KR870000894B1 - Process for preparing quinolone carboxylic acids - Google Patents

Abstract

Quinolone carboxylic acids of formula(I) or its pharmaceutically useful salts are prepd. by reacting (II) with A(CO)2O. R1=radical CO- R6;R6=C2-3 carboxyl-substd. alkyl or halogen opt. substd. carboxyl substd. phenyl; R2,R3,R4 and R5 are H; X=H or halgen; A=C2-3 opt. substd. alkylene chain or phenylene radical. Prepg. quinolone carboxylic acid is esp. 7-[4-(3-carboxypropionyl) -piperazine-1-il!- 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid.

Description

Process for preparing quinolone carboxylic acid

Novel quinolone carboxylic acids of the general formula (I), pharmaceutically useful acid addition salts thereof, alkali metal salts, alkaline earth metal salts and hydrates, useful as antimicrobial agents against Gram-positive and Gram-negative bacteria of the present invention .

In the above formula,

R ¹ is radical CO—R ⁶ , CN, SO ₂ —R ⁷ or SR ⁸ ;

R ⁶ is hydrogen, optionally substituted straight or branched alkyl having 1 to 6 carbon atoms, optionally substituted aryl having 6 or 10 carbon atoms, substituted aralkyl having 6 carbon atoms in the aryl moiety and 1 to 3 carbon atoms in the alkyl moiety, Optionally substituted alkoxy or alkylthio having 1 to 6 carbon atoms, optionally substituted aryloxy having 6 carbon atoms, optionally substituted benzyloxy, amino, optionally substituted alkylamino or dialkylamino having 1 to 6 carbon atoms, or Optionally substituted phenylamino;

R ⁷ is optionally substituted straight or branched chain alkyl, phenyl or methylphenyl having 1 to 5 carbon atoms;

R ⁸ is methoxycarbonyl, trichloromethyl, trifluoromethyl or dichlorofluoromethyl;

R ² , R ³ , R ⁴ and R ⁵ are the same or different and are hydrogen, methyl, ethyl, n-propyl or isopropyl;

X is hydrogen, halogen, preferably fluorine or chlorine, or nitro.

Preferred compounds of formula (I) are

R ¹ is CO-R ⁶ , CN, SO ₂ -R ⁷ , SR ⁸ ;

R ⁶ is optionally substituted by 1 to 3 substituents selected from hydrogen, amino, chlorine, alkoxycarbonyl having 1 to 4 carbon atoms, carboxyl, alkoxy having 1 to 4 carbon atoms, hydroxy and trifluoromethylthio Linear or branched alkyl of 1 to 5 carbon atoms; Phenyl optionally substituted by 1 to 5 substituents selected from fluorine, chlorine, hydroxyl, methoxy, amino and carboxyl; Benzyl optionally substituted by amino; C1-C1, optionally substituted by fluorine, chlorine, pyrazol-1-yl, 1,2,3-triazol-1-yl, or N-oxido-2-,-3- or-4-pyridyl 5 alkoxy or alkylthio; Benzyloxy; Amino; Alkoxycarbonyl having 1 to 3 carbon atoms in the alkyl portion, or alkylamino having 1 to 5 carbon atoms optionally substituted by benzyloxycarbonyl or carboxyl; Or phenylamino;

R ⁷ is C 1-4 straight or branched chain alkyl, phenyl or methylphenyl optionally substituted by 1 to 3 substituents selected from fluorine and amino;

R ⁸ is methoxycarbonyl, trichloromethyl or dichlorofluoromethyl;

R ² , R ³ , R ⁴ and R ⁵ are hydrogen, methyl or ethyl;

X is a compound that is hydrogen, fluorine, chlorine or nitro.

Particularly preferred compounds of formula (I) are;

R ¹ is CO-R ⁶ , CN, SO ₂ -R ⁷ , SR ⁸ ;

R ⁶ is hydrogen; Straight or branched chain alkyl of 1 to 4 carbon atoms optionally substituted with 1 or 2 substituents selected from amino and alkyl groups having 1 to 3 alkoxy and trifluoromethylthio; Phenyl optionally substituted by 1 to 5 substituents selected from chlorine, hydroxyl, amino and carboxyl; Benzyl optionally substituted with amino; Alkoxy having 1 to 4 carbon atoms optionally substituted with pyrazol-1-yl, 1,2,3-triazol-1-yl, N-oxido-2-,-3- or -4-pyridyl; Alkylthio having 1 to 2 carbon atoms; Benzyloxy; Amino; Or alkylamino having 1 to 5 carbon atoms optionally substituted by alkoxycarbonyl or carboxyl having 1 to 3 carbon atoms in the alkyl site;

R ⁷ is C 1 to C 3 straight or branched chain alkyl, phenyl or methylphenyl;

R ⁸ is methoxycarbonyl, trichloromethyl or dichlorofluoromethyl;

R ² is hydrogen, methyl or ethyl; R ³ is hydrogen;

R ⁴ is hydrogen or methyl; R ⁵ is hydrogen;

X is a compound that is hydrogen, fluorine, chlorine or nitro.

In particular, the present invention reacts a compound of formula (II) with an anhydride of formula (V) to give a compound of formula (I), ie, a compound of formula (Ib), wherein R ¹ is -CO-A-COOH. It relates to a manufacturing method.

In the above formula,

A is an optionally substituted alkylene chain or arylene radical having 2 or 3 carbon atoms.

Surprisingly, the quinolonecarboxylic acids according to the invention are known 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7- (piperazin-1-yl) -quinoline-3-carboxylic acid [norfloxacin (norfloxacin)] has significantly greater antimicrobial activity. Therefore, the compound according to the present invention has made progress in the pharmaceutical field.

For example, 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (piperazin-1-yl) in the reaction of compound (II) with (V) according to the invention When -quinoline-3-carboxylic acid and glutaric anhydride are used as starting compounds, the reaction pathway can be represented by the following scheme.

Compounds of formula (II) used as starting compounds can be prepared by reacting compounds of formula (VI) with piperazine or piperazine derivatives of formula (VII):

The reaction is carried out at diluents such as dimethyl sulfoxide, hexamethyl phosphate triamide, sulfolane, water, alcohol or pyridine, at a temperature of 20 ° to 200 ° C, preferably 80 ° to 180 ° C. In carrying out this reaction, 1 to 15 moles of compound (VII), preferably 1 to 6 moles of compound (VII) per mole of carboxylic acid (VI) are used. When the same amount of carboxylic acid (VI) and piperazine derivative (VII) are used, the reaction is carried out with triethylamine, 1,4-diazabicyclo- [2,2,2] -octane or 1,8-diazabicyclo [ 5,4,0] in the presence of an acid binder such as undec-7-ene.

Examples of starting materials of the general formula (II) which can be prepared in this way may refer to the following compounds.

1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-7- (piperazin-1-yl) -quinoline-3-carboxylic acid, 1-cyclopropyl-6-fluoro-1, 4-Dihydro-4-oxo-7- (2, 5-dimethylpiperazin-1-yl) -quinoline-3-carboxylic acid, 1-cyclopropyl-6-fluoro-1, 4-dihydro-4- Oxo-7- (3,5-dimethylpiperazin-1-yl) -quinoline-3-carboxylic acid, 1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-7- (3- Methylpiperazin-1-yl) -quinoline-3-carboxylic acid, 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (3-ethylpiperazin-1-yl)- Quinoline-3-carboxylic acid,

1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (3,5-diethylpiperazin-1-yl) -quinoline-3-carboxylic acid, 1-cyclopropyl-6 -Fluoro-1,4-dihydro-4-oxo-7- (2,3,5-trimethylpiperazin-1-yl) -quinoline-3-carboxylic acid, 1-cyclopropyl-6-fluoro-1 , 4-dihydro-4-oxo-7- (2,3,5,6-tetramethylpiperazin-1-yl) -quinoline-3-carboxylic acid, 1-cyclopropyl-1, 4-dihydro-4 -Oxo-7- (piperazin-1-yl) -quinoline-3-carboxylic acid, 1-cyclopropyl-1, 4-dihydro-6-nitro-4-oxo-7- (piperazin-1-yl) -Quinoline-3-carboxylic acid, and 6-chloro-1-cyclopropyl-1, 4-dihydro-4-oxo-7- (piperazin-1-yl) -quinoline-3-carboxylic acid.

7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo of formula (VIa) (i.e., if X is F in formula (VI)) used as an intermediate product -Quinoline-3-carboxylic acid can be prepared according to the following scheme:

According to the reaction, diethyl malonate (2) was acylated with 2,4-dichloro-5-pullouro-benzoyl chloride (1) in the presence of magnesium alcoholate [German Patent Application No. 3,142,8] 6.8] Acylmalonate (3) is obtained (Organikum, 3rd edition, 1964, p. 438).

The resulting acyl malonate 3 is partially hydrolyzed and decarboxylated using a catalytic amount of p-toluenesulfonic acid in an aqueous medium to give ethylaroyl acetate 4 in high yield. This compound (4) is converted to 2- (2,4-dichloro-5-fluoro-benzoyl) -3-ethoxy-acrylate (5) using triethyl 0-formate / acetic anhydride. Reaction of the resulting compound (5) with cyclopropylamine in a solvent such as methylene chloride, alcohol, chloroform, cyclohexane or toluene gives a slight exothermic reaction to give the desired intermediate (6).

The ring closure reaction from compound (6) to compound (7) is carried out at a temperature in the range of 60 ° to 280 ° C, preferably 80 ° to 180 ° C.

Dioxane, dimethyl sulfoxide, N-methyl-pyrrolidone, sulfolane, hexamethyl phosphate triamide, and preferably N, N-dimethylformamide can be used as diluent.

Suitable acid binders for this reaction step are potassium tert-butanolate, butyl-lithium, lithium-phenyl, phenyl magnesium bromide, sodium methylate, sodium hydride and, particularly preferably potassium carbonate or sodium carbonate. It may be desirable to use an excess of 10 mole percent base.

In the last step, ester hydrolysis of compound (7) under basic or acidic conditions leads to 7-chloro-1-cyclopropyl-6-pulluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid ( VIa) is generated.

3-fluoro-4,6-dichlorotoluene (10) necessary for the preparation of 2,4-dichloro-5-fluoro-benzoyl chloride (1) and the corresponding carboxylic acid and (1) used as starting material in the synthesis route. ) Is prepared according to the following scheme starting from 2,4-dichloro-5-methyl-aniline (8):

According to the reaction, 2,4-dichloro-5-methyl-aniline (8) is diazotized with NaNO ₂ and the resulting diazonium salt is converted to triazine (9) using dimethylamine.

When triazine (9) is dissolved in excess of anhydrous HF, triazine decomposes into 2,4-dichloro-5-methyl-diazonium fluoride and dimethylamine. Without separating the intermediate, the resulting solution is pyrolyzed at 130 to 140 ° C. and N ₂ is separated off to give 3-fluoro-4,6-dichlorotoluene (10). Yield: 77.7% of theory

3-fluoro-4,6-dichlorotoluene (10) is chlorinated at 110 to 160 ° C. under UV irradiation to give 2,4-dichloro-5-fluoro-1-trichloromethylbenzene (11). .

Hydrolysis of the compound (11) with 95% sulfuric acid gave 2,4-dichloro-5-fluoro-benzoic acid (12), which was dissolved in carboxylic acid chloride (1) by boiling thionyl chloride (boiling point: 120 ° C / 20 mbar: n _D ^{2 O} 1.5722).

The following quinolonecarboxylic acids used as intermediate products are also prepared in a similar manner. 7-Chloro-1-cyclopropyl-1, 4-dihydro-4-oxo-quitoline-3-carboxylic acid (VIb) (melting point: 308 ° C) was prepared from 2,4-dichlorobenzoylchloride. [J. Chem. Soc. 83, 1,213 (1903)]:

6,7-dichloro-1-cyclopropyl-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (VIc) (melting point: 265 ° C.) was prepared from 2,4,5-trichlorobenzoyl chloride. [See: Liebigs Ann. Chem. 152, 238 (1896)]

7-chloro-1-cyclopropyl-1,4-dihydro-6-nitro-4-oxo-quinoline-3-carboxylic acid (VId) from 4,5-dichloro-5-nitro-benzoylchloride (melting point: 265) sowl 275 ° C., decomposition) is produced by Liebigs Ann. Chem. 677, 8 (1964)]:

Anhydrides (V) which can be used according to the invention are known and examples thereof include the following compounds: succinic anhydride, methyl succinic anhydride, glutaric anhydride, phthalic anhydride and tetrachlorophthalic anhydride .

The reaction of compound (II) with (V) is carried out in a diluent such as N, N-tomethylformamide, dioxane, tetrahydrofuran, pyridine or water, or a mixture of these diluents. The reaction temperature can be changed photometrically. Typically the reaction is carried out at about 0 ° to 140 ° C, preferably 10 ° to 100 ° C.

The reaction can be carried out under atmospheric pressure as well as under elevated pressure. Typically, the reaction is carried out under a pressure of about 1 to 100 bar, preferably 1 to 10 bar.

All conventional inorganic and organic acid binders can be used as acid binders, which are preferably alkali metal hydroxides, alkali metal carbonates, pyridine and triethylamine and 1,4-diazabicyclo [2,2,2 ] Tertiary amines such as octa.

In carrying out the process according to the invention, 1 to 3 moles, preferably 1 to 1.3 moles of compound (V) per mole of compound (II) are used.

As examples of the novel antimicrobial-active compounds according to the invention, the following compounds may be mentioned:

7- [4-formyl-piperazin-1-yl] -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid, 7- [4-acetyl- Piperazin-1-yl] -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid, 7- [4-chloroacetyl-piperazin-1-yl] -1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid, 7- [4-trifluoromethylthioacetyl-piperazin-1-yl] -1- Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid.

7- [4-propionyl-piperazin-1-yl] -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid.

7- [4-Butylyl-piperazin-1-yl] -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid. 7- [4- (4-Chlorobutyryl) -piperazin-1-yl] -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid, 7- [4- (3-Methylbutyryl) -piperazin-1-yl] -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid. 7- [4- (3-methoxypropionyl) -piperazin-1-yl] -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid.

7- [4-benzoyl-piperazin-1-yl] -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid. 7- [4- (4-Nitrobenzoyl) -piperazin-1-yl] -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid.

7- [4- (4-Aminobenzoyl) -piperazin-1-yl] -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid.

7- [4- (3-carboxypropionyl) -piperazin-1-yl] -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid.

7- [4- (4-carboxybutyryl) -piperazin-1-yl] -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid.

7- [4- (2-carboxybenzoyl) -piperazin-1-yl] -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid.

7- [4- (2-carboxy-3,4,5,6-tetrachlorobenzoyl) -piperazin-1-yl] -1-cyclopropyl-6-fluoro-1,4-dihydro-4- Oxo-quinoline-3-carboxylic acid.

7- [4- (3-methoxycarbonylpropionyl) -piperazin-1-yl] -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid .

7- [4- (hydroxyacetyl) -piperazin-1-yl] -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid.

7- [4- (aminoacetyl) -piperazin-1-yl] -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid.

7- [4- (2-Aminopropionyl) -piperazin-1-yl] -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid.

7- [4- (2-Amino-3-methyl-butyryl) -piperazin-1-yl] -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3 -Carboxylic acid.

7- [4- (2-Amino-4-methylpentanoyl) -piperazin-1-yl] -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3- Carboxylic acid.

7- [4- (2-hydroxy-4-amino-butyryl) -piperazin-1-yl] -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline- 3-carboxylic acid.

7- [4-methoxycarbonyl-piperazin-1-yl] -1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-quinoline-3-carboxylic acid.

7- [4-ethoxycarbonyl-piperazin-1-yl] -1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-quinoline-3-carboxylic acid.

7- [4-n-butoxycarbonyl-piperazin-1-yl] -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid.

7- [4-tert-butoxycarbonyl-piperazin-1-yl] -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid.

7- {4- [2- (1-pyrazolyl) -ethoxycarbonyl] -piperazin-1-yl} -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo- Quinoline-3-carboxylic acid.

7- {4- [2- (1,2,3-triazol-1-yl) -ethoxycarbonyl] -piperazin-1-yl} -1-cyclopropyl-6-fluoro-1,4 -Dihydro-4-oxo-quinoline-3-carboxylic acid.

7- [4- (2-Chloroethyloxycarbonyl) -piperazin-1-yl] -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid.

7- {4-[(N-oxido-3-pyridyl) methyl] -piperazin-1-yl} -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline 3-carboxylic acid.

7- [4-carbamoyl-piperazin-1-yl] -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid.

7- [4-Methylcarbamoyl-piperazin-1-yl] -1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-quinoline-3-carboxylic acid.

7- [4-hexylcarbamoyl-piperazin-1-yl] -1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-quinoline-3-carboxylic acid.

7- [4-phenylcarbamoyl] -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid.

7- {4-[(3-methoxycarbonylpropyl) -carbamoyl] -piperazin-1-yl} -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline 3-carboxylic acid.

7- {4-[(5-methoxycarbonylpentyl) -carbamoyl] -piperazin-1-yl} -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline 3-carboxylic acid.

7- {4-[(3-carboxypropyl) -carbamoyl] -piperazin-1-yl} -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3- Carboxylic acid.

7- {4-[(5-carboxypentyl) -carbamoyl] -piperazin-1-yl} -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3- Carboxylic acid.

7- {4-[(2-propoxycarbonyl) -carbamorph] -piperazin-1-yl} -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline- 3-carboxylic acid.

7- {4-[(2-carboxyethyl) -carbamoyl] -piperazin-1-yl} -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3- Carboxylic acid.

7- [4-Dimethylcarbamoyl-piperazin-1-yl] -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid.

7- {4-[(4-chlorobutyl) -carbamoyl] -piperazin-1-yl} -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3- Carboxylic acid.

7- [4-cyano-piperazin-1-yl] -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid.

7- [4-Trichloromethanesulphenyl-piperazin-1-yl] -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid.

7- [4-methoxycarbonylsulphenyl-piperazin-1-yl] -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid.

7- [4-Methanesulfonyl-piperazin-1-yl] -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid.

7- [4-Dichloromethanesulfonyl-piperazin-1-yl] -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid.

7- [4-N-propanesulfonyl-piperazin-1-yl] -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid.

7- [4- (5-Chlorobutane-1-sulfonyl) -piperazin-1-yl] -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3- Carboxylic acid.

7- [4-Perfluorobutane-1-sulfonyl-piperazin-1-yl] -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid.

7- [4-acetyl-3-methyl-piperazin-1-yl] -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid.

7- [3-Methyl-4-propionyl-piperazin-1-yl] -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid.

7- [3-Methyl-4-methylcarbamoyl-piperazin-1-yl] -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid.

7- [2,5-dimethyl-4-formyl-piperazin-1-yl] -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid.

7- [2,5-dimethyl-4-butyryl-piperazin-1-yl] -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid.

7- [3,5-Dimethyl-4-acetyl-piperazin-1-yl] -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid.

7- [3,5-Dimethyl-4-carbamoyl-piperazin-1-yl] -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid.

7- [4-Butyryl-piperazin-1-yl] -1-cyclopropyl-1,4-dihydro-6-nitro-4-oxo-quinoline-3-carboxylic acid.

7- [4-butyryl-piperazin-1-yl] -6-chloro-1-cyclopropyl-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid.

7- [4-Butylyl-piperazin-1-yl] -1-cyclopropyl-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid.

7- [4- (2-Aminopropionyl) -3-methyl-piperazin-1-yl] -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3- Carboxylic acid and

7- [4-Butylyl-3,5-dimethyl-piperazin-1-yl] -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid.

The compounds of formula (I) according to the invention may optionally be converted into salts by reaction with organic and inorganic acids. Examples of suitable acids for salt formation include hydrochloric acid, hydrobromic acid, halogenated acids such as hydroiodic acid, sulfuric acid, acetic acid, citric acid, ascorbic acid, methanesulfonic acid and benzenesulfonic acid. Preferred alkali or alkaline earth metal salts are sodium salts, potassium salts, calcium salts and magnesium salts.

Examples of Preparation of Derivative Compounds:

Example A

A mixture of 19.7 g of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid, 30.1 g of anhydrous piperazine and 100 ml of dimethylsulfoxide was prepared. To 140 ° C. for 2 hours. The solvent is distilled off in vacuo, the residue is suspended in H ₂ O, filtered off and washed with water. For further purification, the wet crude product is boiled with 100 ml of water, filtered at room temperature, washed with H ₂ O and dried at 100 ° C. on CaCl ₂ in a vacuum drying oven until the weight is constant. Let's do it. 19.6 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (piperazin-1-yl) -quinoline-3-carboxylic acid are obtained which decompose at 255 to 257 ° C. .

7-Chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (VIa) used as starting material was prepared as follows:

24.3 g of magnesium turning is suspended in 50 ml of absolute ethanol. 5 ml of carbon tetrachloride are added and when the reaction starts, a mixture of 160 g of diethyl malonate, 100 ml of absolute ethanol and 400 ml of anhydrous ether is added dropwise and refluxed vigorously. After the reaction was stopped, the mixture was heated at boiling point for 2 hours, cooled to -5 ° C to -10 ° C with dry ice / acetone, and then 227,5g 2,4-deck in 100ml anhydrous ether. A solution of Roro-5-fluoro-benzoyl chloride (1) is slowly added dropwise at temperature. The mixture is stirred at 0 ° C. to −5 ° C. for 1 hour, left to come to room temperature overnight and then added to a mixture of 400 ml of ice water and 25 ml of concentrated sulfuric acid while cooling with ice. The phases are separated and extracted twice with ether. The combined ether solutions are washed with saturated NaCl solution, dried over Na ₂ SO ₄ and the solvent is evaporated in vacuo. 349.5 g of diethyl 2,4-dichloro-5-fluoro-benzoyl-malonate (3) are obtained as a crude product.

0.15 g of p-toluenesulfonic acid is added to an emulsion of 34.9 g of crude diethyl 2,4-dichloro-5-fluoro-benzoyl-malonate (3) in 50 ml of water. The sufficiently stirred mixture was heated at boiling point for 3 hours, the cooled emulsion was extracted several times with methylene chloride, then the combined CH ₂ Cl solution was washed once with saturated NaCl ₂ solution and dried over Na ₂ SO ₄ , The solvent is distilled off under vacuum. The residue was fractionated in vacuo to give 21.8 g of ethyl 2,4-dichloro-5-fluoro-benzoyl-acetate 4 (boiling point: 127 to 142 ° C./0.9 mbar).

A mixture of 21.1 g of ethyl 2,4-dichloro-5-fluoro-benzoyl-acetate (4), 16.65 g of ethyl O-formate and 18.55 g of acetic anhydride is heated to 150 ° C. for 2 hours. The volatile components are distilled under vacuum from a water pump and finally distilled under vacuum at a bath temperature of 120 ° C. 25.2 g of crude ethyl 2- (2,4-dichloro-5-benzoyl) -3-ethoxy-acrylate (5) is obtained. This material is pure enough for the next reaction.

A solution of 4.3 g of cyclopropylamine stirred and ice-cooled of 24.9 g of ethyl 2- (2,4-dichloro-5-fluoro-benzoyl) -3-ethoxy-acrylate (5) in 80 ml of ethanol Drop by. When the exothermic reaction was stopped, further stirring at room temperature for 1 hour, the solvent was evaporated in vacuo, and the residue was recrystallized from cyclohexane / petroleum ether. 22.9 g of ethyl 2- (2,4-dichloro-5-fluoro-benzoyl) -3-cyclopropyl-amino-acrylate (6) having a melting point of 89 to 90 ° C are obtained.

3.44 g of 80% sodium hydride is stirred with 31.9 g of ethyl 2- (2,4-dichloro-5-fluoro-benzoyl) -3-cyclofill-amino-acrylate (6) in 100 ml of anhydrous dioxane To the ice-cooled solution. The mixture is then stirred at room temperature for 30 minutes and at reflux for 2 hours, then the dioxane is evaporated in vacuo. The residue (40.3 g) is suspended in 150 ml of water, 6.65 g of caustic alkali is added and the mixture is refluxed for 1.5 h. The warm solution is filtered off and the residue is washed with H ₂ O. The ice-cold filtrate is added to pH 1-2 with 50% concentrated hydrochloric acid, the precipitate is filtered off with suction, washed with water and dried under vacuum at 100 ° C. Thus, 27.7 g of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (VIa) (melting point: 234 to 237 ° C) is obtained.

Example B

5.1 g (0.051 mol) with 2.8 g (0.01 mol) of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid in 6 ml of dimethyl sulfoxide The mixture of 2-methylpiperazine of was heated to 140 ° C. for 2 hours. The solvent is then distilled off under high vacuum, 6 ml of hot water is added to the residue, and the mixture is kept at 95 ° C. for 1 hour. The mixture is cooled with ice, the separated precipitate is filtered off with suction, washed with a small amount of water and dissolved in a mixture of 0.8 ml of acetic acid and 10 ml of water at 90-100 ° C. The filtrate is adjusted to pH 8 with potassium hydroxide solution (0.75 g KOH in 0.7 ml water) and the separated precipitate is recrystallized from methanol. 1.8 g (52% of theory) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (3-methylpiperazin-1-yl) that decomposes at 230-232 ° C. -Quinoline-3-carboxylic acid semianhydride is obtained.

Example C

9.3 g (0.03 mol) of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid and 12.9 g (0.15 mol) in 60 ml of dimethyl sulfoxide The mixture of piperazine of was heated to 120 ° C. for 15 minutes. After a while, the precipitate is separated from the thermal solution. The mixture is evaporated under high vacuum, stirred with 30 ml of water and then heated to 95 ° C. for 30 minutes. The pH of the mixture is adjusted to 8 with 2N hydrochloric acid, the precipitate is suction filtered off and washed with water and methanol. 5.8 g (54% of theory) of 1-cyclopropyl-1,4-dihydro-6-nitro-4-oxo-7- (piperazin-1-yl) -quinoline-3 degraded at 296 to 298 ° C -Separate the carboxylic acid.

Example D

In a similar manner to Example C, 6-7-dichloro-1-cyclopropyl-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid is decomposed 1-cyclopropyl-6- at 295 to 298 ° C. Convert to chloro-1,4-dihydro-4-oxo-7- (piperazin-1-yl) -quinoline-3-carboxylic acid.

Example E

In a similar manner to Example C, 7-chloro-1-cyclopropyl-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid was reacted with piperazine to degrade 1-cyclopropyl at 298 to 300 ° C. -6-Chloro-1,4-dihydro-4-oxo-7- (piperazin-1-yl) -quinoline-3-carboxylic acid is obtained.

Examples of preparation of the final product according to the invention:

Example 1

0.4 g of 20 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (piperazin-1-yl) -quinoline-3-carboxylic acid in 20 ml of water Is dissolved in a solution of sodium hydroxide, and a solution of 1 g of succinic anhydride in 10 ml of dioxane and 0.4 g of sodium hydroxide in 10 ml of water are added simultaneously at room temperature. Stir at room temperature for 2 hours, acidify the mixture with 2N hydrochloric acid, then remove the separated precipitate by suction filtration and wash with water and methanol. 3.4 g (79% of theory) of 7- [4- (3-carboxypropionyl) -piperazin-1-yl] -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo -Quinoline-3-carboxylic acid (decomposition point: 284-286 degreeC) is obtained.

In a similar manner to Example 1, the following compounds were prepared:

EXAMPLE

The compounds according to the invention have good activity against gram positive and gram negative bacteria. The following table shows the minimum inhibitory concentrations of the compounds according to the invention for several bacteria. These are the values obtained by the agar incorporation test method on DST medium.

Claims (2)

A process for preparing a quinolone carboxylic acid of formula (I) or a pharmaceutically useful salt thereof, characterized by reacting a compound of formula (II) with an anhydride of formula (V).

In the above formula, R ¹ is a radical CO-R ⁶ , R ⁶ is carboxyl-substituted alkyl having 2 or 3 carbon atoms, or carboxyl-substituted phenyl optionally substituted by halogen, R ² , R ³ , R ⁴ and R ⁵ are hydrogen, X is hydrogen or halogen, A is an optionally substituted alkylene chain or phenylene radical having 2 or 3 carbon atoms. The compound of claim 1, wherein 7- [4- (3-carboxypropionyl) -piperazin-1-yl] -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline- Process for preparing 3-carboxylic acid.