Derivatives of 5-amino-8-methyl-7-pyrrolidineethanol-3 - carboxylic acid, methods for their preparation, pharmaceutical composition, method of treatment, the intermediate product

 

(57) Abstract:

Derivatives of 5-amino-8-methyl-7-pyrrolidineethanol-3-carboxylic acid of the formula I, where R1- H; R2- H, lower alkyl, halogenated lower alkanoyl or the residue of the ether carboxylic acid; R3is hydrogen or lower alkyl, or two of R4, R5, R6can together form -(CH2)ngroup, where n = 2, their stereoisomers or their pharmacologically acceptable salts have excellent antibacterial activity. 6 C. and 11 C.p. f-crystals, 11 PL.

The scope of the invention

The invention relates to new derivatives of 5-amino-8-methyl-7-pyrrolidineethanol-3-carboxylic acids and their stereoisomers and their pharmacologically acceptable salts, have excellent antibacterial activity, and to methods for their preparation. The invention also relates to a pharmaceutical preparation containing an effective amount of a derivative and is applicable for the treatment of infectious diseases, for treatment and to intermediate compounds for the synthesis of derivatives.

Description prototypes

Ciprofloxacin belongs to a well-documented antibacterial agent LASS="ptx2">

Attempts to improve ciprofloxacin were aimed at the introduction of various substituents at positions 5, 7 and 8, however, the present invention relates to a first received quinolone derivative with the amino group in 5-position and a methyl group at the 8-position in combination with pyrrolidinyloxy group in the 7 position.

Currently, the antibacterial activity of quinolone derivatives or insufficient, and if sufficient, accompanied by severe adverse effects such as toxicity, chromosomal aberration, convulsions and so on, whereby a last resort, create a security problem.

The following links have documented above problems associated with quinolone antibacterial agents.

1) "Quinolone antimicrobial agents", 2nd edition, Chapter 26, as amended D. C. Hooper and J. S. Wolfson,

American society for Microbiology, Washington D. K., 1993, page 489 (we are talking about phototoxicity, chromosomal aberrations, convulsions and so on).

2) Analysis of mutagenicity, 2 (3), page 154 (1993) (chromosomal aberration, and so on).

3) Environ. Mol. Mutagen, 13, page 238 (1989) (chromosomal aberration, and so on).

The following highlights the relationship konkretnye, that the introduction of a relatively bulky substituent such as a chlorine atom or a methyl group at the 8 position of the quinoline nucleus is desirable for antimicrobial activity, however, many compounds having 8 position as Deputy, a chlorine atom, create severe adverse effects such as toxicity, chromosomal aberration, and so on, and connection with methyl Deputy also create severe adverse effects such as chromosomal aberration, and so on, the Use of such compounds is associated with great difficulties from the point of view of their safety.

It is widely used in the 5-position of the substituents include an amino group, halogen atom or methyl group, and so on, but these substituents have the disadvantage in lowering antimicrobial activity, and also create severe adverse effects such as toxicity, chromosomal aberration, and so on, causing a security problem.

In addition, the introduction of a 7 position piperazinilnom group does not generate sufficient antimicrobial activity, and the introduction of 3-aminopyrrolidine group has sufficient antimicrobial activity, leads to Vozniknovenie.

EP 0248361 discloses a pharmaceutical composition exhibiting antibacterially synergistic activity. This composition includes a cephalosporin derivative (I) and a derivative of the antibiotic Panama (II). The composition exhibits a synergistically enhanced activity against wide spectrum of gram-positive and negative bacteria, including (1)-resistant strains and anaerobes.

Summary of the invention.

Research aimed at solving the above problems, has led to the present invention, namely, the creation of derivative 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoindole-3-carboxylic acid with 5-amino, 8-stands and 7-pyrrolidinium in the quinoline nucleus.

Compounds of the present invention possess a very effective antibacterial activity, moreover, their use does not lead to severe adverse effects of phytotoxicity, chromosomal aberrations, seizures, and so on, contrary to what might be expected based on earlier attempts. In addition, the compounds of the present invention are characterized by excellent tissue distribution, allowing you to quickly achieve a high concentration of the compound in the target tissues of the lung,by 5-amino-8-methyl-7-pyrrolidineethanol-3-carboxylic acid of General formula (I):

< / BR>
where R1represents hydrogen or lower alkyl;

R2represents hydrogen, lower alkyl, lower alkanoyl, halogenated lower alkanoyl or the residue of the ether carboxylic acid; R3represents hydrogen or lower alkyl;

R4, R5and R6each independently represents hydrogen or lower alkyl, or two of R4, R5and R6can together form -(CH2)ngroup, where n = 1 or 2, their stereoisomeric or their pharmacologically acceptable salts.

Given also the method of obtaining such compounds, pharmaceutical preparations containing an effective amount of these compounds and methods of treatment of infectious diseases by administration to patients an effective amount of such compounds.

According to another embodiment of the present invention provides new derivatives of 8-methylinosine-3-carboxylic acid of formula (II):

< / BR>
where R7is lower alkyl;

R8is the nitro-group or amino group;

X represents a halogen atom,

which is an effective intermediate compounds for obtaining vysheupomyanutyh compounds of formula (I).

Detailed description of image (I);

1) where R1, R2and R3each represents a hydrogen atom,

2) where R4and R5together form -(CH2)2group

3) where R4, R5and R6each represents a hydrogen atom,

4) where R4is methyl; R5and R6each represents a hydrogen atom. In addition, the recommended embodiment of the present invention include a method of obtaining such compounds, pharmaceutical preparations containing an effective amount of such compounds, and methods of treatment of infectious diseases by the administration to patients of effective amounts of these compounds and intermediate compounds for their preparation.

In the above formulas (I) and (II) the lower alkyl represented by R1, R2, R3R4, R5, R6and R7contains 1-4 carbon atoms, for example; methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, etc.; R2is also lower alkanoyl, halogenated lower alkanoyl or the residue of the ether carboxylic acid. If R2represents the lowest alkanoyl, this group contains 1-6 carbon atoms, such as formyl, acetyl, propanol, butteroil or trimethylacetyl and so on; ecatomb halogen, moreover, some of the halogen atoms include fluorine atoms, chlorine, bromine and so on, examples of such groups include: peracetyl, divercity, TRIFLUOROACETYL, chloroacetyl, dichloroacetyl, trichloroacetyl and so on; if R2represents the residue of the ether carboxylic acids, the remainder is alkoxycarbonyl or aryloxyalkyl, for example: benzyloxycarbonyl, etoxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl and so on; the halogen atom represented by X may be, for example: a fluorine atom, a chlorine atom, a bromine atom and so on

In addition, two of R4, R5and R6together form -(CH2)ngroup (where n = 1 or 2), for example, R4and R5combined with the formation of-CH2-group or -(CH2)2group, similarly, R5and R6together with the formation of-CH2-group or -(CH2)2group.

Compounds of the present invention of General formula (I), if desired, can be converted into pharmacologically acceptable salts, and the salts can then be again converted into the free compounds of formula (I).

Pharmacologically acceptable salts of the compounds of the present invention of General formula (I) may be salts, the image of the salts of mineral acids, for example: hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, phosphate, etc. and organic acid salts, such as acetate, maleate, fumarate, citrate, oxalate, malate, methanesulfonate, p-toluensulfonate, mandelate, 10-camphorsulfonate, tartrate, lactate, etc. Examples of salts with bases include salts of inorganic bases, for example: salts of sodium, potassium, calcium, magnesium, ammonium, etc. and salts of organic bases, for example: salts of ethanolamine, N,N-dialkylamino etc.

Compounds of the above General formula (I) have one or more asymmetric carbon atoms, such molecule compounds, any stereoisomer or mixture of stereoisomers are encompassed by the scope of the invention.

The following compounds can be cited as actual examples of derivatives of 5-amino-8-methyl-7-pyrrolidineethanol-3-carboxylic acid, but they are not limited examples of the compounds of the present invention.

(1) 5-Amino-7-(7-amino-5-azaspiro/2.4/hept-5-yl)-1-cyclopropyl-6-fluoro-1,4 - dihydro-8-methyl-4-oxoindole-3-carboxylic acid.

(2) 5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(7-methylamino-5-azaspiro/ 2,4/hept-5-yl/-4-oxoindole-3-carboxylic acid.

(3) 5-Amino-1-cyclopropyl-7-(7 5-Amino-7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4 - oxoindole-3-carboxylic acid,

(5) 5-Amino-7-(3-amino-4-methyl-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4 - dihydro-8-methyl-4-oxoindole-3-carboxylic acid.

(6) 5-Amino-7-(3-amino-4,4-dimethyl-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4 - dihydro-8-methyl-4-oxoindole-3-carboxylic acid.

(7) 5-Amino-7-(3-amino-3-methyl-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4 - dihydro-8-methyl-4-oxoindole-3-carboxylic acid,

(8) 5-Amino-7-(3-amino-4-methylene-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4 dihydro-8-methyl-4-oxoindole-3-carboxylic acid,

(9) 5-Amino-7-(1-amino-3-azabicyclo/3.1.0/Gex-3-yl)-1-cyclo-propyl-6-fluoro-1,4 - dihydro-8-methyl-4-oxoindole-3-carboxylic acid,

(10) 5-Amino-1-cyclopropyl-7-(3-dimethylamino-1-pyrrolidinyl)-6-fluoro-1,4 - dihydro-8-methyl-4-oxoindole-3-carboxylic acid,

(11) 5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(3-methylamino-1 - pyrrolidinyl)-4-oxoindole-3-carboxylic acid,

their stereoisomers or their pharmacologically acceptable salts.

Of these compounds especially suitable compounds (1), (4) and (5), their stereoisomers and their pharmaceutically acceptable salts.

According to the present invention provides a variety of ways to obtain new derivatives of 5-amino-8-methyl-7-pyrrolidineethanol-3-to the person receiving should not be considered, as an exhaustive list.

According to one example of the method of producing of the present invention compounds of General formula (I) can be obtained by reaction in a solvent derived 7-halogenated quinoline-3-carboxylic acid of General formula (III)

< / BR>
where R1and X agree to the above values,

with a derivative of pyrrolidine General formula (IV):

< / BR>
where R2, R3, R4, R5and R6take the above values,

in the presence or absence of a base, followed, if necessary, by hydrolysis.

In the method of the present invention can be used by any acceptable solvent. Examples of inert solvents include: alcohols, such as methanol, ethanol, n-propanol, isopropanol, tert-butanol, etc.; aprotic polar solvents such as acetonitrile, N,N-dimethylformamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, hexamethylphosphorotriamide and so on; aromatic hydrocarbons, such as benzene, toluene and so on; organic bases, such as pyridine, picoline, lutidine, kallidin, etc.; or mixtures of these solvents. Can be used for the following reasons: triethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo/5.4.0/-7-University whom I bicarbonate of potassium, etc. in Addition, if an organic base is used as a solvent, such base may be used instead of the above.

The reaction can be carried out in the temperature range from the temperature bath with ice to the boiling temperature used in the reaction solvent.

The hydrolysis can be carried out by known methods in the presence of acid or alkali. In the reaction, acid hydrolysis can be used such acids as hydrochloric acid, sulfuric acid, etc. and the reaction of alkaline hydrolysis can be applied such bases as sodium hydroxide, potassium hydroxide, etc. These acids or bases can be used in the form of aqueous solutions or in the form of a solution in an organic solvent, such as methanol, ethanol, n-butanol, sec-butanol, tert-butanol etc., possibly with the addition of water.

The hydrolysis reaction can be carried out in the temperature range from room temperature to the boiling temperature used in the reaction solvent.

According to the second example of the preparative method of the present invention compounds of the above formula (I) can be obtained by the reaction of p is,

with a derivative of pyrrolidine the above formula (IV) in the presence or absence of a base, followed, if necessary, the destruction of the chelate in the proton polar solvent in the presence or absence of a base.

In the reaction of compounds of General formula (V) with compounds of General formula (IV) can be used by any acceptable solvent. Examples of inert solvents include: alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, and so on; aprotic polar solvents such as acetonitrile, N, N-dimethylformamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, hexamethylphosphorotriamide and so on ; aromatic hydrocarbons such as benzene, toluene, etc.; organic bases, such as pyridine, picoline, lutidine, kallidin and so on; halogenated hydrocarbons, for example: dichloromethane, 1,2-dichloroethane, chloroform, etc. or a mixture of any of perechislennih solvents. May apply to the following reasons: triethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo/5.4.0/-7-undecene, 1,2,2,6,6-pentamethylpiperidin, 1,4-diazabicyclo-/2.2.2/octane, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, etc. in Addition, when using organic bases as RA the temperature range from the temperature bath with ice to the boiling temperature used in the reaction solvent.

Used in the destruction of the chelate-proton polar solvents include: alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, etc. , water or a mixture of these solvents, or a mixture of aprotic solvents, such as acetonitrile, N,N-dimethylformamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, hexamethylphosphoramide, benzene, toluene, pyridine, picoline, lutidine, collidine, dichloromethane, 1,2-dichloroethane, chloroform, etc., with proton polar solvent, e.g. alcohol, water and so on, the Reaction can be carried out in the temperature range from the temperature bath with ice to the boiling temperature used in the reaction solvent.

According to a third example of the preparative method of the present invention compounds of the above formula (I), where R2is a hydrogen atom, can be obtained by hydrolysis of compounds of formula (I), where R2represents the lowest alkanoyl or halogenated lower alkanoyl, or by treating compound of formula (I), where R2represents the residue of the ether carboxylic acid, in a solvent or without solvent acid in the presence or absence of a chip off the cation of the agent.

The hydrolysis can be carried out from outside the s acid, as hydrochloric acid, sulfuric acid, etc. and the reaction of alkaline hydrolysis can be applied such bases as sodium hydroxide, potassium hydroxide, etc. These acids or bases can be used in aqueous solution or in solution in an organic solvent, such as methanol, ethanol, n-butanol, sec-butanol, tert-butanol etc., possibly with the addition of water. The hydrolysis reaction can be carried out in the temperature range from room temperature to the boiling temperature used in the reaction solvent.

The removal of residual ether carboxylic acids can be carried out in a solvent such as, for example, acetic acid, ethyl acetate, dioxin, water, methanol, ethanol or mixtures thereof; as a chip off the cation agent may apply such as anisole, thioanisole and so on; the acid may use hydrochloric acid, Hydrobromic acid, triperoxonane acid etc., the Removal of residual ether carboxylic acids can be carried out in the temperature range from the temperature bath with ice to the boiling point of the employed solvent.

According to a fourth example of the preparative method of the present and the t lower alkyl, can be obtained by reaction of compounds of formula (I), where R2and/or R3each represents a hydrogen atom, halogenated lower alkyl, in a solvent in the presence or absence of a base or with alldigital following General formula (VI):

R9-CHO (VI)

where R9represents a hydrogen atom or lower alkyl,

in the presence of formic acid.

In this preparative method, when using halogenated lower alkyl can be applied solvent, such as, for example: N,N-dimethylformamide, acetone, ethanol, tetrahydrofuran, benzene, chloroform, etc., and such grounds as, for example triethylamine, potassium carbonate, etc., In the case of the use of the aldehyde of General formula (VI) examples of such aldehydes include formaldehyde, acetaldehyde, Propionaldehyde and so on, and preferably the use of formaldehyde in aqueous solution (formalin), and in the case of acetaldehyde or Propionaldehyde desirable for their use in nitrobenzene as a solvent. All these reactions may be carried out in the temperature range from room temperature to the boiling temperature used in the reaction solvent.

In the preparative method of the present Ibom, the details of which are given in the following examples.

In addition, compounds of General formula (VII) below, are known compounds (see unexamined patent publication Japan N 62-215572).

where X takes values above and Y represents a halogen atom.

Stage I).

3-Methyl-2,4,5-trichloranisole acid (VII) nitrous with the formation of compound (VIII). At this stage, as nitrouse tools you can use nitric acid, potassium nitrate, ammonium nitrate, etc. and the solvent can be used sulfuric acid, acetic acid, acetic anhydride, triperoxonane acid, etc.

Stage 2).

The compound (VIII) is treated gloriouse agent, e.g. thionyl chloride, oxalicacid, etc. in a solvent or without it, for example: chloroform, methylene chloride, 1,2-dichloroethane, etc. in the presence or absence of N,N-dimethylformamide with the formation of the acid chloride (IX).

Stage 3). The compound (IX) and diethyl ether ethoxymethylenemalonic acid (obtained separately from ethanol, diethylmalonate and magnesium) condense in a solvent, such as benzene, toluene, etc. with getting southwestem with water in the presence of acid, for example: hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, etc. to obtain, respectively, of the compound (XI).

Stage 5).

Conducting the reaction of the compound (XI) with atlantogenata in the presence or absence of a Lewis acid such as zinc chloride, etc., in acetic anhydride to obtain, respectively, of the compound (XII).

Stage 6).

The reaction of the compound (XII) with cyclopropylamine in solvent receive the compound (XIII). At this stage may be any acceptable inert solvent, including: alcohols, such as methanol, ethanol and so on ; halogenated hydrocarbons, such as chloroform, 1,2-dichloroethane and so on ; aromatic hydrocarbons, such as benzene, toluene, etc. or aprotic polar solvents, such as acetonitrile, N,N-dimethylformamide, etc.

Stage 7).

The compound (XIII) cyclist action of the base solvent in the presence or absence of a catalyst to obtain respectively the compounds (XIV) (II). At this stage, as the basis of a possible application of potassium carbonate, sodium hydride, tert-butoxide potassium and so on; as a solvent can be applied ethers, such as dioxane, tetrahydrofur is alistore you can apply crown-ethers, tetrabutylammonium, benzyltrimethylammonium etc.

Stage 8).

The compound (XIV) (II)) to regenerate in the presence of a catalyst, such as Raney Nickel, palladium on charcoal, platinum oxide, etc. or restore in acidic conditions with metals such as iron, tin, zinc, etc. with obtaining, respectively, of compound (III-a(II)). At this stage, the solvent can be applied acetic acid, water, methanol, ethanol, N,N-dimethylformamide, and so on, as in reactions with metals can be used such acids as hydrochloric acid, acetic acid, Hydrobromic acid, etc.

Stage 9).

The compound (III-a(II) hydrolyzing in a solvent, for example: water, acetic acid, alcohol, water-alcohol, etc., in acidic conditions, in the presence of, for example: hydrochloric acid, acetic acid, Hydrobromic acid, etc. to obtain, respectively, of compound (III-b).

Stage 10).

The reaction of the compound (III-b) with efratom boron TRIFLUORIDE in a solvent, such as ether, acetone, isobutyl ketone, etc. are respectively of the compound (V).

Pharmaceutical preparation containing an effective colicensee formula (I), its stereoisomer or its pharmacologically acceptable salt, obtained in the aforementioned manner, may be in the form of capsules, tablets, fine granules, granules, powder, syrup, etc. for oral administration or may be in the form of injections, suppositories, eye drops, eye ointments, ear solution or dermatological dosage forms. The pharmaceutical preparation of the present invention can be prepared by mixing the pharmaceutically acceptable additives derived from 5-amino-8-methyl-7-pyrrolidineethanol-3-carboxylic acid, its stereoisomer or its pharmacologically acceptable salt with subsequent normal processing of the mixture. Upon receipt of a pharmaceutical preparation suitable for oral administration, or suppository additive may be a diluent, for example: lactose, D-mannitol, corn starch, kristallicheskuyu cellulose and so on; strukturator, for example, carboxymethylcellulose, calcium carboxymethylcellulose, and so on; the binder, for example: hydroxypropylcellulose, hypromellose, polyvinylpyrrolidone, and so on; a lubricant such as magnesium stearate, talc and so on; covering means, for example: hydrocellulose, sucrose, titanium oxide, etc.; plasticized the practical preparation suitable for injection or applied in the form of eye drops or ear drops, can contain media such as: solubilizers vehicle or solvent, for example: distilled water for injection, saline solution, propylene glycol, etc. used to prepare aqueous preparations or preparations for preparing an aqueous solution before use; regulate the pH of the tool, for example: inorganic and organic acids and bases; making isotonicity tools, such as sodium chloride, glucose, glycerol and so on; stabilizers, etc. In the manufacture of a pharmaceutical product used in the form of eye ointment or dermatological products, can be used additives, for example, pharmaceutical acceptable ingredients, such as white petrolatum, macrogol, glycerin, liquid paraffin, fabric and so on, used in obtaining ointments, creams or poultices.

The use of a pharmaceutical preparation of the present invention is the introduction to the patient the above drug is oral or parenteral. Dose for an adult patient, as a rule, is 10-1000 mg / day when administered orally or 1-500 mg parenteral; dose mo the ideological effect.

Compounds of the present invention are 5-aminirovanie, 8-methylated or 7-pyrrolidinylcarbonyl analogues of the following reference compounds. The superiority of the compounds of the present invention on reference compounds exceeds expectations based on prior art.

The creators of the present invention have found that the simultaneous introduction of an amino group, a methyl or pyrrolidinyl groups, respectively, in 5-, 8 - and 7-position of the quinolone nucleus reduces chromosomal aberration activity of such compounds. A similar effect of substituents to this time was not known, and it could not be expected based on the known prior art, namely, on the basis of the structural transformations of the reference compounds. This is shown by the following results of the analysis of chromosomal aberrations (methods of analysis below).

The results are shown in tables 1-3 (see below).

The following compounds were used as reference.

Reference compound A: 7-((S)-7-amino-5-azaspiro/2,4/-hept-5-yl)-1 - cyclopropyl-6-fluoro-1,4-dihydro-4-oxoindole-3-carboxylic acid hydrochloride (known compound, pending PATENTSCOPE-6-fluoro-1,4 - dihydro-4-oxoindole-3-carboxylic acid hydrochloride (new connection).

Reference connection C: 7-((S)-7-amino-5-azaspiro/2,4/hept-5-yl)-cyclopropyl-6-fluoro-1,4-dihydro - 8-methyl-4-oxoindole-3-carboxylic acid (known connection unexamined patent publication Japan N 95176 /1991).

Reference compound D: 7-((S)-3-amino-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoindole - 3-carboxylic acid (known connection unexamined patent publication Japan N 258855/1988).

Reference compound E: 5-amino-7-((S)-3-amino-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4 - dihydro-4-oxoindole-3-carboxylic acid (new connection).

Reference compound F: 7-((S)-3-amino-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl - 4-oxoindole-3-carboxylic acid (new connection).

Reference compound G: 5-amino-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-piperazineethanol-3 - carboxylic acid (known connection unexamined patent publication Japan N 28157/1999).

Reference connection H: 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4-oxo-7-piperazineethanol-3 - carboxylic acid hydrochloride (known connection unexamined patent publication Japan N 215572/1987).

Reference compound I: 5-amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-m publication Japan N 215572/1987).

1) 5-Amidation (5-H_____ 5NH2)

Table 1 shows the following.

Monitoring the relative activity of the reference compounds A and B((-) ___ (+)), D and E((-) ___ (3+)) should lead to the conclusion that the introduction of an amino group in the 5-position of the quinolone nucleus should increase chromosomal aberration activity.

Thus, it is expected that the compound of the present invention (examples 10 and 12), described as 5-aminirovanie analogues reference compounds C and F, should show a higher activity than the reference compounds C and F, respectively, characterized by high chromosomal aberration activity. Contrary to such expectations compounds of the present invention are characterized by (-). Similar results could not be predicted on the basis of the prototype.

2) Methylation (8-H ___ 8-Me)

Table 2 shows the following.

Based on our review of the relative activity of the reference compounds A and C((+) ___ (3+)), D and F((-) ___ (3+)) it can be expected that the introduction of a methyl group at the 8-position of the quinolone nucleus should increase chromosomal aberration activity.

Thus, it can be expected that the compounds of the present invention (examples 1 who want to make a comparison with reference examples B and E, respectively, showing chromosomal aberration activity. Contrary to such expectations compounds of the present invention are characterized by (-). Similar results could not be foreseen on the basis of the prototype.

3) 7-Pyrrolidinedione (7-piperazinil ___ 7-pyrrolidinyl)

From table 3 it should.

Based on our review of the relative activity of the reference compounds can be expected that the replacement piperazinilnom group 7-polozhenii quinolone nucleus pyrrolidinyloxy group should increase chromosomal aberration activity.

Thus, it is expected that the compounds of the present invention (examples 10 and 12), described as 7-pyrrolidinedione analogs of the reference compounds 1, will give positive results in a higher activity than the reference compounds 1. Contrary to such expectations compounds of the present compounds are characterized by (-). Such results cannot be predicted on the basis of the prototype. (A special feature of the compounds of the present invention).

Beautiful effect of the compounds of the present invention are summarized in tables 4-6, (see the end of the description) in which the results of analysis of the following indicators: Antibes is participating infectious diseases, chromosomal aberration induction of micronucleus, phototoxicity, the induction of convulsions and tissue distribution. Reference compound served as ciprofloxacin (Catalogue company Merck, II-nd edition, 2315 N).

1. Antibacterial activity

Minimum inhibitory concentration (MIC) of the tested compounds is determined by the method of dilution agar described in the standard method of the Japanese society of chemotherapy (Chemotherapy (Tokyo), 29, I, 76 (1981)). Used the following strains:

Staphylococcus aureus (S. aureus)

Enterococcus faecalis (E. faecalis)

Escherichia coli (E. coli)

Klebsiella pheumoniae (K. pneumoniae)

Serratia marcescens (S. marcescens)

Enterobacfer cloacae (E. cloacae)

Acinetobacter calcoaceticus (A. calcoaceticus)

The results are shown in tables 4-A and 4-B.

Compounds of the present invention exhibit excellent antibacterial activity against selected clinically strains, and the results obtained are superior to the results for the reference compounds (ciprofloxacin). In particular, there is a notable difference in activity against gram-positive bacteria.

2. Analysis of chromosomal aberrations

Analysis of chromosomal aberrations is performed on cell lines Chinese hamster lung is spituality compounds cultivated for 6 h at 37oC in humidified air with 5% CO2. After treatment for 6 h, the cells washed. To the washed cells and add fresh medium and the cultivation continued for another 18 hours To collect metaphase cells for 2 h before fixation of chromosomal drug culture add colcemid. The frequency of chromosomal aberrations in CHL cells treated with 100 μg/ml of the tested compounds are given in table 5-A.

Obtained for all compounds of the present invention, the data in all cases are characterized by (-).

3. Analysis of micronucleus

In this analysis use BDFI mice aged 9 weeks. Compound injection intraperitoneally at a dose of 250 mg/kg After 24 h mice kill and collect the bone marrow of the femur. Smears of bone marrow is fixed on slides with methanol and the usual procedure paint Giemsa. For each animal under a microscope to count the number microkernel polychromatic erythrocytes (MNPA) 1000 polychromatic erythrocytes (PCE). As a positive control used cyclophosphamide. The likelihood of MNPA (% number MNPA per 1000 PCE) are shown in table 5-B.

Compounds of the present invention do not create statistics">

4. Phototoxicity

Male Guinea pigs line Hartley injected compound in a dose of 10 mg/kg and immediately irradiated from the back of UV radiation for 90 minutes. At 24 h after UV irradiation, explores erythema on the backs. The number of Guinea pigs with eritem listed in table 5-C.

None of the compound of the present invention is not phototoxicity.

5. Cramps

1) Intraperitoneal (C. B.) introduction

Fixed ICR male mice at the age of five weeks orally administered, fenbufen at a dose of 100 mg/kg of Thirty minutes later the mice injection intraperitoneally compound at a dose of 100 mg/kg then register the occurrence of seizures. The number of mice with seizures are listed in table 5-C.

None of the compound of the present invention does not cause any seizures.

2) Intracerebroventricularly (I. C.in.) introduction

Male Wistar rats weighing 180-220 g anaesthetize pentobarbital sodium (45 mg/kg, B. B.) and fixed in stereotaxic apparatus. For intracerebroventricular injection, each rat implanted guide cannula stainless steel with a diameter of 0.6 mm, the cannula is 1.5 mm above the left side is the volume and close thin probe of stainless steel with a diameter of 0.3 mm To prevent infection intramuscularly injection 10,000 units of eliptically G. Rats leave for a few days alone to recover from surgery.

To determine cramps 30 minutes after intraperitoneal injection of 50 mg/kg of fenbufen, injected with 20 μg of the test compound. The compound is injected through the cannula stainless steel with a diameter of 0.3 mm with a plastic catheter, which is 1.5 mm longer than the guide cannula so that the catheter was in the right ventricle of brain (H +1). In each study tested three rats, and the absence or signs of seizures see at least four hours. Position intracerebroventricular cannula confirmed by injection of 10 µl of 1% Evans blue with subsequent dissection of the brain of each participating in experiments with rats.

The number of suspected seizures in rats are shown in table 5-C.

None of the compound of the present invention does not cause any seizures.

(Reference)

De Groot, J (1959). Forebrain of rats with stereotaxic coordinates. Ver. Kon. Ned. Acad. Wet., Natuurkunde 52, 1-40.

6. Tissue distribution

In the experiments used rat Sprague farm 5 mg/kg Interval 0,083, 0,25, 0,5, 1, 2, 4, 6, 8, 12 and 24 h after injection rats anaesthetize ether and from the abdominal aorta taken blood samples. From blood samples from the conventional way obtain plasma samples. After blood collection remove the lungs and kidneys, and homogeneous with 4 ml and 7 ml of 1 M HCl-citrate buffer (pH 4).

The concentration of the tested compounds in biological fluids (plasma and each analyzed tissue) define method ghvd. To 0.5 ml of plasma or 0.5 g of each tissue homogenate add hydrochloric acid and ether. The mixture was shaken and centrifuged. After removal of the organic phase to the aqueous phase add aq. NaOH solution, phosphate buffer (pH 7) and chloroform. The mixture was shaken and centrifuged. The organic phase is then concentrated. The residue is dissolved and subjected to ghvd. The concentration of the tested compounds in each of the biological fluid at Tmax(time to maximum plasma concentration) are shown in table 6.

(Conditions ghvd)

Column - TSK-gel ODS 80TM< / BR>
The mobile phase - 0.03 M phosphate buffer-CH3CN (3:1, pH 2,5)

The flow rate of 1.2 ml/min

Injectively volume of 100 µl

Detection UV at 308 nm

The concentration of the compounds of the present invention. In addition, the ratio (tissue/plasma) for compounds of the present invention were also higher, respectively 8.6 and 4.2 times relations for ciprofloxacin. The obtained data indicate that the compounds of the present invention have good tissue distribution.

Beautiful effect of the compounds of the present invention was compared with the effect of similar compounds having only one different Deputy of the 5-, 7 - and 8-substituents in the compounds of the present invention. The comparison results are given in tables 7 and 8 (see end of description).

All data on antibacterial activity, chromosomal aberration activity, phototoxicity and inducing convulsions obtained by the same methods of analysis as described above. From these results, data on antibacterial activity, are shown in tables 7 and 8 presents the values of MIC (minimum inhibitory concentration) relative to the selected clinically strains (HPC527, HPC308 and HPC292) S. aureus, which is characteristic of gram-positive bacteria.

Table 7 shows:

The compound of the present invention (example 10) shows a higher antibacterial activity than any from the compounds of the present invention). The compounds of the present invention there is also no toxicity (chromosomal aberration and phototoxicity) observed in connection B.

The compound of the present invention (example 10) shows excellent antibacterial activity, as high as those of the reference compound C has only one different substituent in the 5-position, than and different from the compounds of the present invention), and also does not show toxicity (chromosomal aberration) observed in the reference compounds C. Although the reference compound C and the compound of the present invention, does not show phototoxicity, the introduction of a reference connection has caused the death of one of the five Guinea pigs. The results show that the reference compound C is more toxic than the compound of the present invention.

The compound of the present invention (example 10) shows a much higher antibacterial activity than the reference compound 1 (has only one different substituent in the 7-position, than and different from the compounds of the present invention), and also does not show toxicity (convulsions) observed in the reference compounds 1.

the. Chicago, Illinois, abstract N 1507 (1991)), concerning high chromosomal aberration activity of the reference compound C.

Table 8 illustrates the following.

The compound of the present invention (example 12) shows a much higher antibacterial activity than the reference compound E (has only one different substituent in the 8-position, than and different from the compounds of the present invention), and also does not show toxicity (chromosomal aberration) observed in the reference compounds E. Although the reference compound E, and the connection of the present invention, does not show phototoxicity, the introduction of reference compounds E led to the deaths of two of the five Guinea pigs. The results show that the reference compound E is much more toxic than the compound of the present invention.

The compound of the present invention (example 12) shows a higher antibacterial activity than the reference compound F (has only one different substituent in the 5-position, and what is its difference from the compounds of the present invention), and also does not show toxicity (chromosomal aberration and phototoxicity) observed in silicine activity than the reference compound 1 (has only one different substituent in the 7-position, than and different from the compounds of the present invention), and also does not show toxicity (convulsions) observed in the reference compounds 1.

Toxicity (for example: chromosomal aberration, toxicity and convulsions), characteristic of some antibacterial agents with quinoline nucleus, creates serious difficulties for the clinical application of such tools. Compounds of the present invention solve this problem, therefore have great potential as the next generation of antibiotics.

Antibacterial activity MIC (μg/ml) of the test compounds against 3 strains of S. aureus: HPC527, HPC308 and HPC292 (upper values: HPC527, average: HPC308, lower value: HPC292).

Chromosomal aberration: the frequency of chromosomal aberrations in CHL cells treated with 100 μg/ml of test compounds. ( - : < ; 10%, +: 10-20%, 2+: 20-50%, 3+: & gt; 50%).

Phototoxicity: Guinea pigs, 10 mg/kg, W. B.

Convulsions: mouse 100 mg/kg century B. and rats, 20 ág, I. C.in.

1) All participating in experiments mouse had symptoms sedative effect, considered to be strains of S. aureus: HPC527, HPC308 and HPC292 (upper values: HPC527, averages HPC308, lower value: HPC292).

Chromosomal aberration: the frequency of chromosomal aberrations in CHL cells treated with 100 μg/ml of test compounds. ( - : < ; 10%, +: 10-20%, 2+: 20-50%, 3+: & gt; 50%).

Phototoxicity: Guinea pigs, 10 mg/kg, centuries

Convulsions: mouse. 100 mg/kg, B. B. and rats, 20 ág, I. C.in.

Examples

The present invention is further illustrated by the following examples. The examples are only for illustrative purposes and should not be considered as exhaustive.

Example 1

2,4,5-Cryptor-3-methyl-6-nitrobenzoic acid

To stir a mixture of 370 ml conc. sulfuric acid and to 61.2 ml of 70% nitric acid is added under stirring portions at 55-70oC 36,6 g 2,4,5-Cryptor-3-mediansalary acid. After incubation for 2 hours at room temperature, the reaction mixture was poured into ice and extracted with isopropyl ether. The combined extracts washed with brine, dried, evaporated and receive in the form of yellow crystals of 30.6 g of target compound.

NMR spectrum (CD3OC) h/million: to 2.29 (3H, T., J = 2 Hz).

Example 2

Diethyl ether (2,4,5-Cryptor-3-methyl-6-nitrobenzoyl)malonic acid

Suspened in 270 ml of methylene chloride is stirred for 2 hours at room temperature. Evaporation of the reaction mixture get 2,4,5-Cryptor-3-methyl-6-nitrobenzoate. Separately to the suspension is 3.08 g of magnesium and a few drops of carbon tetrachloride 6.4 ml of absolute ethanol at 50oC added dropwise a solution of 19.2 ml of diethylmalonate in 12 ml of absolute ethanol and then stirred for 1.5 hours at the same temperature. The reaction mixture was evaporated, dissolved in toluene and again evaporated. To a solution of the obtained residue in 30 ml of toluene under ice cooling was added dropwise a solution of 2,4,5-Cryptor-3-methyl-6-nitrobenzonitrile obtained previously, in 30 ml of toluene. After incubation for 2 hours at room temperature to the reaction mixture was added 100 ml of 5% sulfuric acid and the resulting solution was extracted with diethyl ether. The combined organic extracts washed with brine, dried and after evaporation receive in the form of a brown oil 4, 7,3 target compound.

The NMR spectrum (CDCl3) ppm: 1,1 (3H, t, J = 7.5 Hz), to 1.38 (3H, T., J = 7.5 Hz), 2,33 (3H, t, J = 2 Hz), 3,36, 14,18 (total 1H, each s) 4,07 (2H, K, J = 7.5 Hz), to 4.38 (2H, K, J = 7.5 Hz).

Example 3

Ethyl ether (2,4,5-Cryptor-3-methyl-6-nitrobenzene)acetic acid.

Suspension of 45.3 g of diethyl ether (2,4,5-Cryptor-3-methyl-6-nitrobenzoyl)malonic the shape diethyl ether. The combined organic extracts are dried after washing with brine and evaporation receive in the form of a brown oil of 34.2 g of target compound.

NMR-spectrum / (CDCl3) ppm: 1.26 in, 1,34 (total 3H, each t, J = 7 Hz), 2,33, 2,35 (total 3H, each t, J = 2.5 Hz), 3,91, 5,48, 12,34 (total 2H, each s), 4,2, 4,28 (total 2H, each, J = 7 Hz).

Example 4

Ethyl ester of 3-cyclopropylamino-2-/2,4,5-Cryptor-3-methyl-6-nitrobenzoyl)acrylic acid

A mixture of 31.9 per g of ethyl ether (2,4,5-Cryptor-3-methyl-6-nitrobenzoyl)acetic acid, 26,2 ml etilamfetamine and 23.8 ml of acetic anhydride is boiled for 1 hour. Evaporation of the reaction mixture get 46.2 g of ethyl ester of 3-ethoxy-2-(2,4,5-Cryptor-3-methyl-6-nitrobenzoyl)acrylic acid in the form of a brown oil. To a solution of 45.4 received in connection 328 ml of ethanol under ice cooling and stirring, added dropwise to 9.6 ml cyclopropylamine. After keeping for 30 minutes at room temperature, the reaction mixture was evaporated and purification of the residue column chromatography (silica gel, n-hexane-methylene chloride (1: 1) obtained as yellow crystals 28.8 g of target compound. By recrystallization from isopropyl ether receives a yellow needles with so pl. 115-115,5oC.

Analysis for C16

Ethyl ester of 1-cyclopropyl-6,7-debtor-1,4-dihydro-8-methyl-5-nitro-4-oxoindole - 3-carboxylic acid

The solution is 27.1 g of ethyl ester of 3-cyclopropylamino-2-(2,4,5-Cryptor-3-methyl-6-nitrobenzoyl)acrylic acid in 270 ml of 1,4-dioxane portions added 3.2 g of sodium hydride (60% dispersion in mineral oil) and stirred for one hour at room temperature. To the reaction mixture is added 300 ml of water, precipitated precipitated crystals are separated by filtration and obtained as colorless crystals of 19.5 g of the target compounds by recrystallization from N,N-dimethylformamide get colorless needles with so pl. 260-263oC.

Analysis for C16H14F2N2O5:

Calculated %: C 54,55, H 4,01, N 7,95.

Found %: C 54,51, H 4,00, N OF 7.90

Example 6

Ethyl ester of 5-amino-1-cyclopropyl-6,7-debtor-1,4-dihydro-8-methyl-4-oxoindole - 3-carboxylic acid

A suspension of 18.5 g of ethyl ester of 1-cyclopropyl-6,7-debtor-1,4-dihydro-8-methyl-5-nitro-4-oxoindole - 3-carboxylic acid, 10 ml of Raney Nickel in 300 ml of acetic acid hydronaut 1.5 hours at room temperature and atmospheric pressure. The catalyst is filtered off and the resulting filtrate is evaporated. To the residue, add 150 ml of 10% aqueous rastopirenimi obtain 14.8 g of target compound in the form of slightly yellow crystals, by recrystallization from acetonitrile get a slightly yellow needles with so pl. 182,5-185,5oC.

Analysis for C16H16F2N2O3:

Calculated %: C 59,62, H 5,00, N 8,69.

Found %: C 59,74, H 5,08, N 8,60

Example 7

5-Amino-1-cyclopropyl-6,7-debtor-1,4-dihydro-8-methyl-4-oxoindole - 3-carboxylic acid

A mixture of 14.8 g of ethyl ester of 5-amino-1-cyclopropyl-6,7-debtor-1,4-dihydro-8-methyl-4-oxoindole-3-carboxylic acid, or 37.2 ml of hydrochloric acid and 150 ml of 90% acetic acid is boiled for 2 hours. After cooling saducees the crystals are filtered and washed with water to obtain 11.8 g of the target compound as yellow crystals. Subsequent recrystallization from N, N-dimethylformamide get yellow crystals with so pl. 290,5oC (decomp.).

Analysis for C14H12F2N2O3:

Calculated %: C 57,15, H 4,11, N 9,52.

Found %: C 57,10, H is 4.03, N AT 9.53

Example 8

/5-amino-1-cyclopropyl-6,7-debtor-1,4-dihydro-8-methyl-4-oxoindole-3 - carboxylato-O3, O4/diversion (5-amino-1-cyclopropyl-6,7-debtor-1,4-dihydro-8-methyl-4-oxoindole-3 - carboxylic acid-BF2chelate).

A mixture of 5 g of 5-amino-1-cyclopropyl-6,7-debtor-1,4-dihydro-8-methyl-4-oxopyrimidine saducees the crystals are filtered and washing with diethyl ether get 5,38 g of target compound as yellow crystals.

NMR spectrum (DMSO-d6) ppm: 1,08-of 1.15 (2H, m), 1,21-1,3 (2H, m) to 2.67 (3H, d, J= 2.5 Hz), to 4.52-4,59 (1H, m), 7,28 (2H, sh.C) to 9.1 (1H, s).

Example 9

5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4-oxo-7-((S)-7 - triptorelin-5-azaspiro/2,4/hept-5-yl)quinoline-3-carboxylic acid

A mixture of 2.13 g /5-amino-1-cyclopropyl-6,7-debtor-1,4-dihydro-8-methyl-4-oxoindole-3 - carboxylato-O3,O4/diversion, 2.28 g of the hydrochloride of (S)-7-triptorelin-6-azaspiro/2,4/-heptane ([]D20-54,1o(s= 0,1, H2O)), 3.12 ml of triethylamine and 8.5 ml of dimethylsulfoxide is stirred for 4 days at 30oC. To the reaction mixture under ice cooling, water is added. The resulting mixture was acidified with 10% hydrochloric acid to pH 3, extracted with methylene chloride, the combined organic extracts washed with brine, dried over sodium sulfate and after evaporation receive 2,04 g dark brown crystals. Cleaning crystals column chromatography (silica gel, methylene chloride-methanol (50:1-10:1) gain of 0.38 g of yellow crystals. A mixture of 0.38 g of the obtained crystals of 0.38 ml of triethylamine and 8 ml of methanol is boiled for 9 hours and then evaporated. To the residue water is added, the precipitated precipitated crystals are filtered off and, after washing with water, isopropanol and the her from a mixture of methylene chloride with methanol obtain yellow crystals with so pl. 246,5-248oC.

Analysis for C22H22F4N4O4:

Calculated: C 54,77, H 4,6, N 11.61 PERCENT

Found: C 54,57, H 4,7, N TO 11.56%

Specific rotation //2D0-135,6o(s = 0,1, DMF).

Example 10

5-Amino-7-((S)-7-amino-5-azaspiro/2,4, hept-5-yl)-1-cyclopropyl - 6-fluoro-1,4-dihydro-8-methyl-4-oxoindole-3-carboxylic acid

A mixture of 0.26 g of 5-amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4-oxo-7-((S)-7 - triptorelin-5-azaspiro/2,4/-hept-5-yl)quinoline-3-carboxylic acid, 0.18 g of potassium hydroxide and 1.8 ml of water is stirred for 0.5 hour at room temperature. The reaction mixture is neutralized 10% hydrochloric acid to pH 8, precipitated precipitated crystals are filtered off and, after washing with water to obtain 0.21 g of the target compound by recrystallization from acetonitrile obtain 0.16 g of yellow prisms with so pl. 216,5-218oC

Analysis for C20H22FN4O3:

Calculated %: C 62,16, H 6, N 14,50

Found %: C 62,13, H 6, N 14,64

Specific rotation //2D0-48o(=0,05, DMF)

Example 11

5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4-oxo-7-((S)- 3-trichoroethylene-1-pyrrolidinyl)quinoline-3-carboxylic acid

A mixture of 2.5 g (5-amino-1-cyclopropyl-6,7-di is oracleloggingprovider //2D0-28,1o(C 1, MeOH)), 3,26 ml of triethylamine and 10 ml of dimethylsulfoxide is stirred for 3 days at 30oC. the Reaction mixture is acidified with 10 ml of 10% hydrochloric acid, extracted with methylene chloride, the combined organic extracts are dried and after evaporation receive 3,66 g of yellow crystals. The mixture 3,66 g of the obtained crystals, and 3.8 ml of triethylamine and 30 ml of methanol is boiled for 3.5 hours. Precipitated precipitated crystals are filtered out and get to 0.72 g of the target compound as yellow crystals. Subsequent recrystallization from acetonitrile get 0,41 g of yellow crystals with so pl. 238,5-240oC.

Analysis of C20H20F4N4O4:

Calculated %: C 52,63, H 4,42, N TO 12.28

Found %: C 52,64, H 4,37, N 12,35.

Specific rotation //2D0- 28,2o(s = 0,1, DMSO).

Example 12

5-Amino-7-((S)-3-amino-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro - 4-oxoindole-3-carboxylic acid hydrochloride

A mixture of 0.62 g of 5-amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4-oxo-7-((S)- triptorelin-1-pyrrolidinyl)quinoline-3-carboxylic acid, or 0.57 g of potassium hydroxide and 10 ml of water is stirred for 1 hour at room temperature. The reaction mixture is neutralized 10% hydrochloric CI is t evaporated. To a solution of the residue in acetone add ethanol solution of hydrogen chloride and filtering the formed crystals gain of 0.53 g of yellow crystalline product. Subsequent recrystallization of the product from methanol receive 40 mg of target compound in the form of yellow crystals with so pl. 263,5oC (decomp.).

Analysis for C18H21FN4O3HCl:

Calculated %: C 54,48, H 5,59, N 14,12

Found %: C 54,22, H 5,61, N 13,88

Specific rotation //2D0-37,4o(s = 0,1, H2O)

Example 13

5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(CIS-4-methyl-3 - triptorelin-1-pyrrolidinyl)-4-oxoindole-3-carboxylic acid

A mixture of 4 g of (5-amino-1-cyclopropyl-6,7-debtor-1,4-dihydro-8-methyl-4-oxoindole-3 - carboxylato-O3, O4)diversion, 4,08 g of the hydrochloride CIS-4-methyl-3-triftoruranmetilidina, 5,09 ml of N,N-diisopropylethylamine and 16 ml of dimethylsulfoxide is stirred for 3 days at 30oC. To the reaction mixture while cooling with ice, add water and methylene chloride and the resulting mixture was stirred at room temperature. Precipitated precipitated crystals are filtered off and washing with methylene chloride receive 0,99 g yellowish-brown crystals (A). odoi residue chloride methylene get to 1.15 g of yellowish brown crystals (B). The filtrate is evaporated and the residue purified column chromatography (silica gel, methylene chloride-methanol (100:1) to obtain 0.25 g of a yellowish-brown crystals (C). The mixture 2,39 g of the obtained crystals (A, B and C), 2,42 ml of triethylamine, 48 ml of methanol and 24 ml of 1,2-dichloroethane boiled for 9 hours and then evaporated. To the residue water is added and the mixture is acidified with 10% hydrochloric acid to pH 4. Precipitated precipitated crystals are filtered off and, after washing with water, isopropanol and diethyl ether to obtain 2.24 g of the target compound as yellow crystals. Subsequent recrystallization of the crystals from a mixture of N,N-dimethylformamide ethanol receives a yellow needles with so pl. 253-254,5oC.

Analysis for C21H22F4N4O4:

Calculated: C 53,62, H 4,71, N 11,91%

Found: C 53,41, H 4,92, N 11,70%

Example 14

5-Amino-7-(CIS-3-amino-4-methyl-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4 - dihydro-8-methyl-4-oxoindole-3-carboxylic acid.

A mixture of 2 g of 5-amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(CIS-4-methyl-3 - triptorelin-1-pyrrolidinyl)-4-oxoindole-3-carboxylic acid, 1.4 g of potassium hydroxide and 14 ml of water is stirred for 1 hour at room temperature and then neutralized 10% aqueous hydrochloric acid to pH 8. Gchat of 1.65 g of the target compound as yellow crystals. Subsequent recrystallization of the crystals from a mixture of methylene chloride with methanol gain of 1.32 g of yellow prisms with so pl. 213,5-215oC.

Analysis for C19H23FN4O3:

Calculated %: C 60,95, H is 6.19, N 14,96

Found %: C 60,83, H 6,35, N 14,83.

Example 15

5-Amino-1-cyclopropyl-7-((S)-4,4-dimethyl-3-TRIFLUOROACETYL-amino-1-pyrrolidinyl)- 6-fluoro-1,4-dihydro-8-methyl-4-oxoindole-3-carboxylic acid.

A mixture of 4 g of (5-amino-1-topropel-6,7-debtor-1,4-dihydro-8-methyl-4-oxoindole-3 - carboxylato-O3,O4)diversion, 4,32 g of the hydrochloride of (S)-4,4-dimethyl-3-triftoruranmetilidina (//2D0+25,6o(C = 1, MeOH)), 5,09 ml of N, N-diisopropylethylamine and 16 ml of dimethylsulfoxide is stirred for 3 days at 30oC. the Reaction mixture while cooling with ice, diluted with water, acidified with 10% hydrochloric acid to pH 3 and extracted with methylene chloride. The combined organic extracts washed with water and brine, dried over sodium sulfate and evaporated. The residue is purified column chromatography (silica gel, methylene chloride-methanol (100:1) and receive a yellowish-brown crystals, washing them diethyl ether gain of 0.68 g of yellowish brown crystals. Smeserver. To the residue water is added, the formed crystals are filtered and after washing with water, get 0,57 g of target compound as yellow crystals. By recrystallization of the crystals from methanol receives a yellow bars with so pl. 253,5-255oC.

Analysis for C22H24F4N4O4:

Calculated %: C 54,54, H 4,99, N 11,57

Found %: C 54,33, H 4,88, N 11,63.

Specific rotation //2D0+ +42,6o(s = 0,1, MeOH).

Example 16

5-Amino-7-((S)-3-amino-4,4-dimethyl-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro - 1,4-dihydro-8-methyl-4-oxoindole-3-carboxylic acid

A mixture of 0.47 g of 5-amino-1-cyclopropyl-7-((S)-4,4-dimethyl-3-triptorelin-1-pyrrolidinyl)- 6-fluoro-1,4-dihydro-8-methyl-4-oxoindole-3-carboxylic acid, 0.32 g of potassium hydroxide and 3.2 ml of water is stirred for 1 hour at room temperature. The reaction mixture is neutralized 10% hydrochloric acid to pH 8 and extracted with methylene chloride. The combined organic extracts washed with water and brine, dried over sodium sulfate and evaporated. Treatment of the residue with a mixture of acetone with diethyl ether to obtain 0.3 g of the target compound as yellow crystals. Subsequent recrystallization of the crystals from acetonitrile, the floor is C 61,84, H OF 6.49, N 14,42%

Found: C 61,70, H 6,51, N 14,32%

Specific rotation //2D0+ 190,0o(s = 0,1, 0.1 G. of NaOH).

Example 17

5-Amino-7-(3-tert-butoxycarbonylamino-3-methyl-1-pyrolidine)-1-cyclopropyl - 6-fluoro-1,4-dihydro-8-methyl-4-oxoindole-3-carboxylic acid.

A mixture of 3 g of (5-amino-1-cyclopropyl-6,7-debtor-1,4-dihydro-8-methyl-4-oxoindole - 3-carboxylato-O3, O4-diversion, 2,11 g of 3-tert-butoxycarbonylamino-3-methylpyrrolidine, 1,53 ml of N,N-diisopropylethylamine and 12 ml of dimethylsulfoxide is stirred for 2.5 days at 30oC. the Reaction mixture was diluted with water and extracted with methylene chloride. The combined organic extracts washed with brine, dried over sodium sulfate and evaporated. The residue is purified column chromatography (silica gel, methylene chloride-methanol (99:1)) and obtain 0.97 g of yellow crystals. A mixture of 0.97 is obtained crystals, 1 ml of triethylamine and 40 ml of methanol is boiled for 2.5 hours and then evaporated. To the residue water is added, the precipitated precipitated crystals are filtered off and, after washing with water to obtain 0.84 g of the target compound as yellow crystals by recrystallization from acetonitrile get 0,76 g of yellow needles with so pl. 198-201oC.

Analysis on the P> Example 18

5-Amino-7-(3-amino-3-methyl-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro - 1,4-dihydro-8-methyl-4-oxoindole-3-carboxylic acid

To 0,76 g of 5-amino-7-(3-tert-butoxycarbonylamino-3-methyl-1-pyrrolidinyl)-1-cyclopropyl - 6-fluoro-1,4-dihydro-8-methyl-4-oxoindole-3-carboxylic acid add 1.1 ml of hydrochloric acid and then stirred for 2 hours at room temperature. To the reaction mixture while cooling with ice add 0,89 g of potassium hydroxide in 1.8 ml of water and the resulting mixture is neutralized 10% hydrochloric acid to pH 8. Precipitated precipitated crystals are filtered off and washing with water to obtain 0.33 g of the target compound as yellow crystals. Subsequent recrystallization of the product from a mixture of methylene chloride with methanol obtain 0.3 g of yellow crystals with so pl. 217-221oC.

Analysis for C19H23FN4O31/4 H2O:

Calculated %: C 60,23, H 5,26, N 14,79.

Found %: C 59,98, H 6,25, N 14,53.

Example 19

5-Amino-7-((S)-7-tert-butoxycarbonylamino-5-azaspiro/2,4/- hept-5-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4-oxoindole-3 - carboxylic acid

A mixture of 6 g of (5-amino-1-cyclopropyl-6,7-debtor-1,4-dihydro-8-methyl - 4-oxoindole-3-carboxylato-O3, O4)diversion, 5,59 g (S)-7-tiletamine and 24 ml of dimethylsulfoxide is stirred for 3 days at 30oC. the Reaction mixture is diluted with water, neutralized 10% hydrochloric acid to pH 7 and extracted with methylene chloride. The combined organic extracts washed with water and brine, dried over sodium sulfate and evaporated. The residue is purified column chromatography (silica gel, methylene chloride-methanol (100: 1)) to give yellow crystals, which are washed with a mixture of methylene chloride with diethyl ether. Received 3,17 g of pale yellow crystals. A mixture of 3.14 g of the obtained crystals, 3,09 ml of triethylamine, 62 ml of methanol and 31 ml of 1,2-dichloroethane boiled for 14 hours and then evaporated. The residue is diluted with water and neutralized 10% hydrochloric acid to pH 7. The formed crystals are filtered and after washing with water, isopropanol and diethyl ether get and 2.79 g of the target compound as pale yellow crystals by recrystallization from a mixture of methylene chloride with methanol obtain pale yellow needles with so pl. 217,5-219oC.

Analysis for C25H31FN4O5:

Calculated %: C 61,72, H 6.42 per, N TO 11.52

Found %: C 61,71, H 6,48, N IS 11.39

Specific rotation //2D0- 96,6o(C = 0.1 DMF).

Example 20

5-Amino-7-((S)-7-amino-5-azaspiro/2,4/hept-5-yl)-1-cyclo the amino-5-azaspiro/2,4/hept-5-yl)- 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4-oxoindole-3-carboxylic acid add 11 ml of hydrochloric acid and then stirred for 1.5 hours at room temperature. To the reaction mixture while cooling with ice add a solution of 10.5 g of potassium hydroxide in 32 ml of water and the resulting mixture is neutralized 10% hydrochloric acid to pH 8. The formed crystals are filtered and washed with water. Crystals diluted with methylene chloride, the inorganic substance is filtered off and the resulting filtrate is evaporated. Finally diethyl ether get 5.53 g of the target compound as yellow crystals. By recrystallization from acetonitrile receives a yellow prisms, identified as the compound of example 10.

The usual procedure, the following salts.

Methansulfonate

Appearance: yellow or (EtOH-H2O)

so pl. 263-264oC (decomp.)

Analysis for C20H23FN4O3CH4O3S:

Calculated: C 52,27, H 5,64, N 11.61 PERCENT

Found: C 52,02, H 5,54, N 11,53%

Specific rotation //2D0- 93,6o(s = 0,1, MeOH).

p-Toluensulfonate

Appearance: yellow crystals (EtOH) so pl. 188-189,5oC.

Analysis for C20H23FN4O3C7H8O3S 1/2 H2O:

Calculated %: C 57,13, H of 5.68, N 9,87

Found %: C 56,95, H 5,85, N 9,77

Specific rotation //2D0- 73,1o(the PLN).

Analysis for C20H23FN4O3HCl:

Calculated %: C 56,80, H 5,72, N 13,25

Found %: C 56,72, H 5,79, N 13,04.

Example 21

5-amino-7-(3-tert-butoxycarbonylamino-3-methyl-1-pyrrolidinyl)-1 - cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4-oxoindole-3-carboxylic acid (isomer A).

A mixture of 3 g of (5-amino-1-cyclopropyl-6,7-debtor-1,4-dihydro-8-methyl-4-oxoindole - 3-carboxylato-O3, O4)diversion, 2,11 g of 3-tert-butoxycarbonylamino-3-methylpyrrolidine (isomer A, //2D0+ 7,4o(C = 0.5 in MeOH)), 1,53 ml of N,N-diisopropylethylamine and 12 ml of dimethylsulfoxide is stirred for 1.5 at 30oC. Then the reaction mixture is transferred into 60 ml of ice water. To the reaction mixture add 60 ml methylene chloride. After stirring at room temperature, the insoluble matter is filtered off, the aqueous layer was separated and extracted with methylene chloride. Merged layers methylene chloride washed with brine, dried over sodium sulfate and evaporated. The residue is purified column chromatography (silica gel, methylene chloride and methylene chloride-methanol (100:1) and obtain 1.18 g of yellow crystals. A mixture of 1.18 g of the obtained crystals, 1,19 ml of triethylamine and 24 ml of methanol is boiled for 3 hours and then Ispat 0.96 g of the target compound as yellow crystals, by recrystallization from acetonitrile get pale yellow needles with so pl. 213,5-214,5oC.

Analysis for C24H31FN4O5:

Calculated %: C 60,75, H to 6.58, N 11,81

Found %: C 60,63, H 6,55, N 11,80

Specific rotation //2D0+ 47o(s = 0,1, MeOH).

Example 22

5-Amino-7-(3-amino-3-methyl-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4 - dihydro-8-methyl-4-oxoindole-3-carboxylic acid (isomer A) methanesulfonate

To 0.8 g of 5-amino-7-(3-tert-butoxycarbonylamino-3-methyl-1-pyrrolidinyl)-1 - cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4-oxoindole-3-carboxylic acid (isomer A, obtaining see example 21) under cooling with ice add to 0.98 ml of hydrochloric acid, then stirred for 2 hours at room temperature. To the reaction mixture of 0.93 g of potassium hydroxide in 3.1 ml of water and stirred for 1 hour at room temperature. The resulting mixture is neutralized 10% hydrochloric acid to pH 8. Precipitated precipitated crystals are filtered off and, after washing with water to obtain 0.55 g of yellow crystals, which in the usual manner into a methanesulfonate. By recrystallization from ethanol-water (9:1) gain of 0.43 g of target compound in the form of yellow needles with so pl. 261-262,5oC.

Deno %: C 50,89, H TO 5.93, N 11,78.

Specific rotation //2D0- 50,6o(of 0.1, MeOH).

Example 23

5-Amino-7-(3-tert-butoxycarbonylamino-3-methyl-1-pyrrolidinyl)-1 - cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4-oxoindole-3-carboxylic acid (isomer B)

A mixture of 3 g of (5-amino-1-cyclopropyl-6,7-debtor-1,4-dihydro-8-methyl-4-oxoindole-3 - carboxylato-O3,O4)diversion, 3-tert-butoxycarbonylamino-3-methylpyrrolidine (2,11 g, isomer B, []2D0- 8,2o(C = 0.5 in MeOH)), 1,53 ml of N, N-aminobutiramida ethylamine and 12 ml of dimethylsulfoxide is stirred for 2 days at 30oC. the Reaction mixture was transferred into 60 ml of ice water and add 60 ml methylene chloride. After stirring at room temperature, the insoluble matter is filtered off, the aqueous layer was separated and extracted with methylene chloride. Merged layers methylene chloride washed with brine, dried over sodium sulfate and evaporated. The residue is purified column chromatography (silica gel, methylene chloride and methylene chloride-methanol (100:1)) and gain of 0.91 g of yellow-orange crystals. A mixture of 0.91 g of the obtained crystals of 0.92 ml of triethylamine and 18 ml of methanol is boiled for 3 hours and then evaporated. To the residue water is added, the resulting s with so pl. 214,5-215,5oC

Analysis for C24H31FN4O5:

Calculated %: C 60,75, H to 6.58, N 11,81

Found %: C 60,85, H 6,57, N 11,76.

Specific rotation //2D0- 47,8o(s = 0,1, MeOH).

Example 24

5-Amino-7-(3-amino-3-methyl-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4 - dihydro-8-methyl-4-oxoindole-3-carboxylic acid (isomer B) methanesulfonate

To 0.7 g of 5-amino-7-(3-tert-butoxycarbonylamino-3-methyl-1-pyrrolidinyl)-1-cyclopropyl - 6-fluoro-1,4-dihydro-8-methyl-4-oxoindole-3-carboxylic acid (isomer B, obtaining see example 23) under cooling with ice add 0,86 ml of hydrochloric acid, then stirred for 2 hours at room temperature. To the reaction mixture add a solution of 0.82 g of potassium hydroxide in 2.7 ml of water and then stirred for 1 hour at room temperature. The resulting mixture is neutralized 10% hydrochloric acid to pH 8. Precipitated precipitated crystals are filtered off and, after washing with water, get to 0.48 g of yellow crystals, which in the usual manner into a methanesulfonate. By recrystallization from ethanol-water (9:1) to obtain 0.31 g of the target compound in the form of yellow needles with so pl. 260,5-262oC.

Analysis for C19H23FN4O3CH4O3+ 46,6o(s = 0,1, MeOH).

Example 25

5-Amino-7-((S)-3-tert-butoxycarbonylamino-1-pyrrolidinyl)-1-cyclopropyl - 6-fluoro-1,4-dihydro-8-methyl-4-oxoindole-3-carboxylic acid

A mixture of 2 g of (5-amino-1-cyclopropyl-6,7-debtor-1,4-dihydro-8-methyl-4-oxoindole - 3-carboxylato-O3, O4)diversion, 1.63 g (S)-3-tert-butoxycarbonylmethylene (//2D0- -25o(C = 1, MeOH)), of 1.02 ml of N,N-diisopropylethylamine and 8 ml of dimethylsulfoxide is stirred for 22 hours at 30oC. the Reaction mixture was diluted with water and extracted with methylene chloride. The combined organic extracts washed with water and brine and evaporated. The residue is purified column chromatography (silica gel, methylene chloride-methanol (100: 1)) to give a yellowish-brown oil, rinse which a mixture of acetone with diethyl ether to obtain 1.07 g of yellowish-brown crystals. A mixture of 1.07 g of the obtained crystals, 1,11 ml of triethylamine, 22 ml of methanol and 11 ml of 1,2-dichloroethane boiled for 10 hours and then evaporated. The residue is diluted with water, the resulting mixture is neutralized 10% hydrochloric acid to pH 7, saducees the crystals are filtered and after washing with water to obtain 0.95 g of the target compound as yellow kristala C23H29FN4O5:

Calculated %: C 59,99, H 6,35, N 12,17.

Found %: C 59,98, H 6,45, N 11,99

Specific rotation //2D0- 33,3o(s = 0,1, DMF).

Example 26

5-Amino-7-((S)-amino-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-8 - methyl-4-oxoindole-3-carboxylic acid

To 4,07 g of 5-amino-7-((S)-3-tert-butoxycarbonylamino-1-pyrrolidinyl)-1-cyclopropyl - 6-fluoro-1,4-dihydro-8-methyl-4-oxo-quinoline-3-carboxylic acid at room temperature add to 5.2 ml of hydrochloric acid, then stirred for 30 minutes at room temperature. To the reaction mixture while cooling with ice add a solution of 4.9 g of sodium hydroxide in 16 ml of water with establishing pH 11, then get the mixture is neutralized 10% hydrochloric acid to pH 8. The aqueous layer was decanted and the oil washed with a small amount of methanol. The crystals are filtered and washed with isopropanol get 3,05 g of yellow crystals. Crystals diluted with ethanol, insoluble matter is filtered off and the resulting filtrate is evaporated. The residue is diluted with a mixture of methylene chloride with methanol (19:1), the insoluble matter is filtered and after evaporation of the filtrate obtain 2.58 g of target compound in the form of Gatot pale yellow crystals with so pl. 202-204oC (decomp.).

Analysis for C18H21FN4O3H2O:

Calculated %: C 57,13, H 6,13, N 14,81

Found %: C 57,36, H 5,91, N 14,70

Specific rotation //2D0- 11o(s = 0,1, DMF).

The usual procedure, the following salts.

Methanesulfonate

Appearance: yellow needles (MeOH)

so pl. 280-281,5oC (decomp.)

Analysis for C18H21FN4O3CH4O3S 1/4 H2O:

Calculated %: C 49,5, H 5,58, N 12,15

Found %: C 49,5, H 5,58, N A 12.03

Specific rotation //2D0- 27,7o(s = 0,1, H2O)

p-Toluensulfonate

Appearance: yellow needle (izo-D-H2O)

so pl. 238-241oC (decomp.)

Analysis of C18H21FN4O3C7H8O3S 1/2H2O:

Calculated :% C 55,44, H 5,58, N 10,34

Found :% C 55,47, H 5,56 N 10,22

Specific rotation //2D0- 24oC (C = 0,1, H2O).

Example 27

5-Amino-1-cyclopropyl-7-((S)-3-dimethylamino-1-pyrrolidinyl)-6-fluoro-1,4 - dihydro-8-methyl-4-oxoindole-3-carboxylic acid

A mixture of 3 g of (5-amino-1-cyclopropyl-6,7-debtor-1,4-dihydro-8-methyl - 4-oxoindole-3-carboxylato-O3, O4)diversion, 1.2 g ((S)-3-dimethylamine is and stirred for 2 days at 30oC. the Reaction mixture was diluted with water and extracted with methylene chloride. The combined organic extracts washed with water, dried over sodium sulfate and evaporated. The residue is purified column chromatography (silica gel, methylene chloride and chloride metrometer 30:1) and obtain 1.18 g of yellowish-orange crystals. A mixture of 1.18 g of the obtained crystals of 1.42 ml of triethylamine, 24 ml of methanol and 12 ml of 1,2-dichloroethane is boiled for 4 hours and then evaporated. The residue is diluted with water and neutralized 10% aqueous solution of sodium hydroxide to pH 8. Precipitated precipitated crystals are filtered off and, after washing with water to obtain 0.96 g of the target compound as yellow crystals. By recrystallization from acetonitrile receives a yellow needles with so pl. 204-205,5oC.

Analysis for C20H25FN4O3:

Calculated :% C 61,84, H of 6.49, N 14,42

Found %: C 61,72, H 6,46, N 14,44.

Specific rotation //2D0+ 156o(s = 0,1, MeOH).

Example 28

5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4-oxo-7-/3-(TRIFLUOROACETYL) (methyl)amino-1-pyrrolidinyl/quinoline-3-carboxylic acid

A mixture of 3 g of (5-amino-1-cyclopropyl-6,7-debtor-1,4-dihydro-8-methyl-4-oxigenation-3 - carboxylato-O3, O4oC. the Precipitate is filtered, the resulting filtrate is diluted with water and the resulting crystals filtered off. Washing the crystals with water and ethyl acetate to obtain a yellowish brown crystalline product, the purification of which column chromatography (silica gel, methylene chloride and methylene chloride-methanol (50:1)) get to 0.92 g of a yellow-orange crystals. A mixture of 0.9 g of the obtained crystals of 0.91 ml of triethylamine, 18 ml of methanol and 9 ml of 1,2-dichloroethane is boiled for 5 hours and then evaporated. To the residue water is added and filtration of precipitated precipitated crystals gain of 0.77 g of yellow crystalline product by recrystallization from methanol obtain yellow crystals with so pl. 189-190oC.

Analysis for C21H22F4N4O4:

Calculated %: C 53,62, H 4,71, N 11,91

Found %: C 53,50, H 4,42, N 11,84

Example 29

5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(3-methyl-amino-1 - pyrrolidinyl)-4-oxoindole-3-carboxylic acid

A mixture of 0.6 g of 5-amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4-oxo-7-/3-(TRIFLUOROACETYL) methyl)amino-1-pyrrolidinyl/quinoline-3-carboxylic acid, or 0.38 g of potassium hydroxide and 3.8 ml of water is stirred for 1 hour at room temperature. The reaction mixture it is th gain of 0.47 g of the target compound as yellow crystals, by recrystallization from methanol receives a yellow bars with so pl. 200,5-202oC.

Analysis for C19H23FN4O3:

Calculated %: C 60,95, H is 6.19, N 14,96

Found %: C 60,78, H 6,17, N 15,01

Example 30

5-Amino-7-((S)-7-tert-butoxycarbonylamino-7-azaspiro/2,4/-hept-5-yl)- 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4-oxo-quinoline-3-carboxylic acid

A mixture of 20 g of 5-amino-1-cyclopropyl-6,7-debtor-1,4-dihydro-8-methyl-4-oxoindole-3 - carboxylic acid, of 28.9 g (S)-7-tertbutoxycarbonyl-5-azaspiro/2,4/heptane (//2D0- 47,2o(C = 1, MeOH)) and 80 ml of dimethyl sulfoxide is heated for 36 hours at 100oC. the Reaction mixture was transferred into 500 ml ice water, the resulting crystals are filtered, washed with water and isopropanol and after recrystallization from a mixture of methylene chloride with methanol gain of 14.7 g of target compound, identical to the compound of example 19.

Example 31

Ethyl ester of 1-cyclopropyl-6,7-debtor-1,4-dihydro-8-methyl-5-nitro-4-oxoindole-3 - carboxylic acid

To a solution of 10 g of ethyl ester of 3-cyclopropylamino-2-(2,4,5-Cryptor-3-methyl-6-nitrobenzoyl)acrylic acid and 0.1 g of 18-crown-6-ether in 100 ml of tetrahydrofuran type of 8.04 g of potassium carbonate and polycarbosilane-tetrahydrofuran, water and acetone receive 8,56 g of target compound. By recrystallization from N,N-dimethylformamide get colorless needles, identified as the compound of example 5.

Example 32

The pharmaceutical preparation of the present invention in the form of tablets get in the usual manner using the following components:

The compound of example 10 to 110 mg

Lactose - as needed

Corn starch - 34 mg

Magnesium stearate 2 mg

The hypromellose 8 mg

Polyethylene glycol 6000 0.5 mg

The titanium oxide is 0.5 mg to 210 mg

Example 33

The pharmaceutical preparation of the present invention receive the usual manner in the form of capsules using the following components:

The compound of example 10 to 110 mg

Lactose - as needed

Carboxymethylcellulose 15 mg

Hydroxypropylcellulose 2 mg

Magnesium stearate 2 mg - 160 mg

Example 34

The pharmaceutical preparation of the present invention in powder form get in the normal way using the following components:

The compound of example 10 to 110 mg

Lactose - as needed

D-Mannitol 500 mg

Hydroxypropylcellulose 5 mg

Talc 5 mg - 1000 mg

Example-Finance the following components:

The compound of example 10 to 50 mg

Glucose - 1000 mg

Hydrochloric acid as needed

Distilled water for injection as needed 20 ml

Example 36

The pharmaceutical preparation of the present invention receive the usual way as suppository using the following components:

The compound of example 10 to 100 mg

Tallow - 1300 mg, 1400 mg

Example 37

The pharmaceutical preparation of the present invention receive the usual way in the form of ointments by the following components:

The compound of example 10 and 5 mg

White petrolatum - as needed

Liquid paraffin - 70 mg - 1000 mg

Reference compounds (A-1) synthesized according to the methods described in examples 9 and 10.

Reference compound A

7-((S)-7-Amino-5-azaspiro/2,4/-hept-5-yl)-1-cyclopropyl-6-fluoro-1,4 - dihydro-4-oxoindole-3-carboxylic acid hydrochloride

Appearance: pale yellow needles

so pl. 284-288oC (decomp.)

Reference compound B

5-Amino-7-((S)-7-amino-5-azaspiro/2,4/-hept-5-yl)-1-cyclo-propyl-6-fluoro - 1,4-dihydro-4-oxoindole-3-carboxylic acid hydrochloride

Appearance: pale yellow crystals

so pl. 276-279oC (decomp.)

Reference connect the acids

Appearance: colorless crystals

so pl. 176,5-178oC.

Reference compound D

7-((S)-3-Amino-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4 - oxoindole-3-carboxylic acid

Appearance: colorless crystals

so pl. 253-254oC (decomp.)

Reference compound E

5-Amino-7-((S)-3-amino-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4 - oxoindole-3-carboxylic acid

Appearance: pale yellowish-brown crystals

so pl. 226-228,5oC (decomp.).

Reference compound F

7-((S)-3-Amino-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4 - oxoindole-3-carboxylic acid

Appearance: pale brown crystals

so pl. 192-193,5oC (decomp.).

Reference compound G

5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazineethanol - 3-carboxylic acid

Appearance: pale yellow needles

so pl. 213-214,5oC.

Reference connection H

1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4-oxo-7-piperazineethanol - 3-carboxylic acid hydrochloride

Appearance: pale brown needles

So pl. 279-281oC (decomp.)

Reference connection I

5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4-oxo-7-Pipera is 2">

1. Derivatives of 5-amino-8-methyl-7-pyrrolidineethanol-3-carboxylic acid of General formula I

< / BR>
where R1represents a hydrogen atom;

R2selected from the group including a hydrogen atom, lower alkyl, halogenated lower alkanoyl and the residue of the ether carboxylic acid;

R3selected from the group comprising a hydrogen atom and lower alkyl;

R4, R5and R6each independently represents a hydrogen atom or lower alkyl, or two of R4, R5and R6can together form - (CH2)ngroup, where n = 2,

their stereoisomers or their pharmacologically acceptable salts.

2. Connection on p. 1, where R2and R3each represents a hydrogen atom, its stereoisomers, or its pharmaceutically acceptable salt.

3. Connection under item 1 or 2, where R4, R5and R6each independently represents a hydrogen atom or lower alkyl, its stereoisomers, or its pharmaceutically acceptable salt.

4. Connection on p. 3, where the lower alkyl represented by stands, its stereoisomers, or its pharmaceutically acceptable salt.

5. Connection on p. 3, where R4, R5and R6each represents a hydrogen atom, Mawlay methyl and R5and R6each is hydrogen, its stereoisomers, or its pharmaceutically acceptable salt.

7. Connection under item 1 or 2, where two of R4, R5and R6together form -(CH2)ngroup, where n = 2, its stereoisomers, or its pharmaceutically acceptable salt.

8. Connection on p. 7, where R4and R5together form a group -(CH2)n-, where n = 2, or its stereoisomers, or its pharmaceutically acceptable salt.

9. Connection on p. 1, representing 5-amino-7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4-oxoindole-3-carboxylic acid, its stereoisomers, or its pharmaceutically acceptable salt.

10. Connection on p. 1, representing 5-amino-7-(3-amino-4-methyl-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4-oxoindole-3-carboxylic acid, its stereoisomers, or its pharmaceutically acceptable salt.

11. Connection on p. 1, representing 5-amino-7-(7-amino-5-azaspiro[2,4] hept-5-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4-oxoindole-3-carboxylic acid, its stereoisomers, or its pharmaceutically acceptable salt.

12. Pharmacological composition for treating bacterial diseases,x connections on PP.1 - 11, their stereoisomers or their pharmacologically acceptable salts and pharmaceutically acceptable additives.

13. A method of treating bacterial diseases, characterized in that it is administered to the patient an effective amount of one or more compounds according to paragraphs.1 to 11, their stereoisomers or their pharmacologically acceptable salts, or containing pharmaceutical compositions.

14. The method of obtaining compounds on p. 1, their stereoisomers or their pharmacologically acceptable salts, characterized in that carry out the reaction of a derivative of 7-halogenated quinoline-3-carboxylic acid of General formula III

< / BR>
where X represents a halogen atom and R1accept above values,

with a derivative of pyrrolidine General formula IV

< / BR>
where R2, R3, R4, R5and R6accept these values,

followed, if necessary, by hydrolysis.

15. The method of obtaining compounds on p. 1, their stereoisomers or their pharmacologically acceptable salts, characterized in that carry out the reaction of compounds of General formula V

< / BR>
where X represents a halogen atom,

with a derivative of pyrrolidine General formula IV

< / BR>
where R2, R3, R

16. The method according to PP.14 and 15, characterized in that the compound obtained of General formula I, in which R2is halogenated lower alkanoyl, by hydrolysis into a compound of formula I, where R2means hydrogen, or, if R2means the residue of the ether carboxylic acid is treated with this compound acid.

17. Derived 8-methylinosine-3-carboxylic acid of General formula II

< / BR>
where R7is lower alkyl;

R8- the nitro-group or amino group;

X is a halogen atom.

 

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