Derivatives of 1,8-benzo(b)naphthiridine and pharmaceutical composition based on them

 

(57) Abstract:

Usage: in medicine as an antibacterial agent. The inventive products: derivatives of 1,8-benzo-(b)naphthiridine f-ly 1, where R1hydrogen, the hydroxy-group or alkyl, R2hydrogen, alkyl, foralkyl, cycloalkyl containing from 3 to 6 carbon atoms, alkyloxy or alkylamino-group, R3phenyl or alkylphenyl, possibly substituted by one or more halogen atoms or radicals: alkyl, cycloalkyl, cyano, amino, R4hydrogen or fluorine. Reagent 1: piperazine f-crystals 2. Reagent 2: naphthiridine f-crystals 3. Reaction conditions: in a medium of an organic solvent in the presence of hydrogen chloride. 2 S. p. f-crystals. The structure of the compounds f-l 1, 2, 3:

The invention relates to new derivatives of benzo(b)naphthiridine-1,8 General formula

RNN

(I) in which

R1is a hydrogen atom or a hydroxy radical or alkyl;

R2is a hydrogen atom or an alkyl radical, the alkyl fluoride, cycloalkyl containing from 3 to 6 carbon atoms, alkyloxy-;

R3is a phenyl radical or alkylphenyl, possibly substituted by one or more halogen atoms or alkyl radicals, C is oxyalkylene, hydroxyalkyl, hydroxyalkyloxy, methylendioxy-, aminoalkyl, alkylamino - alkyl or dialkylaminoalkyl or dialkylanilines, whose alkyl part may form with the nitrogen atom to which they are bound, a 5 - or 6-membered heterocycle, or is a 5-membered heterocyclic radical containing 1 or 2 heteroatoms selected among nitrogen, oxygen or sulfur, and

R4is a hydrogen atom or a fluorine atom, and in which the alkyl radicals are unbranched or branched and contain from 1 to 4 carbon atoms, in the form of its isomers or their mixtures, as well as its salts with metals, salts connection with nitrided bases, salts joining with acids and its hydrated forms, exhibiting bacteriostatic activity.

In U.S. patent [1,2] have been described derivatives naphthiridine the following structure:

< / BR>
in which X may be oxygen, and two adjacent radicals from R1to R5may form a benzene cycle.

These products are used as inhibitors of gastric juice.

The patent application DE 3 302 126 describes substances, lowering blood pressure with total SUB>5where the radicals R5may form a benzene cycle.

The aim of the invention is to develop on the basis of known techniques of new compounds with high bactericidal activity.

Products with the General formula (I) may exist in hydrated form and these hydrates are also included in the scope of the invention.

In the General formula (I), when R3is a heterocyclic radical, the latter can be selected among foreleg, tackiling, pyrrolidino, N-alkylpyridinium, imidazolidine, parasailing or thiazolidine radicals.

The products of General formula (I) can be obtained by substitution reaction of a piperazine of General formula:

RNNH (II) in which R1and R3defined as before, with 1,8-benzo (b) naphthiridine General formula:

(III) in which R2defined above, Hal is a fluorine atom, chlorine or bromine, if R4is hydrogen, or Hal and R4are both fluorine atoms, and if necessary, if R1is a hydrogen atom and if you want to obtain a derivative of benzo (b) naphthiridine to 1.8, in which R1is a methyl radical, after substitution, transformation in the General formula (II) usually occurs in the presence of excess of this derivative as an acid acceptor in organic solvents. It is possible to operate as a solvent, and at temperatures of prisoners between 30 and 120aboutC. When working in the presence of a solvent, the reaction with success runs in solvents such as pyridine, dimethylformamide, dimethylsulfoxide or acetonitrile.

Prefer to work in the presence of an acid acceptor, such as nitrated organic base (triethylamine), carbonate of an alkali metal, for example sodium carbonate, or hydroxide of an alkaline or alkaline-earth metal.

When the radical R2the product of General formula (III) is a hydrogen atom or when R3contains amino, alkylamino, aminoalkyl or acylaminoalkyl Deputy prefer to pre-protect the original product. Protection and removal of the protecting radical is carried out in accordance with conventional methods.

Protection can be implemented using any compatible group, the introduction and removal do not affect the rest of the molecule. In particular, you can use the technique described in the books: T. C. green. Protective groups in organic synthesis. The Wiley-Intersience Publican, 1981 or Mac-Omi, Protective groups in Ikhlov: trimethylsilyl, benzhydryl, tetrahydropyranyl, formyl, acetyl, chloroceryle, trichloroethylene, trifluoracetyl, ethoxycarbonyl, tert-butoxycarbonyl, trihlorizozianurova.

If necessary follow-up action methylation piperazinilnom radical occurs with success under the action of formalin in the presence of formic acid. Work usually in an aqueous medium at a temperature that is between 90 and 100aboutC.

Derivatives of benzo-[b]-naphthiridine-1,8 General formula (I) can also be obtained from the corresponding complex ester of General formula:

RNN (IV) in which R1, R3and R4defined as above, R2determined, as described above, or is protected by acylaminoalkyl, and ALK is an alkyl radical containing from 1 to 4 carbon atoms in an unbranched or branched chain, any known method of producing acid from ether complex, without affecting the rest of the molecule, followed, if necessary, by removal of the protective group of acylaminoalkyl, and/or, if you received a product with the General formula (I) in which R1is a hydrogen atom and if you want to get the CE is SS="ptx2">

To obtain isomers derived benzonitriles General formula (I) carry out the separation of isomeric forms of piperazines of General formula (II) according to any known and compatible with the molecule method. As an example, the separation is carried out when the acylation by acid or reactive derivative chiral acid, separation of the isomers by high performance liquid chromatography, then diallylammonium acid hydrolysis.

In the following examples isomer (-) is called the isomer (s) derived benzonitriles General formula (I), in which the rotational ability in acetic acid solution, negative, and isomer obtained on the basis of a derivative of piperazine, which has the rotational ability in ethanol positive, is called the isomer (+).

You can also directly the synthesis of chiral piperazine as described below in examples 20 and 21, the isomer (R) derived benzonitriles General formula (I), in which the rotational ability in acetic acid solution, positive, obtained from the derivative of piperazine, which has the rotational ability in ethanol is negative.

New products according to the Kimi physical methods, as crystallization or chromatography.

The products can be converted into metal salts or salts of joining with nitrided bases in accordance with known methods. These salts can be obtained by the action of base metal (for example, alkaline or alkaline-earth), ammonia or amine in the product according to the invention in a suitable solvent such as alcohol, simple ester or water, or by exchange reaction with a salt of an organic acid. The obtained salt precipitates after concentration (if necessary) from your solution, it is separated by filtration, decantation or freeze-drying (vacuum drying).

New products according to the invention can also be converted into salts joining with acids. Products with the General formula (I) are obtained in the form of these salts can be isolated and converted into the salts of other acids in accordance with conventional methods.

As examples of pharmaceutically suitable salts can specify salts of alkali metals (sodium, potassium, lithium) or alkaline earth (magnesium, calcium), ammonium salt, salt nitrided bases (ethanolamine, diethanolamine, trimethylamine, triethylamine, methylamine, Propylamine, Diisopropylamine, diphenylethylamine, benzhydrylamine, quinine, choline, arginine, lysine, leucine, dibenzylamine.

The following examples are not limiting, illustrate the invention.

P R I m e R 1. Suspension consisting of 1.84 g of 8-chloro-7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo[b]naphthiridine - 3-carboxylic acid in 20 cm3pyridine, of 5.82 g of 2-phenylpiperazine (RS) and 1.24 g of triethylamine is heated at a temperature close to 115aboutWith over 5 hours After cooling at about the 20aboutWith the formed precipitate is centrifuged, washed with 2 times 5 cm3pyridine, 2 times 5 cm3isopropyl alcohol, 2 times 5 cm3ethanol and 1 in every 20 cm3ethyl ether. After one recrystallization from a mixture of 40 cm3of dimethylformamide and 40 cm3the ethanol 0,920 g of 7-fluoro-1-methyl-4-oxo-8-(3-phenyl-1 - piperazinil)-1,4-dihydro-1,8-benzo[b]natteri - Dean-3-carboxylic acid (RS) in a solid yellow color, melting at 265aboutC.

8-Chloro-7-fluoro-1-methyl-4-oxo-1,4-dihyd - ro-1,8-benzo[b] naphthiridine-3 - carboxylic acid can be obtained in the following way.

a suspension consisting of 15 g of 8-chloro-3-etoxycarbonyl-7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b]naphthiridine is the atur, close to 100aboutC for 4 h under stirring. After cooling at a temperature close to 20aboutWith, the product is centrifuged, washed with 2 times 100 cm3water, washed 2 times in 150 cm3ethanol, then 2 times in 100 cm3ethyl ether. Obtain 12.7 g of 8-chloro-7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo[b] nafta-ridin-3 - carboxylic acid in the form of a solid beige color, vazhneyshego at 400-450aboutC, which is used without further purification in the subsequent stages. 8-Chloro-3-etoxycarbonyl-7-fluoro-1-me-til-4-oxo-1,4-dihydro-1,8-benzo [b]-naphthiridine is prepared in the following stages.

Under stirring, the suspension consisting of 19.3 g of 2-(2,7-dichloro-6-fluoro-3-hinolincarbonova)-3-dimethylaminomethylene - LVL 250 cm3ethanol, maintained at a temperature between 10 and 15aboutWith that bubbled methylamine to the absorption of 16 g of gas. Allow the temperature to rise to about 20aboutWith add 0.8 g diaza-1,8-bicyclo-[5,4.0. indacene-7 (DBU) and heated at a temperature close to the 75aboutWith over 2 hours After cooling to about 20aboutThe product is centrifuged, washed 2 times with 150 cm3ethanol and 2 times 100 cm3ethyl ether. Receive 15 g of 8-chloro-3-etoxycarbonyl-7-ft is UP>aboutC, which is used without further purification in the subsequent stages.

2-(2,7-Dichloro-6-fluoro-3-hinolinova-Neil)-3-dimethylaminoethylacrylate is prepared in the following way:

a suspension consisting of 16.5 g of 3-(2,7-dichloro-6-fluoro-3-chinolin)-3 - accouterment 160 cm3ethyl acetate and 19 cm3dimethylacetal N,N-dimethylformamide is heated at a temperature close to the 75aboutC for 2 h under stirring. The reaction mixture is concentrated to dryness under reduced pressure (20 kPa) and at the 50aboutC. the Dry extract was dissolved in 50 cm3isopropyl ether, centrifuged, washed with 2 times 10 cm3isopropyl ether. Get 16,57 g 2-(2,7-dichloro-6-fluoro-3-hinolincarbonova)-3 - dimethylaminoethylacrylate in a solid orange color, melting at 122aboutC. This product is used without further purification in the subsequent stages.

3-(2,7-Dichloro-6-fluoro-3-chinolin)-3-oxo - ethylpropane is prepared in the following way:

a suspension consisting of 38,75 g of 2,7-dichloro-6-fluoro-quinoline-3-carboxylic acid 410 cm3trichlormethane and 24 cm3chloride tonila, is heated at a temperature close to 60aboutC for 6 h under stirring. Recip is 2 times 200 cm3(total) toluene and again concentrated under reduced pressure under the same conditions as before. The obtained solid yellow, melting at 124aboutC, dissolved in 230 cm3anhydrous tetrahydrofuran. The resulting solution was injected drop by drop under stirring between 5 and 10aboutWith over 30 min 200 cm3solution magnesium chelate in tetrahydrofuran. Allow the temperature to rise to 20aboutC and stirred at this temperature for 15 hours the resulting solution is introduced drop by drop with vigorous stirring and the temperature close to 5aboutWith in 1 l of 0.5 N. sulfuric acid. Allow the temperature of the resulting suspension to rise to 20aboutC and stirred for further 2 h at this temperature.

The extraction is carried out through 1 l of ethyl acetate, filtered water and the organic phase through detonirovanie silica for filtration, which allows easy to remove insoluble portion, the aqueous phase is extracted with twice 500 cm3ethyl acetate. The combined organic extracts are washed with 2 times 500 cm3water, dried on magnesium sulfate, filtered and concentrated to dryness under reduced pressure (20 kPa) and at 40aboutC. the Residue is extracted by 100 cm3isopropyl-(2,7-dichloro-6-fluoro-3-chinolin)-3-accouterment in a solid beige color melting at 112-114aboutC. This product is used without further purification in the subsequent stages.

Preparation of the magnesium chelate of monoethylamine:

to 6,9 g of magnesium filings consistently add 5 cm3absolute ethanol, 0.2 cm3carbon tetrachloride and 2 g of monoethylamine. After heating add 15 min a solution of 23.8 g of monoethylamine 450 cm3of ethanol. The mixture is heated for 20 hours at a temperature close to 78aboutWith concentrate under reduced pressure (20 kPa) and at the 50aboutC. the Residue is extracted 2 times with 100 cm3toluene and concentrated under reduced pressure in the same conditions as before. The obtained gray powder was transferred into solution by the addition of anhydrous tetrahydrofuran to obtain a total volume of 200 cm3.

Monoethylamine was prepared in accordance with the method described by D. S. Breslow, Baumgarten, C. R. Hauser, I. Am.Chem.Soc. 66, 1287 (1944) and was converted under reduced pressure (boiling point 132aboutFrom (2.7 kPa).

2,7-Dichloro-6-ftorhinolon-3-carbon-Wai acid is prepared in the following way:

with stirring to a cooled to 10aboutWith a suspension consisting of of 69.5 g of 2,7-dichloro-6-fluoro-3-formyl-1,4-dihydroquinoline, 28 aboutWith a solution comprising 89.3 g of potassium permanganate in 1.4 l of water. Allow the temperature to rise to about 20aboutC and stirred for further 30 min at this temperature. Added 27 g of dithionite sodium, stirred for 10 min at a temperature close to 20aboutC, filtered through detonirovanie silica for filtration, washed 2 times with 250 cm3water. The filtrate and the aqueous phase after washing are combined and added 90 cm335% aqueous solution chloroethanol acid. The precipitate is extracted with 4 times 500 cm3ethyldiamine. The organic extracts are combined, washed 3 times with 500 cm3water, dried on magnesium sulfate, filtered and concentrated under reduced pressure (20 kPa) and at the 50aboutC. the Residue is extracted by 350 cm3ethyl ether, centrifuged, washed 2 times with 200 cm3ethyl ether. Get 45 g of 2,7-dichloro-6-fluoro-quinoline-3-carboxylic acid in the form of a solid beige color, melting at 230aboutC, which is used without further purification in the subsequent stages. With vigorous stirring was added a mixture of 250 cm3water and 250 g of crushed ice. The obtained solid is centrifuged at about -5aboutC and washed 4 times 125 cm3in water at 90aboutWith so much to maintain a pH of about 6. Stirred for further 15 min at 90aboutTo give the temperature drops to approximately the 50aboutC, centrifuged at this temperature and washed 3 times with 250 cm3water about 20aboutC. Get to 54.3 g of 2,7-dichloro-6-fluoro-3-formyl-1,4-dihydroindeno in a solid yellow color, melting at 260aboutC, which is used in this form in subsequent stages.

7-Chloro-6-fluoro-3,4-dihydroxybutyl is prepared in the following way:

to of 174.4 g of 3'-chloro-4'-fluoro-3-N-chloropropionaldehyde added with vigorous stirring for 5 min, 350 g of aluminium chloride. The solid mixture is heated for 30 minutes to approximately 60aboutC. Temperature independently rises to approximately 80aboutC and the reaction mixture becomes liquid. Then heated to 110aboutWith over 15 min and incubated for between 110 and 120aboutC for 3 hours, the Reaction mixture (at about 110about(C) pour out for 10 min with vigorous stirring in a mixture of 550 cm335% chloroethanol acid and 500 g of crushed ice. Allow the temperature to rise to 20aboutC, centrifuged, washed 6 times with 500 cm3water.

The wet product is recrystallized from 1.2 l of ethanol. Obtain 108 g of 7-chloro-6-fluoro-3,4-d-fluoro-3-N-chloropropionyl - lead was prepared in the following way:

at a temperature close to 55aboutC, to a solution consisting of 291 g of 3-chloro-4-foronline 500 cm3acetone is added with stirring for 35 min, a solution of 127 g of the chloride of 3-chloro-propionic acid in 200 cm3acetone and kept at this temperature for 2 hours After cooling to about 20aboutWith the insoluble portion removed by filtration and washed 2 times with 200 cm3of acetone. The filtrate and wash mixture unite, poured with stirring into a mixture of 2 l of water and 1 kg of ice. Allow the temperature to rise to about 20aboutWith, extracted 2 times 500 cm3dichloromethane. The combined organic extracts are washed with 3 times 500 cm3, dried on magnesium sulfate, stirred for 15 min with 6 g of charcoal, filtered through detonirovanie silica to filter and concentrate under reduced pressure (2.7 kPa) and at the 50aboutC. the Obtained solid is recrystallized from a mixture of 133 cm3cyclohexane and 67 cm3isopropyl ether. Get 176 g of 3'-chloro-4'-fluoro-3-N-chloropropionaldehyde in a solid beige color, melting at 94aboutC, which is used in this form in subsequent stages.

P R I m m e R 2. 1-Cyclopropyl-7-fluoro-4-oxo-8-(3-phenyl-1-p the EPA 11, but from 2 g of 8-chloro-1-cyclopropyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo[b] naphthiridine - 3-carboxylic acid, 4.9 g of 2-phenylpiperazine (RS) and 1.7 cm3of triethylamine. After recrystallization from a mixture of 40 cm3of dimethylformamide and 50 cm3ethanol gain of 1.16 g of 1-cyclopropyl-7-fluoro-4-oxo-8-(3-phenyl-1-piperazinil)-1,4 - dihydro-1,8 - benzo[b] naphthiridine-3-carboxylic acid (RS) in a solid yellow color, melting at 254aboutC.

8-Chloro-1-cyclopropyl-7-fluoro-4-oxo-1,4 - dihydro-1,8-benzonitrile-3 - carboxylic acid is prepared under the conditions of example 1, but according to 6.1 g of 8-chloro-1-cyclopropyl-3-etoxycarbonyl-7-fluoro-4-oxo-1,4-dihydro - 1,8 - benzo[b] naphthiridine. Get 4,85 g of 8-chloro-1-cyclopropyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo[b] naphthiridine-3-carboxylic acid in a solid yellow color, melting at 330aboutC, which is used without further purification in the subsequent stages.

8-Chloro-1-cyclopropyl-3-taxicab - Nile-7-fluoro-4-oxo-1,4-dihydro-1,8 - benzo[b]naphthiridine is prepared under the following conditions:

a solution consisting of 20.6 g of 2-(2,7-dichloro-6-fluoro-3-hinolincarbonova)-3-dimethyl - aminoacetanilide and 6 g of cyclopropylamine 100 cm3trichlormethane, stirred at the temperature, b isC. the Residue is extracted through 180 cm3ethanol and 10 g of DBU, and the resulting solution is heated at a temperature close to 78aboutWith over 4 hours After cooling at a temperature close to 20aboutWith the obtained precipitate is centrifuged and washed 2 times 60 cm3of ethanol. Get 13,65 g of 8-chloro-1-cyclopropyl-3-etoxycarbonyl-7-fluoro-4-oxo-1,4-dihydro-1,8 - benzo[b]-naphthiridine in the form of a solid pale yellow color, melting at 256aboutC, which is used without further purification in the subsequent stages.

P R I m e R 3. 7-Fluoro-1-(2-foradil)-4-oxo-8-(3-phenyl-1-piperazinil)-4-oxo-1,4 - dihydro-1,8-benzo[b] naphthiridine-3-Carbo-new acid (RS) is prepared under the following conditions:

a suspension consisting of 0,095 g of 7,8-debtor-1-(2-fluoro-ethyl-oxo-1,4-dihydro-1,8 - benzo[b] naphthiridine-3-carboxylic acid and 1.05 g of 2-phenylpiperazine (RS) 10 cm3dimethyl sulfoxide is heated at a temperature close to 100aboutWith stirring for 20 minutes After cooling, approximately at 20aboutWith insoluble part centrifuged and washed 3 times 10 cm3ethanol at about 70aboutC. Obtain 1.3 g of the expected product in the form of a solid yellow color decomposing at 305aboutC.

7,8- suspension, consisting of 2.3 g of 3-etoxycarbonyl-7,8-debtor-1-(2-foradil)-4-oxo - 1,4-dihydro-1,8-benzo [b]naphthiridine 20 cm3acetic acid and 20 cm35 N. chloroethanol acid, heated under stirring and at a temperature close to 100aboutWith, within 1 hour, the Insoluble part centrifuged at about 70aboutC and washed 3 times 10 cm3water and 3 times with 10 cm3of ethanol. Obtain 1.47 g of the expected product in the form of a solid beige color, melting at 291aboutC.

3-Etoxycarbonyl-7,8-debtor-1-(2-fluoro - ethyl)-4-oxo-1,4-dihydro-1,8-benzo [b]-naphthiridine prepared in the following way:

with stirring to a mixture of 1.46 g of the hydrochloride of 2-foretelling and of 2.06 cm3of triethylamine in 30 cm3trichlormethane added at about 10aboutWith 2.58 g of 2-(2-chloro-6,7-debtor-3-henrichemont)-3 - dimethylaminoethylacrylate. After 16 hours stirring at about 20aboutThe mixture is concentrated under reduced pressure (20 kPa) at a temperature close to the 50aboutC. the Residue is transferred into the solution through a 30 cm3ethanol with the addition of 2.3 cm3of triethylamine. The mixture is heated with stirring to about 75aboutC. the Insoluble part centrifuged and washed 3 times 5 cm3of ethanol. P which was used without further purification in the subsequent stages.

2-(2-Chloro-6,7-debtor-3-hinolinova-Neil)-3-dimethylaminoethylacrylate can be obtained as described below in example 39.

P R I m e R 4. A suspension consisting of 1.6 g of 8-chloro-7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo[b] naphthiridine-3 - carboxylic acid and 3.7 g of 2-(4-forfinal)-piperazine (RS) 16 cm3pyridine is heated at a temperature close to 115aboutWith, within 24 hours, the Reaction mixture was concentrated under reduced pressure (20 kPa) and at a temperature of about 60aboutC. the Residue is extracted by 40 cm3ethanol and again concentrated under reduced pressure in the above-mentioned conditions. The obtained solid is extracted using a 10 cm3water, mixed with a 1.75 cm310% acetic acid, centrifuged, washed with 2 times 10 cm3water and 2 times with 10 cm3of ethanol. After two precrystallization every time from 10 cm3of dimethylformamide obtain 1.1 g of 7-fluoro-[(4-forfinal)-3-piperazinil-1]-8 - methyl-1,4-oxo-1,4-dihydro - 1,8-benzo[b] naphthiridine-3-carboxylic acid (RS) in a solid yellow color, melting at 270-275aboutC.

2-(4-Forfinal)-piperazine (RS) was prepared according to the method described for 2-phenylpiperazine (RS) in the work of R. Roderick et coll.I.Med.Chem.9, 181 (1966).

Based on 60 g of 1-bromo-1-(4-forfinal)-acetic acid ethyl ester and 30 g of Ethylenediamine get 30 g of 2-(4-forfinal)-3-oxo-piperazine (RS) as a colourless solid, melting at 115aboutC.

1-Bromo-1-(4-forfinal)-acetic acid ethyl ester was prepared according to I. W. Epstein et.coll. I. Med.Chem. 24, 181 (1981), on the basis of (4-forfinal)-acetic acid ethyl ester.

(4-Forfinal)-acetic acid ethyl ester was prepared according to the method described by I. W. Corse et coll. I. Am.Chem.Soc. 70, 2837 (1948).

P R I m e R 5. A solution consisting of 2.1 g of 7-fluoro-8-[3-(4-forfinal)-1-piperazinil)-1-methyl-4-oxo-1,4-dihydro - 1,8-benzo[b] naphthiridine-3-carboxylic acid (RS) 1.8 cm398% formic acid and 4.4 cm330% aqueous formaldehyde solution is heated at a temperature close to 100aboutWith over 2 hours, the Reaction mixture was concentrated under reduced pressure (20 kPa) and at approximately the 50aboutWith, mixed with 10 cm3water and 1.2 cm32 N. of an aqueous solution of alkaline potassium, and heated at about 100aboutC for 2 min After cooling at a temperature close to 20aboutWith insoluble part centrifuged and washed with 2 times 20 cm3water. After two precrystallization every once in 15 cm3of dimethylformamide get the (RS) in a solid yellow color, decomposing at 213-314aboutC.

P R I m e R 6. Conduct the reaction under the conditions of example 16, but on the basis of 1.3 g of 7,8-debtor-1-methyl-4-oxo-1,4-dihydro-1,8-benzo[b] naphthiridine-3-carboxylic acid and 1.8 g of 2-[3-forfinal]-piperazine (RS). After one recrystallization 50 cm3a 50% aqueous solution of dimethylformamide in ethanol gain of 1.74 g of 7-fluoro-8-[3-(3-forfinal)-1-piperazinil)-1-methyl-4-oxo-1,4 - dihydro - 1,8-benzo[b]naphthiridine-3-carboxylic acid (RS) in a solid yellow color, melting at 254aboutC.

P R I m e R 7. Conduct the reaction under the conditions of example 4, but on the basis of 1.5 g of 8-chloro-1-ethyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo [b]naftopidil-3 - carboxylic acid and 3.4 g of 2-(4-forfinal)-piperazine (RS) 15 cm3pyridine. Get to 0.92 g of 1-ethyl-7-fluoro-4-oxo-8-[3-(4-forfinal-1-piperazin - nil)-1,4-dihydro - 1,8-benzo[b]naphthiridine-3-carboxylic acid (RS) in a solid yellow color, melting at 298aboutC.

8-Chloro-1-ethyl-7-fluoro-4-oxo-1,4-dihyd - ro-1,8-benzo[b] naphthiridine-3 - carboxylic acid is prepared under the conditions of example 1, but from a 10.5 g of 8-chloro-7-fluoro-3-etoxycarbonyl-1-ethyl-4-oxo-1,4-dihydro - 1,8-benzo[b]naphthiridine. Obtain 9.3 g of 8-chloro-1-ethyl-7-fluoro-4-oxo-1,4-dihydro-, 8-benzo[b] naphthiridine-3 - carboxylic acid in wiecki in subsequent stages.

8-Chloro-7-fluoro-3-etoxycarbonyl-1-ethyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthiridine prepared in the following way:

under stirring, the suspension consisting of 13.5 g of 2-(2,7-dichloro-6-fluoro-3-hinolincarbonova)-3-dimethylaminoethylacrylate 135 cm3ethanol was added for 5 min between 10 and 15aboutWith 16 g of ethylamine, allow the temperature to rise to about 20aboutWith add 0.5 g of DBU and heated with stirring for 2 h at a temperature close to the 75aboutC. After cooling to a temperature close to 20aboutC, the precipitate centrifuged, washed with 2 times 100 cm3ethanol and 2 times 100 cm3ethyl ether.

Obtain 10.4 g of 8-chloro-7-fluoro-3-etoxycarbonyl-1-ethyl-4-oxo-1,4-dihydro-1,8-benzo [b]naphthiridine in a solid yellow color, melting at 300-301aboutC, which is used without further purification in the subsequent stages.

P R I m e R 8. Conduct the reaction under the conditions of example 16, but on the basis of 1.5 g of 1-ethyl-7,8-debtor-4-oxo-1,4-dihydro-1,8-benzo[b] naphthiridine-3-carboxylic acid and 1.98 g of 2-[3-forfinal]-piperazine (RS) will receive 2 g of 1-ethyl-7-fluoro-8-[3-(3-forfinal)-1-piperazinil] -4-oxo-1,4-dihydro - 1,8-benzo(b)the naphthiridine-3-carboxylic acid (RS) in the form of a yellow substance, melting at 284aboutaboutC.

3-Etoxycarbonyl-1-ethyl-7,8-debtor-4-oxo-1,4-dihydro-1,8-benzo [b]naphthiridine to 1.8 can be obtained as described below in example 32.

2-(3-Forfinal)-piperazine (RS) was prepared according to the method described in the application for a French patent 2 351 108. On the basis of 24 g of 3-florfenicol obtain 6.3 g of the expected product in the form of liquid oil yellow.

3 Florfenicol was prepared according to the method described in the work of Nathan Kornblum et.coll. I. Am.Chem.Soc. 79, 6562, (1957). On the basis of 40 g of 3-fluoro-2-bromoacetophenone obtain 24 g of the expected product in the form of liquid oil yellow.

3'-fluoro-2-bromoacetophenone was prepared according to the method described in the work of D. V. C. Awang et. coll. Canad.I.Chem. 47, 706 (1969). According to 25.8 g of 3-fortetienne obtain 40 g of the expected product in the form of liquid oil greenish color.

P R I m e R 9. Conducting the reaction under the conditions of example 16, but on the basis of 1.5 g of 1-ethyl-7,8-debtor-4-oxo-1,4-dihydro-1,8-benzo[b] naphthiridine-3 - carboxylic acid and 1.5 g of 2-[2-forfinal]-piperazine (slots (RS) in a solid yellow color, melting at 306aboutC.

2(2-Forfinal)-piperazine (RS) was prepared according to the same method that was used in example 8.

According to 26.8 g of 2-florfenicol get 6 g of 2-[2-forfinal]-piperazine (RS), melting at 70aboutC.

On the basis of the 40.3 g of 2'-fluoro-2-bromoacetophenone get 26,8 g 2 florfenicol used without further purification in the subsequent stages.

On the basis of 20 g of 2'-fortetienne gain of 32.6 g of 2'-fluoro-2-bromoacetophenone in the form of a yellow oil greenish colors used without further purification in the subsequent stages.

P R I m e R 10. 1-Cyclopropyl-7-fluoro-8-[3-(4-forfinal)-1-piperazinil)] -4-oxo-1,4-dihydro-1,8-benzo-[b]naphthiridine-3-CT-oil acid (RS) is prepared under the conditions shown below in example 11, but from 2 g of 8-chloro-1-cyclopropyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo[b] the naphthiridine-3-carboxylic acid and 6,534 g of 2-[4-fluoro - phenyl]-piperazine (RS) and 9 cm3of triethylamine. The reaction mixture was concentrated under reduced pressure (20 kPa) and at temperatures close to 60aboutC. the Dry extract is extracted by 20 cm3water and 0.5 cm3of acetic acid. The insoluble part centrifuged and washed 2 times with 5 is to obtain 1.07 g of 1-cyclopropyl-7-fluoro-8-[3-(4-forfinal)- 1-piperazinil] -4-oxo-1,4-dihydro-1,8-benzo[b] naphthiridine-3-carboxylic acid (RS) in a solid yellow color, melting at 306aboutC.

P R I m e R 11. A suspension consisting of 1.84 g of 8-chloro-7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo[b] naphthiridine - 3-carboxylic acid in 20 cm3pyridine, of 5.83 g of 2-(4-were)-piperazine (RS) and 1.24 g of triethylamine is heated at a temperature close to 115aboutWith over 37 hours After cooling to about 20aboutWith insoluble part centrifuged, washed with 2 times 5 cm3ethanol and 2 times 5 cm3atalogo ether. After recrystallization from 25 cm3of dimethylformamide obtain 0.8 g of 7-fluoro-1-methyl-8-[3-(4-were)-1-piperazinil] -4-oxo-1,4-dihydro - 1,8-benzo[b] naphthiridine-3-carboxylic acid (RS) in a solid yellow color decomposing at 282aboutC.

2-(4-Were)-piperazine was prepared according to the method described in the patent application FP 2 351 108; on the basis of the 38.6 g of 4-methylphenylsiloxane (produced from 4-methylacetophenone), get 11,55 g of 4-methyl-2-phenylpiperazine (RS) in a solid yellow color, melting at 96-97aboutC.

P R I m e R 12. A suspension consisting of 1.45 g of 7,8-debtor-1-methyl-4-oxo-1,4-dihydro-1,8-benzo(b)naphthiridine - 3-carboxylic acid and 1.92 g of 2-(4-methoxyphenyl)-piperazine (RS) 14 cm3dimethyl sulfoxide, heating isIn the reaction mixture was added 20 cm3water. The insoluble part centrifuged and washed with 2 times 5 cm3water. After one recrystallization 150 cm3of dimethylformamide obtain 1.35 g of 7-fluoro-8-[3-(4-methoxyphenyl)-1-piperazinil] -1 - methyl-4-oxo-1,4-dihydro-1,8-benzo(b) naphthiridine-3-carboxylic acid (RS) in a solid yellow color decomposing at 312aboutC.

7,8-Debtor-1-methyl-4-oxo-1,4-dihyd-ro-1,8-benzo(b)naphthiridine-3 - carboxylic acid is prepared in the following way:

a suspension consisting of 8 g of 3-etoxycarbonyl-7-8-debtor-1-methyl - 4-oxo-1,4-dihydro-1,8-benzo(b) naphthiridine 80 cm3of 17.5% aqueous solution chloroethanol acid and 80 cm3acetic acid, heated under stirring and at a temperature close to 100aboutWith, within 1.5 hours After cooling to about 20aboutWith the solid is centrifuged and washed 6 times with 100 cm3water. After one recrystallization 160 cm3of dimethylformamide get 6,44 g of 7,8-debtor-1-methyl-4-oxo-dihydro-1,8-benzo(b) naphthiridine - 3-carboxylic acid in a solid yellow color decomposing at 360aboutC.

3-Etoxycarbonyl-7,8-debtor-1-methyl - 4-oxo-1,4-dihydro-1,8-benzo-(b) naftiran according to the method described in the patent application FP 2 351 108, according to 23.4 g of 2-(4-methoxyphenyl)-glyoxal and 10,26 g of Ethylenediamine, get 6,21 g of 2-(4-methoxyphenyl)-piperazine (RS) in the form of an oily product, which is used as it is.

4 Methoxyphenylacetyl can be prepared according to the method described in the work of Nathan Kornblum et coll. I. Am.Chem.Soc. 79, 6562 (1957). According to 45.4 g of 2-bromo-4-methoxyacetophenone 200 cm3dimethyl sulfoxide get to 23.4 g of 4-methoxyphenylacetyl in the form of a yellow oil of orange color, which is used without further purification in the subsequent stages.

2-Bromo-4'-methoxyacetophenone was prepared according to N. G. P. H. Bun. Hoi et coll. I. Chem.Soc. 255 (1951).

P R I m e p 13. A suspension consisting of 2 g of 7,8-debtor-1-methoxy-4-oxo-1,4-dihydro-1,8-benzo(b)naphthiridine-3 - carboxylic acid and 2.1 g of 2-phenylpiperazine (RS) 30 cm3dimethyl sulfoxide is heated with stirring for 15 minutes at about 50aboutC. After cooling to about 20aboutTo the reaction mixture was poured to 100 cm3water where add 1.2 cm3of acetic acid. The insoluble part centrifuged, washed with 3 times 10 cm3water and recrystallized from 80 cm3dimethyl - formamide. Receive 2 g Verdugo substances yellow decomposing at 284aboutC.

7,8-Debtor-1-methoxy-4-oxo-1,4-dihyd - ro-1,8-benzo[b] naphthiridine - 3-carboxylic acid is prepared under the following conditions:

a suspension consisting of 2,78 g 3-etoxycarbonyl-7,8-debtor-1-methoxy-4-oxo-1,4 - dihydro-1,8 - benzo[b] naphthiridine 30 cm317,5% chloroethanol acid and 30 cm3acetic acid is heated at a temperature close to 100aboutWith, within 1 h After cooling at about the 20aboutTo the reaction mixture was poured to 100 cm3water. Formed precipitate is centrifuged, washed with 3 times 30 cm3water and 2 times 5 cm3of ethanol. After one recrystallization from 100 cm3of dimethylformamide with 20% ethanol 2,03 g of 7,8-debtor-1-methoxy-4-oxo-1,4-dihydro-1,8-benzo[b]naphthiridine-3 - carboxylic acid in a solid yellow color, melting at 325-327aboutC.

3-Etoxycarbonyl-7,8-debtor-1-labels - si-4-oxo-1,4-dihydro-1,8 - benzo[b] naphthiridine receive the following conditions:

to a suspension consisting of 1.7 g of the hydrochloride methoxyamine 40 cm3trichlormethane add to 2.13 g of triethylamine. After 15 minutes stirring at a temperature close to 20aboutWith, to the resulting solution was added of 3.69 g of 2-(2-chloro-6,7-debtor-3-chinoline concentrated to dryness under reduced pressure (20 kPa) and at temperatures close to 50aboutC. the Residue is extracted by 70 cm3ethanol and 3.6 g of triethylamine and heated for 30 minutes at a temperature close to 75aboutC. After cooling to about 20aboutWith the obtained precipitate is centrifuged and washed with 3 times 30 cm3of ethanol. Obtain 2.67 g of 3-etoxycarbonyl-7,8-debtor-1-methoxy-4 - oxo-1,4-dihydro-1,8-benzo(b) naphthiridine in the form of a solid pale yellow color, melting at 266-268aboutC.

2-(2-Chloro-6,7-debtor-2-hinolinova-Neil)-3-dimethylaminoethylacrylate can be obtained as described below in example 20.

P R I m e R 14. 8-[3-(4-Cyanophenyl)-1-piperazinil]-7-fluoro-1-methyl-oxo-1,4-dihyd - ro - 1,8-benzo[b]naphthiridine-3-carboxylic acid (RS) is prepared under the conditions of example 11, but on the basis of 1.84 g of 8-chloro-7-fluoro-1-methyl-4 - oxo-1,4-dihydro-1,8-benzo[b] naphthiridine-3-carboxylic acid, 5,61 g of 2-(4-cyanophenyl)-piperazine (RS) and 1.7 cm3triethylamine get to 1.15 g of 8-[3-(4-cyanophenyl)-1-piperazinil] -7-fluoro-1-me-til-4-oxo-1,4 - dihydro-1,8-benzo[b]naphthiridine-3-carboxylic acid in a solid yellow color decomposing at 332aboutC.

2-(4-Cyanophenyl)-piperazine (RS) can be prepared according to the method described in the patent application FP 2 351 108, based on 45 g of 4-cyanoject in this form in subsequent stages. 4-Cyano-phenylglyoxal is prepared on the basis of 4-cyanoacetate.

P R I m e R 15. Carrying out the reaction as in example 16, but according to 1.16 g of 7,8-debtor-1-methyl-4-oxo-1,4-dihydro-1,8-benzo[b] - piridin-3 - carboxylic acid and is 1.82 g of 2-(4-methoxymethyl)-piperazine (RS) obtain 1.70 g of 7-fluoro-8-[3-(4-methoxymethyl)-1 - piperazinil] -1-methyl-4-oxo-1,4-dihydro-1,8-benzo[b]the naphthiridine - 3-carboxylic acid (RS) in a solid yellow color decomposing at 284aboutC.

2-(4-Methoxymethyl)-piperazine (RS) was prepared according to the method described in the patent application FP 2 351 108, based on a 33.5 g of 4-methoxymethylethoxy and 13,48 g of Ethylenediamine. The crude product was purified by chromatography on 750 g of silica (230-400 mesh mesh) in a suspension containing a mixture of 70% dichloromethane, 26% ethanol, 4% of triethylamine, with elution by 1.8 liters of the same mixture. After concentration of the eluate under reduced pressure (20 kPa) and about 50aboutTo get 12,15 g of the expected product in the form of a solid orange color, melting at 79aboutC.

4 Methoxypolyethyleneglycol was prepared according to the method described in the patent application FP 2 351 108, based on 30,8 g of 4-methoxybutyrophenone and 24 g is without further purification in the subsequent stages.

4-Methoxyethylamine was prepared according to the method described in H. B. Rass et coll. I. Am.Chem.Soc. 71, 1767, (1949), based on 4-methoxyethylamine, derived from 4-cyanobenzaldehyde.

P R I m e R 16. A suspension consisting of 1,015 g of 7,8-debtor-1-methyl-4-oxo-1,4-dihydro-1,8-benzo[b] naphthiridine-3 - carboxylic acid and 1.7 g of 2-[4-(2-hydroxy - ethoxy)-phenyl] -piperazine (RS) 15 cm3dimethyl sulfoxide is heated with stirring for 2.5 h at a temperature close to 100aboutC. After cooling to about 20aboutWith the suspension is mixed with 30 cm3water, centrifuged, washed with 3 times 10 cm3water. After recrystallization in 15 cm3of dimethylformamide obtain 1.2 g of 7-fluoro-8-[3-/4-(2-hydroxyethoxy)-phenyl] -1-piperazinil/-1-methyl-4 - oxo-1,4-dihydro-1,8-benzo[b] naphthiridine-3-carboxylic acid (RS) in a solid yellow color, melting at 276aboutC.

2-[4-(2-Hydroxyethoxy)-phenyl] -Pipera - Zin (RS) can be prepared according to the method described in the patent application FP 2 351 108, based on an 18.5 g of 2-[4-(2-hydroxyethoxy)-phenyl]-glyoxal & 6.86 g of Ethylenediamine. Get 4 g of 2-[4-(2-hydroxyethoxy)- phenyl]-piperazine (RS) in a solid beige color, melting at 141aboutWhen the Nathan Kornblum et coll. I. Am.Chem.Soc. 79, 6562 (1957). On the basis of 30.5 g of 4-(2-hydroxyethoxy)-2-bromoacetophenone gain of 18.5 g of 2-[2-hydroxyethoxy)-phenyl]-glyoxal in the form of a yellow oil yellow color, which is used without further purification in the subsequent stages.

4'-2'-Hydroxyethoxy-(2-bromoacetophenone) can be prepared according to the method described by N. G. P. H. Buu Hoi et coll. I. Chem.Soc. 255 (1951). On the basis of 27 g of 4-(2-hydroxyethoxy)-acetophenone get 28,85 g of 4'-(2'-hydroxyethoxy)-2-bromoacetophenone in a solid beige color, melting at 78aboutC.

4-(2-Hydroxyethoxy)-acetophenone was prepared according to C. Rufer et coll. I. Med.Chem. 18 (3), 263 (1975).

P R I m e R 17. Conduct the reaction under the conditions of example 16, but on the basis of 1.45 g of 7,8-debtor-1-methyl-4-oxo-1,4-dihydro-1,8-benzo[b] naphthiridine-3 - carboxylic acid and of 2.09 g of 2-(3,4-dimetilfenil) piperazine (RS) obtain 2.15 g of 7-fluoro-1-methyl - 8-[3-(3,4-dimetilfenil)-1-piperazinil]-4-oxo - 1,4 - dihydro-1,8-benzo[b] the naphthiridine-3-carboxylic acid (RS) in a solid yellow color, melting at 276aboutC.

2-(3,4-Dimetilfenil) piperazine (RS) was prepared according to the method described in the patent application FP 2 351 108. Based on 42,4 g of 3,4-dimethylphenylamine obtain 7.9 g of 2-(3,4-dimetilfenil)-perpixel can be obtained according to the method described in the work of Nathan Korn blum et coll. I. Am.Chem.Soc. 79, 6562 (1957). Based on 60 g of 3',4'-dimethyl-2-bromoacetophenone get to 40.4 g of 3,4-dimethylphenylamine in the form of liquid oil.

3', 4'-Dimethyl-2-bromoacetophenone was prepared according to the method described in R. M. Laird et R. E. Parker I. Am.Chem.Soc. 83, 4277 (1961).

P R I m e R 18. Conducting the reaction under the conditions of example 16, but according to 1.16 g of 7,8-debtor-1-methyl-4-oxo-1,4-dihydro-1,8-benzo[b] naphthiridine-3 - carboxylic acid and is 1.82 g of 2-(4-amino-3-methoxyphenyl)-1 - piperazinil)-1-methyl-4-oxo-1,4-dihydro-1,8-benzo[b] naphthiridine - 3-carboxylic acid (RS) in a solid yellow color, decomposing at 259aboutC.

2-(4-Amino-3-methoxyphenyl)-piperazine (RS) was prepared in the following way:

in a solution containing 18 g of 2-(3-methoxy-4-nitrophenyl)-piperazine (RS) 150 cm3ethanol and heated with stirring to about 75aboutWith add for 10 min a solution containing 53 g of sodium hydrosulphate 200 cm3water. The mixture was kept under stirring for 1 h at the same temperature. The reaction mixture was concentrated under reduced pressure (20 kPa) and about 60aboutC. the Residue is extracted by 150 cm33,75 N. aqueous solution of alkali of sodium and 50 g of potassium carbonate. The mixture of the magnesium, filter and concentrate under reduced pressure (20 kPa) and about 40aboutC. 13 g of the expected product in the form of liquid oil brown color, which is used without further purification in the subsequent stages.

2-[3-Methoxy-4-nitrophenyl] piperazine (RS) was prepared according to the method described in the patent application FP 2 351 108, but based on 36 g of 3-methoxy-4-nitrophenylglyoxylate and 12.1 g of Ethylenediamine. The crude product is purified by chromatography on 800 g of silica (230-400 mesh mesh) in a suspension containing a mixture of 70% dichloromethane, 26% ethanol, 4% of triethylamine, and the elution 2 liters of the same mixture. After concentration of the eluate under reduced pressure (20 kPa) and at approximately the 50aboutTo obtain 18 g of the expected product in the form of a yellow oil red, which was used without further purification in the subsequent stages.

3-Methoxy-4-nitrophenylglyoxylate was prepared according to the method described in the patent application FP 2 351 108, but based on a 33.6 g of 3-methoxy-4-nitroacetophenone and 22 g of selenium dioxide. Get 35 g of the expected product in the form of liquid brown oil that was used without further purification in the subsequent stages.

3-Methoxy-4-nitroacetophenone was. Astor containing 1.07 g of 3-etoxycarbonyl-7-fluoro-1-methyl-4-oxo-8-(3-phenyl-1-piperazinil)- 1,4-dihydro-1,8-benzo[b]naphthiridine (RS) 10 cm3acetic acid and 10 cm3of 17.5% aqueous solution chloroethanol acid, is heated at a temperature close to 100aboutWith over 40 minutes, the Reaction mixture is concentrated to dryness under reduced pressure (20 kPa) and about 60aboutC. the Dry residue is extracted using a 10 cm3ethanol, centrifuged, washed with 2 times 10 cm3ethanol and 2 times 10 cm3ethyl ether. The obtained solid was transferred into a slurry with 30 cm3water and heated to the temperature close to 95aboutC. After adding 2 N. aqueous solution and stirring for 30 min, the solid is centrifuged for approximately 95aboutC, washed with 3 times 20 cm3water at about 80aboutWith 3 times 15 cm3ethanol is approximately 60aboutWith 3 times 20 cm3ethyl ether. After one recrystallization in a mixture of 12 cm3of dimethylformamide and 6 cm3ethanol obtain 0.7 g of 7-fluoro-1-methyl-4 - oxo-8-(3-phenyl-1-piperazinil)-1,4-dihydro-1,8-benzo[b]-piridin-3 - carboxylic acid (RS) in a solid yellow color, melting at 265aboutC.

3 Toxica the following way.

a suspension consisting of 3 etoxycarbonyl-7,8-debtor-1-methyl-4-oxo-1,4-dihyd - ro-1,8-benzo[b] naphthiridine 0,265 g of sodium carbonate and 0.5 g of 2-phenylpiperazine (RS) 25 cm3dimethyl sulfoxide is heated at a temperature close to 95aboutWith over 2 hours After cooling to about 20aboutTo the reaction mixture was poured to 75 cm3water and extracted with 4 times 50 cm3dichloromethane. The combined organic extracts are washed with 3 times 40 cm3water, dried on magnesium sulfate, filtered and concentrated to dryness under reduced pressure (20 kPa) and about 50aboutC. Obtain 1.07 g of 3-etoxycarbonyl-7-fluoro-4-oxo-8-[3-phenyl - 1-piperazinil)-1,4-dihydro - 1,8-benzo[b]naphthiridine (RS) in a solid yellow color, melting at 220-222aboutC, which is used without further purification in the subsequent stages.

3-Etoxycarbonyl-7,8-debtor-1-methyl - 4-oxo-1,4-dihydro-1,8-benzo(b) naphthiridine is prepared as follows.

Under stirring, the suspension comprising of 22.3 g of 2-(2-chloro-6,7-debtor-3-hinolincarbonova)-3-dimethylaminomethylene - LVL 480 cm3ethanol, maintained at a temperature close to 0aboutC, add 10 min honey 0 and 5aboutWith a solution containing at primers to approximately 25aboutC and stirred for further 16 h at the same temperature. The insoluble part centrifuged, washed with 3 times 100 cm3ethyl ether. After one recrystallization 250 cm3of dimethylformamide obtain 16 g of 3-etoxycarbonyl-7,8-debtor-1-methyl-4-QA - with-1,4-dihydro-1,8-benzo(b) naphthiridine in a solid yellow color, melting at 323-324aboutC.

2-(2-Chloro-6,7-debtor-3-hinolinova-Neil)-3-dimethylaminoethylacrylate is prepared in the following way:

a suspension consisting of of 6.17 g of 3-oxo-3-(2-chloro-6,7-debtor-3-chinolin)-ethylpropyl - onate in to 7.15 g of N,N-dimethylformamidine and 60 cm3ethyl acetate is heated at a temperature close to the 75aboutWith over 1 h 15 min, the Reaction mixture is concentrated to dryness under reduced pressure (20 kPa) and about 50aboutC. the Residue is extracted by 50 cm3isopropyl ether, centrifuged, washed with 3 times 25 cm3the same solvent. Get of 6.65 g of 2-(2-chloro-6,7-debtor-3-hinolincarbonova)-3-di - methylenedianiline in a solid orange color, melting at 140aboutC.

3-Oxo-3-(2-chloro-6,7-debtor-3-chinolin) -ethylpropane is prepared in the following way:

a suspension consisting of 14,13 g 2-chloro temperature, close to 60aboutWith over 4 hours the resulting solution was concentrated to dryness under reduced pressure (20 kPa) and about 60aboutC. the resulting residue is extracted by 75 cm3n-hexane, centrifuged, washed 2 times 60 cm3the same solvent. 14.4 g of the obtained yellow substance was transferred to a solution of 115 cm3 of tetrahydrofuran.

This solution is injected drop by drop under stirring for 35 min between 5 and 10aboutWith 70 cm3solution of the magnesium chelate of monoethylamine in tetrahydrofuran, which was prepared under the conditions described below. The temperature is allowed to rise to about 20aboutC and stirred for further 2 h under the same conditions. The resulting solution was injected drop by drop under stirring for 30 minutes at a temperature close to 5aboutWith, at 560 cm30,5 N. sulfuric acid. The temperature of the resulting suspension spontaneously increased to 20aboutC and stirred for another 1.5 h at this temperature. The extraction is carried out 3 times with 250 cm3ethyl acetate. The combined organic extracts are washed 2 times with 250 cm2water, dried on magnesium sulfate, filtered and concentrated to dryness under reduced pressure (20 kPa) and at the 50aboutC. the resulting residue is extracted by 50 cm33isopropanol with 30% n-hexane. Get 11,84 g of 3-oxo-3-(2-chloro-6,7-debtor-3-chinolin)-ethylpropane in the form of a cream solid color, melting at 107aboutC.

Prepare magnesium chelate monoethylamine as follows.

To 2,78 g of magnesium filings consistently add 2 cm3absolute ethanol, 0.1 cm3carbon tetrachloride and 1 g of monoethylamine. After heating add 15 min a solution containing 9 g of monoethylamine 180 cm3of ethanol. The mixture is heated for 20 hours at a temperature close to 75aboutWith concentrate under reduced pressure (20 kPa) and at the 50aboutC. the Residue is extracted 2 times by 100 cm3toluene and concentrated under reduced pressure under the same conditions as before. The obtained gray powder was transferred into solution by the addition of anhydrous tetrahydrofuran to obtain a total volume of 70 cm3.

2-Chloro-6,7-divergingly-3-carbon-Wai acid was prepared as follows:

with stirring to a cooled to 10aboutWith a suspension consisting of 70,18 g of 2-chloro-6,7-debtor-3-formyl-1,4-dihydro-hee-nolina at 970 cm31 N. aqueous potassium alkali is added over 1 h, keeping the temperature between 10 and 14aboutWith, ramashiva another 30 min at this temperature. Add a 38.5 g dithionite sodium, stirred for 10 min at a temperature close to 20aboutC, filtered through detonirovanie silica, washed 3 times with 200 cm3water. The filtrate and wash water phases are combined and add 140 cm335% aqueous solution chloroethanol acid. Formed precipitate is extracted with 4 times 800 cm3ethyl acetate. The combined organic extracts are washed with 2 times 500 cm3water, dried on magnesium sulfate, filtered and concentrated under reduced pressure (20 kPa) and at the 50aboutC. the Residue is extracted by 400 cm3ethyl ether, centrifuged, washed 2 times with 200 cm3the same solvent. Receive and 49.2 g of 2-chloro-6,7-debtor - quinoline-3 - carboxylic acid in the form of a solid beige color, melting at 232aboutC, which is used without further purification in the subsequent stages.

2-Chloro-6,7-debtor-3-formyl-1,4-dihyd - rhinolin was prepared in the following way

to a mixture containing 800 cm3trichlormethane and 74,35 cm3of dimethylformamide is added over 30 minutes under stirring between 10 and 15aboutWith 76,9 cm3chloride fosforito and stirred for 1 h at a temperature close to 20aboutC. To the obtained solution of the scientists, the suspension is heated to a temperature close to 60aboutC and kept at this temperature for 2 hours, the Reaction mixture was concentrated under reduced pressure (20 kPa) and at the 50aboutTo obtain a pasty mixture. With vigorous stirring was added a mixture of 500 g of ice and 500 cm3water. The obtained solid is centrifuged at 5aboutC and washed 3 times with 300 cm3water in 5aboutC. the Obtained wet product and 60 g of sodium acetate added simultaneously over 1 hour to 1.5 liters of water at 90aboutWith so much to maintain a pH of about 6. Stirred for further 30 minutes at 90aboutTo give the temperature drops to about 50aboutC, centrifuged at this temperature and washed 3 times with 300 cm3water at about 20aboutC. Get 70,18 g of 2-chloro-6,7-debtor-3 - formyl-1,4-dihydroquinoline in a solid yellow color, melting at 260aboutC, which is used in this form in subsequent stages.

6,7-Debtor-3,4-dihydroxybutyl is obtained in the following way

to 67 g of 3',4'-debtor-3-N-chloropropionyl added with vigorous stirring 134 g of aluminum chloride, then after about 2 minutes add again in small portions over 15 min to 135.9 g of 3',4'-debtor-3-N-chloropropionaldehyde and 272 g of aluminium chloride. The temperature itself is SUP>aboutWith over 20 min and incubated for between 110 and 120aboutC for 2 h, the Reaction mixture (at about 110aboutC) poured in 10 min with vigorous stirring to a mixture of 840 cm335% chloroethanol acid and 1 kg of crushed ice. Allow the temperature to rise to about 20aboutC, centrifuged, washed 2 times 600 cm3, 300 cm3ethanol in 5aboutWith and 2 times 400 cm3ethyl ether at about the 20aboutC. Get 131,58 g of 6,7-debtor-1,4-dihydroorotase in a solid beige color, melting at 216aboutC, which is used in this form in subsequent stages.

3',4'-Debtor-3-N-chloropropionitrile is prepared as follows

to a solution containing 125 g of 3,4-diferencia 80 cm3pyridine and 1.5 l of acetone, heated to the temperature close to 55aboutC, add with stirring for 1.5 h 139,16 g of the chloride of 3-chloropropionic acid and kept at this temperature for 1.5 hours, After cooling to about 20aboutWith the solution prilisaetsa with stirring to a mixture of 1 l of water and 500 g of crushed ice. Allow the temperature to rise to about 20aboutAnd the extraction is carried out 3 times 500 cm3dichloromethane. The combined organic extracts promyvatelem under reduced pressure (20 kPa) and about 50aboutC. the Obtained solid is extracted by 500 cm3n-hexane, centrifuged, washed with 2 times 100 cm3the same solvent. Get 202,9 g 3'.4'-debtor-3-N-chloropropionaldehyde in a solid beige color, melting at 76aboutC, which is used without further purification in the subsequent stages.

2-Phenylpiperazin (RS) was prepared according to the method described in W. R. Roderick et coll. I. Med.Chem. 9, 181 (1966). perazine) (S) as a colourless solid, melting at 258aboutC.

//D20-9,9aboutof 0.9 (0.5; dimethylformamide).

According to 17.5 g of 2-phenylethylenediamine (S) get to 22.5 g of 2-phenyl-1,4-di(p-sulfonylurea)-Ethylenediamine (S) in a solid yellow color, melting at 164aboutC.

//D20+17,2 0,7 (0,7; dimethylformamide.

On the basis of 20 g-aminophenylacetamido (S) gain of 17.5 g of 2-phenylethylenediamine (S) in the form of liquid oil yellow, which is immediately applied to the next stage.

Based on 45,1 g of 2-phenylmethylene (S) receive a 21.5 g-aminophenylacetamido (S) as a colourless solid, melting at 137-138aboutC.

//D20+114about

P R I m e R 21. Conducting the reaction under the conditions of example 20, but according to 66.3 g of 3-etoxycarbonyl-7-fluoro-1-methyl-4-oxo-8-(3-phenyl-1-piperazinil)-1,4 - dihydro-1,8-benzo[b] naphthiridine (RS) is obtained without recrystallization 59,15 g of 7-fluoro-1-methyl - 4-oxo-8-(3-phenyl-1-piperazinil)-1,4-di - hydro-1,8-benzo [b] the naphthiridine-3-carboxylic acid (R) in a solid yellow color decomposing at 276-278aboutC.

//D20+39,8about0,6 (1; acetic acid).

Conduct the reaction under the conditions of example 20, but according to 51.6 g of 3-etoxycarbonyl-7,8-debtor-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthiridine and 31.7 g of 2-phenylpiperazine (R) receive 66,86 g 3-etoxycarbonyl-7-fluoro-1-methyl-4-oxo-8-(3-phenyl-1 - piperazinil)- 1,4-dihydro-1,8-benzo[b]naphthiridine (R) in the form of solid yellow, melting at 221aboutC.

//D20+43about1 (0.5; acetic acid).

2-Phenylpiperazin (R) can be obtained in the following way

a mixture consisting of 10 g of 2-phenyl-1,4-(p-sulfonylurea)-piperazine (R) and 9.4 g of phenol in 100 cm348% Hydrobromic acid is heated under strong stirring for 5 h at a temperature close to 120aboutC. After cooling to about 80aboutTo the reaction mixture which have concentrated under reduced pressure (20 kPa) and at approximately 80aboutC. the Residue is extracted by 100 cm3ethyl acetate, cooled to 5aboutWith and mixed between 5 and 20aboutWith 100 cm330% aqueous alkali solution of sodium. The organic phase is separated, and the aqueous phase is again subjected to extraction with 3 times 100 cm3ethyl acetate.

The combined organic extracts are washed 4 times 20 cm35 N. of an aqueous solution of alkali sodium, dried on magnesium sulfate, filtered and concentrated to dryness under reduced pressure (20 kPa) and about 30aboutC. the resulting residue is extracted through a 15 cm3isopropyl ether at about 0aboutC, centrifuged and washed at the same temperature 10 cm3the same solvent. Obtain 2.3 g of 2-phenylpiperazine (R) as a colourless solid, melting at 117aboutC.

/ /D2038about0,6 (2; ethanol).

2-Phenyl-4-di(p-sulfonylurea)-PI-perazin (R) was prepared as follows:

a mixture of 11 g of 2-phenyl-1,4-di(p-sulfonylurea)-Ethylenediamine (R) and 13,82 g of potassium carbonate and 110 cm3of dimethylformamide, heated under stirring and at 60aboutC for 30 min, then mixed with an 18.8 g of 1,2-dibromethane and heated at 115aboutWith during the traction 3 times with 200 cm3dichloromethane. The combined organic extracts washed 3 times 120 cm3water, dried on magnesium sulfate and concentrate under reduced pressure (20 kPa) and about 30aboutC. the Residue is extracted by 50 cm3ethyl ether, centrifuged, washed with 3 times 15 cm3the same solvent. Get 10,55 g of the expected product in the form of a colorless solid, melting at 258aboutC.

/ /D20+9,6about0,8 (0,5; dimethylformamide),

2-Phenyl-1,4-di(p-sulfonylurea-these - Indiamen (R) was prepared according to the method described in the work of Douglas G. Neilson et coll. I. Chem.Soc. 393 (1966), but on the basis of 7.5 g of 2-phenylethylenediamine (R) gain of 12.9 g of the expected product in the form of a solid yellow color, melting at 164aboutC.

//D20-18,2 0,7 (0,7; dimethylformamide).

2-Phenylethylenediamine (R) was prepared according to the method described by A. C. Brown et coll. I. Am.Chem.Soc. 86, 3566 (1964), but on the basis of 11 g-aminophenylacetamido (R) and 293 cm31M solution of borane in tetrahydrofuran. Obtain 7.5 g of the expected product in the form of a yellow liquid, which being unstable is used immediately in the next stage.

-Aminophenylacetamido (R) b is echinata (R) obtained after one recrystallization 135 cm3ethyl acetate 26% methanol 12,93 g of the expected product in the form of a colorless solid, melting at 137-138aboutC.

/ /D20-115about3 (0.5; ethanol).

2-Phenylmethylene (R) was prepared according to the method described in the work of Douglas G. Neilson et coll, I. Chem.Soc. 393 (1966), but on the basis of 43 g of 2-phenylglycine (R) and 22.8 cm3chloride tiomila 85 cm3methanol receive in the form of liquid oil yellow.

Nanomeasurement 7-fluoro-1-methyl-4-oxo-8-(3-phenyl-1-piperazinil)-1,4-di - hydro-1,8 - benzo[b]naphthiridine-3-carboxylic acid (R) was prepared in the following way

a suspension consisting of 3.5 g of 7-fluoro-1-methyl-4-oxo-8-(3-phenyl-1-piperazinil)-1,4-dihydro-1,8-benzo[b] naphthiridine-CT - oil acid (R) 70 cm3water, mixed with 100 cm30.1 G. of an aqueous solution of methanesulfonate and heated to approximately 90aboutC. After cooling to about 20aboutWith insoluble part centrifuged and washed with 3 times 25 cm3water. Gain of 3.9 g of the expected salt in a solid yellow color decomposing at 335-340aboutC.

//D20-19 2 (0.2; water with 50% ethanol).

7-Fluoro-1-methyl-4-oxo-8-(3-phenyl-1-PI - pyrazinyl)-1,4-dihydro-1,8 - benzo[b] Natterer-4-oxo-8-(3-phenyl-1-piperazinil)-1,4-dihydro-1,8-benzo [b]naphthiridine-3-carboxylic acid (R) 30 cm3methanol, add 2,72 cm345% aqueous solution of choline in methanol. To the resulting solution was added 200 cm3isopropyl ether. The precipitate centrifuged, washed 3 times with 60 cm3the same solvent, then 3 times 60 cm3of acetone. Gain of 3.97 g of the expected salt in a solid yellow color, melting at 234aboutC.

//D20 -33,9about0,9 (C1; methanol).

Memoization 7-fluoro-1-methyl-4-oxo-8-(3-phenyl-1-piperazinil)-1,4-dihydro-1,8 - benzo[b]naphthiridine-3-carboxylic acid was prepared as follows:

to a suspension consisting of 1 g of 7-fluoro-1-methyl-4-oxo-8-(3-phenyl-1 - piperazinil)-1,4-dihydro-1,8-benzo[b] naphthiridine-3-CT - oil acid (R) 40 cm3water with 50% ethanol, add 2.6 cm31 N. aqueous solution isetionate acid. After dissolution at 80aboutC and subsequent cooling to 10aboutWith insoluble part centrifuged, washed 2 times 15 cm3water with 50% ethanol, 2 times 15 cm3water and 3 times 15 cm3of ethanol. Receive 1 g of the expected salt in a solid yellow color decomposing at 334aboutC.

/ /D20+111about6 (0,1; dimethyl sulfoxide).

P R I m e R 22. 7-Fluoro-1-methyl-4-oxo-8-(3-phenyl-1 is BOM, that 7-fluoro-1-methyl-4-oxo-8-(3-phenyl-1-piperazinil)-1,4-dihydro-1,8-Ben - zo [b]naphthiridine-3-carboxylic acid (RS) in example 10, but on the basis of 4.4 g of 3-etoxycarbonyl-7-8-debtor-1-methyl-4-oxo-1,4-Digi draw-1,8-benzo[b] naphthiridine 2.7 g of 2-phenylpiperazine (+) (//D20+35,4about0,3 (2; ethanol) and 1.48 g of sodium carbonate obtain 6.3 g solid yellow, melting at 226aboutC.

After acid hydrolysis under the same conditions that were described for 3-etoxycarbonyl-7-fluoro-1-methyl-4-oxo-8-(3-Fe - Neil-1-piperazinil)-1,4 - dihydro-1,8-benzo[b] naphthiridine (RS), gain of 3.95 g of 7-fluoro-1-methyl-4-oxo-8-(3-phenyl-1-piperazin - nil)-1,4-dihydro-1,8[b] the naphthiridine-3-carboxylic acid (S) isomer (-), in a solid yellow color, melting at 276-278aboutC.

/ /D20-40,4about1 (1; acetic acid).

2-Phenylpiperazin (R) isomer (-), and 2-phenylpiperazin (S) isomer ( + ) were prepared by acid hydrolysis of two diastereoisomeric compounds (R and S) corresponding to the structure of 1-(2'-trifluoromethyl-2-methoxyphenylacetyl)-3-finalpaper - zine, called a and B. These last two compounds obtained by acylation of 2'-phenylpiperazine (RS) chloride chiral acid; chloride of 2-trifluoromethyl-2-methoxy who -25aboutWith the solution containing 12,77 g 2-phenylpiperazine (RS) 220 cm3trichlormethane, add drop by drop for 25 min with stirring, a solution containing 19,89 g of the chloride of 2-trifluoromethyl-2-methoxyphenyl - acetic acid (R) isomer (-), 80 cm3the same solvent, maintaining the temperature between -30 and -25aboutC. After 15 minutes of mixing under these conditions allow the temperature to rise to about 0aboutTo add between 0 and 5aboutWith 50 cm32 N. of an aqueous solution of alkali sodium, allow the temperature to rise to about 20aboutWith and add 150 cm3water. The organic phase is separated, and the aqueous phase is again extracted with 2 times 200 cm3trichlormethane. The combined organic extracts are washed once with 200 cm3a 0.5 n solution of alkali sodium, 4 times with 200 cm3water, dried on magnesium sulfate, filtered and concentrated to dryness under reduced pressure (20 kPa) and about 40aboutC. the Residue (29,8 g) containing 2 diastereoisomer and transferred to a solution of 500 cm3dichloromethane. This mixture is separated by HPLC on 2 columns with a diameter of 57 mm and a length of 300 mm, each of which contains 300 g of silicon dioxide (55-105 mesh), by introducing 5 samples of 100 cm in the faction, enclosed between 2.5 and 3.5 L. Diastereoisomer elute In 2 liters of the same mixture in a fraction that is between 4 and 6 liters After concentration under reduced pressure (20 kPa) and at approximately the 50aboutWith each of the two fractions are respectively 13,62 g of compound As a colourless solid, melting at 102aboutC, and 14 g of compound In the same species, melting at 130aboutC. 13,62 g connection And extracted by a mixture of 140 cm348% aqueous Hydrobromic acid and 26 cm3acetic acid and heated for 30 hours at a temperature close to 110aboutC. the Reaction mixture is concentrated to dryness under reduced pressure (20 kPa) and at approximately 80aboutC. the resulting residue is extracted by 200 cm3ethyl acetate. The resulting suspension is cooled to approximately 10aboutWith and mixed between 10 and 20aboutWith 160 cm330% aqueous alkali solution of sodium. The organic phase is separated and the aqueous phase again extracted with 3 times 100 cm3ethyl acetate. The combined organic extracts washed once with 80 cm34 N. of an aqueous solution of alkali sodium, 3 times 80 cm330% aqueous solution of sodium chloride and concentrated to dryness under reduced pressure. After WPI is Finance 3 times 100 cm3ethyl acetate the aqueous phase is mixed with 120 cm330% aqueous alkali solution of sodium and extracted 4 times with 150 cm3ethyl acetate. The combined organic extracts are washed with 3 times 80 cm330% aqueous solution of sodium chloride, dried on magnesium sulfate, filtered and concentrated under reduced pressure (20 kPa) and at temperatures close to the 50aboutC. the resulting residue is extracted by 30 cm3isopropyl ether, centrifuged and washed with 10 cm3the same solvent. Gain of 2.45 g of 2-phenylpiperazine, isomer (+) as a colourless solid, melting at 114aboutC.

//D20+35,4about0,5 (2; ethanol).

14 g of compound In treated under the same conditions as the compound a, the result is 3.08 g of 2-phenylpiperazine, isomer (-), as a colourless solid, melting at 114aboutC.

//D20-37,5about0,5 (2; ethanol).

P R I m e R 23. 7-Fluoro-1-methyl-4-oxo-8-(3-phenyl-1-piperazinil)-1,4-dihydro-1,8 - benzo(b)naphthiridine-3-carboxylic acid (+) was obtained in the same way that 7-fluoro-1-methyl-4-oxo-8-(3-phenyl-1-Pipera - sinil)-1,4-dihydro-1,8 - benzo(b)naphthiridine-3-carboxylic acid (RS) in example 19, the outcome is20-37about0,5 (with ethanol) and 1.48 g of sodium carbonate obtain 6.3 g solid yellow, melting at 226aboutC. After acid hydrolysis under the same conditions described in example 12 3-etoxycarbonyl-7-fluoro-1-methyl-4-oxo-8-(3-phenyl-1-piperazinil)- 1,4-dihydro-1,8-benzo(b)naphthiridine (RS), receive 4.26 deaths g of 7-fluoro-1-methyl-4-oxo-8-(3-phenyl-1-piperazinil)-1,4-dihydro-1,8 - benzo(b)the naphthiridine(3-carboxylic acid (RS), isomer (+), in a solid yellow color, melting at 276-278aboutC.

//D20+40,6about1 (1; acetic acid).

P R I m e R 24. A suspension consisting of 2 g of 3-etoxycarbonyl-7,9 - debtor-1-methyl-4-oxo-8-(3-phenyl-1(piperazinil)-1,4-dihyd-ro-1,8-benzo (b)naphthiridine (RS) 25 cm3ethanol and 15 cm31 N. aqueous alkali solution of potassium is heated with stirring for 2 h at a temperature close to the 75aboutC. the resulting solution at about 75aboutWith mixed with 9 g of 10% aqueous solution of acetic acid. The result is centrifuged at a temperature close to the 75aboutWith, and washed with 3 times 30 cm3water at about 20aboutC. After one recrystallization 40 cm4of dimethylformamide get 1.5 g of 7,9 - debtor-1-methyl-4-oxo-8-(3-phenyl-1-pipefishes at 298aboutC. 3-Etoxycarbonyl-7,9-debtor-1-methyl-4-oxo-8-(3-phenyl-1-piperazinil) 1,4-dihydro-1,8-benzo(b)naphthiridine (RS) is prepared as follows:

a suspension consisting of 1.8 g of 3-etoxycarbonyl-7,8,9-Cryptor-1 - methyl-4-oxo-1,4-dihydro-1,8-benzo-(b)naphthiridine and 3.2 g of 2-phenylpiperazine (RS) 30 cm3dimethyl sulfoxide is heated at a temperature close to 100aboutWith, and under stirring for 1.5 hours the resulting solution at 100aboutWith poured with stirring to a mixture containing 150 cm3water and 50 g of ice. The resulting suspension is extracted with 3 times 40 cm3trichlormethane at 20aboutC. the combined organic extracts are washed with 2 times 50 cm3water,dried on magnesium sulfate, filtered and concentrated to dryness under reduced pressure (20 kPa) and at the 50aboutC. the resulting material is recrystallized from a mixture of 40 cm3of dimethylformamide and 40 cm4of ethanol. Receive 2 g of 3-etoxycarbonyl-7,9-debtor-1-methyl-4-oxo-8-(3-phenyl-1-piperazinil)- 1,4-dihydro-1,8-benzo(b)naphthiridine-(RS) in a solid yellow color, melting at 216aboutC.

3-Etoxycarbonyl-7,8,9-Cryptor-1-methyl-4-oxo-1,4-dihydro-1,8 - benzo(b)naphthiridine is prepared in the following way

when mixing in susp is a, maintaining the temperature close to the 50aboutC, add 10 minutes between 5 and 10aboutWith a solution containing at approximately 5aboutWith 10 g of methylamine in 50 cm3ethanol, stirred for 1 h between 5 and 10aboutWith and allow the temperature to rise to about 20aboutC. the resulting solution is mixed with 7.6 g DBU and heated for 1 h at about 30aboutC. After cooling to a temperature close to 20aboutWith, the product is centrifuged, washed with 2 times 100 cm3ethanol and 2 times 100 cm3isopropyl ether. Get a 13.4 g of 3-etoxycarbonyl-7,8,9-Cryptor-1-methyl-4-oxo-1,4-dihydro-1,8-benzo (b)naphthiridine in a solid yellow color, melting at 320aboutC, which is used without further purification in the subsequent stages. ethanol and 15 cm31 N. aqueous alkali solution of potassium is heated with stirring for 2 h at a temperature close to the 75aboutC. the resulting solution at about 75aboutWith mixed with 9 g of 10% aqueous solution of acetic acid. The result is centrifuged at a temperature close to the 75aboutWith, and washed with 3 times 30 cm3water at about 20aboutC. After one recrystallization 40 cm4of dimethylformamide get 1.5 g of 7,9 - debtor-1-methyl-4-oxo-8-(OGO color, melting at 298aboutC.

3-Etoxycarbonyl-7,9-debtor-1-methyl-4-oxo-8-(3-phenyl-1-piperazinil) 1,4-dihydro-1,8-benzo(b)naphthiridine (RS) is prepared as follows:

a suspension consisting of 1.8 g of 3-etoxycarbonyl-7,8,9-Cryptor-1 - methyl-4-oxo-1,4-dihydro-1,8-benzo-(b)naphthiridine and 3.2 g of 2-phenylpiperazine (RS) 30 cm3dimethyl sulfoxide is heated at a temperature close to 100aboutWith, and under stirring for 1.5 hours the resulting solution at 100aboutWith poured with stirring to a mixture containing 150 cm3water and 50 g of ice. The resulting suspension is extracted with 3 times 40 cm3trichlormethane at 20aboutC. the combined organic extracts are washed with 2 times 50 cm3water,dried on magnesium sulfate, filtered and concentrated to dryness under reduced pressure (20 kPa) and at the 50aboutC. the resulting material is recrystallized from a mixture of 40 cm3of dimethylformamide and 40 cm4of ethanol. Receive 2 g of 3-etoxycarbonyl-7,9-debtor-1-methyl-4-oxo-8-(3-phenyl-1-piperazinil)- 1,4-dihydro-1,8-benzo(b)naphthiridine-(RS) in a solid yellow color, melting at 216aboutC.

3-Etoxycarbonyl-7,8,9-Cryptor-1-me-til-4-oxo-1,4-dihydro-1,8 - benzo(b)naphthiridine prepared following spongecola-relate 150 cm3ethanol, keeping the temperature close to the 50aboutC, add 10 minutes between 5 and 10aboutWith a solution containing at approximately 5aboutWith 10 g of methylamine in 50 cm3ethanol, stirred for 1 h between 5 and 10aboutWith and allow the temperature to rise to about 20aboutC. the resulting solution is mixed with 7.6 g DBU and heated for 1 h at about 30aboutC. After cooling to a temperature close to 20aboutWith, the product is centrifuged, washed with 2 times 100 cm3ethanol and 2 times 100 cm3isopropyl ether. Get a 13.4 g of 3-etoxycarbonyl-7,8,9-Cryptor-1-methyl-4-oxo-1,4-dihydro-1,8-benzo (b)naphthiridine in a solid yellow color, melting at 320aboutC, which is used without further purification in the subsequent stages. 2-(2-Chloro-6,7,8-Cryptor-3-fineliner-bonyl)-3-dimethylaminoethylacrylate can be prepared in the following way:

a suspension consisting of 26.7 g of 3-(2-chloro-6,7,8-Cryptor-3-quinoline)-3-oxo-ethyl - propionate 270 cm3ethyl acetate and 32 cm3N,N dimethylformamidine, is heated at a temperature close to the 75aboutWith, and under stirring for 2 h

The reaction mixture is concentrated to dryness under reduced pressure (20 kPa) and at approximately the 50about< is 35 cm3the same solvent. Get 19.32 g of 2-(2-chloro-6,7,8-Cryptor-3-hinolincarbonova)-3-dimethylaminoethylacrylate in a solid orange color, melting at 118aboutC, which is used without further purification in the subsequent stages.

3-(2-Chloro-6,7,8-Cryptor-3-quinoline)-3 - oxoethylidene is prepared in the following way:

a suspension consisting of of 46.3 g of 2-chloro-6,7,8-triptorelin-3-carboxylic acid in 640 cm3trichlormethane and 84 cm3chloride tonila, heated under stirring for 6 h at a temperature close to 60aboutC. the resulting solution was concentrated to dryness under reduced pressure (20 kPa) and at approximately the 50aboutC. the Obtained dry residue is extracted by 140 cm3petroleum ether (40-60), centrifuged, washed 2 times 60 cm3the same solvent. 47,61 g of the obtained solid yellow translate into a solution of 400 cm3tetrahydrofuran (THF). This solution drop by drop is injected under stirring for 1.5 h between 5 and 10aboutWith 250 cm3solution of the magnesium chelate of monoethylamine in tetrahydrofuran, which was prepared under the conditions of example 19. Allow the temperature to rise to about 20aboutC and stirred for further 2 h in these is UP>about
With that in 1750 cm30,5 N. sulfuric acid. Stirred for further 2 h at this temperature, extracted by approximately 5aboutWith 3 times 600 cm3ethyl ether. The combined organic phases are washed with 3 times 500 cm3water, dried on magnesium sulfate and concentrate under reduced pressure (20 kPa) and at temperatures close to the 30aboutC. the Dry residue is extracted by a mixture of 135 cm3isopropyl ether and 15 cm3n-hexane, centrifuged at 5aboutC, washed 2 times 115 cm3the same mixture at the same temperature. Get to 47.4 g of 3-(chloro-6,7,8-Cryptor-3-quinoline)-3-accouterment in a solid beige color, melting at 78-80aboutC, which is used without further purification in the subsequent stages.

2-Chloro-6,7,8-Cryptor-quinoline-3-Carbo - new acid is prepared in the following way:

with stirring to a cooled to about 10aboutWith a suspension consisting of of 45.7 g of 2-chloro-6,7,8-Cryptor-3-formyl-1,4-dihydro-quinoline-585 cm31 N. potassium alkali is added over 1 h, keeping the temperature between 10 and 14aboutWith the solution containing 69,65 g of potassium permanganate in 730 cm3water. Stirred for further 30 minutes at about 10aboutC. Add 12 g dition is eaten and washed 3 times with 400 cm3water. The filtrate and wash water are combined and added to 70 cm335% aqueous solution chloroethanol acid. Formed precipitate is extracted with 3 times 500 cm3ethyl acetate. The combined organic extracts are dried on magnesium sulfate, filtered and concentrated under reduced pressure (20 kPa) and at the 50aboutC. the Residue is extracted by a mixture of 100 cm3ethyl ether and 100 cm3isopropyl ether, centrifuged, washed with 100 cm3the same mixture. Get 46,43 g of 2-chloro-6,7,8 - Cryptor-Hino - Lin-3-carboxylic acid as a colourless solid, decomposing at 225-230aboutC, which is used without further purification in the subsequent stages.

2-Chloro-6,7,8-Cryptor-3-formyl-1,4-di-hydrochinon is prepared in the following way:

to a mixture of 525 cm3trichlormethane and 49 cm3of dimethylformamide is added over 40 minutes under stirring between 5 and 10aboutWith 50 cm3chloride of fostoria, stirred for 15 min at this temperature and allow the temperature to rise to about 20aboutC. To the resulting solution was added for 20 min at about 20aboutWith strong stirring gradually to 46.8 g of 6,7,8-Cryptor-3,4-dihydroorotase. Mix 30 m the re for 2.5 hours. The reaction mixture was concentrated under reduced pressure (20 kPa) and at approximately the 50aboutC. the Oily residue is poured with vigorous stirring to 500 g of ice. Add in small portions over 30 min, 100 g of sodium acetate. The resulting suspension is poured over 15 min with vigorous stirring to 1 liter of water, previously heated to approximately 90aboutC, and stirred for further 15 min at the same temperature. The insoluble part centrifuged at approximately 90aboutC and washed 3 times with 250 cm3water. Get of 47.7 g of 2-chloro-6,7,8-Cryptor-3-formyl-1,4-dihydroquinoline in the form of a colorless solid, decomposing at 220aboutC.

6,7,8-Cryptor-3,4-dihydroxybutyl is prepared in the following way:

24,35 g of 6,7,8-triptoreline in the form of a suspension in a mixture of 450 cm3ethanol and 150 cm3of dimethylformamide hydronaut under stirring and at approximately the 50aboutIn the presence of 5 g of Raney Nickel at a pressure of 1 ATM to stop the absorption of hydrogen. The Raney Nickel used as a W-2, pre-washed with 50 cm32% aqueous solution of acetic acid, 2 times 50 cm3and 3 times 50 cm3of ethanol. The reaction mixture was mixed with 250 cm3of dimethylformamide, filtered at about 50 the RNO 70aboutC. the Dry residue is extracted by 150 cm3water, centrifuged and washed with 2 times 50 cm3water. Get to 23.6 g of 6,7,8-Cryptor-3,4-dihydrocarbamazepine in the form of a solid light beige color, melting at 217aboutC, which is used without further purification in the subsequent stages.

6,7,8-Triptoreline is prepared in the following way:

a suspension consisting of 60,83 g of 4-chloro-6,7,8-triptoreline at 520 cm3acetic acid and 38,15 cm3of triethylamine, hydronaut at a pressure of 1 ATM, in the presence of 5.25 g of palladium on coal (10%) before the termination of the absorption of hydrogen at a temperature close to 25aboutC. the Reaction mixture is then heated to approximately 40aboutWith, is filtered at the same temperature through detonirovanie silica for filtration. The filtrate is concentrated under reduced pressure (20 kPa) and at temperatures close to the 50aboutC. the Dry residue is extracted by 400 cm3water. The insoluble part centrifuged, washed 4 times 170 cm3water, 2 times 110 cm3ethanol and 2 times 110 cm3isopropylalcohol ether. Get 48,35 g of 6,7,8-triptoreline in the form of a colorless solid, vazhneyshego at 288aboutWith to otovitsa in the following way:

a suspension consisting of of 70.4 g of 4-chloro-2-ethoxy-6,7,8-triptorelin 170 cm335% aqueous solution chloroethanol acid, 420 cm3acetic acid and 250 cm3water, heated under stirring and at a temperature close to 100aboutWith, within 2.5 hours After cooling to about 20aboutTo the reaction mixture was poured to 1100 cm3water at about 5aboutC, stirred for 15 min at the same temperature, and then the insoluble part centrifuged and washed 3 times 220 cm3water. Obtain 61 g of 4-chloro-6,7,8-triptoreline in a solid beige color, melting at 213aboutC, which is used without further purification in the subsequent stages.

4-Chloro-2-ethoxy-6,7,8-triptorelin is prepared in the following way:

a suspension consisting of of 69.5 g of 2-ethoxy-6,7,8-Cryptor-4-hydroxyquinoline solution at 430 cm3chloride of fostoria, heated under stirring and at a temperature close to 100aboutWith, within 30 minutes the resulting solution was concentrated under reduced pressure (20 kPa) and at 60aboutWith up to a volume of 100 cm3. The residue is extracted through 750 cm3ethyl acetate. The resulting solution was poured with stirring over 10 min to a mixture of 400 cm3water and 200 g of the two extracted 2 times 250 cm3ethyl acetate. The combined organic extracts are washed with 2 times 250 cm3water, dried on magnesium sulfate and concentrate under reduced pressure (20 kPa) and at 40aboutC. the Obtained oily residue is extracted through 370 cm3petroleum ether (40-60). After filtration through detonirovanie silica, the filtrate is concentrated to dryness under reduced pressure (20 kPa) and about 30aboutC. Get to 70.7 g of 4-chloro-2-ethoxy-6,7,8-triptorelin in a solid beige color, melting at 45aboutC, which is used without further purification in the subsequent stages.

2 Ethoxy-6,7,8-Cryptor-4-hydroxyI-nolin can be prepared as follows:

the solution containing 122 g of 2,3,4-Cryptor-N-[(1'-ethoxy-2'-etoxycarbonyl)-utili - den]-aniline in 120 cm2oxide phenyl, injected dropwise over 25 min with stirring at 600 cm3oxide phenyl, with the temperature close to 250aboutWith, continuously removing the formed ethanol by distillation. After stirring for 15 min at the same temperature, the solution is cooled to 20aboutWith and mixed with 750 cm3n-hexane. Formed precipitate is centrifuged and washed 3 times with 200 cm3n-hexane. Get 69,5 g toroe used without further purification in the subsequent stages.

2,3,4-Cryptor-N-[(1'-ethoxy-2'-ethoxy - carbonyl)ethylidene] -aniline may be prepared in the following way

to a solution containing 90 g of the hydrochloride of 2-etoxycarbonyl-1 amoxicillinonline 820 cm3ethanol was added at once with stirring to 58.8 g of 2,3,4-triptorelin. After 48 h stirring at a temperature close to 20aboutWith the obtained suspension is filtered and the filtrate concentrated under reduced pressure (20 kPa) and at temperatures close to the 50aboutC.

The oily residue is extracted by 250 cm3water. The resulting mixture is extracted with 3 times 200 cm3ethyl ether. The combined organic extracts are washed 4 times with 150 cm3water, dried on magnesium sulfate and concentrate under reduced pressure (20 kPa) and at 30aboutC. Obtain 122 g of 2,3,4-Cryptor-N-[(1'-ethoxy - 2'-etoxycarbonyl)-ethylidene] -analine in the form of liquid oil yellow color, which is used without further purification in the subsequent stages.

Hydrochloride 2-etoxycarbonyl-1 amoxicillinonline was prepared according to the method described in A. Pinner et coll. Ber Dtsch.Chem.Ges. 28, 478 (1895).

P R I m e R 25. Conducting the reaction under the conditions of example 39, but on the basis of 0,978 g 3-etoxycarbonyl-7,9 is lisali 25 cm3of dimethylformamide 0,540 g of 7,9-debtor-1-methyl-4-oxo-8-(3-phenyl-1-piperazinil)-1,4-dihydro - 1,8-benzo(b)naphthiridine-3-carboxylic acid (R) in a solid yellow color decomposing at 270-272aboutC.

//D20+113about5 (2; trichloromethane).

Conducting the reaction under the conditions of example 30, but according to 1.21 g of 3-etoxycarbonyl-7,8,9-Cryptor-1-methyl-4-oxo-1,4-dihydro-1,8 - benzo(b)naphthiridine and 0.7 g of 2-phenylpiperazine (R) after recrystallization 22 cm3ethanol with 30% of dimethylformamide gain of 1.02 g of 3-etoxycarbonyl-7,9-debtor-1-methyl-4-oxo-8-(3-phenyl-1-piperazinil)- 1,4-dihydro-1,8-benzo(b)naphthiridine in a solid yellow color, melting at 216aboutC.

//D20+98about2 (0.5; acetic acid).

P R I m e R 26. Conducting the reaction under the conditions of example 25, but on the basis of 1,33 g 3-etoxycarbonyl-7,9-debtor-1-methyl-4-QA - with-8-(4-phenyl-1-piperazinil)- 1,4-dihydro-1,8-benzo(b)naphthiridine-(s) receive 0,779 g of 7,9-debtor-1-methyl-4-oxo-8-(3-phenyl-1-piperazinil)-1,4-dihydro-1,8 - benzo(b)the naphthiridine-3-carboxylic acid (s) in a solid yellow color decomposing at 270-272aboutC.

//D20+118about5 (0,2; trichloromethane).

Conducting the reaction in ukoug 2-phenylpiperazine (s), get 1,02 g 3-etoxycarbonyl-7,9-debtor-1-methyl-4-oxo-8-(3-phenyl)-1-piperazinil)- 1,4-dihydro-1,8-benzo(b)naphthiridine-(s) in a solid yellow color, melting at 216aboutC.

//D20-99about2 (0.5; acetic acid).

P R I m e R 27. 1-Cyclopropyl-7,9-debtor-4-oxo-8-(3-phenyl-1-piperazinil)-1,4-dihydro - 1,8-benzo(b)naphthiridine-3-carboxylic acid (RS) are obtained in the conditions of example 24, but on the basis of 1.8 g of 1-cyclopropyl-3-etoxycarbonyl-7,9-di - fluoro-4-oxo-8-(3-phenyl-1 - piperazinil)-1,4-dihydro-1,8-benzo(b)naphthiridine-(RS). After recrystallization from a mixture of 30 cm3of dimethylformamide and 20 cm3ethanol obtain 1.2 g of 1-cyclopropyl-7,9-debtor-4-oxo-8-(3-phenyl-1-piperazinil)-1,4-dihydro - 1,8-benzo(b)naphthiridine-3-carboxylic acid (RS) in a solid yellow color, melting at 274aboutC.

1-Cyclopropyl-3-etoxycarbonyl-7,9-debtor-4-oxo-8-(3-phenyl-1 - piperazinil)-1,4-dihydro-1,8-benzo(b)naphthiridine-(RS) are obtained in the conditions of example 19, but on the basis of 1.8 g of 1-cyclopropyl-3-etoxycarbonyl-7,8,9-Cryptor-4-oxo-1,4-dihydro-1,8 - benzo(b)naphthiridine and 3.2 g of 2-Felipe - Razin (RS). After recrystallization from a mixture of 5 cm3of dimethylformamide and 40 cm3ethanol obtain 1.8 g of 1-cyclopropyl-3-ethoxycarbonyl color, melting at 242aboutC.

1-Cyclopropyl-3-etoxycarbonyl-7,8,9-Cryptor-4-oxo-1,4-dihydro - 1,8-benzo(b)naphthiridine can be obtained in the following conditions:

in a solution containing 7 g of 2-(2-chloro-6,7,8-Cryptor-3-hinolincarbonova)-3-dime-tramadolcanada 100 cm3trichlormethane, maintained at a temperature close to 20aboutC, add 5 min 4.12 g of cyclopropylamine and stirred for further 4 h at the same temperature. The reaction mixture was concentrated under reduced pressure (20 kPa) and at the 50aboutC. the Obtained oily residue is extracted by 100 cm3ethanol and 3 g of DBU. The mixture is heated to 80aboutAnd stirring is maintained at this temperature for 1.5 hours After cooling to about 20aboutWith insoluble part centrifuged, washed with 2 times 30 cm3ethanol and 2 times 30 cm3isopropyl ether. Receive 4.5 g 1-cyclopropyl-3-ethoxy-(carbonyl-7,8,9 - tri - fluoro-4-oxo-1,4-dihydro-1,8-benzo(b)nafta - ridin in the form of a colorless solid, melting at 260aboutC.

P R I m e R e 28. Conducting the reaction under the conditions of example 39, but on the basis of 2.4 g of 3-etoxycarbonyl-7,9-debtor-1-(2-foradil) -4-oxo-8-(3-phenyl-1 - piperazinil)-1,4-dihydro-1,8-benzo(b)naphthiridine (RS) produces the (RS) in a solid yellow color, decomposing at 307-310aboutC.

3-Etoxycarbonyl-7,9-debtor-1-(2-fluoro - ethyl-4-oxo-8-)3-phenyl-1- (piperazinil)-1,4-dihydro-1,8-benzo(b)naphthiridine (RS) was prepared in the following conditions:

a suspension consisting of 2.8 g of 3-etoxycarbonyl-1-(2-foradil)-7,8,9-Cryptor-4 - oxo-1,4-dihydro-1,8 - benzo(b)naphthiridine, 1.7 g of 2-phenylpiperazine (RS) and 1.1 g of sodium carbonate in 40 cm3dimethyl sulfoxide is heated with stirring for 2 hours at a temperature close to 100aboutC. After cooling to about 20aboutTo the reaction mixture was poured to 200 cm3water and extracted with 3 times 100 cm3trichlormethane. The combined organic extracts washed with 1 in every 50 cm3water and concentrate under reduced pressure (20 kPa) and at temperatures close to the 40aboutC. the Oily residue is extracted by 100 cm3ethanol and concentrated again under reduced pressure in the above-described conditions. The obtained solid is recrystallized from 100 cm3ethanol with 20% DMF (dimethylformamide), centrifuged and washed with 2 times 20 cm3of ethanol. Obtain 2.4 g of the desired product in the form of a solid yellow color, melting at 208aboutC.

3-Etoxycarbonyl-1-(2-foradil-7,8,9-Cryptor-4-7,8-Cryptor-3 hinolincarbonova)-dimethylaminoethylacrylate, 3 g of the hydrochloride of 2-foretelling, 4.2 cm2of triethylamine in 100 cm3of ethanol. After adding 1.8 cm3DBU solution is heated for 2 hours at 80aboutC. Receive as a result of processing of the reaction mixture as in example 24, 2.8 g of 3-etoxycarbonyl-7,8,9-Cryptor-1-(2-foradil)-4-oxo-1,4-dihydro - 1,8-benzo(b)naphthiridine in a solid yellow color, melting at 302-304aboutC.

2-(2-Chloro-6,7,8-Cryptor-3-fineliner-bonyl)-dimethylaminoethylacrylate can be prepared as described in example 24.

P R I m e R 29. A suspension consisting of 2.65 g of 8-(3-benzyl-1 - piperazinil)-3-etoxycarbonyl-7-fluoro-1-methyl-4-oxo-1,4-dihyd - ro - 1,8-benzo(b)naphthiridine-(RS) 14 cm31 N. aqueous alkali potassium and 20 cm3ethanol is heated at a temperature close to 80aboutWith over 20 min, mixed at this temperature with 32 cm35% acetic acid and stirred for 20 minutes, the Insoluble part centrifuged, washed with 2 times 20 cm3water, 2 times 20 cm3ethanol and 2 times 20 cm3ethyl ether. After two precrystallization 50 cm3(each time) of dimethylformamide gain of 2.05 g of 8-(3-benzyl-1-piperazinil)-7-fluoro-1-methyl-4-oxo - 1,4-dihydro-1,8-benzo(b)naphthiridine-3-carboxylic acid (RS) in the form of solid fuel shall arbonyl-7-fluoro-1-methyl-4-oxo - 1,4-dihydro-1,8-benzo(b)naphthiridine-(RS) is prepared in the following way:

a suspension consisting of 1.3 g of 3-etoxycarbonyl-7,8-debtor-1-methyl-4-oxo-1,4 - dihydro-1,8-benzo(b) naphthiridine and 1.3 g of 2-benzylpiperazine (RS) 25 cm3dimethyl sulfoxide is heated at approximately 90aboutC and under stirring for 1 h 45 min After cooling to a temperature close to 20aboutC, the reaction mixture is added to 100 cm3water, extracted with 3 times 30 cm3trichlormethane. The combined organic extracts are washed with 3 times 30 cm3water, dried on magnesium sulfate, filtered and concentrated to dryness at approximately the 50aboutWith under reduced pressure (20 kPa). After one recrystallization from a mixture of 4 cm3of dimethylformamide and 1 cm3of ethanol and 1.6 g of 8-(3-benzyl-1-piperazinil)-3-etoxycarbonyl-7-fluoro-1-methyl-4-oxo-1,4 - dihydro-1,8-benzo(b)naphthiridine-(RS) in a solid yellow color, melting at 190aboutC.

2-Benzylpiperazine (RS) can be prepared by hydrogenation of 2-benzylpyridine obtained according to the method described in 26, 3379 (1961).

A solution containing 8 g of 2-benzylpiperazine 60 cm3acetic acid, mixed with 0.8 g of platinum dioxide and hydronaut at a pressure of 1 ATM. at about the 20aboutC. After the absorption Bogoroditsa pressure (20 kPa) and at approximately the 60aboutC. the Dry residue was transferred to a suspension of 40 cm3ethanol is mixed with about 20aboutWith solution ethylate sodium, prepared on the basis of 1.49 g of sodium in 40 cm3of ethanol. After 2 h stirring at about 20aboutWith the suspension is concentrated to dryness under reduced pressure (20 kPa) and at 30aboutC. the Dry residue is extracted by 60 cm3ethyl ether. The insoluble portion removed by filtration through detonirovanie silica. The filtrate is concentrated to dryness under reduced pressure under conditions similar to the previous one. The dry residue is extracted through a 20 cm3isopropyl ether, centrifuged and washed with 2 times 5 cm3the same solvent. Get 5.32 g 2-benzylpiperazine (RS) in the form of a solid light beige color, melting at 90aboutC. naftaplin and 1.08 g of 2-(2-forfinal)-piperazine (RS). After recrystallization in 60 cm3of dimethylformamide with 50% ethanol obtain 1.3 g of the expected product in the form of a solid yellow color, melting at 228aboutC.

P R I m e R 31. 7,9-Debtor-8-[3-(4-forfinal)-1-piperazinil]-1-methyl-4-oxo-1,4 - dihydro-1,8-benzo(b)naftopidil-3-CT-oil acid (RS) was prepared in the conditions of example 24, but iridia-(RS). After one recrystallization from 30 cm3of dimethylformamide receive 1 g of 7,9-debtor-8-[3-(4-forfinal)-1-piperazinil] -1 - methyl-4-oxo-1,4 - dihydro-1,8-benzo(b)naftopidil-3-carboxylic acid (RS) in a solid yellow color, melting at 266aboutC. 3-Etoxycarbonyl-7,9-debtor-3-[3-(4-forfinal)-1-piperazinil)-1-methyl - 4-oxo-1,4-dihydro-1,8-benzo(b)naftopidil-(RS) was prepared in the conditions of example 39, but from 2 g of 3-ethoxy-carbonyl-7,8,9-Cryptor-1-methyl-4-oxo-1,4-dihydro-1,8 - benzo(b)naftaplin and 4 g of 2-(4-forfinal)-piperazine (RS). After one recrystallization from a mixture of 3.5 cm3of dimethylformamide and 31.5 cm3ethanol obtain 2.1 g of 3-ethoxy(carbonyl)-7,9-debtor-8-[3-(4-forfinal)-1-piperazinil]-1-methyl - 4-oxo-1,4-dihydro-1,8-benzo(b)naftifine - DIN (RS) in a solid beige color, melting at 242aboutC.

P R I m e R 32. 1-Ethyl-7-fluoro-8-[8-(4-methoxyphenyl)-1-piperazinil]-4-oxo-1,4 - dihydro-1,8-benzo(b)naftopidil-3-carbon - Wai acid (RS) was prepared under the conditions described below in example 33, but on the basis of 1.5 g of 3-etoxycarbonyl-1-ethyl-7 - fluoro-8-[3-(4-methoxyphenyl)-1 - piperazinil)-4-oxo-1,4-dihydro-1,8-benzo(b)nafta - pyridine (RS). After recrystallization 30 cm3of dimethylformamide gain of 0.85 g of 1-ethyl-solid yellow melting at 270aboutC.

3-Etoxycarbonyl-1-ethyl-7-fluoro-8-[3- (4-methoxyphenyl)-1-piperazinil] 4-oxo-1,4-dihydro-1,8-benzo(b)naftopidil-(RS) was obtained in the conditions of example 33, but on the basis of 1,99 g 3-etoxycarbonyl-1-ethyl-7,8-debtor-4-oxo-1,4-dihydro-1,8-benzo(b) naftaplin and 2.3 g of 2-(4-methoxyphenyl)-piperazine (RS). Obtain 2.2 g of 3-etoxycarbonyl-1-ethyl-7-fluoro-8-(3-4-methoxide-Neil-1-piperazinil)- 4-oxo-1,4-dihydro-1,8-benzo(b)naftaplin (RS) in a solid beige color, melting at 210-212aboutC.

3-Etoxycarbonyl-1-ethyl-7,8-debtor-4-oxo-1,4-dihydro-1,8-benzo(b) naftopidil was prepared under the following conditions

in a suspension consisting of 20 g of 2-(2-chloro-6,7-debtor-3-hinolincarbonova)-3-di - methylenedianiline 200 cm3ethanol with 2aboutC, add 10 min between 2 and 5aboutWith stirring the solution with a temperature of about 2aboutWith containing 14.6 g of ethylamine in 200 cm3ethanol is stirred for further 40 min between 2 and 5aboutWith, then allow the temperature to rise to about 20aboutWith over 2 hours After 24-hour incubation at about 20aboutWith insoluble part centrifuged, washed with 2 times 30 cm3ethanol and 2 times 50 cm3isopropyl ether. Get 16,35 g 3 ethoxy is masegosa at a temperature of 290aboutC.

P R I m e R 33. 1-Cyclopropyl-7-fluoro-3-[3-(4-methoxyphenyl)-1-piperazinil]-4-oxo - 1,4-dihydro-1,8-benzo(b)naftopidil-3 - carboxylic acid-(RS) was prepared in the conditions of example 29, but on the basis of 1.5 g of 1-cyclopropyl-3-etoxycarbonyl-7-fluoro-8-[3-(4-methoxyphenyl)-1 - piperazinil]-4-oxo-1,4-dihydro-1,8-benzo(b)naftaplin-(RS) of 18.4 cm31 N. aqueous solution of alkaline potassium and 18.4 cm3of ethanol. After one recrystallization from 50 cm3of dimethylformamide get 1.5 grams of 1-cyclopropyl-7-fluoro - 8-[3-(4-methoxyphenyl)-1 - piperazinil)-4-oxo-1,4-dihydro-1,8-benzo(b)naftopidil-3 - carboxylic acid-(RS) in a solid yellow color decomposing at 287aboutC.

1-Cyclopropyl-3-etoxycarbonyl-7 - fluoro-8-[3-(4-methoxyphenyl)-1 - piperazinil] -4-oxo-1,4-dihydro-1,8-benzo(b)nafta - pyridine-(RS) was prepared in the following way:

a suspension consisting of 2 g of 1-cyclopropyl-3-etoxycarbonyl-7,8-debtor-4-QA - with-1,4-dihydro-1,8 - benzo(b)naftaplin and 2.3 g of 3-(4-methoxyphenyl)-piperazine (RS) 20 cm3dimethyl-sulfoxide is heated at a temperature close to the 90aboutWith, within 1.5 hours After cooling to about 20aboutWith insoluble part centrifuged, washed with 3 times 15 cm3water and precrystallization-8-[3-(4-methoxyphenyl)-1 - piperazinil] -4-oxo-1,4-dihydro-1,8-benzo(b)naftaplin- (RS) in a solid yellow color, melting at 199aboutC.

1-Cyclopropyl-3-etoxycarbonyl-7,8-debtor-4-oxo-1,4-dihydro-1,8 - benzo(b)naftopidil was prepared in the following way:

a solution containing 20 g of 2-(2-chloro-6,7-debtor-3-hinolincarbonova)- 3-dimethylaminoethylacrylate and a 9.25 g cyclepro - pilipina 80 cm3trichlormethane, stirred at a temperature close to 20aboutWith over 2 hours the Solution is concentrated under reduced pressure (20 kPa) and at 40aboutC. the Residue is extracted by 300 cm3ethanol, mix from 8.2 g of DBU and heated under stirring and at about the 75aboutC for 30 minutes After cooling to 20aboutWith insoluble part centrifuged, washed with 2 times 30 cm3of ethanol. Obtain 11.1 g of 1-cyclopropyl-3-etoxycarbonyl-7,8-debtor-4-oxo-1,4-dihydro-1,8 - benzo(b)naftaplin in a solid yellow color, melting at 230aboutC.

P R I m e R 34. 7,9-Debtor-8-[3-(4-methoxyphenyl)-1-piperazinil]-1-methyl-4-oxo - 1,4-dihydro-1,8-benzo[b]naphthiridine-3-CT - oil acid (RS) was obtained in the conditions described in example 39, from 2.8 g of 3-etoxycarbonyl-7,9-debtor-8-[3-(4-methoxyphenyl)-1 - piperazinil]-1-methyl-4-oxo-1,4-dihydro-1,8-benzo[b] NAF - dipyridine-(RS) 24 cm31 N. methyl-4-oxo-1,4 - dihydro-1,8-benzo[b]naftopidil-3-carbon - howl acid RS in a solid yellow color, melting at 288-290aboutC.

3-Etoxycarbonyl-7,9-debtor-8-[3-(4-methoxyphenyl)-1-piperazinil]-1 - methyl-4-oxo-1,4-dihydro-1,8-benzo[b]naftifine - DIN(RS) was prepared in the following circumstances:

A suspension consisting of 2.5 g of 3-etoxycarbonyl-7,8,9-Cryptor-1 - methyl-4-oxo-1,4-dihydro-1,8-benzo[b] naftaplin and 3.5 g of 2-(4 - methoxyphenyl)-piperazine (RS) 40 cm3dimethyl sulfoxide is heated under stirring and at a temperature close to 95aboutWith over 2 hours After treatment of the reaction mixture under the conditions described for example 39, obtain 2.8 g of 3-etoxycarbonyl-7,9-debtor-8-[3-(4-methoxy - phenyl)-1-piperazinil]-1 - methyl-4-oxo-1,4-dihydro-1,8-benzo[b] naftaplin-(RS) in a solid yellow color, melting at 209aboutC, which is used without further purification in the subsequent stages.

3-Etoxycarbonyl-7,8,9-Cryptor-1-me-til-4-oxo-1,4-dihydro-benzo[b] naphthiridine to 1.8 can be obtained as described in example 24.

2-(4-Methoxyphenyl)-piperazine (RS) was prepared according to the method described in example 12.

P R I m e R 35. Conducting the reaction under the conditions of example 39, but from 0.9 g of 8-[3-(4-AMINOPHENYL)-1-piperazinil] -3-adoxical-bonyl-7-fluoro-1-methyl - 4-oxo-1,4-digiteo[b] naphthiridine-3-carboxylic acid (RS) in a solid yellow color, decomposing at 315aboutC.

8-[3-(4-AMINOPHENYL)-1-piperazinil] -3-etoxycarbonyl-7-fluoro-1-methyl - 4-oxo-1,4-dihydro-1,8-benzo[b] naphthiridine-(RS) was prepared in the following conditions:

suspension, consisting of 0.7 g of 3-etoxycarbonyl-7-fluoro-1-methyl-8-[3-(4-nitrophe-nil)-1-piperazinil] -4 - oxo-1,4-dihydro-1,8-benzo[b]naftaplin-(RS) and 5 g of Raney Nickel at 150 cm3ethanol, hydronaut at a pressure of 1 ATM at a temperature of about 20aboutC for 7 h, which allows you to absorb theoretically required amount of hydrogen (100 cm3at 20aboutC and 1 ATM). After adding 50 cm3of dimethylformamide catalyst is removed by filtration and the filtrate is concentrated to dryness under reduced pressure (20 kPa) and at the 50aboutC. the resulting residue (0,550 g) chromatographic on 15 g of silica (230-400 mesh mesh) in a suspension consisting of chloroform with 20% ethanol, and elute 200 cm3the same mixture of solvents. After concentration to dryness under conditions similar to the previous one, obtain 0.3 g of 8-[3-(4-AMINOPHENYL)-1-piperazinil)-3-etoxycarbonyl-7-fluoro-1-methyl - 4-oxo-1,4-dihydro-1,8-benzo[b]naphthiridine-(RS) in the form of a solid, melting at 180-182aboutC.

3-Etoxycarbonyl-7-fluoro-1-methyl-8-[3-(4-nitrophenyl)-1-piperazine is of IMT-7,8-debtor-1-methyl-4-oxo-1,4-dihydro-1,8-benzo[b] naphthiridine and 0.5 g of 2-(nitrophenyl)-piperazine (RS). After crystallization in 10 cm3of dimethylformamide obtain 0.7 g of the desired product in the form of a solid yellow color, decomposing at about 300aboutC.

2-(4-Nitrophenyl)-piperazine (RS) was prepared in accordance with the same methods that were used previously in example 8.

On the basis of 18 g of 4-nitrophenylglyoxylate obtain 6.2 g of the expected product in the form of liquid oil brown color, which is used without further purification in the subsequent stages.

P R I m e R 36. Conducting the reaction under the conditions of example 39, but on the basis of 2.2 g of 3-etoxycarbonyl-7,9-debtor-8-{ 3-[4-(2-guide - roxilox)- phenyl]-1-piperazinil} -1-methyl-4-oxo-1,4-dihydro-1,8-benzo[b] naphthiridine (RS) are obtained 1.6 g of 7,9-debtor-8-{3-[4-(2-hydroxyethoxy)-Fe - Neil]-1-piperazinil}-1-methyl - 4-oxo-1,4-dihydro-1,8-benzo[b] naphthiridine-3-Carbo-new acid (RS) in a solid yellow color, melting at 226-228aboutC.

3-Etoxycarbonyl-7,9-debtor-8-{3-[4- (2-hydroxyethoxy)-phenyl]-1 - piperazinil} -1-methyl-4-oxo-1,4-dihydro-1,8-benzo[b]naphthiridine-(RS) was prepared in the conditions of example 39, but on the basis of the 1.9 g of 3-etoxycarbonyl-7,8,9-Cryptor-1-methyl-4-oxo-1,4-di - hydro-1,8-benzo[b] naphthiridine and 1.6 g of 2-[4(2-hydroxyethoxy)-phenyl]-/SUP>C.

3-Etoxycarbonyl-7,8,9-Cryptor-1-me-til-4-oxo-1,4-dihydro-benzo[b] naphthiridine to 1.8 can be obtained as described above in example 24.

P R I m e R 37. Conducting the reaction under conditions close to the conditions of example 39, but on the basis of 2.4 g of 1-cyclopropyl-3-etoxycarbonyl-7,9-debtor-8-{3-[4-(2-hydroxy - ethoxy)- phenyl]-piperazinil}-4-oxo-1,4-dihydro-1,8-benzo[b] naphthiridine-(RS), adding 100 cm3ethanol with 50% water to the reaction mixture prior to the introduction of methansulfonate, get 1.4 g of 1-cyclopropyl-7,8,9-{3-[4-(2-hydroxyethoxy)-phenyl] -1-PI-pyrazinyl} -4 - oxo-1,4-dihydro-1,8-benzo[b] naphthiridine-3-carboxylic acid-(RS) in a solid yellow color, melting at 228-230aboutC. 1-Cyclopropyl-3-etoxycarbonyl-7,9-debtor-8-{ 3-[4-(2-hydroxyethoxy)- phenyl]-1-piperazinil}-4-oxo-1,4-dihydro-1,8-Ben - zo[b] naphthiridine-(RS) was prepared in the conditions of example 39, but from 2 g of 1-cyclopropyl-3-etoxycarbonyl-7,8,9-Cryptor- -4-oxo-1,4-dihydro-1,8 - benzo[b]naphthiridine and 1.6 g of 2-[4-(2-hydroxyethoxy)-phenyl]-piperazine (RS) to obtain 2.4 g of the desired product in the form of a solid yellow color, melting at 225-226aboutC. 1-Cyclopropyl-3-etoxycarbonyl-7,8,9-Cryptor-4-oxo-1,4-dihydro-benzo[b] naphthiridine-1,8 prepared as described in the ptx2">

P R I m e R 38. Conducting the reaction under the conditions of example 39, but on the basis of 2.1 g of 3-etoxycarbonyl-7-fluoro-1-methyl-8-{3-[(3,4-METI - landice)-phenyl]-1 - piperazinil} -4-oxo-1,4-dihydro-1,8-benzo[b]naphthiridine-1,8 (RS) is obtained after recrystallization in 30 cm3of dimethylformamide and 1.6 g of 7-fluoro-1-methyl-8-{ 3-[(3,4-methylenedioxy)-phenyl]-1-PI-pyrazinyl}-4-oxo - 1,4-dihydro-1,8-benzo[b] naphthiridine-3-carboxylic acid-(RS) in a solid yellow color decomposing at 255aboutC.

3-Etoxycarbonyl-7-fluoro-1-methyl-8-{ 3-[(3,4-methylenedioxy)-phenyl] -1 - piperazinil} -4-oxo-1,4-dihydro-1,8-benzo[b] nafta - ridin was prepared in conditions close to the conditions of example 39, but according to 1.59 g of 3-etoxycarbonyl-7,8-debtor-1-methyl-4-QA - with-1,4-dihydro-1,8-benzo[b] naphthiridine of 1.25 g of 2-(3,4-dioxymethylene)-piperazine-(RS) and 0.64 g of sodium carbonate obtain 2.15 g of 3-etoxycarbonyl-7-fluoro-1-me - Teal-8-{3-[(3,4-methylenedioxy)-phenyl] -1-PI - pyrazinyl} -4-oxo-1,4-dihydro-1,8-benzo[b] naphthiridine (RS) in a solid yellow color, melting at 252aboutC.

2-(3,4-Methylenedioxyphenyl)-piperazine (RS) was prepared according to the method described in the patent application FP 2 351 108.

P R I m e R 39. A suspension consisting of 1.3 g of 3-etoxycarbonyl-7-fluoro-8-[3-(2-furyl)-1-piperaz>ethanol, heated for 1 h at a temperature close to 80aboutWith, then mixed at the same temperature with 6 cm31 N. aqueous solution of methanesulfonate. After cooling to about 20aboutWith insoluble part centrifuged, washed with 3 times 10 cm3water, 3 times 10 cm3ethanol, 3 times 10 cm3ethyl ether and recrystallized from a mixture of 13 cm3ethanol and 27 cm3of dimethylformamide. Get 0,570 g of 7-fluoro-8-[3-(2-furyl)-1-piperazinil]-1-me - til-4-oxo-1,4-dihydro - 1,8-benzo[b]naphthiridine-3-carboxylic acid (RS) in a solid yellow color, melting at 258-260aboutC.

3-Etoxycarbonyl-7-fluoro-8-[3-(2-furyl) -1-piperazinil] -1-methyl-4 - oxo-1,4-dihydro-1,8-benzo[b] naphthiridine-(RS) was prepared in the following way:

a suspension consisting of 0.96 g of 3-etoxycarbonyl-7,8-debtor-1-methyl-4-oxo-1,4-dihydro-1,8-benzo[b] naphthiridine 0.6 g of 2-(2-furyl)-piperazinil-(RS) and 0.38 g of sodium carbonate in 20 cm3dimethyl sulfoxide is heated at about 95aboutWith over 5,5 hours After cooling to 20aboutThe mixture is poured to 50 cm3water at a temperature close to 5aboutWith, and extracted with 3 times 50 cm3water, dried on magnesium sulfate, filtered and concentrated to dryness when stripperwhat, washed with 2 times 20 cm3ethanol and 3 times 30 cm3ethyl ether. Obtain 1.3 g of 3-etoxycarbonyl-7-fluoro-8-[3-(2-furyl)-1-piperazinil] -1-methyl-4-QA-with - 1,4-dihydro-1,8-benzo[b]naphthiridine prepared as described in example 19.

2-(2-Furyl)-piperazine (RS) was prepared according to the method described in the patent application FP 230 053.

P R I m e R 40. Conducting the reaction under the conditions of example 39, but on the basis of a 1.25 g of 1-cyclopropyl-3-etoxycarbonyl-7-fluoro-8-[3-(2-furyl)-1 - piperazinil]-4-oxo-1,4-dihydro-1,8-benzo[b] naphthiridine-(RS) obtain 0.95 g of 1-cyclopropyl-7-fluoro-8-[3- (2-furyl)-1-piperazinil] -4-oxo-1,4-dihyd - ro - 1,8-benzo(b)naphthiridine-3-carboxylic acid (RS) in a solid yellow color, melting at 240-241aboutC.

1-Cyclopropyl-3-etoxycarbonyl-7 - fluoro-8-[3-(2-furyl)-1-piperazinil] 4-oxo-1,4-dihydro-1,8-benzo(b)naphthiridine-(RS) was prepared in the conditions of example 39, but according to 1.05 g of 1-cyclopropyl-7,8-debtor-3-etoxycarbonyl-4-oxo-1,4-dihydro-1,8 - benzo(b)naphthiridine and 0.6 g of 2-(2-furyl)-piperazine (RS)get 1.3 g 1-cyclopropyl-3-etoxycarbonyl-7-fluoro-8-[3-(2-furyl) -1 - piperazinil]-4-oxo-1,4-dihydro-1,8-benzo(b) naphthiridine in a solid yellow color, melting at 182aboutC.

1-Cyclopropyl-3-ethoxy-720 g of 2-(2-chloro-6,7-debtor-3-hinolincarbonova)-3-dimethylene - eatingrelated and a 9.25 g cyclopropylamine 80 cm3trichlormethane, stirred at a temperature close to 20aboutWith over 5 hours the Solution is concentrated under reduced pressure (20 kPa) and at 40aboutC. the Residue is extracted by 300 cm3ethanol, mix from 8.2 g of DBU and heated under stirring and at about the 75aboutC for 30 minutes After cooling to 20aboutWith insoluble part centrifuged, washed with 2 times 30 cm3of ethanol. Obtain 11.1 g of 1-cyclopropyl-3-etoxycarbonyl-7,8-debtor-4-oxo-1,4-dihydro-1,8 - benzo(b)naphthiridine in a solid yellow color, melting at 230aboutC.

P R I m e R 41. Conducting the reaction under the conditions of example 39, but based on 1,58 g 3-etoxycarbonyl-7,9-debtor-8-[3-(2-furyl)-1-PI - pyrazinyl)-1-methyl-4 - oxo-1,4-dihydro-1,8-benzo(b)naphthiridine (RS) obtain 1.07 g of 7,9-debtor-8-[3-(2-furyl)-1-piperazinil]-1-methyl-4-oxo-1,4-dihydro - 1,8-benzo(b) naphthiridine-3-carboxylic acid (RS) in a solid yellow color, melting at 295-296aboutC.

3-Etoxycarbonyl-7,9-debtor-8-[3-(2-furyl)-1-piperazinil]-1-methyl - 4-oxo-1,4-dihydro-1,8-benzo(b)naphthiridine-(RS) was prepared in the conditions of example 39, but on the basis of 1.85 g of 3-etoxycarbonyl-7,8,9-Cryptor-1-methyl-4-oxo-1,4-dihydro-1,8-benzo(b) naphthiridine and 1 g of 2-(2-furyl)-PI is but 40aboutWith the solid residue is recrystallized from 100 cm3of ethanol. Get 1,72 g 3-etoxycarbonyl-7,9-debtor-8-[3-(2-furyl)-1-PI - pyrazinyl] -1-methyl-4 - oxo-1,4-dihydro-benzo[b]naphthiridine-(RS) in a solid yellow color, melting at 208-210aboutC.

P R I m e R 42. Conducting the reaction under the conditions of example 39, but from 2 g of 3-etoxycarbonyl-7-fluoro-1-methyl-4-oxo-8-[3-(2-tie - nil)-1 - piperazinil)-1,4-dihydro-benzo(b)naphthiridine-(RS) is obtained without recrystallization 1.8 g of pure 7-fluoro - 1-methyl-4-oxo-8-[3-(2-thienyl)-1-piperazin-Nile)-1,4-dihydro-1,8 - benzo(b) naphthiridine-3-carboxylic acid-(RS) in a solid yellow color, melting at 268-270aboutC.

3-Etoxycarbonyl-7-fluoro-1-methyl-4-QA - with-8-[3-(2-thienyl)-1-(piperazinil)- 1,4-dihydro-1,8-benzo(b) naphthiridine-(RS) was prepared in the conditions of example 39, but according to 1.59 g of 3-etoxycarbonyl-7,8-debtor-1-methyl-4-oxo-1,4-dihydro-1,8-benzo(b) naphthiridine and of 1.02 g of 2-(2-thienyl)-piperazine-(RS). Obtain 2.25 g of 3-etoxycarbonyl-7-fluoro-1-methyl-4-oxo-8-[3-(2-thienyl)-1-PI - perazine)- 1,4-dihydro-1,8-benzo(b)naphthiridine (RS) in a solid yellow color, melting at 228aboutC.

2-(2-Thienyl)-piperazine (RS) was prepared in accordance with the conditions described in RA what conditions, described in Ieffrey W. H. Watthey et coll. I. Med.Chem. 26, 1116 (1983).

P R I m e R 43. Conducting the reaction under the conditions of example 39, but from 2 g of 1-cyclopropyl-3-etoxycarbonyl-7-fluoro-4-oxo-8-[3-(2-thienyl)- 1-piperazinil] -1,4-dihydro-1,8-benzo(b)naphthiridine-(RS) gain of 1.75 g of 1-cyclopropyl-7-fluoro-4-oxo-8-[3-(2-thienyl)-1-piperazinil]-1,4 - dihydro-1,8-benzo(b)the naphthiridine-3-carboxylic acid-(RS) in a solid yellow color, melting at 245aboutC.

1-Cyclopropyl-3-etoxycarbonyl-7 - fluoro-4-oxo-8-[3-(2-thienyl)-1 - piperazinil] -1,4-dihydro-1,8-benzo(b)naphthiridine-(RS) was prepared in the conditions of example 39, but on the basis of 1.7 g of 1-cyclopropyl-7,8-debtor-3-etoxycarbonyl-4-oxo-1,4-dihyd - ro-1,8 - benzo(b) naphthiridine and 1 g of 2-(2-thienyl)-piperazine (RS) to obtain 2.2 g of 1-cyclopropyl-3-etoxycarbonyl-7-fluoro-4-oxo - 8-[3-(2-thienyl)- 1-piperazinil] -1,4-dihydro-benzo(b)naphthiridine-1,8 (RS) in the form of a solid yellow color, melting at 210-212aboutC.

P R I m e R 44. Conducting the reaction under the conditions of example 39, but on the basis of 1.6 g of 3-etoxycarbonyl-7,9-debtor-1-methyl-4-QA - with-8-[3-(2-thienyl)-1-piperazinil] -1,4-dihydro-1,8-benzo(b)naphthiridine-(RS) obtain 0.75 g of 7,9-debtor-1-methyl-4-oxo - 8-[3-(2-thienyl)-1-piperazinil] 1,4-dihydro-benzo(b) the naphthiridine-3-carboxylic acid (RS) in the form of a solid vessel)-1 - piperazinil] -1,4-dihydro-1,8-benzo(b)naphthiridine-(RS) was prepared in the conditions of example 39, but on the basis of 1.68 g of 3-etoxycarbonyl-7,8,9-Cryptor-1-methyl-4-oxo-1,4-dihydro-1,8 - benzo(b) naphthiridine and 1.01 g of 2-(2-thienyl)-piperazine-(RS) receive thus 1.68 g of 3-etoxycarbonyl-7,9-debtor-1-methyl-4-oxo-8-[3-(2-thienyl)-1 - piperazinil]-1,4-dihydro-benzo(b)naphthiridine (RS) in a solid yellow color, melting at 220aboutC.

P R I m e R 45. Conducting the reaction under the conditions of example 39, but on the basis of 3.2 g of 3-etoxycarbonyl-7-fluoro-8-[4-hydroxy-1-piperazinil] -1-methyl-4 - oxo-1,4-dihydro-1,8-benzo(b) naphthiridine obtain 2.86 g of 7-fluoro-8-[4-hydroxy-1-piperazinil] -1-me - til-4-oxo-1,4-dihydro-1,8 - benzo(b)the naphthiridine-3-carboxylic acid in a solid yellow color, melting at 290aboutC.

3-Etoxycarbonyl-7-fluoro-8-[4-hydro - XI-1-piperazinil] -1-methyl-4-oxo - 1,4-dihydro-1,8-benzo(b) naphthiridine was prepared under the conditions of example 39, but on the basis of 3 g of 3-etoxycarbonyl-7,8-debtor-1-methyl - 4-oxo-1,4-dihydro-1,8-benzo(b)naphthiridine, 1,97 g dichlorhydrate 1-hydroxypiperidine and 1.99 g of sodium carbonate obtain 3.25 g of 3-etoxycarbonyl-7-fluoro-8-[4-hydroxy-1-piperazinil]-1-methyl-4-oxo - 1,4-dihydro-1,8-benzo(b)naphthiridine in a solid yellow color, melting at 258-260aboutC.

Dichlorhydrate-1-hydroxyprop is 46. Conducting the reaction under the conditions of example 39, but on the basis of 1.4 g of 3-etoxycarbonyl-7,9-debtor-8-[4-hydroxy-1-PI - pyrazinyl]-1-methyl-4 - oxo-1,4-dihydro-1,8-benzo(b)naphthiridine obtain 0.5 g of 7,9-debtor-8-[4-hydroxy-1-piperazinil] -1-me - til-4-oxo-1,4-dihydro - 1,8-benzo(b)the naphthiridine-3-carboxylic acid in a solid yellow color, melting at 285-288aboutC.

3-Etoxycarbonyl-7,9-debtor-8-[4-guide - Roxy-1-piperazinil] -1-methyl-4 - oxo-1,4-dihydro-1,8-benzo(b)naphthiridine was prepared under the conditions of example 39, but on the basis of the 1.9 g of 3-etoxycarbonyl-7,8,9-Cryptor-1-methyl-4-oxo-1,4-dihydro-1,8-benzo(b) naphthiridine, 1 g dichlorhydrate 1-hydroxide - perazine and 1.6 g of potassium carbonate obtain 1.4 g of 3-etoxycarbonyl-7,9-debtor-8-[4-hydroxy-1-piperazinil] -1-methyl-4 - oxo-1,4-dihydro-1,8-benzo(b)naphthiridine in a solid yellow color, melting at 255-258aboutC.

P R I m e R 47. Working as in example 16, but use of 1.16 g of 7,8-debtor-1-methyl-4-oxo-1,4-dihydro-1,8-benzo(b)nafta-ridin-43 - carboxylic acid and 1.8 g (b) 2-(4-dimethylaminophenyl)-piperazine is obtained after heating for about 55 minutes or a temperature of about 100aboutWith subsequent recrystallization 70 cm3DFA, 1.6 g of 7-fluoro-8-3(4-dimethylaminophenyl)-1-piperazine is masegosa at 322aboutC.

(RS) 2-(4-dimethylaminophenyl)-piperazine can be obtained according to the method described in the application for French patent 2 351 108, but using as the source of 4.7 g of 4-dimethylamino-phenylglyoxal and 2.1 cm2Ethylenediamine is obtained 3.1 g (RS) 2-(4-dimethylaminophenyl)-piperazine derivatives in the form of a solid yellow product, melting at 122aboutC.

New derivatives of benzo(b) naphthiridine-1,8 General formula (I) and their pharmaceutically suitable salts are particularly interesting antibacterial properties. They have shown considerable activity in vitro and in vivo in bacteria gram-positive and normal activity against the bacteria responsible for most infections upper and lower respiratory tract.

In tests in vitro, the products of General formula (I) are active at a concentration that is between 0.12 and 4 µg/cm3in relation to the Golden aureus IP 8203.

In tests in vivo, the products of General formula (I) are active against experimental infections Staphylococcus aureus IP 8203 mouse at doses concluded between 2 and 200 mg/kg subcutaneous injection, or at doses of prisoners between 4 and 150 mg/kg for oral administration.

Another inter the introduction of the mouse.

On the other hand, the products are particularly interesting for the prevention and treatment of AIDS (acquired immune deficiency syndrome) and related syndromes (ARC (AIDS related complex).

The studied products slow down cytopathogenic effect of the HIV virus (HIV) in cell culture at concentrations that eliminate cytotoxic and cytostatic effect.

The activity in relation to cytopathology the effect of the HIV virus. Products in powder form were introduced into the solution at 2 mg of product per 1 ml (approximately 4.10-3M) in a mixture of dimethyl sulfoxide (DMSO and L-lysine (base) in a volume ratio of 1:19. First add 1 volume DMSR and dissolve the product as best as possible, then add the 19 volumes of the solution of base L-lysine (4.10-3M) in distilled water. The mixture is aged for 15 min at 60aboutC. in This way we obtain a stock solution with a concentration of DMSO 5% and with a content molar ratio of the product/lysine, close to 1. The test is carried out on the offspring lymphoblastoid THIS clone 13. Microplastic with 96 holes placed 25 µl/well of the test solution in isotonic phosphate buffer (IFB) or one IFB in the event of a control. Strait of cell suspension SEM (between 5 and 8.104cells in 1 ml) in RPMI medium containing 10% calf serum germ (embryo), 100 U/ml penicillin, 100 μg/ml streptomycin and 2 mmol/ml glutamine, and microplastic kept for 1 h at 37aboutC in an atmosphere containing 5% carbon dioxide. For each concentration, the experience is divided into two parts: one part (3 holes) for infected cells to determine the antiviral activity and the other part (3 holes) for uninfected cells to determine the cytotoxicity of the products. Then infect the first series by HIV-1 (100 μl per well of a suspension of virus LAV-I-RU containing 200-300 TSD), whereas other series receives 100 μl of RPMI medium, which was defined previously.

At the end of the 7th day of incubation, 150 μl of cells are taken for analysis to measure cell viability (as determined by the modified method described by R. Pouwels et coll. I. Virol.Meth. 20, 309-321 (1988). Add in the taken sample 10 µl of a solution containing 7 mg MGT (bromide 4,5-dimethyl-thiazol-2-yl-2, 5-diphenyltetrazolium) in 1 ml of isotonic phosphate buffer. After 3 h incubation at 37aboutWith the emerged part removed.

MTT is converted into the salt of formazan (blue) inside living cells and in proportion to their canola (containing 0.04 mol/l chloroethanol acid), and microplastic shaken to dissolve the blue formazan. The absorbance at 540 nm is recorded using an automatic device ELISA on microplastics. This absorption is proportional to the number of living cells.

The results obtained on the 14th day, are shown below in table.1.

Biological tests in vitro. In a series of test tubes containing a certain amount (20 cm3suitable nutrient medium (agar Muller-Hinton) was added 1/10 of this volume of the series, diluted in a geometric progression (2), the test product. The tubes were inoculable using multipoint inoculator, which gave the spot 104columns formed units of the microorganism in soy broth, incubated for 18 h at 37aboutC and diluted in a ratio of 1/100 of the same environment.

After insulinopenia tubes were incubated for 24 h at 37aboutC.

The minimum inhibitory concentration is the lowest concentration at which inhibit the growth of microorganisms.

Activity against intraperitoneal infection in mice. Mice were made intraperitoneal injection of 0.5 cm3appropriate culture for 18 h test selected animals within 24-48 hours This test compound was administered subcutaneously twice at an interval of 5 hours per day of inoculation, the first dose was given 1 h after inoculation with the microorganism. Used with a single dose containing volume 50 cm3/kg.

A therapeutic dose of 50% (SD50) represents the dose of the test compounds, each injection which causes half of the treated animals survive during the test period (8 days).

Activity in vitro and in vivo is shown in table.2 activity in vitro and in vivo in a table.3.

The present invention relates also to pharmaceutical compositions suitable for use in medicine, particularly in veterinary medicine, which contain as the active product, at least one product with the General formula (I) in a pure state (in free form or in salt form or in the form of a mixture with one or more diluents or additives, which is a joint and pharmaceutically acceptable. These compositions can be applied to oral, parenteral or rectal routes.

As solid compositions for oral assignments can be used as tablets, pills, powders or granules. In these compositions, the active product is mixed with about Tavi may also contain in addition to diluents other substances, for example, a lubricant such as magnesium stearate.

As liquid compositions for oral assignments can be used pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents such as water or paraffin oil. These compositions may also contain in addition to diluents other substances, for example wetting, softening or flavouring products.

The parenteral compositions of the destination can be a sterile aqueous or nonaqueous solutions, suspensions or emulsions. As a solvent or a binder can be used propylene glycol, polyethylene glycol, liquid vegetable oils, especially olive oil, or organic esters, which can be injected, for example atreat. These compositions can also contain additives, especially wetting, emulsifying or dispersing agents. Sterilization can be accomplished in several ways, for example, using a bacteriological filter, by introducing the composition sterilizing agents, by irradiation or by heating. They can also be prepared in the form of sterile solid compositions which when used will dissolve in sterile in the program are rectal suppository or capsule, which may contain in addition to the active product of indifferent substances such as cocoa butter or beeswax.

In therapeutic treatment of a human or veterinary compositions particularly useful in the treatment of infections of bacterial origin.

In General, the physician will determine the dosage which he deems most appropriate, depending on age, weight, degree of infection and other factors inherent to the patient to be treated. Usual doses are between 0.2 and 1 g of active product twice a day oral or parenteral routes for adult.

The following examples illustrate the compositions according to the invention.

P R I m e R A. are Prepared in accordance with conventional tablets with a dose of 250 mg of active product having the following composition: (in mg) of 7-fluoro-1-methyl-4-oxo-8-(3-phenyl-1-piperazinil)-1,4-dihydro - benzo(b)naphthiridine-1,8-3-carboxylic acid. (R) 250 Starch 50 Lactose 35 Talc 15

P R I m e R Cent. Prepared in accordance with conventional tablets with a dose of 250 mg of active product having the following composition: (in mg) of 7-fluoro-8-[3-(2-furyl)-1-piperazinil] -1-methyl-4 - oxo-1,4-dihydro-benzo(b) naphthiridine-1,8-3-carboxylic acid (R) 250 Starch 50 Lactose 35 Talc 15

About the plants.

On the other hand, the products of General formula (I) can also be used as agents of preservation and disinfection of organic or inorganic substances. Including in the manufacture of dyes, fats, paper, wood, polymer, or also in the textile industry, in the food industry or in water treatment.

1.Derivatives of 1,8-benzo(b)naphthiridine General formula

< / BR>
where R is hydrogen, the hydroxy-group or alkyl;

R2hydrogen, alkyl, foralkyl, cycloalkyl containing 3 to 6 carbon atoms, alkyloxy or alkylamino;

R3phenyl or alkylphenyl, possibly substituted by one or more halogen atoms or radicals, the alkyl, cycloalkyl containing 3 to 6 carbon atoms, alkyloxy-, cyano-, amino-, alkylamino, dialkylamino, alkyloxyalkyl, hydroxyalkyl, gidroksikislotny, methylendioxy, aminoalkyl, acylaminoalkyl or dialkylaminoalkyl or is fullam or Tienam;

R4hydrogen or fluorine,

moreover, the alkyl radicals are unbranched or branched and contain 1 to 4 carbon atoms,

in the form of their isomers or mixtures of isomers, or salts with metals, or salts obtained by attaching nitrogen based the composition, possess antibacterial activity and activity against the AIDS virus, containing the active principle on the basis of a derivative of piperazine and pharmaceutically acceptable carrier, characterized in that the active agent contains a compound of the formula under item 1 in the form of isomers, or mixtures thereof, or the salt, or hydrate in the amount of 0.2 to 1.0 g per dose.

Priority signs:

30.10.89 when R1hydrogen, alkyl; R2hydrogen, alkyl, foralkyl, cycloalkyl containing 3-6 carbon atoms, alkyloxy or alkylamino; R3phenyl or alkylphenyl, possibly substituted by one or more halogen atoms or radicals: alkyl, cycloalkyl containing 3 to 6 carbon atoms, alkyloxy-, cyano-, amino-, alkylamino or dialkylamino; R4hydrogen or fluorine.

10.07.90 when R1hydroxy, R3alkylphenyl, possibly substituted radicals: alkyloxyalkyl, hydroxyalkyl, hydroxyalkyloxy, methylendioxy, aminoalkyl, acylaminoalkyl, or is fullam or Tienam.

 

Same patents:

The invention relates to new mevalonate with pyrazolopyrimidine ring, processes for their preparation, pharmaceutical compositions containing them and their pharmaceutical use, especially as antihyperlipidemic, hypolipoproteinemia and antiatherosclerotic agents, and to intermediate products useful for their preparation and methods of producing such intermediates

The invention relates to a number of optical active derivatives of endoventricular who possess excellent antiarrhythmic activity, and also provides a stereospecific method of producing the compounds, and methods and compositions which are not used

The invention relates to new derivatives of benzo(b)naphthiridine General formula

R(I) where R1hydrogen, alkyl or hydroxyl radical;

R2hydrogen, linear or branched C1-C4-alkyl, foralkyl, cycloalkyl, alkyloxyalkyl or alkylamino radical;

R3WITH1-C4-alkyl, and R4and R5different and mean hydrogen or C1-C4-alkyl;

or R3hydrogen or alkyl, or cycloalkyl and R4and R5individually, each means hydrogen;

R6hydrogen or fluorine;

n is 1 or 2, or their salts, possess antibacterial property

The invention relates to heterocyclic carbon compounds with medicinal and bioactive properties, to their preparation and use

The invention relates to compounds of the formula I

(I) or pharmaceutically acceptable salt accession acids him or stereoisomeric form of the compound, where

-A1= AND2- A3= AND4- bivalent radical having the formula

-CH=CH-CH=CH- (a-1)

-N=CH-CH=CH- (a-2)

-CH=CH-CH=N (a-5) or

-N=CH-N=CH- (and-6),

n=1 or 2

IN - NR4or CH2< / BR>
R4is hydrogen or C1-C6alkyl

L is hydrogen, C1-C6alkyl, C1-C6allyloxycarbonyl, or a radical of the formula

-Alk - R5(b-1),

-Alk - Y - R6(b - 2),

-Alk - Z1- C(=X) - Z2- R7(b-3), or

-CH2- SNON - CH2- O - R8(b-4), where R5is cyano, phenyl optionally substituted C1-C6alkyloxy; pyridinyl; 4,5-dihydro-5-oxo-1-N-tetrazolyl; 2-oxo-3-oxazolidinyl; 2,3-dihydro-2-oxo-1-N-benzimidazolyl; or bicycling radical of formula (C-4-a)

Gwhere G2- CH=CH-CH=CH-, -S-(CH2)3,- -S-(CH2)/2-, -S-CH=CH - or-CH=C(CH3)-O-;

R6- C1-C6-alkyl, pyridinyl optionally substituted by nitro; pyrimidinyl; feast
R7- C1-C6-alkyl; halophenol; 1-methyl-1H-pyrrolyl; furanyl, thienyl, or aminopyrazine;

R8- halophenol;

Y is O or NH;

Z1or Z2each independently NH or a direct link X-O

each Аlk independently - C1-C6alcander

The invention relates to the derivatives of uracil and their use in agriculture, namely use as herbicides

The invention relates to a series of racemic and optically active derivatives of pyrido[1,2-a] pyrazine, which are used as antidepressants and anxiolytics, as well as intermediates of these derivatives

The invention relates to the production of new proizvodnyh of thiazolidine that are used in pharmaceutical compositions

The invention relates to a series of racemic and optically active derivatives of pyrido[1,2-a] pyrazine, which are used as antidepressants and anxiolytics, as well as intermediates of these derivatives

The invention relates to the field of organic synthesis and the way to obtain new derivatives of N-oilpipe - rationalcanada

FIELD: organic chemistry, medicine, ophthalmology, pharmacy.

SUBSTANCE: invention relates to new derivatives of nitrogen-containing heterocyclic compounds of the general formula (I): wherein X1, X2, X3, X4 and X5 mean -CH2 or one of them represents -NH and another X1-X5 represent -CH2; k = 0, 1 or 2; when t = 2, then radicals R1 are similar or different; R1 represents direct or branched (C1-C8)-alkyl or (C1-C8)-alkoxy-group; A means phenyl or pyridinyl; R2 means hydrogen atom (H), hydroxyl, halogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group; n = 0, 1-4; radicals R2 are similar or different, when n > 1; p = 0 or 1-5; Y means -OC(O); Z means -CH, or to their pharmaceutically acceptable salts. Compounds of the formula (I) possess agonistic activity with respect to muscarinic receptors and can be used in medicine as medicinal preparations for treatment of neurodegenerative diseases or diseases associated with increased intraocular pressure.

EFFECT: valuable medicinal properties of derivatives.

6 cl, 1 tbl, 2 dwg, 16 ex

FIELD: organic chemistry.

SUBSTANCE: claimed method includes reaction of C60-fullerene with 1,2-diaminepropane in presence of Cp2TiCl2 as catalyst in toluene medium at room temperature (approximately 20°C) for 44-52 hours. Yield of target product is 73-90 %. Compound of present invention is useful as chelating agent, sorbent, biologically active compound and for production of new materials with desired electronic, magnetic and optical properties. .

EFFECT: new compound; method of increased yield and selectivity.

1 tbl, 1 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to compounds of formula I , wherein G is carbon or nitrogen atom; A is i) phenyl substituted with any from -COOH, -CONH2, COOCH3, -CN, -NH2 or -COCH3; ii) naphthyl, benzophuranyl, and quinolinyl; and iii) formulae , , .

Compounds of present invention are useful in particular in pain treatment.

EFFECT: new agents for pain treatment.

58 ex

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