DD283640A5 - PROCESS FOR THE PREPARATION OF NEW CHINOLINE DERIVATIVES - Google Patents

Abstract

A method of making * or * is described. The acids are used for the treatment of infectious diseases caused by bacteria. {Procedure; manufacture; quinoline; Links; antibacterial activity; antibacterial agents}

Description

The invention relates to a process for the preparation of novel quinoline derivatives having very good antibacterial activity and to a process for the preparation of an antibacterial agent containing such a quinoline derivative.

Characteristic of the known SiQnd <2 $ θΙ & le & 1y} tIC

The known solutions relating to pharmacologically active compounds in this area are briefly explained below.

In EP-A-78 362 and the corresponding JA-OS 74667/1983 are l-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazinyl-quinoline-3-carboxylic acids of the following formula (10 )

2 53 6 4

COOH

(10)

wherein R is H, CH ₃ , C ₃ H ₅ or HOCH-CH, and their pharmaceutically acceptable acid addition salts or hydrates.

In EP-A-113 093 and the corresponding JA-OS 130880/1984 compounds of the following formula (11)

12

COOH

(11)

, 11

wherein R is H or an optionally OH-substituted alkyl group having 1 to 12 carbon atoms and

12

R ¹³ ,

14 15 R and R are the same or different

and each represents an alkyl group having 1 to 4 carbon atoms, with the proviso that at least

12 15 one of the substituents R to R denotes an alkyl group,

their pharmaceutically acceptable acid addition salts, alkali metal or alkaline earth metal salts or hydrates.

U.S. Patent No. 4,556,658 and corresponding Japanese Patent Laid-Open No. 212474/1984 discloses a compound represented by the following formula (12).

Ο £ 3 6 4 O

> COOH

(12)

wherein R ^> N groups including a given -R

if substituted piperazinyl or pyrrolidinyl group, and their pharmaceutically acceptable salts.

US-PS 4,665,079 and corresponding JA-OS 214773/1985 disclose compounds of the following general formula (13)

(13)

wherein Z is a specific pyrrolidinyl or spiro-amino group or other heterocyclic groups, X ³¹ CH, OCl, CF, N, etc., Y ³¹ H, F, Cl, Br, R -... H, C ₁ , -alkyl or a cation and R... C _1-4 -alkyl, vinyl, haloalkyl, C ₀ -hydroxyalkyl or C 1 -9-cycloalkyl,

or their pharmaceutically acceptable acid addition or

Base salts described.

The compounds of formulas (10), (11), (12) and (13), as follows from these formulas, have no substituent in the 5-position of the quinoline ring.

163 6 4 ϋ

In EP-A-276 700 and the corresponding JA-OS 201170/1988 compounds of the following general formula (14)

CN

(14)

41 in which Y is COOH, CN, an ester group or an amide

41 44

X, H, NO, alkyl or halogen, X H, halo

44

or alkyl and

- an optional sub-

meaning substituted heterocyclic group,

and their pharmaceutically useful hydrates, salts or esters are described ·

Object of the invention:

The object of the present invention is to provide a process for the preparation of quinoline derivatives of the formula I and their pharmaceutically acceptable esters and salts.

The quinoline derivatives prepared according to the invention are represented by the following general formula (I)

COOH

wherein R _{1 is} a lower alkyl group having 1 to 5 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms

O Ρ, ο

6 4 0

and X represents a hydrogen atom or a halogen atom, Z is a hydrogen atom or a halogen atom;

R.

R ₂ -N R

N-

or

(CH

2 η

N-

in which R_, R ₃ , R ₄ , R ₅ and R, are the same or different and each represents a hydrogen atom or a lower alkyl group having 1 to 5 carbon atoms and η is 0 or 1.

According to the invention, a process for the preparation of an ester or a salt of the derivative or of the ester of a compound of the formula (I) is furthermore to be made available.

In the above formula (I), examples of a halogen atom are fluorine and chlorine, and fluorine is particularly preferable. The alkyl group may be linear or branched and may be, for example, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, t-butyl or pentyl.

The compound of the formula (I), its ester and its salts are generally referred to as compounds prepared according to the invention.

The compounds prepared according to the invention can also occur as hydrates. The invention likewise provides a process for the preparation of these hydrates.

The compounds prepared according to the invention are those which have asymmetric carbon atoms (in particular

536 4 O

For example, when R is an alkyl group having 1 to 5 carbon atoms in the formula (I), the carbon atom to which the alkyl group is bonded may be asymmetric), and therefore the compounds are in optically active forms. They thus include D-isomers, L-isomers and their mixtures.

Some of the compounds prepared according to the present invention have a plurality of asymmetric carbon atoms (for example, when both R 1 and R 2 are alkyl groups of 1 to 5 carbon atoms, the two carbon atoms to which R 1 and R 5 are attached), and they can therefore be considered as Stereoisomers occur with different configurations. These stereoisomers and their mixtures are also encompassed by the term compounds prepared according to the invention.

The esters of the compounds of the formula (I) are, for example, aliphatic esters, in particular Niedrigalky1 esters having 1 to 5 carbon atoms, such as the methyl and ethyl esters; and esters whose alcohol moieties can be readily cleaved in vivo and converted into the compounds of formula (I), for example the acetoxymethyl esters, pxvaloyloxymethyl esters, ethoxycarbonyl-oxyethyl esters, choline esters, aminoethyl esters (such as the dimethylaminoethyl esters or piperidinoethyl esters), 5-indanyl esters , Phthalidyl esters and hydroxyalkyl esters (such as the 2-hydroxyethyl esters and 2,3-dihydroxypropyl esters).

JJ The salt of the compound of formula (I) or the salt

of its ester is a salt formed between the compound of formula (I) or its ester with a pharmaceutically acceptable acid or base. Examples

ό 6 4 υ

for salts, the salts of the compound of the formula (I) or their esters with inorganic acids, such as chlorinated

Substance acid and phosphoric acid; with organic acids, such as J

Acetic acid, lactic acid, oxalic acid, succinic acid, methane |

sulfonic acid, maleic acid, malonic acid and gluconic acid; with |

acidic amino acids such as aspartic acid and glutamic acid; J

with metals such as sodium, potassium, calcium, magnesium, zinc i

and silver; with organic bases such as dimethylamine, triethylamine, dicyclohexylamine and benzylamine; and with basic amino acids, such as lysine and arginine.

The invention is therefore based on the object, a process for the preparation of new quinoline derivatives. (I) and their pharmaceutically acceptable esters and salts, which have excellent antibacterial activity in vitro and in vivo against both gram-positive and gram-negative bacteria.

According to the invention, a process for the preparation of compounds is to be provided which have a broad antibacterial spectrum and exhibit excellent activity against the genera mycoplasm a as well as Chlamydia .

Another object of the present invention is to provide a process for producing a pharmaceutical preparation containing an effective amount of a compound of the formula (I) or its pharmaceutically acceptable ester or salt.

According to the invention, bacterial infections of warm-blooded animals can be treated by using a compound prepared according to the invention or a compound according to the invention.

4 O

provided pharmaceutical preparation is administered to the animal.

The compounds prepared according to the invention show excellent antibacterial activity and a broad antibacterial spectrum in in vitro tests. They are not only highly effective against Gram-negative bacteria containing Pseudomonas aeruginosa and the genus Seratia , but also highly effective against Gram-positive bacteria containing Streptococci and Methicillin-resistant Staphylococcus aureus against which the known quinolone-type antibacterial agents have relatively low activity , In addition, they are highly active against GIucose non-fermenters, anaerobes and the genera mycoplasma , Chlamydia and Mycobacterium , against which there are few effective drugs.

The compounds prepared according to the invention show excellent in vivo protection against topical or systemic infections caused by various bacteria and have low toxicity in the general animal toxicity tests.

The compounds prepared according to the invention are thus useful as antibacterial agents which can be administered orally or by injection.

Explanation of the essence of the invention:

The invention relates to a process for the preparation of the compounds of the formula (I).

2 a 3 6 4 ο '

substitution reaction

The compounds of the invention can be prepared by reacting a compound of the following general formula

COOY

(II)

wherein

a halogen atom, Y is a hydrogen atom

or a lower alkyl group having 1 to 5 carbon atoms, and R ₁ and X have the definitions given in the formula (I), with a compound of the following general formula

Z-H

(III)

wherein Z has the above definition.

This reaction can be carried out by stirring the starting compounds (II) and (III) at 10 to 18O ° C for 10 minutes to 24 hours in an inert solvent. Examples of inert solvents are alcohols such as ethanol, ethers such as dioxane, tetrahydrofuran and 1,2-dimethoxyethane, aromatic hydrocarbons such as benzene, toluene and xylene, acetonitrile, dimethylformamide, dimethyl sulfoxide, pyridine and water.

Preferably, the above reaction is in the presence of an acid acceptor using the starting compound of formula (III) in equivalent or slightly excess

Amount, based on the starting compound (II) prepared. If desired, the starting compound (III) can be used in excess so that it simultaneously serves as an acid acceptor. Examples of an acid acceptor are sodium hydrogencarbonate, sodium carbonate, potassium carbonate, triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.θ] undecene-7 (DBÜ) and pyridine.

The starting compound (III) to be used in this reaction may be used, if possible, in the form of a derivative protected by a protective group as described below in Reaction C, and after the reaction, the protecting group may be converted to ah be removed in a known manner.

The starting compound (II) can be prepared by the methods as described in Reference Examples 1 to 3 or according to methods substantially corresponding thereto.

B. halogenation via the diazonium salt

The compounds of the invention can be prepared by diazotization of a compound of the following general formula

CH., 0

' JL XOOY

(IV)

wherein R, Y and Z have the abovementioned definitions,

and halogenating the resulting diazonium salt.

2 8304 O

The diazotization reaction is carried out by stirring the compound (IV) and a diazotizing agent, usually under cooling, in water, an organic solvent such as ethanol, tetrahydrofuran, dioxane, acetonitrile or acetic acid, or a mixture thereof with water in the presence or absence of a base such as Hydrochloric acid, sulfuric acid, phosphoric acid or nitric acid.

Examples of a diazotizing agent are nitrous acid, nitrites such as sodium nitrite, organic derivatives of nitrous acid such as isoamyl nitrite or t-butyl nitrite, and nitrosyl sulfuric acid.

The halogenation reaction is prepared by stirring the resulting diazonium compound with or without isolation and a halogenating agent at 0 to 150 ⁰ C in such a solvent as described above, and in the case of fluorination by decomposition of the resulting diazonium salt.

Examples of the halogenating agent are copper (I) chloride, copper hydrochloric acid, tetrafluoroboric acid, hexafluorophosphoric acid and hexafluorosilicic acid.

The decomposition is carried out by heating the diazonium salt to 50 to 170 ^° C. directly or in a diluent or in an organic solvent. Examples of the diluent are sand, barium sulfate and sodium fluoride. Examples of solvents are petroleum ether, cyclohexane, n-heptane, benzene, toluene, xylene, biphenyl, chloroform, carbon tetrachloride, ethyl acetate, dioxane or quinoline.

The starting compound (IV) used in this reaction may be used, if possible, in the form of a derivative protected by a protective group as described below in the reaction C, and after the reaction, the protective group may be removed in a manner known per se become.

The starting compound (IV) can be prepared by the method as described in Reference Examples 4 to 5 or according to methods corresponding thereto.

Removal of the amino-protecting group

According to the invention, the compound of the formula (I) can be obtained by removal of the protective group by solvolysis (ie hydrolysis) or by reduction of a compound of the general formula

COOY

(V)

wherein R ₁ , X and Y have the abovementioned definitions and Z '

R-

^or

wherein R 'and R' represent a protecting group and R-, R, R, and η have the abovementioned definitions.

¹³ 2 63640

The protecting group may be any protecting group that can be removed without destroying the structure of the compounds of the invention formed in the reaction. Groups which are normally used as protective groups for the amino group in the field of peptide, amino sugar, nucleic acid or β-lactam compound chemistry can be used in the present invention.

The amino-protecting groups can be removed by solvolysis (including hydrolysis) or by reduction depending on the properties of the protecting groups.

Specific examples of protective groups which can be removed by solvolysis are acyl groups such as formyl, acetyl and trifluoroacetyl; substituted or unsubstituted alkoxycarbonyl groups such as ethoxycarbonyl, t-butoxycarbonyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl and β- (p-toluenesulfonyl) -ethoxycarbonyl; a trityl group, a trimethylsilyl group, an o-nitrophenylsulfenyl group; a diphenylphosphinyl group and a tetrahydropyranyl group. ,

This reaction can be 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 the acid are inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid; organic acids such as acetic acid, trifluoroacetic acid, formic acid and toluenesulfonic acid; Lewis acids, such as boron tribromide and aluminum chloride. Examples of a base are the hydroxides, such as sodium hydroxide and barium hydroxide; Carbonates, such as sodium carbonate and potassium carbonate

nat; Alkali metal alkoxides such as sodium methoxide and sodium ethoxide; and sodium acetate. Usually, water is used as a solvent. Depending on the property of the compound, another solvent such as ethanol, dioxane, ethylene glycol dimethyl ether, benzene or acetic acid, or a solvent mixture of such a solvent and water may be used.

Examples of protective groups which can be removed by reduction are arylsulfonyl groups such as p-toluenesulfonyl; a methyl group which is substituted by phenyl or benzyloxy, such as benzyl, trityl or benzyloxymethyl; Arylmethoxycarbonyl groups such as benzyloxycarbonyl and p-methoxybenzyloxycarbonyl; and haloethoxycarbonyl groups such as β, β, β-trichloroethoxycarbonyl and β-iodoethoxycarbonyl.

In this reaction, different reaction conditions are used depending on the property of the protecting group (s) to be removed. For example, deprotection may be accomplished by treating the compound with a stream of hydrogen in an inert solvent at 10 to 60 ^° C in the presence of a catalyst such as platinum, palladium or Raney nickel (catalytic reduction), or by treatment with metallic sodium in liquid ammonia are usually carried out at -50 to -20 ⁰ C, or by treatment with a metal such as zinc in acetic acid or in an alcohol such as methanol. Examples of solvents in the catalytic reduction are ethylene glycol dimethyl ether, dioxane, dimethylformamide, ethanol, ethyl acetate and acetic acid.

The starting compound (V) is a new compound and can be prepared according to reactions A and B above.

.ί 6 4

When the compounds of the invention obtained according to the above processes are esters, they can be converted into compounds of formula (I) by hydrolysis of the ester moiety in a manner known per se. If necessary, the compounds of the formula (I) can be esterified in a manner known per se to form the esters of the compounds of the formula (I).

Pharmaceutically acceptable salts of the compounds of formula (I) or their esters can be prepared by treating the compounds of formula (I) or their esters with acids or by treating the compounds (I) with bases or metal salts. Acids suitable for the salting are, for example, hydrochloric, phosphoric, acetic, lactic, oxalic, succinic, methanesulfonic, maleic, malonic, gluconic, aspartic and glutamic acid. Bases or metal salts suitable for salt formation are, 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 invention prepared as described above are isolated and purified in a manner known per se and can be obtained in the form of a salt or a free acid, depending on the conditions of isolation and purification. They can be converted into each other to form the desired compounds prepared according to the invention.

The stereoisomers of the compounds according to the invention can be prepared by methods known per se, such as by fractional crystallisation or chromatography,

2836 4 o

to be obtained. It is possible to prepare the compounds of the present invention having a specific configuration according to the above-described reactions, using as starting compounds those having the corresponding configuration.

The optically active isomers of the compounds prepared according to the invention can be separated by methods known per se.

The compounds (I), their esters and their salts thus obtained are all novel compounds and valuable as antibacterial agents since they have a very high antibacterial activity. The compounds (I) and their salts can be used not only as drugs for humans and animals but also as fish drugs, agricultural chemicals and food preservatives. The esters of the compounds (I) are of course valuable as starting materials for the synthesis of the compounds (I). When the esters can be easily converted to the compounds (I) in vivo, they can exhibit an equivalent effect and are also useful as antibacterial agents.

When the compounds of the present invention are used as antibacterial agents for humans, it is recommended that they be administered at a dose of 5 mg to 5 g per day once or several times daily, "although the dose is according to age, body weight and symptom of the patient, the route of administration, etc. The compounds can be administered orally or parenterally.

ti. Q -J O

The compounds prepared according to the invention may be administered in powder form as they are obtained, but are usually administered in the form of a pharmaceutical preparation together with pharmaceutically acceptable adjuvants. Specific examples of pharmaceutical preparations are tablets, solutions, capsules, granules, fine granules, pellets, powders, syrups, injections and ointments. These pharmaceutical preparations are prepared by methods known per se. Adjuvants for oral administration are those commonly used in the art of preparing pharmaceutical preparations which do not react with the compounds of the present invention, such as starch, mannitol, crystalline cellulose, CMC-Na, water, ethanol, etc. Adjuvants for Injection are those commonly used in the injection field, such as water, isotonic sodium chloride solution, glucose solution and transfusion solution.

The above liquid preparations and ointments can also be used for topical treatments in otolaryngology or ophthalmology.

The following exemplary embodiments explain the method according to the invention for producing the connections in more detail.

Reference Example 1

l-cyclopropyl-6,7,8-trifluoro-5-methy1-1,4-dihydro-4-oxoquinoline-3-carboxylic acid:

(1) 32 g of 2,3,4,5-tetrafluoro-6-methylbenzoic acid, a known compound, are treated with thionyl chloride (27.5 g) and

is 2 8 3

Dimethylformamide (0.5 ml) to give 30.8 g of 2,3,4,5-tetrafluoro-6-methylbenzoyl chloride, b.p. 77 to 80 ^° C. (19 mmHg).

(2) The above compound (30.8 g) is reacted with diethyl ethoxymagnesium malonate to give diethyl 2,3,4,5-tetrafluoro-6-methylbenzoylmalonate (43.9 g). Water (400 ml) and p-toluenesulfonic acid monohydrate (0.40 g) are added to the above ester, and the mixture is refluxed for 2 hours. After cooling, the mixture is neutralized with saturated aqueous sodium bicarbonate solution and extracted with chloroform. The extract is dried and evaporated under reduced pressure, and the residue is purified by silica gel chromatography to give ethyl 2,3,4,5-tetrafluoro-6-methylbenzoylacetate (23.5 g), b.p. 122-128 ° C (5 mmHg ).

(3) A mixture of the above compound (6.0 g), acetic anhydride (5.5 g) and ethyl orthoformate (4.8 g) is refluxed for 3 hours. The mixture is evaporated to dryness under reduced pressure. The residue is dissolved in isopropyl ether (70 ml) and cyclopropylamine (1.23 g) is added at room temperature. The mixture is stirred for 1 hour. η-Hexane is added to the mixture and the precipitated crystals are filtered off. The recrystallization from η-hexane gives ethyl 3-cyclopropylamino-2- (2,3,4,5-tetrafluoro-6-methylbenzoyl) acrylate (7.4 g), m.p. 76-77 ° C.

(4) The above compound (7.40 g) is dissolved in dry tetrahydrofuran (70 ml), and potassium t-butoxide (2.4 g) is added under ice-cooling. After stirring for 1 hour, ice-water is added to the mixture and the precipitated crystals are filtered off. Recrystallization from ethyl acetate gives ethyl 1-cyclopropyl-6,7,8-trifluoro-5-

233 6 4 O

methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (5.5 g), m.p. 176-177 ° C.

(5) To the above compound (5.2 g) is added a solvent mixture (50 ml) of conc. Sulfuric acid, ice cream sauces and water (1: 8: 6), and the mixture is heated at 100 ⁰ C for 1 hour with stirring. After cooling, water is added and the precipitated crystals are filtered off. Recrystallization from acetonitrile gives 1-cyclopropyl-6,7,8-trifluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (4.2 g), mp 242-243 ° C.

Reference Example 2

6,7,8-trifluoro-1- (2,4-difluorophenyl) -5-methyl-l, 4-dihydro-4-oxoquinoline-3-carboxylic acid:

(1) In the same manner as described in Reference Example 1 (3), ethyl 2,3,4,5-tetrafluoro-6-methylbenzoylacetate (6.0 g), acetic anhydride (5.5 g), ethyl orthoformate (4.8 g) and 2,4-difluoroaniline (2.78 g), whereby ethyl 3- (2,4-difluoroanilino) -2- (2,3,4,5-tetrafluoro-6-methylbenzoy1) acrylate (7 , 9 g), which is recrystallized from n-hexane. Mp 69-71 ° C.

(2) The above compound (7.5 g) is treated with potassium t-butoxide in the same manner as described in Reference Example 1 (4), whereby ethyl 1-6,7,8-trifluoro-1- (2,4-) difluorophenyl) -5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (6.5 g), which is recrystallized from ethyl acetate. Mp 152-154 ° C.

(3) The above compound (6.0 g) is treated in the same manner as described in Reference Example 1 (5), wherein

ο 3 6 · Λ 0

6,7,8-trifluoro-1- (2,4-difluorophenyl) -5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (5.1 g), m.p. 217-219 ° C, is obtained.

Reference Example 3

1-Cyclopropyl-6,7-difluoro-5-methyl-1-1,4-dihydro-4-oxoquinoline-3-carboxylic acid:

(1) 200 g of 2,4,5,6-tetrafluoroisophthalonitrile, a known compound, are treated with diethyl malonate (160 g) in the presence of potassium fluoride to give 2,5,6-trifluoro-4- (diethoxycarbonylmethy1) isophthalonitrile (332 g) reacted as oil.

(2) The above compound (181 g) is hydrolyzed with 60% sulfuric acid to give 4-carboxymethyl-2,5,6-trifluoroisophthalic acid (125 g), m.p. 212-214 ° C.

(3) The above compound (28 g) in dimethyl sulfoxide is at 140 ⁰ C in the presence of triethylamine to give 3,4,6-trifluoro-2-methyl-benzoic acid (13 g), mp. 114-115 ° C, heated.

(4) The above compound (24 g) is 98 to 100 ⁰ C (40 mmHg) treated with thionyl chloride to form 3,4,6-trifluoro-2-methylbenzoyl chloride, bp.

This compound is reacted with diethyl natriumum malonate in dry toluene to give diethyl (3,4,6-trifluoro-2-methylbenzoyl) malonate.

To this compound are added water and a catalytic amount of p-toluenesulfonic acid. The mixture is heated at reflux for 4 hours, whereby ethyl (3,4,6-trifluoro-

21 '- *. ö j 6 4 ö

2-methylbenzoyl) -acetate (15.2 g) is obtained as an oil. Boiling point 112 to 116 ° C (3 mmHg).

(5) The above compound (5.0 g) is treated with ethyl orthoformate and acetic anhydride to give ethyl 3-ethoxy-2- (3,4,6-trifluoro-2-methylbenzoyl) acrylate, which is then treated with cyclopropylamine wherein ethyl 3-cyclopropylamino-2- (3,4,6-trifluoro-2-methylbenzoyl) acrylate. (4.5 g), mp. 79 to 80 ⁰ C, is obtained.

(6) The above compound (4.25 g) is dissolved in tetrahydrofuran (35 ml), and potassium t-butoxide (1.53 g) is added under ice-cooling. The mixture is stirred at room temperature for 15 minutes, ice-water (100 ml) is added and the precipitated crystals are filtered off. Chloroform and water are added to the crystals, and the chloroform layer is separated and dried over anhydrous sodium sulfate. The chloroform is evaporated at reduced pressure and the residue is recrystallized from acetonitrile to give ethyl 1-cyclopropyl-6,7-difluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (3.59 g) is obtained. Mp 198 to 200 ^° C.

(7) A mixture of the above compound (3.30 g), glacial acetic acid (8 ml), water (6 ml) and conc. Sulfuric acid (1 ml) is heated at 120 ⁰ C for 1 hour with stirring. After cooling, water (50 ml) is added to the mixture, and the precipitated crystals are filtered off and washed with water. Recrystallization from acetonitrile gives 1-cyclopropyl-6,7-difluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (2.85 g). Mp 229-231 ° C.

22 2 3 3 6 4 0

EMBODIMENT 1

l-cyclopropyl-6,8-difluoro-5-methy1-7- (cis-3,5-dimethyl-lpiperaziny1) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid:

A mixture of 1-cyclopropyl-6,7,8-trifluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.50 g), cis-2,6-dimethylpiperazine (0.61 g) and pyridine (30 ml) is heated at reflux for 4 hours. The solvent is evaporated off. "Ethanol is added to the residue and the precipitated crystals are filtered off, the crystals are dissolved in 3% aqueous acetic acid, the solution is treated with charcoal and the pH is brought to about 8.0 Adjust in aqueous sodium hydroxide and cool with ice The precipitated crystals are filtered off, washed with water and dried to give 1-cyclopropyl-6,8-difluoro-5-methyl-7- (cis-3,5-dimethyl -l-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.42 g), mp. 200-202 ⁰ C., is obtained. [hydrochloride, mp. 290-295 ° C (dec.) ].

EMBODIMENT 2

l-cyclopropyl-6,8-difluoro-5-methy1-7- (3-methyl-l-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid:

1-Cyclopropyl-6,7,8-trifluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.50 g) and 2-methylpiperazine (0.54 g) are prepared in the same manner as in Example 1 wherein 1-cyclopropyl-6,8-difluoro-5-methyl-7- (3-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.40 g), m.p. 188 to 191 ° C.

EXPLORATION EXAMPLE 3

) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid:

i-cyclopropyl-e-y-trifluoro-S-ethyl-i, 4-dihydro-4-oxoquinoline-3-carboxylic acid (0.50 g) and anhydrous piperazine (0.50 g) are prepared in the same manner as in Example 1 reacted with i-Gyclopropyl-GJS-difluoro-5-methyl-7- (I-piperazinyl) -1 ^ -dihydro ^ -oxochinolin-3-carboxylic acid (0.42 g), Pp 210 -. 211 ⁰ C obtained becomes, -

EXAMPLES OF EXPLOITATION 4

7- (3-amino-1-pyrrolidinyl) -1-cyclopropyl-6,8-difluoro-5-ßiethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid:

-i, 4-dihydro-4-oxoquinoline-3-carboxylic acid (0.50 g) and 3-A-minopyrrolidine (0.7 eil) are reacted in the same way as described in Example 1, v; obei 7- (3-amino-1-pyrrolidinyl) -1-cyclopropyl-6,8-difluoro-5-methyl-1,4 ~ dihydro-4-oxoquinoline-3-carboxylic acid (0.43 g), mp. 232-234 ⁰ G, is obtained.

EXTRA CHAPTER 5

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

-i, 4-dihydro-4-oxoquinoline-3-carboxylic acid (0.50 g) and 3-aminomethylpyrrolinediamine (0.50 g) are reacted in the same manner as described in Example 1, whereby 7- (3-acainomethyl- 1-pyrrolidinyl) -1-cyclopropyl-6,8-difluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.42 g) is obtained *

ι τ.

24 283 6 Λ (j

The compound melts at 109 to 112 ° C and solidifies and then melts at 178 to 179 ° C.

EMBODIMENT 6

1-Cyclopropyl-6,8-difluoro-5-methyl-V- (4-methyl-1-piperazinyl) 1,4-dihydro-4-oxoquinoline-3-carboxylic acid:

1-Cyclopropyl-6,7,8-trifluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 1-methylpiperazine are reacted in the same manner as described in Example 1, wherein 1-cyclopropyl-6 , 8-Difluoro-5-methyl-7- (4-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid, m.p. 228-229 ° C.

EMBODIMENT 7

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

6,7,8-Trifluoro-1- (2,4-difluorophenyl) -5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.50 g) and anhydrous piperazine (0.50 g) are reacted in the same manner as described in Example 1 using 6,8-difluoro-1- (2,4-difluorophenyl) -5-methyl-1- (1-piperazinyl) -1,4-dihydro-4-oxoquinoline. 3-carboxylic acid (0.40 g), m.p. 274-277 ° C.

EMBODIMENT 8

6,8-Difluoro-1- (2,4-difluorophenyl) -5-methyl-1-7- (3-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid:

6,7,8-Trifluoro-1- (2,4-difluorophenyl) -5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.50 g) and 2-methylpiperazine (0.50 g ) are processed in the same way as in the

25 p. < V -JO -

reacted with 6,8-difluoro-1- (2,4-difluorophenyl) -5-methyl-7- (3-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3 carboxylic acid (0.32 g), m.p. 236-238 ° C.

EMBODIMENT 9

6,8-difluoro-l- {2,4-difluorophenyl) -5-methy1-7- (cis-3,5-dimethy1-1-piperaziny1) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid:

6,7,8-Trifluoro-1- (2,4-difluorophenyl) -5-methyl-1,4-. f

I dihydro-4-oxoquinoline-3-carboxylic acid (0.50 g) and cis-2,6-1

Dimethylpiperazine (0.50 g) is prepared in the same way as [

implemented in the embodiment 1, wherein I

6,8-Difluoro-1- (2,4-difluorophenyl) -S-methyl- ^ - (cis-3,5-di-f

methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid |

(0.51 gn ^ mp. 134 to 135 ° C, 240 to 243 ° C, is obtained.

EMBODIMENT 10

1-Cyclopropyl-6-fluoro-5-methyl-7- (1-piperazinyl) -1,4-dihydro-4-oxoquinoline in 3 -carboxylic acid e:

A mixture of 1-cyclopropyl-6,7-difluoro-5-methyl-

1,4-dihydro-4-oxoquinoline-3-carboxylic acid (300 mg), water!

free piperazine (660 mg) and pyridine (5 ml) becomes 45 min

heated to reflux. The solvent is reduced at -J

Gertem pressure evaporated. Acetonitrile becomes the residue ^: f

added, and then cooled with ice. The failed π

Crystals are filtered and dissolved in 4% aqueous sodium:

dissolved hydroxide. The pH of the solution is 10%!

aqueous acetic acid adjusted to 8, and then with j.

Ice cooled. The precipitated crystals are filtered off,;

washed with water and dried to give 1-cyclo-1

propyl 6-fluoro-S-methyl -? - (1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid (332 mg), m.p. 223-234 ° C.

In the same manner as described in Embodiment 10, the connections of the following embodiments 11 to 15 are obtained.

EMBODIMENT 11

1-Cyclopropy1-6-fluoro-5-methyl-7- (4-methyl-l-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid. Mp. 229 to 230 ⁰ C.

EMBODIMENT 12

l-cyclopropyl-6-fluoro-5-methyl-7- (3-methyl-l-piperaziny1) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid. Mp 208-211 ° C.

EMBODIMENT 13

l-cyclopropyl-6-fluoro-5-methyl-7- (cis-3,5-dimethyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid. Mp 245-246 ° C.

EMBODIMENT 14

7- (3-amino-l-pyrrolidiny1) -1-cyclopropy1-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. Mp 268-271 ° C.

EMBODIMENT 15

7- (3-aminomethyl-l-pyrrolidiny1) -1-cyclopropy1-6-fluoro-5-methyl-l, 4-dihydro-4-oxoquinoline-3-carboxylic acid. Mp. 207-210 ⁰ C.

2 8 3 6 4 Ö

EMBODIMENT 16

l-cyclopropyl-6-fluoro-S-methyl-V- (1-piperaziny1) -1,4-dihydro-4-oxoquinoline-3-carbönsäure:

(1) 1-Cyclopropyl-6,7-difluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 1-acetylpiperazine are reacted in the same manner as described in Example 10, using 7- (4 acetyl-l-piperazinyl) -l-cyclopropyl-6-fluoro-5-methyl-l, 4-dihydro-4-oxoquinoline-3-carboxylic acid,

Mp 276-277 ° C.

(2) A mixture of the above compound and 20% hydrochloric acid is refluxed for 5 hours. The mixture is treated with charcoal and evaporated at reduced pressure. Acetonitrile is added to the residue and the precipitated crystals are filtered off to give 1-cyclopropyl-6-fluoro-5-methyl-7- (1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid, m.p. 233-234 ° C.

Reference Example 4

7- (4-acetyl-1-piperazinyl) -S-amino-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid:

(1) To a mixture of 7- (4-acetyl-1-piperazinyl) -1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (20 g) and acetic anhydride (200 ml) is added a solvent mixture of fuming nitric acid (40 ml) and acetic anhydride (80 ml) dropwise at below 12 ⁰ C under ice cooling. The mixture is stirred for 30 minutes and ice-water is added. The precipitated crystals are filtered off and washed with water. Recrystallization from chloroform-ethanol gives 7- (4-acetyl-1-pipera-

cinyl) -1-cyclopropyl-6-fluoro-5-methyl-8-nitro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (13.3 g), m.p. 243-244 ° C.

(2) The above compound (0.55 g) is hydrogenated in glacial acetic acid (20 ml) at 60 ^° C. in the presence of 5% palladium on carbon (80 mg) as a catalyst. After the theoretical amount of hydrogen is absorbed, the catalyst is filtered off and the filtrate is evaporated to dryness under reduced pressure. Water and chloroform are added to the residue and the chloroform layer is separated and evaporated at reduced pressure. Recrystallization of the residue from chloroform-ethanol gives 7- (4-acetyl-1-piperazinyl) -S-amino-1-cyclopropyl-G-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.35 g), mp 140-142 ° C.

Reference Example 5

8-amino-l-cyclopropyl-6-fluoro-5-methyl-7- (4-methyl-l-piperaziny1) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid:

(1) 1-Cyclopropyl-6-fluoro-5-methyl-7- (4-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid (1.7 g) is treated with fuming nitric acid (3.4 ml) and acetic anhydride (21 ml) are treated in the same manner as described in Reference Example 4 (1), whereby 1-cyclopropyl-6-fluoro-5-methyl-7- (4-methyl-1-piperazinyl) - Obtained 8-nitro-l, 4-dihydro-4-oxoquinoline-3-carboxylic acid (0.7 g), which is recrystallized from Chlorof orm-ethanol. Mp. 238-240 ⁰ C.

(2) The above compound (0.61 g) is hydrogenated in the same manner as described in Reference Example 4 (2) using e-amino-1-cyclopropyl-6-fluoro-5-methyl-7- (4-methyl) 1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.38 g),

Mp 211-212 ° C.

29 2 83 * 4-0

EMBODIMENT 17

e-Chloro-l-cyclopropyl-e-fluoro-S-methyl-7- (1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid:

(1) A mixture of t-butylnitrite (0.42 g) and acetonitrile (30 ml) is heated at 65 ° C and copper (I) chloride (0.38 g) is added. To this mixture is added 7- (4-acetyl-1-piperazinyl) -e-amino-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (1.0 g), and the mixture is stirred at 65 ° C for 35 minutes. After the insoluble materials are filtered off, the filtrate is evaporated to dryness under reduced pressure and water and chloroform are added to the residue. The chloroform layer is separated, dried over sodium sulfate and evaporated under reduced pressure. The residue is purified by column chromatography to give 7- (4-acetyl-1-piperazinyl) -e-chloro-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ( 0.31 g), which is recrystallized from chloroform-ethanol. Mp 214-215 ° C.

(2) A mixture of the above compound (0.25 g) and 15% hydrochloric acid is refluxed for 5 hours. The mixture is treated with charcoal and evaporated at reduced pressure. The residue is crystallized from ethanol-water to give e-chloro-1-cyclopropyl-6-fluoro-5-methyl-7- (1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0, 16 g), mp.> 300 ° C, is obtained.

EMBODIMENT 18

S-Chloro-1-cyclopropyl-6-fluoro-5-methyl-7- (4-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid:

30 2 ν 3 ό 4 Ο

e-Amino-1-cyclopropyl-6-fluoro-5-methyl-7- (4-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid (1.8 g) is made to be the same Treated as described in Example 17 (1), whereby e-chloro-1-cyclopropyl-6-fluoro-5-methyl-7- {4-methyl-1-piperazinyl} -1,4-dihydro-4-oxoquinoline 3-carboxylic acid (0.62 g), m.p. 225-227 ° C (dec.).

EMBODIMENT 19

l-cyclopropyl-6,8-difluoro-5-methy1-7- (4-methyl-l-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid:

To a mixture of S-amino-1-cyclopropyl-6-fluoro-5-methyl-1-7- (4-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.2 g) and in hydrochloric acid. (33 ml), which was cooled to 0 ^° C., a solution of sodium nitrite (0.43 g) in water (2 ml) is added. To this mixture is added 60% hexafluorophosphoric acid (2 ml) at below 5 ^° C., and the mixture is stirred for 10 minutes. The precipitated crystals are collected and washed successively with ethanol, chloroform and ether. A mixture of the crystals and n-hexane (50 ml) is heated at 80 ^° C. for 30 minutes with stirring. The crystals are filtered off and water and chloroform are added. After the water layer has been neutralized, the chloroform layer is separated and dried over anhydrous sodium sulfate. The solvent is evaporated at reduced pressure and the residue is purified by column chromatography to give 1-cyclopropyl-6,8-difluoro-5-methyl-7- (4-methyl-1-piperazinyl) -1,4-dihydro-4 oxoquinoline-3-carboxylic acid (0.07 g), m.p. 228-229 ° C.

Embodiments 20 to 22 illustrate pharmaceutical preparations containing the compounds prepared according to the invention as active ingredients.

31 2 Ö3 6 4 O

EMBODIMENT 20

produced according to the invention

Compound 250 g

Thickness 50 g

Lactose 35 g

Talc 15 g

The above components are mixed with ethanol and granulated and filled in 1,000 capsules according to known methods.

EMBODIMENT 21 .

produced according to the invention

Compound 250 g

Starch 54 g

Calcium carboxymethylcellulose 40 g

microcrystalline cellulose 50 g

Magnesium stearate 6 g

The above components are granulated with ethanol and processed into tablets in a manner known per se. 1,000 tablets are produced, each weighing 400 mg.

EMBODIMENT 22

produced according to the invention

Compound 50 g

Lactic acid 120 g

The above components are dissolved in distilled water sufficient to give 10 liters of solution.

The pH of the solution is adjusted to about 4 with an aqueous sodium hydroxide solution, and then the solution is filled into ampoules (10 ml) to give an injectable solution.

The chemotherapeutic activities and some other properties of the compounds according to the invention will be explained in the following examples 23 to 28. The tested connections are:

Compound 1: Compound 2: Compound 3: Compound 4: Compound 5: Compound A:

Compound B: Compound C:

1-Cyclopropy1-6,8-difluoro-5-methy1-7- (cis-3,5-dimethyl-l-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid,

1-Cyclopropy1-6,8-difluoro-5-methyl-7- (1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid,

7- (3-amino-1-pyrrolidinyl) -1-cyclopropy1-6,8-difluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid,

l-cyclopropyl-6-fluoro-5-methyl-7- (cis-3,5-dimethyl-1-piperaziny1) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid,

1-Cyclopropy1-6-fluoro-5-methy1-7- {1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid,

1-Cyclopropyl-6-fluoro-7- (1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride (ciprofloxacin),

1-Cyclopropy1-6,8-difluoro-7- (1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid,

1-cyclopropyl-6,8-difluoro-7- (cis-3,5-dimethyl-1-piperazinyl) -1,4-dihydro-4-oxo-amino-3-carboxylic acid,

ο ο 6 4 ϋ

Compound D: 'e-cyano-1-cyclopropyl-6-fluoro-5-methyl-7-

(1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

EMBODIMENT 23

The antibacterial activity in vitro is shown in Table 1. The figures in the table show the minimum inhibitory concentration (MIC) (μg / ml) calculated for the free base. The minimum inhibitory concentration (minimum inhibitory concentration) is determined according to the dual agar dilution method recommended by the Japan Society of Chemotherapy (Chemotherapy, 2_9 (1), 76 (1981)). Mueller-Hinton agar is used. An eyelid full of overnight culture of the test organisms in Mueller Hinton broth is used to inoculate 10 ml of drug-containing agar layers in petri dishes. The bacterial inocula contain about 10 colony-forming units. Bacterial growth is determined after 20 hours incubation at 37 ° C. MIC is defined as the lowest drug concentration that prevents visible bacterial growth.

TABLE 1 In Vitro Antibacterial Activity

Tribe \ S. - ^^ _ ^ connection 0 1 0 2 3 0 4 0 5 0 A 0 B 0 C 0 D S. aureus 209 JC-I O ₁ 05 0 , 025 0.0125 0 , 025 0 .05 0 ♦ 1 0 "1 0 • ι 0 S. aureus Terajima 0 05 0 , 025 0.0125 0 , 025 0 _r 025 0 rl 0 A 0 ,1 0 "ι Gram + S. aureus no. 80 0 0125 0 , 0125 0.0125 0 , 05 0 , 0125 0 , 39 0 »2 0 "ι 0 ti S. epidermidis no. 8th 0 025 0 , 025 0.0125 0 , 05 0 , 025 0 .1 0 ,1 0 ,1 1 .1 E. pyogenes A65 0 2 0 »39 0.2  O ,1 0 , 39 0 2 0 .39 0 , 78 0 , 56 E.S. coli NIHJ JC-2 0, 0, 025 0 0 , 0063 0.0125 0 0 , 0125 0 0 , 0125 0 0 , 0063 0 0 , 0063 0 0 , 0125 0 0 , 0125 Grief - P. coli P-5101 marcescens S-9 0 025 39 0 _r 0063, 1 0.0125 0.05 0 , 025, 39 0 , 0125 »2 0 , 0063, 05 0 , 0063 .05 0 , 0125 , 2 ο , 0125, 39 aeruginosa 12 2 2 0.2 2 rl .1 ,1 , 78 , 39

35 2 23 64 Q

EMBODIMENT 24

Antichlamydia activity is given in Table 2. The figures in the table show the minimum inhibitory concentration (MIC) (μg / ml) calculated for the free base.

The minimum inhibitory concentrations (MIC) are determined as follows. McCoy cells are freshly cultured in Eagle's minimum essential medium (EMEM) (Flow) supplemented with 4% fetal bovine serum and 0.03% L-glutamine. The cells are trypsinized or treated with trypsin and suspended in the same culture medium at a cell concentration of 1-2 × 10 cells / ml. 1 ml of cell suspension is pipetted into flat bottom plastic containers (14 mm diameter) containing a cover glass (12 mm diameter). The containers are incubated in a 5% CO ₃ -Luft at 36 ⁰ C for 20 hours. Half a milliliter of a chlamydial suspension (about 1-4 x 10 10 units of incorporation) is added to each container, which is then centrifuged at 1500 x g for 60 minutes. The containers are incubated for 1 hour at 36 ° C. The medium is replaced with 1 ml of EMEM supplemented with 8% fetal bovine serum, 0.03% L-glutamine, 1 μg / ml cycloheximide and 0.5% glucose containing drug at various concentrations. After another incubation at 36 ° C for 40 to 48 hours, the cells on the coverslips are stained with Giemsa's solution. Inclusion bodies in the cells on the coverslips are observed with a microscope at a magnification of 200 to 400. MIC is defined as the lowest drug concentration at which no inclusion bodies were observed in the cells on the coverslips.

TABLE 2 Antichlamydia activity

^ _ ^ __ connection 'organism - ^^ _ ^ Trachomatics G / ur 931 0 1 0 2 0 3 A 0 B 0 C D C. Trachomatics G / ur 1242 0 , 013 0 , 05 0 , 013 1 0 , 39 0 r2 1.56 C. Trachomatics G / ur 1317 0 , 025 0 10 0 , 013 1 0 _f 39 0 2 3.13 C. Trachomatics G / ur 1448 0 ♦ 013 0 10 0 , 013 2 0 , 39 0 »2 3.13 C. , 025 10 , 013 1 , 39 »2 3.13

₃₇ £ 33 6 4 ϋ

EMBODIMENT 25

The antimycoplasma activity is given in Table 3. The figures in the table show the minimum inhibitory concentrations (MIC) (μg / ml) calculated for the free base.

The minimum inhibitory concentrations (MIC) are determined according to the double agar dilution method. The media used are Chanock broth and agar (PPLD broth and agar (Difco) supplemented with 20% horse serum and 10% fresh yeast extract). A 2 to 3 day old broth culture of the organisms is diluted with Chanock broth to a cell density of about 10 cells / ml. One eye full (about 1 μL) of the organisms dilution is spotted on 10 ml drug-containing Chanock agar in petri dishes using a multiple inoculator (Cathra International). The Petri dishes are at 37 ° C for 7 and 2 days for Mycoplasma pneumoniae or other Mycoplasma spp. incubated. Incubation was anaerobic using the Gaspak anaerobic system (BBL) for M. buccale, M. fermentans, M. hominis, M. oral and M. salivarium and aerobic for the other Mycoplasma spp. The MIC is defined as the lowest concentration of the compound at which no growth of the organisms was observed.

·, Ν 3 ö 4 O

TABLE 3: Antimycoplasma activity

pneumoniae Mac 0 1 0 A 0 C laidlawii PG-8 0 _r 05 0 »78 0 .2 Connection organism arginini G-230 0 , 05 0 »39 0 .39 M. buccal CH-20249 0 , 025 0 »39 0 , 39 A. fermentan PG-18 0 , 025 0 »39 0 2 M. hominis PG-21 0 , 025 1 »2 0 "1 M. oral CH-19299 0 , 05 1 , 56 0 »2 M. salivarium PG-20 0 »2 3 »56 0 .78 M. hyorhinis BST-7 0 .1 0 13 0 »78 M. , 025 »39 "1 M. M.

EMBODIMENT 26

The in vivo efficacy against systemic infections in mice is given in Table 4.

Each of the compounds is suspended in 0.4% carboxymethylcellulose. Each of the suspensions is orally administered to mice infected with each of the test organisms using the following conditions. The mean effective dose (ED ^ _n ) is calculated by probit analysis. The numbers in the table show ED _t - "- values (mg / kg) calculated for the free base.

³⁹ '. OJ6

Test conditions :

Mice: Male mice (Std-ddY) weighing about 20 g. Infection:

Streptococcus pyogenes A65

Intraperitoneal infection with 3 × 10 cells per mouse, suspended in brain-heart infusion broth.

Pseudomonas aeruginosa 12

Intraperitoneal infection at approximately 5 x 10 6 cells per mouse suspended in Tryptosoja broth with 4% mucin.

Medication:

Twice immediately and 6 hours after infection.

Observation:

During 7 days.

TABLE 4 In vivo Efficacy against Systemic Infections in Mice

^ ~ ^ ~ - ^ - ~ ^ ____ ^ Compound Organism "" ~ --- ~ ^ ___ ^ 5 1 8th 2 7 4 23 A 13 B D 64 S. pyogenes A65 1 , 01 1 , 36 1 # 74 2 , 9 1 »0 > 50 P. aeruginosa 12 , 46 , 05 , 88 , 78 , 22 1.

283 * 4 ΰ

EMBODIMENT 27

A suspension y: ny ^of: containing compounds according to the invention at various concentrations is administered in a dose of 0.1 ml per 10 g body weight, orally to male mice (ddY). The number of dead mice is determined after 7 days, and the value of the mean lethal dose (LD., Mg / kg) is calculated according to the Behrens-Kaerber method. The results are shown in Table 5.

TABLE 5

Acute oral toxicity in mice

connection ^LD 50 ^(m 9 ^{/ k} 9> 1 > 2000 2 > 2000 3 > 2000 4 > 2000 5 > 2000

EMBODIMENT 28

A suspension containing Compound 1 is orally administered to mice at a dose of 5 mg / kg. Urine is collected over 24 hours after administration. The content of the compound in the urine is determined according to the thin-layer cup-plating method using Escherichia coli kp as an indicator organism.

^ 5364

TABLE 6

Urinary Excretion in Mice

connection 7, 1 Concentrate ion 14 5 / Ag / ml volume 0.1 0 ml \ \ Amount 12 05 mg Urine recovery for 24 hours 7 %

Claims (2)

COOH wherein R represents an IT-lower alkyl group having 1 to 5 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms or an optionally substituted phenyl group, X represents a hydrogen atom or a halogen atom, Z -I I or ^ H (OH.) in which Rp, R ^ ,. R., R ₁ - and Rg are the same or different and each represents a V / asserstoffatoia or Miedrigalkylgruppe having 1 to 5 carbon atoms, and η 0 or 1, or one of its pharmaceutically acceptable esters or a pharmaceutically acceptable salt of the derivative or of the ester and optionally of a pharmaceutical preparation, characterized in that (i) a compound of the formula GOOY • 'J 0 0 0-4 (ID wherein X 1 represents a halogen atom, Y represents a hydrogen atom or a lower alkyl group containing 1 to 5 carbon atoms and R 1 and R p have the abovementioned definitions, with a compound of the formula Z-H (III) where Z has the definition given above, reacted and, if desired, the resulting compound hydrolyzed, (ii) a compound of the formula COOY (IV) R ₁ , Y and Z are the definitions given above wherein
sit, diazotized and the resulting diazonium compound is halogenated and, if desired, the resulting compound is hydrolyzed or ;;. ϋ O O * i (iii) the protecting group of a compound of formula wherein R ,, X and Y have the abovementioned definitions and Z ¹ _or j, in which R 'and RJ- denote a protective group and R-3, R, Rg and η have the definitions given above, removed and, if desired, the resulting compound hydrolyzed and , (IV) if desired, converting the compound thus prepared to one of its pharmaceutically acceptable salts, and optionally converting the compound thus prepared into a pharmaceutical preparation by mixing the compound of formula 1 or one of its pharmaceutically acceptable salts or its active third part as an active ingredient with a pharmaceutically acceptable carrier. 2β procedure according to. Claim 1, characterized in that a compound is prepared in which R _{1 represents} a cyclopropyl group, Process according to claim 1, characterized in that a compound is prepared in which X represents a fluorine atom. 4. Process according to claim 1, characterized in that 1-cyclopropyl-6,8-aifluoro-5-methyl-7- (cis-3,5-dimethyl-1-piperazinyl) -1,3'-dihydroxy- ^ oxoquinoline-carboxylic acid and its pharmaceutically acceptable acid addition salt, 5. Process according to claim 1, characterized in that i-cyclopropyl-GjS-difluoro-S-methyl-T-cipiperazinyl-1-dihydro-oxoquinoline-O-carboxylic acid and its pharmaceutically acceptable acid addition salt are prepared, . Process according to claim 1, characterized in that 1-cyclopropyl-6-fluoro-5-methyl-7- (cis-3,5-dimethyl-1-piperazinyl) -1-dihydro-oxoquinoline-carboxylic acid and its pharmaceutically acceptable acid addition salt can be prepared « A process according to claim 1, characterized in that 1-cyclopropyl-6-fluoro-5-methyl-7- (1-piperazinyl) -1-dihydro-1-oxoquinoline-carboxylic acid and its pharmaceutically acceptable acid addition salt are prepared ,