Derivatives, quinoline or naphthyridinone acids and methods for their production

 

(57) Abstract:

The present invention relates to new quinolone compound having a high antibacterial activity. More specifically the present invention relates to new quinoline derivative (naphthiridine) carboxylic acid represented by the following formula, which has a 4-aminomethyl - 3-oksipiridilovykh the substituent in position 7 of the quinolone nucleus and exhibits a high antibacterial activity and contrast known quinolone antibacterial agents that have low activity against strains of gram-positive bacteria, and also has a broad antibacterial spectrum and greatly improved farmakokineticheskie properties:

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where R, R1, R2, R3, R4and Q are the same as specified in the description. 3 S. and 8 C.p. f-crystals, 27 PL.

The present invention relates to new quinoline derivative (naphthiridine) carboxylic acid, exhibiting excellent antibacterial activity. More specifically the present invention relates to new quinoline derivative (naphthiridine) carboxylic acid represented by the following formula (I), which has a 4-aminomethyl-3-eximport in contrast to the known quinolone antibacterial agents, showing weak activity against strains of gram-positive bacteria, and also has a broad antibacterial spectrum and greatly improved pharmacokinetic properties:

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and its pharmaceutically acceptable non-toxic salts, physiologically hydrolyzable ether complex, MES and isomer,

where

R represents hydrogen, methyl or amino;

Q represents C-H, C-F, C-Cl, C-OH, C-CH3C-O-CH3or N;

R1is cyclopropyl, ethyl or phenyl, which is substituted by one or more atom(s) fluorine;

R2represents one of the following a) to e):

a) hydrogen, unbranched or branched C1-C4aklil, cyclopropyl, cyclopropylmethyl, C3-C6quinil, 2 - halogenated, methoxymethyl, methoxycarbonylmethyl, aryl or allyl,

b) a group of the following formula (I)

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where

X represents hydrogen, 2 -, 3-or 4 - fluoro, cyan, nitro, methoxy, C1-C4alkyl or 2,4 - debtor,

c) a group of the following formula (2)

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d) heteroaromatic the following formula (3)

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e) a group of the following formula (4)

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where

n=0 or 1;

m = 0,1 or 2;

X is methylene, O, or N;

R3and R4independently from the mu they are attached, may form a ring.

The present invention relates to a method for obtaining compounds of formula (I), defined above, and antibacterial compositions containing a compound of the formula (I) as an active ingredient.

Since for the first time in 1962, was put into use as a treatment for urinary tract infections nalidixic acid (see G. I. Zesher, et al/ J. Med. Chem., 5, 1063 - 1065, (1962)), we developed many different antibacterial drugs from quinoline-carboxylic acids, including oxolinic acid, rosoxacin, piperidino acid and so on, But these previously developed antibacterial agents have low activity against strains of gram-positive bacteria and were therefore used only against gram-negative strains.

Was recently created norfloxacin, which is a quinolone compound having fluorine at position 6 (see H. Koda, et al., J. Med. Chem., 23, 1358 - 1363 (1980)), after that was conducted extensive research on the development of various quinolone antibacterial compounds. But since norfloxacin shows low antibacterial activity against gram-positive strains of bacteria and poorly distributed and the inlet of the urinary tract and gastrointestinal tract, sexually transmitted diseases, etc., were Then created ciprofloxacin (see R. Wise, et al., Antimicrob. Agents Chemother, 23, 559 (1983)), ofloxacin (see K. Sata, et al, Antimicrob. Agents Chemother, 22, 548, (1982)), etc., These antibacterial agents are high and broad antibacterial activity in comparison with the previously developed bacterial compounds and therefore found wide practical application for the treatment of diseases in the clinical setting.

Used or undergoing clinical trials connections are mostly derived with pieperazinove the substituent in position 7 of the quinolone nucleus, as ciprofloxacin or ofloxacin. However, the research on the development of quinolone compounds having higher and broad antibacterial activity, it was found that compound with 3 - amino - or 3 - aminomethylpyrrolidine group entered in the 7 - position, shows higher activity against gram-positive strains compared with compounds having a 7 - pieperazinove group, while maintaining high activity against gram-negative strains. But, unfortunately, the connection with pyrolidine Deputy, have low solubility in water compared to A, as activity in vitro. Therefore, we carried out further numerous studies to eliminate the disadvantage mentioned compounds having pyrolidine Deputy, that is, to increase the water solubility and improved pharmacokinetic properties.

In the result there have been many reports of such studies. For example, it was described that the derivatives of (( 2S, 4S)-4-amino-2-methylpyrrolidinyl) naphthiridine (see Rosen, T. Chu, D. T. W., and T. D., J. Med. Chem, 1988, 31, 1598 - 1611) or derivative (TRANS-3 - amino-4-methylpyrrolidinyl) naphthiridine (see Matsumoto J. , et al., Proceedings of the 14 th International Congress of Chemtheropy; Ishigami I., Ed.; Uniwersity of Tokyo Press: Tokyo, 1985, pp. 1519-1520) show a 20-40 - fold increase in water solubility, increased bioavailability and improved pharmacokinetic properties compared with compounds that do not have a methyl group at the same antibacterial activity in vitro.

In addition, attempts have been made to reduce the disadvantages of previously developed quinolone compounds, such as the relatively low antibacterial activity against strains of gram-positive bacteria, low solubility in water and poor pharmacokinetic properties, by introducing various functional groups (instead of the which the connections having axisgroup entered in 7 - amine fragment quinolone compounds. For example, researchers F. "Abbot" reported in a scientific journal (J. Med. Chem. , 1992, 35, 1392-1398), quinolone compound having the below General formula [A], in which the substituent in position 7 of the quinolone nucleus is a 3 - oxime (or methyloxime) pyrolidine group or 4 - oxime (or methyloxime) - piperidino group, exhibits good antibacterial activity against gram-positive strains:

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where

R represents cyclopropyl or 2,4-differenl;

R' represents hydrogen or methyl;

X represents C-H, C-F or N; and

n is 1 or 2.

Connection [And] has some drawbacks, namely that it exhibits a sufficiently high antibacterial activity against gram-positive strains, but relatively low activity against gram-negative strains, and also exhibits relatively low antibacterial activity when tested in vivo.

In addition, in Japanese laid patent publication N (Hei) 01-100165 (1989) described a compound having the following General formula [V]:

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where

R represents cyclopropyl, 2,4-differenl or 4-hydroxyphenyl;

In particular, in the above-mentioned Japanese laid published as substituent R' is a very wide group derived from an oxime or hydroxylaminopurine. But specifically as an example only 3 - hydroxylaminopurine [the following formula (a)], 3-methoxyaniline [the following formula (b)]; 3-amino-4-methoxyaniline [the following formula (c)], 3 - oksipiriridina [the following formula (d)] and 3 - methoxypyridine [the following formula (e)] group, and pyrolidine Deputy, and having 3-oxime and 4 aminomethyl group, anywhere not specifically mentioned.

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Further, in the publication of the earlier European patent N 0541086 disclosed quinolone compound of the following General formula [C]:

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where

R and R1independently from each other represent hydrogen or C1- C5-alkyl;

R2is hydrogen, amino, fluorine or hydroxy;

R3- C3- C7-cycloalkyl;

R4- methoxy or fluorine;

R5and R6may be the same or different from each other and independently from each other represent hydrogen or alkyl, or R5and R6together may C] , disclosed in said publication of the European patent, the typical substituent in position 7 of the quinolone nucleus is a group having the following structure:

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However, the connection formula [C] does not include compounds having as axisgroup and aminomethyl group in position 7 and, therefore, different from the compounds in accordance with the present invention.

A common hallmark of a well-known oxime - or hydroxyamine-derived compounds, as mentioned above, is that they exhibit relatively high activity against gram-positive strains, including strains MR SA (Methicillin Resistant Staphyloccus aureus), compared to more equal than developed quinolone compounds, but show low activity against gram-negative strains in comparison with antibacterial agents, including ofloxacin or ciprofloxacin. Therefore, we can say that their antibacterial spectrum may be narrower than the antibacterial spectrum of known antibacterial compounds ofloxacin or ciprofloxacin.

Therefore, based on the above-described prior art, these inventors have conducted extensive studies on the development of new pathogenic strains, including resistant strains, and improved pharmacokinetic properties and high absorbability in the living body, through the introduction of various substituted pyrrolidinone groups in the 7-position of the quinoline nucleus and determine the pharmacological activity of the resulting compounds. In the result it was found that quinolone compounds of the above General formula (I) is entered in the 7-position of the quinoline nucleus 4-aminomethyl-3- (optionally substituted) oxime-pyrrolidinone group can meet these requirements and therefore to constitute the present invention.

Thus, the present invention is to create a new quinoline derivative (naphthiridine) carboxylic acids of the above formula (I) having a high antibacterial activity against a broad spectrum of pathogenic strains, including both gram-positive and gram-negative strains of bacteria, and also has a good pharmacological properties.

Another objective of the present invention is a method of obtaining a new quinoline derivative (naphthiridine) - carboxylic acid, having the formula (I).

And another object of the present invention is the notes of the formula (I) as an active ingredient.

Above are some of the more important objectives of the present invention. These tasks should be considered as merely illustrating some of the more significant features and applications of the present invention. By applying the present invention or otherwise modifying it within its expanded volume, you can get other useful results. So other tasks and more complete understanding of the present invention will be apparent from the following detailed description in addition to the scope of the invention defined in the claims.

First, in accordance with the present invention offers a new quinoline derivative(naphthiridine)carboxylic acid having the following formula I

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and its pharmaceutically acceptable non-toxic salt, physiologically hydrolyzable ester, MES and isomer,

where

R is hydrogen, methyl or amino;

Q - C-H, C-F, C-Cl, C-OH, C-CH3C-O-CH3or N;

R1- cyclopropyl, ethyl or phenyl, substituted by one or more atom(s) fluorine;

R2- one of the following a) to e):

a) hydrogen, unbranched or branched C1- C4alkyl, cyclopropyl, cyclopropylmethyl, C3
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where X is hydrogen, 2,3 or 4-fluoro, cyano, nitro, methoxy, C1- C4-alkyl or 2,4-debtor, c) a group of the following formula (2)

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d) heteroaromatic the following formula (3)

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e) a group of the following formula (4)

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where n = 0 or 1; m = 0, 1 or 2 and X is methylene, O, or N;

R3and R4independently from each other represent hydrogen or C1- C3-alkyl, or R3and R4together with the nitrogen atom to which they are attached, may form a ring.

Of the compounds of the above formula (I) having excellent antibacterial activity, broad antibacterial spectrum and excellent pharmacokinetic properties, preferred are those in which Q is C-H, C-F, C-Cl, C-OMe or N, R represent hydrogen or amino group, R1is cyclopropyl or 2,4-differenl, R2represents hydrogen, methyl, ethyl, isopropyl, tert-butyl, phenyl, propargyl, homeprepared, 2-foretel, benzyl, 2-terbisil or 2-tenbensel and R3and R4represents hydrogen.

More preferred compounds of formula (I) include those in which Q is C-H, C-Cl, C-F or N, R is hydrogen or an amine, R1is cyclepro>
represent hydrogen.

In pyrrolidinones part of the compounds of formula (I) 4-carbon atom which is substituted by an aminomethyl group, is an asymmetric carbon atom and therefore the connection can be in the form of R - or S - or a mixture of R - and S-isomers. In addition, due to (optionally substituted) axisgroup in position 3 pyrolidine fragment of the compound of formula (I) may be in the form of SYN - and anti-isomers, depending on their geometrical structure. Thus, the present invention also covers all of these geometric isomers and mixtures thereof.

The compound of formula (I) in accordance with the present invention can form pharmaceutically acceptable non-toxic salt. This salt is a salt with inorganic acids such as hydrochloric, Hydrobromic, phosphoric, sulfuric, etc., salt with organic carboxylic acids such as acetic, triperoxonane, citric, maleic, oxalic, succinic, benzoic, tartaric, fumaric, almond, ascorbic or Apple, or with sulfonic acids, such as methanesulfonate, paratoluenesulfonyl, etc. and salts with other acids, which are generally known and traditional is charged in accordance with the traditional way of transformation.

Secondly, in accordance with the present invention offers a method of obtaining new compounds of formula (I).

In accordance with this invention the compound of formula (I) can be obtained by chemical interaction of the compounds of formula (II) with the compound of the formula (III) or its salt, as shown in the following scheme 1 reaction:

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In the above scheme, R, R1, R2, R3, R4and Q - such as above, and X represent a halogen atom, preferably chlorine, bromine or fluorine.

According to the above scheme 1 reaction of compounds of formula (I) in accordance with the present invention can be obtained by moving the compounds of formula (II) and compounds of formula (III) in the presence of a solvent for 1 to 20 hours at a temperature between room temperature and 200oC with the addition of a suitable base. In this reaction, the compound of formula (III) can be used in the form of the free compounds or salts with an acid, such as hydrochloric, Hydrobromic or triptocaine.

As solvent for the reaction described above may be used any solvent which has no adverse effect is DMSO), pyridine or hexamethylphosphoramide (HMPA - GMFA).

This reaction is usually carried out in the presence of an acid acceptor. In this case, to increase the yield of the reaction at a relatively expensive starting material (II), the reagent (III) is used in an excessive amount, for example, equimolecular up to 10-fold molar amount, preferably equimolecular up to 5-fold molar amount, relative to the starting material (II). When using the Regent (III) in excess, unreacted compound of formula (III), which remains after the reaction can be recovered and re-used in another reaction. The acid acceptor, which preferably can be used in this reaction includes inorganic bases such as sodium bicarbonate, potassium carbonate, etc. and organic bases such as triethylamine, diisopropylethylamine, pyridine, N,N-dimethylaniline, N,N-dimethylaminopyridine, 1,8-diazabicyclo[5.4.0]under-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), etc.

The compound of formula (I) in accordance with the present invention can be also obtained by the method shown in the following reaction scheme 2, wherein introducing the protective group P in od is inane formula (III'), in which the amino group is protected by P-protected compound of formula (III') is injected into the interaction with the compound of the formula (II) under the same conditions as in scheme I, reaction, and then the obtained compound of the formula (I') are exempt from protection, removing the protective group P, to form the desired compounds of formula (I).

Scheme 2 reaction

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In the above scheme, R, R1, R2and Q such as the above; and P represents aminosidine group.

In the reaction according to the above scheme 2, the compound of formula (III') can be used in the form of the free compounds or salts with hydrochloric, Hydrobromic or triperoxonane acid as the compound of the formula (III) used in the scheme 1 reaction.

As a suitable amino-protective group P in the compound of formula (III') can be used any protective group conventionally used in organic chemistry, which can be easily removed after the reaction without destroying the structure of the target compound. Specific examples of protective groups which can be used for this purpose include formyl, acetyl, TRIFLUOROACETYL, benzoyl, para-toluensulfonyl, methoxycarbonyl, etoxycarbonyl, tert-is carbonyl, benzyl, para-methoxybenzyl, trityl, tetrahydropyranyl etc.

After the reaction of the amino protective group in the resulting compound of the formula (I') can be removed by hydrolysis, solvolysis or recovery depending on the properties of the used protective group. For example, the compound of formula (I') is treated in a solvent in the presence or absence of acid or base at a temperature of 0-130oC to remove the protective group. As acids which may be used for this purpose, may be called inorganic acid, such as hydrochloric, Hydrobromic, sulfuric, phosphoric, etc. and organic acid such as acetic, triperoxonane, formic, toluensulfonate and so on, and a Lewis acid, such as tribromide boron, aluminised, etc. as the basis for this purpose you can use the hydroxide of alkali or alkaline earth metal, such as sodium hydroxide, barium hydroxide, and so on, a carbonate of an alkali metal such as sodium carbonate, calcium carbonate and so on, the alkali metal alkoxide such as sodium methoxide, ethoxide sodium and so on , or sodium acetate, etc., the Reaction can be carried out in the presence of a solvent, on SNA acid, etc. or mixtures of such organic solvent and water. If necessary, this reaction may also be carried out in the absence of any solvent.

In addition, when the protective groups are para-toluensulfonyl, benzyl, trityl, para-methoxybenzyl, benzyloxycarbonyl, para-methoxybenzeneboronic, trichlorocyanuric, beta-iodoxybenzoic and so on , these groups can be effectively removed by recovery. Although the reaction conditions of recovery for the removal of the protective group can be changed depending on the properties of the used protective group, usually the recovery may be carried out by a jet of gaseous hydrogen in an inert solvent in the presence of a catalyst, such as platinum, palladium, Raney Nickel, etc. at a temperature of 10-100oC or metallic sodium or metallic lities in ammonia at a temperature of from -50 to -10oC.

The compound of formula (I) used as starting material in the present invention, is a known compound and can be easily obtained by a known method described in earlier publications (see J. M. Domogala et al. , J. Med. Chem., 34, 1142 (1991); J. M. Domogala et al., J. Med. Chem. 31, 991 (1988); D. Bougard et al., J. Med. Chem. 35, 518 (1992 the Rial, can be easily obtained in accordance with the method presented in the following schemes 3, 4 and 5 reactions.

Scheme 3 reactions.

Reaction scheme 3.

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Scheme 4 reaction.

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In the above schemes 3 and 4 protective groups P and P' independently from each other represent the same amino-protective group as mentioned for P in connection with the compound of the formula (III'), and may be the same or different from each other; and Py is pyridine.

The following is a specific description of the method presented in schemes 3 and 4.

In accordance with scheme 3 first cyanoethyl [1], having a protected amino group may be introduced into interaction with ethoxide sodium in a solvent (such as ethanol) to obtain 3-keto-4-cianergoline [2]. The resulting zanperrion [2] restore gaseous hydrogen and in the presence of a platinum catalyst to obtain amerosport [3]. In this case, zanperrion [2] can be replaced by means of another reducing agent to obtain amerosport [3]. For example, ketone and ceanography can be restored with lithium aluminum hydride (LAH), complex borohydride sodium - chloride cobalt (NaBH4and then restore ceanography lithium aluminum hydride (LAH). Then the amino group thus obtained of amerosport [3] selectively protect, to obtain the protected amine [4], which is then treated with a mixture of sulfur trioxide (SO3) - pyridine in dimethylsulfoxide solvent (see Parikh J. R. and W. Doering, U. E., J. Am. Chem. Soc. , 1967, 89, 5505) or oxidize other oxidizing agent, to obtain a ketone compound [5] . The obtained ketone compound [5] then enter into interaction with O-substituted hydroxyimino formula R2ONH2to obtain the target substituted accesoire [6], which can be unsecured appropriate method is selected depending on the type of protective group, to obtain the target accesoire (III) in which R3and R4is hydrogen, i.e. the compounds of formula (III-a).

In accordance with another variant, shown in figure 4, the ketone compound [5] enter into interaction with hydroxyamino to get the target oxycoedone [7] and the compound [7] enter into interaction with an electrophilic compound of formula R2X, which can enter the desired R2the group, in the presence of a base, to obtain axispointe Volpi, as in scheme 3 to obtain the target oxycoedone (III-a).

The compound of formula (III), where R3and R4aminomethyl group in position 4 of pyrrolidine is other than hydrogen, i.e. the compound of formula (III-b) can be obtained by the following reaction scheme 5.

Scheme 5 reaction.

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In the above scheme, R'3and R'4same as specified for R3and R4in connection with the compound of the formula (I), provided that they cannot be hydrogen.

In accordance with the method according to scheme 5 first amine compound [3] process C1- C3aldehyde and then restore, to obtain the substituted amine compound [8], and the obtained amine compound [8] is treated with a mixture of sulfur trioxide (SO3) - pyridine in dimethylsulfoxide solvent or oxidize other oxidizing agent, to obtain a ketone compound [9]. The obtained ketone compound [9] can be treated in the same way as in the method of processing the ketone compound [5] in schemes 3 and 4, in order to synthesize the target compound of the formula (III-b).

The above-described synthesis methods will be more specifically explained in the following examples of the preparation.

In the unity of formula (I), above, or its pharmaceutically acceptable salt as an active ingredient and a pharmaceutically acceptable carrier. Using this antibacterial compositions for clinical purposes it can be prepared in the form of solid, semi-solid or liquid pharmaceutical preparations for oral, parenteral or local administration by combining the compounds of formula (I) with pharmaceutically acceptable inert carrier. Pharmaceutically acceptable inert carrier, which can be used for this purpose may be solid or liquid. For the preparation of solid or semi-solid pharmaceutical preparation in the form of powders, tablets, dispergiruyushchie powders, gelatin capsules, starch capsules (those capsules), suppositories and ointments usually use solid media. Used solid media preferably comprise one or more substances selected from the group consisting of diluents, flavouring and aromatic substances, solubilizers, lubricating, suspendida, binding loosening substances and so on, or substance enclosed in the capsule. In the case of a powder of the drug it contains finely ground active to eat magnesium, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragakant, methylcellulose, sodium carboxymethyl cellulose, low-boiling wax, cocoa butter, etc. Due to the ease of their introduction pills, powders and starch and gelatin capsules are the most suitable solid dosage forms for oral administration.

Liquid dosage forms include solutions, suspensions and emulsions. For example, injectable dosage form for parenteral administration may be made in the form of water or water-propylene glycol solution, isotonicity, pH, etc. can be adjusted in accordance with the physiological state of a living organism. The liquid preparation may be made in the form of a solution in water polietilenglikolja solution. Aqueous solution for oral administration can be produced by dissolving the active component in water and adding thereto suitable coloring, flavoring, stabilizing and thickening agents. Aqueous suspension suitable for oral administration can be produced by dispersing finely ground active ingredient in viscous substances such as natural or synthetic Kameda is especially suitable to produce the above-mentioned pharmaceutical preparations in the form of uniformly dosed medicinal forms for easy introduction and uniform dosage. Unified dosage form of the drug is physically separate elements, suitable for use as a unified (single) dose and each containing a specified quantity of active ingredient calculated to obtain the desired therapeutic effect. Such a dosage form at one time can be manufactured in a Packed form, for example in the form of tablets, capsules or powder poured into a vial or ampoule, or ointment, gel or paste in a tube or bottle.

Although the number of the active component contained in the unified dosage form may vary, it usually can be adjusted from 1 to 100 mg depending on the effectiveness of selected active component.

When using the active compounds of formula (I) in accordance with the present invention as a drug for the treatment of bacterial infectious diseases, it is preferably introduced in an amount of about 6 to 14 mg per kilogram of body weight in the first stage. However, the injected dose can be changed in accordance with the need of the individual patient, the severity of a subject to treatment of infectious diseases, sibrandolini expert in this traditional way. Usually, therapeutic treatment begins with a number smaller than the optimum dose of the active connection, and then enter the dose gradually increase until you get the optimal therapeutic effect. For convenience, the total daily dose may be divided into several portions and entered a few times.

As mentioned above, the connection in accordance with the present invention exhibits a high bacterial activity against a wide range variety of pathogenic organisms, including strains of gram-positive and gram-negative bacteria. Antibacterial activity of the proposed compounds against gram-negative strains comparable to or higher than the antibacterial activity of known antibiotics (eg, ciprofloxacin), and, in particular, the antibacterial activity of the proposed compounds against gram-positive strains is much higher than in the known antibacterial agents. In addition, the proposed connection is also showing very high antibacterial activity against strains resistant to known quinolone compounds.

With regard to the pharmacokinetic properties, the connection in accordance with this the image is known quinolone compounds), featuring a very high bioavailability. The biological half-time of existence of the proposed compounds in the body much longer than in the known quinolone compounds, and because the proposed connection, you can enter once per day, which is sufficient for use as an antibacterial agent.

In addition, since the connection in accordance with the present invention is less toxic, it can be effectively used for the prevention and treatment of disease caused by bacterial infections in warm-blooded animals, including humans.

The present invention is more specifically explained by the following examples. However, it should be understood that the following receive and examples are intended to illustrate the present invention and not in any way limit the present invention.

Receiving 1.

Synthesis of ethyl ether (2 Cinetrain)acetic acid

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In 80 ml of distilled water was dissolved 139,6 g (1 mol) of the hydrochloride of the ethyl ester of glycine, and to the resulting solution was added 230 ml of an aqueous solution to 67.3 g (1.2 mol EQ. ) of potassium hydroxide. Then to the reaction solution was added 1 the camping was stirred for 5 hours with heating and then separated the organic layer. The aqueous layer was extracted with diethyl ether and the extract was combined with the above-mentioned separated organic layer. The combined organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to remove solvent. The residue was distilled under reduced pressure (100 - 150oC/ 10.25 mm RT. century), and as a result got 65,6 g (yield: 48%) specified in the connection header.

1H NMR (CDCl3M. D.): 4,20 (2H, q), of 3.48 (2H, s), 2,96 (2H, t), of 2.54 (2H, t), of 1.30 (3H, t) MS (FAB, m/e): 157 (M + H)

Getting 2.

Synthesis of 4-cyano-1-(N-tert-butoxycarbonyl)-pyrrolidin-3-one

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In the formula above, and then Boc represents tert-butoxycarbonyl. 29 g (0,186 mol) of the compound obtained in the obtaining 1, was dissolved in 200 ml of chloroform and the resulting solution was poured into a flask with a volume of 1 L. Then there was added 45 g (1.1 mol EQ.) di-tert-butoxycarbonylamino, and the reaction mixture was stirred for 17 hours at room temperature. The reaction solution was concentrated, and the residue was diluted with 250 ml of absolute ethanol. The resulting solution was added to a solution of ethoxide sodium (Na OEt) obtained by adding 6 g of turning chips of metallic sodium is one school hours while heating under reflux. The reaction solution was concentrated under reduced pressure, and the residue was diluted with water, and then washed with methylene chloride. Brought the pH of the aqueous layer to 4 with 1 N. HCl and was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated, resulting in a stoichiometric amount specified in the connection header in the raw state.

1H NMR (CDCl3M. D.): 4,5 - 3,5 (5H, m), and 1.5 (9H, s), MC (FAB, m/e): 211 (M + H)

Getting 3.

Synthesis of the hydrochloride of 4-aminomethyl-1-(N-tert-butoxycarbonyl)- pyrrolidin-3-ol

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In a mixture of 357 ml of absolute ethanol and 7 ml of chloroform was dissolved 3 g (14 mmol) of the compound obtained in the Obtaining 2, and the resulting solution was poured into the flask. Then there was added a catalytic amount of platinum oxide (Pt O2). After removal of air from the reaction flask under reduced pressure the reaction mixture was stirred 72 hours at room temperature by purging with gaseous hydrogen from a cylinder filled with gaseous hydrogen. The reaction solution was filtered and the filtrate was concentrated, resulting in a stoichiometric amount specified in the connection header.

Synthesis of 4-(N-tert-butoxycarbonyl)aminomethyl-1- (N-butoxycarbonyl)pyrrolidin-3-ol

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Method A.

In a mixture of 456 ml of dioxane and 268 ml of distilled water was dissolved 20 g (0,094 mol) of the compound obtained in the Obtaining 3, and the resulting solution was adjusted to 1 N. aqueous sodium hydroxide solution to pH 9. Then to the solution was added to 30.9 g (1.5 mol EQ.) di-tert-butoxycarbonylamino, and the reaction mixture was stirred for 30 minutes at room temperature and then concentrated under reduced pressure. The residue was diluted with methylene chloride. After adding to the reaction solution, water was separated organic layer and the aqueous layer was acidified to pH 4 and then were extracted with methylene chloride. The extract was combined with the organic layer previously separated, and the combined solution was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography, resulting in 17 g (yield: 57%) specified in the connection header.

1H NMR (CDCl3M. D.): of 4.95 (1H, m), 4,1 (1H, m), 3,5 (2H, m) of 3.3 to 3.0 (4H, m), 2,1 (1H, M), of 1.45 (18H, C);

MC (FAB, m/e): 317 (M + H)

Method B.

In a flask with a capacity of 1 liter was introduced 10 g (0,047 mol) of the compound obtained in the Obtaining 2, and then dissolved it put the sodium and then added to it in portions over 20 minutes of 3.8 g (0,094 mol) of lithium aluminum hydride (LAH). After the addition the reaction mixture was stirred for one hour under a water bath with ice. After the reaction mixture was carefully added sequentially 4 ml of water, 4 ml of 15% aqueous sodium hydroxide solution and 12 ml of water. The whole mixture was intensively stirred for 3 hours at room temperature and was added thereto 10 g of anhydrous magnesium sulfate. This mixture was stirred and then filtered, and the filtrate was concentrated to stoichiometric receipt of the product. The obtained product was diluted with 200 ml of a mixture (2:1 by volume) of dioxane and water was added thereto at room temperature of 12.3 g (0,056 mol) di-tert-butoxycarbonylmethylene. The reaction solution was stirred for one hour at room temperature until completion of the reaction, and then concentrated. The residue was dissolved again in ethyl acetate, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and then the residue was purified by column chromatography using as eluent a mixture (2:1 by volume) hexane and ethyl acetate, which resulted in an 8.2 g (yield: 55%) specified in the connection header.

Method C.

4 l what mobetron the reaction vessel with a capacity of 6 liters The internal temperature of the reaction vessel was lowered to 10oC under bath with dry ice and acetone. To the vessel was added by portions 76 g (2 mol) of sodium borohydride (NaBH4), while maintaining the internal temperature in the vessel at the level of 10-13oC. After the addition the reaction mixture was stirred another 30 minutes at the same temperature, so that the entire ketone could be restored in alcohol. Then to the reaction mixture were added within 10 minutes 243 g (1 mol) of hydrate of cobalt chloride. After the reaction resulting solid complex was dissolved in 4 l of ammonia water and this solution was diluted to 8 liters of water and then was extracted with ethyl acetate. The organic layer was washed with saturated brine, was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and mixed with a mixture of 1.5 liters of dioxane and 0.5 l of distilled water. To the mixture was added 212 g of di-tert-butoxycarbonylamino, and the whole mixture was stirred 2 hours at room temperature. After the reaction, the reaction mixture was concentrated under reduced pressure, was dissolved again in dichloromethane, washed with water, dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated and then purified by XP is receiving 2:1), that resulted in 202 g (yield: 64%) specified in the connection header.

Method D.

In a flask with a capacity of 1 liter was introduced 10 g (0,047 mol) of the compound obtained in the Obtaining 2, and dissolved it by adding 500 ml of methanol. This solution was cooled under ice bath, and added to it in portions over 20 minutes 3.6 g (0,094 mol) sodium borohydride. The reaction mixture was stirred for further 30 minutes to complete the reaction, and then concentrated under reduced pressure, diluted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated, resulting in a connection to the desired ketone group, restored in alcohol. to 10.1 g (0,047 mol) of the obtained alcohol compound was dissolved in 200 ml of dry tetrahydrofuran, and the solution was cooled to -5oC under a bath of ice and salt. To the solution was added within 20 minutes of 2.6 g (of 0.066 mol) of lithium aluminum hydride. The reaction mixture was stirred another 30 minutes at the same temperature to complete the reaction, and then to the mixture was added in order to 2.6 ml of water, 2.6 ml of 15% sodium hydroxide solution and 7.8 ml of water. This mixture was stirred for one hour at room temperature. After adding 6 g bezwodniki-water (2:1 by volume) was added thereto by portions of 12.3 g (0,056 mol) di-tert-butoxycarbonylmethylene. The mixture was stirred 30 minutes to complete the reaction, and then concentrated, diluted with ethyl acetate, washed with saturated brine, was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated and the residue was purified by column chromatography, resulting in 12.3 g (yield: 83%) specified in the connection header.

Getting 5.

Synthesis of 4-(N-tert-butoxycarbonyl)aminomethyl-1-(N-tert - butoxycarbonyl)pyrrolidin-3-one.

< / BR>
In 64 ml of dimethyl sulfoxide was dissolved 14 g (0,044 mol) of the compound obtained in the Obtaining 4, and to the resulting solution was added 18.5 ml (3 mol EQ.) of triethylamine. This mixture was cooled under ice bath. When the wall of the reaction flask was begun frozen, to the mixture was added portions of 12.7 g (1.8 mol EQ. ) oxidant pyridine-sulfur trioxide (Py-SO3). After adding ice bath was removed and the reaction solution was stirred for 3 hours at room temperature, was diluted with water and then was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated to obtain a stoichiometric amount specified in the title compound in crude form.

1H-NMR (CDCl

Synthesis of 1-(N-tert-butoxycarbonyl)-4-(N-tert-butoxycarbonyl)- aminomethylpyrrolidine-3-noxema.

< / BR>
In a mixture of 6 ml of 95% ethanol and 3 ml of tetrahydrofuran (THF) was dissolved 300 mg of the compound obtained in the Obtaining 5, and this solution was poured into the reaction vessel with a capacity of 30 ml of it was added 232 mg (3.5 mol EQ.) hydroxylaminopurine (NH2OHHCl), then added 281 mg (3.5 mol EQ. ) of sodium bicarbonate, dissolved in 1.5 ml of distilled water. The reaction mixture was stirred 40 minutes at 40oC under oil bath to complete the reaction, cooled and then concentrated under reduced pressure. The residue was diluted with methylene chloride, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated, and the filtrate was subjected to column chromatography on silica gel, elwira mixture (1:1 by volume) hexane-ethyl acetate, resulting in a received 230 mg (yield 73%) specified in the connection header.

1H NMR (CDCl3, M. D.): to 9.70 (1H, Shir. C) of 5.05 (1H, Shir. (C) and 4.2 (2H, W); a 3.83 (1H, m), 3,5 - 3,2 (3H, m), and 3.0 (1H, m); of 1.42 (18H, s).

MS (FAB, m/e): 330 (M+H).

Getting 7.

Synthesis of 1-(N-tert-butoxycarbonyl)-4-(N-tert-butoxide, received in Receiving 6, 193 mg of Tetra-n-butylammonium and 855 mg benzylbromide, after which the resulting mixture was added 5 ml of 15% aqueous sodium hydroxide solution. The reaction mixture was stirred for 30 minutes at room temperature. The organic layer was separated, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure, and the residue was purified by chromatography on glass columns, resulting in 776 mg (yield: 92%) specified in the connection header.

1H NMR (CDCl3, M. D.): 7,38 (5H, m) to 5.13 (2H, s) to 4.92 (1H, m), 4,13 (2H, m), 3,76 (1H, m) to 3.41 (1H, m) of 3.25 (2H, m), to 3.02 (1H, m) of 1.50 (9H, s), for 1.49 (9H, s).

MS (FAB, m/e): 420 (M+H)

Get 8 - 17.

The amino compounds listed in the following table 1, were obtained in accordance with the same procedure as in Obtaining 7, except that instead of benzylbromide used the corresponding derivatives of benzylbromide having such a structure R2what is presented in table 1.

< / BR>
Used in the next data tables symbols and abbreviations have the following meanings:

Prep. Getting

NMR NMR (Nuclear magnetic resonance)

MS MS (Mass spectrum)

ppm m is ipled)

dd DD. (doublet of doublets)

b, br broad

Ex., Examp. Example

NMR solv. The solvent for NMR

Reac. time (min, hr) reaction Time (min, h)

Yield Output

DMSO DMSO (dimethyl sulfoxide)

Et ethyl

Ph phenyl

t-Bu tert-butyl

Getting 18

Synthesis dihydrochloride 4-aminomethylpyrrolidine-3-he-benzyloxy,

< / BR>
20 ml of methanol was cooled to 5oC, and then thereto was slowly added 10 ml of acetylchloride. This mixture was stirred for 30 minutes, and thereto were added to 990 mg obtained in the obtaining 7 compounds dissolved in 10 ml of methanol. The reaction mixture was stirred for 50 minutes at room temperature and then concentrated under reduced pressure. The residue was washed with ethyl acetate and dried, resulting in 648 mg (yield: 94%) indicated in the title compound as a yellow solid.

1H NMR (DMCO - d6, M. D.) rating: 10.0 (1H, m) 8,35 (2H, m), 7,40 (5H, m), is 5.18 (2H, s), of 4.00 (2H, s) of 3.69 (1H, m), X 3,40 (2H, m), 3,12 (2H, s)

MC (FAB,m/ e): 220 (M+H)

Get 19 - 28.

The compounds obtained in the following table 2 were derived from amino compounds obtained in the Receive 8 - 17, in accordance with the same procedure as in Obtaining 18.

< / BR>
Getting 29.

Synthesis of 1-(N-Tr the organisations, received in the Receiving 5, was dissolved in a mixture of 6 ml of 95% ethanol and 3 ml of tetrahydrofuran (THF), and the solution was poured into the reaction vessel with a capacity of 30 ml of it was added 487 mg (3.5 mol EQ.) o-tert-butylhydroxyanisole and then added 281 mg (3.5 mol EQ) of sodium bicarbonate, dissolved in 1.5 ml of distilled water. The reaction mixture was stirred for 40 minutes at 40oC under oil bath to complete the reaction, and then cooled, concentrated under reduced pressure, diluted with methylene chloride, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated and the residue was subjected to column chromatography on silica gel, elwira mixture (1:1 by volume) hexane and ethyl acetate, and the result was 285 mg (yield: 80%) specified in the connection header.

1H NMR (CDCI3, M. D.): 5,10 (1H, Shir. C) of 4.05 (2H, s), 3,71 (1H, DD), 3,43 (1H, Shir.) the 3.2 (2H, t) of 3.0 (1H, m) of 1.42 (18H, s) of 1.30 (9H, s)

MC (FAB, m/e): 386 (M+H)

30.

Synthesis of 1-(N-tert-butoxycarbonyl)-4-(N-tert-butoxycarbonyl)-aminomethylpyrrolidine-3-one-3-butenyloxy

< / BR>
A. Synthesis of 3-butenylamine.

In 15 ml of dry tetrahydrofurane the solution was then added within 30 minutes of 1.05 g (6 mmol) of diethylazodicarboxylate. The mixture was stirred for 10 minutes at room temperature, and then distilled under reduced pressure to remove solvent. To the residue was added 50 ml of a mixture (1:1%) of ethyl acetate and hexane. The precipitated solid material was filtered, and the filtrate was concentrated. The residue was purified by column chromatography (hexane-ethyl acetate, 9: 1 o/o). The obtained white solid [0.54 g, yield 50%, 1H NMR (CDCI3, M. D.): a 7.85 (2H, m), of 7.75 (2H, m), 4.2V (2H, t), 2,8 (2H, DD), 2,5 (2H, DD), 2,1 (1H, s) FAB MC (POS): [M+H]+=216] was dissolved in 12 ml of methylene chloride and the resulting solution was added dropwise 0.25 g (5 mmol) of hydrazine hydrate diluted with 4 ml of methanol. The precipitated solids were filtered off and the filtrate was concentrated at a low temperature under reduced pressure, resulting in 0.2 g (yield 93%) specified in the connection header.

1H NMR (CDCI3, M. D.) to 9.5 (2H, W), 4,5 (2H, t), 2,8 (2H, m) 2.4 (2H, m), is 2.05 (1H, s)

MC (FAB, m/e): 86 (M+H)+< / BR>
B. Synthesis of compounds specified in the header.

In 5 ml of methanol was dissolved 0.45 g (1,43 mmol) of the compound obtained in the Obtaining 5 and 0.2 g (2,35 mmol) 3-butanilicaine, and reaction was performed for 12 hours at 60oC. the Reaction solution was concentrated the ATA which received 0,59 g (stoichiometric amount) specified in the connection header.

1H NMR (CDCI3, M. D.): 5,0 (1H, m), is 4.15 (2H, t), 4,0 (2H, in), 3.75 (1H, m), 3,6 - 3,2 (3H, m) 3,0 (1H, m), and 2.5 (2H, m), 2,0 (1H, s) of 1.45 (18H, s)

FAB MC (POS): 382 (M+H)+< / BR>
Get 31 - 36.

The amino compounds listed in the following table 3 were obtained in accordance with the same procedure as in Obtaining 30, except that instead of 3-butynol used the corresponding alcohol derivatives having a structure of R2what is presented in table 3.

Table 3

Getting 37.

Synthesis of 1-(N-tert-butoxycarbonyl)-4-(N-tert-butoxycarbonyl)- aminomethylpyrrolidine-3-he-propargyloxy

< / BR>
To 15 ml of dichloromethane was added 659 mg of the compound obtained in the Obtaining 6, 193 mg of Tetra-n-butylammonium and 855 mg propylbromide and to the mixture was added 5 ml of 15% aqueous sodium hydroxide solution. This mixture was stirred for 30 minutes at room temperature. The organic layer was separated, dried over anhydrous magnesium sulfate and then filtered. The filtrate was distilled under reduced pressure, and the residue was purified by chromatography on a glass column, resulting in 776 mg (yield 92%) specified in the connection header.

1H NMR (CDCI3,39.

The amino compounds listed in the following table 4 were obtained in accordance with the same procedure as in Position 37, except that instead of propargyl used the corresponding derivatives of alkyl having presented in table 4 structure of R2.

< / BR>
Getting 40.

Synthesis of 4-aminomethylpyrrolidine-3-he-tert-butyloxycarbonyl

< / BR>
5 ml of methanol was cooled to 0oC and slowly added thereto 3 ml of acetylchloride. This mixture was stirred for 10 minutes and added to it 640 mg received in the Receiving 29 compounds dissolved in 10 ml of methanol. The reaction mixture was stirred for 20 minutes at room temperature and then concentrated under reduced pressure. The residue was filtered and washed with diethyl ether, and dried, resulting in 390 mg (yield 91%) indicated in the title compound as a white solid.

1H NMR (DMCO-d6, memorial plaques) are 10.0 and 9.6 (2H, Shir, x 2), to 8.20 (3H, Shir.) are 3.90 (2H, DD), 3,61 (1H.C.), 3,40 (2H, Shir. C) of 3.12 (2H Shire. C.), 1,25 (9H, s)

MS (FAB, m/e) : 186 (M + H)

Get 41 - 50.

Connection Receive 41-50 listed in the following table 5 were obtained from the compounds obtained in the Receiving 30-40 wet-butoxycarbonyl)aminomethyl-1- (N-tert-butoxycarbonyl)pyrrolidin-3-one-O-methyloxime

< / BR>
260 mg (8,28 10-4mol) of the compound obtained in the Obtaining 5, was dissolved in a mixture of 5 ml of 95% ethanol and 2.5 ml of tetrahydrofuran, and the resulting solution was poured into the reaction vessel. To the solution was added 256 mg (3.7 mol EQ.) methoxyacetanilide, and 257 mg (3.7 mol EQ.) of sodium bicarbonate (NaHCO3), dissolved in 2.5 ml of distilled water. The reaction mixture was stirred for 1 hour at 40oC in the oil bath, concentrated under reduced pressure, washed sequentially with an aqueous solution ammonium chloride and an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated, resulting in 250 mg (yield 88%) specified in the connection header.

1H NMR (CDCl3, M. D.) : to 4.98 (1H, Shir.C.), 3,81 (3H, s), 3.75 to 2,80 (7H, m) of 1.40 (18H, s)

MS (FAB, m/e) : 344 (M+H)

Get 52 and 53

The compounds listed in the following table 6 were obtained in accordance with the same procedure as in Obtaining 51, except that instead of methoxyacetanilide used phenoxyalkanoic or ataxiatelangiectasia.

< / BR>
Getting 54.

Synthesis of 4-aminomethylpyrrolidine-3-one-O-methyloxime, and the resulting mixture was stirred for 20 minutes at room temperature. The reaction mixture was concentrated under reduced pressure, was dissolved in the least amount of acetonitrile and then led into the solid state, diethyl ether, resulting in 220 mg (yield 84%) specified in the connection header in a clean condition.

1H NMR (CD3OD, M. D.) : 4,1 (2H, s), of 3.96 (3H, s), 3,83 (1H, DD), of 3.7 and 3.2 (6H, m)

MS (FAB, m/e) : 144 (M+H)

Get 55 - 57

Appropriate connections Receive 55-57 were obtained from the compounds obtained in the Receive 6, 52, 53 (respectively) in accordance with the same procedure as in Obtaining 54.

< / BR>
Example 1.

Synthesis of 7-(4-aminomethyl-3-benzyloxypyrrolidine-1-yl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid.

< / BR>
622 mg of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8 - naphthiridine-3-carboxylic acid and 643 mg of the compound obtained in the Obtaining 18, suspended in 15 ml of acetonitrile. This suspension was cooled under a water bath with ice, and then thereto was slowly added 1.0 ml of 1,8 - diazabicyclo[5.4.0]-undec-7-ene (DBU). The reaction mixture was stirred for 1.5 hours at room temperature and after adding mawali water and ethanol, and got the result 584 mg (yield 57%) specified in the connection header.

1H NMR (DMCO-d6, M. D.) : 8,59 (1H, s), 8,03 (1H, d), 7,40 (5H, m), 5,14 (2H, s), and 4.75 (2H,s), 4,18 (1H, m), of 3.94 (1H, m), 3,83 (1H, m) to 3.35 (2H, m), 3,05 (1H, m), of 2.81 (1H, m), 2,73 (1H, m), 1,25 - of 1.05 (4H, m)< / BR>
MS (FAB, m/e) : 466 (M+H)

Examples 2 to 11.

The same starting material as in Example 1 was introduced into interaction with each of the compounds obtained in the Receiving 19 - 28, in accordance with the same as in Example 1, procedure and obtained the respective compounds listed in the following table 8.

Example 12.

Synthesis of 7-(4-aminomethyl-3-benzyloxypyrrolidine-1-yl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoindole-3-carboxylic acid.

< / BR>
530 mg of 1-cyclopropyl-6,7-debtor-1,4-gidro-4-oxoindole-3-carboxylic acid and 584 mg of the compound obtained in the Obtaining 8, suspended in 15 ml of acetonitrile. This suspension was cooled under a water bath with ice, and then was slowly added thereto 913 mg of 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU). The reaction mixture was stirred for 2 hours at 80oC and then, after adding 15 ml of water, concentrated. The concentrated suspension was filtered. The filtered solid product was washed with water and SUB>6, M. D.) : at 8.60 (1H, s), 7,92 (1H, d), 7,38 (5H, m), 5,10 (2H, s), to 4.87 (2H, s), 4,10 (1H, m), of 3.94 (1H, m), 3,86 (1H, m), 3,37 (2H, m), to 3.02 (1H, m), of 2.38 (1H, m), 2,73 (1H, m), 1,25 - of 1.05 (4H, m)< / BR>
MC (FAB, m/e) : 465 (M+H)

Examples 13-22.

The same starting material as in Example 12, was introduced into interaction with each of the compounds obtained in the Receiving 19-28, in accordance with the same as in Example 12, the procedure and obtained the respective compounds listed in the following table 9.

Examples 23.

Synthesis of 7-(4-aminomethyl-3-benzyloxypyrrolidine-1-yl)cyclopropyl-6,8 - debtor-1,4-dihydro-4-oxoindole-3-carboxylic acid

< / BR>
566 mg 1-cyclopropyl-6,7,8-Cryptor-1,4-dihydro-4-oxoindole-3-carboxylic acid and 584 mg of the compound obtained in the Obtaining 8, suspended in 15 ml of acetonitrile. The resulting suspension was cooled under a water bath with ice and then slowly added thereto 913 mg of 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU). The reaction mixture was stirred for 2 hours at 80oC and then after adding 10 ml of water was concentrated. The concentrated suspension was filtered. The filtered solid product was washed with water and ethanol, resulting in 704 mg (yield 73%) specified in the connection header.1H NMR (DMSO-d6
MC (FAB, m/n) : 483 (M+H)

Examples 24 to 33.

The same starting material as in Example 23, was introduced into interaction with each of the compounds obtained[ in the Receiving 19-28, in accordance with the same as in Example 23, the procedure and obtained the respective compounds listed in the following table 10.

Examples 34

Synthesis of 7-(4-aminomethyl-3-benzyloxypyrrolidine-1-yl)-8-chloro-1-cyclopropyl - 6-fluoro-1,4-dihydro-4-oxoindole-3-carboxylic acid.

< / BR>
598 mg of 8-chloro-1-cyclopropyl-6,7-debtor-1,4-dihydro-4-oxoindole-3-carboxylic acid and 584 mg of the compound obtained in the Obtaining 8, suspended in 15 ml of acetonitrile, and then the resulting suspension was slowly added 913 mg of 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU). The reaction mixture was stirred 3 hours at 80oC and after adding 15 ml of water was concentrated. The concentrated suspension was filtered. The filtered solid product was washed with water and diethyl ether, resulting in 510 mg (yield 52%) specified in the connection header.

1H NMR (DMSO - d6M. D.) : / 8,78 (1H, s), to $ 7.91 (1H, d), 7,41 (5H, m), 5,16 (2H, s), 4,74 (2H, s) to 4.16 (1H, m), 3,90 (1H, m), 3,85 (1H, m) to 3.35 (2H, m), to 3.02 (1H, m), 2,82 (1H, m) of 2.75 (1H, m), 1.30 and 1,10 (4H, m)< / BR>
MC (FAB, m/e) : 499 (M+H)

the m connections received in the Receiving 19-28, in accordance with the same as in Example 34, the procedure and obtained the respective compounds listed in the following table 11.

Example 45.

Synthesis of 7-(4-aminomethyl-3-benzyloxypyrrolidine-1-yl)-1-cyclopropyl-6 - fluoro-8-methoxy-1,4-dihydro-4-oxoindole-3-carboxylic acid.

< / BR>
590 mg of 1-cyclopropyl-6,7-debtor-8-methoxy-1,4-dihydro-4-oxoindole-3-carboxylic acid and 584 mg of the compound obtained in the Obtaining 8, suspended in 15 ml of acetonitrile, and the resulting suspension was slowly added 913 mg of 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU). The reaction mixture was stirred for 2 hours at 80oC and then, after adding 15 ml of water, stirred for another 30 minutes at room temperature and was filtered. The filtered solid product was washed with water and diethyl ether and obtained in the result of 465 mg (yield 47%) specified in the connection header.

1H NMR (DMSO-d6, M. D.) : 8,61 (1H, s), to 7.99 (1H, d), 7,40 (5H, m), of 5.15 (2H, s), 4,74 (2H, s), 4,17 (1H, m), of 3.95 (1H, m), 3,83 (1H, m), of 3.60 (3H, s) to 3.35 (2H, m), to 3.02 (1H, m),2,80 (1H, m), 2,71 (1H, m), 1,30 - 1,10 (4H, m)

MC (FAB, m/e) : 495 (M+H)

Examples 46-55.

The same starting material as in Example 45, was introduced into interaction with each of the responsible compounds listed in the following table 12.

Example 56

Synthesis of 5-amino-7-(4-aminomethyl-3-benzyloxypyrrolidine-1-yl)-1-cyclopropyl-6,8-debtor-1,4-dihydro-4-oxoindole-3-carboxylic acid

< / BR>
448 mg of 5-amino-1-cyclopropyl-6,7,8-Cryptor-1,4-dihydro-4-oxoindole-3-carboxylic acid and 438 mg of the compound obtained in the Obtaining 8, suspended in 15 ml of acetonitrile, and then the resulting suspension was slowly added 585 mg of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The reaction mixture was heated for 6 hours at 80oC and add to it 10 ml of water. The resulting suspension was filtered. The filtered solid product was washed with water, acetonitrile and diethyl ether, resulting in 395 mg (yield 53%) specified in the connection header.

1H NMR (DMSO-d6, M. D.) : to 8.62 (1H, s), 7,92 (1H, d), 7,40 (5H, m), 6,10 (2H, Shir.C.), to 5.13 (2H, s), to 4.73 (2H, s), is 4.15 (1H, m), of 3.95 (1H, m), 3,82 (1H, m) to 3.35 (2H, m), 3,01 (1H, m), 2,80 (1H, m), 2,73 (1H, m), 1,25 - of 1.05 (4H, m)

MC (FAB, m/e) : 498 (M+H)

Examples 57-66.

The same starting material as in Example 56, entered into interaction with each of the compounds obtained in the Receiving 19 - 28, in accordance with the same as in Example 56, the procedure and obtained the respective compounds listed in following the-1-(2,4-differenl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid

< / BR>
806 mg of 7-chloro-1-(2,4-differenl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthiridine-3 - carboxylic acid and 438 mg of the compound obtained in the Obtaining 8, suspended in 15 ml of acetonitrile, and the resulting suspension was slowly added 913 mg of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The reaction mixture was stirred for one hour at room temperature and after adding 15 ml of water was stirred for another 30 minutes and was filtered. The filtered solid product was washed with water and acetonitrile, resulting in 524 mg (yield 65%) specified in the connection header.

1H NMR (DMSO-d6, M. D.) : 8,82 (1H, s), 8,21 (1H, d), a 7.85 (1H, m), 7,56 (1H, m), 7,40 (6H, m), 5,16 (2H, s), was 4.76 (2H, c), 4,18 (1H, m), of 3.94 (1H, m), 3,81 (1H, m) to 3.34 (2H, m), 3.04 from (1H, m), 2,82 (1H, m) 2,73 (1H, m) of 1.30 to 1.00 (4H, m)

MC (FAB, m/e) : 538 (M+H)

Examples 68-77.

The same starting material as in example 67, was introduced into interaction with each of the compounds obtained in the Receiving 19-28, in accordance with the same as in example 67, procedure and obtained the respective compounds listed in the following table 14.

Example 78.

Synthesis of 7-(4-aminomethyl-3-benzyloxypyrrolidine-1-yl)-1-ethyl-6,8-debtor-1,4-dihydro-4-oxoindole-3-carboxylic acid

< / BR>
353 mg of 1-ethyl-6,7,8-three is in 15 ml of acetonitrile, and then to the resulting suspension was slowly added 593 mg of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The reaction mixture was stirred for 2.5 hours at 80oC, and then after adding 15 ml of water was stirred for another 30 minutes under a bath of cold water and filtered. The filtered solid product was washed with water, acetonitrile and diethyl ether, resulting in 391 mg (yield 64%) specified in the connection header.

1H NMR (DMSO-d6, M. D.) : 8,8 (1H, s), and 7.8 (1H, d), 7,40 (5H, m), 5,10 (2H, s), and 4.6 (2H, HF), 4,4 (2H, DD.); 4,0 (1H, m), 3,1 (1H, m), and 3.7 (1H, m), 2,8 (2H, DDD); of 1.46 (3H, etc)

MC (FAB, m/e) : 471 (M+H)

Examples 79-88 [in Russian].

The same starting material as in Example 78, entered into interaction with each of the compounds obtained in the Receiving 19-28, in accordance with the same as in Example 78, procedure and obtained the respective compounds shown in the following table 15.

Example 89.

Synthesis of 7-(4-aminomethyl-3-tert-butyloxybenzylidene-1-yl)-1-cyclopropyl - 6-fluoro-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid

< / BR>
141 mg (0.5 mmol) of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1.4-dihydro-[1,8] naphthyridin-3-carboxylic acid and 143 mg (0.55 mmol) of 4-aminomethylpyrrolidine-3-he-tert-butyloxycarbonyl carefully Cyclo [5.4.0] undec-7-ene. The reaction mixture was stirred for 30 minutes at room temperature and after adding 1 ml of water was intensively mixed for 10 minutes and filtered. The filtered solid product was washed successively with a mixture (4:1 by volume, 2 ml) of acetonitrile and water and acetonitrile (2 ml x 2) and then diethyl ether, and dried, resulting in 132 mg (yield 61%) specified in the connection header.

1H NMR (DMSO-d6, M. D.) : / 8,6 (1H, s), and 8.1 (1H, d), and 4.6 (2H, s), 4.2V (1H, DD), 3,9 (1H, DD), and 3.7 (1H, m), and 3.3 (1H, DD), 2,9 - 2,7 (2H, DDD), a 1.3 (9H, s), 1,2 (2H, m), 1,1 (2H, m)

FAB MC (POS) : 432 (M+H)+< / BR>
Example 90.

Synthesis of 7-(3-aminomethyl-4-tert-butyloxybenzylidene-1-yl)-1-cyclopropyl-6,8 - debtor-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

< / BR>
141 mg (0.5 mmol) 1-cyclopropyl-6,7,8-Cryptor-4-oxo-1,4-dihydroquinoline-3-carboxylic acid and 143 mg (0.55 mmol) of 3-aminomethyl-4-tert-butylacetohydroxamic was heated under reflux as in Example 89, for 2.5 hours and cooled to room temperature. Then the obtained product was separated and purified by preparative HPLC, resulting in 151 mg (yield 67%) specified in the connection header.

1H NMR (DMCO-d6, M. D.): 8,6 (1H, s), and 7.7 (1H, the example 91.

Synthesis of 8-chloro-1-cyclopropyl-6-fluoro-[7-(3-aminomethyl-4-tertbutyloxycarbonyl - 1-yl)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

< / BR>
150 mg (0.5 mmol) of 8-chloro-1-cyclopropyl-6,7-debtor-4-oxo-1,4-dihydroquinoline-3 - carboxylic acid was introduced into the reaction as in example 90. Then the reaction solution was concentrated and the residue was purified by preparative HPLC, which resulted in 148 mg (yield 64%) specified in the connection header.

1H NMR (DMCO-d6, M. D.) : 8,7 (1H, s), and 7.9 (1H, d), 4,4 (2H, s), 4,3 (1H, m), and 3.8 (1H, m) to 3.7 (1H, m), and 3.0 (1H, m), 2,9 - 2,7 (2H, m), 1,3 (N, C), 1,2 - 0,9 (4H, m)

FAB MC (POS) : [M + H]+= 465

Example 92.

Synthesis of 7-(3-aminomethyl-3-tert-butyloxybenzylidene-1-yl)- 1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

< / BR>
132 mg (0.5 mmol) 1-cyclopropyl-6,7-debtor-4-oxo-1,4-dihydroquinoline-3-carboxylic acid was heated under reflux as in Example 89, for 3.5 hours. Then the obtained residue was subjected to preparative HPLC and the result was 129 mg (yield 60%) specified in the connection header.

1H NMR (DMCO-d6, M. D.) : 8,6 (1H, s), and 7.8 (1H, d), 7,2 (1H, d), 4,4 (2H, s) of 3.9 (1H, m), and 3.8 (1H, m), and 3.7 (1H, m) 3,0 (1H, m), 2,9 - 2,7 (2H, m), and 1.4 (9H, s), 1,3 - 1,1 (4H, m)

FAB MC (POS) : [M + H]+= 431

-dihydroquinoline-3-carboxylic acid

< / BR>
148 mg (0.5 mmol) of 5-amino-1-cyclopropyl-6.7,8-Cryptor-4-oxo-1,4-dihydroquinoline-3-carboxylic acid was heated under reflux as in Example 89, within 8 hours. Then the obtained residue was purified by preparative HPLC and the result was 151 mg (yield 65%) specified in the connection header.

1H NMR (DMCO-d6, M. D.) : 8,6 (1H, s), and 7.5 (2H, W), the 4.3 (2H, s), of 4.0 to 3.8 (3H, m), and 3.2 (1H, m), 2,8 - 2,6 (2H, m) and 1.3 (9H, s), 1,1 (4H, m)

FAB MC (POS) : [M + H]+= 464

Example 94.

Synthesis of 7-(3-aminomethyl-4-tert-butylacetamide-pyrrolidin-1-yl)-1 - cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

< / BR>
148 mg (0.5 mmol) 1-cyclopropyl-6,7-debtor-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid was heated under reflux as in Example 89, for 10 hours. Then the obtained residue was purified by preparative HPLC and the result was 92 mg (yield 40%) specified in the connection header.

1H NMR (DMCO-d6, M. D.) : / a 8.9 (1H, s), and 7.8 (1H, d), and 4.5 (2H, s), 4,3 (1H, m), 4,1 (1H, m) of 3.9 (1H, m), and 3.0 (1H, m), 2,8 - 2,7 (2H, m), 2,7 (3H, s), 1,3 (9H, s), 1,25 (2H, m), and 0.9 (2H, s)

FAB MC (POS) : [M + H]+=461

Example 95.

Synthesis of 7-(3-aminomethyl-4-tert-butyloxybenzylidene-1-yl)-1-(2,4-differenl)-6 - fluoro-4-oxo-1,4-Digi tilidin-3-carboxylic acid and 143 mg (0.55 mmol) of 3-aminomethyl-4-tert-Butylochka-aminopropyldimethylamine suspended in 3 ml dry acetonitrile. To the resulting suspension were added 230 mg (1.5 mmol) of 1.8-diazabicyclo [5.4.0] undec-7-ene and the reaction mixture was stirred for 15 minutes at room temperature and then treated as in example 89, resulting in 203 mg (yield 81%) specified in the connection header.

1H NMR (DMCO-d6, M. D.): 8,9 (1H, s), and 8.1 (1H, d), and 7.8 (1H, m), and 7.7 (1H, DD), and 7.3 (1H, DD), a 4.3 (2H, s), 4,0 (1H, m) of 3.9 (1H, m), and 3.0 (1H, m), 2,8 - 2,6 (2H, m) and 1.3 (9H, s)

FAB MC (POS) : [M + H]+= 504

Example 96.

Synthesis of 7-(3-aminomethyl-4-tert-butyloxybenzylidene-1-yl)- 6,8-debtor-1-ethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

< / BR>
136 mg (0.5 mmol) 1-ethyl-6,7,8-Cryptor-4-oxo-1,4-dihydroquinoline-3-carboxylic acid was heated under reflux as in example 89, for 5 hours. Then the obtained residue was purified by preparative HPLC and the result was 170 mg (yield 78%) specified in the connection header.

1H NMR (DMCO-d6, M. D.) : 8,8 (1H, s), and 7.8 (1H, d), and 4.5 (2H, square), 4,4 (2H, s), 4.2V (1H, m) of 3.9 (1H, m), 3,1 (1H, m), 2,9 - 2,7 (2H, m) of 1.45 (3H, etc) and 1.3 (9H, s)

FAB MC (POS) : [M + H]+= 437

Examples 97 - 176.

The amino compounds obtained in the Receiving 41 - 50, was treated in accordance with the same as in Examples 89 - 96, procedure and received the corresponding LASS="ptx2">

Synthesis of 7-(4-amino-3-methoxykynuramine-1-yl)-1-cyclopropyl - 6,8-debtor-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

< / BR>
23 ml of dry acetonitrile was added 2.83 g (10 mmol) 1-cyclopropyl-6,7,8-Cryptor-4-oxo-1,4-dihydroquinoline-3-carboxylic acid and 4,27 g (11.5 mmol) of 4-aminomethylpyrrolidine-3-one-O-methoxytryptamine. Then to the mixture was added 4.6 g (30 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene, and the mixture was heated under reflux for 1.5 hours and then cooled to room temperature. To the reaction solution was added 15 ml of distilled water. The precipitated solid product was separated and dried, resulting in 2.24 g (yield 55%) specified in the connection header.

1H NMR (DMCO-d6, M. D.): 8,6 (1H, s), of 7.75 (1H, d), 4,35 (2H, s), 4,1 - 3,9 (2H, m), and 3.8 (3H, s), and 3.7 (1H, m) to 3.35 (1H, m), 2,9 - 2,6 (2H, m), 1,25 (2H, d), of 0.95 (2H, s)

FAB MC (POS) : [M + H] = 407

Example 178.

Synthesis of 7-(4-aminomethyl-3-methoxykynuramine-1-yl)-8-chloro-1 - cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

< / BR>
141 mg (0.5 mmol) 1-cyclopropyl-8-chloro-6,7-debtor-4-oxo-1,4 - dihydroquinoline-3-carboxylic acid and 205 mg (0.55 mmol) of 4-aminomethylpyrrolidine-3-one-O-methoxytryptamine was introduced into the reaction for one hour so the th HPLC, receiving 88 mg (yield 42%) specified in the connection header.

1H NMR (DMCO-d6, M. D.): 8,7 (1H, s), a 7.85 (1H, d), and 4.4 (1H, m in), 3.75 (3H, s), and 3.7 (3H, m), 3,4 (2H, m), 3,0 - 2,7 (2H, m), 1,25 (2H, d), and 1.0 (2H, s)

FAB MC (POS) : [M + H] = 423

Example 179.

Synthesis of 7-(4-aminomethyl-3-methoxyamphetamine-1-yl)-1 - cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

< / BR>
132 mg (0.5 mmol) 1-cyclopropyl-6,7-debtor-4-oxo-1,4 - dihydroquinoline-3-carboxylic acid and 205 mg (0.55 mmol) of 4-aminomethylpyrrolidine-3-one-O-methoxytryptamine was introduced into the reaction for 3 hours in the same manner as in Example 177. Then the reaction solution was concentrated and the residue was purified by preparative HPLC, resulting in 73 mg (yield 37%) specified in the connection header.

1H NMR (DMCO-d6, M. D.): / 8,6 (1H, S), 7,86 (1H, d), 7,2 (1H, d), 4,4 (2H, d), a 3.9 (1H, m), 3,85 (3H, s), 3,8 - the 3.65 (2H, m), and 3.0 (1H, m), 2,9 - 2,7 (2H, m), 1,3 (2H, m), 1,1 (2H, m)

FAB MC (POS) : [M + H] = 389

Example 180.

Synthesis of 7-(4-aminomethyl-3-methoxykynuramine-1-yl)-1 - cyclopropyl-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthiridine-3-carboxylic acid

< / BR>
141 mg (0.5 mmol) 1-cyclopropyl-7-chloro-6-fluoro-4-oxo-1,4-dihydro[1,8] naphthiridine-3-carboxylic acid and 205 mg (0.5 mmol) 4-aminomethylpyrrolidine-3-one-O - metlox (yield 85%) specified in the connection header.

1H NMR (DMCO-d6, M. D.): 8,6 (1H, s), with 8.05 (1H, d), 4,55 (2H, s), 4,3 (1H, m), 3,85 (3H, s) (1H, m), and 3.7 (1H, m), and 3.1 to 3.0 (2H, m), 1,2 - 1,0 (4H, m)

FAB MC (POS) : [M + H] = 390

Example 181

Synthesis of 7-(4-aminomethyl-3-methoxykynuramine-1-yl)-1-(2,4 - differenl)-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthiridine-3-carboxylic acid

< / BR>
177 mg (0.5 mmol) of 1-(2,4-differenl)-7-chloro-6-fluoro - 4-oxo-1,4-dihydro-[1,8] naphthiridine-3-carboxylic acid and 205 mg (0.55 mmol) of 4-aminomethylpyrrolidine-3-one-O-methoxytryptamine was introduced into the reaction for 0.5 hour as in example 177, and the result was 59 mg (yield 25%) specified in the connection header.

1H NMR (DMCO-d6, M. D.) : cent to 8.85 (1H, s), with 8.05 (1H, d), of 7.75 (1H, DD), and 7.6 (1H, DD), 7,35 (1H, DD), a 4.3 (2H, m), and 3.8 (3H, s, 1H, m) to 3.6 (1H, m), and 3.0 (1H, m), 2,7 (2H, m)

FAB MC (POS) : [M+H] = 462

Example 182.

Synthesis of 1-cyclopropyl-5-amino-6,8-debtor-7- (4-aminomethyl-3-methoxykynuramine-1-yl)- 4-oxo-1,4-dihydroquinoline-3-carboxylic acid

< / BR>
148 mg (0.5 mmol) 1-cyclopropyl-5-amino-6,7,8-Cryptor - 4-oxo-1,4-dihydroquinoline-3-carboxylic acid and 205 mg (0.55 mmol) of 4-aminomethylpyrrolidine-3-one-O-methoxytryptamine was heated under reflux as in example 177, within 4 hours. Then the reaction solution was concentrated, and the residue was purified UP>H NMR (DMCO-d6, M. D.) : 8,49 (1H, s), 7,28 (2H, Shir. C) a 4.3 (2H, s), 3,9 (2H, m), and 3.8 (3H, s), and 3.7 (1H, m), 2,6 - 2,8 (3H, m) of 1.05 (4H, m)

FAB MS (POS) : [M+H]+= 422

Examples 183 - 202.

Connections received in the Receiving 40 and 55-57, were processed in accordance with the same, as in the examples 177-182, procedure and obtained the corresponding compounds 183-202, the data of NMR and MS for which are shown in the following table 24.

Biological example 1

The test for antibacterial activity in vitro.

Antibacterial activity of compounds in accordance with the present invention was determined by measuring their minimum inhibitory concentration (MIC, μg/ml) against standard strains of clinically isolated strains and strains resistant to some antibacterial agents. In this test, as funds were used for comparison of known antibacterial compounds (ofloxacin and ciprofloxacin). Minimum inhibitory concentration was determined by diluting the compounds for testing in accordance with the method of two-fold dilution, dispersion diluted test compounds in agar medium Mueller-Hinton and then planting 5 ál of the standard strain with 107

Minimum inhibitory concentration of the tested compounds (μg/ml) is shown in table. 25.

Note to the table. 25: FLX - ofloxacin, FLX - ciprofloxacin.

Biological example 2.

Pharmacokinetic test.

The parameters of the pharmacokinetic properties of compounds in accordance with the present invention was determined using SD rats (males) weighing approximately 230 10, In particular, the test compounds in accordance with the present invention was administered at 20 mg/kg of body weight in the test rats via the femoral vein. Then at certain intervals after administration of the test compounds was taking blood from the femoral vein and analyzed by the method of agar cell to measure the concentration of the test compounds in the blood, which was calculated pharmacokinetic parameters : the period of existence of the medicinal substance in the body (T1/2) and AUC (area under the curve). The obtained pharmacokinetic parameters are presented in table. 26

Biological example 3.

Test acute oral toxicity

To determine the acute oral toxicity of the compounds obtained in examples 1 and 34, oral introduced ispy is TBE 10 ml per kg of body weight. Within 7 days after administration of the observed mortality and the status of the tested mice, these observations was calculated LD50(mg/kg). The results obtained are presented in table. 27.

Although the present invention is described in preferred specific embodiment, its implementation, for specialists in this field it is clear that the description of the preferred embodiment is made only for example and that can be made various changes in details of structure, combination and arrangement of parts within the essence and scope of the present invention.

1. Derivatives, quinoline or naphthyridinone acid of the formula (I)

< / BR>
where R represents hydrogen or an amino group;

Q represents C-H, C-F, C-Cl, C-O-CH3or N;

R1is cyclopropyl or phenyl substituted by one or more atom(s) fluorine;

R2represents hydrogen, an unbranched or branched C1- C4-alkyl, cyclopropylmethyl, C3- C6-quinil, 2-halogenated, methoxymethyl, benzyl, allyl, phenyl, cycloalkyl C4- C6or a group of the formula

< / BR>
where X is hydrogen, 2 -, 3-or 4-fluoro, cyano, nitromethane, C1- C4-alkyl or 2,4-dif methylene, O or N;

R3and R4- hydrogen.

2. Connection on p. 1, where Q is C-H, C-F, C-Cl, C-OMe or N, R is hydrogen or amino group, R1- cyclopropyl or 2,4-differenl and R2is methyl, isopropyl, tert-butyl, phenyl, homeprepared, 2-foretel, benzyl, 2-tormentil, 2-methylbenzyl or 2-methoxybenzyl.

3. Connection on p. 2, where Q represents C-H, C-F, C-Cl or N, R is hydrogen or amino group, R1- cyclopropyl and R2is methyl, tert-butyl, homeprepared, 2-foretel, benzyl, 2-terbisil or 2-methoxybenzyl.

4. The method of obtaining derivatives of quinoline or naphthyridinone acid of the formula (I)

< / BR>
where R represents hydrogen or an amino group;

Q - C-H, C-F, C-Cl, C-O-CH3or N;

R1- cyclopropyl or phenyl substituted by one or more atom(s) fluorine;

R2represents hydrogen, an unbranched or branched C1-C4-alkyl, cyclopropylmethyl, C3-C6-quinil, 2-halogenated, methoxymethyl, benzyl, alkyl, phenyl, cycloalkyl C4- C6or a group of the formula

< / BR>
where X is hydrogen, 2,3 or 4-fluoro, cyano, nitro, methoxy, C1- C4-alkyl or 2,4-debtor,

or a group of the formula

< / BR>
< / BR>
< / BR>
< / BR>
where n = 0 or 1;

m = 0, 1, or compounds of formula II

< / BR>
where Q, R, and R1same as above;

X is halogen,

with the compound of the formula III

< / BR>
where R2, R3and R4- same as above

in a solvent in the presence of an acid acceptor.

5. The method according to p. 4, characterized in that the compound of formula III used in the form of salts with hydrochloric, Hydrobromic or triperoxonane acid.

6. The method according to p. 4, characterized in that the compound of formula III is used in an amount of from equimolar to 10-fold molar amount relative to the compound of formula II.

7. The method according to p. 4, wherein the solvent is selected from the group consisting of acetonitrile, dimethylformamide, dimethyl sulfoxide, pyridine, hexamethylphosphoramide, dimethyl sulfoxide, pyridine, hexamethylphosphoramide, N-methylpyrrolidinone, ethanol and water mixture.

8. The method according to p. 4, characterized in that the acid acceptor selected from inorganic bases consisting of sodium bicarbonate and potassium carbonate, and organic bases, consisting of triethylamine, diisopropylethylamine, pyridine, N,N-dimethylaniline, N,N-dimethylaminopyridine, 1,8-diazabicyclo[5,4,0]undec-7-ene and 1,4-dianabanana 200oC.

10. The method of obtaining derivatives of quinoline or naturalienkabinett acid of General formula I

< / BR>
where R represents hydrogen or an amino group;

Q - C-H, C-F, C-Cl, C-O-CH3or N;

R1- cyclopropyl or phenyl substituted by one or more atom(s) fluorine;

R2is hydrogen, unbranched or branched C1- C4-alkyl, cyclopropylmethyl, C3- C6-quinil, 2-halogenated, methoxymethyl, benzyl, allyl, phenyl, cycloalkyl C4- C6or a group of the formula

< / BR>
where X is hydrogen, 2,3 or 4-fluoro, cyano, nitro, methoxy, C1- C4-alkyl or 2,4-debtor;

or a group of the formula

< / BR>
< / BR>
< / BR>
< / BR>
where n = 0 or 1;

m = 0, 1, or 2;

X is methylene, O, or N;

R3and R4is hydrogen,

characterized in that carry out the reaction of the compound of formula II

< / BR>
where Q, R, and R1same as above;

X is halogen,

with the compound of the formula III

< / BR>
where R2- same as above;

P - aminosidine group,

in the presence of a base, and then the obtained compound is removed aminosidine group P.

11. The method according to p. 10, characterized in that as aminosidine gruppeegenskaber, tert-butoxycarbonyl, benzyloxycarbonyl, paramethoxyamphetamine, trichlorocyanuric, benzyl, parametersjpanel, trityl or tetrahydropyranyl.

 

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< / BR>
where R1aryl with 6-10 carbon atoms, unsubstituted or once-three times substituted by identical or different substituents from the group comprising halogen atom, a nitro-group, cyano, trifluoromethyl, cryptometer and triptoreline,

or substituted unbranched or branched alkyl with 1-8 carbon atoms, which is not substituted or substituted aryl with 6-10 carbon atoms, or substituted unbranched or branched alkoxygroup or alkoxycarbonyl with 1-8 carbon atoms, carboxypropyl, an amino group or a group of the formula-NR4R5in which

R4and R5the same or different and mean a hydrogen atom, an unbranched or branched alkyl with 1-8 carbon atoms, phenyl or benzyl,

or thienyl,

R2a hydrogen atom or cycloalkyl with 5-8 carbon atoms or an unbranched or branched alkyl, alkenyl, alkadienes, or quinil with 1-10 carbon atoms, unsubstituted or once or twice substituted od the cyano and nitro-group, or unbranched or branched alkylthiol, alkoxygroup, alkoxycarbonyl, acyl or alloctype with 1-8 carbon atoms, or cycloalkyl with 3-8 carbon atoms, fenoxaprop or phenyl, the latter is not substituted or once or twice substituted by identical or different substituents from the group comprising halogen atom, an unbranched or branched alkyl and alkoxygroup with 1-6 carbon atoms, or substituted by the group-NR4R5in which R4and R5have the above values,

R3a hydrogen atom or an unbranched or branched alkyl with 1-8 carbon atoms,

mixtures of their isomers or their individual isomers and their salts, mainly their physiologically tolerable salts
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