8-cyan-1-cyclopropyl-7-(2,8-diazabicyclo(4.3.0)-nonan-8-yl)- 6-fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid, their derivatives and pharmaceutical composition having antibacterial activity

 

(57) Abstract:

The invention relates to new compounds of General formula (I), where R1is hydrogen, alkyl with 1 to 4 carbon atoms, R2hydrogen, (5-methyl-2-oxo-1,3-dioxol-4-yl)-methyl, residues of formula-CH=CH-COOR3CH2CH2COOR3, -CH2CH2CN, -CH2CH2COCH3, -CH2PINES3where R3means methyl or ethyl, or a residue of the General formula R4- NH-CHR5-CO-, where R4denotes hydrogen, alkyl with 1 to 3 atoms wereda R5denotes hydrogen, alkyl with 1 to 4 carbon atoms, or benzyl, the Invention also concerns a pharmaceutical composition having antibacterial activity, containing the compounds of formula (I). 2 S. and 2 C.p. f-crystals, 2 tab.

The invention relates to biologically active derivatives of quinoline-carboxylic acids, in particular 8-cyan-1-cyclopropyl-7- (2,8-diazabicyclo[4.3.0] -nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3 - quinoline-carboxylic acids, their derivatives, their pharmaceutically acceptable hydrates, acid additive salts, and salts of alkali metal, alkaline earth metal, silver and guanidine corresponding carboxylic acid and a pharmaceutical composition having antibacterial 4-oxo-3 - quinoline-carboxylic acid, possess antibacterial activity (see application EP N 0391152, class C 07 D 487/08, publ. 10.10.1990 year).

Object of the invention is the expansion of the range of the derivatives of quinoline-carboxylic acid, which has antibacterial activity.

The problem is solved by the proposed 8-cyan-1-cyclopropyl - 7-(2,8-diazabicyclo[4.3.0]-nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo - 3-quinoline-carboxylic acids and their derivatives of General formula (I)

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where

R1is hydrogen, alkyl with 1-4 carbon atoms;

R2is hydrogen, (5-methyl-2-oxo-1,3-dioxol-4-yl)-methyl, residues of formula-CH= CH-COOR3, -CH2CH2COOR3, -CH2CH2CN, -CH2CH2COCH3, -CH2COCH3where R3means methyl or ethyl, or a residue of the General formula R4-NH-CHR5-CO-, where R4denotes hydrogen, alkyl with 1 to 3 carbon atoms, a R5denotes hydrogen, alkyl with 1-4 carbon atoms, or benzyl, their pharmaceutically acceptable hydrates, acid additive salts and salts of alkaline metal, alkaline earth metal, silver and guanidine corresponding carboxylic acids.

Preferred compounds of General formula (I), in which

R1is hydrogen, alkyl with 1-4 carbon atoms 2COOR3, -CH2CH2CN, -CH2COCH3where R3means methyl or ethyl, or a residue of General formula

R4-NH-CHR5-CO-, where R4denotes hydrogen, alkyl with 1 to 3 carbon atoms, a R5denotes hydrogen, alkyl with 1 to 4 carbon atoms or benzyl, their pharmaceutically acceptable hydrates, acid additive salts and salts of alkaline metal, alkaline earth metal, silver and guanidine corresponding carboxylic acids.

Particularly preferred 8-cyan-1-cyclopropyl-7-(2,8 - diazabicyclo[4.3.0]-nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3 - quinoline-carboxylic acid and its esters.

Compounds of General formula (I) can be obtained by known methods, for example, the fact that the compounds of formula (II)

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where R1have the above significance and

X represents halogen, in particular fluorine or chlorine,

subjected to interaction with 2,8-diazabicyclo[4.3.0] -nonanes formula (III)

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where R2has the abovementioned meaning, if appropriate in the presence of acid acceptors. If necessary, an ester of carboxylic acid is then split. If necessary, the compounds of formula (I), where R2means hydrogen, can be then N-alkyl is,4 - dihydro-4-oxo-3-quinoline-carboxylic acid and 2,8-diazabicyclo[4.3.0]-nonan, the reaction proceeds according to the following scheme:

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The compounds of formula (I) can also be obtained due to the fact that after the interaction of the compounds of formula (II) with 2,8 - diazabicyclo[4.3.0]-nonanol the resulting product is subjected to further reaction. Thus it is possible to obtain the compounds of formula (I), where R2means the residue-CH=CH-COOEt, where Et means ethyl, for example, according to the following scheme:

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The compounds of formula (I), where R2means hydrogen, can be well-known manner to expose the N-alkylation, N-alkenylamine or N-acylation.

For N-alkylation using the corresponding residue R2alkylhalogenide, alkylperoxide or corresponding residue R2alkenyl.

For N-alkenylamine use appropriate balance R2alkinyl.

For N-acylation using the appropriate residue R2acylhomoserine, in particular chlorides, or anhydrides.

As alkylhalogenide can be called: benzylchloride, alkilinity, were synthesized and alkylchloride with 1-3 carbon atoms, complicated methyl or ethyl ester chlorocarbonic acid, chlorate;

as alkenyl or alkinyl should be called: complex marked the acid;

and as allelochemical or anhydrides can lead to: acetylchloride, pivaloyloxy, N-tert.butyloxycarbonyl-L-alanine-N-carboxyanhydride.

N-alkylation with alkylhalogenide preferably carried out in an environment of a diluent, such as, for example, dimethylsulfoxide, N,N-dimethylformamide, sulfolane or acetonitrile.

As acid acceptors can be used with standard inorganic and organic acid acceptors, such as alkali metal hydroxides, alkali metal carbonates or organic amines.

The reaction temperature can be varied in a wide range. In General operate at a temperature of 20 to 200oC, preferably 50 to 150oC.

N-alkylation with the corresponding residue R2alkenylamine and N-alkenylamine with the corresponding residue R2akinleye preferably carried out in an environment of a diluent, such as, for example, dimethylsulfoxide, N,N-dimethylformamide, N-methyl-pyrrolidone, glycol, methylglycol or diethylene glycol.

The reaction temperature can be varied in a wide range. In General operate at a temperature of 20 to 200oC, preferably 50 to 180oC.

The reaction can be carried out in the presence of an acid acceptor or the same without him.

As the acid acceptor can be applied to standard inorganic and organic acid acceptors such as, for example, triethylamine, 1,4-diazabicyclo[2.2.2]octane, azabicyclo[5.4.0]undec-7-ene.

The reaction temperature can be varied in a wide range. In General operate at a temperature of -10oC - +200oC, preferably 0 to 150oC.

Used as starting compounds, the compounds of formula (II) are known from U.S. patent N 4990517 or they can be obtained by known methods. Can be called, for example, the following connections:

7-chloro-8-cyan-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid,

methyl ester of 7-chloro-8-cyan-1-cyclopropyl-6-fluoro-1,4 - dihydro-4-oxo-3-quinoline-carboxylic acid,

8-cyan-1-cyclopropyl-6,7-debtor-1,4-dihydro-4-oxo-3 - quinoline-carboxylic acid,

complex ethyl ester 8-cyan-1-cyclopropyl-6,7-debtor-1,4-dihydro-4 - oxo-3-quinoline-carboxylic acid.

The compounds of formula (II) can be obtained, for example, by the formula (V), the resulting product of formula (VI) is subjected to interaction with cyclopropylamino with obtaining the compounds of formula (VII), after which they receive a compound of the formula (II):

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In this scheme,

Me means methyl,

X is halogen, in particular fluorine or chlorine, and

R6is alkyl with 1-4 carbon atoms, in particular methyl or ethyl.

The compound of formula (IV) can also directly be subjected to the interaction with a complex ether-cyclopropylamino-acrylic acid:

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(In these formulas, X and R6have the above meaning)

The intermediate product of formula (IV), where X = F, can be obtained, for example, according to the following scheme:

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The compound of formula (VIII) is known from the application DE N 3631906.

The interaction of compounds of the formula (II) with compounds of the formula (III), wherein the compounds of formula (III) can also be used in the form of their salts, such as hydrochloride, preferably carried out in an environment of a diluent, such as, for example, dimethylsulfoxide, N,N-dimethylformamide, N-organic, triamide hexamethylphosphoric acid, sulfolane, acetonitrile, water, environment, alcohol, such as methanol, ethanol, n-propanol, isopropanol, simple glycolmonomethyl ether Il is to alsowhat any standard inorganic and organic acid acceptors. Here preferably include alkali metal hydroxides, alkali metal carbonates, organic amines and amidine. A particularly suitable acid acceptors should be called: triethylamine, 1,4-diazabicyclo[2.2.2] octane, 1,8-diazabicyclo-[5.4.0] undec-7-ene or excess amine (III).

The reaction temperature can be varied in a wide range. In General operate at a temperature of about 0 to 200oC, preferably 20 to 180oC.

The reaction can be performed at atmospheric pressure and at an elevated pressure. In General operate at pressures of 1 to 100 bar, preferably 1 to 10 bar.

In the implementation of the method described above on 1 mol of the compounds of formula (II) use 1 to 15 mol, preferably 1 to 6 mol of compound of formula (III).

During the reaction of the free amino group can be protected using suitable aminosidine groups, such as remnant rubs. butoxycarbonyl, and at the end of the reaction aminosidine group can be removed by treatment with a suitable acid, for example hydrochloric acid or triperoxonane acid (see Houben-Weyl, Methods der Organischen Chemie, volume E4, page 144 (1983); J. F. W. McOmie, Protective Groups in Organic Chemistry (1973), page 43).

Offer is about acid, which can be protected at the nitrogen atom with a protective group such as, for example, remnant rubs. butoxycarbonyl, with derivative halogenoalkane in the environment of a solvent, such as, for example, dimethylformamide, dimethylacetamide, N-organic, dimethylsulfoxide or tetramethylrhodamine, at temperatures from about 0 to 100oC, preferably from 0 to 50oC.

Acid additive salts of the proposed compounds are usually obtained, for example, by dissolving the betaine in a sufficient amount of the aqueous acid and precipitating the salt by using miscible with water, an organic solvent, such as, for example, methanol, ethanol, acetone, acetonitrile. You can also heat the equivalent amount of betaine and acid in water or in alcohol, for example glycolmonomethyl ether, then evaporated to dryness or suck precipitated salt. As pharmaceutically acceptable salts include, for example, salts of hydrochloric acid, sulfuric acid, acetic acid, glycolic acid, lactic acid, succinic acid, citric acid, tartaric acid, methanesulfonate, 4-toluenesulfonic acid, galacturonic acid, gluconic acid, monowai acid, glutamic acid or Aspara is x2">

Acid additive salts of the proposed compounds can be obtained and due to the fact that the ester of carboxylic acid of the formula (I), where R1means, for example, methyl or ethyl, is subjected to saponification with a sufficient amount of the appropriate acid with obtaining a carboxylic acid of the formula (I), where R1means hydrogen, and the subsequent transfer in an acid additive salt.

Salts of alkaline metal or alkaline earth metal offer carboxylic acids get, for example, by dissolving the betaine in insufficient quantity of hydroxide of alkali or alkaline earth metal, filtering of nerastvorimogo betaine and evaporation of the filtrate to dryness. Pharmaceutically acceptable salts are sodium, potassium or calcium. As a result of interaction of salts of alkaline metal or alkaline earth metal with a suitable silver salt, e.g. silver nitrate, get the appropriate silver salt.

Salts of alkaline or alkaline earth metals offer carboxylic acids can also be obtained due to the fact that the ester of carboxylic acid of the formula (I), where R1means, for example, methyl or ethyl, is subjected to saponification with sufficient gidrookislov metal.

The proposed compounds have strong antibiotic action with low toxicity possess a broad antibacterial spectrum against gram-positive and gram-negative bacteria, particularly against bacteria showing resistance to various antibiotics, such as penicillins, cephalosporins, aminoglycosides, sulfonamides, tetracyclines.

These valuable properties allow you to use these compounds as chemotherapeutic active principles in medicine and veterinary medicine and as substances for preservation of inorganic and organic materials, in particular all types of organic materials such as polymers, lubricants, paints, fibres, leather, paper and wood, food and water.

The proposed compounds are active against a very broad spectrum of microorganisms. You can use them to fight gram-positive and gram-negative bacteria and bacteriorhodopsin microorganisms, as well as to prevent, improve and/or cure caused by these pathogens.

The proposed compounds differ enhanced activity against resistant microbes and Mick is such microorganisms. They are therefore particularly suitable for the prophylaxis and chemotherapy caused by these agents of local and systemic infections in medicine and veterinary.

In addition, the compounds are suitable for combating protagonizada and worms.

Thanks to the antibacterial activity of the proposed connections additional object of the invention is a pharmaceutical composition having antibacterial activity, which in addition to the pharmaceutically acceptable carrier contains compounds of the above General formula (I).

The proposed pharmaceutical composition may be in the form of any standard of drug, which include tablets, pills, capsules, pills, granules, suppositories, solutions for injections and solutions for oral villas, suspensions and emulsions, and pastes, ointments, gels, creams, lotions, powders and sprays.

In case of favourable toxicity to warm-blooded animals active principle preferably suitable for combating bacterial diseases present in the area of keeping and breeding animals production, breeding, zoo, laboratory, experimental and domestic animals. If this is normal sensitive strains. In the fight against bacterial diseases the number of cases of illness, death and reduce performance (for example in the production of meat, milk, wool, hides, eggs, honey, etc.,) should be reduced, so that through the use of active principles provide a more economical and simple animals.

Among usability and breeding animals include mammals such as, for example, cattle, horses, sheep, pigs, goats, camels, Indian Buffalo, donkeys, rabbits, fallow deer, reindeer, fur-bearing animals such as mink, chinchillas, raccoons, birds such as, for example, chickens, geese, turkeys, ducks, pigeons, birds for keeping at home and in zoos. Besides, there are usability and ornamental fish.

Among the laboratory and experimental animals include mice, rats, Guinea pigs, Golden hamsters, dogs and cats.

Pets are dogs and cats.

To achieve effective results in General were preferential to give the active principle in an amount of about 0.5 to 50 mg, preferably 1-20 mg per kg of body weight per day.

The active agent can be fed together with the feed or drinking naivnogo began in combination with a suitable edible material.

Such feed means or the food product can be used both for therapeutic and preventive purposes.

Such feed or food product is produced by mixing the concentrate or the initial mixture containing 0.5 - 30%, preferably 1 to 20 wt.% the active agent in a mixture with an edible organic or inorganic carrier, with a standard feed means.

Edible carriers are, for example, corn flour or corn and soybean flour or mineral salts, which preferably contain a small amount of edible oil to prevent dust formation, such as corn oil or soybean oil. Thus obtained the initial mixture can then be added to the complete feed means before it is fed to animals.

The minimum concentration of inhibition of the proposed compounds was determined by means of the implementation experience with a gradient of dilution on agar plates using a set of ISO - Sensitest company Oxoid. Subjects substances were applied to agar plates containing the appropriate substance in decreasing concentrations. Then the plates were inoculable with what would each Cup contained approximately 104forming bacterial colonies of pathogens. Inoculated agar plates were incubated at 37oC and about 20 hours later determined the growth of crops. The minimum concentration of inhibition of compound (μg/ml) represents the lowest concentration of active principle, in which the naked eye growth is not observed. Determination of the minimum concentration of inhibition was performed using the microscope after incubation period of 5 to 7 days.

Table 1 shows the minimum concentration of inhibition of the proposed compounds compared with enrofloxacin as a comparative compound.

The proposed compounds belong to the category of low-toxic substances.

The compound of example 1 of this application shows the best antibacterial activity than the well-known connection similar to the patterns described in example 1 above, the closest analogue. Well-known compound has the following structural formula:

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The results of the comparative experiments described in this way are summarized in table 2.

Receipt of the proposed compounds of formula (I) is illustrated by the following examples which noonkanbah acid

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690 mg (2.25 mmol) of 7-chloro-8-cyan-1-cyclopropyl-6-fluoro-1,4 - dihydro-4-oxo-3-quinoline-carboxylic acid together with 312 mg (2,47 mmol) of (1S,6S)-2,8-diazabicyclo[4.3.0] nonane and 504 mg (4,50 mmol) of 1,4-diazabicyclo[2.2.2]octane in a mixture of 6.6 ml of dimethylformamide and 6.6 ml of acetonitrile is stirred at room temperature overnight. All volatile components are removed under vacuum, the residue is served in water and the resulting solution was adjusted to pH 7 with dilute hydrochloric acid. The formed precipitate is sucked off, the filtrate is extracted with dichloromethane, the combined organic phases are dried over sodium sulfate and concentrated in vacuum.

Yield: 650 mg (73%)

T. p.: 246 - 248oC (decomp.)

Example 2

Hydrochloride, 8-cyan-1-cyclopropyl-7-((1S. 6S)- 2,8 - diazabicyclo[4.3.0] nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3 - quinoline-carboxylic acid

to 5.00 g (12.6 mmol) of 8-cyan-1-cyclopropyl-7-((1S,6S)-2,8 - diazabicyclo[4.3.0] nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3 - quinoline-carboxylic acid is stirred for 2 hours in 95 ml of a mixture of 4 G. hydrochloric acid and dioxane in a ratio of 1 : 1 at a temperature of 60oC. the Reaction mixture was concentrated in vacuo and the residue will recrystallized from ethanol.

Output: 4,45 g (82% of theory)

T. p.: 280oC (decomp.)

Example 3

Mezei

250 mg (0,63 mmol) 8-cyan-1-cyclopropyl-7-((1S,6S)-2,8 - diazabicyclo[4.3.0]-nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3 - quinoline-carboxylic acid are dissolved in 2 ml of water and mixed with 1 equivalent of methansulfonate. The solution is stirred for 30 minutes at room temperature, after which the mixture is poured into 20 ml of ethanol. The formed precipitate is sucked off and dried.

Yield: 201 mg (65% of theory)

Etc.: 118 - 124oC

Example 4

Toilet 8-cyan-1-cyclopropyl-7-((1S,6S)-2,8 - diazabicyclo[4.3.0]nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3 - quinoline-carboxylic acid

250 mg (0,63 mmol) 8-cyan-1-cyclopropyl-7-((1S,6S)-2,8 - diazabicyclo[4.3.0]-nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3 - quinoline-carboxylic acid are dissolved in 2 ml of water and mixed with 1 equivalent of base. The solution is stirred for 30 minutes at room temperature, after which the mixture is poured into 20 ml of ethanol. The formed precipitate is sucked off and dried.

Output: 309 mg (86% of theory)

Etc.: 222-230oC

Example 5

Triptorelin 8-cyan-1-cyclopropyl-7-((1S, 6S)-2,8 - diazabicyclo[4.3.0] nonan-8-yl)-6-fluoro-1.4-dihydro-4-oxo-3 - quinoline-carboxylic acid

200 mg (0.50 mmol) of 8-cyan-1-cyclopropyl-7-((1S,6S)-2,8 - diazabicyclo[4.3.0]-nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3 - hinolinova the I solution heated under reflux for 30 minutes, then cool. The formed precipitate is sucked off and washed with diethyl ether.

Yield: 208 mg (81% of theory)

Etc.: 170-178oC

Example 6

8-cyan-1-cyclopropyl-7-[(1S, 6S)-2-(2-etoxycarbonyl-vinyl)- 2,8 - diazabicyclo[4.3.0] nonan-8-yl] -6-fluoro-1.4-dihydro-4-oxo-3 - quinoline-carboxylic acid

< / BR>
400 mg (1.01 mmol) of 8-cyan-1-cyclopropyl-7-((1S,6S)-2,8 - diazabicyclo[4.3.0]-nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3 - quinoline-carboxylic acid and 1.03 ml (10.1 mmol) of a compound ethyl ester propionovoi acid in 7.5 ml of methylglycol within the hour, heated to 120oC. the Reaction mixture is concentrated under vacuum, the residue is stirred with water and sucked off. The resulting crude product is recrystallized from ethanol. Output: 302 mg (61% of theory)

Etc.: 180 - 182oC

Example 7

8-cyan-1-cyclopropyl-7-[(18,68)-2-(5-methyl-2-oxo - 1,3-dioxol-4-yl)-methyl-2,8-diazabicyclo[4.3.0] nonan-8-yl] -6 - fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid

< / BR>
100 mg (0.25 mmol) of 8-cyan-1-cyclopropyl-7-((1S,6S)-2,8 - diazabicyclo[4.3.0] -nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3 - quinoline-carboxylic acid, 59 mg (0.30 mmol) of 4-methyl bromide-5-methyl - 1,3-dioxol-2-she and 30 mg of potassium bicarbonate and heated in 2 ml of dimethylformamide to 140oC for 30 minutes. The reaction mixture is thickened in VA is in a vacuum. The resulting residue is stirred with water, sucked off and dried.

Yield: 99 mg (77% of theory)

T. p.: 175oC (decomp.)

Example 8

8-cyan-1-cyclopropyl-7-[(1S, 6S)-2-(3-oxo-butyl)- 2,8-diazabicyclo[4.3.0]nonan-8-yl]-6-fluoro-1,4-dihydro-4-oxo-3 - quinoline-carboxylic acid

< / BR>
300 mg (from 0.76 mmol) 8-cyan-1-cyclopropyl-7-((1S,6S)-2,8 - diazabicyclo[4.3.0]-nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3 - quinoline-carboxylic acid and 0.63 ml (7.6 mmol) of methyl vinyl ketone are in 5 ml of methylglycol heated under reflux for 2 hours. The reaction mixture is concentrated under vacuum, the residue is stirred with water and sucked off.

Yield: 245 mg (69% of theory)

T. p.: 158 - 160oC(decomp.)

Example 9

8-cyan-1-cyclopropyl-7-[(1S, 6S)-2-(2-Tianeti)-2,8-diazabicyclo [4.3.0] nonan-8-yl]-6-fluoro-1.4-dihydro-4-oxo-3-quinoline-carboxylic acid

< / BR>
400 mg (1.01 mmol) of 8-cyan-1-cyclopropyl-7-((1S.6S)- 2,8 - diazabicyclo[4.3.0]-nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3 - quinoline-carboxylic acid and 1.03 ml (10.1 mmol) of the nitrile of acrylic acid in 7.5 ml of methylglycol heated to 120oC for one hour. The reaction mixture is concentrated under vacuum, the residue is stirred with water and sucked off. The resulting crude product is recrystallized from ethanol.

Yield: 136 mg (91% of theory)

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Analogously to example 7 as a result of interaction with chloroacetone get the target connection.

Etc.: 74-75oC

Example 11

8-cyan-1-cyclopropyl-7-[(1S, 6S)-2-(2 - etoxycarbonyl-ethyl)- 2,8-diazabicyclo[4.3.0] nonan-8-yl] -6-fluoro - 1,4-dihydro-4-oxo-3-quinoline-carboxylic acid

< / BR>
Analogously to example 8 as a result of interaction with complex ethyl ester, acrylic acid get the target connection.

Etc.: 148-150oC

Example 12

Hydrochloride, 8-cyan-1-cyclopropyl-7-[(1S. 6S)-2- ((S)-alanyl)-2,8-diazabicyclo[4.3.0] nonan-8-yl] -6-fluoro-1.4 - dihydro-4-oxo-3-quinoline-carboxylic acid

< / BR>
250 mg (0.63 mmol) of 8-cyan-1-cyclopropyl-7-((1S,6S)-2,8 - diazabicyclo[4.3.0] -nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3 - quinoline-carboxylic acid, 150 mg (0.69 mmol) of N-tert.- butyloxycarbonyl-L-alanine-N-carboxyanhydride and 12.5 mg of N,N - dimethylaminopyridine dissolved in 7.5 ml of dimethylformamide. The solution is stirred for 3 hours at room temperature, then concentrated in vacuo. The residue is mixed with 20 ml of 4-N. a mixture of hydrochloric acid and dioxane in a ratio of 1 : 1 and heated to 60oC for 3 hours. The reaction mixture was concentrated in vacuo, after which the remainder will recrystallized from acetonitrile.


Analogously to example 12 by the interaction with N-tert.- butyloxycarbonyl-D-alanine-N-carboxyanhydride get the target connection.

Etc.: 213oC (decomp.)

Example 14

Hydrochloride, 8-cyan-1-cyclopropyl-7-[(1S. 6S)-2- ((S)-valinol)-2,8-diazabicyclo[4.3.0] nonan-8-yl] -6-fluoro-1,4 - dihydro-4-oxo-3-quinoline-carboxylic acid

Analogously to example 12 by the interaction with N-tert.- butyloxycarbonyl-L-valine-N-carboxyanhydride get the target connection.

T. p.: 255oC (decomp.)

Example 15

Hydrochloride, 8-cyan-1-cyclopropyl-7-[(1S. 6S)-2- ((S)-i.e. phenylalanyl)-2,8-diazabicyclo[4.3.0] nonan-8-yl] -6-fluoro-1,4 - dihydro-4-oxo-3-quinoline-carboxylic acid

Analogously to example 12 by the interaction with N-tert.- butyloxycarbonyl-L-phenylalanine-N-carboxyanhydrides get the target connection.

Etc.: 230oC (decomp.)

Example 16 Hydrochloride 8-cyan-1-cyclopropyl-7-[(1S, 6S)-2- ((S)-leucinol)-2,8-diazabicyclo[4.3.0] nonan-8-yl] -6-fluoro-1,4 - dihydro-4-oxo-3-quinoline-carboxylic acid

Analogously to example 12 by the interaction with N-tert.- butyloxycarbonyl-L-leucine-N-carboxyanhydride 8-cyan-1-cyclopropyl-7-[(18,68)-2,8-diazabicyclo [4.3.0]nonan-8-yl]-6-fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid

< / BR>
200 mg (of 0.625 mmol) of a compound methyl ester 8-cyan-1 - cyclopropyl-7-chloro-6-fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid, 86 mg (0,683 mmol) of (1S,6S)-2,8-diazabicyclo- [4.3.0]nonane and 150 mg (1,34 mmol) of 1,4-diazabicyclo[2.2.2] octane are stirred in 6 ml of acetonitrile for 48 hours at room temperature. Evaporated and partitioned between 15 ml of chloroform and 20 ml of a saturated solution of sodium carbonate. The organic phase is separated, the aqueous phase is additionally extracted with chloroform, the combined extracts dried over sodium sulfate and then evaporated. The residue is purified by chromatography on silica gel using as eluent a mixture of ethyl acetate, ethanol and 25% aqueous ammonia solution.

Yield: 140 mg

Etc.: 231oC (decomp.)

Example 18

Complex ethyl ester 8-cyan-1-cyclopropyl-7-[(1S.6S)-2,8 - diazabicyclo[4.3.0]nonan-8-yl]-6-fluoro-1.4-dihydro-4-oxo-3 - quinoline-carboxylic acid

< / BR>
14,32 g (45 mmol) of a compound ethyl ester 8-cyan-1 - cyclopropyl-6,7-di-fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid, of 6.31 g (50 mmol) of (1S, 6S)-2,8-diazabicyclo-[4.3.0] nonane and 10,22 g (101 mmol) of triethylamine is refluxed in 270 ml of acetonitrile for 4 hours. The reaction mixture is left to stand in the melt with acetonitrile and dried. Obtain 15.6 g of beige solid (82% of theory).

Etc.: 209-210oC.

Example 19

Sodium salt of 8-cyan-1-cyclopropyl-7-[(1S.6S)- 2,8-diazabicyclo[4.3.0] nonan-8-yl]-6-fluoro-1.4-dihydro-4-oxo-3 - quinoline-carboxylic acid

< / BR>
2,12 g (5 mmol) of a compound ethyl ester 8-cyan-1-cyclopropyl-7-[(1S, 6S)-2,8-diazabicyclo[4.3.0] nonan-8-yl] -6-fluoro-1,4-dihydro - 4-oxo-3-quinoline-carboxylic acid and 0.21 g (5.2 mmol) of sodium hydroxide in 10 ml of ethanol is heated under reflux for 2 hours. A large part of the ethanol is removed in vacuo. The residue is mixed with hexane, and the obtained solid is sucked off and dried. Get 2,07 g of a beige solid, which accounted for 98.9% of theory).

Etc.: 235oC (decomp.)

Example 20

Ethyl-8-cyan-1-cyclopropyl-6,7-debtor-1,4-dihydro - 4-oxo-3-quinoline carboxylate

Stage a):

Methyl-3-bromo-2,4,5-triterpenoid

< / BR>
To 772 g of 3-bromo-2,3,5-Cryptor-benzoyl-fluoride in 1460 ml of methanol under ice cooling was added dropwise 340 g of triethylamine. The mixture is stirred for one hour at room temperature. The reaction mixture was concentrated in vacuum and the residue is served in water and methylene chloride. Both phases are separated and the aqueous phase is again treated with methylene chloride. Phase chloride meyhod: 752,4 g; boiling point: 122oC/20 mbar.

Stage b):

Methyl-3-cyan-2,4,5-triterpenoid

< / BR>
A mixture of 269 g of methyl 2-bromo-2,4,5-triterpenoid, 108 g of copper cyanide (I) and 400 ml of dimethylformamide is heated under reflux for 5 hours. All volatile components are distilled off in vacuum. In the fractional distillation 133 g of the desired compound with a boiling point of 88 - 89oC/0.01 mbar.

Stage b):

3-cyan-2,4,5-triptoreline acid

< / BR>
A solution of 156 g of methyl-3-cyan-2,4,5-triterpenoid in a mixture of 960 ml of glacial acetic acid, 140 ml of water and 69 ml conc. sulfuric acid is heated under reflux for 8 hours. Acetic acid is distilled off and the residue is served in the water. The precipitate is filtered off, washed and dried. Output: 118,6 g of white powder.

Etc.: 187-190oC

Stage d):

3-cyan-2,4,5-Cryptor-benzoyl-chloride

< / BR>
111 g of 3-cyan-2,4,5-triterpenoids acid, 84 g of oxalicacid and a few drops of dimethylformamide in 930 ml of dry methylene chloride is stirred at room temperature for 5 hours. The mixture is concentrated and the residue is distilled in vacuum.

Output: of 117.6 g of yellow oil

Stage d):

Ethyl-2-(3-cyan-2,4,5-Cryptor-benzoyl)-3-dimethylamino the Ino-acrylate and 26.5 g of triethylamine in 140 ml of toluene was added dropwise at a temperature of 50 55oC. the Reaction mixture is stirred for 2 hours at 50oC, then concentrated in vacuo. The crude product without further purification served to the next stage.

Stage e):

Ethyl-2-(3-cyan-2,4,5-Cryptor-benzoyl)-3-cyclopropylamino

< / BR>
30 g of glacial acetic acid was added dropwise at 20oC to the crude product of stage d). Then added dropwise of 15.75 g cyclopropylamine in 30 ml of toluene. The mixture was stirred at 30oC for one hour. Then add 200 ml of water and stirred for further 15 minutes. The organic phase is separated, extracted with 100 ml of water, dried over sodium carbonate and concentrated in vacuum. The crude product without further purification served to the next stage.

Stage g):

Ethyl-8-cyan-1-cyclopropyl-6,7-debtor-1,4-dihydro - 4-oxoindole-3-carboxylate

< / BR>
A mixture of the crude product of stage (e) of 27.6 g of potassium carbonate and 80 ml of dimethylformamide is stirred at room temperature for 16 hours. The reaction mixture is poured into 750 ml of ice water, the precipitate filtered off, washed with 80 ml of cold methanol and dried.

Yield: 47 g

Etc.: 209-211oC

The proposed pharmaceutical composition is illustrated by the following examples.

silt alcohol

to 100 ml of water for injection.

This solution is prepared as follows.

The compound of example 1 and sodium chloride are dissolved in 80% of the water used. To the resulting solution was added benzyl alcohol, then add the remaining water. The resulting solution is sterile-filtered, filled into suitable containers and, if necessary, subjected to autoclaving.

Example 22

Oral appliciruemah solution

1 g of compound of example N 1

1 g of highly disperse silicic acid

to 100 ml of medium chain triglycerides.

This solution is prepared as follows.

Stirring, the compound of example 1 and highly dispersed silicic acid served in medium chain triglycerides, the resulting mixture is subjected to homogenization and fill into suitable containers.

Example 23

Tablet weight 68 mg

25 mg of the compound of example 1

39 mg of mannitol

3,25 mg polyvinylpyrrolidone

0.75 mg of magnesium stearate.

This tablet is prepared as follows.

The compound of example 1 and mannitol granularit with a solution of polyvinylpyrrolidone in water. The resulting product is dried and sieved. Receive the Il-7-(2,8-diazabicyclo[4.3.0]-nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acids and their derivatives of General formula (I)

< / BR>
where R1is hydrogen, alkyl with 1 to 4 carbon atoms;

R2is hydrogen, (5-methyl-2-oxo-1,3-dioxol-4-yl)-methyl, residues of formula-CH= CH-COOR3, -CH2CH2COOR3, -CH2CH2CN, -CH2CH2COCH3, -CH2COOH3where R3means methyl or ethyl, or a residue of the General formula R4-NH-CHR5-CO-, where R4denotes hydrogen, alkyl with 1 to 3 carbon atoms, and R5denotes hydrogen, alkyl with 1 to 4 carbon atoms, or benzyl,

their pharmaceutically acceptable hydrates, acid additive salts and salts of alkaline metal, alkaline earth metal, silver and guanidine corresponding carboxylic acids.

2. Compounds of General formula (I) under item 1, where R1is hydrogen, alkyl with 1 to 4 carbon atoms; R2is hydrogen, (5-methyl-2-oxo-1,3-dioxol-4-yl)-methyl, residues of formula-CH= CH-COOR3, -CH2CH2COOR3, -CH2CH2CN, -CH2COCH3where R3means methyl or ethyl, or a residue of the General formula R4-NH-CHR5-CO-, where R4denotes hydrogen, alkyl with 1 to 3 carbon atoms, and R5denotes hydrogen, alkyl with 1 to 4 carbon atoms or benzyl, their pharmaceutically acceptable hydrates, acid additive salts and salts of alkaline metanoia General formula (I) under item 1, representing 8-cyan-1-cyclopropyl-7-(2,8-diazabicyclo[4.3.0] nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid and its esters.

4. Pharmaceutical composition having antibacterial activity, containing a pharmaceutically acceptable carrier and an active ingredient, characterized in that the active substance it contains compounds of General formula (I)

< / BR>
where R1is hydrogen, alkyl with 1 to 4 carbon atoms;

R2is hydrogen, (5-methyl-2-oxo-1,3-dioxol-4-yl)-methyl, residues of formula-CH= CH-COOR3, -CH2CH2COOR3, -CH2CH2CN, -CH2CH2COCH3, -CH2COCH3where R3means methyl or ethyl, or a residue of the General formula R4-NH-CHR5-CO-, where R4denotes hydrogen, alkyl with 1 to 3 carbon atoms, and R5denotes hydrogen, alkyl with 1 to 4 carbon atoms, or benzyl,

their pharmaceutically acceptable hydrates, acid additive salts and salts of alkaline metal, alkaline earth metal, silver and guanidine corresponding carboxylic acids.

Priority points:

23.02.1996 - PP.1, 4, where R1is hydrogen, alkyl with 1 to 4 carbon atoms; R2is hydrogen;

22.08.1996 - PP.1, 4, where R22CN, -CH2CH2COCH3, -CH2COCH3; R3means methyl or ethyl, or a residue of the General formula R4-NH-CHR5-CO-; R4denotes hydrogen, alkyl with 1 to 3 carbon atoms; R5denotes hydrogen, alkyl with 1 to 4 carbon atoms or benzyl.

 

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< / BR>
in13C-NMR spectrum of which has a characteristic peak at 168,1 M. D.
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