CS277016B6 - Novel derivatives of quinoline, process of their preparation and a pharmaceutical based thereon - Google Patents

Description

Technical field

The invention relates to novel quinoline derivatives having very good antibacterial activity, to processes for their preparation and to an antibacterial composition comprising a quinoline derivative. BACKGROUND OF THE INVENTION

First of all, the prior art relating to pharmacologically active compounds of this type will be briefly discussed.

European Published Patent Application No. 78,362 and its corresponding Japanese Published Patent Application No. 74,667 / 1983 describing 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazinyl-quinoline-3-carboxylic acid of the formula 10

wherein R is H, CH ₃ , C ₂ H ₅ or HOCH ₂ CH ₂ and pharmaceutically acceptable acid addition salts or hydrates thereof.

European Patent Application Publication No. 113 093 and its corresponding Japanese Patent Application Publication No. 130 880/1984 disclose compounds of formula 11

(11) wherein R ¹ is H or an optionally hydroxy-substituted alkyl group having 1 to 12 carbon atoms and

R ² , R ³ , R ⁴ and R ⁵ are the same or each represent an alkyl group having 1 to 4 carbon atoms, wherein at least one of R ² to R ⁵ is an alkyl group, a pharmaceutically acceptable acid addition salt thereof, alkali metals or alkaline earth metals or hydrates. The compounds of formulas 10 and 11 have no substituent at the 5-position of the quinoline ring, as is evident from these formulas.

Japanese Published Patent Application No. 174,367 (1983) and its annotation is disclosed in the Derwitts World Patent Index, Publication No. 83-823272] discloses compounds of Formula 12

/ 12 / i

wherein R is H or lower alkyl.

European Published Patent Application No. 172,651 and its corresponding Japanese Published Patent Application No. 43,186/1986 disclose compounds of Formula 13.

(13) wherein Z is a specific pyrrolidinyl or spiroamino group, X is CH, CF or N,

X is CH, CF or N, β · 1_ is H, an alkyl group having 1 to 6 carbon atoms or a cation, and

R ₂ is C 1 -C 4 alkyl, vinyl, haloalkyl, C 2 -C 4 hydroxyalkyl or C 3 -C 6 cycloalkyl

However, these patents do not disclose compounds of formula 13 wherein Z is piperazinyl.

European Patent Application Publication No. 202 763 and its corresponding Japanese Patent Application Publication No. 243 077/1987 describing compounds of formula 14

where

Z is a specific pyrrolidinyl group or the spiroamino group X is CF or Na

R ₁ and R ₂ have the meanings given in formula 13.

These applications neither disclose nor suggest compounds of formula 14 wherein Z is piperazinyl.

European Patent Application Publication No. 2121463 and its corresponding Japanese Patent Application Publication No. 277 362/1987 disclose compounds of Formula 15:

COOH (15) where

Z is amino or halogen,

R f is H, CH ₃ or C ₂ H ₅ ,

R ₂ is H, CH ₃ or CH ₂ F,

R ₃ and R ₄ are the same or different and each represents H or CH ₃ and n is 1 or 2 and pharmaceutically acceptable esters or salts thereof.

European Published Patent Application No. 226,961 and its corresponding Japanese Published Patent Application disclose compounds of Formula 16

/ 16 / where

R is H, a cation or alkyl of 1 to 6 carbon atoms,

Rf is amino, OH or (C1-C3) alkoxy,

X is ch, CBr, CCl, CF, CCF ₃ or N and three

_R2 groups independently represent H or alkyl ε 1 to 6 carbon atoms.

However, the examples in these applications describe only two compounds wherein Rf is amino and X is CF, one compound where Rf is amino and X is CC1 and one compound wherein Rf is OH and X is CF. The preparation, properties and antibacterial effects of other compounds within the scope of the above general formula are not described in these applications.

U.S. Patent No. 4,668,680, which arises from U.S. Patent Application No. 4,808,102, one of the two priority applications of the previously cited European Published Patent Application No. 226,961 and Japanese Published Patent Application No. 187,459/1987, claims only two compounds of the formula 16, wherein R ₁ is amino and X is CF, based on the teachings in the specific examples.

It is an object of the invention to provide novel quinoline derivatives of the formula I and their pharmaceutically acceptable salts.

It is a further object of the invention to provide novel quinoline derivatives of the formula I and their pharmaceutically acceptable salts, which have an excellent antibacterial effect in vitro and in vivo against both Gram-positive and Gram-negative bacteria.

It is yet another object of the invention to provide compounds having a broad antibacterial spectrum and exhibiting activity against the genus Mycoplasma as well as Chlamydia.

Yet another object of the invention is to provide novel compounds of formula I and their pharmaceutically acceptable salts, which have excellent drug properties, such as considerably high water solubility, good light stability in aqueous solution and good urinary excretion.

Another object of the invention is to provide a process for the preparation of novel compounds.

Yet another object of the invention is to provide a pharmaceutical composition comprising an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

Other objects of the invention together with the following description.

their advantages will be evident

According to the invention, the quinoline derivative fulfills these objectives and advantages

where

Z is amino, halogen, acylamino of 1 to 5 carbon atoms or benzylamino, is hydrogen, alkyl of 1 to 5 carbon atoms, acyl of 1 to 5 carbon atoms, alkoxycarbonyl of 1 to 5 carbon atoms or benzyl,

R ₂ and R ₃ are the same or different and each represents a hydrogen atom or a C 1 -C 5 alkyl group;

Y is hydrogen, C 1 -C 5 alkyl, di / acyloxy / boryl wherein the acyl has 1 to 5 carbon atoms, or difluoroboryl, or a pharmaceutically acceptable salt thereof.

Examples of halogen atoms are fluorine and chlorine, and fluorine is particularly preferred.

The C 1 -C 5 alkyl group may be straight or branched and is, for example, methyl, ethyl, propyl, isopropyl butyl, sec-butyl, isobutyl, tert-butyl or pentyl.

The compound of formula I and its salts are generally referred to as compounds of the invention.

The compounds of the invention may also exist as hydrates. Therefore, these hydrates are also included in the compounds of the invention.

The compounds of the invention also include compounds having asymmetric carbon atoms (e.g. when R ₂ is an alkyl group having 1 to 5 carbon atoms in Formula I, it is the carbon atom to which the alkyl group is attached) and therefore existing in optically active forms . Therefore, they include the D-isomers, the L-isomers and mixtures thereof.

Some compounds of the invention have multiple asymmetric carbon atoms (for example, when both R ₂ and R ₃ are C 1 -C 5 alkyl groups, they are two carbon atoms to which R ₂ and R ₃ are attached) and therefore may exist as stereoisomers having different configurations. These stereoisomers and mixtures thereof are also included within the scope of the compounds of the invention.

A salt of a compound of the invention is a salt formed from a compound of Formula 1 and a pharmaceutically acceptable acid or base. Examples of salts include salts of compounds of formula I with inorganic acids such as hydrochloric acid and phosphoric acid, with organic acids such as acetic acid, lactic acid, oxalic acid, succinic acid, methanesulfonic acid, maleic acid, malonic acid and gluconic acid, acidic amino acids such as aspartic acid and glutamic acid with metals such as sodium, potassium, calcium, magnesium, zinc and silver, with organic bases such as dimethylamine, triethylamine, dicyclohexylamine and benzylamine and with basic amino acids such as lysine and arginine.

The compounds of the invention exhibit excellent antibacterial activity and broad antibacterial spectrum in in vitro assays. They are highly effective not only against gram-negative bacteria, including Pseudomonas aeruginosa and the genus Seratia, but also against gram-positive bacteria, including Streptococci and Staphylococcus aureus resistant to methicillin, against which the usual quinol-type antibacterial agents are relatively ineffective. In addition, they are highly effective against glucose-free anaerobes and against the genera Mycoplasma, Chlaroydia and Mycobacterium, against which only a few drugs are effective.

The compounds of the invention show an excellent protective effect in vivo on topical or systemic infections caused by various bacteria and low toxicity to animals in general toxicity tests.

Furthermore, these compounds exhibit good water solubility, good light stability in aqueous solutions, which are important properties for injection forms, and are well excreted in the urine.

Therefore, the compounds of the invention are useful as antibacterial agents that can be administered orally or by injection.

Methods for preparing compounds of the invention are described below.

A. Substitution reactions

The compounds of the invention can be prepared by reacting compound II

where

X is a halogen atom,

Z 'is amino, halogen, C 1 -C 5 acylamino or benzylamino; and

Y je is hydrogen, (C 1 -C 5) alkyl, di (acyloxy) -boryl, wherein the acyl group has 1 to 5 carbon atoms, or difluoroboryl with a piperazine derivative of the general formula III (111)

where

R 1 is hydrogen, C 1 -C 5 alkyl, C 1 -C 5 alkyl, C 1 -C 5 alkoxycarbonyl, or benzyl; and

R ₂ and R ₃ are as defined in formula I, and if desired, the resulting compound is hydrolyzed, wherein Y ¹ is C 1 -C 5 alkyl, di / acyloxy / boryl wherein the acyl group has 1 to 5 carbon atoms or a difluoroboryl group, and optionally converting the compound thus prepared into a pharmaceutically acceptable salt.

The 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 inert solvents 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, piridine and water.

Preferably, the above reaction is carried out in the presence of an acid binding agent, wherein the starting compound of formula III is used in an equivalent amount or in a slight excess relative to the starting compound of formula II. Optionally, the starting compound of formula (III) can be used in excess, which then serves simultaneously as an acid acceptor. Examples of acid acceptors are sodium bicarbonate, sodium carbonate, potassium carbonate, triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] undecen-7 (DBU), and pyridine.

Hydrolysis can be accomplished by reacting a compound wherein Y 'is alkyl, di (acyloxy) boryl or difluoroboryl with an acid or base in a solvent. Examples of acids are hydrochloric acid, sulfuric acid and p-toluenesulfonic acid. Examples of bases are sodium hydroxide, potassium hydroxide and triethylamine. Solvents are not specifically limited, but water and water-containing solvents are preferred. The reaction temperature is 10 to 150 ° C. When R1 is acyl or alkoxycarbonyl, the group is hydrolyzed simultaneously.

The starting compound of formula (II) can be prepared by the methods described in Comparative Examples 1 to 5 or by analogous methods.

B. Animation reactions

The compounds of the invention may be prepared by reacting a compound of Formula IV

(IV) where

.)

X is a fluorine atom,

R 1 is hydrogen, C 1 -C 5 alkyl, C 1 -C 5 acyl, C 1 -C 5 alkoxycarbonyl or benzyl,

Y 'is hydrogen or C 1 -C 5 alkyl and R ₂ and R ₃ are as previously defined, with ammonia and, if desired, hydrolyzing the resulting compound, wherein:

Y * is an alkyl group having from 1 to 5 carbon atoms, and the compound thus prepared is optionally converted to a pharmaceutically acceptable salt.

The 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 an alcohol such as ethanol, pyridine, dimethylformamide or water, preferably in a sealed tube.

The reaction is carried out in the presence of an acid binding agent using ammonia in an equivalent amount or a slight excess relative to the starting compound of formula IV. Suitably, ammonia is used in excess while serving as an acid acceptor. Instead of ammonia, a salt such as ammonium acetate may be used.

The hydrolysis is carried out in the same manner as described above.

The starting compound of formula (IV) is new and can be prepared by the procedure of Reaction A.

C. Deprotection

The compound of the invention may be prepared by deprotection, for example by solvolysis (also by hydrolysis), or by reduction of a compound of formula V described below.

at

More specifically, the compound of the invention may be prepared by hydrolysis and / or reduction of a compound of formula V

Z * 0

where

Z 'is amino, halogen, benzylamino or acylamino of 1 to 5 carbon atoms

R 6 is hydrogen, C 1 -C 5 alkyl, benzyl, C 1 -C 5 acyl or C 1 -C 5 alkoxycarbonyl,

Y 'is hydrogen or (C 1 -C 5) alkyl and R ₂ and R ₃ are as defined in formula I, provided that even when Z' is amino or halogen, R 1 is benzyl, acyl and (ii) when R je is hydrogen or alkyl of 1 to 5 carbon atoms, then Z 'is benzylamino of 1 to 5 carbon atoms, then Z' is benzylamino or acylamino ε And optionally converting the resulting compound into a pharmaceutically acceptable salt. .

The protecting group can be any protecting group that can be removed without destroying the structure of the compounds of the invention. Groups that are commonly used as protecting groups in the chemistry of peptides, amino sugars, nucleic acids, or beta-lactam compounds can be used.

Amine protecting groups (including hydrolysis) or reductions in protecting groups.

can be cleaved by solvolysis of the property

Specific examples of protecting groups that can be removed by solvolysis include acyl groups such as formyl, acetyl and trifluoroacetyl; substituted or unsubstituted alkoxycarbonyl groups such as ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl and beta- (p-toluenesulfonyl) ethoxycarbonyl; trityl, trimethylsilyl

1.1, o-nitrophenylsulfonyl, 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 acids 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 bases are hydroxides such as sodium hydroxide and barium hydroxide, carbonates such as sodium carbonate and potassium carbonate; alkali metal alkoxides such as sodium methoxide and sodium ethoxide; and sodium acetate. Water is usually used as the solvent. Depending on the properties of the compound, other solvents such as ethanol, dioxane, ethylene glycol dimethyl ether, benzene or acetic acid or a mixture of this solvent and water may be used.

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

Different reaction conditions are used in this reaction depending on the properties of the protecting group to be cleaved. For example, the compound is contacted 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 contacting the compound with sodium metal in liquid ammonia, usually at -50 to -20 ° C; or contacting the compound with a metal such as zinc in an alcohol such as methanol. Examples of catalytic reduction solvents include ethylene glycol dimethyl ether, dioxane, dimethylformamide, ethanol, ethyl acetate, and acetic acid.

The starting compound of formula (V) is new and can be prepared by reactions A or B as described above.

When the compound of formula (V) is an ester, it is also converted to the carboxylic acid by the hydrolysis described above.

The pharmaceutically acceptable salts of the compounds of formula I may be prepared by reacting the compounds of formula I with acids, bases or metal salts. Suitable salts for forming the salt are, for example, acetic acid, phosphoric acid, acetic acid, lactic acid, oxalic acid, succinic acid, methanesulfonic acid, maleic acid, malonic acid, gluconic acid, aspartic acid and glutamic acid. Suitable metal bases or salts for salt formation 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 invention, prepared as described above, are isolated and purified in a conventional manner and, depending on isolation and purification conditions, can be obtained in salt form or in free form. They can be converted into one another to form the compounds of the invention in the desired forms.

The stereoisomers of the compounds of the invention may be isolated by conventional means, such as fractional crystallization or chromatography. It is possible to prepare compounds of the invention having a specific configuration by the reactions described previously using starting materials of the corresponding configuration.

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

The compounds of formula (I) thus obtained and their salts are all novel and, since they have a very high antibacterial effect, are valuable as antibacterial agents. 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, as agrochemicals and food preservatives. Compounds of formula I wherein Y is alkyl are, of course, valuable as starting materials for the synthesis of compounds of formula I wherein Y is hydrogen.

When the compounds of the 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 in one or more doses, although the dose may vary depending on the patient's age, weight and symptoms. administration, etc. The compounds may be administered orally or parenterally.

The compounds of the invention may be administered in the form of powders as prepared, but are usually administered in the form of a pharmaceutical preparation together with pharmaceutically acceptable excipients. Specific examples of pharmaceutical formulations are tablets, solutions, capsules, granules, fine granules, pills, 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 preparation of pharmaceutical preparations and which do not react with the compounds of the invention, such as starch, mannitol, crystalline cellulose, sodium carboxymethylcellulose, water, ethanol, etc. Adjuvants for injection are also commonly used. the substances used in the preparation of injections such as water isotonic sodium chloride solution, glucose solution and transfusion solution.

The above liquid preparations and ointments may also be used for topical treatment in otorhinolaryngology or ophthalmology.

The following examples illustrate the preparation of the compounds of the invention in more detail.

DETAILED DESCRIPTION OF THE INVENTION

Comparative Example 1 1-Cyclopropyl-5,6,7-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

1/3 8.8 g of 2,3,4,6-tetrauorbenzoic acid, a known compound, is reacted with thionyl chloride to give 36 g of 2,3,4,6-tetrafluorobenzoyl chloride as an oil, mp 87-89 ° C (4.80 kPa).

2/36 g of the title compound was reacted with sodium diethyl malonate in anhydrous toluene to give diethyl 2,3,4,6-tetrafluorobenzoyl malonate as an oil. Water and a catalytic amount of p-toluenesulfonic acid are added and the mixture is refluxed for 2.5 hours to give 28.4 g of ethyl-2,3,4,

6-tetrafluorobenzoylacetate as an oil, b.p. 103-104 ° C (400 Pa).

3 / 28.4 g of the title compound are reacted with ethyl orthoformate and acetic anhydride to convert to ethyl 3-ethoxy-2- / 2 ', 3', 4 ', 6'-tetrafluorobenzoyl / acrylate, and this compound is then reacted with cyclopropylamine to give 32.8 g of ethyl 3-cyclopropylamino-2- / 2 ', 3', 4 ', 6'-tetrafluorobenzoyl / acrylate, m.p. Mp 107-108 ° C.

4) A mixture of the title compound (g), potassium fluoride (8.85 g) and dimethylformamide (100 ml) was stirred at 150-160 ° C for 2 hours and then allowed to cool to room temperature. 300 ml of water are added to the reaction mixture and the crystals are filtered off. Chloroform was added to the crystals, and the aqueous layer was basified with saturated aqueous sodium carbonate. The chloroform layer was separated and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography to give the following compounds.

Ethyl 1-cyclopropyl-5,6,7-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (2 g), m.p. Mp 220-221 ° C.

Ethyl 1-cyclopropyl-5,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (27 g), m.p. Mp 211-212 ° C.

5 / A mixture of 1.54 g of ethyl 1-cyclopropyl-5,6,7-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate, 8 ml of glacial acetic acid, 6 ml of water and 1 ml of concentrated sulfuric acid was stirred at 120 ° C for 1.5 hours. After cooling, the precipitated crystals were filtered off and washed with sufficient water and ethanol to give 1.34 g of 1-cyclopropyl-5,6,7-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid as colorless needles, m.p. 295 DEG-297 DEG C. (decomposition). Comparative Example 2

5-Amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

1) a mixture of 2.57 g of ethyl 1-cyclopropyl-5,6,7-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate, 1.8 ml of benzylamine and 180 ml of trichloroCS 277016 B6 is heated for 3 hours. hours and 40 minutes to reflux. Water and 10% hydrochloric acid were added to the reaction mixture to keep the aqueous layer acidic. The trichlorethylene layer was separated and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was separated and purified by silica gel column chromatography to give 2.78 g of ethyl 5-benzylamino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3. -carboxylate, mp Mp 144-145 ° C.

2 / 2.78 g of the compound obtained are dissolved in 100 ml of glacial acetic acid and catalytically reduced at 60 DEG C. using 0.2 g of 5% palladium on carbon catalyst. After the theoretical amount of hydrogen had been consumed, the catalyst was filtered off and the solvent was evaporated under reduced pressure. The residue was recrystallized from acetonitrile to give 2.1 g of ethyl 5-amino-1-cyclopropyl-6,7-1,4-dihydro-4-oxoquinoline-3-carboxylate as colorless needles, m.p. 240-241 ° C.

3) A mixture of 2.09 g of the compound obtained, 8 ml of glacial acetic acid, 6 ml of water and 1 ml of concentrated sulfuric acid was stirred at 110 ° C for 1.5 hours. Water (30 ml) was added to the reaction mixture, and the precipitated crystals were filtered off and washed well with water and ethanol. 1.71 g of 5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid are obtained in the form of pale yellow needles, m.p. higher than 300 ° C.

Comparative example

5-Amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

1) A mixture of 19.4 g of 2,3,4,6-tetrafluorobenzoic acid, 200 ml of dioxane and 35.3 ml of benzylamine is heated under reflux for 3 hours. The reaction mixture was concentrated to dryness under reduced pressure. Water was added to the residue and the pH of the solution was adjusted to 3 by addition of hydrochloric acid. The solution was then extracted with ethyl acetate. The extract is dried, treated with charcoal and concentrated. Ether and n-hexane were added to the residue and the crystals were filtered off. It is obtained

20.2 g of 2-benzylamino-3,4,6-trifluorobenzoic acid, m.p. Mp 140-141 ° C.

2) A mixture of the title compound (21.7 g), acetic anhydride (16.8 ml) and chloroform (200 ml) was heated at reflux for 9 hours. The reaction mixture was extracted with an aqueous solution of sodium hydroxide, pH 9-10. The extract was adjusted to pH 3-4 with hydrochloric acid, then extracted with ethyl acetate. The extract was dried and concentrated under reduced pressure. Isopropyl ether is added to the residue and the precipitated crystals are filtered off. 17.6 g of 2- (N-acetylbenzylamino) -3,4,6-trifluorobenzoic acid are obtained, m.p. 150-153 ° C.

3) A mixture of 1.6 g of the compound obtained, 0.99 ml of triethylamine and 10 ml of toluene is cooled with ice and 3 ml of toluene solution of 0.62 ml of ethyl chlorocarbonate are added dropwise over 10 minutes. The mixture was stirred for 1 hour and the precipitate was filtered off (reaction mixture A). To a toluene solution of 1.67 mL of diethyl malonate was added 780 mg of 92% sodium ethoxide and the mixture was stirred at room temperature for 1 hour. The ethanol formed was evaporated and reaction mixture A was added dropwise to the residue at room temperature and stirred for 2 hours. Reaction of sodium hydroxide and hydrochloric acid to extract pH 10 to pH 3-4 dried and concentrated by extraction with aqueous solution

11. Acidify the extract and then extract with ethyl acetate. to dryness under reduced pressure. The residue was purified by chromatography on silica gel (eluent: chloroform) to give 2.3 g of diethyl 3- (acetylbenzylamino) -3,4,6-trifluorobenzoyl malonate. 10 ml of water and 480 mg of p-toluenesulfonic acid monohydrate were added and the mixture was heated under reflux for 1 hour. After cooling, the mixture was extracted with ethyl acetate. The extract was dried and then concentrated under reduced pressure. 1.9 g of ethyl 2- (N-acetylbenzylamino) -3,4,6-trifluorobenzoylacetate are obtained.

4) A mixture of 1 g of the title compound, 0.6 g of acetic anhydride and 0.64 ml of ethyl orthoformate was heated at reflux for 1.5 hours. The reaction mixture was concentrated to dryness under reduced pressure. The residue was dissolved in isopropyl ether and 0.2 ml of cyclopropylamine was added under ice-cooling. The reaction mixture was stirred for 1 hour. 10 ml of n-hexane are then added to the reaction mixture. The precipitated crystals were filtered off to give 993 mg of ethyl 2- (N-acetyl-2'-benzylamino-3 ', 4', 6 ', - trifluorobenzoyl) -3-cyclopropylaminoacrylate, m.p. Mp 119-121 ° C.

5 / 26.3 g of the title compound are dissolved in 150 ml of tetrahydrofuran and 7.1 g of the target are gradually added under ice-cooling. of potassium butoxide and the mixture was stirred for 30 minutes. The mixture was further stirred at room temperature for 1.5 hours. Ice water was added and the mixture was adjusted to pH 4-5 with hydrochloric acid and extracted with chloroform. The extract is dried and then concentrated to dryness under reduced pressure. Ether was added to the residue and the crystals were filtered off. 21.4 g of ethyl 5- (N-acetylbenzylamino) -1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate are obtained, m.p. Mp 147-150 ° C.

6) The resulting compound (1 g) was dissolved in ethanol and crystallized at 50-55 ° C using palladium on carbon catalyst. The catalyst is filtered off and the filtrate is concentrated to dryness under reduced pressure. Ethyl 5-acetylamino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate is obtained.

7) 10 ml of a mixed solution of concentrated sulfuric acid, glacial acetic acid and water (1: 8: 6) were added to the obtained compound, and the mixture was heated under reflux for 2 hours, water was added to the reaction mixture and the precipitated crystals were filtered and washed with ethanol. 0.3 g of 5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid is obtained, m.p. more than 300 ° C.

Comparative Example 4

5-Benzylamino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 1: 8: 6 concentrated sulfuric acid, glacial acetic acid and water was added to 4 4 g of ethyl 5- (N-acetyl) 277016 B6 benzylamino] -1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate and the mixture was heated under reflux for 6 hours . After cooling, water was added to the reaction mixture, and the crystals were filtered off and washed well with water and ethanol. The crystals were recrystallized from chloroform-ethanol to give 3.0 g of 5-benzylamino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, m.p. Mp 214-216 ° C.

Example 1

5-Amino-1-cyclopropyl-6-fluoro-7- (1-piperazinyl) -1-dihydro-4-oxoquinoline-3-carboxylic acid

A mixture of 0.42 g of 5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 0.39 g of anhydrous piperazine and 10 ml of pyridine is heated for 2.5 hours to reflux. The reaction mixture was concentrated to dryness under reduced pressure, washed with ethanol and then dissolved in water and 1N aqueous sodium hydroxide solution. The solution was neutralized with 10% aqueous acetic acid. The precipitated crystals are filtered off, washed with water and dried. 0.44 g of 5-amino-1-cyclopropyl-6-fluoro-7- (1-pyperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid is obtained in the form of pale yellow needles, m.p. Mp 214-216 ° C.

Example 2

5-Amino-1-cyclopropyl-6-fluoro-7- (4-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

5-Amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 1-methylpiperazine were reacted together in dimethylformamide (room temperature, 24 hours), dioxane (reflux) , 5 hours), acetonitrile (50 ° C, 1 hour), water (60 ° C, 1 hour), xylene (at reflux, 3 hours) or in dimethylsulfoxide (150 ° C, 2 hours) and treated in the same manner as in Example 1 to give 5-amino-1-cyclopropyl-6-fluoro-7- (4-methyl-1-pyperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid, m.p. Mp 216-218 ° C.

Example 3

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

A mixture of 1.0 g of 5-amino-1-cyclopropyl-6,7-dihydro-4-oxoquinoline-3-carboxylic acid, 1.18 g of 2-methylpiperazine and 10 ml of pyridine is heated under reflux for 3 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in 28% aqueous ammonia. The solution was neutralized with a 10% aqueous acid solution, cooled with ice. The crystals are filtered, dissolved in 10% aqueous acetic acid, treated with active, adjusted to pH 8-9 with 29% aqueous ammonia and cooled with ice. The crystals were filtered off and washed well with water and ethanol. 0.80 g of 5-amino-1-cyclopropyl-6-fluoro-7- (3-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-317 carboxylic acid is obtained, m.p. Mp 181-183 ° C.

Example 4

5-Amino-1-cyclopropyl-6-fluoro-7- (cis-3,5-dimethyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid and its hydrochloride

1 / A mixture of 280 mg of 5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 542 mg of cis-2,6-dimethylpiperazine and 10 ml of pyridine is heated to under reflux for 2.5 hours. The solvent was evaporated under reduced pressure. A 1N aqueous sodium hydroxide solution was added to the residue and the insoluble material was filtered off. A 10% aqueous acetic acid solution was added to the filtrate to adjust the pH to 8. The solution was then extracted with chloroform. The chloroform layer was dried over sodium sulfate and concentrated under reduced pressure. Acetonitrile was added to the residue and the mixture was cooled with ice. The crystals are filtered off and recrystallized from aqueous ammonia. 250 mg of 5-amino-1-cyclopropyl-6-fluoro-7- (cis-3,5-dimethyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid are obtained, m.p. 253 DEG-254 DEG.

2) The resulting compound was dissolved in 1N aqueous sodium hydroxide solution and 10% hydrochloric acid was added thereto to acidify the solution. The precipitated crystals are filtered off and washed with sufficient water and ethanol. 5-Amino-1-cyclopropyl-6-fluoro-7- (cis-3,5-dimethyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride, m.p. Deň: 32 ° C. Example 5

5-Amino-1-cyclopropyl-6,7-difluoro-1,4-oxoquinoline-3-carboxylic acid

1) Ethyl 5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylate and cis-2,6-dimethylpiperazine were reacted in the same manner as 4 to give ethyl 5-amino-1-cyclopropyl-6-fluoro-7- (cis-3,5-dimethyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylate. This was recrystallized from ethyl acetate, m.p. Mp 194-196 ° C.

2) Concentrated acetic acid, glacial acetic acid and water (1: 8: 6) were added to the resulting compound and the mixture was heated to reflux. The reaction mixture was worked up as in Example 4 to give 5-amino-1-cyclopropyl-6-fluoro-7- (cis-3,5-dimethyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3. -carboxylic acid, m.p. 253 DEG-254 DEG.

Comparative example

Chelate cyclopropyl-5,6,7-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid with B / OCOCH _3/2

A mixture of 0.41 g of boric acid and 5 ml of acetic anhydride is heated at 80 ° C for 1.5 hours and 1.25 g of 1-cyclopropyl-5,6,7-trifluoro-1,4-dihydro- 4-oxoquinoline-3-carboxylic acid. The mixture was refluxed for 2 hours and evaporated under reduced pressure. The residue was recrystallized from a mixture of chloroform and ethyl acetate. To give 1.62 g of the chelate of 1-Cyclopropyl-5,6,7-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid with B / OCOCH _3/2, mp over 300 ° C.

Example 6

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

A mixture of 411 mg chelate cyclopropyl-5,6,7-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid with B / OCOCH _3/2, 0.11 mL

Of 1-methylpiperazine, 0.17 ml of triethylamine and 4 ml of dimethylformamide was stirred at room temperature for 2 hours and the reaction mixture was concentrated to dryness under reduced pressure. The residue was dissolved in 2 ml of acetone and 1.5 ml of concentrated hydrochloric acid was added. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated to dryness under reduced pressure. The residue was dissolved in water, neutralized with 1N aqueous sodium hydroxide solution and then extracted with chloroform. The solvent was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate to give 320 mg of 1-cyclopropyl-5,6-difluoro-7- (methyl-1-piperazinyl) -1,4-dihydro-4-dihydro-4-oxoquinoline-3-carboxylic acid, m.p. 253 DEG -255 DEG C. (decomposition).

Example 7

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

1 / chelate A mixture of l-cyclopropyl-5,6,7-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid with B / OCOCH _3/2, 1-formylpiperazine, triethylamine and ethanol was stirred 1 hour at room temperature. The reaction mixture was worked up as in Example 6 to give 1-cyclopropyl-5,6-difluoro-7- (4-formyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid, mp 297 up to 299 ° C (decomposition).

2) A mixture of 120 mg of the compound obtained and 5 ml of 20% hydrochloric acid was stirred at 100-120 ° C for 1.5 hours. The reaction mixture was concentrated to dryness under reduced pressure. The residue was dissolved in water and treated with activated carbon. The solution was basified with concentrated aqueous ammonia. The precipitated crystals are filtered off, washed with water and dried. 80 mg of 1-cyclopropyl-5,6-difluoro-7H-piperazinyl] -1,4-dihydro-4-oxoquinoline-3-carboxylic acid are obtained, m.p. more than 300 ° C.

Example 8

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

Chelate A mixture of l-cyclopropyl-5,6,7-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid with B / OCOCH _3/2, 2-methylpiperazine, triethylamine and dimethyl sulfoxide was stirred for 30 minutes at room temperature . Water was added to the reaction mixture and the precipitated crystals were filtered off. 1N aqueous sodium hydroxide solution was added and the mixture was stirred at 80 ° C for 10 minutes. The reaction mixture was neutralized with acetic acid and the precipitated crystals were filtered off. There was thus obtained 1-cyclopropyl-5,6-difluoro-7- (3-methyl-1-piperisinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

Example 9

1-Cyclopropyl-5,6-difluoro-7 (cis-3,5-dimethyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid

0.32 g of the chelate of l-cyclopropyl-5,6,7-trifluoro-l, 4-dihydro-4-oxoquinoline-3-carboxylic acid with B / OCOCH _3/2 was dissolved in 6 ml of dimethylformamide. A solution of 89 mg of cis-2,6-dimethylpiperazine and 0.13 ml of triethylamine in 2 ml of dimethylformamide was added thereto, and the mixture was stirred for 30 minutes. The mixture was then stirred for 40 minutes at room temperature and 3 ml of concentrated hydrochloric acid was added. The mixture was stirred at room temperature overnight. The crystals were filtered off and dissolved in a 10% aqueous acetic acid solution. The solution was adjusted to pH 8 with 1N aqueous sodium hydroxide solution. After cooling with ice, the crystals are filtered off. The crystals were dissolved in 1N aqueous sodium hydroxide solution. The solution was adjusted to pH 8 with 10% aqueous acetic acid and cooled with ice. The crystals were filtered off and washed with water. 80 mg of 1-cyclopropyl-5,6-difluoro-7- (cis-3,5-dimethyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid are obtained, mp 259-260 ° C. C.

Example 10

1-Cyclopropyl-5,6-difluoro-7- (cis-3,5-dimethyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid

1 / A mixture of 5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 1-acetyl-2-methylpiperazine and pyridine is heated under reflux for 5 hours. . The reaction mixture was concentrated under reduced pressure and the residue was dissolved in aqueous ammonia. The solution was neutralized with aqueous acetic acid and cooled with ice. The crystals were filtered to give 7- (4-acetyl-3-methyl-1-piperazinyl) -5-amino-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, recrystallized is obtained from a mixture of ethanol and chloroform, m.p. Mp 569-271 ° C.

2) A mixture of the resulting compound, 10% aqueous sodium hydroxide solution and ethanol was heated to reflux for 12 hours. The reaction mixture was neutralized with aqueous acetic acid. The precipitated crystals were filtered off to give 5-amino-1-cyclopropyl-6-fluoro-7- (3-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid, m.p. Mp 181-183 ° C.

Example 12

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

1 / A mixture of 3.0 g of 5-benzylamino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 2.5 g of 2-methylpiperazine and 30 ml of pyridine is heated for 5 hours. hours to reflux. The reaction mixture was concentrated under reduced pressure. Water was added to the residue and the solution was acidified with acetic acid and treated with activated carbon, then neutralized with aqueous ammonia. The precipitated crystals were filtered off to give 2.9 g of 5-benzylamino-1-cyclopropyl-6-fluoro-7 (3-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid, m.p. Mp 129-130 ° C.

2) The resulting compound was dissolved in a mixture of acetic acid and ethanol and catalytically reduced using 5% palladium on carbon catalyst. The catalyst is filtered off and the filtrate is concentrated under reduced pressure. Water was added to the residue and the pH of the solution was adjusted to 8 with aqueous ammonia. The precipitated crystals are filtered off to give 5-amino-1-cyclopropyl-6-fluoro-7- (3-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid, m.p. Mp 181-183 ° C.

Example 13

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

1 / A mixture of 5-benzylamino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 1-acetyl-2-methylpiperazine and pyridine is heated to reflux. The reaction mixture was concentrated under reduced pressure, water was added to the residue. The mixture was extracted with chloroform. The extract was dried and the chloroform evaporated. Ethanol was added to the residue and the crystals were filtered off. It is obtained

7- (4-acetyl-3-methyl-1-piperazinyl) -5-benzylamino-1-cyclopropyl-6-fluoro-1,4-dihydro-4-4-oxoquinoline-3-carboxylic acid. This was recrystallized from a mixture of ethanol and diisopropyl ether. M.p. 235-236 ° C.

2) The resulting compound was catalytically reduced as in Example 12 and then hydrolyzed as in Example 11 (2). There was obtained 5-amino-1-cyclopropyl-6-fluoro-7- (3-methyl-1-piperazine) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid, m.p. 181-183 ° C.

Example 14

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

1) 5-Benzylamino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and cis-2,6-dimethylpiperazine are reacted and treated as in Example 12) 1 /. 5-Benzylamino-1-cyclopropyl-6-fluoro-7- (cis-3,5-dimethyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid is obtained.

2) The resulting compound was catalytically reduced in the same manner as in Example 12 (2) to give 5-amino-1-cyclopropyl-6-fluoro-7 - [cis-3,5-dimethyl-1-piperazinyl] -1. 4-dihydro-4-oxoquinoline-3-carboxylic acid, m.p. 253 DEG-254 DEG.

Example 15

5-Amino-1-cyclopropyl-6-flurr-7- (cis-3,5-dimethyl-1-piperidinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid

1) Ethyl 5-benzylamino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate and cis-2,6-dimethylpiperazine were reacted in the same manner as in Example 12/1 and the reaction mixture is worked up in the usual manner. Ethyl 5-benzylamino-1-cyclopropyl-6-fluoro-7- (cis-3,5-dimethyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylate is obtained.

2) The resulting compound was catalytically reduced in the same manner as in Example 12 (2) and then hydrolyzed by refluxing with concentrated sulfuric acid, glacial acetic acid and water (1: 8: 6). There was thus obtained 5-amino-1-cyclopropyl-6-fluoro-7- (cis-3,5-dimethyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid, m.p. 253 DEG-254 DEG.

Example 16

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

1) Ethyl 5-acetylamino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate and 1-methylpiperazine were reacted in the same manner as in Example 12 (1). Ethyl 5-acetylamino-1-cyclopropyl-6-fluoro-7- (4-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylate is obtained.

2) The resulting compound was hydrolyzed in the same manner as in Example 11 / 2. Obtained 5-amino-1-cyclopropyl-6-fluoro-7- (4-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline -3-carboxylic acid, m.p. Mp 216-218 ° C.

Example 17

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

1/5-Benzylamino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 1-benzyl-2-methylpiperazine were reacted in the same manner as in Example 12/1. It is obtained

5-Benzylamino-7- (4-benzyl-3-methyl-1-piperazinyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

2) The resulting compound was catalytically reduced in the same manner as in Example 12/2. There was thus obtained 5-amino-1-cyclopropyl-6-fluoro-7- (3-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid, m.p. Mp 181-183 ° C.

> 0 »

Example 18

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

1-cyclopropyl-5,6,7-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 1-ethoxycarbonylpiperazine were reacted in the same manner as in Example 12/1 and worked up in the usual manner. There was thus obtained 1-cyclopropyl-7- (4-ethoxycarbonyl-1-piperazinyl) -5,6-difluoro-4-oxoquinoline-3-carboxylic acid.

2) The resulting compound is hydrolyzed in the same manner as in Example 11/2. There was thus obtained 1-cyclopropyl-5,6-difluoro-7- (1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid, m.p. more than 300 ° C.

Example 19

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

1 / chelate cyclopropyl-5,6,7-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid with B / OCOCH _3/2 and 1-benzylpiperazine were reacted in the same manner as in Example 7 / 1 /. 7- (4-Benzyl-1-piperazinyl) -1-cyclopropyl-5,6-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid is obtained.

2) The resulting compound was catalytically reduced in the same manner as in Example 12 (2). There was obtained 1-cyclopropyl-5,6-difluoro-7- [1-piperazinyl] -1,4-dihydro-4-oxoquinoline-3-carboxylic acid, m.p. > 300 ° C.

Example 20

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

1 / chelate cyclopropyl-5,6,7-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid with B / OCOCH _3/2 and l-acetyl-2-methylpiperazine were reacted in the same manner as in Example 7 (1). 7- (4-Acetyl-3-methyl-1-piperidinyl) -1-cyclopropyl-5,6-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid is obtained.

2) The resulting compound was hydrolyzed in the same manner as in Example 11 (2). There was thus obtained 1-cyclopropyl-5,6-difluoro-7- (3-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

Example 21

5-Amino-1-cyclopropyl-6-fluoro-7- (1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid 1-cyclopropyl-5,6-difluoro-7- / 1 -piperazinyl / -1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 28% aqueous ammonia are heated at 100 ° C for 48 hours in a sealed tube. The reaction mixture was concentrated to dryness under reduced pressure. The residue was dissolved in 1N aqueous sodium hydroxide solution and neutralized with 10% aqueous acetic acid. The precipitated crystals were filtered off to give 5-amino-1-cyclopropyl-6-fluoro-7- (1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid, m.p. Mp 214-216 ° C.

Example 22

5-Amino-1-cyclopropyl-6-fluoro-7- (methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid 1-cyclopropyl-5,6-difluoro-7- / 4 -methyl-1-piperazinyl / -1,4-dihydro-4-oxoquinoline-3-carboxylic acid in a sealed tube is aminated with ammonia and ethanol as in Example 21 to give 5-amino-1-cyclopropyl-6-fluoro-7 - (4-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid, mp Mp 216-218 ° C.

Example 23

5-amino-l-cyclopropyl-6-fluoro-7- _/ ^/ 3-methyl-l-piperazinyl / -l, 4-dihydro-4-oxoquinoline-3-carboxylic acid cyclopropyl-5,6-difluoro-7 - (3-Methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid was aminated in ammonia and dimethylformamide as in Example 21 in a sealed tube to give 5-amino-1-cyclopropyl-6. -fluoro-7- (3-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid, mp 181-183 ° C.

Example 24

5-Amino-1-cyclopropyl-6-fluoro-7- (cis -3,5-dimethyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid 1-cyclopropyl-5,6- Difluoro-7- (cis-3,5-dimethyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 28% aqueous ammonia were heated in a sealed tube at 100 ° C for 48 hours. The reaction mixture was concentrated under reduced pressure. 1N aqueous sodium hydroxide solution was added to the residue and the insoluble material was filtered off. A 10% aqueous acetic acid solution was added to the filtrate to adjust the pH to 8 and the solution was then extracted with chloroform. The extract was dried and concentrated. Acetonitrile was added to the residue and the mixture was cooled with ice. The crystals are filtered off and recrystallized from aqueous ammonia. 5-Amino-1-cyclopropyl-6-fluoro-7-cis-3,5-dimethyl-1-piperazinyl / 1,4-dihydro-4-oxoquinoline-3-carboxylic acid is obtained, m.p. 253 DEG-254 DEG. · ·

Example 25

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

1/1-Cyclopropyl-7- (4-ethoxycarbonyl-1-piperazinyl) -5,6-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and ammonia were reacted in the same manner as in the example. It is obtained

5-Amino-1-cyclopropyl-7- (4-ethoxycarbonyl-1-piperazinyl) -6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

2) The resulting compound is hydrolyzed in the same manner as in Example 11 (2). There was obtained 5-amino-1-cyclopropyl-6-fluoro-7- (1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid, m.p. Mp 214-216 ° C.

Example 26

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

1 / 7- (4-Acetyl-3-methyl-1-piperazinyl) -1-cyclopropyl-5,6-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and ammonia were reacted in the same manner as in of Example 24. 7- (Acetyl-3-methyl-1-piperazinyl) -5-amino-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid is obtained, which is recrystallized from a mixture of ethanol and chloroform, m.p. Mp 269-271 ° C.

2) A mixture of the resulting compound, 10% aqueous sodium hydroxide solution and ethanol was heated to reflux for 12 hours. The reaction mixture was neutralized with aqueous acetic acid. The precipitated crystals were filtered off to give 5-amino-1-cyclopropyl-6-fluoro-7- (3-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid, m.p. Mp 181-183 ° C.

The chemotherapeutic effects and some other properties of the compounds of the invention are shown in Examples 27-33 below. The following compounds were tested:

compound 1: 5-amino-1-cyclopropyl-6-fluoro-7- (1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid compound 2: 5-amino-1-cyclopropyl-6- fluoro-7- (cis-3,5-dimethyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid compound A: 1-cyclopropyl-6-fluoro-7- (1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride (ciprofloxacin) compound B: 5-amino-1-cyclopropyl-6,8-difluoro-7 - [(piperazinyl)] - 1,4-dihydro -4-oxoquinoline-3-carboxylic acid.

Example 27

The in vitro antibacterial effect is shown in Table 1. The numbers in the table indicate the minimum inhibitory concentrations (MIC) (µg / ml) calculated for the free base. Minimum inhibitory concentrations were determined by a two-fold dilution agar method recommended by the Japanese chemotherapeutic company (Chemotherapy, 29 (1), 76 (1981)) using Muller-Hinton agar. One seed of the test organism culture, grown organism, overnight in Muller-Hinton broth was inoculated into a 10 ml agar layer in Petri dishes containing drug. The bacterial inoculum contains approximately 10 ° colony forming units. Bacterial growth was observed after incubation for 20 hours at 37 ° C. MIC is defined as the lowest drug concentration that prevents visible bacterial growth.

Table 1

Antibacterial effect in vitro

S.aureus 209 JC-1 0,025 0.1 0.1 0.05 S.aureus Terajima 0.05 0.05 0.1 0,025 S.aureus No. 80 0.05 0,025 0.39 0.05 S. epidermidis No. 8 0,025 0.1 0.1 0.05 S. pyogenes Cook 0.2 0.39 0.2 . 0.2 E. coli NIHJ JC-2 0,0063 0,025 0,0063 0,0063 E. coli P-5101 0,0063 0,025 0,0063 0,0063 S. mercescens TFO 3736 0/1 0.78 0.05 0.1 P. aeruginosa 0.05 0.39 0,1 ' 0.1 Flavobacterium sp 0.1 0.1 0.39 0.1

P-7201

Example 28

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

Each compound was suspended in 0.4% carboxymethylcellulose. Each of the suspensions was orally administered to mice infected with each of test organisms under the conditions specified below and the median effective dose / ED ₅₀ / was calculated by probit analysis.

The numbers in the table indicate the values of ED ₅₀ / mg / kg /, converted to free base.

CS 277016 B6

Experimental conditions:

mice: male mice (Std-ddY) weighing about 20 g infection: Staphylococcus aureus 50774 mice are infected intravenously with 5 χ 10 ⁸ cells suspended in saline

Streptococcus pneumoniae 1 Neufeld mouse is infected intraperitoneally with 3 χ 10 ³ cells suspended in infusion broth from brain and heart

Streptococcus pyoqenes A65 mice are infected intraperitoneally with 3 x 10 'cells suspended in infusion broth from brain and heart Pseudomonas aeruginosa 12 about mice are intraperitoneally infected with 5 x 10 ³ cells suspended in tryptosoy broth with 4% mucin treatment: four times, immediately, 6 times , 24 and 30 hours after infection for Streptococcus pneumoniae 1; twice, immediately and 6 hours after infection for other organisms observations: 14 days for Staphylococcus aureus 50774 and Streptococcus pneumoniae 1 Neufeld, 7 days for other organisms

Table 2

Efficacy in vivo against systemic infections in mice

- ^ compound organism ---_____ 2 AND (B) S. aureus 50774 1.41 8.24 - S. pyogenes A65 11.6 23.9 > 50 S. pneumoniae Neufeld 10.2 31.3 20.8 P. aeruginosa 1.98 2.78 -

Example 29

The antimycoplasmic activity is shown in Table 3. The numbers in the table indicate the minimum inhibitory concentration (MIC), µg / ml, calculated for the free base.

The minimum inhibitory concentration (MIC) is determined by a two-fold dilution agar method. The media used were Chanock's broth and agar (PPLD broth and agar / Difco) supplemented with 20% horse serum and 10% fresh yeast extract. ml. One loop (about 1 micron) of the diluted organism is placed on 10 ml of drug-containing Chanock agar in Petri dishes using a multiple inoculator (Cathra International). Petri dishes are incubated at 0 ° C for 7 days for Mycoplasma pneumoniae and for 2 days for other Mycoplasma spp. Incubation is performed anaerobically using the Gaspak anaerobic system (BBL) for M. buccale, M. fermentans, M. orale and M. salivarium. aerobically for others Mycoplasma spp. MIC is defined as the lowest concentration of compound at which no growth of the organism is ensured.

Table 3

Antimycoplasmatic activity ——— Compound 1 organism · —____ 2 AND M. pneumoniae Mac 0.1 0.1 0.78 A. laidlawii PG-8 0/1 0.05 0.39 M. Arginini G-230 0/1 0.05 0.39 M. buccale CH-20249 0.1 0.05 0.39 M. fermentans PG-18 0.1 0,025 0.2 M. hominis PG-21 0.39 0.1 1.56 M. Orale CH-19299 0.39 0.39 1.56 M. salivarium PG-20 1.56 0.39 3.13 M. hyorhinis BST-7 0.1 0.05 0.39

Example 30

The activity against Chlamydia is shown in Table 4. The numbers in the table indicate the minimum inhibitory concentration (MIC), (µg / ml) calculated for the free base.

The minimum inhibitory concentration (MIC) is determined as follows. McCoy's ankles are freshly cultured in Eagle's minimal base medium (EMEM) liquid supplemented with 4% fetal bovine serum and 0.03% L-glutamine. Cells are trypsinized and suspended in the same culture medium at a concentration of 1-2 x 10 6 cells / ml. 1 ml of cell suspension was pipetted into a flat bottom plastic tube (14 mm in diameter) containing a removable cover (12 mm in diameter). The tubes were incubated in air with 5% CO _{2 for} 20 hours at 36 ° C. 0.5 ml of Chlamydia suspension (about 1 to 4 x 10 ³ units made up of similar bodies) was added to each tube, and the tubes were then centrifuged at 1,500 g for 60 minutes.

The tubes were incubated at 36 ° C for 1 hour. The medium is exchanged for 1 ml EMEM supplemented with 8% fetal bovine serum, 0.03% L-glutamine, 1 µg- / mk cycloheximide and 0.5% glucose and containing various drug concentrations. After prolonged incubation at 36 ° C for 40 to 48 hours, cells on the coverslips were stained with Giemsa solution. Inclusion bodies in cells on the coverslips are observed under a microscope at a magnification of 200 and at the lowest drug concentration when inclusion bodies are observed.

Table 4

Effectiveness against Chlamydia

400. The MIC is defined as not on the cover in any

C. trachomatics G / ur 931 0.25 0,063 1 C. trachomatics G / ur 1317 0.25 0,063 2 C. trachomatics G / ur 1467 0.25 0,063 1 C. trachomatics G / ur 1483 0.25 · 0,063 1

Example 31

Acute toxicity

A suspension containing each of the compounds of the invention at various concentrations is orally administered to male mice (ddY) at a dose of 0.1 ml per 10 g body weight. The number of mice sent is counted after 7 days and the mean lethal dose (LD ₅₀ , mg / kg) is calculated according to the Behrens-Kaerber method. The results are shown in the table

5.

Table 5

Acute oral toxicity in mice Compound ^LD 50 / ^m 9 / kg />2000> 2000. 29

Example 32

The light stability of the aqueous solution is shown in Table 6.

Each of the compounds was dissolved in 0.1 N hydrochloric acid to give an acidic solution (0.3 mg / ml for compound 2, 0.5 mg / ml for the other compounds), or 0.1 N aqueous sodium hydroxide solution, thereby an alkaline solution (0.5 mg / ml for all compounds) was obtained. The solution in a 10 ml colorless vial is exposed to light of a fluorescent lamp (6000 lux) at 100 ° C for 100 hours. The amount of compound in solution at the beginning and after 100 hours was determined by high resolution liquid chromatography. The numbers in the table indicate the percentage remaining (%) after 100 hours.

Table 6

Example 33

A suspension containing each compound is orally administered to mice at a dose of 5 mg / kg. Urine is collected 24 hours after administration. Compound levels in urine were determined by the thin-layer cup-plated method using Escherichia coli Kp as an indicator organism.

Table 7

Urinary excretion in mice of compound 2 urinary excretion for 24 /% /

8.33 4.51 Compound C: 5-amino-1-cyclopropyl-6,8-difluoro-7- (3,5-dimethyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid acid

Claims (12)

PATENT CLAIMS A quinoline derivative of the general formula I wherein Z is amino, halogen, C 1 -C 5 acylamino or benzylamino, R 1 is hydrogen, C 1 -C 5 alkyl, C 1 -C 5 acyl, C 1 -C 5 alkoxy, or benzyl, R ₂ and R ₃ are the same or different and each represents a hydrogen atom or a C 1 -C 5 alkyl group; Y is hydrogen, alkyl of 1 to 5 carbon atoms, di / acyloxy / boryl wherein the acyl has 1 to 5 carbon atoms, or difluoroboryl, or pharmaceutically acceptable salts thereof. 2. The compound of item 1, wherein Z is amino and R 1, R ₂ R ₃ a Y is as defined in claim 1. 3. The compound of item 1, wherein Z is a halogen atom and R ₁₁ is a halogen atom R _2, R ₃ and Y are as defined in claim 1. 4. 5-Amino-1-cyclopropyl-6-fluoro-7 '(3,5-dimethyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid and a pharmaceutically acceptable acid addition salt thereof. 5. 5-Amino-1-cyclopropyl-6-fluoro-7- (3-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid and a pharmaceutically acceptable acid addition salt thereof. 6. 5-Amino-1-cyclopropyl-6-fluoro-7- (1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid and a pharmaceutically acceptable acid addition salt thereof. 7. 1-Cyclopropyl-5,6-difluoro-7- (3,5-dimethyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid and a pharmaceutically acceptable acid addition salt thereof. 8. 1-Cyclopropyl-5,6-difluoro-7- (3-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid and a pharmaceutically acceptable acid addition salt thereof. 9. A process for preparing quinoline derivatives according to item l, wherein Z, R, R _2, R ₃ and Y are as defined in claim 1 or a pharmaceutically acceptable salt thereof, characterized by reacting a compound of formula II wherein X is a halogen atom, Z 'is amino, halogen, C 1 -C 5 acylamino or benzylamino; and Y 'is hydrogen, alkyl of ε 1 to 5 carbon atoms, di (acyloxy) boryl wherein acyl contains 1 to 5 carbon atoms or difluoroboryl with piperazine derivative of the general formula III (111) R f is hydrogen, C 1 -C 5 alkyl, C 1 -C 5 acyl, C 1 -C 5 alkoxycarbonyl or benzyl; and R ₂ and R ₃ are as previously defined and, if desired, hydrolyzing the compound obtained, wherein Y 1 is C 1 -C 5 alkyl, di / acyloxy / boryl in which the acyl group contains 1 to 5 carbon atoms, or and optionally converting the compound thus prepared into a pharmaceutically acceptable salt. 10.Způsob preparing a quinoline derivative of the formula I according to 'claim 1, wherein Z is amino, R, R ₂ and R ₃ are as defined in claim 1 and Y is hydrogen or an alkyl group having 1-5 carbon atoms, or a pharmaceutically acceptable salts, characterized by reacting a compound of formula IV (IV) wherein X is a fluorine atom, R '1 is hydrogen, C 1 -C 5 alkyl, C 1 -C 5 acyl, C 1 -C 5 alkoxycarbonyl, or benzyl, Y 'is a hydrogen atom or an alkyl group having from 1 to 5 carbon atoms; and R ₂ and R ₃ are as defined above with ammonia and, if desired, the compound obtained is hydrolyzed, wherein Y' is an alkyl group having 1 to 5 carbon atoms and optionally converting the compound thus prepared into a pharmaceutically acceptable salt. 11. A process for the preparation of a quinoline derivative of the Formula I according to item 1, wherein Z is amino or halogen, R 1, R ₂ and R ₃ are the same or different and each represents a hydrogen atom or an alkyl group of 1 to 5 carbon atoms and Y is hydrogen or a (C 1 -C 5) alkyl group, or a pharmaceutically acceptable salt thereof, characterized in that a compound of formula (V) is hydrolyzed and / or reduced wherein: Z 'is amino, halogen, benzylamino or acylamino of 1 to 5 carbon atoms, R 1 is hydrogen, C 1 -C 5 alkyl, benzyl, C 1 -C 5 acyl or C 1 -C 5 alkoxycarbonyl, Y 'is hydrogen or C 1 -C 5 alkyl and λ, R ₂ and R ₃ are as defined above, with the proviso that even if Z' is amino or halogen, R 1 is benzyl, acyl ε 1 and (ii) when R ^ is hydrogen or alkyl of 1 to 5 carbon atoms, then Z 'is benzylamino or acylamino of 1 to 5 carbon atoms, and optionally obtained the compound is converted to a pharmaceutically acceptable salt. 12. An antibacterial composition comprising as active ingredient a compound of claim 1 together with a pharmaceutically acceptable carrier.