NL8501172A - 4-OXO-1,4-DIHYDRONAFTYRIDINE DERIVATIVES AND THEIR SALTS, METHOD FOR THE PREPARATION THEREOF, AND ANTI-BACTERIAL PREPARATIONS CONTAINING THEM. - Google Patents

Description

4-oxo-1,4-dihydronaphthyridine derivatives and salts thereof, process for their preparation, and antibacterial preparations containing them.

This invention relates to new 4-oxo-1,4-dihydronaphthyridine derivatives with unsubstituted or substituted aryl group in the 1 position and a halogen atom or a substituted or unsubstituted cyclic amino-5 group in the 7 position, as well as their salts, a method of preparing them, and antibacterial preparations containing them.

Nalidix acid, pyramidic acid, pipemidic acid and the like have hitherto been widely used as synthetic antibacterial agents. But none of these substances have sufficient therapeutic effect against Ps infections. aeruginosa and gram-positive bacteria, which cause persistent diseases. Therefore, various compounds of the pyridone carboxylic acid type have been developed, eg, 1-ethyl-6-fluoro-4-oxo-7-piperazino-1,4-dihydroquinoline-3-carboxylic acid (norfloxacin), etc. as a replacement for the previously known synthetic antibacterial agents. These compounds have excellent anti-bacterial effects against various gram negative bacteria, including Ps. aeruginosa, but they are insufficiently effective against gram-positive bacteria. Therefore, a broad spectrum synthetic antibacterial agent was desirable, which acts not only against gram negative but also gram positive bacteria.

Now, after extensive research, these inventors have found that certain new 4-oxo-1,4-dihydronaphthyridine derivatives and their salts can meet these needs. The invention therefore provides new 4-oxo-1,4-dihydronaphthyridine derivatives and salts thereof, with excellent properties, for example, strong anti-bacterial activity against gram-posi -tive and gram-negative bacteria, in particular against bacteria which have become resistant to antibiotics and which give high blood levels after oral and parenteral administration and are also very safe.

Furthermore, this invention also provides a method of preparing these new 4-oxo-1,4-dihydronaphthyridine derivatives and their salts, as well as antibacterial preparations containing the said new compounds as active substances.

The invention provides 4-oxo-1,4-di-hydronaphthyridine derivatives of the general formula 1, wherein R 1 represents a hydrogen atom or a carboxyl protecting group, R 1 represents an unsubstituted or substituted aryl-15 group and a halogen atom or represents an unsubstituted or substituted cyclic amino group and its salts.

Carboxyl protecting groups include ester-forming groups which can be removed by catalytic reduction, chemical reduction or other treatments under mild conditions, ester-forming groups that are easily removable in the living body, organic silicon-containing groups organic phosphorus-containing groups and organic tin-containing groups that are easily removed by treatment with water or an alcohol, and various other well-known ester-forming groups. This includes, for example, the carboxyl protecting groups described in Japanese Patent Application Laid-Open No. 80,665 / 84. The aryl group R ^ can be, for example, phenyl, naphthyl and the like. The aryl group may be unsubstituted or substituted by halogen atoms, for example, fluorine, chlorine, bromine, iodine, etc., alkyl groups, for example, straight or branched C 1 -C 6 q alkyl-35 groups such as methyl, ethyl, n-propyl , isopropyl, n-butyl, isobutyl, sec.-butyl, tert-butyl, pentyl, hexyl, heptyl, ss. 1 1 7? . 1,3-octyl-ed, hydroxy groups, alkoxy groups, for example straight or branched C 1 -C 6 alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert -butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, ed, cyano and amino groups, acylamino groups, for example C 1 -C 6 -acylamino groups such as for-mylamino, acetylamino, propionylamino, butyrylamino, ed and trihaloalkyl- groups, for example with 1-4 carbon atoms such as trifluoromethyl, trichloromethyl etc.

The halogen atom which can be R 1 is, for example, fluorine, chlorine or bromine. The cyclic amino group which can be R ^ has at least one nitrogen atom and can additionally have one or more oxygen atoms in the ring, and it can be a five-ring or six-ring such as pyrrolidino, piperidino, piperazino, morpholino, etc. The cyclic mentioned amino groups may carry one or more substituents, including straight chained or branched C 1 -C 2 alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert. -butyl, the amino-20 group, aminoalkyl groups with 1-4 carbon atoms such as aminomethyl, 2-aminoethyl, 3-aminopropyl, etc., hydroxy-alkyl groups with 1-4 carbon atoms, such as hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, etc. the hydroxy group, alkenyl groups with 2-4 carbon atoms such as vinyl, allyl, etc., acyl groups with 1-4 carbon atoms, such as formyl, acetyl, propionyl, butyryl, etc., alkylamino groups with 1-4 carbon atoms, such as methylamino, ethylamino, n-pro-pylamino, isopropylamino, etc., dialkylamino groups with 1-4 carbon atoms in any alkyl group such as dimethyl-30 amino, diethylamino, di-n-propylamino, methyl ethylamino, etc., the cyano group, an oxygen atom, aralkylamino groups having 1-4 carbon atoms in the alkyl portion such as benzylamino, phenethylamino, etc., acylamino groups with 1-4 carbon atoms, such as acetylamino, propionylamino, butyrylamino, etc., alkoxycarbonyl groups with 1-4 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, n-propoxyn 79 'x, V *. * - * · te «> - 4 - carbonyl, isopropoxycarbonyl, etc., and N-acyl-N-alkylamino groups of 1-4 carbon atoms in both N substituents.

Among the compounds represented by the general formula 1, preference is given to those in which 5 in 1 * 2 represents a fluorine-substituted phenyl group and R 1 represents a substituted or unsubstituted pyrrolidino or piperazino group, and in particular those in which R2 is a 2,4-difluorophenyl group and R2 is a 3-aminopyrrolidino group.

Salt formation with the compounds of the general formula 1 can occur both on basic substituents such as amino groups and on acidic substituents such as carboxyl groups. Inorganic and organic acids such as hydrochloric acid, sulfuric acid, oxalic acid, formic acid, trichloroacetic acid, trifluoroacetic acid, methanesulfonic acid, p-toluene sulfonic acid and naphthalenesulfonic acid are suitable for the former. For salts with carboxyl groups, alkali metals such as sodium, potassium, etc., alkaline earth metals such as calcium, magnesium, etc., ammonium 20 and organic nitrogen bases such as procaine, dibenzylamine, N-benzyl-3-phenethylamine, 1-phenphenamine, N, N di-benzylethylenediamine, triethylamine, trimethylamine, tributylamine, pyridine, Ν, Ν-dimethylaniline, N-methyl-piperidine, N-methylmorpholine, diethylamine, dicyclohexyl amine and the like.

If a compound of the general formula 1 has isomers (eg optical isomers, geometric isomers, tautomers, etc.) then all isomers, crystal forms and hydrates are within the scope of this invention.

The antibacterial actions and the acute toxicities of some representative compounds of the invention are now shown.

1. Anti-bacterial effect 3 5 Test method.

According to the standard method of the 8 5 G 1 1 7 2 <* - 5 -

Japanese Chemotherapy Association / Chemotherapy 29 (1) (1981), 76-79 /, a plate of heart infusion agar containing the substance to be tested was seeded with a bacterial suspension obtained by cultivation at 37 ° C in a heart infusion for 20 hours. bouil-5 Ion (from Eiken Kagaku), after cultivation at 37 ° C for 20 hours, it was checked whether bacteria were growing on it, the minimum concentration that stopped the growth of bacteria was determined, this being the MIC (in jig / mL). The seed was 10 cells per plate (106 cells / ml). The MIC values found are shown in Table A. In this table, penicillinase-forming bacteria are designated with * 1 and cephalosporinase-forming bacteria with * 2; in two cases, designated * 3, the seed 8 was 10 cells / ml.

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The LD ^ g values, measured in mice (the ICR strain, male, 18-24 grams), which received test substances No. 5, 6 and 12 intravenously, were 200 mg / kg or higher .

The compounds of the invention are prepared in a manner known per se for analogous compounds. Typically, this can be done according to the reaction scheme given herein, in which R 1 and 10 have the previously given definitions, R 1 a represents a carboxyl protecting group, R 3a represents a halogen atom and R 3 represents a substituted or unsubstituted cyclic amino group. Depending on the result, the salts of the given compounds can also be used and the resulting products can be recovered as salts.

Compounds of the general formula 3 or of the general formula 5 can be obtained by reacting an acetal such as N, N-diethylformamide-dimethyl-acetal, Ν, Ν-dimethylformamide-diethylacetal, etc. with a compound of the formula 2 or of the formula respectively 4, and then with an amine of the formula R ^ -NH ^ ·

The solvent to be used in these reactions can be any solvent that is inert under the reaction conditions, including aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as dioxane and tetrahydrofuran, anisole, dimethoxyethane, etc., halohydrocarbons such as methylene chloride, chloroform and dichloroethane, amides such as Ν, Ν-dimethylformamide and N, N-dimethylacetamide and sulfoxides such as dimethyl sulfoxide, etc.; these solvents can be used alone or in combinations.

The amount of acetal used is preferably 1 mol or more, in particular 1.0-1.3 mol per mol of compound 35 according to formula 2 or 4. The reaction generally takes place between 0 ° and 100 ° C, preferably between 50 ° and 80 ° C, 35 011 /> - 10 - and generally takes between 20 minutes and 50 hours, usually between 1 and 3 hours. 1 mol or more of the amine is used per mol of the compound of formula 2 or 4, and the reaction proceeds between 0 ° and 100 ° C, preferably between 10 ° and 60 ° C, and takes between 20 minutes and 30 hours, usually between 1 and 5 o'clock.

Alternatively, it is also possible to react a compound of the general formula 2 or of the formula 4 in the presence of acetic anhydride with ethyl chloroformate or methyl orthoformate, and then with an amine of formula R ^ -NH ^ · Also, a compound is obtained according to formula 3 or according to formula 5 or a salt thereof.

The compound of general formula 15a or a salt thereof is obtained by causing a ring closure in a compound of formula 3 or formula 5 (preferably under heating).

The solvent to be used in this reaction can be any solvent which is inert in the reaction, including amides such as N, N-dimethylformamide and Ν, Ν-dimethylacetamide, ethers such as dioxane, anisole and dimethoxyethane, and sulfoxides such as dimethyl sulfoxide etc. These solvents can be used alone or in combination. The base may be, for example, NaHCO3, K2CO3, KO-t-Bu, NaH, etc. The amount of base to be used is between 0.5 and 5 moles per mole of the compound of formula 3 or 5. The reaction generally takes place between 20 ° and 160 ° C, preferably between 100 ° and 150 ° C, and costs generally between 5 minutes and 30 hours, usually between 5 minutes and 1 hour.

A compound according to general formula 4, according to general formula 5 or according to general formula Ib can be obtained by reacting a compound 35 according to general formula 2, respectively formula 3 or formula la with a cyclic amine according to 8501172 it - 11 - the general formula R ^ -H.

The solvent to be used in that reaction may be any inert liquid in the reaction, including aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as dioxane, tetrahydrofuran, anisole and dimethoxyethane, halohydrocarbons such as methylene chloride, chloroform and dichloroethane, amides such as Ν, Ν-dimethylformamide and Ν, Ν-dimethylacetamide, sulfoxides such as dimethyl sulfoxide, etc., alcohols such as methanol and ethanol, and nitriles such as acetonitrile, etc.; these solvents can be used alone or in combinations. An excess of the cyclic amine is preferably used, most preferably between 2 and 5 moles per mole of the compound of formula 2, 3 or 1a.

It is also possible to suffice with 1 to 1.3 moles of cyclic amine if there is also 1 mole of acid scavenger present per mole of the compound of formula 2, 3 or 1a. Acid scavengers include organic and inorganic bases such as triethyl amine, 1,8-diazabiscyclo (5,4,0) undecene-7, KO-t-Bu, 20 K2CO3 'Na2CO3' NaH e * d *

The amine according to the formula R ^ -H can also be used as salt. The reaction generally takes place between 0 ° and 150 ° C, preferably between 50 ° and 100 ° C, and generally lasts between 5 minutes and 30 hours, usually between 30 minutes and 3 hours.

A compound of the general formulas 1a, 1b, 3 and 5, wherein represents a carboxyl protecting group, and the salts thereof may, if desired, be converted to the corresponding free acids by hydrolysing them conventionally with acid or base, generally between 0 ° and 100 ° C, preferably between 20 ° and 100 ° C which takes between 5 minutes and 50 hours, usually between 5 minutes and 4 hours. Furthermore, a compound of formula Ia, 1b, 3 or 5 can be converted into a salt or an ester in a known manner. When the compound of formula Ia, 3, 4 or 5 has an active group. «| ƒ / V! 7 ti '* - 12 - (for example a hydroxy or amino group) in places other than the place intended for reaction, it is then possible to protect that active group in a known manner first and afterwards of the reaction to remove that protecting group.

The compounds obtained can be isolated and purified in a conventional manner, using methods such as column chromatography, recrystallization, extraction, etc.

The compounds of the general formula 1 and the salts thereof in which represents a halogen atom (i.e. a compound of the formula la) is also useful as an intermediate in preparing a compound in which a substituted or unsubstituted cyclic 15 amino group (that is a compound according to formula lb).

When the compound of the invention is used as a medicament, it is suitably combined with carriers customary in the pharmaceutical preparations. The compositions may be in the form of tablets, capsules, powders, syrups, granules, suppositories, ointments, injections and the like. The mode of administration, the dosages used and the number of dosages can be varied as needed depending on the symptoms of the patients; usually they will be administered orally or parenterally (for example, by injection, by instillation or through the rectum) at a dose between 0.1 and 100 mg / kg per day, optionally in multiple portions.

The invention is now further illustrated by the following preparations, preparation examples and preparation examples.

Preparation 1

A solution of 21 g of 2,6-dichloro-35 5-fluoro-nicotinic acid, 23.8 g of thionyl chloride and 0.1 g of dimethylformamide in 210 ml of chloroform was allowed to stand for 2 hours. λ i 1 7?

v * /. j I. J J

- react at 13 - 70 ° C. Solvent and excess thionyl chloride were removed by distillation under reduced pressure and the residue was taken up in 21 ml of tetrahydrofuran.

A solution of 25.1 g of diethyl-5 ethoxymagnesium malonate in 110 ml of tetrahydrofuran was cooled to between -40th and -30 ° C, and the above-mentioned solution of 2,6-dichloro-5-fluomicotinoyl chloride was stirred at the same temperature over 30 minutes. dripped. This mixture was stirred at the same temperature for an additional 1 hour and then the mixture was allowed to warm gradually to room temperature. The solvent was removed by distillation 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 hydrochloric acid. The organic layer 15 was separated and dried successively with 50 ml water, 50 ml 5% NaHCO 2 solution and 50 ml saturated NaCl solution, and finally dried over MgSO 2. The solvent was distilled off under reduced pressure and 50 ml of water and 0.15 g of p-toluene-20 sulfonic acid were added to the residual oil and the mixture was allowed to react at 100 ° C for 2 hours with vigorous stirring. The reaction mixture was then extracted with 100 ml of chloroform and the organic layer was washed with 50 ml of saturated NaCl solution and dried over MgSO 4, after which the solvent was distilled off under reduced pressure. The residue thus obtained was purified by column chromatography with toluene on Wako Silica Gel C-200, adding 23.5 g of ethyl (2,6-dichloro-5-fluoro-nicotinoyl) acetate with mp. 64-65 ° C.

IR (in KBr) cm ”1: v 1650, 1630, 1620 30 NMR (CDCLi) δ values: 1.25 (1.29H, t, J = 7Hz), 1.33 (1.71 H, t, J = 7Hz), 4.07 (1.14 H, s), 4.28 (2H, q, J = 7Hz), 5.82 (0.43 H, s), 7.80 (1H, d, J = 7 Hz), 12.62 (0.43 H, s).

Preparation 2 35 A solution of 8.8 g of ethyl (2,6-dichloro-5-fluomicotinoyl) acetate and 4.5 g of N, N-dimethyl-3521172-14-formamide dimethyl acetal in 40 ml of benzene was left React at 70 ° C for 1 hour. Then 4.1 g of 2,4-difluoroaniline was added and that mixture was allowed to stand at room temperature for 4 hours. The solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography (with chloroform on Wako silica gel C-200), yielding 9.0 g of ethyl 2- (2,6-dichloro-5-fluoro-nicotinoyl) -3- (2,4-difluorophenylamino) acrylate with smp. 138-139 ° C.

10 IR (in KBr) cm 1: vc_Q 1690 NMR (CDCl 3) 6 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 the same manner, the compounds listed in Table B were obtained.

Table B

Compounds of formula 3, R = COH and R = Cl. la 25 ra 20 __

Compound_- Characteristics_ R „Melting point IR (in KBr) __ ^ __ cm ~ 1 Vo phenyl 87-89 1690 25 4-fluorophenyl 110-114 1710, 1680 3-fluorophenyl 92-93 1710, 1680 2-fluorophenyl 135-137 1720 ( sch), 1690 3.4-difluorophenyl 78-80 1690 30 2,5-difluorophenyl oil 1705, 1680 (sch) * 2,6-difluorophenyl 154-155 1720 (sch), 1685 2.3.4-trifluorophenyl 100-101 1700 (sch ), 1685 4-chlorophenyl 123-125 1710, 1680 4-bromophenyl 145-146 1705, 1680 35 4-methylphenyl 147-149 1685 4-methoxyphenyl oil 1695 * 85 0 1 1 7 2 '

Table B (cont.) - 15 - Compound__Features_ R2 Melting point IR (in KBr) 5 __ (° C) and'1 ve = 0 '2-methoxyphenyl 119-121 1700 4-cyanophenyl oil 1700 * 4- (acetylamino) phenyl 183-186 1685, 1670 4-trifluoromethylphenyl 136-138 1705, 1680 10 4-fluoro-2-methylphenyl 114-116 1680 4-fluoro-2-methoxyphenyl 137,5-139 1725 (sch), 1680 2-fluoro-4-methoxyphenyl 92 -95 1705 2-methoxy-4-methylphenyl 125-126 1700 (sch), 1660 4-methoxy-2-methylphenyl 91-92 1705, 1690 15 ___ * The IR spectrum was measured on the substance as such, not in KBr .

Preparation 3 (1) A solution of 5.5 g of ethyl (2,6-dichloro-5-fluomicotinoyl) acetate, 2.37 g of N-methylpiperazine and 2.37 g of triethylamine in 55 ml of chloroform react at 60-65 ° C for 2 hours. The reaction mixture was now washed with 30 ml of water, dried over MgSO 4 and evaporated to dryness under reduced pressure. The resulting residue was purified by column chromatography (with chloroform on Wako silica gel C-200) to give 5.4 g of ethyl- / 2-chloro-5-fluoro-6- (4-methyl-piperazino) nicotinoyl / acetate, an oil.

IR (oil) cm-1: v 1750, 1695 NMR (CDCl3) 5 values: 1.25 (3H, t, J®7 Hz), 2.32 (3H, s), 30 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 (1H, d , J = 13 Hz).

Likewise, ethyl / 2-chloro-5-fluoro-6- (4-acetylpiperazino) nicotinoyl / - 35 acetate was also obtained, m.p. 67-71 ° C, in the IR spectrum one

§ 5 0 1 1L

16 - -1 peak at 1730 cm for C = 0.

(2) To a solution of 4.5 g of ethyl / 2-chloro-5-fluoro-6- (4-methylpiperazino) nicotinoyl / acetate in 22.5 ml of benzene, 1.87 g of N, N-dimethylformamide di -5 methyl acetal added, and that mixture was allowed to stand at 70 ° C for 2 hours. 1.8 g of 4-methoxy-2-methylaniline were added to the reaction mixture and the mixture was allowed to stand at room temperature for 4 hours. Then the solvent was removed by distillation under reduced pressure and the residue was purified by column chromatography (with 1% ethanol in chloroform over Wako silica gel C-200). There was thus obtained a crystalline substance which was washed with 10 ml of diethyl ether, yielding 5.0 g of ethyl-2- / 2-chloro-5-fluoro-6- (4-methylpiperazino) -nicotinoyl / - 3- (4-methoxy- 2-methyl-15 phenylamino) acrylate with m.p. 141-142 ° C.

IR (in KBr) cm ”1. · vc = 0 1710 (sch), 1695 NMR (CDCl 3) δ 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), 5.65 - 7.25 (3H, m), 7.20 (1H, d, J = 13 Hz), 8.48 (1H, d, J = 13 Hz), 12.82 (1H, d, J = 13Hz).

In the same manner, the compounds listed in Table C were also obtained.

25

Table C

Compounds of formula 5 _Connection__Features_ 30 R ^ Melting point IR (*)

___ (“Cl c..-1 vCjQ

phenyl 4-methyl oil * 2 piperazino 1720 (sch), 1715 2,4-difluorodem oil * 2 35 phenyl 1735.1700 85 0 117 2

Table C (continued) - 17 - Compound__Features_ R2 R3b Melt- IR (*) _ point -1 5 ___ (ac) Cm VC = 0 3-methoxyphenyl 4-methyl oil * 2 piperazine 1695 4- (acetylamino) - idem 161 -164 * 1 phenyl 1635, 1670 10 3-luor-4-methidem oil * 2 0Xyphenyl 1720 (sch), 1715 4-methoxy-3-idem 132-136 * 1 methylphenyl 1705 (sch), 1635 15 4 -methoxy-2- 4-acetyl oil * 2 methylphenyl piperazine 1720 (sch), _ | _1_ 1700_

Note: * 1 in KBr * 2 to the oil itself.

20

Example I

To a solution of 9.0 g of ethyl 2- (2,6-dichloro-5-fluoro-nicotinoyl) -3- (2,4-difluorophenylamino) acrylate in 90 ml of dimethylformamide was added 3.6 g of NaHCO3 and mixture was heated at 120 ° C for 20 minutes

kept. The solvent was then distilled off under reduced pressure and the residue was taken up in 50 ml of chloroform. This solution was washed successively with 30 ml of water and 30 ml of saturated NaCl solution 30 and then dried over MgSO 4. The solvent was distilled off under reduced pressure and the crystalline residue was washed with 30 ml of diethyl ether to give 7.0 g of ethyl 7-chloro-6-fluoro-1- (2,4-difluorophenyl) -4-oxo-1, 4-dihydro-1,8-naphthyridine-3-carboxylate with m.p. 220-222 ° C.

35 QSM] 79 UW v ί <<fa - 18 - IR (in KBr) cm: VQ = 0 1730, 1690 NMR (CDC13) δ values: 1.36 (3H, t, J = 7 Hz), 4, 30 (2H, q, J = 7Hz), 6.80-7.60 (3H, m), 8.27 (1H, d, J = 7Hz), 8.42 (1H, s).

In the same manner, the compounds shown in Table D were obtained.

Table 4

Compounds of formula 1, R1 - C2H5 'R3 - C110 ___Connection__Features_ R „Melting point IR (in KBr) 1 (° C) -1 cm V“ Λ ___; ___ C = 0 phenyl 222-224 1730, 1685 15 4- fluorophenyl 231-232 1730, 1705 3-fluorophenyl 239-241 1685 2-fluorophenyl 205-208 1735, 1685 3.4-difluorophenyl 244-246 1720, 1680 2.5-difluorophenyl 207-209.5 1730, 1690 20 2,6-difluorophenyl 210 -214 1735 (sch), 1705 2,3,4-trifluorophenyl 207-208 1730, 1680 4-chlorophenyl 181-186 1730, 1685 4-bromophenyl 204-205 1730, 1685 4-methylphenyl 216-218 1735, 1695 25 4 -methoxyphenyl 196-198 1735, 1685 2-methoxyphenyl 156-160 1730, 1690 4-cyanophenyl 231-236 1730, 1685 4- (acetylamino) phenyl 270-273 1730, 1690 4-trifluoromethylphenyl 199-201 1730, 1680 30 4- fluoro-2-methylphenyl 199-202 1735, 1685 4-fluoro-2-methoxyphenyl 208-211 1730, 1695 2-fluoro-4-methoxyphenyl 142-144 1740, 1695 2-methoxy-4-methylphenyl 163-165 1730, 1695 4-methoxy-2-methylphenyl 160-162 1735, 1690 35 S * 1 4 * 1 “7 C xj] s / d, - 19 -

Example II

(1) A solution of 3.5 g of ethyl 7-chloro-6-luor-1- (2,4-difluorophenyl) -1-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate 1.5 g of N-acetylpiperazine 5 and 1.6 g of triethylamine in 35 ml of chloroform were kept at 60 ° C for one hour and then the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (with 3% ethanol in chloroform over Wako silica gel C-200) to obtain 3.5 g of ethyl 7- (4-acetylpipera-10 zino) -6-fluoro-1- (2,4-difluorophenyl 4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate with m.p. 207-209 ° C.

IR (in KBr) cm vc_0 1730, 1695 NMR (CDCl3) θ values: 1.38 (3H, t, J = 7 Hz), 2.05 (3H, s), 3.53 (8H, bs), 4.30 (2H, q, J = 7 Hz), 6.80-15 7.75 (3H, m), 8.00 (1H, d, J = * 13 Hz), 8.30 (1H, s ).

Likewise, the compounds listed in Table E were also obtained.

Table E

Compounds of formula 1, R ^ = ethyl _ Compound__ Characteristics_ 25 R R, Melt-IR (in KBr) point -1

___ ra__ ™ _C = Q

phenyl 4-acetyl- 216-218 1730,1690 (sch) piperazino 4-fluorophenyl 4- (acetyl- 155-156 1730, 1690 3q methylamino) - piperidino idem 4-methyl- 217-218 1730, 1695 piperazino idem 3-methyl - 144-146 1730, 1690 piperazino 35 ditto 2,6-dimethyl- 143 1730 piperazino ditto 2,5-dimethyl- 198-202 1725, 1690 .¾ - 4 * _piperazino_ V \ ii I 1 lil

Table E (continued) - 20 - _Connection _ Characteristics_ R R Melt-IR (in KBr) point -1

___ TC) __ C = Q

4-fluorophenyl 4- (| 3-hydroxy- 220-222 1730, 1695 ethyl) piperaz ino idem 4-acetyl- 235-255 1730, 1690 piperazino idem morpholino 203-205 1730, 1700 3-fluorophenyl 4-acetyl- 211- 213 1735 piperazino 2-fluorophenyl idem 206 1725, 1690 3.4-difluoro- 4-methyl- 193-194 1730, 1700 phenyl piperazino idem 4-acetyl- 244-246 1725, 1690 piperazino 2.4-difluor- 4- (acetyl- 186- 187 1725, 1690 (sch) phenyl methylamino) - piperidino idem 3-methyl-155-157 1720, 1685 piperazino idem 3,4-dimethyl-153-154 1730, 1700 piperazino idem 2,4-dimethyl-153-155 1730, 1695 piperazino idem 4-allyl- 166-168 1730 (sch), 1690 piperazino idem 4- (ethoxycar- 202-204 1730, 1690 bonyl) -2-methylpiperazino 2.5-difluoro-4-acetyl- 230-231 1725 ( sch), 1695 phenyl piperazino 2.6-difluorodem 193-194 1720 (sch), 1680, phenyl 1675 4-chlorophenyl 4-methyl-207 1725, 1695 piperazino idem 4-acetyl-254 1730, 1690 piperazino 4-bromophenyl 4- methyl 208 1730, 1690 piperazino 85 0 1 1 7>

Table E (continued) - 21 - Compound_______ Characteristics__ R „R_ Melting point IR (in KBr) (° C) -1 cm v__“ __I ____ c = o 4-bromophenyl 4-acetylpipera- 246-247 1730, 1690 zino 4-meth.ylphenyl 4 -methylpiperazino 167-169 1730, 1695 idem 4-acetylpiperazino 206-207.5 1730, 1690 4-methoxyphenyl piperidino 163-165 1735, 1700 idem 4-methylpiperazino 174-176 1730, 1690 idem 4-ethylpiperazino 180-181 1735, 1695 ditto 4-n-propyl- 171-172,5 1730, 1685 piperazino ditto 4-isopropyl- 208,5-210 1730, 1690 piperazino ditto 4- (β-hydroxy- 200-202 1730, 1690 ethyl) ditto 4- allylpiperazino 162-163 1725, 1690 idem 4-acetylpiperazino 197-199 1735, 1690 2-methoxyphenyl 4-methylpiperazino 136-138 1725, 1685 4-cyanophenyl 4-acetylpiperazino 270-272 1730, 1690 4- (acetylamino) - idem 245- 249 1730, 1695 phenyl 4-trifluozme-4-acetylpiperazino 249-252 1730, 1695 thylphenyl 4-fluoro-2-idem 263-264 1730 methylphenyl 4-fluoro-2-meth-4-methylpiperazino 166-169 1730, 1685

oxyphenyl I.

ditto 4-acetylpiperazino 222,5-223, »1730, 1690 2-fluoro-4-meth- 4-methylpiperazino 165-168 1730, 1685 oxyphenyl ditto 4-acetylpiperazino 215-219 1730, 1695 2-methoxy-4-me- 4-methylpiperazino 170-171 1725, 1690 thylphenyl 4-methoxy-2- 4-acetylpiperazino 169-172 1725, 1690 methylphenyl ______ [______ 8501172 - 22 - (2) A solution of 2.5 g ethyl-7- (4-ace tylpiperazino) -6-fluoro-1- (2,4-difluorophenyl) -4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate in 25 ml 6N hydrochloric acid was refluxed for 2 hours. After cooling to room temperature, the pH was adjusted to 12 with N NaOH solution, then 6.5 with acetic acid. The then separating crystals were collected by filtration, washed with water (30 ml) and then dried to give 1.8 g of 6-fluoro-1- (2,4-difluorophenyl) -7-piperazino-4-oxo-1,4- di-10 gave hydro-1,8-naphthyridine-3-carboxylic acid.

NMR (TFA-d ^ δ values: 3.30-4.50 (8H, m), 7.00-7.85 (3H, m), 8.33 (1H, d, J = 13 Hz), 9.21 (1H, s) Likewise, the compounds listed in Table F were obtained.

Table F

Compounds of formula 6. ______Connection_____ Characteristics_ R „R Melting point IR (in KBr) 2 ^ (on) -1 20 ___ Vc = 0 phenyl piperazino 252,5-254,5 1730 4-fluorophenyl 4- (methylamino) -> 280 * piperidino 1720 (sch) idem piperazino 279 -280 1725 (sch) 25 3-fluorophenyl idem 234-236 1720 2-fluorophenyl idem 222-224 1725 3.4-difluorodem> 280 1720 phenyl 2.4-difluoro- 4- (methylamino) - 254-258 1725 phenyl piperidino 30 2 , 5-difluorobiperazino 205-207 1730 phenyl 2,6-difluorodem 225-227 1725 phenyl 4-chlorophenyl idem> 280 1725 4-bromophenyl idem 273-277 1720 35 4-methylphenyl idem 245-246 1725 4-cyanophenyl ditto> 280 1725 4-aminophenyl ditto __> 280 1730, 1710_ 3501172

Table F (continued) - 23 - _Connection_____Features_ R R Melting point IR (in KBr) 2 3 (° C) -1 5 cm Λ

3____CO

4- (acetylamino) -4-methyl-232-236 1725, 1710, 1690 phenyl piperazino 4-trifluorophenyl piperazino> 280 1725 4-fluoro-2-modem 230-232 1730 thylphenyl * IR spectrum measured in nujol.

Example III

(1) A solution of 0.50 g of ethyl 7-chloro-6-fluoro-1- (2,4-difluorophenyl) -4-oxo-1,4-dihydro-15,8-naphthyridine-3-carboxylate 0.20 g of 3-fecetylamino) pyrrolidine and 0.15 g of triethylamine in 5 ml of chloroform were kept at 60 ° C for one hour. The solvent was then distilled off under reduced pressure and the residue was purified by column chromatography (with 3% ethanol in chloroform over Wak o silica gel C-200) to obtain 0.5 g of ethyl 7- (3-acetylaminopyrrolidino) -6-fluoro- 1- (2,4-difluorophenyl) -4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate, mp 233-235 ° C.

IR (in KBr) cm -1: να-ο 1725, 1700

25 NMR (CDC1_) θ values: 1.32 (3H, t, J = 7 Hz), 1.77-2.27 (m), CrM

3 2.08 (s) H5H) 3.12-3.74 (4H, m), 4.02-4.74 (m), 4.29 (q, J = 7Hz) M '6.75-7 .60 (4H, m), 7.93 (1H, d, J = 8Hz), 8.24 (1H, s). Likewise, the compounds listed in Table 30G were obtained.

«3 G 1 i - - 4> - - 24 -

Table G

Compounds of formula 1, R ^ = ethyl 5 _ Compound__ Characteristics_ RR Melting point IR (in KBr) (° C) nrrT1 „cm v _ ____ C = 0 4-fluorophenyl 3-hydroxypyrrolidino 231-233 1730, 1700 ditto 3- (dimethylamino) - 156 1730, 1690 10 pyrrolidino idem 3- (acetylamino) - 203-205 1725, 1690 pyrrolidino idem 3- (acetylmethyl- 201-202 1725,1695 amino) pyrrolidino 15 2,4-difluoro- 3- (dimethylamino) - 165 1730, 1690 phenyl pyrrolidino idem 3- (acetylmethyl- 196-197 1730, 1695 amino) pyrrolidino 2,3,4-trifluoro- 3- (acetylamino) - 241-244 1725, 1700 20 phenyl pyrrolidino 4-methdxyphenyl pyrrolidino 153-155 1735 idem 3-hydroxy- 185-187 1730, 1690 pyrrolidino.

(2) A solution of 0.25 g of ethyl-7- (3-ace-tylaminopyrrolidino) -6-fluoro-1- (2,4-difluorophenyl) -4-oxo-1,4-dihydro-1,8 Naphthyridine-3-carboxylate in 2.5 ml of 6N hydrochloric acid was refluxed for 2 hours. After cooling to room temperature, the pH of the mixture was adjusted to 12 with N NaOH and then to 6.5 with acetic acid.

The crystals deposited therein were collected by filtration, washed with 2 ml of water and dried. This gave 0.18 g of 7- (3-aminopyrrolidino) -6-fluoro-1- (2,4-difluorophenyl) -4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid.

NMR (in TFA-d ^) δ values: 2.25-2.85 (2H, m), 3.37-4.69 (5H, m), 6.93-7.81 (3H, m) 8.22 (1H, d, J = 11Hz), 9.16 (1H, s).

In the same manner, the compounds listed in Table H were obtained.

85 0 1 1 7 '; - 25 -Table Η

Compounds of formula 6.

_Connection__Features_ 5 R R- Melting point IR (in KBr) (° C) nm'1 ____ ^ Vo 4-fluorophenyl 3-aminopyr- 260-263 1720 rolidino idem 3- (methylamino) - 259-261 1720 (sch) 10 pyrrolidino 2.4 - difluorodem 275-278 1720 (sch) phenyl 2.3.4- tri- 3-amino- 278-280 1720 fluorophenyl__pyrrolidino __ [__

Example IV

(1) A solution of 2.0 g of ethyl 2,6-dichloro-5-fluomicotinoyl acetate, 0.96 g of 3- (acetylamino) pyrrolidine and 0.8 g of triethylamine in 20 ml of chloroform was allowed to stand at 60- for 2 hours. React at 65 ° C. The reaction mixture was washed with 30 ml of water and then dried over MgSO4.

The solvent was distilled off under reduced pressure and the residue purified by column chromatography (benzene / ethyl acetate 1: 1 over Wako silica gel C-200) to give 1.8 g ethyl / 2-chloro-5-fluoro-6- (3- acetylaminopyrrolidino) - gave nicotinoyl / acetate as an oil.

IU (of the oil) cm v 1740, 1650

C ^ O

NMR (in CDCl3) δ 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 = 13Hz).

(2) A solution of 0.7 g of ethyl 2-chloro-5-fluoro-6- (3-acetylaminopyrrolidino) nicotinoyl acetate and 0.235 g Ν, Ν-dimethylformamide dimethyl acetal was left at 70 ° for 2 hours C respond. 0.243 g of 2,4-difluoroaniline was added to the reaction mixture and the mixture was allowed to react at room temperature for 8 hours.

5301172 - 26 -

Now the solvent was removed by distillation under reduced pressure and the resulting residue was purified by column chromatography (benzene / ethyl acetate 1: 1 on Wako silica gel C-200). The oil thus obtained was stirred with 5 diisopropylether, yielding 0.25 g of ethyl 2- / 2-chloro-5-fluoro-6- (3-acetylaminopyrrolidino) nicotinoyl / - 3- (2,4-di-fluorophenylamino) acrylate with smp. 82-85 ° C.

IR (in KBr) cm S V 1695 (sch), 1660

v “U

NMR (in CDCl3) δ 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) To a solution of 0.2 g ethyl-2- 15/2-chloro-5-fluoro-6- (3-acetylaminopyrrolidino) nicotinoyl / - 3- (2,4-difluorophenylamino) acrylate in 3 ml dimethylform- amide, 0.04 g of NaHCO 2 was added and that mixture was kept at 120 ° C for 1 hour. The solvent was then removed by distillation under reduced pressure and the residue was taken up in 10 ml of chloroform. This solution was washed successively with 10 ml water and 10 ml saturated NaCl solution and then dried over MgSO 4. The solvent was distilled off under reduced pressure and the crystalline substance thus obtained was washed with 5 ml of diethyl-25 ether to give 0.13 g of ethyl 7- (3-acetylamino pyrrolidino) -6-fluoro-1- (2,4-difluorophenyl) 4-oxo-1,4-di-hydro-1,8-naphthyridine-3-carboxylate with m.p. 233-235 ° C.

Likewise, ethyl 7-30 (3-acetylaminopyrrolidino) -6-fluoro-1- (4-fluorophenyl) -4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate was also obtained; the characteristics of this product were identical to those of the product obtained in Example III- (1).

Example V

35 (1) A suspension of 0.50 g of ethyl-7-chloro-6-fluoro-1- (2,4-difluorophenyl) -4-oxo-1,4-dihydro- -y * λ, 1 «3 “7 Λ # · \ i ί a IJ / <=! A-27-1,8-naphthyridine-3-carboxylate in 15 ml of 6N hydrochloric acid was refluxed for 3 hours. The reaction mixture was then diluted with 50 ml of water and extracted with 3 x 50 ml of chloroform. The extracts were washed together with 100 ml of saturated NaCl solution and dried over MgSO4. The solvent was distilled off under reduced pressure and the crystalline substance thus obtained was washed with 15 ml of diethyl ether, giving 0.40 g of 7-chloro-6-fluoro-1- (2,4-difluorophenyl) -4-oxo-1,4 dihydro-1,8-naphthyri-10 dine-3-carboxylic acid with m.p. 244-248 ° C.

IR (in KBr) cm-1: VC = Q 1720 NMR (in d.-DMSO) δ values: 7.26-8.56 (3H, m), 8.86 6 (1H, d, J * 7 Hz) and 9.18 (1H, s).

(2) To a suspension of 0.30 g of 7-chloro-6-fluoro-1- (2,4-difluorophenyl) -4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid in 0.25 g of N-methylpiperazine was added 3 ml of dimethylsulfoxyd and this suspension was allowed to react at 60 ° C for 30 minutes. The solvent was then distilled off under reduced pressure and 30 ml of water were added to the residue. The pH of the mixture was adjusted to 12 with 10% NaOHrop solution, then to acetic acid with 7. The crystalline precipitate was collected by filtration and washed with 5 ml of water to give 0.24 g of 6-fluoro-1- (2.4 -difluorophenyl) -7- (4-methylpiperazino) -4-25 oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid, m.p.

208-209 ° C.

-1 IR (in KBr) cm: vc = 0 1730 NMR (in TFA-d ^) δ values: 3.30 (3H, s), 3.45-5.25 (8H, m), 7.12 -8.10 (3H, m), 8.49 (1H, d, 30 J = 13 Hz) and 9.38 (1H, s).

Example VI

To a solution of 5.0 g of ethyl 2- / 2-chloro-5-fluoro-6- (4-methylpiperazino) nicotinoyl-3- (4-methoxy-2-methylphenylamino) acrylate was added 1.03 g NaHCO4 35 and that mixture was allowed to react at 120 ° C for 3 hours. Now the solvent was distilled off by distillation under 4 ^ 7 V ^. ·; - 28 - low pressure removed and the residue was dissolved in 50 ml of chloroform. This solution was washed successively with 30 ml of water and 30 ml of saturated NaCl solution and dried over MgSO 4. The solvent was removed under reduced pressure and the resulting crystalline matter was washed with 30 ml of diethyl ether to add 2.38 g of ethyl 6-fluoro-1- (4-methoxy-2-methylphenyl) -7- (4-methyl-piperazino) 4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate with m.p. 144-145 ° C.

10 IR (in KBr) cm "1: vc = Q 1730, 1690 NMR (in CDCl3) δ 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).

Likewise, the compounds listed in Table I were obtained.

Table I

Compounds according to formula 1, R ^ = ethyl 20 __-Compound__ Characteristics_ R „R, Melting point IR (in KBr) 1 6 (° C) -1 cm v“ ____ c = o phenyl 4-methyl- 199-202 1725, 1685 25 2,4-difluorophenyl enemrazine 168-171 1735, 1720 3-methoxyphenyl idem 174-175 1730, 1695 4- (acetylamino) - idem amorphous 1725, 1690 phenyl 30 3-fluoro-4-methidem 186-189 1725, 1690 oxyphenyl 4-methoxy-3-modem 166-168 1730, 1695 thylphenyl 4-methoxy-4-acetylpi- 169-172 1725, 1690 35 2-methylphenyl perazine 8501172 - 29 -

Example VII

A solution of 2.0 g of ethyl-6-fluoro-1- (4-methoxy-2-methylphenyl) -7- (4-methylpiperazino) -4-oxo-1,4-dihydro-1,8-naphthyridine-3 carboxylate in 5 ml of 47% hydrobromic acid was kept at 120 ° -125 ° C for 2 hours. Then the pH was adjusted to 13 with 10% NaOH and then to 6.5 with acetic acid. The crystals that precipitate were collected by filtration and washed with 10 ml of water to give 1.8 g of 6-fluoro-1- (4-hydroxy-2-methylphenyl) -7- (4-methyl-1-piperazino) -4-oxo- 1,4-dihydro-1,8-naphthyridine-3-carboxylic acid with m.p. > 280 ° C.

XR (in KBr) cm 1: vc_Q 1725, 1700 (sch) NMR (in TFA-d ^) S 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 the same manner, the compounds listed in Table J were obtained.

Table J

Compounds according to formula 6 20___Connection__Features_ | Melt- iR (in KBr) R ~ R, point j

__ __ (° C) cnT vc = Q

4-hydroxyphenyl piperidino 143-146 1725, 1710 25 idem piperazino> 280 1710 idem 4-methylpiperazino> 280 1710 idem 4-ethylpiperazino> 280 1730 idem 4-n-propylpiperazino> 280 1725 idem 4-isopropylpiperazino> 280 1715 30 idem 4- (8-hydroxyethyl) pipe- 200-205 1720, 1705 razid idem 4-allylpiperazino> 280 1725 3-hydroxyphenyl 4-methylpiperazino 245-250 1725, 1700 (dec.) (Sch) 35 2-hydroxyphenyl idem> 280 1725, 1690 4- fluoro-2-hypiperazino 220-224 1725, 1710 droxyphenyl___ · * S Λ * £ “W? ^ V i 11 £ 30 -

Table J (continued) _Connection_________Features_

Melting point IR (in KBr) c R2 R3 (° C) -1 5 cm _

____ C = Q

4-fluoro-2-hy-4-methylpiperazino> 280 1730, 1710 (sch) droxyphenyl 3-fluoro-4-hydidein> 280 1730 droxyphenyl 10 idem piperazino> 255 1725 2-fluoro-4-hy-4-methylpiperazino 251-252 1720 droxyphenyl 2-hydroxy-4-idem> 280 1725 (sch), methylphenyl 1700 15 4-hydroxy-idem 228-230 1730,1700 3-methylphenyl (sch) 4-hydroxy-piperazino 275 1720 2-methylphenyl ____ ] __

Example VIII

20 A solution of 0.40 g of ethyl 6-fluoro-1- (4-methoxyphenyl) -7-pyrrolidino-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate in 10 ml 47% hydrobromic acid was kept at 120-125 ° C for 2 hours. Then the pH was adjusted to 13 with 10% NaOH and then to 6.5 with acetic acid. The crystals which precipitate out were collected by filtration and washed with 4 ml of water to give 0.30 g of 6-fluoro-1- (4-hydroxyphenyl) -7-pyrrolidino-4-oxo-1,4-dihydro-1,8-naphthyridine -3-carboxylic acid with mp. 263-265 ° C.

30 IR (in KBr) cm ”1: vc = Q 1725, 1705 NMR (in TFA-dj) δ values: 1.54-2.40 (4H, m), 3.14-4.14 (4H, m), 6.95-7.69 (4H, m), 8.09 (1H, d, J = 12Hz), 9.14 (1H, s).

Likewise, the 6-fluoro-1- (4-hydroxyphenyl) -7- (3-hydroxy-pyrrolidino) -4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid, m.p.

Obtained at 180-183 ° C.

IR (in KBr) cm: VC = Q 1725, 1705.

r λ & £ · ί-ί1 J s J v; i i - 31 -

Example IX

In a mixture of 2 ml IN aqueous NaOH

and 2 ml of ethanol, 100 mg of ethyl 7- (4-acetylpiperazino) -6-fluoro-1- (4-fluorophenyl) -4-oxo-1,4-dihydro-1,8-naphthyriine-5-carboxylate was dissolved and that solution was kept at 40-50 ° C for 10 minutes. Then the pH of the mixture was adjusted to 6.5 with acetic acid. Then it was extracted with 2 x 5 ml of chloroform. The combined extracts were washed successively with 5 ml water and 5 ml saturated NaCl solution and dried over MgSO 4. The solvent was removed by distillation under reduced pressure and the crystalline substance thus obtained was washed with 2 ml of diethyl ether to give 80 mg of 7- (4-acetylpiperazino) -6-fluoro-1- (4-fluorophenyl) -4-oxo- 1,4-dihydro-1,8-naphthyridine-3-carboxylic acid with m.p. > 280 ° C.

-1 IR (in KBr) cm: VC_Q 1730 NMR (in d - DMSO) (S values: 2.05 (3H, s), 3.57 (8H, bs), o 7.13-7.80 (4H, m), 8.13 (1H, d, J = 13Hz), 8.70 (1H, s).

In the same manner, the compounds indicated in Table K were also obtained.

Table K.

Compounds according to formula 6 25 _Connection_Features_ R, Melting point IR (in KBr) 2 _____ ^ __ »vqq phenyl 4-methylpiperazino 277-280 1720 30 4-fluorophenyl idem 282-290 1725, 1700 (sch) idem 3-methylpiperazino 268-270 1725 idem 3,5-dimethylpipe- 283-285 1720 razino ^ idem 2,5-dimethylpipe- 267-270 1730 razino 4-fluorophenyl 4- (β-hydroxyethyl) - 138-139 1690 __piperazino____ 8531172 4 - 32 -

Table K (continued) _Connections__Features_

Melting point IR (in KBr) R2 R2 j CC) -1 5 ____ cm; vc = o 4-fluorophenyl morpholino> 280 1730, 1700 (sch) 3.4-difluoro-4-methylpiperazino> 280 1720 phenyl 2.4-difluorodem 208-209 1730 10 phenyl idem 3-methylpiperazino> 280 1720 idem 3,4-dimethyl - 210-211 1735 piperazino idem 2,4-dimethyl- 225-226 1720 15 piperazino idem 4-allylpiperazino 219-220 1730 4-chloro-4-methylpiperazino 283-284 1730,1700 (sch) phenyl 4-bromophenyl idem 277- 280 1730.1700 (sch) 20 4-Methylphenyl idem 271-274 1725 4-Methoxyphenyl idem__250-252__1725_

Example X.

A mixture of 100 mg ethyl-6-fluoro-1-25 (4-fluorophenyl) -7- (3-hydroxypyrrolidino) -4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate, 2 mL N NaOH solution and 2 ml ethanol was kept at 40-50 ° C for 10 minutes. Then the pH was adjusted to 6.5 with acetic acid. Then the mixture was extracted with 2 x 5 ml of chloroform. The combined extracts were washed successively with 5 ml water and 5 ml saturated NaCl solution and then dried over MgSO 4. The solvent was removed by distillation under reduced pressure and the crystalline substance thus obtained was washed with 2 ml of diethyl ether to give 80 mg of 6-fluoro-1- (4-fluorophenyl) -7- (3-hydroxy-pyrrolidino) -4-oxo- 1,4-dihydro-1,8-naphthyridine-3-carboxylic acid with m.p. > 280 ° C.

rt E Λ A -¾ “7 ft tf 0 rJ I 1 i 4> - 33 - IR (in KBr) cm-1: Vc_0 1730 NMR (in cL-DMSO) δ values: 1.92-2.52 ( 2H, m), 3.22-5.00

O

(5H, m), 6.97-7.60 (4H, m), 8.01 (1H, d, J 11 Hz), 9.00 (1H, s).

Likewise, the compounds listed in Table L were obtained.

Table L

Compounds of formula 6.

10 _Connection__Features_

Melting point IR (in KBr) 2 3 (° C) -1 cm s ____ C = 0 4-fluorophenyl 3- (dimethylamino- 264-265 1725

Eyrtolidino 15 2,4-difluorodem 227 1725 phenyl__

Example XI

To a solution of 250 mg of 6-fluoro-1-20 (4-hydroxy-2-methylphenyl) -4-oxo-7-piperazino-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid in 2.5 ml of concentrated hydrochloric acid were added 20 ml of ethanol and that mixture was stirred at room temperature for 15 minutes. The crystals which precipitate out were collected by filtration and washed with 5 ml of ethanol, some 200 mg of hydrochloride of 6-fluoro-1- (4-hydroxy-2-methylphenyl) -4-oxo-7-piperazino-1,4-dihydro- 1,8-naphthyridine-3-carboxylic acid with m.p. > 280 ° C.

In the IR spectrum (in KBr) signals at 1725 (sch) and 30 1705 cm ”1.

Likewise, the compounds listed in Table M were also obtained.

35 8501172 A «- 34 -

Table Μ

Hydrochlorides of acids according to formula 6 _ Compound__ Characteristics____ 5 RR Melting point IR (in KBr) 2 3 (° C) -1 cm Λ ____ c = o 4-fluorophenyl 4-methylpiperazino 283 1730 3,4-difluoropiperazino 275-278 1720 phenyl 10 2 , 4-difluorodem 249-252 1730 phenyl (dec.) 4-hydroxyphenyl idem> 280 1710 idem 4-methylpiperazine 280-282 1730 2-fluoro-4-hypiperazine 279-283 1720 (sch), 1705 15 droxy phenyl idem 4-methylpiperazine 266-269 1720 (sch), 1700 4-hydroxy-2 idem 282 1730 methylphenyl____

Example XII

To a solution of 2.0 g of 7- (3-amino-pyrrolidino) -6-fluoro-1- (2,4-difluorophenyl) -4-oxo-1,4-dihydro-1,8-naphthyridine-3- carboxylic acid in 20 ml of concentrated hydrochloric acid, 200 ml of ethanol were added and that mixture was stirred at room temperature for 15 minutes. The crystals thus formed were collected by filtration and washed with 40 ml of ethanol to give 1.4 g of hydrochloride of 7- (3-aminopyrrolidino) -6-fluoro-1- (2,4-difluorophenyl) -4-oxo-1,4 dihydro-1,8-naphthyridine-3-carboxylic acid with m.p. 247-250 ° C (dec.).

-1

In the IR spectrum (in KBr) a signal at 1730 cm. Example XIII

(1) A solution of 0.5 g of ethyl 2- (2,6-dichloro-5-fluoro-nicotinoyl) -3- (2,4-difluorophenylamino) -35 acrylate, 0.143 g of N-methylpiperazine and 0.145 g of triethylamine it was refluxed for 3 hours in 2.5 ml of chloroform. The reaction mixture was then washed successively with 3 ml water and 3 ml saturated NaCl solution and dried over MgSO 4. The solvent was removed by distillation under reduced pressure and the residue thus obtained was purified by column chromatography (with 2% ethanol in chloroform over Wako silica gel C-200). This gave 0.294 g of ethyl 2- / 2-chloro-5-fluoro-6- (4-methylpiperazino) -nicotinoyl 7-3- (2,4-difluorophenylamino) acrylate as oil.

-1 IR (as oil) cm: 1735, 1700 10 NMR (in CDCl 3) 6 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 (1H, d, J = 13 Hz), 12.50 (1H, d, J = 13 Hz).

(2) By 200 mg of ethyl 2- / 2-chloro-5-fluoro-6- (4-methylpiperazino) nicotinoyl / -3- (2,4-difluorophenyl-amino) acrylate in the same manner as in Examples VI and IX, 120 mg of 6-fluoro-1- (2,4-difluorophenyl) -7- (4-methylpiperazino) -4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid with mp. 208-209 ° C.

Example XIV

A mixture of 300 mg of ethyl 1-7- (4-ethoxy-carbonyl-2-methylpiperazino) -6-fluoro-1- (2,4-difluorophenyl) -4-oxo-1,4-dihydro-1,8-naphthyridine -3-carboxylate, 5 ml N 25 aqueous NaOH solution and 5 ml ethanol were heated at 90 ° C for 2 hours

kept. Then acetic acid was added to the mixture to a pH of 6.5. The resulting crystals were filtered off, washed with water and dried, yielding 200 mg of 6-fluoro-1- (2,4-difluorophenyl) -7- (2-methylpiperazino) -30-4-oxo-1,4-dihydro-1,4 8-naphthyridine-3-carboxylic acid with m.p.

230-239 ° C.

IR (in KBr) cm 1730 NMR (in TPA-d ^) δ values: 1.50 (3H, s), 3.20-5.15 (7H, m), 7.00-7.90 (3H , m), 8.35 (1H, d, J - 13 Hz), and 9.20 (1H, s).

Q? 0 Ü i i ί i.

- 36 -

Example XV

2.06 g of triethylamine was added to a suspension of 1.0 g of 3-amino-pyrrolidine dihydrochloride in 20 ml of ethanol, whereby everything was dissolved. Now 2.0 g of ethyl-7-chloro-6-fluoro-1- (2,4-difluorophenyl) -4-oxo-1,4-dihydro-1,8-naphthri was added at 30 ° C over 15 minutes dinin-3-carboxylate was added, and that mixture was allowed to react at that temperature for 3 hours. After the reaction was completed, 30 ml of water was added and the crystals precipitated therein were collected by filtration and washed with 4 ml of water. The crystals thus obtained were suspended in 13 ml of 6N hydrochloric acid and the suspension was refluxed for 2 hours. After cooling, the resulting crystals were collected by filtration and washed with 2 x 2 ml of water, yielding 1.97 g of hydrochloride of 7- (3-aminopyrrolidino) -6-fluoro-1- (2,4-difluorophenyl) - 4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid.

-1

In the IR spectrum (in KBr) a signal at 1730 cm. Example XVI

20 To a suspension of 10.0 g of 7- (3-amino-pyrrolidino) -6-fluoro-1- (2,4-difluorophenyl) -4-oxo-1,4-di-hydro-1,8-naphthyridine 3-carboxylic acid in 75 ml of ethanol was added 5.2 g of p-toluenesulfonic acid monohydrate at 40 ° C, and that mixture was stirred at room temperature for 30 minutes. Then, the mixture was cooled to 15 ° C and the precipitated crystals were filtered and washed with a mixture of 5 ml of ethanol and 5 ml of water to give 12.8 g of p-toluenesulfonate of 7- (3-aminopyrrolidino) -6-fluoro- 1- (2,4-difluorophenyl) -4-oxo-1,4-dihydro-1,8-naphthyridin-3-carboxylic acid, m.p. 258-260 ° C.

-1

In the IR spectrum (in KBr) a signal at 1735 cm.

NMR (in DMSO-d.) Δ values o 1.82-2.42 (m) 3.12-4.30 (5H, m), 6.92-8.17 (8H, m) 2.27 (s) * (5H), 35 and 8.79 (1H, s).

Likewise, the 8501172 - 37 - oxalic acid salt of 7- (3-aminopyrrolidino) -6-fluoro-1- (2,4-difluorophenyl) -4-oxo-1,4-dihydro-1,8 -naphthyridine-3-carboxylic acid with sup. 250-253 ° C.

-1

In the IR spectrum (in KBr) a signal at 1730 cm.

Example XVII

To a solution of 1.6 g of methanesulfonic acid in 25 ml of acetic acid was added 5.0 g of 7- (3-aminopyrro-lidino) -6-fluoro-1- (2,4-difluorophenyl) -4-oxo-1, 4-Dihydro-1,8-naphthyridine-3-carboxylic acid was added and the mixture was stirred at room temperature until dissolved. To that solution was added 100 ml of ethanol over 40 minutes at 40-45 ° C. That mixture was cooled to room temperature and then stirred for 30 minutes. The precipitated crystals were collected by filtration and washed with 3 x 20 ml of ethanol to give 3.12 g of methanesuonate of 7- (3-aminopyrrolidino) -6-fluoro-1- (2,4-difluorophenyl) -4- oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid with m.p. > 300 ° C.

In the IR spectrum (in KBr) a signal at 1735 cm 2. Similarly, the sulfuric acid salt of 7- (3-aminopyrrolidino) -6-fluoro-1- (2,4-di-fluorophenyl) 4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid, m.p. 220-230 ° C.

In the IR spectrum (in KBr) a signal at 1735 cm * 25 (for C = 0).

Example XVIII

From a mixture of 50 g of 6-fluoro-1- (2,4-difluorophenyl) -4-oxo-7-piperazino-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid, 49 g of crystalline cellulose, 30 50 g of corn starch and 1 g of magnesium stearate were punched 1000 flat-type tablets.

Example XIX

1000 were mixed with a mixture of 100 g of 6-fluoro-1- (2,4-difluorophenyl) -4-oxo-7-piperazino-1,4-dihydro-1,8-35 naphthyridine-3-carboxylic acid with 50 g of corn starch capsules filled.

Ó ΰ V S i i -

Example XX

\ r - 38 -

From a mixture of 50 g of 7- (3-amino-pyrrolidino) -1- (2,4-difluorophenyl) -6-fluoro-4-oxo-1,4-di-hydro-1,8-naphthyridine-3- carboxylic acid, 49 g of crystalline cellulose, 50 g of corn starch and 1 g of magnesium stearate were crushed 1000 tablets of the flat type.

Example XXI

With a mixture of 100 g of 7- (3-amino-pyrrolidino) -1- (2,4-difluorophenyl) -6-fluoro-4-oxo-1,4-di-10 hydro-1,8-naphthyridine-3 -carboxylic acid and 50 g corn starch, 1000 capsules were filled.

15 8501172

Claims (7)

1. The 4-alpha-1,4-dihydronaphthyridine derivatives of general formula 1, wherein R 1 represents a hydrogen atom or a carboxyl protecting group, R 2 represents an unsubstituted or substituted aryl group and R 1 represents a halogen atom or a substituted or unsubstituted cyclic amino group and its salts. 2. The 4-oxo-1,4-dihydronaphthyridine derivative or salt thereof according to claim 1, wherein R 2 represents a substituted or unsubstituted phenyl group. The 4-oxo-1,4-dihydronaphthyridine derivative or salt thereof according to claim 2, wherein represents a phenyl group represented by one or more halogen atoms, alkyl, hydroxy, alkoxy, cyano, amino , acylamino and / or trihaloalkyl groups may be substituted. 4. 4-oxo-1,4-dihydronaphthyridine derivative or salt thereof according to claim 3, wherein R 2 represents a phenyl group substituted by at least one halogen atom. The 4-oxo-1,4-dihydronaphthyridine derivative or salt thereof according to claim 4, wherein R2 represents a 4-fluoro-phenyl or 2,4-difluorophenyl group. 6. 4-oxo-1,4-dihydronaphthyridine derivative or salt thereof according to any one of the preceding claims, wherein R 1 represents an unsubstituted or substituted pyrrolidino, piperidino, piperazino or morpholino group. The 4-oxo-1,4-dihydro-naphthyridine of its vessel or salt according to claim 6, wherein the substituent of the pyrrolidino, piperidino, piperazino or morpholino group is an alkyl, amino -, aminoalkyl, hydroxyalkyl, hydroxy, alkenyl, acyl, alkylamino, dialkyl amino, cyano, oxo, aralkylamino, acylamino, alkoxycarbonyl or N-acyl-N -alkylamino group. 8501172 S-Hd-8,4-oxo-1,4-dihydronaphthyridine derivative or salt thereof according to claim 7, wherein the substituent of the pyrrolidino, piperidino, piperazino or morpholino group is an alkyl, amino -, hydroxyalkyl, hydroxy, alkenyl, acyl, alkylamino, dialkylamino, acylamino, alkoxycarbonyl or N-acyl-N-alkylamino group. 9. 4-oxo-1,4-dihydronaphthyridine derivative or salt thereof according to any one of claims 2 to 8, wherein represents a substituted or unsubstituted pyrrolidino group. The 4-oxo-1,4-dihydrous tyridine derivative or salt thereof according to claim 9, wherein represents a pyrrolidino group which is substituted by an amino or acylamino group. 11. The 4-oxo-1,4-dihydronaphthyridine derivative or salt thereof according to claim 10, wherein represents a 3-aminopyrrolidino group. A 4-oxo-1,4-dihydronzftyridine derivative or salt thereof according to any one of claims 1 to 6, wherein R 1 represents a piperazino group consisting of one or more alkyl, hydroxyalkyl, alkenyl , acyl, and / or alkoxy-carbonyl groups may be substituted. 13. 4-oxo-1,4-dihydronaphthyridine derivative or salt thereof according to claim 12, wherein R 1 represents an unsubstituted piperazino group. 14. The 7-chloro-1- (2,4-difluorophenyl) -6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid and its salts. 15. The 7- (3-aminopyrrolidino) -1- (2,4-30 difluorophenyl) -6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid and its salts. 16. The 1- (2,4-difluorophenyl) -6-fluoro-4-oxo-7-piperazino-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid and its salts. 17. The 7- (3-aminopyrrolidino) -6-fluoro-1- (4-fluorophenyl) -4-oxo-1,4-dihydro-1,8-naphthyridine-3-car-8531172. -w - carboxylic acid and its salts. 18. Process for the preparation of compounds according to any one of the preceding claims, characterized in that a 4-oxo-1,4-dihydronaphthyridine derivative according to formula 1, wherein R 1, R 1 and R 1 is the above have given meanings or whether a salt thereof is prepared in a manner known per se for analogous compounds. 19. An antibacterial composition containing a compound according to any one of claims 1 to 17 or a salt thereof as an active ingredient. as o 117i.