CS250684B2 - Method of 1,4-dihydro-4-oxonaphthyridine derivatives production - Google Patents

Abstract

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

Description

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

To date, nalidixic acid, piromidic acid, pipemidic acid and the like have been widely used as synthetic antibacterial agents. However, none of these agents has a satisfactory therapeutic effect on infections caused by Pseudomonas aeruginosa and Gram-positive bacteria, which are economical and difficult to treat diseases. Thus, various pyridonecarboxylic acid compounds such as 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl) -3-quinolinecarboxylic acid (norfloxacin) have been 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. Thus, it is desirable to develop synthetic antibacterial agents with a broad spectrum of activity, which would be effective not only against Gram-negative bacteria but also against Gram-positive bacteria.

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

SUMMARY OF THE INVENTION The present invention provides a process for the preparation of novel 1,4-dihydro-4-oxonaphthyridine derivatives and their salts, which have excellent properties, for example, strong antibacterial activity against Gram-positive and Gram-negative bacteria, in particular antibiotic-resistant bacteria. application occur in the blood in high concentration and are very safe.

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

O (AND) R ³ 1, R ²

in which

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

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

R ³ is 1-pyrrolidinyl, piperidinyl, 1-piperazinyl or morpholino 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, dialkylamino groups of 1 to 4 carbon atoms in each alkyl moiety, hydroxyalkyl groups of 1 to 4 carbon atoms, alkenyl groups of 2 to 4 carbon atoms, acylamino groups of 1 to 4 carbon atoms, acyl groups of 1 to 4 carbon atoms, N- acyl-N-alkylamino groups containing from 1 to 4 carbon atoms in both the acyl and alkyl moieties and alkoxycarbonyl groups having 1 to 4 carbon atoms in the alkoxy moiety, and salts thereof, characterized in that the compound of the formula II

CS 250 684 B2 (II) in which

represents a hydrogen atom or a carboxyl function protecting group. represents a halogen atom and has the above meaning, or a salt thereof, with a compound of formula III

-H (III) wherein

is as defined above, or with a salt thereof.

The term c ^h r ^{a ck} c ^s sJcup ^{on the} Ar ^b oxy ^l b ^{s f} functions in the meaning of ^Y MboI R ^Ia with ^H rnuje to ^an example, ^a ester-forming groups that can be removed by catalytic reduction, chemical reduction or other reactions occurring under mild conditions, ester-forming groups that are readily cleaved in the living body, silicon-containing organic groups, phosphorus-containing organic groups and tin-containing organic groups that are readily cleavable by water or alcohol, and other various well known ester-forming groups.

Of these carboxyl function protecting groups, the preferred protecting groups are, for example, the carboxyl function protecting groups described in Japanese Patent Application Publication No. 80 665/84.

The phenyl group R may be substituted by one, two or three substituents selected from the group consisting of halogen atoms such as fluorine, chlorine, bromine, iodine and the like, alkyl groups of 1 to 10 carbon atoms, for example straight or branched alkyl groups of 1 up to 10 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl and the like, hydroxyl, alkoxy of 1 to 10 atoms carbon, for example straight or branched alkoxy of 1 to 10 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, hexyloxy, hexyloxy, hexyloxy, hexyloxy, hexyloxy, hexyloxy, hexyloxy, hexyloxy, hexyloxy, hexyloxy, hexyloxy; , amino, C 1 -C 4 acylamino, such as formylamino, acetylamino, propionylam and a trihaloalkyl group having 1 to 4 carbon atoms in the alkyl moiety, such as trifluoromethyl, trichloromethyl and the like.

1-pyrrolidinyl, piperidino, 1-piperazinyl and morpholino group represented by R ^J may be substituted with one or two substituents selected from the group consisting of alkyl groups having 1 to 4 carbon atoms, for example straight or branched alkyl groups having 1 to 4 carbon atoms, as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl, amino, hydroxyalkyl of 1 to 4 carbon atoms in the alkyl moiety, such as hydroxymethyl, 2-hydroxyethyl, 3- hydroxypropyl and the like, hydroxyl, alkenyl groups of 2 to 4

CS 250 684 B2 carbon atoms such as vinyl, allyl and the like, acyl groups of 1 to 4 carbon atoms, such as formyl, acetyl, propionyl, butyryl and the like, alkylamino groups of 1 to 4 carbon atoms such as methylamino, ethylamino, n propylamino, isopropylamino and the like, dialkylamino groups in each alkyl moiety each having up to 4 carbon atoms, such as dimethylamino, diethylamino, di-n-propylamino, methylethylamino and the like, acylamino of 1 to 4 carbon atoms, such as acetylamino, butylamino, propionylamino. C1-C4alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and the like, and N-acyl-N-alkylamino groups each containing from 1 to 4 carbon atoms in the acyl and alkyl portions, the nitrogen atom in the above-mentioned alkylamino group is substituted with acyl C 1 -C 4 -alkyl such as acetyl, propionyl, butyryl and the like.

The halogen atom represented by ^R4 is such ^CART ice ^{fluorine atom,} chloro or bromo.

'2

Among the compounds of formula (I) above, those in which R represents a 4-fluorophenyl or 2,4-difluorophenyl group and R represents an optionally substituted 1-pyrrolidinyl or 1-piperazinyl group as described above and are more preferred are those compounds in which R represents a 2,4-difluorophenyl group; and

R is 3-amino-1-pyrrolidinyl.

Salts of compounds corresponding to formulas I and II above include conventional salts on basic groups such as amino and the like, and on acid groups such as carboxyl, and the like. Salts on basic groups include, for example, salts with mineral acids such as hydrochloric acid. , sulfuric acid and the like; salts with organic carboxylic acids such as oxalic acid, formic acid, trichloroacetic acid, trifluoroacetic acid and the like; salts with sulfonic acids such as methanesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid and the like. include, for example, alkali metal salts such as sodium, potassium, and the like, alkaline earth metal salts such as calcium, magnesium, and the like, ammonium salts and salts with nitrogenous organic bases such as procaine, dibenzylamine, N-benzyl. i-phenethyl-.

amine, 1-efenamine, Ν, Ν-dibenzylethylenediamine, triethylamine, trimethylamine, tributylamine, pyridine, Ν, dim-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine and the like.

When a compound of Formula I or II, or a salt thereof, may exist in the form of isomers (e.g., optical isomers, geometric isomers, tautomers, and the like), the invention includes all such isomers, crystalline forms and hydrates thereof.

The following section describes antibacterial activities and acute toxicity for typical compounds produced by the process of the invention.

1. Antibacterial efficacy

Test performance

According to standard methods^y I^pan Soc^andet^y O^F Chemo ^ erapy ^ Chemotherapy ,, 29,⁽¹⁾, 76 to (1981) with a bacterial solution blended with Ku^ltivací na^ofivn^E soil with infusion from heart after d^Ob^at 20 hours^při te^plot^E Deň: 32 ° C^andno^tomakes agar with infusion from the sewer, o^bsahu^hertostova substance^pr^eparát s^E Cultures for 20 hours^při te^plot³⁷ ° C, then you^hodno^tí r^atwith^tbif ± erie.

The minimum concentration that inhibits bacterial growth (MIC) in µg / ml is determined. I ^no kulaks ^nus dose Bakt ^e ry 'is 10 ^{4 b} un ^EK / ^pl otnu ^Ek CLO ⁶ cells / ml. The values of m ^and the ^AL n ^e c ^h inh them ^IBIC concentration (MIC) for each test compound are shown in Table 1.

The individual symbols used in Table 1 have the following meanings:

CS 250 684 B2 ^χ ) inoculation dose of 10 ⁸ cells / ml Me = methyl group

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

Test microorganisms shall be identified in capital letters according to the following key:

A = St. Aureus FDA 209P

В = 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. Anitratus A-6

I = Ps. aeruginosa IFO3445

J = Ps. aeruginosa GN918 producing cephalosporinase

Test substances correspond

Table 1 compound no. organism ^R2 F R ² : R ² : ^H0— - ^H ° - © ~ ^ho - © h · R * R ³ : R ³ : / - \ MeN N- O- O- 1 2 3

AND 0.1 <0.05 <0.05 В 0.1 <0.05 <0.05 C 0.1 <0.05 <0.05 D <0.05 0.39 0.1 E <0.05 0.2 <0.05 F <0.05 0.1 <0.05 G 0.39 6.25 1.56 H 0.2 0.2 <0.05 AND 3.13 12.5 3.13 J 0.39 3.13 0.78

CS 250 684 B2 organism compound no.

AND 0.1 0.2 (B) 0.1 0,39 ^X ) C 0.1 0.2 D <0.05 <0.05 E <0.05 <0.05 F <0.05 <0.05 G 1.56 0.39 H 0.1 0.2 AND 3.13 0.78 J 0.78 0.39

r ~ _ HN N—

7. 8.

AND 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 AND 1.56 12.5 6.25 J 0.78 3.13 1.56

CS 250 684 B2

Ί Compound no.

organism

ен ₂ =

CH / __

CH ₂ N ^ __ N-

A B C D G F I H

9 10 11 0.2 0.2 «0.05 0.2 0.39 <0.05 0.2 0.2 <0.05 <0.05 0.39 <0.05 <0.05 0.1 <0.05 CO, 05 0.1 «0.05 3.13 6.25 0.2 0.2 0.2 <0.05 3.13 12.5 0.2 3.13 3.13 0.1

compound no.

organism

R ² . R ² :

12 13 14 AND <0.05 0.2 0.2 (B) 0.1 0.2 0.2 C 0.1 0.1 0.2 D <0.0 5 <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 AND 0.2 1.56 1.56 J 0.1 0.39 0.39

2. Acute toxicity

LD _C q values determined by intravenous administration of test compounds Nos. 5 and 12 (see

CS 250 684 B2 Table 1) to mice (male ICR strain, body weight 18-24 g) is 200 mg / kg or less.

Thus, in accordance with the invention, the compounds of formula I or salts thereof are obtained by reacting a compound of formula II, or a salt thereof, with a compound of formula III, or a salt thereof.

The process of the invention will be discussed in more detail in the following.

Any solvent inert under the reaction conditions can be used in the reaction of the invention. These solvents are not critical and include, for example, aromatic hydrocarbons such as benzene, toluene, xylene and the like, ethers such as dioxane, tetrahydrofuran, anisole, diethyl ether of diethylene glycol and the like, halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane and the like; amides such as Ν, Ν-dimethylformamide, N, N-dimethylacetamide and the like; sulfoxides such as dimethylsulfoxide and the like; alcohols such as methanol, ethanol and the like; nitriles such as acetonitrile and the like; containing two or more of these solvents. The cyclic amine of the above formula (III) or a salt thereof is preferably used in excess, most preferably in an amount of from 2 to 5 moles for each mole of the compound of formula (I) or a salt thereof. When the cyclic amine is used in an amount of about 1 to 1.3 moles, it is sufficient to use an acid binder in an amount of 1 mole for each mole of the compound of formula (I) or a salt thereof. Acid binding agents include organic and inorganic bases such as triethylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene, potassium t-butoxide, potassium carbonate, sodium carbonate, sodium hydride and the like.

The salts of the cyclic amine (III) include the same salts as those on the basic group of the compounds of formula (I).

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

A compound of formula II wherein R represents ^a carboxyl protecting group, or a salt thereof, can optionally be converted to the corresponding free carboxylic acid by hydrolysis in the presence of an acid or base conventionally used in hydrolysis. This hydrolysis is generally carried out at a temperature of from 0 ° 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. Further, the compound of formula (I) or a salt thereof may optionally be converted by a known salt-forming reaction or esterification to the corresponding salt or ester. If the compound of formula (I) or a salt thereof contains an active group (for example, a hydroxyl group, an amino group and the like) at other positions than the reaction, the active group may be protected in the usual manner and cleaved again after the reaction.

The compounds thus obtained can be conveniently isolated and purified, such as by column chromatography, recrystallization, extraction and the like.

The starting materials of the formula II can be prepared, for example, by reacting the compounds of the formulas IV and V according to the following reaction scheme:

O | i R ⁴ (IV)

CS 250 684 B2

in which

.COOR ^1a

NH-R ²

, COOR ^1a (V) or salt (II) or salt

means a carboxyl function protecting group; and

^And R, R ² and R ⁴ are as defined above.

The salts of the compounds of the general formula V are the same as those mentioned for the compounds of the general formulas I and II.

(i) A compound of formula V or a salt thereof is obtained by reacting a compound of formula IV with an acetal such as,, Ν-diethylformamide-dimethylacetal, N, N-dimethylformamide diethyl acetal and the like, and then with an amine of formula

in which

is as defined above.

Any of the solvents inert to the reaction may be used for the above reactions. Such non-critical solvents include aromatic hydrocarbons such as benzene, toluene, xylene and the like, ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol dimethyl ether and the like, halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane and the like, amines, such as N, N-dimethylformamide, Ν, Ν-dimethylacetamide and the like, sulfoxides such as dimethylsulfoxide and the like, etc., the solvents being used alone or as mixtures of two or more of these solvents.

Acetal is used in an amount of preferably 1 mole or more, in particular in an amount of about 1.0 to 1.3 moles, for each mole of the compound of formula II. These reactions are usually performed ^at te lo ^{p I} from 0 ° ^C to ¹⁰⁰ ° C with the above !, Oda ^{h at} te ^pl of ^{TE 5} 0 ° C to ⁸⁰ ° C, ^generally lasting ^{s 20} m ^and nut to 50 hours, preferably 1 to 3 hours. The amine is used in an amount of 1 mole or more per mo compound ^{No. l i} n ^y en general ^eh of formula ^IV. Realcce is usually carried out ^{even with} the ^p lo ^you on ^{d 0 d} about ¹⁰⁰ ° C, above ^h o ^d ou on ^{d 10 d 60} ° C, ^C o ^d a ^b u ^p by ^Hyb UJ ^I C ^Í a ^{b d e} o ECN mine ^{20 30 TD} him ^di n where ^h Oda above 1 to 5 hours. .

Alternatively, the compound of formula (IV) may be reacted with ethyl ortho-formate or methyl-orthoformate in the presence of acetic anhydride, followed by an amine of formula R-NH 2 or a salt thereof to form a compound of formula V or a salt thereof.

(Ii) The compound of formula (II) or a salt thereof is obtained by subjecting a compound of formula (V) or a salt thereof to a cyclization reaction (preferably with heating) in the presence or absence of a base.

The solvent usable for this reaction may be any solvent inert under the reaction conditions. Examples of such solvents that do not play a critical role include amides such as Ν, Ν-dimethylformamide, Ν, Ν-dimethylacetamide and the like, ethers such as dioxane, anisole, diethylene glycol dimethyl ether and the like, sulfoxides such as dimethylsulfoxide and the like, etc. These solvents may be used alone or as mixtures of two or more thereof. Suitable bases include, for example, sodium bicarbonate, potassium carbonate, potassium tert-butoxide, sodium hydride and the like. The base is preferably used in an amount of from 0.5 to 5 moles for each mole of the compound of formula (V) or salt thereof. The reaction is usually carried out at a temperature of from 20 ° C to 160 ° C, preferably from 100 ° C to 150 ° C and generally takes from 5 minutes to 30 hours, preferably from 5 minutes to 1 hour.

For use in medicine, the compounds are conveniently combined with carriers used in conventional pharmaceutical preparations and formulated into tablets, capsules, powders, syrups, granules, suppositories, ointments, injectables and the like in a manner known per se. The routes of administration, dose levels and number of applications can be varied accordingly depending on the symptoms of the disease in the patient. The disclosed compounds are generally administered orally or parenterally (e.g., by injection, infusion or rectal) to adult patients at a daily dose of 0.1 to 100 mg / kg, which may be administered in a single dose or in divided doses.

The following Reference Examples, Examples and Preparations illustrate the invention but are not intended to limit the scope of the invention in any way.

The symbols used in the examples have the following meanings:

Me = methyl

Et = ethyl n-Pr = n-propyl i-Pr = isopropyl. Ac = acetyl group allyl group / XZ = ethylene group

Signal shapes in NMR spectra are designated by the following common abbreviations:

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

Reference Example 1

21 g of 2,6-dichloro-5-fluoronicotinic acid and 23.8 g of thionyl chloride are dissolved in 210 ml of chloroform and 0.1 g of Ν, Ν-dimethylformamide is added to the solution. The resulting mixture was allowed to react at 70 ° C for one hour, then the solvent and excess thionyl chloride were distilled off under reduced pressure, and the residue was dissolved in 21 ml of tetrahydrofuran. In 110 ml tetrahydroCS 250 684 B2 furan was dissolved 25.1 g of diethyl ethoxymagnesiummalonátu, cooled to -40 ° C to ^-30 ° ^{C and tet t} e ^pl of ^{thee him} It runs ^{30 h} i ^ em nut ^when dripping ^{Pla d} em ^conn Raven zt ^y ° ^of the ^2, 6-dichloro-5-fluoronicotinoyl. The mixture was stirred at the above temperature for 1 hour, then 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 6 N hydrochloric acid, the organic layer was separated, washed successively with 50 ml. 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 g of p-toluenesulfonic acid were added to the oily residue, and the resulting mixture was allowed to react at 100 ° C with vigorous stirring for 2 hours. 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 silica gel column chromatography. Elution with toluene gave 23.5 g of ethyl (2,6-dichloro-5-fluoronicotinyl) acetate, m.p. 64-65 ° C.

IC (KBr): ^Ό C _{= Q} 1,650 ^, 1,630, 1,620 cm ^-1 .

NMR (CDCl3): 1.25 (1.29H, t, J = Hz), 1.33 (1.71H, t,

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

Reference Example 2

In 40 ml of benzene were dissolved 8.8 g of ethyl (2,6-dichloro-5-fluoronicotinoyl) acetate to a solution of 4.5 g Ν, Ν-dimethylformamide dimethylacetal and the resulting mixture was left for ^1, 5 ^d him in ^y rea ^g ovata ^BC i te ^pl OTE ⁷⁰ ° C. After ^also given ^{at 4,} 1 g of ^2,4-d i ^fl fluoroanilino ^where nu is privileged. direction ^of the stand 4 'hours of reaction at room temperature, whereupon the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel using chloroform as eluent, 9.0 g of ethyl 2- (2,6-dichloro-5-fluoronicotinoyl) -3- (2,4-difluorophenyl ^{l l amino)} acrylate ^la have a ^pl of ^T e n ^{e I th 138} 1З to ⁹ ° C.

iC (KBr-technique ^to a): C_ _o ^{1 690} cm \

NMR (CDCl3): 1.08 (3H, t, J = 7Hz), 4.10 (2H, q, J = 7Hz), 6.77-7.40 (4H, m), 8.50 (1 H, d, J = 13 Hz),

12.70 (1H, d, J = 13Hz).

In a similar manner, the compounds shown in Table 2 were prepared:

Table 2

Compound

Physical properties

Melting point (° C) IC (KBr) cm -1 J _{c = Q}

87-89

690

CS 250 684 B2

Table 2 continued

Compound Physical properties

oil 1 705, 1680 (arm) *) 154-155 1 720 (arm), 1685 100-101 1 700 (arm), 1685 123-125 1 710, 1680 145-146 1 705, 1680 147-149 1 685 oil 1 695 ^x)

About me

CS 250 684 B2

Compound

Physical properties

Melting point (° C)

IC (KBr) [nu] _C-O

Table 2 continued

119-121 oil

700

700 ^x)

Me

183-1861

136-1381

114-1161

92-951

137.5-1391

125-126 .1

685, 1670

705, 1680

680

705

725 (arm), 1680

700 (arm), 1660

About me

91-92

705, 1690 x 1

Legend: The iC spectrum was not measured by the KBr technique but in the substance

Reference Example 3

9.0 g of ethyl 2- (2,6-dichloro-5-fluoro-nicotinoyl) -3- (2,4-difluorophenylamino) -acrylate are dissolved in 90 ml of Ν, form-dimethylformamide; 6 g of sodium bicarbonate were added and the mixture was allowed to react at room temperature for 20 minutes

CS 250 684 B2 at 120 ° C. The solvent was distilled off under reduced pressure, the residue was dissolved in ⁵⁰ ml of chloroform, the solution was washed successively with 30 ml of water and 30 ml of saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the crystalline residue was washed with 30 ml of diethyl ether. 7.0 g of ethyl 7-chloro-6-fluoro-l- (2,4-difluorophenyl ^ Hl ^ -dihydro ^ -oxo-l ^ -on ^ ^^ yriílJÍn artoxy ^ te ^pl of the rpm ^of t ^á the ²²⁰ and ^{from 222} ° C.

IC (KBr): 1730, 1690 ^{cm first}

NMR (CDCl3): 1.36 (3h, t, J = 7Hz), 4.30 (2H, q, J = 7Hz),

6.80 to 7.60 (3H, n), 8.27 (1H, d, J = 7Hz), ‘8.42 (1H, s).

In a similar manner, the compounds shown in Table 3 are obtained:

Table 3

Compound

Physical properties

Melting point (° C)

IR (KBr) cm ^_1: ^ _{C = 0}

222-224 1,730, 1,685

231-232 1,730, 1,705

239-241

685

205-208 1,735, 1,685

244-246 1,720, 1,680

207-209,5

730, 1690

210-214

735 (arm), 1 705

CS 250 684 B2

Table 3 continued

Compound

R

Physical properties

Temp t ^{and the} melting point (° C) IR (KBr) ^cm-1: _{C =} J _Q

207-208

181-186

204-205

216-218

196-198

156-160

730, 1680

730, 1685

730, 1685

735, 1695

735, 1685

730, 1690

231-236

730, 1685

CN

270-273

730, 1690

NHAc

199-201

730, 1680

CF ₃

199-202

735, 1685

F

CS 250 684 B2

Table 3 continued

Compound

Physical properties

Melting point (° C) IR (KBr) cm -1 ^{:? С} _{= 0}

208-211 1,730, 1,695

About me

About me

142-144 1740, 1695

163-165 1,730, 1,695

160-162 1,735 / 1,690

EXAMPLE 1 (a) 3.5 g of ethyl 7-chloro-6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8 are dissolved in 35 ml of chloroform. naphthyridine-3-carboxylate and 1.5 g of N-acetyl, treated with ^1, 6 ^{g trimethyl} et ^{hy phenylamino} Nu bui ^l EDN ^and the mixture NEC ^{hook 1 d} yne react it ^{at t} e OTE ^{60 pl} Deň: 32 ° C. Extended on ^p Oust ^dl was distilled off under reduced pressure and the residue was purified by column chromatography on silica gel using a mixture of chloroform and ethanol (30: 1 by volume) as eluant. 3.5 g of ethyl 7- (4-acetyl-1-piperazinyl) -6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-8-naphthyridine are obtained. ³ - ^b ar ^to oxyl ^and have a lot ^of te ^{p th} n ^{s 207,} and ^{from 209} ° C.

IR (KBr): 1730, 1695 cm ^-1 .

NMR (CDCl3): 1.38 (3H, t, J = 7Hz), 2.05 (3H, s), 3.53 (8H, bs),

4.30 (2H, q, J = 7Hz), 6.80-7.75 (3H, m), 8.00 (1H, d, J = 13Hz), 8.30 (1H, s)

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

Table · 4

Physical properties of Te ^p lo ^t at ^{ck (C)}

AcN N—

X___f

216-218

730, 1,690 ()

CS 250 684 B2

Table 4 continued

Compound

Physical properties

К

Melting point (° C)

155-156

217-218

144-146

143

198-202

220-222

253-255

203-205

211-213

206

IC (KBr) cm -1 XJc-o

730,

730,

730,

730

725,

730,

730,

730,

735

725,

690

695

690

690

695

690

700

690

193-194

730,

700

CS 250 684 B2

Table 4 continued

Compound

Physical properties

Temperature T ^ck (C) '

IR (KBr) cm &^lt; -1 & gt _;

AcN NX ____ /

Ac

Me

\ _У

MeN__N—

Г ~ \

AcN N—

Ac

AcN NV_7

244-246

186-187

155-157

153-154

153-155

166-168

202-204

230-231

193-194

207

725, 1690

725, 1 690 (arm)

720, * 1,685

730, 1700

730, 1695

730 (arm), 1,690

730, 1690

725 (arm), 1695

720 (arm), 1680, 1675

725, 1695

254

730, 1690

Cl

CS 250 684 B2

Table 4 continued

Compound

Physical properties

Te ^pl ota t ^{ck (C)}

IC (KBr) cm ^-1 : ^y _{= c}

208

730, 1690

246-247

730, 1690

Br

Me

Me

About me

About me

About me

About me

About me

HIM

About me

About me

AcN N -

/ --- \

MeN N— ___ / --- \

EtN N— \ __ /

i —PrN N / - \

N N____f

167-169

206-207.5

163-165

174-176

180-181

171-172.5

208,5-210

200-202

162-163

730, 1695

730, 1690

735, 1700

730, 1690

735, 1695

730, 1685

730, 1690

730, 1690

725, 1690

CS 250 684 B2

Table 4 continued

Compound

Physical properties

/ \ 270-272

AcN N1 730, 1690

CN

Γ ~ \

AcN Nw

245-249

730, 1695

NHAc

CF3

About me

Me

/ —X

AcN N \ - /

AcN NX ___ /

249-252

263-264

166-169

222.5-223.5

165-168

170-171

730, 1695

730

730, 1685

730, 1690

730, 1685

730, 1695

725, 1690

CS 250 684 B2

Table 4 continued

Compound

Physical properties

amorphous substance

725, 1690

NHAc

About me

About me

186-189

166-168

725, 1690

730, 1695

2) 2.5 g of ethyl 1- (4-acetyl-1-piperazinyl) -6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4 are dissolved in 25 ml of 6 N hydrochloric acid. oxo-1,8-naphthyridine-3-carboxylate and the resulting solution was heated at reflux for 2 hours. The reaction mixture was cooled to room temperature and its pH was first adjusted to 12 with 1 N aqueous sodium hydroxide and then to 6.5 with acetic acid. The crystals formed 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, δ): 3.30 to 4.50 (8H, m), 7.00 to 7.85 '(3H, m), 8.33 (1H, d, J = 13 Hz) 9.21 (1H, s).

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

у

CS 250 684 B2

Table 5

Compound

Physical properties

Melting point (° C)

IC (KBr) cm ^-1 = 1

HN N \ ___ /

MeHN NHN N-

252 / 5-254.5

730> 280

279-280

234-236

222-224 ^χ ) 1,720 (arm)

725 (arm)

720

725

280

720

254-258

205-207

225-227

725

730

725> 280

725

CS 250 684 B2

Table 5 continued

Compound

R

Physical properties

Melting point (° C) IR (KBr) cm -1 = 0

HN N-

273-277

245-246

280> 280

232-236> 280

230-232

720

725

725

730, 1710

725, 1710, 1690

725

730

X)

Legend: IR spectrum is not measured by KBr technique but in nujol

Example 2

1) 0.50 g of ethyl 7-chloro-6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3- is dissolved in 5 ml of chloroform. of carboxylate, 0.20 g of 3-acetylaminopyrrolidine and 0.15 g of triethylamine are added to the solution, and the resulting mixture is allowed to react at 60 ° C for 1 hour. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography using a 30: 1 by volume mixture of chloroform and ethanol as eluent. 0.5 g of ethyl 7- (3-acetylamino-1-pyrrolidinyl) -6-fluoro-1- (2,4-difluorophenyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3) is obtained. -carboxylate, m.p. 233-235 ° C.

IR (KBr): 1725, 1700 cm ^1st

NMR (CDCl3): 1.32 (3H, t, J = 7 Hz), 1.77 to 2.27 (m)

2.08 (s)

CS 250 684 B2

J - 8 Hz)

In a similar manner, the compounds shown in Table 6 are obtained:

Table 6

Compound

3.12 to 3.74 (4H, m) 6.75 to 7.60 (4H, m) 8.24 (1 H, s).

4.02 to 4.74

4.29 (q, J =

7.93 (1 H, d,

(m)

Hz)

Physical properties

R ³ Te ^p Iota melting point (° ^C) IR (KBr) cm ^-1 J

IN 231-233 1,730, 1,700 Μθ2Ν. Ъ- 156 1,730, 1,690 AcHN Ъ- 203-205 1725, 1690 ΜβΝ ^А Ъ- 201-202 1725, 1695 Me ₂ N. D- 165 1,730, 1,690

730, 1695

725, 1,700 (3H)

CS 250 684 B2

Table 6 continued

Compound

R

Physical properties

Melting point (° C) IR (KBr) cm ^"1 \)

735

730, 1690

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

NMR (deuterated trifluoroacetic acid, δ values): 2.25 to 2 , 85 (2H, m) 3.37 to 4.69 (5H, m), 6.93 to 7.81 (3H, m), 8.22 (1 H, d, J = 11Hz) 9.16 (1H, s).

In a similar manner, the compounds shown in Table 7 are obtained:

Table 7 ‘

COOH

Compound Physical properties

CS 250 684 B2

Table 7 continued

Compound Physical properties

1) 0.50 g of ethyl 7-chloro-6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine is suspended in 15 ml of 6 N hydrochloric acid. The 3-carboxylate and suspension were refluxed for 3 hours. The reaction mixture was diluted with 50 ml of water and extracted three times with 50 ml of chloroform each. The combined extracts were washed with 100 ml of saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. After washing the crystalline residue with 15 ml of diethyl ether, 0.40 g of 7-chloro-6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid is obtained. acid; th ^tup 244-248 ° C.

IR (KBr): \) q _{c =} 1720 cm ^1st

NMR (CDCl 3): 7.26-8.56 (3H, m), 8.86 (1H, d, J = 7Hz), 9.18 (1H, s).

2) 0.30 g of 7-chloro-6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid is suspended in 3 ml of dimethylsulfoxide. to the suspension was added 0.25 g of ^N-methyl-p i ^p erazinu and bui ^l EDN ^and the mixture NEC ^{hook 30} minutes rea ^{g ovata, PR} and ^PL te rt ^{of 60} ° C. Extended ou ^{p N l} o now is distilled off under reduced pressure and to the residue was added 30 ml of water. The pH of the reaction mixture was first adjusted to 12 with 10% aqueous sodium hydroxide solution and then to 7 with acetic acid. The precipitated crystalline material was filtered off and washed with 5 ml of water. 0.24 g of 6-fluoor-1- (2,4-difluorophenyl) -1,4-dihydro-7- (4-methyl-l-piperazinyl) -4-oxo-l, 8-naphthyridine N- ^di 3-carboxamide ^b ox ^yl memory sel ^{alkyl and} n ^y o te ^pl ol ^{E t} U ^{s? 2 208} and 09 ° C.

IR (KBr)) λ ^c _{= 0} 1730 cm ^-1 .

NMR (deuterated trifluoroacetic acid values): 3.30 (3H, s), 3.45-5.25 (8H,

m), 7.12-8.10 (3H, m), 8.49 (1H, d, J = 13Hz), 9.38 (1H, s).

Example4

2.0 g of ethyl 6-fluoro-1,4-dihydro-1- (4-methoxy-2-methylphenyl) -7- (4-methyl-1-piperazinyl) -4 are dissolved in 5 ml of 47% hydrobromic acid. oxo-l, 8-naphthyridine-3-carboxylate and ^expanded stream to let him ^{and 2 d y} in and respond ^instance te ^pl of ^{120 i} and ^{from 125} ° C. H ° ^{of unit in} R ap ^{H ESPONDING} the SRN ^of a first 10% aqueous sodium hydroxide solution was adjusted to 13 and then with acetic acid to pH 6.5. The crystals formed 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 are obtained. 3-carboxylic acid taj ^{y s} c ^{s 2} above 80 ° C.IČ (KBr techn ^{IK): 1} 7 ^{25, 1700} c ^m-1 amencj

NMR (deuterated trifluoroacetic acid, δ): 2.08 (3H, s), 3.12 (3H, s),

2.88 to 5.12 (8H, m);

7.62 (3H, m); 9.25 (1H, s);

9.43 (1H, d, J = 13Hz).

In a similar manner, the compounds shown in Table 8 are prepared:

CS 250 684 B2

Table 8

Compound

Physical properties of Te ^pl OTA ^th n ⁱ (° C)

IC (KBr) cm -1 _{= 0}

o143-146

725, 1710

OH

Γ—

Γ-N> 280

710

OH

/ - \

MeN ^ .N> 280

710

OH

/ - \ EtN N> 280

730

OH

n — PrN N— \ _7

OH

/ - \ i - PrN N-> 280)> 280

725

715

OH

200-205

720, 1,705

OH

r — λ

MeN N— \ ___ f> 280

725

245-250 (decomposition)

725, 1700 (arm)

CS 250 684 B2

T a b u 1ka 8 continued

Compound

Physical properties

X

MeN NMeN NV / // —X

MelY N / --- \

MeN ___ Example 5> 280

251-252> 280

228-230

275

730

725

720

725

730

720 (arm), 1700

700 (arm)

0.40 g of ethyl 6-fluoro-1,4-dihydro-1- (4-methoxy-benzene) -7- (1-p-pyrrolidinyl) -4-oxo-1,8-naphthyridine is dissolved in 10 ml of 47% hydrobromic acid. 3-carboxylate and the resulting solution was allowed to react at 120-125 ° C for 2 hours. The pH of the reaction mixture was first determined

It is 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 (-r-1,4-dihyrr-1- (4-hydroxy-phenylphenyl) -1,7- (1-pysoxirinyl) 14,4-xo-1,8-naphthyridine-3-) is obtained. 263 DEG-265 DEG.

CS 250 684 B2

IR (KBr): 9 _{C- O} 1 725, 1 705 cm ^-1 .

NMR of deuterated trifluoroacetic acid, values of 5): 1.54-2 , 40 (4H, m) 3.14 to 4.14 (4H, m), 6.95 to 7.69 . (4H, m), 8,09 (1 H, d, J = 12Hz) 9.14 (1H, s).

Similarly, 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 180-183 ° C.

IC (KBr) ^: δ _{C = Q} 1,725, 1,705 ^{cm -1} .

Example 6

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 was added 2 ml of 1 N aqueous sodium hydroxide and 2 ml ^TH yes e ^l u ^d Nu mites of results obtained ^for the NEC ^{hook 10} minutes ^at ovata rea ^g te ^p lot ^of 50 ° C. ^P H value of reaction ^mixture to acetic acid adjusted to pH 6.5 and extracted twice with 5 ml of chloroform. The combined extracts were washed successively with 5 ml of water and 5 ml of saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The crystalline product thus obtained, after washing with 2 ml of diethyl ether, gives 0.08 g of 7- (4-acetyl-1-piperazinyl) -6-fluoro-1- (4-fluorophenyl) -1,4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic YSE ^{if the} melting ny ^{2 and} over 80 ° C. .

^IR (KBr techrnika) ^J _ ° _C ^{1730 cm 1st} '

NMR (CDCl 3, δ): 2.05 (3H, s), 3.57 (8H, bs), 7.13-8.

7.80 (4H, m), 8.13 (1H, d, J = 13Hz), 8.70 (1H, s).

In a similar manner, the compounds shown in Table 9 are obtained:

Table 9

Compound

Physical properties

Melting point (° C)

277-280

720

F

282-290

725, 1700 (arm)

Me

HN N—

268-270

725

W

F

CS 250 € 85 B2

Table 9 continued

Compound

Physical properties

Te ^pl ota t ^ck (° C)

IC (KBr) cm ^-1 = ^c ₌ ⁰

283-285

267-270

138-139> 280

210-211

225-226

219-220

720

730

690

730, 1700 (arm)

720

720

735

720

730

283-284

730, 1700 (arm)

CS 250 684 B2

Table 9 continued

Compound Physical properties

Example 7

0.10 g of ethyl 6-fluoro-1- (4-fluorophenyl) -1,4-dihydro-7- (3-hydroxy-1-pyrrolidinyl) -4-oxo-1,8-naphthyridine-3-carboxylate was added 2 ml of 1 N aqueous sodium hydroxide and 2 ml of ^L and ^H ua yes bui ^l EDN ^and the mixture NEC ^{HA 10} landmine ^t rea ^g ovata ^at te ^pl OTE ^{40-50 o} C ^{d H} o note pH of the reaction mixture, Acetic acid was adjusted to 6.5 and extracted twice with 5 ml of chloroform each. The combined extracts were washed successively with 5 ml of water and 5 ml of saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The crystalline residue, after washing with 2 ml of diethyl ether, affords 0.08 g of 6-fluoro-1- (4-fluorophenyl) -1,4-dihydro-7- (3-hydroxyl-1-pyrrolidinyl) -4-oxo-1,8. naphthyridine-3-carboxylic acid in ^{kY y l i} Ci taj ^d to ^{280 o} C.

IR (KBbt-technique): _c = ^{0 730} cm ^b .

NMR (CDCl3): 1.92 to 2.52 (2H, m), 3.22 to 5.00 (5H,

m), 6.97-7.60 (4H, m), 8.01 (1H, d,

J = 11 Hz), 9.00 (1 H, s).

The compounds of Table 10 are obtained in an analogous manner:

Table 10 0 R ³ 1, R ^z Compound Physical properties

CS 250 684 B2

Example 8

0.25 g of 6-fluoro-1,4-dihydro-1- (4-hydroxy-2-methylphenyl) -4-oxo-7- (1-piperazinyl) -1 is dissolved in 2.5 ml of concentrated hydrochloric acid, Of 8-naphthyridine-3-carboxylic acid, 20 ml of ethanol are added to the solution, and the mixture is stirred at room temperature for 15 minutes. 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. of an acid melting above 280 ° C.

IR (KBr): \) _{C = 0} 1725 (shoulder), 1705 cm ^1st

The compounds of Table 11 are obtained in an analogous manner:

Table 11

Hydrochlorides of the compound represented by the general formula

Compound

Physical properties

Melting point (° C) ♦

IR (KBr) cm ^"1 -) _{C = 0}

OH

283

730

HN N—

275-278

720

V_7

Ηΐϊ N-

249-252 (decomposition)> 280

730

710

730

720 (arm) 1 705

CS 250'684 B2

Table 11 continued

Compound Physical properties ______ ^r2 ________________ ^r3 ________________ Melting point (° C) IR (KBr) cnT ¹ ^ _{C = Q}

OH

/ - \ MeN N - W 266-269 1,720 (arm) l 700 * ГЛ MeN N ~ 282 1 720

OH

Example 9

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

IC (KBr): c = 0 ^{730 cm}

Example 10

0.3 g of ethyl 7- (4-ethoxycarbonyl-2-methyl-1-piperazinyl) -6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8 -naphthyridine-3-carboxylate was added with 5 ml of 1 N aqueous sodium hydroxide solution and 5 ml of ethanol, and the resulting mixture was allowed to react at 90 ° C for 2 hours. The pH of the reaction mixture is adjusted to 6.5 by the addition of acetic acid, the precipitated crystals are filtered off and, after washing with water, dried. 0.2 g of 6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-7- (2-methyl-1-piperazinyl) -4-oxo-1,8-naphthyridine-3- is obtained. m.p. 230-239 ° C.

IR (KBr): J _{c = 0} 1730 cm ^1st

NMR (deuterated trifluoroacetic acid, δ): 1.50 (3H, s), 3.20-5.15 (7H,

m), 7.00 to 7.90 (3H, m), 8.35 (1H, d, J = 13Hz), 9.20 (1H, s).

Example 11

1.0 g of 3-aminopyrrolidine dihydrochloride is suspended in 20 ml of ethanol, and the suspension is brought into solution by the addition of 2.06 g of triethylamine. To this solution was added 2.0 g of ethyl 7-chloro-6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8 at 15 ° C over 15 minutes. -naphthyridine-3-carboxylate and the resulting mixture was allowed to react at the same temperature for 3 hours. After completion of the reaction, 30 ml of water are added to the reaction mixture, the precipitated crystals are filtered off and washed with 4 ml of water. The crystalline material was suspended in 13 ml of 6 N hydrochloric acid and refluxed for 2 hours. The reaction mixture was cooled, the precipitated crystals were filtered off and washed twice with 2 ml of water each time. 1.97 g of 7- (3-amino-1-pyrrolidinyl) -6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3 hydrochloride are obtained. -carboxylic acids.

IR (KBr): Ό _{c = 0} 1730 cm ^1st

CS 250 684 B2

Example 12

10.0 g of 7- (3-amino-1-pyrrolidinyl) -6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4- is suspended in 75 ml of ethanol and 75 ml of water. oxo-1,8-naphthyridine-33-carboxylic acid, 5.2 g of p-toluenesuffonic acid monohydrate were added at 40 ° C and the mixture was 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-thionyl-1-yyrrolidinyl) -. Alpha.-fluoro-N- (1,4-dihydro-4-oxo-1,8-naphthyridine) are obtained. -3-carbooylic acid with p-tololeisufonic acid monohydrate, m.p. 258-260 ° C.

IR (KBr): C _{= O} 1735 cm ^1st

NMR (δ): 1.82-2.42 (m) \

2.27 (s) / '

3.12 to 4.30 (5H, m), 6.92 to 8.17 (8H,

m), 8.79 (1 H, s).

Similarly, 7- (3-amino-1-tyrrolidinyl) -1,6-fluoro- (2,4-fluoro-phenyl) -1,4-furo-4-oxone-8-naphthyridine-3-carbooronic acid salt with acid 250 DEG-253 DEG.

iC (К-techn)::): J _{C = Q} 1,730 cm

EXAMPLE 13

To a solution of 1.6 g of methanesulfonic acid in 25 ml of acetic acid, add 5.00 g of 7- (3-amino-1-tyrolol-1-yl) -1,6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-ol. Oxo-1,8-naphthyridinium-3-carboxylic acid, the resulting suspension was stirred at room temperature until a solution was added, and 100 ml of ethanol were added to the solution over 30 minutes at 40-45 ° C. The reaction mixture is cooled to room temperature, stirred for 30 minutes, the precipitated crystals are washed with 3 times 20 ml of ethanol each time. There were obtained 3.12 g of 7- ^(3-amino-> LT cJ ^ -pyridine-id-хоуП б Зт-1- (2,4-diilunrieiyl) -1,4-dihydro-4-oxonl 8- naphthyrifine-3-carbooylic acid with methanesulfonic acid, melting at 300 ° C.

IR (KKR-Techno ^to a): ý ^{1735 cm 1}

There is obtained the salt of 7- (3-amino-l-pyrrolidfnil) -l6 ololl Il ^ (2 ^ ^^ feoyl difluorophenyl) l1,4ldihydro-4-oxo-lla, ^8-to-3 naftyridίn arbooylové acid with sulfuric acid, m.p. 220-230 ° C.

IR (KEBrtechoIka): J _{c = 0} 1735 cm ^1st

Preparation of 1 g .alpha.-fluoro-1- (2, 4-dimethylenedio) -1,4-dihydrol-4-oneol-7-1-pyrazinyl) -1,8-trans-3-pyrrolidinic acid 49 g of crystalline cellulose, 50 g of corn starch and 1 g of magnesium stearate are mixed, and 1000 flat tablets are pressed from the mixture.

Preparation 2

100 g of .alpha.-fluoro-b (2,4-difluoro (1,4-dihydro) -1,4-dihrdro-4-oneon-17- (1-piperazinyl) -M-piperazinic acid are mixed with 50 g of corn starch and the resulting mixture is filled 1,000 pockets.

Preparation of 3 g of 7- (3-amino-4-pyrrolidinyl) -1- (2,4-difluorophenyl) -1,6-fluoro-1,4-dihrdol-4-oxyl, 8CS 250 684 B2

The naphthyridine-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 compressed from the mixture.

\

Preparation 4

100 g of 7- (3-amino-1-pyrrolidinyl) -1- (2,4-difluorophenyl) -6-fluoro-1,4-oxo-4-oxo-1,8-naphthyridine-3-carboxylic acid is mixed with 50 g of corn starch and filled with 1000 capsules.

Claims (23)

OBJECT OF THE INVENTION A process for the preparation of 1,4-dihydro-4-oxonaphthyridine derivatives of the general formula I (I) wherein: 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 is 1-pyrrolidinyl, piperidinyl, 1-piperazinyl or morpholino 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, dialkylamino groups of 1 to 4 carbon atoms in each alkyl moiety, hydroxyalkyl groups of 1 to 4 carbon atoms, alkenyl groups of 2 to 4 carbon atoms, acylamino groups of 1 to 4 carbon atoms, acyl groups of 1 to 4 carbon atoms, N- acyl-N-alkylamino groups containing from 1 to 4 carbon atoms in both the acyl and alkyl moieties and alkoxycarbonyl groups having 1 to 4 carbon atoms in the alkoxy moiety, and salts thereof, characterized in that the compound of the formula (II) in which is hydrogen or protecting group of the carboxyl function, represents a halogen atom and (II) CS 250 684 B2 or a salt thereof, reacted with a compound of formula III (III) as defined above, -H in which has the abovementioned meaning, ^{because its} axis of ^ ¹ then, after ^possibly and ^{DE substituents} in R ^la is converted to R ¹ .. 2. A process according to claim 1, wherein the corresponding starting materials are used to form compounds of formula (I) wherein R is phenyl substituted by one, two or three halogen atoms and the remaining general symbols are as in point 1. . 3. A process according to claim 2, wherein the corresponding starting materials are used to give compounds of formula (I) wherein R is 4-fluorophenyl and the remaining formulas are as in 1. 4. A process according to claim 2, wherein the corresponding starting materials are used, wherein R is 2,4-difluorophenyl and the remaining general symbols are as in point 1. 5. A process according to claim 1, wherein the corresponding starting materials are used to form compounds of formula I wherein R is 1-pyrrolidinyl, optionally bearing a substituent selected from the group consisting of amino, hydroxyl, alkylamino groups of 1 to 5 4 carbon atoms, acylamino groups having 1 to 4 carbon atoms, N-acyl-N-alkylamino groups having 1 to 4 carbon atoms in each of the acyl and alkyl moieties and dialkylamino groups having 1 to 4 carbon atoms in each alkyl moiety, and the remaining general symbols have meaning as in point 1. 6. Method according to claim 5, characterized in that appropriate substances are used to produce compounds of formula I wherein R ³ represents a 1-pyrrolidinyl group substituted by amino or acylamino as defined above and the remaining symbols are defined as in point 1. 7. A process according to claim 6, wherein the corresponding substances are used after o give compounds of formula I wherein R is phenyl substituted with one, two not ^b o ^t SEM ^and hydrogen ^yh alo ^g en ^, ^R3, m ^and meaning as ^b ODU 6, and R ¹ is as j and ^k o ^b o ^d at ⁶ and R @ ^1, m ^{and b} in the meaning of ^d in the first 8. A method according to claim 7, wherein the corresponding substances are used For the formation of compounds of formula (I) wherein R is 4-fluorophenyl, R is as defined in 6 and R ¹ is as described in 1. 9. A method according to claim 7, characterized in that the application of the corresponding agent, to give compounds of formula I wherein R is 2,4-ďΐfluorfenylovou group, R 'is as defined in ^b o u ^{d 6} and has the meaning I ^d s ^to bo in ^{the first} 10. A method according to claim 1, wherein the corresponding compounds are used to form compounds of formula (I) wherein R @ ³ represents a 3-amino-1-pyrrolinedinyl group and the remaining general symbols are as in point 1. 11. The method of claim 10, wherein the corresponding starting material is used CS 250 684 B2 compounds to give compounds of formula I wherein R is phenyl, ^{B t} STI formula --NR one, two not of ^{class b} em ^and carbon cjen ha ^ ^ ^R3 represents a 3 ^{- amino -l- pyrrolidin} dinylovou s ^to u ^when u and R ¹ is as defined in point 1. 12. substances, on behalf of the group a Way . origin 3 1 R and R are as in point 11. according to claim 11, characterized in that a corresponding starting compounds of the formula I wherein R ² represents 4-fluorophenyl 13. to form a R ³ and R ³ Process according to claim 11, characterized in that using the corresponding starting materials, compounds of formula I wherein R is 2,4-difluorophenyl group have ^the meanings as in ^b o ^d u 11th 14. forming an optionally alkyl group with an alkenyl group of a nyl group having 1 meaning as in point The method of claim 1, wherein the corresponding starting materials of the compounds of formula I are used, wherein R 3 is a 1-piperazinyl group substituted with one or two substituents selected 4 carbon atoms, hydroxyalkyl groups having up to 4 carbon atoms, acyl groups having 1 to carbon atoms in the alkoxy moiety, and the remaining general symbols have 1 to 2 to 4 1. from the group consisting of 1-4 carbon atoms, 4 carbon atoms and alkoxycarb 15. substances, on behalf of the group a The method of clause 14, wherein the corresponding starting materials of formula I are used, wherein R ³ is 1-piperazinyl the remaining moieties are as defined in clause 14. 15. A method according to claim 15, wherein the corresponding starting materials of the formula I are used in which R represents a phenyl group. 16. Substances substituted after one or two halogen atoms and the remaining general symbols have the meanings given in point 15. 17. substances, on behalf of the group a The method of clause 16, wherein the corresponding starting materials of the formula I are used, wherein R is 4-fluorophenyl, and the remaining moieties are as defined in clause 16. 18. substances, on behalf of the group a The method of claim 16, wherein the corresponding starting material is used 2. to give compounds of formula (I) wherein R is 2,4-difluorophenyl the remaining general symbols are as in 16. 7. The method of claim 1, wherein the corresponding starting materials are 7-chloro-1- (2,4-difluorophenyl) -6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine. 3-carboxylic acid 19 Dec to form an acid or a salt thereof. 20. The process of claim 1, wherein the corresponding starting materials are used to give 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 0 ° C to 150 ° C.