CS277409B6 - Novel derivatives of quinoline, their esters and salts - Google Patents

Abstract

General quinoline derivatives are disclosed of formula I wherein Z is amino or a halogen atom, R 1. is hydrogen, methyl or ethyl, R2 is hydrogen or methyl or fluoromethyl the group, R 3 and R 4 are the same or different and are hydrogen or methyl n is 1 or 2 and Y is a hydrogen atom or an alkyl group having 1 to 5 carbon atoms and pharmaceutically acceptable salts, processes for their preparation and pharmaceuticals compositions suitable for bacterial control infections that contain compounds of Formula I As active ingredient.

Description

The present invention relates to novel quinoline derivatives having very high antibacterial activity, to processes for the preparation of these compounds and to pharmaceutical compositions containing them.

The compounds of the invention are quinoline derivatives of formula I.

wherein Z represents an amino group or a halogen atom,

R 2 represents a hydrogen atom or a methyl or ethyl group,

R ₂ represents a hydrogen atom or a methyl or fluoromethyl group,

R 8 and R ₄ are the same or different and represent a hydrogen atom or a methyl group, n has the value 1 or 2 and

Y represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, or salts of these compounds. .

Salts of the compounds of formula I may be salts of the compounds of formula I with pharmaceutically acceptable acids or bases. Salts of the compounds of the invention are salts derived from inorganic acids such as hydrochloric acid or phosphoric acid; from organic acids such as acetic acid, lactic acid, oxalic acid, succinic acid, methausulfonic acid, maleic acid, malonic acid or gluconic acid; from acidic amino acids such as aspartic acid or glutamic acid; metals (eg sodium, potassium, calcium, magnesium, zinc or silver); organic bases such as dimethylamine, triethylamine, dicyclohexylamine, or benzylamine; from basic amino acids such as lysine or arginine.

Esters of compounds of formula I not only substituted or unsubstituted aliphatic esters, especially lower alkyl esters having 1 to 5 carbon atoms such as methyl or ethyl esters, but also esters which can be at least partially converted to compounds of formula I by chemical hydrolysis or enzymatic hydrolysis in vivo such as acetoxymethyl esters, pivaloyloxy methyl esters, ethoxycarbonyloxyathyl esters, choline esters, aminoethyl esters (e.g. dimethylaminoethyl or 1-piperidinylethyl esters) 5-indanyl esters, phthalidyl esters and hydroxyalkyl esters (e.g. 2-hydroxyethyl or 2,3-dihydrodroxypropyl ester).

The compounds of formula I, their esters and salts of these compounds are collectively referred to herein as the compounds of the invention.

The compounds of the invention may also exist as hydrates. These hydrates are also included in the compounds of the invention.

The compounds of the invention also include those compounds which have asymmetric carbon atoms in the piperazine ring in position 7 and thus exist in optically active forms. Thus, they include D isomers, L isomers and mixtures thereof.

Some of the compounds of the invention have two asymmetric carbon atoms in the piperazine ring in position 7 and may therefore exist as stereoisomers having different configurations (cis or transform). These stereoisomers and mixtures thereof are also included among the compounds of the invention.

The pharmaceutical activity of the compounds will be described below.

Japanese Patent Laid-Open Publication No. 174367/1983 (the abstract of which is disclosed in Derwent World Patent Index, No. 83-823272) discloses that compounds of formula (10)

(10) wherein R represents a hydrogen atom or a lower alkyl group, they exhibit antibacterial activity. However, the compounds of the present invention have higher antibacterial activity than the known compounds mentioned above.

South African Patent Publication No. 8502369 discloses the following compounds of formula (11)

The description does not mention a cyclopropyl group in the meaning of the substituent R in formula 11.

European Patent Application Publication No. 172651 discloses compounds of the following general formula 12

The description does not mention a piperazinyl group in the meaning of the substituent Z in the general formula 12.

U.S. Patent No. 4,556,658 discloses compounds of the following general formula 13. '0 T-.

However, these compounds do not have an amino group in position 5 of the quinoline ring, as can be seen from formula 13.

It is an object of the present invention to provide novel quinoline derivatives of formula I which have high antibacterial activity against Gram-positive and Gram-negative bacteria, their esters and pharmaceutically acceptable salts of these compounds.

The invention further relates to pharmaceutical compositions comprising an effective amount of a compound of formula I, an ester thereof or a pharmaceutically acceptable salt of any of these compounds.

The invention further relates to methods of treating bacterial infections in warm-blooded animals which comprise a component of the compounds or pharmaceutical compositions of the invention.

These and other aspects of the invention will be described in more detail in the following description.

The compounds of the invention include the following compounds.

5-Amino-1-cyclopropyl-6,8-difluoro-7- (3-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid (Compound 1) of formula

5-Amino-1-cyclopropyl-6,8-difluoro-7- (3,5-dimethyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid (Compound 2) of the formula:

5-Amino-1-cyclopropyl-6,8-difluoro-7- (1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid (Compound 3) of the formula:

5-Amino-1-cyclopropyl-6,8-difluoro-7- (4-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid (Compound 4) of the formula:

•O*

5-Amino-1-cyclopropyl-6,8-difluoro-7- (4-ethyl-1-piperazinyl) 1,4-dihydro-4-oxoquinoline-3-carboxylic acid (Compound 5) of the formula:

5-Amino-1-cyclopropyl-6,8-difluoro-7- (3-fluoromethyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid (Compound 6) of the formula:

5-Amino-1-cyclopropyl-6,8-difluoro-7- (2-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid of the formula:

5-Amino-1-cyclopropyl-6,8-difluoro-7- (2,5-dimethyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid of the formula:

5-Amino-1-cyclopropyl-6,8-difluoro-7- (2,3-dimethyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid of the formula:

5-Amino-1-cyclopropyl-6,8-difluoro-7- (4-methyl-1-homopiperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid of the formula:

5-Amino-1-cyclopropyl-6,8-difluoro-7- (1-homopiperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid of the formula:

1-Cyclopropyl-5,6,8-trifluoro-7- (1-piperazinyl-1,4-dihydro-4

-oxoquinoline-3-carboxylic acid of formula:

>

1-Cyclopropyl-5,6,8-trufluoro-7- (4-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid of the formula:

1-Cyclopropyl-5,6,7-trifluoro-7- (3-methyl-1-piperazinyl) -1,4

-dihydro-4-oxoquinoline-3-carboxylic acid of formula:

The compounds of the invention show excellent antibacterial activity and a broad antibacterial spectrum in in vitro tests. Furthermore, these compounds show an excellent anti-infective effect in vivo against topical and systemic infections caused by Gram-positive and Gram-negative bacteria.

The compounds of the invention also have outstanding anti-mycoplasma activity.

Methods for preparing the compounds of the invention are described below.

A. Substitution reactions with piperazine derivatives. .

The compounds of the invention may be prepared by reacting a carboxylic acid or an ester thereof (preferably a C 1 -C 4 alkyl ester) of the following general formula:

(II) wherein Z represents an amino group or a halogen atom, X is a halogen atom and Y is a hydrogen atom or an aliphatic group, provided that when Z represents a halogen atom, Y represents a hydrogen atom, with a compound of the following general formula III

wherein Rp R ₂ , R ₃ , R ₄ and n are as defined in formula I.

Examples of halogen atoms in the meaning of the substituent X in the formula II are fluorine, chlorine or bromine atoms.

This reaction can be carried out by stirring the starting compounds of formulas II and III at 10 to 180 ° C for 10 minutes to 24 hours in an inert solvent. Examples of this inert solvent include alcohols such as ethanol, ethers such as dioxane, tetrahydrofuran and 1,2-dimethoxyethane, aromatic hydrocarbons such as benzene, toluene and xylene, acetonitrile, dimethylformamide, dimethylsulfoxide, pyridine and water.

In general, the above reaction is carried out in the presence of an acid acceptor using the starting compound of formula III in an amount equivalent to or in a slight excess relative to the starting compound of formula III. If desired, the starting compound of formula III may be used in excess and then serve as an acid acceptor. Examples of acid acceptors are sodium bicarbonate, sodium carbonate, potassium carbonate, triethylamine, pyridine and picoline.

The starting compounds of formula III used in this reaction may, if desired, be used in protected form and after the reaction the protecting group is removed in a conventional manner. The protecting group must be such that it does not disturb the structure of the compounds formed in said reaction. Common groups are protecting groups used in the chemistry of peptides, amino sugars, nucleic acids or beta-lactam compounds; these compounds can be used in the process of the invention.

Amino protecting groups can be cleaved by solvolysis (including hydrolysis) or reduction depending on the properties of the protecting group.

Specific examples of protecting groups suitable for cleavage by solvolysis are acyl groups such as formyl, acetyl and trifluoroacetyl; substituted or unsubstituted alkoxycarbonyl groups such as ethosycarbonyl, tert, butoxycarbonyl, benzyloxycarbonyl, p-methosybenzyloxycarbonyl and beta - (p-toluenesulfonyl) ethoxycarbonyl; trityl, trimethylsilyl, o-nitrophenylsulfenyl, diphenylphosphinyl and tetrahydropyranyl.

The reaction is carried out in a solvent at 0 to 150 ° C in the presence or absence of a catalyst such as an acid or a base.

Examples of these acids are inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid; organic acids such as acetic acid, triufluoroacetic acid, acid, formic acid, and toluenesulfonic acid; Lewis acids such as boron tribromide and aluminum chloride. Examples of bases are alkali metal hydroxides such as sodium hydroxide and barium hydroxide, alkali metal carbonates such as sodium and potassium carbonate; alkali metal alkoxides such as sodium methoxide and sodium ethoxide; and sodium acetate. Usually water is used as the solvent. Depending on the nature of the compounds, other solvents such as ethanol, dioxane, ethylene glycol dimethyl ether, benzene or acetic acid, or mixtures of these solvents with one another and with water, may be used.

Examples of protecting groups that can be removed by reduction include arylsulfonyl groups such as p-toluenesulfonyl; a methyl group substituted by phenyl or benzyloxy such as benzyl, trityl or benzyloxymethyl; arylmethoxycarbonyl groups such as benzyloxycarbonyl and p-methoxybenzyloxycarbonyl; haloethoxycarbonyl groups such as beta, beta, betatrichlorethoxycarbonyl and beta-iodoethoxycarbonyl.

Different reaction conditions can be used in this reaction depending on the properties of the protecting groups to be cleaved. For example, it is carried out by treatment with hydrogen in an internal solvent at 10 to 60 ° C in the presence of a catalyst such as platinum, palladium or Raney nickel; or treated with sodium metal in liquid ammonia at -50 to -20 ° C; or by treatment with a metal such as zinc in acetic acid or in an alcohol such as methanol. Examples of the solvent for the catalytic reduction include ethylene glycol dimethyl ether, dioxane, dimethylformamide, ethanol, ethyl acetate and acetic acid.

The starting compounds of formula II can be prepared by the procedure described in Reference Example 1 or 2 or by corresponding procedures.

B. Amination reactions

The compounds of the invention may be prepared by reacting a carboxylic acid or an ester thereof (preferably a C ₁ -C ₅ alkyl ester) of the following general formula IV

wherein R _HR R _2, R _3, R _4, X, Y and n are as defined above, with ammonia.

This reaction is carried out by contacting the starting compound of formula IV with ammonia for 1 to 50 hours at 50 to 150 ° C in an inert solvent, for example in an alcohol such as ethanol, pyridine, dimethylformamide or water, preferably in a sealed tube.

This reaction is carried out in the presence of an acid acceptor using ammonia in an equivalent amount, or in a slight excess, based on the starting compound of formula IV. In general, if ammonia is used in excess, it also serves as an acid acceptor. Instead of ammonia, salts such as ammonium acetate can be used.

The compounds of the formula IV used in the reaction can, if desired, be used in protected form - protected by the groups mentioned above in reaction A, and after the reaction the protecting groups are cleaved off in a conventional manner.

The starting compounds of formula IV are novel and can be prepared by the above reaction A.

C. Cleavage of 5-amino protecting groups

The compounds of the invention may be prepared by solvolysis (also hydrolysis) or reduction of compounds of the following general formula V.

HL-HHL 0

wherein W represents an amino protecting group and R 1, R ₂ , R ₃ , R ₄ and Y are as defined above.

Examples of the amino protecting group W in the formula V include alkyl groups such as formyl, acetyl and trifluoroacetyl; alkoxycarbonyl groups such as ethosycarbonyl and benzyloxycarbonyl; substituted methyl groups such as benzyl and benzhydryl, and benzyloxy.

This reaction is performed by any of the procedures outlined above in Reaction A to remove the amino protecting group.

The starting compounds of formula V used in this reaction may be used in the form protected by one of the protecting groups mentioned in Reaction A, and the protecting group is removed in a conventional manner after or simultaneously with said reaction.

The starting compounds of formula V are novel compounds and can be prepared by the procedures described in Reference Examples 3 and 5 below, or by procedures substantially identical thereto. ·

When the compounds prepared according to the invention are by the above methods, they are esters, they can be converted into the compounds of the formula I by hydrolysis of the ester group in a conventional manner. If desired, the compounds of the formula I can be esterified in the customary manner into esters of the compounds of the formula I.

Pharmaceutically acceptable salts or esters of the compounds of formula I or their esters may be prepared by reacting the compounds of formula I or their esters, with acids, or by reacting the compounds of formula I and bases or metal salts. Acids suitable for salt formation include, for example, hydrochloric acid, phosphoric acid, succinic acid, methanesulfonic acid, maleic acid, malonic acid, gluconic acid, aspartic acid and glutamic acid. Bases or metal salts suitable for forming salts include, for example, metal hydroxides such as sodium hydroxide and potassium hydroxide, metal carbonates such as sodium carbonate and potassium carbonate, zinc chloride, zinc sulfate, zinc nitrate and silver nitrate.

The compounds of the present invention prepared by the above methods are isolated and purified by conventional methods and, depending on the isolation and purification conditions, can be obtained in the form of a salt or a free acid. These can be converted into the compounds of the invention in the forms mentioned.

Stereoisomers (cis and trans forms) of the compounds of the invention may be isolated by conventional methods such as fractional crystallization or chromatography. Is possible . to prepare compounds of the invention having the cis or trans configuration, to carry out reaction A using starting compounds of formula III having the cis or trans configuration.

The optically active isomers of the compounds of the invention may be separated by known methods.

The compounds of formula I, their esters and salts of these compounds, are novel compounds. The compounds of formula I and their salts are particularly valuable as antibacterial agents having high antibacterial activity. The compounds of the formula I and their salts can be used not only as medicaments for humans and animals, but also as medicaments for fish, agricultural chemicals and food preservatives. Esters of the compounds of formula I are also suitable as a valuable starting material for the synthesis of compounds of formula I. If esters can be easily transformed in vivo to compounds of formula I, they can have a corresponding effect and are also suitable as antibacterial agents.

Compounds of formula I in which Z is halogen are valuable as starting materials for compounds of formula I in which Z is amino. These also show excellent antibacterial activity, low toxicity, good absorption capacity and good metabolic stability and are suitable as antibacterial agents administered orally or by injection.

When the compounds of the present invention are used as antibacterial agents for humans, they are suitably administered at a dose of from 5 mg to 5 g per day once or several times a day, although the dose may vary according to the age, body weight and symptoms of the patient, route of administration, etc. The compounds may be administered orally or parenterally.

The compounds of the invention may be administered in the form of the powder obtained, but are usually administered in the form of pharmaceutical compositions together with pharmaceutically acceptable excipients. Examples of such pharmaceutical preparations are tablets, solutions, capsules, granules, fine granules, pellets, powders, syrups, injections and ointments. These compositions are prepared by conventional procedures. Excipients for oral administration are those commonly used in the preparation of pharmaceutical compositions which do not react with the compounds of the invention, such as starch, mannitol, crystalline cellulose, CMC Na, water, ethanol, etc. Injectables are excipients commonly used for injection, such as water, isotonic sodium chloride solution, glucose solution and transfusion solutions.

The above-mentioned liquid preparations and ointments can also be used for topical treatment in otino-laryngology or ophthalmology.

The following examples further illustrate the process for the preparation of the compounds of the invention.

Reference Example 1 1-Cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid:

The numbers of the reaction steps given below are identical to the numbers given in the scheme.

1) A mixture of known compounds, ethyl pentafluorobenzoyl acetate (J. Org, Chem., 35, 930 (1970) (25 g)), ethyl chlorotramenate (20 g), and acetic anhydride (23 g) was refluxed for 2 hours. The residue was dissolved in diethyl ether and treated with cyclopropylamine (5.1 g) to give ethyl 2-pentafluorobenzoyl-3-cyclopropylaminoacrylate (28 g), mp 89 ° C.

2) The above compound (28 g) was dissolved in dry tetrahydrofuran and treated with 60% sodium hydride (3.85 g) at room temperature to give ethyl 1-cyclopropyl-5,6,7,8-tetrafluoro-1. , 4-dihydro-4-oxoquinoline-3-carboxylate (18.4 g) m.p. 170-171 ° C.

3) The above compound (10 g) was hydrolyzed by boiling in a mixture of glacial acetic acid (60 ml), water (500 ml) and concentrated sulfuric acid (7 ml) for 30 minutes to give 1-cyclopropyl-5,6,7 , 8-tetrafluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (8.7 g), m.p. 181-182 ° C.

Reference Example 2

5-Amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid:

The numbers of the reaction steps given below are identical to the numbers given in the scheme.

1) A mixture of ethyl-1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-

oxo-quinoline-3-carboxylate (28.2 g) prepared in Reference Example 1 (2), benzylamine (9.8 ml), anhydrous potassium carbonate (23.6 g) and acetonitrile (140 ml) was heated to 100 to 110 ° C for 1 hour to give ethyl 5-benzylamino-1-cyclopropyl-6,7,

-8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (21.4 g), which is recrystallized from ethanol, m.p. 134-135 ° C.

2) The above compound (20 g) was dissolved in acetic acid (100 ml) and ethanol (150 ml) and hydrogenolyzed in the presence of 5% palladium on carbon (0.5 g) to give ethyl 5-amino-1- cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carbosylate (14.1 g), which was recrystallized from chloroform-ethanol, m.p. 236-237 ° C. ·

3) A mixture of the above compound (12.6 g), acetic acid (80 ml), water (50 ml) and concentrated sulfuric acid (9 ml) was heated at 100 to 100 ° C for 40 minutes to give 5-amino-1 -cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (11.1 g), which is recrystallized from a mixture of chloroform and ethanol, m.p. 294-295 ° C.

Example 1

5-Amino-1-cyclopropyl-6,8-difluoro-7- (3-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid and its hydrochloride:

The numbers of the reaction steps below correspond to the numbers in this scheme.

1) A mixture of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (1.25 g), 2-methylpiperazine (2.0 g) and of pyridine (13 ml) was heated at 105-110 ° C for 1 hour with stirring. The reaction mixture was evaporated to dryness under reduced pressure, and water was added to the residue. The mixture was extracted with chloroform, and the extract was dried. After evaporating chloroform, ethanol was added to the residue. The resulting crystals were filtered off and recrystallized from a mixture of chloroform and ethanol to give 5-amino-1-cyclopropyl-6,8-difluoro-7- (3-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3. -carboxylic acid (1.4 g), m.p. 251-253 ° C.

2) The above compound (700 mg) was dissolved in 20% hydrochloric acid (7 ml) and evaporated to dryness under reduced pressure. Ethanol was added to the residue, and the resulting crystals were filtered off and recrystallized from a mixture of water and ethanol to give 5-amino-1-cyclopropyl-6,8-difluoro-7- (3-methyl-1-piperazinyl) -1.4. -dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride (425 mg), m.p. > 300 ° C.

Example 2

5-Amino-1-cyclopropyl-6,8-difluoro-7- (cis-3,5-dimethyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid:

In the same manner as in Example 1 (1), a mixture of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, cis-2,6-dimethylpiperazine, was and dimethylformamide was stirred at room temperature for 24 hours to give 5-amino-1-cyclopropyl-6,8-difluoro-7- (cis-3,5-dimethyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline -3-carboxylic acids, m.p. 258-260 ° C.

Example 3

5-Amino-1-cyclopropyl-6,8-difluoro-7- (1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid and its hydrochloride:

/ 2 /

The numbers of the reaction steps given below correspond to the numbers given in this scheme.

1) In the same manner as in Example 1 (1), a mixture of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, piperazine and dioxane was refluxed for 5 hours. to give 5-amino-1-cyclopropyl-6,8-difluoro-7- (1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid, m.p. 263-264 ° C.

2) The above compound was treated in the same manner as in Example 1 (2) to give 5-amino-1-cyclopropyl-6,8-difluoro-7- (1-piperazinyl) -1,4-dihydro-4- oxoquinoline-3-carboxylic acid hydrochloride, m.p. > 300 ° C

Example 4

5-Amino-1-cyclopropyl-6,8-difluoro-7- (4-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid:

In the same manner as in Example 1 (1), a mixture of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 1-methylpiperazine and xylene was refluxed for 3 hours. , 5-amino-1-cyclopropyl-6,8-difluoro-7- (4-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid is obtained, m.p. 254-255 ° C.

Example 5

5-Amino-1-cyclopropyl-6,8-difluoro-7- (4-ethyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid:

A mixture of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 1-ethylpiperazine and acetonitrile was refluxed for 5 hours. After cooling, the formed crystals were filtered off, washed with water and recrystallized from ethanol to give 5-amino-1-cyclopropyl-6,8-difluoro-7- (4-ethyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline -3-carboxylic acids, mp 236-237 ° C.

Example 6

In the same manner as in Example 5, the following compounds were prepared.

a) 5-Amino-1-cyclopropyl-6,8-difluoro-7- (3-fluoromethyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid, m.p. 237-238 ° C.

b) 5-Amino-1-cyclopropyl-1-cyclopropyl-6,8-difluoro-7- (cis-2,3-

-dimethyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid in the form of the trifluoroacetic acid salt, m.p. 250-252 ° C (dec.)

c) 5-Amino-1-cyclopropyl-6,8-difluoro-7- (trans-2,5-dimethyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid, m.p. 235-238 ° C.

d) 5-Amino-1-cyclopropyl-6,8-difluoro-7- (1-homopiperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid, m.p. 230-233 ° C.

e) 5-Amino-1-cyclopropyl-6,8-difluoro-7- (4-methyl-1-homopiperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid, m.p. 245 to 248 ’C.

Example 7

5-Amino-1-cyclopropyl-6,8-difluoro-7- (3-methyl-1-piperazinyl) -1,4-dihydro-4-oxhoquinoline-3-carboxylic acid hydrochloride:

the numbers of the following Reaction Steps correspond to the numbers in the above scheme.

1) In the same manner as in Example 1 (1) except that 1-acetyl-2-methylpiperazine was used instead of 2-methylpiperazine, 7- (4-acetyl-3-methyl-1-piperazinyl) -5- amino-1-cyclopropyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, m.p. 258-260 ° C.

2) A mixture of the above compound, 20% aqueous sodium hydroxide and ethanol was refluxed for 12 hours. The reaction mixture is treated with activated charcoal and the pH is adjusted to 1 to 2 with 10% hydrochloric acid. After cooling, the formed crystals were filtered off and recrystallized from water-ethanol to give 5-amino-1-cyclopropyl-6,8-difluoro-7- (3-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline- 3-carboxylic acids as the hydrochloride, m.p. > 300 ° C.

Example 8

5-Amino-1-cyclopropyl-6,8-difluoro-7- (2-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid:

The numbers of the reaction steps correspond to the numbers in the above scheme.

1) In the same manner as in Example 1 (1), a mixture of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 1-ethoxycarbonyl-3-methyl -piperazine and dimethylsulfoxide were stirred at 150 ° C for 2 hours to give 5-amino-1-cyclopropyl-6,8-difluoro-7- (4-ethoxycarbonyl-2-methyl-1-piperazinyl) 1,4-dihydro-4- oxoquinoline-3-carboxylic acids, m.p. 220-225 ° C.

2) The above compound was hydrolyzed in the same manner as in Example 7 (2), and then the reaction mixture was neutralized. The resulting crystals were filtered off and recrystallized from acetynitrile to give 5-amino-1-cyclopropyl-6,8-difluoro-7- (2-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid. , tt 224-226 ° C.

Example 9

5-Amino-1-cyclopropyl-6,8-difluoro-7- (1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid:

The numbers of the reaction steps given below correspond to the numbers in the above scheme.

1) In the same manner as in Example 1 (1), except that 1-benzylpiperazinyl was used instead of 2-methylpiperazine, 5-aminol-cyclopropyl-6,8-difluoro-7- (4-benzyl-1-piperazinyl) was obtained. -1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

2) The above compound was catalytically reduced in the presence of 5% palladium and carbon was obtained to give 5-amino-1-cyclopropyl-6,8-difluoro-7 "

- (1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid, m.p. 263-264 ° C.

Example 10

100¾¾

5-Amino-1-cyclopropyl-6,8-difluoro-7- (3-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid as hydrochloric acid. ·

COOK / 2 /

The numbers of the reaction steps given below correspond to the numbers given in this scheme.

1) In the same manner as in Example 1 (1) except that ethyl 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate was used instead of 5- amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, ethyl 5-amino-1-cyclopropyl-6,8-difluoro-7- ( 3-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylate. m.p. 132-134 ° C.

2) The above compound was treated in the same manner as in Example 7 (2) to give 5-amino-1-cyclopropyl-6,8-difluoro-7- (3-methyl-1-piperazinyl) -1,4-dihydro- 4-oxoquinoline-3-carboxylic acid hydrochloride, m.p. > 300 ° C.

Example 11 · 1-Cyclopropyl-5,6,8-trifluoro-7- (3-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid:

A mixture of 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (910 mg), 2-methylpiperazine (320 mg) and pyridine (10 ml) was stirred at 80 ° C for 1 hour. After evaporating the reaction mixture under reduced pressure, the residue was dissolved in dilute aqueous ammonia and treated with activated carbon. The filtrate was evaporated under reduced pressure and the pH was adjusted to 7-8. The resulting crystals were filtered off, washed with water and dried to give 1-cyclopropyl-5,6,8-trifluoro-7- (3-methyl-1-piperazinyl). ) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid (810 mg), m.p. 235-237 ° C. .

Example 12

In the same manner as in Example 11, the following compounds were obtained:

a) 1-Cyclopropyl-5,6,8-trifluoro-7- (1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid, m.p. 208-213 ° C.

b) 1-Cyclopropyl-5,6,8-trifluoro-7- (4-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid, m.p. 256 ° C.

Example 13

5-Amino-1-cyclopropyl-6,8-difluoro-7- (3-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid:

A mixture of 1-cyclopropyl-5,6,8-trifluoro-7- (3-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid (150 ml) and 28% aqueous ammonia (15 ml) are heated at 100 ° C for 48 hours in a sealed tube. The reaction mixture was evaporated to dryness under reduced pressure, and water was added to the residue. The mixture was extracted with chloroform. After drying, the extract was evaporated, and the residue was recrystallized from a mixture of chloroform and ethanol to give 5-amino-1-cyclopropyl-6,8-difluoro-7- (3-methyl-1-piperazinyl) -1,4-dihydro-4-one. -oxoquinoline-3-carboxylic acid (93 mg), m.p. 251-253 ° C.

Example 14

5-Amino-1-cyclopropyl-6,8-difluoro-7- (1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid:

In the same manner as in Example 13, 1-cyclopropyl-5,6,8-trifluoro-7- (1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid was reacted with ammonia in ethanol in a sealed tube to give 5-amino-1-cyclopropyl-6,8-difluoro-7- (1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid, m.p. 263-264 ° C.

Example 15

5 'Amino-1-cyclopropyl-6,8-difluoro-7- (4-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid:

In the same manner as in Example 13, 1-cyclopropyl-5,6,8-trifluoro-7- (4-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid was reacted with ammonia in dimethylformamide in sealed tube to give 5-amino-1-cyclopropyl-6,8-difluoro-7- (4-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid, m.p. 254-255 ° C.

Reference Example 3

5-Benzylamino-1-cyclopropyl-6,8-difluoro-7- (4-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid:

A mixture of 1-cyclopropyl-5,6,8-trifluoro-7- (4-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid (1.0 g), benzylamine (420 mg ) and pyridine (5 ml) was heated at 100-110 ° C for three hours. The reaction mixture was evaporated to dryness under reduced pressure. After adding water to the residue, the mixture was acidified with 10% acetic acid and extracted with chloroform. The extract was dried and evaporated. The resulting crystals were recrystallized from ethanol-ether mixtures to give 5-benzylamino-1-cyclopropyl-6,8-difluoro-7- (4-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid. acids (730 mg), m.p. 132-133 ° C.

Example 16

5-Amino-1-cyclopropyl-6,8, difluoro-7- (4-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid:

A mixture of 5-benzylamino-1-cyclopropyl-6,8-difluoro-7- (4-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid (700 mg), 5% palladium on charcoal (0.2 g), acetic acid (10 ml) and ethanol (15 ml) were stirred at room temperature for 30 minutes in a stream of hydrogen. The catalyst was filtered off and the filtrate was evaporated under reduced pressure. After adding water to the residue, the pH of the mixture was adjusted to 8 with aqueous ammonia. The resulting crystals are filtered off; to give 5-amino-1-cyclopropyl-6,8-difluoro-7- (4-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid (510 mg), m.p. 254-255 ° C.

Reference Example 4

Ethyl 1-cyclopropyl-5-ethoxycarbonylamino-6,8-difluoro-7- (3-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylate:

. In the same manner as in Example 1 (1), ethyl 1-cyclopropyl-5-ethoxycarbonylamino-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate was reacted (m.p. 189-190 ° C) with 2-methyl-piperazine to give ethyl 1-cyclopropyl-5-ethoxycarbonyl-6,8-difluoro-7- (3-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylate .

Example 17

5-Amino-1-cyclopropyl-6,8-difluoro-7- (3-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid as hydrochloride: ·

A mixture of ethyl 1-cyclopropyl-5-ethoxycarbonylamino-6,8-difluoro-7- (3-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylate, 20% aqueous sodium hydroxide and ethanol are refluxed for 12 hours. The reaction mixture is treated with activated charcoal and the pH is adjusted to 1 to 2 with 10% hydrochloric acid. After cooling, the precipitated crystals were filtered off and recrystallized from water-ethanol to give 5-amino-1-cyclopropyl-6,8-difluoro-7- (3-methyl-1-pieprazil) -1,4-dihydro-4-oxoquinoline hydrochloride. 3-carboxylic acids, m.p. > 300 ° C.

Reference Example 5

5-Acetylamino-1-cyclopropyl-6,8-difluoro-7- (4-formyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid:

In the same manner as in Example 1 (1), 5-acetylamino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (m.p. 247-248 ° C) was reacted. ) with 1-formylpiperazine to give 5-acetylamino-1-cyclopropyl-6,8-difluoro-7- (4-formyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

Example 18

5-Amino-1-cyclopropyl-6,8-difluoro-7- (1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride:

5-Acetylamino-1-cyclopropyl-6,8-difluoro-7- (4-formyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid was treated in the same manner as in Example 17 to give 5-amino-1-cyclopropyl-6,8-difluoro-4- (1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride, m.p. > 300 ° C.

Example 19

Ethyl 5-amino-1-cyclopropyl-6,8-difluoro-7- (3-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylate:

5-Amino-1-cyclopropyl-6,8-difluoro-7- (3-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid is suspended in absolute ethanol. Concentrated sulfuric acid was added to the suspension and the mixture was heated to reflux with stirring for 10 hours. After evaporation, ethanol, chloroform and 20% aqueous sodium hydroxide solution were added to the residue, and the pH of the mixture was adjusted to 9. The organic layer was evaporated under reduced pressure. The resulting crystals were collected by filtration to give ethyl 5-amino-1-cyclopropyl-6,8-difluoro-7- (3-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylate, m.p. 132 to 134 “C.

Examples 20 to 22 illustrate pharmaceutical preparations containing the compounds of the invention as active ingredients.

Example 20 compound 1 or 3 250g starch - 50 g lactose 35g talc 15g

The above ingredients are mixed into 1,000 capsules by conventional procedures.

with ethanol and granulated and filled

Example 21 compound 1 or 3 250 g starch 54 g calcium carboxymethylcellulose 50 g microcrystalline cellulose 50 g magnesium stearate 6 g

The above ingredients are mixed with ethanol, granulated and tableted by known methods. 1000 tablets weighing 400 mg are thus obtained.

Example 22 Compound 1 50 g lactic acid 120 g The above ingredients were dissolved in distilled water to obtain ten liters of solution. The pH of the solution was adjusted to 4 with aqueous sodium hydroxide solution and then filled into ampoules (10 ml) as a solution for injection.

The chemotherapeutic activity of the compounds of the invention is shown in Examples 23 to 26 below. Compounds were tested: compound 1: 5-amino-1-cyclopropyl-6,8-difluoro-7- (3-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid, compound 2: 5 -amino-1-cyclopropyl-6,8-difluoro-7- (3,5-dimethyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid,.

compound 3: 5-amino-1-cyclopropyl-6,8-difluoro-7- (1-piperazinyl) 1,4-dihydro-4-oxoquinoline-3-carboxylic acid, compound 4: 5-amino-1-cyclopropyl- 6,8-Difluoro-7- (4-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid, compound 5: 5-amino-1-cyclopropyl-6,8-difluoro-7- (4-ethyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid, compound 6: 5-amino-1-cyclopropyl-6,8-difluoro-7- (3-fluoromethyl-1) -piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid, Compound A: 5-amino-1-ethyl-6,8-difluoro-7- (1-piperazinyl) -1,4-dihydro-4- oxoquinoline-3-carboxylic acid

Example 23

The in vitro antibacterial activity is given in Table 1. The values given in the table show the minimum inhibitory concentrations (MICs) (μ9 / πι1), based on. free base. The minimum inhibitory concentration is determined by the two-fold agar dilution method described in the Japan Society of Chemotherapy (Chemotherapy, 29 (1), 76 (1981)), using Muller-Hinton agar. An overnight loop of the grown culture of the test organism in Muller-Hinton broth is inoculated into 10 ml of drug-containing agar layers in petri dishes. The bacterial wetum contains approximately 10 colony forming units. Bacterial growth was observed after 20 hours of incubation at 37 ° C. MIC was defined as the lowest concentration that prevented visual bacterial growth.

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Example 24

In vivo efficacy against systemic infections in mice is shown in Table 2.

The compounds are individually dissolved in deionized water. Each of the solutions was orally administered to mice infected with each test organism under the conditions described below, and the mean effective dose (ED ₅₀ ) was calculated by probit analysis. The numbers in the table indicate the ED ₅₀ (mg / kg) value, calculated on a free basis.

Experimental conditions:

Mice: male mice (ddY-S) weighing about 20 g.

Infection: Staphylococcus aureus 50774 'intravenous infection with 5 x 10 ⁸ cells suspended in saline per mouse.

Streptococus pneumoniae 1 Neuteld intraperitoneal infection of 3 x 10 ³ cells suspended in infusion medium from brain and heart to mouse.

Streptococcus pyogenes A65 intraperitoneal infection 3 x 10? cells suspended in the infusion medium from brain and heart to mouse.

Pseudomonas aeruginosa 12

Intraperitoneal infection of about 5 x 10 ³ cells suspended in tryptose medium with 4% mucin per mouse.

Medication: Four times, immediately, 5, 24 and 30 hours after infection in the case of Streptococcus pneumoniae 1. Twice, immediately and 6 hours after infection in the case of other diseases.

Observations: 14 days for Staphylococcus aureus 50774 and Streptococcus pneumoniae 1 Neufeld. In 7 days in the case of other organisms.

Table 2

In vivo efficacy against systemic infections in mice Compound 1 A

S.Aureus 50774 1.35S. pneumoniae I Neufeld 10.9S. pyogenes A65 5.26> 25

P. aeruginosa 12 1.1115.0

Example 25

The anti-mycoplasmal activity of Compound 1 is shown in Table 3. The numbers in the table show the minimum inhibitory concentrations (MICs) (μg / ml), calculated on a free basis. The minimum inhibitory concentration is determined by the two-fold dilution method using Chanock agar. Three μΐ cultures of the test microorganism in Chanock's soil are inoculated into drug-containing agar layers (10 ml) in petri dishes. Mycoplasma growth was monitored after incubation at 37 ° C under the conditions described below. MIC was defined as the lowest drug concentration that would prevent microscopic growth of Mycoplasma.

Incubation conditions:

Mycoplasma pneumoniae Aerobically after 7 days. Mycoplasma argini and Acholeplasma laidlawii After 2 days aerobically.

Mycoplasma hyorhinis

After 3 days aerobically.

Other organisms

After 2 days anaerobically.

Table 3

Anti-Mycoplasma activity of compound 1

Strain

M. pneumoniae Mae M. orale Ch.19299 0.025 2.0 M. hominis PG-21 0.05 M. formentans PG-18 0.0063 M. salivarium PG-21 0.2 M. buccale CH-20247 0.0125 A. laidlawii PG-8 0.1 M. arginini G-230 0.1 M. hyorhimis BST-7 0.2

Example 26

The antibacterial activity of Compound 1 against Campylobacter jejuni is shown in Table 4. The numbers in the table indicate the minimum inhibitory concentrations (MICs) (μg / ml), calculated on a free basis. The minimum inhibitory concentration was determined by two-fold dilution using Mueller-Hinton agar containing blood. The culture loop of the test organism in Mueller-Hinton broth is inoculated into 10 ml agar plates containing the drug in petri dishes. Bacterial growth was observed after 48 hours of incubation at 37 ° C under microaerobic conditions. MIC is defined as the lowest concentration of drug that prevents visual bacterial growth.

Table 4

Antibacterial activity against Campylobacter jejuni compound

strain Campylobacter jejuni 10 Campylobacter jejuni 12 Campylobacter jejuni 20

0.0125

0.0125

0.0063

Continuation of table 4

Campylobacter jejuni 77 0.0125 Campylobacter jejuni 170 0.0125 Campylobacter jejuni A-ll-3 0.05 Campylobacter jejuni A-19-3 0.05 Campylobacter jejuni A-24-2 0.05 Campylobacter jejuni 19804 0.0125 Campylobacter jejuni 19805 0.0125 Campylobacter jejuni 19806 0.0125 Campylobacter jejuni 19807 0.0125 Campylobacter jejuni 19812 0.025

Example 27

Acute toxicity

A solution containing compounds 1, 2 and 3 according to the invention, respectively, in various concentrations, was orally administered to male mice (ddY) at a dose of 0.1 ml per 10 g of body weight. The number of dead mice was counted after 7 days and the mean lethal dose (ID ₅₀ , mg / kg). was calculated by the Behrens-Kaerber method. The results are shown in Table 5.

Table 5

Acute oral toxicity in mice

Compound LD ₅₀ (mg / kg) 1 > 2000 2 > 2000 3 > 2000

From the results shown in Table 5, it is clear that compounds 1, 2 and 3 of the invention have low oral toxicity.

Claims (9)

PATENT CLAIMS 1. Quinoline derivatives of general formula I where Z represents an amino group or a halogen atom, R 2 represents a hydrogen atom or a methyl or ethyl group, R ₂ represents a hydrogen atom or a methyl or fluoromethyl group, R ₃ and R ₄ are the same or different and each represents a hydrogen atom or a methyl group, n has the value 1 or 2 and Y represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, or a pharmaceutically acceptable salt thereof. A compound according to claim 1, wherein Y is a hydrogen atom, or a pharmaceutically acceptable salt thereof. A compound according to claim 1, wherein Z is amino. A compound according to claim 1, wherein Z represents a halogen atom. A compound according to claim 1, wherein Y represents an alkyl group having 1 to 5 carbon atoms, or a pharmaceutically acceptable salt thereof. 6. 5-Amino-1-cyclopropyl-6,8-difluoro-7- (3-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid and its pharmaceutically acceptable acid addition salt. . 7. 5-Amino-1-cyclopropyl-6,8-difluoro-7- (3,5-dimethyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid and its pharmaceutically acceptable addition salt. with acid. 8. 5-Amino-1-cyclopropyl-6,8-difluoro-7- (1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid and a pharmaceutically acceptable acid addition salt thereof. - 9. 1-Cyclopropyl-5,6,8-trifluoro-7- (3-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid and a pharmaceutically acceptable acid addition salt thereof. 1,1-Cyclopropyl-5,6,8-trifluoro-7 - (, 1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid and its pharmaceutically acceptable acid addition salt. Pharmaceutical composition for the treatment of diseases caused by bacterial infections, characterized in that it comprises, as active ingredient, the compounds of general formula I according to claim 1 and a pharmaceutically acceptable carrier. Process for the preparation of a quinoline derivative of general formula I where Z represents an amino group or a halogen atom, R 1 represents a hydrogen atom or a methyl or ethyl group, R ₂ represents a hydrogen atom or a methyl or fluoromethyl group, R ₃ and R ₄ are the same or different and each represents a hydrogen atom or a methyl group, n has the value 1 or 2 and Y represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, or a pharmaceutically acceptable salt thereof, characterized in that i) reacting a compound of formula II (II), where X represents a halogen atom and Y and Z have the meanings given above, with the proviso that when Z represents a halogen atom, Y represents a hydrogen atom, with a piperazine derivative of general formula III (III) wherein R _HR R _2, R _3, R ₄ and n are as hereinbefore defined; ii) in the case where Z in the formula I represents an amino group, the compound of the general formula IV is reacted wherein R _HR R _2, R _3, R _4, X, Y and n are as hereinbefore defined, with ammonia; or iii) in the case where Z in formula I represents an amino group, the protecting group W is removed from the compound of formula V by solvolysis or reduction wherein the protecting group W is a formyl, acetyl, trifluoroacetyl, alkoxycarbonyl or benzyl group and R 1, R ₂ , R ₃ , R ₄ , Y and n are as defined above, and if necessary, the compound thus obtained is converted into its a pharmaceutically acceptable salt. ·