrochloric acid, cooled to room temperature, and its pH was adjusted with

21st

673 458

1 normal aqueous sodium hydroxide solution to 12 and then adjusted to 6.5 with acetic acid. The crystals thus deposited were collected by filtration, washed with 30 ml of water and then dried, whereby 1.8 g of 6-flu-or-l- (2,4-difluorophenyl) -1,4-dihydro -4-oxo -7 - (l-piperazi-nyl) -1,8-naphthyridine -3-carboxylic acid were obtained.

NMR (TFA-d,), 5 values:

3.30-4.50 (8H, m), 7.00-7.85 (3H, m), 8.33 (1H, d, J == 13 Hz), 9.21 (1H, s)

The 5 compounds shown in Table 7 were obtained in a similar manner:

Table 7 O

COOH

Connection;

Physical Properties

R2

R3

Melting point (° C)

IR (KBr); cm 1: vc = 0

è

Ht / ^ T-

252.5-254.5

1730

(O)

F

MeHN- ^ \ l-

> 280

*

1720 (Sch)

II

HI ^

279-280

1725 (Sch)

a

234-236

1720

M

222-224

1725

F

»

> 280

1720

¥

F

MeNH- ^ ^ M-

254-258

1725

èf

F

/ ~ \ mw ~

205-207

1730

673 458 22

Table 7 (port setting)

1

lêr *

ti

225-227

1725

to)

Cl tt

> 280

1725

Co)

Br

It

273-277

1720

Me

II

245-246

1725

Co)

CN

II

> 280

1725

(°>

NH2

II

> 280

1730, 1710

CO)

NHAc

/ ~ \ Me! ^

232-236

1725, 1710, 1690

CF3

/ ~ \ HV_ / "

> 280

1725

F

tr

230-232

1730

Footnote: * The Nujobnet method was used instead of the KBr method.

Example 3 added amine, after which the resulting mixture at 60 ° C.

(1) 0.50 g of ethyl 7-chloro-6-fluoro-l- (2,4-dif3uorphenyl) 65 was subjected to the reaction for one hour. Then -1,4-dihydro -4-oxo -1,8-naphthyridine -3-carboxylate, the solvent was dissolved by distillation under min-in 5 ml of chloroform, and the resulting pressure was released to the resulting solution, and the residue obtained was removed 0.20 g of 3-acetylaminopyrrolidine and 0.15 g of triethyl were purified by column chromatography (WAKO SILICA GEL

23

673 458

C-200, eluent: chloroform: ethanol in a volume ratio of 30: 1), 0.5 g of ethyl-7- (3-acetylamino-no-1-pyrrolidinyl) -6-fluoro-1- (2,4-difluorophenyl) ) -1,4-dihy-dro -4-oxo -1,8-naphthyridine -3-carboxylate with a melting point of 233 to 235 ° C were obtained. IR (KBr), cm- ': uc = 0 1725, 1700 NMR (CDC13), S values:

1.32 (3H, t, J = 7Hz), 1.77-2.27 (m) i, m

2.08 (s)

3.12-3.74 (4H, m), 4.02-4.74 (m)) (m)

4.29 (q, J = 7 Hz) J 6.75-7.60 (4H, m), 7.93 (1H, d, J = 8 Hz), 8.24 (1H, s) in a similar manner the compounds given in Table 8 were obtained:

Table 8

connection

Physical Properties

R2

R3

Melting point (° C)

IR (KBr), cm-1: vc = 0

F

no.

^ N-

231-233

1730, 1700

II

Me2N ^

r ~ \

^ N-

156

1730, 1690

II

AcHN \

>

203-205

1725, 1690

II

MeN Ac

_VN-

201-202

1725, 1695

¥

F

Me2N_

D "

165

1730, 1690

II

MeN

l \

Ac

N-

196-197

1730, 1695

&

F

AcHN ^

3 "

241-244

1725, 1700

673 458

24th

Table 8 (continued)

OMe

D-

153-155

1735

II

H0 ^

LA

185-187

1730, 1690

(2) 0.25 g of ethyl 7- (3-acetylamino -2-pyrrolidinyl) -6-fluoro-l- (2,4-difluorophenyl) -1,4-dihydro -4-oxo -1,8-naphthyridine -3-carboxylate was dissolved in 2.5 ml of 6 normal hydrochloric acid and the resulting solution was heated to reflux for 2 hours. Then the reaction mixture was cooled to room temperature, and its pH was adjusted to 12 with 1 normal aqueous sodium hydroxide solution and then to 6.5 with acetic acid. The crystals thus deposited were collected by filtration, with 2 ml

Washed water and then dried, 0.18 g of 7- (3-amino-1-pyrrolidinyl) -6-fluoro-l- (2,4-difluorophenyl) -1,4-dihydro -4-oxo -1.8 -naphthyridine -3-carboxylic acid were obtained 20.

NMR (TFA-d,), Ö values:

2.25-2.85 (2H, m), 3.37-4.69 (5H, m), 6.93-7.81 (3H, m), 8.22 (IH, d, J = 11 Hz), 9.16 (1H, s)

The 25 compounds shown in Table 9 were obtained in a similar manner:

Table 9

COOH

, 3rd

R

connection

Physical Properties

R2

R3

Melting point (° C)

IR (KBr), cm "1: VCrQ

F

H2Nn

N-

260-263

1720

It

MeHN

N-

259-261

1720 (Sch)

¥

.F

II

275-278

1720 (Sch)

£

F

H2N

^ N-

278-280

1720

25th

673 458

Example 4

(1) 2.0 g of ethyl 2,6-dichloro-5-fluoronicotinoylacetate, 0.96 g of 3-acetylaminopyrrolidine and 0.8 g of triethylamine were dissolved in 20 ml of chloroform, and the resulting solution was at 60 to 65 ° C Subjected to the reaction for 2 hours. The reaction mixture was washed with 3 ml of water and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure and the residue so obtained was purified by column chromatography (WAKO SILICA Gel C-200, eluent: benzene: ethyl acetate in a volume ratio of 1: 1), whereby 1.8 g of oily ethyl [2- chlorine -5-fluoro -6- (3-acetylamino-1-pyrrolidinyl) nicotinoyl] acetate were obtained.

IR (neat), cm-1: uc = o 1740.1650

NMR (CDCI3), 5 values:

1.28 (3H, t, J = 7 Hz), 1.97 (3H, s), 1.90-2.62 (2H, m), 4.02 (2H, s), 4.15 (2H , q, J = 7 Hz), 3.50-4.70 (5H, m), 7.06 (1H, d, J = 6 Hz), 7.57 (1H, d, J = 13 Hz)

(2) 0.7 g of ethyl 2-chloro -5-fluoro -6- (3-acetylamino -1-pyrrolidinyl) nicotinoylacetate was dissolved in 10 ml of benzene, and 0.235 g of N, N was added to the resulting solution -Di-methylformamidodimethylacetal added, after which the resulting mixture was subjected to the reaction at 70 ° C for 2 hours. To the reaction mixture was added 0.243 g of 2,4-difluoroaniline, and the resulting mixture was subjected to the reaction at room temperature for 8 hours. The solvent was then removed by distillation under reduced pressure, the residue thus obtained was purified by column chromatography (WAKO SILICA GEL C-200, eluent: benzene: ethyl acetate in a volume ratio of 1: 1), and the oily product thus obtained was triturated with diisopropyl ether. where 0.25 g of ethyl 2- [2-chloro-5-fluoro -6- (3-acetylamino -l-pyrrolidinyl) -nicotinoyl] -3- (2,4-difluorophenylamino) -acrylic lat with a melting point of 82 to 85 ° C were obtained.

IR (KBr), cm-1: uc = D 1695 (Sch), 1660

NMR (CDC13), 5 values:

1.25 (3H, t, J = 7 Hz), 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 = 6 Hz), 6.80-7.50 (4H, m), 8.53 (1H, d, J = 13 Hz), 12.46 (1H, d, J = 13 Hz)

(3) 0.2 g of ethyl -2- [2-chloro-5-fluoro -6- (3-acetylamino -1-pyrrolidinyl) nicotinoyl] -3- (2,4-difluorophenylamino) acrylate was added in 3 ml N, N-dimethylformamide was dissolved and 0.04 g of sodium hydrogencarbonate was added to the resulting solution, after which the resulting mixture was added

120 ° C was subjected to the reaction for one hour. Thereafter, the solvent was removed by distillation under reduced pressure, and the residue thus obtained was dissolved in 10 ml of chloroform. The resulting solution was washed successively with 10 ml of water and 10 ml of saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the crystalline substance thus obtained was washed with 5 ml of diethyl ether, whereby 0.13 g of ethyl 7- (3-acetylamino -1-pyrrolidinyl) -6-fluoro -l- (2nd , 4-difluorophenyl) -1,4-dihydro -4-oxo -1,8-naphthyridine -3-carboxylate with a melting point of 233 to 235 ° C were obtained.

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

Example 5

(1) 0.50 g of ethyl 7-chloro-6-fluoro-l- (2,4-difluorophenyl) -1,4-dihydro -4-oxo -1,8-naphthyridine -3-carboxylate was added in 15 ml 6 normal hydrochloric acid was suspended and the suspension was refluxed for 3 hours. The reaction mixture was then diluted with 50 ml of water and extracted with three portions of 50 ml of chloroform each. The combined extracts were washed with 100 ml of saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the crystalline substance thus obtained was washed with 15 ml of diethyl ether, whereby 0.40 g of 7-chloro -6-fluoro-l- (2,4-difluorophenyl) -1,4- dihydro -4-oxo -1,8-naphthyridine -3-car-15 bonic acid with a melting point of 244 to 248 ° C were obtained.

IR (KBr), cm- ': uc = o 1720 NMR (d6-DMSO), 5 values:

7.26-8.56 (3H, m), 8.86 (1H, d, J = 7 Hz), 9.18 (1H, s) 20 (2) 0.30 g 7-chloro-6-fluorine -l- (2,4-difluorophenyl) -1,4-dihydro -4-oxo -1,8-naphthyridine -3-carboxylic acid was suspended in 3 ml of dimethyl sulfoxide, and then 0.25 g of N-methylpiperazine was added to the resulting Suspension was added and the resulting suspension was reacted at 60 ° C for 30 minutes. Then the solvent was removed by distillation under reduced pressure, and 30 ml of water was added to the residue thus obtained. The pH of the resulting mixture was adjusted to 12 with 10% aqueous sodium hydroxide solution and then to 7 with acetic acid. The deposited crystalline substance was collected by filtration and washed with 5 ml of water, 0.24 g of 6-fluoro-l- (2,4-difluorophenyl) -1,4-dihydro -7- (4-methyl -1-piperazi -nyl) -4-oxo -1,8-naphthyridine -3-carboxylic acid with a melting point of 208 to 209 ° C were obtained.

IR (KBr), cm_1: uc = 0 1730 NMR (TFA-dj), 5 values:

3.30 (3H, s), 3.45-5.25 (8H, m), 7.12-8.10 (3H, m), 8.49 (1H, d, J = 13 Hz), 9 , 38 (1H, s)

40

Example 6

5.0 g of ethyl 2- [2-chloro -5-fluoro -6- (4-methyl -1-piperazi-nyl) -nicotinoyl] -3- (4-methoxy -2-methylphenyl-amino) -acry- lat was dissolved in 50 ml of N, N-dimethylformamide, 45 1.03 g of sodium hydrogen carbonate was added to the resulting solution, and the resulting mixture was subjected to the reaction at 120 ° C. for 3 hours. Then the solvent was removed by distillation under reduced pressure, and the residue 50 thus obtained was dissolved in 50 ml of chloroform. The resulting solution was washed successively with 30 ml of water and 30 ml of saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the crystalline substance obtained was washed with 30 ml of diethyl ether, whereby 2.38 g of ethyl 6-fluoro-1,4-di-hydro-I- (4-methoxy -2-methylphenyl) -7- (4-methyl-1-piper-azinyl) -4-oxo -1,8-naphthyridine -3-carboxylate with a melting point of 144 to 145 ° C. 60 IR (KBr), cm-1: uc = o 1730.1690 NMR (CDCI3), 5 values:

1.33 (3H, t, J = 7 Hz), 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 = 7 Hz), 6 , 60-7.15 (3H, m), 8.02 (1H, d, J = 13 Hz), 8.23 65 (1H, s)

The compounds shown in Table 10 were obtained in a similar manner:

673458

26

Table 10

Connection

Physical Properties

R2

R3

Melting point (° C)

IR (KBr),

-1 m

cm: lC = 0

à

MeN N- \ /

199-202

1725, 1685

¥ ■

F

II

168-171

1735, 1720

OMe t>

174-175

1730, 1695

<§>

NHAc

II

amorphous

1725, 1690

OMe

II

186-189

1725, 1690

T Me OMe n

166-168

1730, 1695

■ Me &

OMe

AcN N-

169-172

1725, 1690

See Example 7, where 1.8 g of 6-fluoro-1,4-dihydro-1- (4-hydroxy -2-

2.0 g of ethyl 6-fluoro-1,4-dihydro-l- (4-methoxy -2-methyl-60 methylphenyl) -7- (4-methyl -1-piperazinyl) -4-oxo -1.8 -naph-

phenyl) -7- (4-methyl -1-piperazinyl) -4-oxo -1,8-naphthyrithyridine -3-carboxylic acid with a melting point of over din -3-carboxylate were in 5 ml of 47% hydrogen bromide 280 ° C were obtained.

acid dissolved, and the resulting solution was at 120 to IR (KBr), cm-1: uc = o 1725.1700 (Sch)

Subject to 125 ° C for 2 hours. The pH-NMR (TFA-d]), 5 values:

The value of the reaction mixture was adjusted with 10% aqueous 65 2.08 (3H, s), 3.12 (3H, s), 2.88-5.12 (8H, m), 6.93-7.62

Sodium hydroxide solution on 13 and then with acetic acid on (3H, m), 9.25 (1H, s), 9.43 (1H, d, J = 13 Hz)

6.5 set. The crystals deposited in this way were similarly collected by filtration as shown in Table 11 and obtained with 10 ml of water:

27th

Table 11 O

connection

Physical Properties

R2

R3

Melting point (° C)

IR (KBr),

-1 ..

cm: l> „„

C = 0

(O)

OH

G-

143-146

1725, 1710

II

Ht / N-

> 280

1710

II

MeN ^ ^ tf- \ /

> 280

1710

tf

EtN

> 280

1730

II

r ~ \

n-PrN ^ N-

> 280

1725

It

/ \

i-PrN ^ N-

> 280

1715

tt

HO- ^ wN \ -

200-205

1720, 1705

tl

/ V-l / N-

> 280

1725

&

OH

MeN VN- \ /

245-250

(Dec.)

1725,

1700 (Sch)

1 OH

M

> 280

1725, 1690

§R ~

F

/ - \

HN N- \ /

220-224

1725, 1710

n r ~ \

MeN ^ N-

> 280

1730,

1710 (Sch)

673 458

28

Table 11 (continued)

- OH

n

> 280

1730

II

/ ~~ \ HN ^ N-

> 255

1725

¥

OH

Mead /

251-252

1720

^ r0H

Me

It

> 280

1725 (Sch), 1700

ex

Me

OH

ti

228-230

1730,

1700 (Sch)

1 Me &

OH

HN

275

1720

Example 8 Example 9

0.40 g of ethyl 6-fluoro-1,4-dihydro-l- (4-methoxyphenyl) 45 2 ml of 1 normal aqueous sodium hydroxide solution and _7- (1-pyrrolidinyl) -4-oxo -1,8-naphthyridine - 3-carboxylate 2 ml of ethanol were dissolved in 0.1 ml of ethyl 7- (4-acetyl-1-piperazi) in 10 ml of 47% hydrobromic acid, and nyl) -6-fluoro-1- (4-fluorophenyl) -1,4-dihydro -4-oxo -1,8-the resulting solution was added at 120 to 125 ° C for 2 hours naphthyridine -3-carboxylate, and the resulting solution was subjected to the reaction. The pH of the reak solution was at 40 to 50 ° C for 10 minutes, the reaction mixture was subjected to 10% aqueous sodium hydrogenation. Subsequently, acetic acid was adjusted to the oxide solution at 13 and then at 6.5 with acetic acid. Reaction mixture added in order to adjust its pH to 6.5. The crystals thus deposited were adjusted by filtration. The mixture was then collected with two portions of and washed with 4 ml of water, with 0.30 g of 5 ml of chloroform being extracted. The combined extracts were

6-fluoro-l, 4-dihydro-l- (4-hydroxyphenyl) -7- (l-pyrrolidinyl) with 5 ml of water and 5 ml of saturated -4-oxo -1,8-naphthyridine -3-carboxylic acid a melted 55 aqueous sodium chloride solution and then obtained above 263-265 ° C. dried anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the crystalline substance thus obtained was washed with IR (KBr), cm-1: uc = Q 1725.1705, 2 ml of diethyl ether, 0.08 g of 7- (4-acetyl -1-pi-

NMR (TFA-d,), 5 values: 60 perazinyl) -6-fluoro -l- (4-fluorophenyl) -1,4-dihydro -4-oxo-

1.54-2.40 (4H, m), 3.14-4.14 (4H, m), 6.95-7.69 (4H, m), 1,8-naphthyridine -3-carboxylic acid with one Melting point 8.09 (1H, d, J = 12 Hz), 9.14 (1H, s) above 280 ° C were obtained.

Similarly, the following compound was obtained - IR (KBr), cm- ': uc = o 1730 th: NMR (d6-DMSO), 5 values:

6-fluoro-1,4-dihydro-1- (4-hydroxyphenyl) -7- (3-hydroxy 65 2.05 (3H, s), 3.57 (8H, bs), 7.13-7.80 (4H, m), 8.13 (1H, -l-pyrrolidinyl) -4-oxo -1,8-naphthyridine -3-carboxylic acid d, J = 13 Hz), 8.70 (1H, s)

Melting point: 180-183 ° C. Similarly, those given in Table 12 were given

IR (KBr), cm-1: uc = o 1725, 1705 compounds obtained:

29

Table 12

673 458

connection

Physical Properties

E2

R3

Melting point (° C)

IR (KBr),

cm: vc = o

IO).

MeN N-

277-280

1720

$

F

n

282-290

1725,

1700 (Sch)

II

Me especially

HN N-

268-270

1725

ti

MeN

/ \ HN N-

Me ^

283-285

1720

ti

Me

) \

. HN N-

N (

Me

267-270

1730

F

HO / ^ N v-

138-139

1690

II

<>

> 280

1730,

1700 (Sch)

F

Mel / N-

> 280

1720

F

II

208-209

1730

Il.

Me

- \ HN ^ N-

> 280

1720

Il

Me

MeN ^ N-

210-211

1735

673 458 30

Table 12 (continued)

II

Me

/ —E

MeN ^ N-

225-226

1720

II

-A

219-220

1730

<§)

Cl

MeN \ -

283-284

1730,

1700 (Sch)

<§)

Br

Met / N-

277-280

1730, - 1700 (Sch)

Me

II

271-274

1725

§

OMe tl

250-252

1725

Example 10

2 ml of 1-normal aqueous sodium hydroxide solution and 2 ml of ethanol were added to 0.10 g of ethyl-6-fluoro-1- (4-fluorophenyl) -1,4-dihydro-7- (3-hydroxy-1-pyrrolidinyl) -4-oxo -1,8-naphthyridine -3-carboxylate was added, and the resulting mixture was subjected to the reaction at 40 to 50 ° C for 10 minutes. Thereafter, acetic acid was added to the reaction mixture to adjust its pH to 6.5. Then the mixture was extracted with two 5 ml portions of chloroform. The combined extracts were washed successively with 5 ml of water and 5 ml of saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the crystalline substance thus obtained was washed with 2 ml of diethyl ether, whereby 0.08 g of 6-fluoro-l- (4-fluoro-orphenyl) -1,4-dihydro -7- (3-hydroxy-1-pyrrolidinyl) -4-oxo 35 -1,8-naphthyridine -3-carboxylic acid with a melting point above 280 ° C were obtained.

IR (KBr), cm-1: uc = o 1730 NMR (d6-DMSO), Ö values:

1.92-2.52 (2H, m), 3.22-5.00 (5H, m), 6.97-7.60 (4H, m), 40 8.01 (1H, d, J = 11 Hz), 9.00 (1H, s)

The compounds shown in Table 13 were obtained in a similar manner:

COOH

connection

Physical Properties

R2

R3

Melting point (° C)

IR (KBr),

cm ~ 1: ^ c = 0

(è)

F

Me2N

N-

264-265

1725

F

II

227

1725

31

673 458

Example 11

0.25 g of 6-fluoro-1,4-dihydro-l- (4-hydroxy-2-methylphenyl) -4-oxo -7- (1-piperazinyl) -1,8-naphthyridine -3-carboxylic acid dissolved in 2.5 ml of concentrated hydrochloric acid, and then 20 ml of ethanol was added to the resulting solution, after which the resulting mixture was stirred at room temperature for 15 minutes. The crystals thus deposited were collected by filtration and washed with 5 ml of ethanol, 0.2 g of the hydrochloride of 6-fluoro-1,4-dihydro-l- (4-hydroxy -2-methylphenyl) -4-oxo -7 - (l-piperazinyl) -1,8-naphthyridine -3-carboxylic acid with a melting point of over 280 ° C were obtained. IR (KBr), cm-1: uc = 0 1725 (Sch), 1705 The compounds given in Table 14 were obtained in a similar manner:

Table 14

Hydrochloride of

F I) COOH

..xxy

connection

I Physical properties

R2

R3

Melting point (° C)

IR (KBr),

-1 ..

cm: C = 0

F

Met / N-

283

1730

F

ffl / N-

275-278

1720

¥

F

II

249-252

(Dec.)

1730

Co)

OH

II

> 280

1710

u

MeN

280-282

1730

¥

OH

r ~ \

HN ^ N-

279-283

1720 (Seh), 1705

¥

OH

Me / N-

266-269

1720 (Sch), 1700

1 me

<¥

OH

tl

282

1730

673 458

32

Example 12

2.0 g 7- (3-amino -l-pyrrolidinyl) -6-fluoro -l- (2,4-difluorophenyl) -1,4-dihydro -4-oxo -1,8-naphthyridine -3- carboxylic acid was dissolved in 20 ml of concentrated hydrochloric acid, 200 ml of ethanol was added to the resulting solution at room temperature, and the resulting solution was stirred for 15 minutes. The crystals thus deposited were collected by filtration and washed with 40 ml of ethanol, 1.4 g of the hydrochloride of 7- (3-amino-1-pyrrolidinyl) -6-fluoro-l- (2,4-difluorophenyl) -1 , 4-dihydro -4-oxo -1,8-naphthyridine -3-carboxylic acid with a melting point of 247 to 250 ° C (decomposition) were obtained.

IR (KBr), cm-1: uc = 0 1730

Example 13

(1) 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 were added in 2.5 ml Chloroform dissolved and the resulting solution was refluxed for 3.5 hours. Then the reaction mixture was washed successively with 3 ml of water and 3 ml of saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure and the residue thus obtained was purified by column chromatography (WAKO SILICA GEL C-200, eluent: chloroform: ethanol in a volume ratio of 50: 1), with 0.294 g of oily ethyl 2- [2- chlorine -5-fluoro -6- (4-methyl-l-piperazinyl) -nicotinoyl] -3- (2,4-difluorophenylamino) -acry-lat were obtained.

IR (neat), cm-1, uc = o 1735.1700

NMR (CDClj), 5 values:

1.13 (3H, t, J = 7 Hz), 2.36 (3H, s), 2.55 (4H, t, J = 5 Hz), 3.70 (4H, t, J = 5 Hz) , 4.15 (2H, q, J = 7 Hz), 6.77-7.90 (4H, m), 8.51 (IH, d, J = 13 Hz), 12.50 (1H, d, J = 13 Hz)

(2) By treating 0.2 g of ethyl -2- [2-chloro-5-fluoro -6- (4-methyl-1-piperazinyl) nicotinoyl] -3- (2,4-difluorophenylamino) - In the same way as in Examples 6 and 9, 0.12 g of 6-fluoro-1- (2,4-difluorophenyl) -1,4-di-hydro -7- (4-methyl-1-piperazinyl) - Obtained 4-oxo -1,8-naphthyridine-3-carboxylic acid with a melting point of 208 to 209 ° C.

Example 14

To 0.3 g of ethyl 7- (4-ethoxycarbonyl -2-methyl-1-piperazinyl) -6-fluoro-l- (2,4-difluorophenyl) -1,4-dihydro -4-oxo -1.8 -naphthyridine -3-carboxylate, 5 ml of 1 normal sodium hydroxide aqueous solution and 5 ml of ethanol were added, and the resulting mixture was subjected to the reaction at 90 ° C for 2 hours. Then acetic acid was added to the reaction mixture to adjust its pH to 6.5. The crystals thus deposited were collected by filtration, washed with water and then dried, whereby 0.2 g of 6-fluoro-l- (2,4-difluorophenyl) -1,4-dihydro -7- (2-methyl -1- piperazinyl) -4-oxo -1,8-naph-thyridine -3-carboxylic acid with a melting point of 230 to 239 ° C.

IR (KBr), cm-1: uc = o 1730

NMR (TFA-d,), 5 values:

1.50 (3H, s), 3.20-5.15 (7H, m), 7.00-7.90 (3H, m), 8.35 (1H, d, J = 13 Hz), 9 , 20 (lH, s)

Example 15

1.0 g of the dihydrochloride of 3-aminopyrrolidine was suspended in 20 ml of ethanol, 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-l- (2,4-difluorophenyl) -1,4-dihydro -4-oxo -1,8-naphthyridine

-3-carboxylate was added to the solution at 30 ° C over 15 minutes, and the resulting mixture was subjected to the reaction at the same temperature for 3 hours. After the reaction was completed, 30 ml of water was added to the reaction mixture, and the crystals thus deposited were collected by filtration and washed with 4 ml of water. The crystalline substance thus obtained was suspended in 13 ml of 6 normal hydrochloric acid, and the resulting suspension was heated to reflux for 2 hours. The reaction mixture was then cooled, and the crystals thus deposited were collected by filtration and washed with two portions of 2 ml of water, 1.97 g of the hydrochloride of 7- (3-amino-1-pyrrolidinyl) -6-fluorine. 1- (2,4-difluorophe-15 nyl) -1,4-dihydro -4-oxo -1,8-naphthyridine -3-carboxylic acid were obtained.

IR (KBr), cm-1: uc = 0 1730

20th

Example 16

10.0 g 7- (3-amino -1-pyrrolidinyl) -6-fluoro -l- (2,4-difluorophenyl) -1,4-dihydro -4-oxo -1,8-naphthyridine -3- carboxylic acid was suspended in 75 ml of ethanol and 75 ml of water. To the resulting suspension was added 5.2 g of p-toluenesulfonic acid monohydrate at 40 ° C, and the resulting mixture was stirred at the same temperature for 30 minutes. The reaction mixture was then cooled to 15 ° C., and the crystals thus deposited were collected by filtration and washed with a mixed solvent of 5 ml of ethanol and 5 ml of water, 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 with a melting point of 258 up to 260 ° C were obtained.

3 * IR (KBr), cm - !: uc = 0 1735 NMR (DMSO-d6), 5 values:

1.82-2.42 (m) | (5H) 3.12-4.30 (5H, m),

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

40 Similarly, the following compound was obtained:

Oxalic acid salt of 7- (3-amino -1-pyrrolidinyl) -6-fluoro-l- (2,4-difluorophenyl) -1,4-dihydro -4-oxo -1,8-naphthyridine-3-carboxylic acid 45 melting point ( C): 250-253 IR (KBr), cm "1: uc = o 1730

Example 17

50 5.00 g of 7- (3-amino-1-pyrrolidinyl) -6-fluoro-l- (2,4-difluorophenyl) -1,4-dihydro were added to a solution of 1.6 g of methanesulfonic acid in 25 ml of acetic acid -4-oxo - 1,8-naphthyridine -3-carboxylic acid was added, after which the resulting suspension was stirred at room temperature to form a solution. 100 ml of ethanol were added to the solution at 40 to 45 C in the course of 30 minutes. The reaction mixture was then cooled to room temperature and stirred for 30 minutes. The crystals thus deposited were collected by filtration and washed 60 with three portions of 20 ml each of ethanol, 3.12 g of the methanesulfonic acid salt of 7- (3-amino-1-pyrrolidinyl) -6-fluoro-l- (2 , 4-difluorophenyI) -1,4-dihydro -4-oxo -1,8-naphthyridine -3-carboxylic acid with a melting point above 300 ° C were obtained.

65 IR (KBr), cm-1: uc = 0 1735

Similarly, the following compound was obtained:

Sulfuric acid salt of 7- (3-amino -1-pyrrolidinyl) -6-flu-

33

673 458

or-l- (2,4-difluorophenyl) -1,4-dihydro -4-oxo -1,8-naphthyri-din -3-carboxylic acid

Melting point (° C): 220-230 IR (KBr), cm-1: uc = o 1735

Production Example 1

49 g of crystalline cellulose, 50 g of corn starch and 1 g of magnesium stearate were mixed with 50 g of 6-fluoro-l- (2,4-difluorophenyl) -1,4-dihydro -4-oxo -7- (1-piperazinyl ) -1,8-naphthyridine -3-carboxylic acid mixed, and the mixture was pressed into 1000 flat tablets.

Production Example 2

50 g of corn starch were mixed with 100 g of 6-fluoro-l- (2,4-difluorophenyl) -1,4-dihydro -4-oxo -7- (l-piperazinyl) -1,8-naph-thyridine -3 -carboxylic acid mixed, and 1000 capsules were filled with the resulting mixture to obtain capsules.

Production Example 3 49 g of crystalline cellulose, 50 g of corn starch and 1 g of magnesium stearate were mixed with 50 g of 7- (3-amino-1-pyrrolidinyl) -l- (2,4-difluorophenyl) -6-fluorine-1,4 -dihydro -4-oxo -1,8-naphthyridine -3-carboxylic acid mixed, and the mixture was compressed into 1000 flat tablets.

10th

Production Example 4 50 g of corn starch were mixed with 100 g of 7- (3-amino-1-pyrrolodinyl) -1- (2,4-difluorophenyl) -6-fluorine-1,4-dihydro-4-oxo-1,8 -naphthyridine -3-carboxylic acid mixed, and 1000 caps-15 were filled with the resulting mixture to obtain capsules.

C.

Claims (82)

673 458 2nd 1. 1, 4-dihydro-4-oxonaphthyridine derivatives of the formula: or their salts, in which R1 denotes hydrogen or a carboxyl-protecting group, R2 denotes a substituted or unsubstituted aryl group and R3 denotes a halogen atom or a substituted or unsubstituted cyclic aminograph. 2. 1,4-dihydro-4-oxonaphthyridine derivatives or their salts according to claim 1, in which R2 represents a phenyl group which can be substituted by at least one substituent consisting of halogen atoms, alkyl groups, hydroxyl groups, alkoxy groups, cyano groups, amino groups, acylamino groups and trihaloalkyl groups is selected. 3. l, 4-dihydro-4-oxonaphthyridine derivatives or their salts according to Claim 2, in which R3 denotes a 1-pyrrolidinyl, pipe-ridino, 1-piperazinyl or morpholino group which can be substituted by at least one substituent which consists of Alkyl, amino, aminoalkyl, hydroxyalkyl, hydroxyl, alkenyl, acyl, alkylamino, dialkylamino, cyano, oxo, aralkylamino, acylamino, alkoxycarbonyl and N-acyl N-alkylamino groups is selected. 4. l, 4-dihydro-4-oxonaphthyridine derivatives or their salts according to claim 3, wherein R3 represents a 1-pyrrolidinyl, pipe-ridino, 1-piperazinyl or morpholino group, which can be substituted by at least one substituent from Alkyl, amino, hydroxyalkyl, hydroxyl, al-kenyl, acyl, alkylamino, dialkylamino, acylamino, alkoxycarbonyl and N-acyl-N-alkylamino groups is selected. 5. l, 4-dihydro-4-oxonaphthyridine derivatives or their salts according to claim 4, wherein R2 represents a 4-fluorophenyl group. 6. l, 4-dihydro-4-oxonaphthyridine derivatives or their salts according to claim 4, wherein R2 denotes a 2,4-difluorophenyl group. 7. l, 4-dihydro-4-oxonaphthyridine derivatives or their salts according to claim 1, wherein R3 represents a 1-pyrrolidinyl group which is substituted by an amino or acylamino group. 8. l, 4-dihydro-4-oxonaphthyridine derivatives or their salts according to claim 7, wherein R2 represents a 4-fluorophenyl group. 9. l, 4-dihydro-4-oxonaphthyridine derivatives or their salts according to claim 7, wherein R2 denotes a 2,4-difluorophenyl group. 10. l, 4-dihydro-4-oxonaphthyridine derivatives or their salts according to claim 1, wherein R3 represents a 3-amino-l-pyrrolidinyl group. 11. l, 4-dihydro-4-oxonaphthyridine derivatives or their salts according to claim 10, wherein R2 represents a 4-fluorophenyl group. 12. l, 4-dihydro-4-oxonaphthyridine derivatives or their salts according to claim 10, wherein R2 denotes a 2,4-difluorophenyl group. 13. l, 4-dihydro-4-oxonaphthyridine derivatives or their salts according to Claim 1, in which R3 denotes a 1-piperazinyl group. 14. l, 4-dihydro-4-oxonaphthyridine derivatives or their Salts according to claim 13, wherein R2 represents a 4-fluorophenyl group. 15. l, 4-dihydro-4-oxonaphthyridine derivatives or their salts according to claim 13, wherein R2 is a 2,4-difluorophenyl 5 group means. 16. 7-chloro-1- (2,4-difluorophenyl) -6-fluoro-1,4-dihydro -4-oxo-naphthyridine -3-carboxylic acid or salts thereof according to claim 1. 17. 7- (3-Amino -1-pyrrolidinyl) -l- (2,4-difluorophenyl) -6- 10 fluorine-1,4-dihydro -4-oxo -1,8-naphthyridine -3-carboxylic acid or its salts according to claim 1. 18. l- (2,4-difluorophenyl) -6-fluoro-1,4-dihydro -4-oxo -7- (1-piperazinyl) -1,8-naphthyridine -3-carboxylic acid or salts thereof according to claim 1. 15 19. 7- (3-Amino-1-pyrrolidinyl) -6-fluoro -l- (4-fluorophenyl) -1,4-dihydro -4-oxo -1,8-naphthyridine -3-carboxylic acid or their Salts according to claim 1. 20. Process for the preparation of 1,4-dihydro -4-oxo-naphthyridine derivatives of the formula: or their salts, in which Rla denotes a carboxyl protecting group, R2 denotes a substituted or unsubstituted aryl group 3 ° and R3 denotes a halogen atom or a substituted or unsubstituted cyclic amino group, characterized in that a compound of the formula: or a salt thereof, in which Rla and R2 and R3 have the above meanings, is subjected to a ring closure reaction. 21. The method according to claim 20, characterized in that R2 represents a phenyl group which can be substituted by at least one substituent which is selected from halogen atoms, alkyl groups, hydroxyl groups, alkoxy groups, cyano groups, amino groups, acylamino groups and trihaloalkyl groups. 50 22. The method according to claim 21, characterized in that R3 is a 1-pyrrolidinyl, piperidino, 1-piperazinyl or morpholino group, which can be substituted by at least one substituent consisting of alkyl, amino, aminoalkyl, Hydroxyalkyl, hydroxyl, alkenyl, 55 acyl, alkylamino, dialkylamino, cyano, oxo, aralkylamino, acylamino, alkoxycarbonyl, and N-acyl-N-alkylamino groups is selected. 23. The method according to claim 22, characterized in that R3 is a 1-pyrrolidinyl, piperidino, 1-piperazinyl-60 or morpholino group, which can be substituted by at least one substituent consisting of alkyl, amino, hydroxyalkyl, Hydroxyl, alkenyl, acyl, alkylamino *, dialkylamino, acylamino, alkoxycarbonyl and N-acyl-N-alkylamino groups is selected. 65 24. The method according to claim 23, characterized in that R2 represents a 4-fluorophenyl group. 25. The method according to claim 23, characterized in that R2 represents a 2,4-difluorophenyl group. 3rd 673 458 26. The method according to claim 20, characterized in that R3 is a 1-pyrrolidinyl group which is substituted by an amino or acylamino group. 27. The method according to claim 26, characterized in that R2 represents a 4-fluorophenyl group. 28. The method according to claim 26, characterized in that R2 represents a 2,4-difluorophenyl group. 29. The method according to claim 20, characterized in that R3 represents a 3-amino-l-pyrrolidinyl group. 30. The method according to claim 29, characterized in that R2 represents a 4-fluorophenyl group. 31. The method according to claim 29, characterized in that R2 represents a 2,4-difluorophenyl group. 32. The method according to claim 20, characterized in that R3 is a 1-piperazinyl group. 33. The method according to claim 32, characterized in that R2 represents a 4-fluorophenyl group. 34. The method according to claim 32, characterized in that R2 represents a 2,4-difluorophenyl group. 35. The method according to claim 20, characterized in that the 7-chloro-l- (2,4-difluorophenyl) -6-fluoro-l, 4-dihydro-4-oxo -1,8-naphthyridine -3-carboxylic acid or make a salt of it. 36. The method according to claim 20, characterized in that the 7- (3-amino-1-pyrrolidinyl) -l- (2,4-difluorophenyl) -6-fluoro-1,4-dihydro -4-oxo -1.8-naphthyridine -3-carboxylic acid or a salt thereof. 37. The method according to claim 20, characterized in that the l- (2,4-difluorophenyl) -6-fluoro-1,4-dihydro -4-oxo -7- (l-piperazinyl) -1,8-naphthyridine -3-carboxylic acid or a salt thereof. 38. The method according to claim 20, characterized in that the 7- (3-amino-1-pyrrolidinyl) -6-fluoro -l- (4-fluorophenyl) -1,4-dihydro -4-oxo -1.8 -naphthyridine -3-car-bonic acid or a salt thereof. 39. The method according to claim 20, characterized in that one carries out the ring closure reaction at a temperature of 20 to 160 ° C. 40. Process for the preparation of 1,4-dihydro -4-oxo-naphthyridine derivatives of the formula: or their salts, in which R1 is hydrogen, R2 is a substituted or unsubstituted aryl group and R3 is a halogen atom or a substituted or unsubstituted cyclic amino group, characterized in that a compound of the formula: - or a salt thereof in which Rla represents a carboxyl protecting group and R2 and R3 have the above meanings, undergoes a ring closure reaction and removes the carboxyl protecting group. 41. The method according to claim 40, characterized in that R2 represents a phenyl group which can be substituted by at least one substituent consisting of halogen atoms, alkyl groups, hydroxyl groups, alkoxy- groups, cyano groups, amino groups, acylamino groups and trihaloalkyl groups is selected. 42. The method according to claim 41, characterized in that R3 is a 1-pyrrolidinyl, piperidino, 1-piperazinyl 5 or morpholino group, which can be substituted by at least one substituent consisting of alkyl, amino, aminoalkyl, hydroxyalkyl, hydroxyl, alkenyl, acyl, alkylamino, dialkylamino, cyano, oxo, aralkyl -amino-, acylamino-, alkoxycarbonyl- and N-acyl-N-alkyl- 10 amino groups is selected. 43. The method according to claim 42, characterized in that R3 is a 1-pyrrolidinyl, piperidino, 1-piperazinyl or morpholino group, which can be substituted by at least one substituent which can be substituted from alkyl, 15 amino, hydroxyalkyl, hydroxyl, alkenyl, acyl, alkylamino, dialkylamino, acylamino, alkoxycarbonyl and N-acyl-N-alkylamino groups is selected. 44. The method according to claim 43, characterized in that R2 represents a 4-fluorophenyl group. 45. The method according to claim 43, characterized in that R2 represents a 2,4-difluorophenyl group. 46. The method according to claim 40, characterized in that R3 represents a 1-pyrrolidinyl group which is substituted by an amino or acylamino group. 47. The method according to claim 46, characterized in that R2 represents a 4-fluorophenyl group. 48. The method according to claim 46, characterized in that R2 represents a 2,4-difluorophenyl group. 49. The method according to claim 40, characterized in 30 net that R3 means a 3-amino-l-pyrrolidinyl group. 50. The method according to claim 49, characterized in that R2 represents a 4-fluorophenyl group. 51. The method according to claim 49, characterized in that R2 represents a 2,4-difluorophenyl group. 35 52. The method according to claim 40, characterized in that R3 is a 1-piperazinyl group. 53. The method according to claim 52, characterized in that R2 represents a 4-fluorophenyl group. 54. The method according to claim 52, characterized in 40 net that R2 means a 2,4-difluorophenyl group. 55. The method according to claim 40, characterized in that the 7-chloro-l- (2,4-difluorophenyl) -6-fluoro-1,4-dihydro -4-oxo -1,8-naphthyridine -3-carboxylic acid or make a salt of it. 45 56. The method according to claim 40, characterized in that the 7- (3-amino -1-pyrrolidinyl) -l- (2,4-difluorophenyl) -6-fluorine-1,4-dihydro -4- oxo -1,8-naphthyridine -3-carboxylic acid or a salt thereof. 57. The method according to claim 40, characterized in 50 net that the l- (2,4-difluorophenyl) -6-fluoro-1,4-dihydro -4-oxo -7- (l-piperazinyl) -1,8-naphthyridine -3-carboxylic acid or a salt thereof. 58. The method according to claim 40, characterized in that the 7- (3-amino-l-pyrrolidinyl) -6-fluoro -l- (4- 55 fhiorphenyl) -1,4-dihydro -4-oxo -1,8-naphthyridine -3-car-bonic acid or a salt thereof. 59. The method according to claim 40, characterized in that one carries out the ring closure reaction at a temperature of 20 to 160 ° C. 60 60. Process for the preparation of 1,4-dihydro-4-oxonaphthyridine derivatives of the formula: 673 458 4th or their salts, in which R1 denotes hydrogen or a carboxyl protecting group, R2 denotes a substituted or unsubstituted aryl group and R3b denotes a substituted or unsubstituted cyclic amino group, characterized in that a compound of the formula: or a salt thereof, in which R3a represents a halogen atom and R1 and R2 have the above meanings, with a compound of the formula: R3b-H or a salt thereof, in which R3b has the meaning given above. 61. The method according to claim 60, characterized in that R2 represents a phenyl group which can be substituted by at least one substituent which is selected from halogen atoms, alkyl groups, hydroxyl groups, alkoxy groups, cyano groups, amino groups, acylamino groups and trihaloalkyl groups. 62. The method according to claim 61, characterized in that R3b represents a 1-pyrrolidinyl group which can be substituted by at least one substituent consisting of amino, aminoalkyl, hydroxyl, alkylamino, dialkylamino, acylamino and N-acyl -N-alkylamino groups is selected. 63. The method according to claim 62, characterized in that R2 represents a 4-fluorophenyl group. 64. The method according to claim 62, characterized in that R2 represents a 2,4-difluorophenyl group. 65. The method according to claim 60, characterized in that R3b represents a 1-pyrrolidinyl group which is substituted by an amino or acylamino group. 66. The method according to claim 65, characterized in that R2 represents a 4-fluorophenyl group. 67. The method according to claim 65, characterized in that R2 represents a 2,4-difluorophenyl group. 68. The method according to claim 60, characterized in that R3b represents a 3-amino-l-pyrrolidinyl group. 69. The method according to claim 68, characterized in that R2 represents a 4-fluorophenyl group. 70. The method according to claim 68, characterized in that R2 represents a 2,4-difluorophenyl group. 71. The method according to claim 60, characterized in that R3b denotes a 1-piperazinyl group. 72. The method according to claim 71, characterized in that R2 represents a 4-fluorophenyl group. 73. The method according to claim 71, characterized in that R2 represents a 2,4-difluorophenyl group. 74. The method according to claim 60, characterized in that the 7- (3-amino-l-pyrrolidinyl) -l- (2,4-difluorophenyl) -6-fluoro-1,4-dihydro -4-oxo -1.8-naphthyridine -3-carboxylic acid or a salt thereof. 75. The method according to claim 60, characterized in that one carries out the reaction at a temperature of 0 to 150 ° C. 76. Antibacterial agent, characterized in that it contains at least one 1,4-dihydro -4-oxonaphthyridine derivative of the formula: or a salt thereof, wherein R1 represents hydrogen or a carb-10 oxyl protecting group, R2 represents a substituted or unsubstituted aryl group and R3 represents a halogen atom or a substituted or unsubstituted cyclic amino group. 77. Antibacterial agent according to claim 76, characterized in that R2 represents a phenyl group which can be substituted by at least one substituent which is selected from halogen atoms, alkyl groups, hydroxyl groups, alkoxy groups, cyano groups, amino groups, acylamino groups and trihaloalkyl groups. 78. Antibacterial agent according to claim 77, characterized in that R3 is a 1-pyrrolidinyl, piperidino, 1-piperazinyl or morpholino group, which can be substituted by at least one substituent which can be substituted from alkyl, amino, aminoalkyl , Hydroxyalkyl, hydro-25 xyl, alkenyl, acyl, alkylamino, dialkylamino, cyano, oxo, aralkylamino, acylamino, alkoxycarbonyl and N-acyl-N-alkylamino groups is selected. 79. Antibacterial agent according to claim 78, characterized in that R3 is a 1-pyrrolidinyl, piperidino, 30 1-piperazinyl or morpholino group which can be substituted by at least one substituent which can be substituted from alkyl, amino, hydroxyalkyl , Hydroxyl, alkenyl, acyl, alkylamino, dialkylamino, acylamino, alkoxycarbonyl and N-acyl-N-alkylamino groups is selected. 35 80. Antibacterial agent according to claim 79, characterized in that R2 represents a 4-fluorophenyl group. 81. Antibacterial agent according to claim 79, characterized in that R2 denotes a 2,4-difluorophenyl group. 40. Antibacterial agent according to claim 76, characterized in that R3 represents a 1-pyrrolidinyl group which is substituted by an amino or acylamino group. 83. Antibacterial agent according to claim 82, characterized in that R2 denotes a 4-fluorophenyl group. 84. Antibacterial agent according to claim 82, characterized in that R2 denotes a 2,4-difluorophenyl group. 85. Antibacterial agent according to claim 76, characterized in that R3 represents a 3-amino-l-pyrrolidinyl group. 86. Antibacterial agent according to claim 85, characterized in that R2 represents a 4-fluorophenyl group. 87. Antibacterial agent according to claim 85, characterized in that R2 denotes a 2,4-difluorophenyl group. 88. The antibacterial agent according to claim 76, wherein R3 represents a 1-piperazinyl group. 89. Antibacterial agent according to claim 88, characterized in that R2 represents a 4-fluorophenyl group. 90. Antibacterial agent according to claim 88, characterized in that R2 represents a 2,4-difluorophenyl group. 91. Antibacterial agent according to claim 76, characterized in that the active ingredient is the 7- (3-amino-1-pyrrolidinyl) -l- (2,4-difluorophenyl) -6-fluorine-1,4-dihydro -4- oxo-1,8-naphthyridine -3-carboxylic acid or a salt thereof. 92. Antibacterial agent according to claim 76, characterized characterized in that the active ingredient is the l- (2,4-difluorophenyl) -6-fluoro-1,4-dihydro -4-oxo -7- (l-piperazinyl) -1,8-naphthyridine -3-carboxylic acid or a salt is the same. 93. Antibacterial agent according to claim 76, characterized in that the active ingredient is the 7- (3-amino-l-pyrro-lidinyl) -6-fluoro-l- (4-fluorophenyl) -1,4-dihydro -4-oxo Is -1,8-naphthyridine -3-carboxylic acid or a salt thereof.