CS250698B2 - Process for the preparation of 1,4-dihydro-4-oxonaphthyridine derivatives - Google Patents

Abstract

A method for producing 1,4-dihydro-4-oxonaphthyridine derivatives of the compound of the general formula I COOR'1 (!) in which the individual general symbols have the meaning given in the subject of the invention, and their salts, are produced by cyclization of the compound of the general formula II, in which Rla represents a protecting group of the carboxyl function and or its salt and the protecting group of the carboxyl function is optionally cleaved from the resulting product. The produced compounds have strong antibacterial activity against gram-positive and gram-negative bacteria, especially bacteria resistant to antibiotics.

Description

The invention relates to a process for the preparation of novel 1,4-dihydro-4-oxonaphthyridine derivatives containing an optionally substituted aryl group in position 1 and a halogen atom or an optionally substituted cyclic amino group in position 7, and their salts.

As synthetic antibacterial agents, nalidixic acid, pyrimidic acid, pipemidic acid, etc. have been widely used until now. However, none of these agents has a satisfactory therapeutic effect on infections caused by Pseudomonas aeruginosa and Gram-positive bacteria, which are persistent and difficult to treat diseases. Therefore, various pyridonecarboxylic acid-type compounds, such as 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid (norfloxacin), etc., are being developed as substitutes for conventional synthetic antibacterial agents. These compounds exhibit excellent antibacterial activity against various Gram-negative bacteria, including Pseudomonas aeruginosa, but have unsatisfactory antibacterial activity against Gram-positive bacteria. Therefore, it is desirable to develop synthetic antibacterial agents with a broad spectrum of activity that are effective not only against Gram-negative bacteria but also against Gram-positive bacteria.

After extensive research, the present inventors have found that novel 1,4-dihydro-4-oxonaphthyridine derivatives and their salts can solve the above problems.

The subject of the invention is a method for producing new 1,4-dihydro-4-oxonaphthyridine derivatives and their salts, which substances have excellent properties, for example strong antibacterial activity against gram-positive and gram-negative bacteria, especially against antibiotic-resistant bacteria, and which, upon oral or parenteral administration, occur in high concentrations in the blood, while being very safe.

Accordingly, the invention describes a process for the preparation of 1,4-dihydro-4-oxonaphthyridine derivatives of general formula I

in which

R ¹ represents a hydrogen atom or an alkyl group with 1 to 5 carbon atoms,

R ² represents a phenyl group optionally substituted with one, two or three substituents selected from the group consisting of halogen atoms, alkyl groups with 1 to 10 carbon atoms, alkoxy groups with 1 to 10 carbon atoms, hydroxyl group, amino group, cyano group, acylamino groups with 1 to 4 carbon atoms and trihaloalkyl groups with 1 to 4 carbon atoms, and

R ³ represents halogen or a 1-pyrrolidinyl, piperidine, 1-piperazinyl or morpholine group, which may be substituted by one or two substituents selected from the group comprising a hydroxyl group, an amino group, alkyl groups with 1 to 4 carbon atoms, alkylamino groups with 1 to 4 carbon atoms, dialkylamino groups containing 1 to 4 carbon atoms in each alkyl part, hydroxyalkyl groups with 1 to 4 carbon atoms, alkenyl groups with 2 to 4 carbon atoms, acylamino groups with 1 to 4 carbon atoms, acyl groups with 1 to 4 carbon atoms, N-acyl-N-alkylamino groups containing 1 to 4 carbon atoms in each acyl and alkyl part and alkoxycarbonyl groups with 1 to 4 carbon atoms in the alkoxy part, and salts thereof, characterized in that the compound of general formula II

in which

^R1a represents a protecting group for the carboxyl function and

R ² and R ³ have the above-mentioned meaning, or a salt thereof, is subjected to a cyclization reaction, and the protecting group of the carboxyl function is optionally cleaved from the resulting product.

The term "carboxyl protecting group" as used ^herein includes, for example, ester-forming groups that can be cleaved by catalytic reduction, chemical reduction, or other reactions under mild conditions, ester-forming groups that are readily cleaved in the living body, organic silicon-containing groups, organic phosphorus-containing groups, and organic tin-containing groups that can be readily cleaved by the action of water or alcohol, and various other well-known ester-forming groups.

Among these carboxyl protecting groups, preferred protecting groups are, for example, the carboxyl protecting groups described in Japanese Patent Application Laid-Open No. 80665/84.

The phenyl group in the meaning of the symbol R ² may be substituted by one or two or three substituents selected from the group comprising halogen atoms, for example fluorine, chlorine, bromine, iodine, etc., alkyl groups with 1 to 10 carbon atoms, for example

253 S 93 straight or branched alkyl groups with 1 to 10 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.butyl, tert.butyl, pentyl, hexyl, heptyl, octyl, etc., hydroxyl group, alkoxy group with 1 to 10 carbon atoms, for example straight 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, etc., cyano group, amino group, acylamino groups with 1 to 4 carbon atoms, such as formylamino, acetylamino, propionylamino, butyrylamino, etc., and trihaloalkyl groups with 1 to 4 carbon atoms in the alkyl portion, such as trifluoromethyl, trichloromethyl, etc.

Halogen atoms in the meaning of the symbol R ³ include, for example, fluorine, chlorine and bromine atoms.

The 1-pyrrolidinyl, piperidino, 1-piperazinyl and morpholine groups in the meaning of the symbol R ³ may be substituted by one or two substituents selected from the group comprising alkyl groups with 1 to 4 carbon atoms, for example straight or branched alkyl groups with 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.butyl and tert.butyl, amino group, hydroxyalkyl groups with 1 to 4 carbon atoms in the alkyl part, such as hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, etc., hydroxyl group, alkenyl groups with 2 to 4 carbon atoms, such as vinyl, allyl, etc., acyl groups with 1 to 4 carbon atoms, such as formyl, acetyl, propionyl, butyryl, etc., alkylamino groups with 1 to 4 carbon atoms, such as methylamino, ethylamino, n-propylamino, isopropylamino, etc., dialkylamino groups containing 1 to 4 carbon atoms in each alkyl part, such as dimethylamino, diethylamino, di-n-propylamino. methylethylamino group and the like, acylamino groups having 1 to 4 carbon atoms, such as acetylamino group, propionylamino group, butyrylamino group and the like, alkoxycarbonyl groups having 1 to 4 carbon atoms in the alkoxy moiety, such as methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, isopropoxycarbonyl group and the like, and N-acyl-N-alkylamino groups in which the nitrogen atom in the above-mentioned alkylamino group is substituted with an acyl group having 1 to 4 carbon atoms, such as acetyl group, propionyl group, butyryl group and the like.

Of the compounds of the above-mentioned general formulas I and II, those in which R ² represents a 4-fluorophenyl or 2,4-difluorophenyl group and R ³ represents a 1-pyrrolidinyl group or a 1-piperazinyl group optionally substituted in the above-mentioned manner are preferred, and even more preferred are those compounds in which R ² represents a 2,4-difluorophenyl group and R ³ represents a 3-amino-1-pyrrolidinyl group.

Salts of compounds corresponding to the above general formula I or II include conventional salts on basic groups, such as an amino group, etc., and on acidic groups, such as a carboxyl group, etc. Salts with basic groups include, for example, salts with mineral acids, such as hydrochloric acid, sulfuric acid, etc., salts with organic carboxylic acids, such as oxalic acid, formic acid, trichloroacetic acid, trifluoroacetic acid, etc., salts with sulfonic acids, such as methanesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, etc. Salts with acidic groups include, for example, salts with alkali metals, such as sodium, potassium, etc., salts with alkaline earth metals, such as calcium, magnesium, etc., ammonium salts, and salts with nitrogenous organic bases, such as procalciuria, dibenzylamine, N-benzyl-jg-phenethylamine, 1-ephenamine, N,N-dibenzylethylenediamine, triethylamine, trimethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexyamine, etc.

If a compound of formula I or II or a salt thereof can exist in the form of isomers (for example, optical isomers, geometric isomers, tautomers, etc.), the invention includes all such isomers, their crystalline forms and hydrates.

The following section describes the antibacterial activities and acute toxicities for typical compounds produced by the method according to the method.

1. Antibacterial efficacy

Performing the test

According to the standard method of the Japan Society of Chemotherapy [Chemotherapy, 29 (1), 76-79 (1981)], a bacterial solution obtained by culturing on a heart infusion medium for 20 hours at 37°C is inoculated onto a heart infusion agar containing the test substance, the preparation is cultured at 37°C for 20 hours, and the growth of the bacteria is evaluated. The minimum concentration that causes inhibition of bacterial growth (MIC) is determined in µg/ml. The inoculation dose of the bacteria is 10 ¹ cells/plate (10 ⁵ cells/ml). The values of the minimum inhibitory concentrations (MIC) for the individual test compounds are shown in the following Table 1.

The individual symbols used in Table 1 have the following meanings: ^z j inoculation dose 10 ⁸ cells/ml

Me = methyl group

Et = ethyl group n-Pr = n-propyl group i-Pr = isopropyl group

Test microorganisms are designated with capital letters according to the following key:

A = St. aureus FDA209P

B = St. epidermidis IID866

C = St. aureus F-137 producing penicillinase

D -= E. coli NIHJ

E = E. coli TK-111

F = E. coli GN5482 producing cephalosporinase

G = Ps. aeruginosa S-68

H = Aci, nitrate A-6

I = Ps. aeruignosa IFO3445

J = Ps. aeruginosa GN918 producing cephalosporinase

The tested substances correspond to the general formula

O

COOH

Table 1

organism ^R2 : ^R2 : compound no. R ² : F HO W R ³ : R ³ : R ³ : / \ MeN N™ \~_/ \ A V—' 1 2

A 0.1 š0.05 <0.05 B 0.1 <0.05 <0.05 C 0.1 <0.05 <0.05 D 0.05 0.39 0.1 E s0.05 0.2 g0.05 F š0.05 0.1 <0.05 G 0.39 6.25 1.56 H 0.2 0.2 g0.05 I 3.13 12.5 3.13 J 0.39 3.13 0.78

organism

^R2 :

compound no. R ² :

F

R ³ :

after

R ³ :

A 0.1 0.2 B 0.1 0.39*) C 0.1 0.2 D ¢0.05 ¢0.05 E š0.05 ¢0.05 F ¢0.05 ¢0.05 G 1.56 0.39 H 0.1 0.2 I 3.13 0.78 J 0.78 0.39

organism compound no.

/—\

HN. N~ \_/ /~λ fVR ² :

Θ 7 8

A 0.2 0.2 0.2 B 0.78 0.2 0.2 C 0.39 0.2 0.2 D <0.05 <0.05 <0.05 E ¢0.05 ¢0.05 ¢0.05 F ¢0.05 ¢0.05 <0.05 G 1.56 3.13 3.13 H 0.2 0.2 0.78 I 1.56 12.5 6.25 J 0.78 3.13 1.56

organism compound no.

CH-CH í | / ^CH z ^N v_+9

CH = CH I r~\

^R2 :

F-<0 ch^n, N10

A 0.2 0.2 <0.05 B 0.2 0.39 <0.05 C 0.2 0.2 <0.05 D <0.05 0.39 <0.05 E <0.05 0.1 <0.05 F <0.05 0.1 <0.05 G 3.13 6.25 0.2 H 0.2 0.2 <0.05 I 3.13 12.5 0.2 J 3.13 3.13 0.1

organism compound no.

^R2 :

^R2 :

^R2 :

R ³ :

R ³ :

R ³ :

A <0.05 0.2 0.2 B 0.1 0.2 0.2 G 0.1 0.1 0.2 D <0.05 <0.05 <0.05 E <0.05 <0.05 <0.05 F <0.05 <0.05 <0.05 G 0.2 0.78 1.56 H <0.05 0.1 0.1 I 0.2 1.56 1.56 J . 0.1 0.39 0.39

230593

2. Acute toxicity

The LD50 values determined by intravenous administration of test compounds Nos. 5 and 12 (see Table 1) to mice (male ICR strain, body weight 18 to 24 g) are 200 mg/kg or even lower.

The method according to the invention will be explained in more detail in the following text.

As stated above, compounds of general formula I and their salts are obtained by cyclization of a compound of general formula II or its salt, carried out in the presence of a base, preferably under heating.

The solvent used for this reaction can be any solvent that is inert under the reaction conditions. Examples of such solvents, which do not play a decisive role, include amides, such as

N,N-dimethylformamide, N,N-dimethylacetamide, etc., ethers such as dioxane, anisole, diethylene glycol dimethyl ether, etc., sulfoxides such as dimethyl sulfoxide, etc., etc. These solvents can be used alone or as mixtures of two or more of them. Suitable bases include, for example, sodium bicarbonate, potassium carbonate, potassium tert-butoxide, sodium hydride, etc. The base is preferably used in an amount of 0.5 to 5 mol per mol of the compound of the general formula II or its salt. The reaction is usually carried out at a temperature of 20°C to 160°C, preferably 100°C to 150°C, and generally lasts from 5 minutes to 30 hours, preferably 5 minutes to 1 hour.

The starting materials of general formula II can be produced, for example, by the following reaction scheme:

.COOR^ ³ ^

X*

(IV)

or its salt in which

R ^3a represents a halogen atom and

R ^1a , R ² and R ³ have the meanings given above.

The salts of the compounds of general formulas III, IV and V are the same salts as in the case of the compounds of general formulas I and II.

(i) The compound of the general formula II or its salt, or the compound of the general formula V or its salt is obtained by reacting the compound of the general formula IV or the compound of the general formula III or its salt with an acetal such as N,N-diethylformamide dimethylacetal, N,N-dimethylformamide diethylacetal, etc., and then with an amine of the general formula

R ² —NH2 in which

R ² has the meaning given above.

Any solvent inert to the reaction can be used for the above reactions. Among these solvents, which do not play a decisive role, are aromatic hydrocarbons such as benzene, toluene, xylene, etc., ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol dimethyl ether, etc., halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane, etc., amines such as N,N-dimethylformamide, N,N-dimethylacetamide, etc., sulfoxides such as dimethyl sulfoxide, etc., and these solvents can be used alone or as mixtures of two or more of these solvents.

The acetal is used in an amount of preferably 1 mol or more, especially in an amount of about 1.0 to 1.3 mol, per mole of the compound of the general formula III or the compound of the general formula IV or its salt. These reactions are usually carried out at a temperature of from 0°C to 100 ^° C, preferably at a temperature of from 50°C to 80°C, and generally take from 20 minutes to 50 hours, preferably 1 to 3 hours. The amine is used in an amount of 1 mol or more per mole of the compound of the general formula III or the compound of the general formula IV or its salt. The reaction is usually carried out at a temperature of from 0°C to 100°C, preferably from 10 to 60°C, after

250696 for a period of time generally ranging from 20 minutes to 30 hours, preferably from 1 to 5 hours.

According to an alternative method, a compound of formula III or a compound of formula IV or a salt thereof can be reacted with ethyl orthoformate or methyl orthoformate in the presence of acetic anhydride, and then with an amine of formula R ² —NH 2 , or a salt thereof, to form a compound of formula V or a salt thereof, or a compound of formula II or a salt thereof.

(ii) A compound of general formula IV or a salt thereof or a compound of general formula II or a salt thereof is obtained by reacting a compound of general formula III or a compound of general formula V or a salt thereof, with a cyclic amine corresponding to the general formula

R ³ —H in which

R ³ has the above meaning, or a salt thereof.

Any solvent inert under the reaction conditions can be used for this reaction. These solvents do not play a decisive role and examples thereof include aromatic hydrocarbons such as benzene, toluene, xylene, etc., ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, etc., halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane, etc., amides such as N,N-dimethylformamide, N,N-dimethylacetamide, etc., sulfoxides such as dimethyl sulfoxide, etc., alcohols such as methanol, ethanol, etc., nitriles such as acetonitrile, etc., and these solvents can be used alone or in mixtures containing two or more of these solvents. The cyclic amine or its salt is preferably used in excess, most preferably in an amount of from 2 to 5 mol per mol of the compound of general formula II, or the compound of general formula V or its salt. When the cyclic amine is used in an amount of about 1 to 1.3 moles, it is sufficient to use 1 mole of the acid-binding agent for each mole of the compound of formula III or the compound of formula V or its salt. The acid-binding agents include organic and inorganic bases such as triethylamine, 1,8-diazahicyclo (5,4,0) undec-7-ene, potassium tert-butoxide, potassium carbonate, sodium carbonate, sodium hydride, and the like.

The salts of the cyclic amine of the general formula R ³ —H include the same salts as the salts on the basic group of the compounds of the general formula I or II.

The above-described reaction is usually carried out at a temperature of from 0°C to 150°C, preferably from 50 ^° C to 100°C, and usually lasts from 5 minutes to 30 hours, preferably from 30 minutes to 3 hours.

The compound of the general formula II, where R ^1a represents a protecting group of the carboxyl function, or its salt, can optionally be converted into the corresponding free carboxylic acid, namely by hydrolysis in the presence of an acid or base commonly used in hydrolysis. This hydrolysis is usually carried out at a temperature of from 0 ^C C to 100 ° C, preferably from 20 ° C to 100 ° C and lasts from 5 minutes to 50 hours, preferably from 5 minutes to 4 hours. Furthermore, the compound of the general formula I, II or V, or its salt, can optionally be converted into the corresponding salt or ester by a known salt-forming reaction or esterification. If the compound of the general formula II, IV or V, or its salt contains an active group (for example a hydroxyl group, an amino group, etc.) in positions other than where the reaction takes place, this active group can be protected in a conventional manner beforehand and then cleaved off after the reaction is completed.

The compounds thus obtained can be isolated and purified by conventional methods, such as column chromatography, recrystallization, extraction, etc.

For the use of the compounds according to the invention in medicine, these substances are expediently combined with carriers used in conventional pharmaceutical preparations and processed into tablets, capsules, powders, syrups, granules, suppositories, ointments, injectable preparations, etc., all in a manner known per se. The routes of administration, dosage levels and number of applications can be varied accordingly depending on the symptoms of the disease in the patient. The compounds described are usually administered orally or parenterally (for example, by injection, infusion or rectally) to adult patients in a daily dose of from 0.1 to 100 mg/kg, which total dose can be administered once or in several partial doses.

The invention is illustrated by the following reference examples, examples of embodiment and preparation, which, however, do not limit the scope of the invention in any way.

The individual symbols used in the examples have the following meanings:

Me = methyl group

Et = ethyl group n-Pr - n-propyl group i-Pr = isopropyl group

Ac = acetyl group = allyl group = ethylene group

The shapes of signals in NMR spectra are denoted by the following common abbreviations:

s = singlet d = doublet t = triplet q = quartet m = multiplet w = wide signal

Reference example 1

In 210 ml of chloroform, 21 g of 2,6-dichloro-5-fluoronicotinic acid and 23.8 grams of thionyl chloride are dissolved, and 0.1 g of N,N-dimethylformamide is added to the solution. The resulting mixture is allowed to react for 2 hours at a temperature of 70 °C, then the solvent and excess thionyl chloride are distilled off under reduced pressure, and the residue is dissolved in 21 ml of tetrahydrofuran. 25.1 g of diethyl ethoxymagnesium malonate is dissolved in 110 ml of tetrahydrofuran, the solution is cooled to -40 °C to -30 degrees C, and at this temperature, the previously prepared solution of 2,6-dichloro-5-fluoronicotinoyl chloride is added dropwise to it over 30 minutes. The mixture is stirred for 1 hour at the above temperature, after which its temperature is allowed to gradually rise to room temperature. The solvent was distilled off under reduced pressure and 200 ml of chloroform and 100 ml of water were added to the residue. The pH was adjusted to 1 with 6N hydrochloric acid, the organic layer was 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, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. 50 ml of water and 0.15 grams of p-toluenesulfonic acid were added to the oily residue and the resulting mixture was allowed to react for 2 hours under vigorous stirring at 100 °C. The reaction mixture was extracted with 100 ml of chloroform, the organic layer was washed with 50 ml of saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column. Elution of the column with toluene gave 23.5 g of ethyl-(2,6-dichloro-5-fluoronicotinoyl)acetate, melting point 64-65°C.

IR (KBr-technique):

Vc-.o 1 650, 1 630, 1 620 cm' ¹ .

NMR (deuterochloroform, values of 5 in ppm):

1.25 (1.29H, t, J = 7 Hz), 1.33 (1.71H, t, J = 7 Hz), 4.07 (1.14H, s), 4.28 (2H, q, J = 7 Hz), 5.82 (0.43H, s), 7.80 (1H, d, J = 7 Hz), 12.62 (0.43H, s).

Reference example 2

8.8 g of ethyl-(2,6-dichloro-5-fluoronicotinoyl)acetate is dissolved in 40 ml of benzene, 4.5 g of N,N-dimethylformamide-dimethylacetate is added to the solution and the resulting mixture is allowed to react for 1.5 hours at 70 °C. After adding 4.1 g of 2,4-difluoroaniline, the resulting mixture is allowed to react for 4 hours at room temperature, after which the solvent is distilled off under reduced pressure. The residue, after purification by chromatography on a silica gel column using chloroform as eluent, gives 9.0 g of ethyl-2-(2,6-dichloro-5-fluoronicotinoyl)-3-(2,4-difluorophenylaminoacrylate with a melting point of 138-139 °C.

ID (KBr-technique): v _c „o 1 690 cm' ¹ .

NMR (deuterochloroform, α values):

1.08 (3H, t, J = 7 Hz), 4.10 (2H, q, J = = 7 Hz), 6.77—7.40 (4H, m), 8.50 (1H, d, J = 13 Hz), 12.70 (1H, d, J = 13 Hz).

In a similar manner, the compounds listed in the following Table 2 are prepared:

Table 2 compound

R2 here

physical properties melting point (°C) IR (KBr) cm ^-1 in _c=o

87—89 1,690

110—114 1,710, 1,680

92—93 1,710, 1,680

135—137 1720 (shoulder), 1690

78—80 1690 oil 1 705.1680(arm)*)

154—155 1720 (shoulder), 1685

100-101 1,700 (shoulder), 1685

123—125 1,710, 1,680 physical properties

IR (KBr) cm- ¹ vc-o compound

^R2 melting point (°C)

145-146

1705,1680

147—149

1685

Me,

oil

1695*)

119—121

1700 oil

1700*)

183—186

138—138

114—116

92—95

1685,1670

1705,1680

1680

1705

137.5—139

1725 (shoulder), 1680

^R2 melting point (°C)

IC (KBr) cm ^-1 in _c -o

280698 compound physical properties

0M&

125—126

1700 (shoulder), 1660

Nz.

91—92

705, 1,690

OMC,

Legend:

*) IR spectrum was not measured by KBr technique, but in substance

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 was reacted at a temperature of 6 to 65°C for 2 hours. The reaction mixture was washed with 30 ml of water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography using chloroform as the eluent. 5.4 g of oily ethyl [2-chloro-5-fluoro-6-(4-methyl-1-piperazinyl) nicotinoyl] acetate was obtained.

IC (in substance): at _c = 1,750, 1,695 cm” ¹ .

NMR (deuterochloroform, ó' values):

1.25 (3H, t, J = 7 Hz), 2.32 (3H, s), 2.12 to 2.70 (4H, m), 3.55—3.96 (4H, m), 4.03 (2H, s), 4.20 (2H, q, J = 7 Hz), 7.78 (1H, d, J = 13 Hz).

In a similar manner, the compound shown in the following Table 3 is obtained:

Table 3

compound

R3 physical properties melting point (°C) IR (KBr) cm ^-1 vc 0 ^*

67—71

1730 (2) 4.5 g of ethyl [2-chloro-5-fluoro-6-(4-methyl-1-piperazinyl)nicotinoyl]acetate was dissolved in 22.5 ml of benzene, 1.87 g of N,N-dimethylformamide dimethylacetal was added to the solution, and the mixture was allowed to react at 70 °C for 2 hours. 1.8 g of 4-methoxy-2-methylaniline was added to the reaction mixture, and the mixture was allowed to react at room temperature for 4 hours, after which the solvent was distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column using a mixture of chloroform and ethanol (110:1 by volume) as the eluent. The crystalline substance obtained gives, after washing 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 with a melting point of 141-142°C.

IC (KBr-technique):

1)0*0 1710 (shoulder), 1 695 cnr ¹ .

NMR (deuterochloroform, í values):

1.08 (3H, t, J = 7 Hz), 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 = = 7 Hz), 6.65-7.25 (3H, m), 7.20 (1H, d, J = 13 Hz), 8.48 (1H, d, J = 13 Hz), 12.82 (1H, d, J = 13 Hz).

In a similar manner, the compounds listed in the following Table 4 are obtained:

Table 4

compound

R2 R ³ physical properties melting point (°C) IC*) cm ^-1 : v _c -o

oil * ² ) 1720 (arms) 1715 oil *2) 1735,1700 oil *2) 1895 /— _x

Ma.N N~ \_/

161—164 *1) 1685,1670

NHAO

0M&

oil *2) 1720 (shoulder), 1715

132—136 *1) 1705 (shoulder), 1685 compound

R ² R ³ physical properties melting point (°C) IR* )cm^ ¹ :v _c ~o

oil *2) i 720 (arm), 1,700

Legend:

^#1 ) KBr-technique * ² jv substance

Example 1 (1) 2.0 g of ethyl 2,6-dichloro-5-fluoronicotinoyl acetate, 0.96 g of 3-acetylaminopyrrolidine and 0.8 g of triethylamine were dissolved in 20 ml of chloroform, and the resulting solution was allowed to react at a temperature of 60 to 65 °C for 2 hours. The reaction mixture was washed with 30 ml of water, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography. The column was eluted with a mixture of equal volumes of benzene and ethyl acetate to obtain 1.8 g of oily ethyl [2-chloro-5-fluoro-6-(3-acetamino-1-pyrrolidinyl) nicotinoyl] acetate.

IR (in substance): vc-o 1,740, 1,650 cm ^-1 .

NMR (deuterochloroform, <S values):

1.28 (3H, t, J = 7 Hz), 1.97 (3H, s), 1.90 to 2.62 (2H, m], 4.02 (2H, s), 4.15 (2H, q, J = 7 Hz]), 3.50-4.70 (5H, mj, 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)nicotinoyl acetate is dissolved in 10 ml of benzene, 0.235 g of N,N-dimethylformamide dimethylacetal is added to the solution and the resulting mixture is allowed to react for 2 hours at 70 °C. After adding 0.243 g of 2,4-difluoroaniline, the reaction mixture is allowed to react for 8 hours at room temperature, then the solvent is distilled off under reduced pressure and the residue is purified by chromatography on a silica gel column, using a mixture of equal volumes of benzene and ethyl acetate as eluent. The oily product thus obtained, after trituration with diisopropyl ether, gives 0.25 g of ethyl 2-[2-chloro-5-fluoro-6-(3-acetylamino-1-pyrrolidinyl)nicotinoyl]-3-(2-,4-difluorophenylamino)acrylate with a melting point of 82 up to 85°C.

IR (KBr-technique):

vc-o 1,695 (shoulder), 1,660 cm cm ¹ .

NMR (deuterochloroform, values 5):

1.25 (3H, t, J = 7 Hz), 2.07 (3H, s), 1.90 to 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 dissolved in 3 ml of N,N-dimethylformamide, 0.04 g of sodium bicarbonate was added to the solution, and the resulting mixture was allowed to react at 120 °C for 1 hour. The solvent was distilled off under reduced pressure, the residue was dissolved in 10 ml of chloroform, the 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 distilled off under reduced pressure, and the crystalline residue was washed with 5 ml of diethyl ether. 0.13 g of ethyl 7-(3-acetylamino-1-pyrrolidinyl) nicotinoyl]-3-(2,4-difluorophenylamino) acrylate was obtained. (2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate with a melting point of 233-235°C.

In an analogous manner, the compounds listed in the following Table 5 are obtained:

compound

R2

physical properties

R ³ melting point (*C) IC (KBr) cm“ ¹ : » _c -o

Λ cN

Mfl.

M <2,

HN _Z ^N ' /

Me ^H V/~

M<£

HO' /—\ 'V' /—\ ^Xc \__/ °\^ ^Ν ~

216—218 1730,1690 (shoulder)

135—150 1730, 1890

217—218 1,730, 1,695

144—146 1,730, 1,690

143 1730

198—202 1725,1890

220—222 1,730, 1,695

253-255 1730,1690

203-205 1730, 1700 physical properties melting point (°C) IR (KBr) cm ^-1 : i>co compound

R ²

R ³

. /~~\

A c.N N— \_/

Γ~\

M a. N. '-\

A cN NM&Ò N\_t

Yes.

MN NΜα

MeN NΜα γΛ.

Yes

EtCFCN. W211—213 1735

206 1,725, 1,690

193—194 1730, 1,700

244—246 1725, 1,690

186-187 1725, 1690 (ramemoi)

155—157 1,720, 1,685

153-154 1,730, 1,700

153—155 1,730, 1,695

166—168 1730 (shoulder), 1690

202-204 1,730, 1,690 physical properties melting point (°C) IC (KBr) cm“ ¹ : v _c -o compound

R2 R3

u. u.

Ma. A N~

230—231 1725 (ramenfo), 1695

193—194 1,720 (counted),

1680,1675

207 1,725.1693

254 1730,1690

208 1,730, 1,690

246—247 1,730, 1,690

167-189 1,730.1,695

208—207.5 1730, 1,690

OM<z.

163-165 1735, 1700

174—176 1730, 1,690

OM<z.

compound physical properties

OM&

n-PrN N\_'

171—172.5

1730, 1,685

OM<z,

Γ~ \

208.5—210

730, 1,690

OM<z.

200—202 1,730, 1,690

OM<z.

OMv„

N~ /~\

162—163 1,725, 1,690 you

About Mg.

CN

NHAc,

with~~\

A ^CN \~/ ^N ~ ^AcN \_7 ^N ~

197—199 1,735, 1,690

136—138 1725, 1,685

270—272 1,730, 1,690

245—249 1,730, 1,695

249-252 1,730, 1,695 physical properties melting point (°C) IR (KBr) cm ^-1 : v _c -o compound

R ² R ³

263—264 1730

166—169 1,730, 1,685

222.5—223.5

165—168

215—219

170—171

169—172

231—233

730, 1,690

730, 1,685

1730, 1695

1725.1 690

1725, 1690

1730, 1700

156 1,730, 1,690

203—205 1 725, 1690 physical properties melting point (°C) IC (KBr) cm ^-1 :*v _c -o compound

R ² R ³

F

201—202 1,725, 1,695

165 1,730, 1,690

196—197 1,730, 1,695

241—244 1,725, 1,700

153—155 1735

185—187 1,730, 1,690

207—209 1,730, 1,695

Example 2

In 50 ml of N,N-dimethylformamide, 5.0 g of ethyl 2-[2-chloro-5-fluoro-6-(4-methyl-1-piperazinyl) nicotinoyl] -3-(4-methoxy-2-methylphenylamino)acrylate is dissolved, 1.03 g of sodium bicarbonate is added to the solution, and the mixture is allowed to react at 120 °C for 3 hours. The solvent is distilled off under reduced pressure, and the residue is dissolved in 50 ml of chloroform. The solution is washed successively with 30 ml of water and 30 ml of saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The crystalline residue, after washing with 30 ml of diethyl ether, 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, melting point 144-145°C.

^5?··

IC (KBr-technique): i>c=o 1730, 1690 cmi.

NMR (deuterochloroform, ó' 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 (1H, s).

In an analogous manner, the compounds listed in the following Table 6 are obtained:

Table 6

COO compound

R ² R ³ physical properties melting point (°C) IR (KBr) cm ^-1 : v _c =.o

199—202

168—171

725, 1,685

735, 1,720

Z/slN

174—175

730, 1,695

Μβ-ΑΛ /vV _/ amorphous substance

725, 1,690 /~~y

Hά, N. n186—189

725, 1,690

OM&

physical properties melting point (°C) IR (KBr) cm ^-1 : v _c -o compound

R ² R ³

Oh1 cw

166—168 1,730, 1,695

X ,

I T /“'Λ

Ac.N NY \~/ f Ma

Example 3

In 25 ml of 6N hydrochloric acid, 2.5 g of ethyl 7-(4-acetyl-1-piperazinyl)-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate were dissolved and the resulting solution was heated to reflux for 2 hours. The reaction mixture was cooled to room temperature and its pH was first adjusted to 12 with 1N aqueous sodium hydroxide and then to 6.5 with acetic acid. The precipitated crystals were

169-172 1,725, 1,690 are filtered off, washed with 30 ml of water and 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 (deuterated trifluoroacetic acid, values 8):

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

In an analogous manner, the compounds listed in the following Table 7 are obtained:

Table 7

COOH compound physical properties

>280 *) 1720 (arm)

F

S~\ ^HN ^·

279—280

1725 (shoulder) compound

R ² R ³ physical properties melting point (°C) IC (KBr) cm ^-1 : v _c -o

234—236 1720

222—224 1725 >280 1720

254—258 1725

205—207 1,730

225—227 1,725 >280 1,725

273—277 1720

245—246 1725 >280 1725 >280 1730,1710 compound physical properties

R2 rs melting point (°C) IR (KBr) cm ^-1 : v _c -o

250658

Ma.N

232—236 1725, 1,710, 1,690

_CFd >280

1725

Mg, hn^n230—232

1730

Legend: *) IR spectrum is not measured with KBr technique, but in Nujol

Example 4

In 2.5 ml of 6N hydrochloric acid, 0.25 g of ethyl 7-(3-acetylamino-1-pyrrolidinyl)-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate is dissolved, the solution is heated to reflux for 2 hours, then the reaction mixture is cooled to room temperature and its pH is first adjusted to 12 with 1N aqueous sodium hydroxide solution and then to 6.5 with acetic acid. The precipitated crystals are filtered off, washed with 2 ml of water and dried.

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 is obtained.

NMR (deuterated trifluoroacetic acid, ó values):

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

and

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

230698

compound physical properties

F

259—261 1720 (shoulder)

275—278 1,720 (shoulder)

278—280 1720

Example 5

In 5 ml of 47% hydrobromic acid, 2.0 g of ethyl 6-fluoro-1,4-dihydro-1-(4-methoxy-2-methylphenyl)-7-(4-methyl-1-piperazinyl)-4-oxo-1,8-naphthyridine-3-carboxylate are dissolved and the solution is allowed to react for 2 hours at a temperature of 120 to 125 °C. The pH of the reaction mixture is first adjusted to 13 with 10% aqueous sodium hydroxide solution and then to 6.5 with acetic acid. The precipitated crystals are filtered off 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)-4-oxo-1,8-naphthyridine-3-carboxylic acid melting above 200 °C is obtained.

IR (KBr technique): λ 1725, 1700 (shoulder) cm ^-1 .

NMR (deuterated trifluoroacetic acid, values <$):

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 = 13 Hz).

In a similar manner, the compound shown in the following Table 9 is prepared:

Table 9

COOH compound

R ² , R ³ physical properties melting point (°C) IR (KBr) cm ^-1 : v _c -o

143—146

1725, 1710 >280

1710 >280 >280 >280

1710

1730

1725 >280 1715

200—205 1,720, 1,705 >280 1,725

5 O 6 9 Π compound

R ² R ³ physical properties melting point (°C) IR (KBr) crrr ¹ : v _{c 0}

245-250 (decomposition) >280

1725, 1700 (shoulder)

725, 1,690

220—224 1,725, 1,710 >280 1,730, 1,710 (shoulder) >280 1,730 >255 1,725

r~\

Me N N ~ \___t

M<z. N N \—J

251—252 1,720 >280 1,725 (ramenloi), 1,700

228-230 1,730.1,700 (shoulder)

ΛΛ «V

275

1720

OH

5 O 6 9 8

Example 6

In 10 ml of 47% hydrobromic acid, 0.40 g of ethyl 6-fluoro-1,4-dihydro-1-(4-methoxyphenyl)-7-(1-pyrrolidinyl)-4-oxo-1,8-naphthyridine-3-carboxylate is dissolved and the resulting solution is allowed to react for 2 hours at a temperature of 120 to 125 °C. The pH of the reaction mixture is first adjusted to 13 with 10% aqueous sodium hydroxide solution and then to 6.5 with acetic acid. The precipitated crystals are filtered off and washed with 4 ml of water. 0.30 g of 6-fluoro-1,4-dihydro-1-(4-hydroxyphenyl)-7-(1-pyrrolidinyl)-4-oxo-1,8-naphthyridine-3-carboxylic acid with a melting point of 263 to 265 degrees C is obtained.

ID (KBr-technique): v _c =o 1725, 1705 cm" ¹ .

NMR (deuterated trifluoroacetic acid, S values):

1.54-2.40 (4H, m), 3.14-4.14 (4H, m),

6.95—7.69 (4H, m), 8.09 (1H, d, J = 12

Hz), 9.14 (1H, s).

In a similar manner, 6-fluoro-1,4-dihydro-1-(4-hydroxyphenyl)-7-(3-hydroxy-1-pyrrolidinyl)-4-oxo-1,8-naphthyridine-3-carboxylic acid is also obtained.

Melting point 180 to 183 °C.

ID (KBr-technique): vc-o 1,725, 1,705 cm" ¹ .

Example 7

To 0.1 g of ethyl 7-(4-acetyl-1-piperazinyl)-6-fluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate, 2 ml of 1N aqueous sodium hydroxide solution and 2 ml of ethanol are added and the resulting solution is allowed to react for 10 minutes at a temperature of 40 to 50 °C. The pH of the reaction mixture is adjusted to 6.5 with acetic acid and the mixture is extracted twice with 5 ml of chloroform each time. The combined extracts are washed successively with 5 ml of water and 5 ml of saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The crystalline substance thus formed provides, after washing 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 acids melting above 280°C.

ID (KBr-technique): v _c " ₀ 1 730 cm" ¹ .

NMR (perdeuterodimethylsulfoxide, δ values):

2.05 (3H, s), 3.57 (8H, ss), 7.13—7.80 (4H, m), 8.13 (1H, d, J = 13 Hz), 8.70 (1H, s).

In a similar manner, the compounds listed in the following Table 10 are obtained:

250698 Table 10 compound

R ² R ³

physical properties melting point (°CJ IC (KBr) cm ¹ : v _c -o

277—280 1720

282—290 1,725, 1,700 (shoulder)

268—270 1725

283—285 1720

267—270 1,730

138—139 1690 >280 1730, 1700 (shoulders) >280 1720 apprenticeship

R ³ physical properties melting point (°C) IR (KBr) cm ^-1 : v _c -o

208—209 1730 >280 1720

210—211 1735

225—226 1720

219—220 1730

283—284 1730, 1700 (rameino)

277—280 1730, 1700 (shoulder)

271—274 1725

OJ

QM<%.

M<z N. N ~ \—J

250—252 1725

Example 8

To 0.10 g of ethyl 6-fluoro-1-(4-fluorophenyl)-1,4-dihydro-7-(3-hydroxy-1-pyrroldinyl)-4-oxo-1,8-naphthyridine-3-carboxylate, 2 ml of 1N aqueous sodium hydroxide solution and 2 ml of ethanol are added, and the resulting mixture is allowed to react for 10 minutes at a temperature of 40 to 50 °C. The pH of the reaction mixture is adjusted to 6.5 with acetic acid, and the mixture is extracted twice with 5 ml of chloroform each time. The combined extracts are washed successively with 5 ml of water and 5 ml of saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The crystalline residue, after washing with 2 ml of diethyl ether, gives 0.08 g of 6-fluoro-1-(4-fluorophenyl)-1,4-dihydro-7-(3-hydroxy-1-pyrrolidinyl)-4-oxo-1,8-naphthyridine-3-carboxylic acid, melting above 280°C.

IR (KBr-technique): v _{c = 0} 1 730 cm ⁴ .

NMR (perdeuterodimethylsulfoxide, aj values:

1.92—2.52 (2H, ni), 3.22—5.00 (5H, mj, 6.97—7.60 (4H, m), 8.01 (1H, d, J = 11 Hzj, 9.00 (1H, sj.

By an analogous procedure, the compounds listed in the following Table 11 are obtained:

Table 11

compound

R ² R ³ physical properties melting point (°C) IR (KBr) cm ⁴ : v _c -o

F

264—265 1725

227 1725

Example 9

In 2.5 ml of concentrated hydrochloric acid, 0.25 g of 6-fluoro-1,4-dihydro-1-(4-hydroxy-2-methylphenyl)-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-3-carboxylic acid is dissolved, 20 ml of ethanol is added to the solution and the mixture is stirred for 15 minutes at room temperature. The precipitated crystals are filtered off and washed with 5 ml of ethanol. 0.2 g of 6-fluoro-1,4-dihydro-1-(4-hydroxy-2-methylphenyl)-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-3-carboxylic acid hydrochloride is obtained, melting above 280 °C.

IR (KBr-technique): p _c=0 1725 (arm), 1705 cm ⁴ .

In an analogous manner, the compounds listed in the following Table 12 are obtained:

250698 Table 12

Hydrochlorides of compounds corresponding to the general formula

compound

R ² R ³ physical properties melting point (°C) IR (KBr) cm' ¹ : v _c -o

283 1,730

275—278 1,720

249—252 1730 (decomposition) >280 1710

280—282 1730

OH

Xκ i Oj T

OH

IN-/

279—283 1720 (shoulder), 1705

T

OH r~\

MizN. N~

266—269 1720 (shoulder), 1700 ^m * ⁿ CZ/ ⁿ ~

282 1730

OH

Example 10

In 20 ml of concentrated hydrochloric acid, 2.0 g of 7-(3-amino-1-pyrrolidinyl)-1,8-naphthyridine-3-carboxylic acid is dissolved, 200 ml of ethanol is added to the solution at room temperature, and the reaction solution is stirred for 15 minutes. The precipitated crystals are filtered off and washed with 40 ml of ethanol. 1.4 g of 7-(3-amino-1-pyrrolidinyl)-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride is obtained, melting at 247-250 °C with decomposition.

IR (KBr-technique): vc~o 1 ⁷ 3θ cnr ^] .

Example 11 (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 dissolved in 2.5 ml of chloroform, and the resulting solution was heated to reflux for 3.5 hours. The reaction mixture was washed successively with 3 ml of water and 3 ml of saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography using a mixture of chloroform and ethanol (50:1 by volume) as the eluent. 0.294 g of oily ethyl 2-[2-chloro-5-fluoro-6-(4-methyl-1-piperazinyl)-nicotinoyl]-3-(2,4-difluorophenylamino)acrylate is obtained.

IR (in substance): i> _c=0 1735, 1700 cm ¹ .

NMR (deuterochloroform, ó 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, ] = Hz), 6.77—7.90 (4H, m),

8.51 (1H, d, J = 13 Hz), 12.50 (1H, d,

J = 13 Hz).

(2) When 0.2 g of ethyl 2-[2-chloro-5-fluoro-6-(4-methyl-1-piperazinyl)nicotinoyl]-3-(2,4-difluorophenylamino)acrylate was reacted in the same manner as in Examples 2 and 7, 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 with a melting point of 208 to 209°C was obtained.

Example 12

To 0.3 g of ethyl 7-(4-ethyloxycarbonyl-2-methyl-1-piperazinyl)-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate, 5 ml of 1N aqueous sodium hydroxide solution and 5 ml of ethanol were added, and the resulting mixture was allowed to react for 2 hours at 90 °C. The pH of the reaction mixture was adjusted to 6.5 by adding acetic acid, the precipitated crystals were filtered off and dried after washing with water. 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 was obtained, melting point 230-239 °C.

ID (KBr-technique j: vc=o 1,730 cm" ¹ .

NMR (deuterated trifluoroacetic acid, 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 (1H, s).

Example 13

10.0 g of 7-(3-amino-1-pyrrolidinyl)-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid are suspended in 75 ml of ethanol and 75 ml of water, 5.2 g of p-toluenesulfonic acid monohydrate are added to the resulting suspension at a temperature of 40 °C and the mixture is stirred at the same temperature for 30 minutes. The reaction mixture is cooled to 15 °C, the precipitated crystals are filtered off and washed with a mixture of 5 ml of ethanol and 5 ml of water. 12.8 g of the 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 p-toluenoic acid monohydrate are obtained, with a melting point of 258-260 °C.

IR (KBr-technique): v _c =o 1,735 cm" ¹ .

NMR (perdeuterodimethylsulfoxide, η values):

1.82—2.42 (m)

2.27 (s) (5H),

3.12—4.30 (5H, m), 6.92—8.17 (8H, m),

8.79 (1H, s).

In a similar manner, the 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 oxalic acid is obtained, with a melting point of 250 to 253 °C (KBr technique): λ 1,730 cm ¹

Example 14

To a solution of 1.6 g of nonethanesulfonic acid in 25 ml of acetic acid is 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, the resulting suspension is stirred at room temperature until a solution is formed, and to this solution is added 100 ml of ethanol over 30 minutes at a temperature of 40 to 45 ° C. The reaction mixture is cooled to room temperature, stirred for 30 minutes, the precipitated crystals are filtered off and washed three times with 20 ml of ethanol each time. 3.12 g of the 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, melting above 300°C, are obtained.

IR (KBr-technique): vc=o 1,735 cm ¹ .

In an analogous manner, the 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 is obtained, with a melting point of 220 to 230 °C.

ID (KBr-technique): v _c „o 1 735 cm ¹ .

Example 15

In 50 ml of N,N-dimethylformamide, 9.0 g of ethyl-2-(2,6-dichloro-5-fluoronico· thiioyl)-3-(2,4-difluorophenylamino) acrylate are dissolved, 3.6 g of sodium bicarbonate are added to the solution and the mixture is allowed to react for 20 minutes at a temperature of 120 C. The solvent is distilled off under reduced pressure, the residue is dissolved in 50 ml of chloroform, the 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 distilled off under reduced pressure and the crystalline residue is washed with 30 ml of diethyl ether. 7.0 g of ethyl 7-chloro-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate with a melting point of 220-222°C are obtained.

ID (KBr-technique): vc-o 1730, 1690 cm ¹ .

NMR (deuterochloroform, ó' 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).

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

Table 13

COOrt

Rí compound

R ² physical properties melting point (°C) IR (KBr) cm ¹ vc-o i

222—224

231—232

239—241

730, 1,685

730, 1,705

1685 ř

(Ol

205—208

735, 1685

IQ

244—246

720, 1,680 physical properties melting point (°C) IR (KBr) cm ^-1 p _c =o compound

R ²

F

207—209.5

210—214

207—208

730, 1,690

1735 (shoulder), 1705

730, 1,680

Cl

181—186

730, 1,685

204—205

730, 1,685

216—218

735, 1,695

Has,

NHAO

196—198

156—160

231—236

270—273

1735, 1,685

730, 1,690

730, 1,685

730, 1,690

199—201

1730, 1,680 ^CF 3 sec?

physical properties melting point (°C) IR (KBr) cm ^-1 in _c -o compound

R ²

Oh my,

199-202

208—211

142-144

1735, 1685

730, 1695

1740, 1,695

Oh my.

163—165

1730, 1,695

M<z.

M#,

160—162

1735, 1,690

OM&

Preparation 1 g of 6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthridine-3-carboxylic acid is mixed with 49 g of crystalline cellulose, 50 g of corn starch and 1 g of magnesium stearate, and 1,000 flat tablets are pressed from the mixture. Preparation 2

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

Preparation 3 g of 7-(3-amino-1-pyrrolidinyl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid are mixed with g of crystalline cellulose, 50 g of corn starch and 1 g of magnesium stearate, and 1,000 flat tablets are pressed from the mixture. Preparation 4

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 are mixed with g of corn starch and 1000 capsules are filled with the resulting mixture.

Claims (23)

A process for the preparation of 1,4-dihydro-4-oxonaphthyridine derivatives of the general formula I in which R ¹ represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, R ² represents a phenyl group optionally substituted by one, two or three substituents selected from halogen atoms, alkyl groups having 1 to 10 carbon atoms, alkoxy having 1 to 10 carbon atoms, hydroxy, amino, cyano, acylamino having from 1 to 4 carbon atoms and C 1 -C 4 trihaloalkyl groups; and R ³ represents halogen or 1-pyrrolidinyl, piperidine, 1-piperazinyl or morpholine, which may be substituted by one or two substituents selected from the group consisting of hydroxyl, amino, (C 1 -C 4) alkyl, (C 1 -C 4) alkylamino C 1 -C 4 dialkylamino, C 1 -C 4 hydroxyalkyl, C 2 -C 4 alkenyl, C 1 -C 4 acylamino, C 1 -C 4 acyl groups, N-acyl-N-alkylamino groups containing from 1 to 4 carbon atoms in each of the acyl and alkyl moieties and alkoxycarbonyl groups having from 1 to 4 carbon atoms in the alkoxy moiety, and salts thereof, characterized in that the compound of the formula II R ^1a represents a carboxyl function protecting group α R ² and R ³ are as defined above, or a salt thereof, is subjected to cyclization reaction, and SUMMARY OF THE INVENTION The carboxyl function protecting group is optionally cleaved from the resulting product. 2. Method according to claim 1, characterized in that the application of the corresponding starting materials, to give compounds of formula I wherein R ² is phenyl substituted with one, two or three halogen atoms, and the other symbols are as defined in point 1. 3. Method according to claim 2, characterized in that the application of the corresponding starting materials, to give compounds of formula I in which R ² represents a 4-fluorophenyl group and the remaining symbols are defined as in point 1. 4. Method according to claim 2, characterized in that the application of the corresponding starting materials, to give compounds of formula I in which R ² represents a 2,4-difluorophenyl group and the other symbols are as defined in throwing the first 5. Method according to claim 1, characterized in that the application of the corresponding starting materials, to give compounds of formula I wherein R ³ is L-pyrroli.dinylovou group optionally having a substituent selected from the group consisting of amino, hydroxyl, alkylamino (C až-C 4) carbons, (C až-C ac) acylamino, (C až-C-) N-acyl-N-alkylamino groups and (C až-C dial) dialkylamino groups in each alkyl moiety, and the remainder the general symbols have the meaning given in point 1. 6. A process according to claim 5, wherein the corresponding starting materials are used to form compounds of formula (I) wherein R @ ³ is 1-pyrrolinedino substituted by amino or acylamino as defined above, and the remaining moieties are as in 1. . 7. A method according to claim 6, characterized in that using the corresponding starting materials, to give compounds of formula I wherein R ² is phenyl substituted with one, two or three halogen atoms, R ³ is as defined in claim 6 and R ¹ is as in point 1. 8. A method according to claim 7, characterized in that the application of the corresponding starting materials, to give compounds of formula I in which R ² represents 4-fluorophenyl, R ³ is as defined in claim 6 and R ¹ is as defined in 1. 9. A method according to claim 7, characterized in that the application of the corresponding starting materials, to give compounds of formula I in which R ² represents 2,4-difluorophenyl, R ³ is as defined in claim 6 and R ¹ has the meaning as in point 1. 10. The method according to claim 1, characterized by using the corresponding starting materials, to give compounds of formula I wherein R ³ is 3-amino-l-pyrrolidinyl group and the remaining symbols are defined as in point 1. 11. The method according to claim 10 characterized in that the application of the corresponding starting materials, to give compounds of formula I in which R ² represents a phenyl group substituted by one, two or three halogen atoms, R ³ is 3-amino-l- and R &lt; ¹ & gt ^; is as defined in 1. 12. The method of claim 11, characterized in that using the corresponding starting materials, to give compounds of formula I in which R ² is 4-fluorophenyl, and R ³ and R ¹ are as defined in the bo: du 11th 13. The method of claim 11, wherein the using the corresponding starting materials, to give compounds of formula I wherein R ² is 2,4-difluorophenyl] uorfenylovou group and R ³ and R ¹ are as defined in paragraph 11 . 14. The method according to claim 1, characterized by using the corresponding starting materials, to give compounds of formula I wherein R ³ represents a 1-piperazinyl group optionally substituted by one or two substituents selected from the group consisting of alkyl groups having 1 to C 4 -C 4 hydroxy, C 1 -C 4 hydroxyalkyl, C 2 -C 4 alkenyl, C 1 -C 4 acyl and C 1 -C 4 alkoxycarbonyl, and the remaining general symbols are defined as in point 1. 15. A process according to claim 14, wherein the corresponding starting materials are used to give compounds of formula (I) wherein R @ ³ is 1-piperazinyl and the remaining moieties are as in point 14. 16. The method of claim 15, wherein the using the corresponding starting materials, to give compounds of formula I in which R ² represents a phenyl group substituted by one or two halogen .atomy and the other symbols have the meanings as stated in the fifteenth 17. The method of claim 16, wherein the using the corresponding starting materials, to give compounds of formula I in which R ² represents a 4-fluorophenyl group and the other symbols have the meanings as stated in the 16th 18. The method according to claim 16, characterized in that using the corresponding starting materials, to give compounds of formula I wherein R ² is 2,4-difluorophenyl group and the other symbols have the meanings as stated in the 16th 19. The process of claim 1, wherein the corresponding starting materials are used to form 7-chloro-1- (2,4-difluorophenyl) -6-fluoro-1,4-dihydro-4-oxo. 1,8-naphthyridine-3-carboxylic acid or a salt thereof. 20. The process of claim 1, wherein the corresponding starting materials are used to provide 7- (3-amino-1-pyrrolidinyl) -1- (2,4-difluorophenyl) -6-fluoro-1. 4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid or a salt thereof. 21. The process of claim 1, wherein the corresponding starting materials are used to give 1- (2,4-difluorophenyl) -6-fluoro-1,4-dihydro-4-oxo-7- ( 1-piperazinyl) -1,8-naphthyridine-3-carboxylic acid or a salt thereof. 22. The process of claim 1, wherein the corresponding starting materials are used to provide 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. 23. The process of claim 1 wherein the reaction is carried out at a temperature of from about 20 ° C to about 160 ° C.