PL120154B1 - Process for preparing ovel derivatives of 1,8-naphtiridine - Google Patents

Description

The subject of the invention is a process for the preparation of new 1,8-naphthyridine derivatives of the general formula I, in which X represents a halogen atom, in particular fluorine, and R represents a hydrogen atom or a lower alkali radical, as well as pharmacologically acceptable salts of these compounds. produced by the method according to the invention are highly bactericidal against Gram-positive and Gram-negative bacteria, including Pseudomonas aeruginosa. The term "lower" is used in the description and in the claims to refer to alkali radicals and groups containing alkyl radicals denotes radicals with 1 to 6 carbon atoms. The compounds of formula I form salts with acids and bases. Various inorganic or organic acids can be used as acids, e.g. hydrochloric, acetic, lactic, succinic, lactobionic and methanesulfonic acids, and as bases are also used inorganic or organic bases which give salts with a carboxyl group in the compounds of formula 1. Examples of such bases are hydroxides and carbonaceous metals such as sodium and potassium. Particularly preferred properties have the salts of the compounds of formula I with hydrochloric acid or methanesulfonic acid. Under certain conditions the compounds of formula I exist in the form of hydrates and the preparation of such hydrates also falls within the scope of the invention. The following compounds and their pharmacologically acceptable salts are: 1-ethyl-6-fluoro-1,4-dihydro-4-keto-7- (1-piperazinyl) -1,8-naphthyridine-3-carboxylic acid of formula U , ethyl ester of an acid of formula II, as well as 1-ethyl-6-chloro-1,4-dihydro-4-keto -7- (1-piperazinyl) -1,8-naphthyridine-3-carboxylic acid The above-mentioned acid of formula U and its salts have the most valuable antimicrobial properties of the compounds according to the invention. As shown later in the description, this compound is highly effective against bacteria in vitro and in vivo, and because at the same time it has negligible toxicity, it can be used in the control of urinary tract infections by Gram-positive and Gram-positive bacteria. - negative, as well as to combat the prohibitions of other systems. Compounds of formula I, in which X is as defined above and R is a lower alkyl radical, also exhibit quite strong antibacterial activity in vivo, and are also useful as intermediate products for the preparation of other compounds of formula (1). The structure is similar to that of compounds of formula I and is known from US Pat. No. 120,154 US Am. No. 4,017,622 piperazine derivatives of the formula 2, in which Rx represents a hydrogen atom, an alkyl radical with 1-4 carbon atoms, a benzyl radical or an acetyl group, R2 is a hydrogen atom, an alkali radical containing 1-4 carbon atoms, • the radical benzyl or vinyl, and R3 represents a hydrogen atom or an alkyl radical of 1-6 carbon atoms. As can be seen from formula 2, these compounds do not have a substituent at position 6 of the naphthyridine ring. In the tests described below, it has been shown that the compounds of the invention are active against gram-negative bacteria, including Pseudornonas aeruginosa, as well as against gram-positive bacteria, surprisingly much more effectively than T ^ in ^ KT ^ in KrifAzor 2.IZ of the printed Japanese manuscript No. 83 590/77, and a summary of which is given in the publishing list. «Sfl * f! by Derwent Fublications Ltd. (Der. No.OffiLfiS ^ fSSl ^^ zriaaiiJsa 6-nitro-1,8-naphthyridine derivatives of formula 3 wherein the group of formula -N (R) (R ') is an amino group, substituted anilino, alkylamino, cycloalkylamino, dialkylaminoalkylamino, hydroxyalkylamino, dialkylamino, alkylallylamino, alkylcycloalkylamino, dihydroxyalkylamino, pyrblidine, piperidine, morpholdnine, and the same description as R 2 and rhodium alkyl. However, the only point is that these compounds are effective against Trichinella and there is no mention of antimicrobial activity. In the report of the 98th Congress of the Japanese pharmaceutical society Jia, p. 223, published on March 10, 1978, there is an information ¬ation of p compounds of formula IV in which R x is ethyl or a corresponding radical, R2 is hydrogen, R3 and R3 are electron-attracting groups and R4 is an electron donating group. Formation, compounds of formula IV in which R3 and R5 are chlorine or fluorine and R4 is a piperazine group, optionally substituted, were investigated to establish the relationship between their structure and properties. It was found that the compounds in which R2 is an ethyl radical , R2 is hydrogen, R3 or. R5 is chlorine or fluorine and R4 is piperazine, have antimicrobial properties stronger than 1-ethyl-1,4-dihydro-7-methyl-4-keto acid -1,8-naphthyridine-3 carboxylic acid. US Am. No. 4, 14, 719, corresponding to Belgian Patent Specification No. 863,429, quinoline derivatives of formula 5 are known, and the Japanese Patent Publication No. 65,887/78 (Derwent No. 52,436 A / 29) discloses quinoline derivatives of the formula On day 6. The results of the tests given in Tables 2 and 3 below show, however, that the compounds produced by the method according to the invention have an activity against gram-negative bacteria, including Pseudornonas aeruginosa bacteria, much stronger than the compounds of the present invention. formulas 5-6. According to the invention, compounds of formula I in which X and R are as defined above are prepared by ethylation of compounds of formula 7 in which X is as defined above, the symbol H ** "Htcrm" "" wTK2 or an amino protecting group, and R4 is a carboxyl group; a lower alkoxycarbonyl group or a group of the formula -R4 in which R'4 is a cyano group, a carbamoyl group or a group of the formula 8 in which Alk is a lower alkyl radical. Known ethylating agents are used in the ethylation process, such as ethyl halides, for example ethyl iodide or ethyl esters, for example diethyl sulfate, ethyl p-toluenesulfonate or triethyl phosphate. The reaction components are usually used in stoichiometrically calculated amounts. and the reactions are carried out in an inert solvent at a temperature of 25 ° -150 ° C. If R3 is a protecting group in the compound of Formula 7, then an excess of ethylating agent is preferably used. Solvents used are, for example, ethanol, methyl ethylene glycol, dimethylformamide, dimethyl sulfoxide and water. The course of the reaction can be accelerated by adding an acid binding agent, for example a base such as an alkali metal carbonate, hydroxide or alkanolate, sodium hydride, pyridine, triethylamine or benzyltrimethylammonium hydroxide. The obtained product, in which R4 represents a group of the formula -R'4, is then hydrolyzed and / or the product in which R3 is a protecting group is subjected to cleavage of this protecting group. Hydrolysis of the R4 group is carried out with water, the addition of an acid or base catalyst to accelerate the reaction. Inorganic or organic acids or bases may be used, for example acids such as hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, trifluoroacetic, formic and toluenesulfonic acids, and, for example, bases such as alkali metal or alkaline earth metal hydroxides. For example, sodium or barium hydroxide, alkali metal carbonates, for example sodium or potassium carbonate, and also sodium acetate. These reactions are preferably carried out by heating the compound to be hydrolyzed in a solvent environment and with the addition of water. Water is usually used as the solvent, but depending on the nature of the compound, solvents such as ethanol, dioxane, ethylene glycol dimethyl ether, benzene or acetic acid mixed with water may be used. The reactions are usually carried out at 0 ° -150 ° C., preferably 30-100 ° C. The protecting group R 3 is cleaved, preferably by solvolysis or hydrogenolysis, depending on the nature of the group. Examples of R3 groups that can be cleaved by solvolysis, including hydrolysis, are formyl, acetyl, trifluoroacetyl, benzyloxycarbonyl, and indi- vidual (butotascarbonyl, p-methoxybenzyloxycarbonyl, vinyloxycarbonyl, vinyloxycarbonyl, - / p-toluene Q-120 134 sulfonylAethoxycarbonyl, "o-nitrophenylsulfenyl, trimethylsilyl, triphenylmethyl, tetrahydropyranyl and diphenylsulfinyl. Solvent reactions are carried out in a solvent or base, optionally in the presence of such an acid, for example. In discussing the hydrolysis of the R4 group, water is usually used as the solvent, but it is also possible to use a mixture of water with solvents such as ethanol, dioxane, ethylene glycol dimethyl ether, benzene or acetic acid. The reaction is carried out at temperatures between 0 ° and 150 ° C. ° C, preferably 30-100 ° C. Examples of Rs groups which can be cleaved by reduction are arylsulfonyl groups such as p-toluene nosulfonyl, methyl substituted groups such as benzyl or benzyloxy groups such as benzyl, triphenylmethyl or benzyloxymethyl groups, or arylmethoxycarbonyl groups such as benzyloxycarbonyl or p-methoxybenzyloxycarbonyl. "" "" In the cleavage of the protecting group K3, the conditions of the hydrogenolysis process are adapted to the nature of the group. Usually, the product to be reacted is treated with hydrogen in the presence of a catalyst such as platinum, palladium, Raney nickel, etc., in an inert solvent. It is also possible to apply reductions with metallic sodium in liquid ammonia or with a metal such as zinc in acetic acid or in an alcohol, for example methanol. Catalytic hydrogenolysis is carried out at room temperature or elevated to 60 ° C. Solvents used are, for example, ethylene glycol, dioxane, dimethylformamide, ethanol or acetic acid. If the protecting group is a benzyl, triphenylmethyl or p-toluenesulfonyl group, this group can be cleaved with sodium metal in liquid ammonia, usually at -50 ° C to -20 ° C. Starting compounds of formula 7 are new compounds. An example of their preparation is shown in the diagram given in the figure. In the formulas in this scheme, Et is the ethyl radical and A- is the boronic acid anion HBF4. In the first stage of the process, the compound of formula 12 is reacted in a known manner with the piperidide of the monoethyl ester of carbonic acid and the compound obtained of formula 13 is aminated at position 2 in a known manner with ammonia in ethanol and then acetylated at this position also in a known manner, producing a compound of formula 14. The nitro group in the 5-position of this compound is diazotized, reduced and in the resulting the compound of formula 15, the amino group in the presence of fluoroboric acid, and heats the resulting compound of formula 17 to give the compound of formula 17. From this compound, by hydrolysis with hydrochloric acid in ethanol, the compound of formula 18 is prepared, which is condensed with Diethyl 2-ethoxyethylene dicarboxylate to give the compound 6 10 20 29 30 33 40 45 50 55 mp of formula 9, which is cyclized by heating at 140-260 ° C. in a solvent. a suitable boiling point, such as, for example, diphenyl ether, diphenyl, phthalate, dibutyl, o-dichlorobenzene, diphenylene oxide or mixtures thereof. The addition of known cyclization accelerators, such as polyphosphoric acid, lower alkyl polyphosphate, concentrated sulfuric acid, phosphoryl chloride or phosphorus pentoxide, may also be used. If the addition of polyphosphoric acid, alkyl polyphosphate or phosphorus pentoxide is used, the reactions are carried out in a solvent such as benzene, dioxane or dimethylformamide, and when sulfuric acid is used the solvent is usually acetic anhydride or acetic acid. If the cyclizing additive has the appropriate properties, it can also act as a solvent. When using a cyclizing agent, the reactions are usually carried out at a temperature lower than the above-mentioned, preferably 100-160 ° C. The compounds prepared by the method according to the invention are isolated and purified by known methods. Depending on the nature of the starting products and the reaction conditions, the compounds of formula I are obtained in the free state or in the form of a salt, and the compounds in the free state can be converted into salts which act with pharmacologically acceptable acids or bases. For this purpose, various inorganic or organic acids should be used, e.g. hydrochloric, acetic, lactic, succinic, lactobionic, oxalic and methanesulfonic acids. As stated above and demonstrated in the tests described below, the compounds produced According to the invention, they have very good properties with low toxicity, so they can be used preventively and in the treatment of bacterial infections in warm-blooded animals, including humans. The dose of these compounds depends on the age, body weight and condition of the patient, the method of drug administration, etc. The daily dose for adults is 0.1-7 g, preferably 0.2-5 g of the compound of formula I or the same. salt. These compounds are used in the form of preparations containing also solids or - liquid pharmacologically acceptable additives, not reactive with the compounds of formula 1. Examples of such additives are: water, gelatin, lactose, starch, cellulose (preferably microcrystalline) , carboxymethylcellulose, methylcellulose, sorbitol, talc, magnesium stearate, vegetable oils, benzyl alcohol, resins, propylene glycol, polyalkylene glycols and methylparaben. Preparations may be in the form of powders, grains, tablets, ointments, capsules, creams, etc. They may be brightened and / or contain preserving, stabilizing and wetting agents. They may also contain other biologically active substances. The following describes tests in which the properties of the compounds prepared according to the invention were compared with those of the known compounds and compounds of formula 10 , which is an rcw-independent derivative of 1,8-naphthydine not covered by the formula-120 154 rem 1. As the method of producing this compound has not been The process is thus illustrated below. To a mixture of 12 ml of 37% formaldehyde and 18 ml of formic acid is added 6.0 g of 1-ethyl-6-fluoro-1,4-dihydro-4-dihydrate. , cat. 7- (1- (piperizitinyl) -11, 8-naphthyridine-3-carboxylic acid and stirring is kept at 120-125 ° C for 4 hours. The mixture is then evaporated to dryness under reduced pressure, the residue is made alkaline with an aqueous solution of sodium bicarbonate to a pH of 8 and extracted with chloroform. The extract is dried, the solvent is evaporated and the residue is recrystallized from a mixture of dichloromethane and ethanol to give 5.0 g of 1-ethyl-6-fluoro-1,4-dihydro-7- (4-methyl-) acid. 1- piperazinyl / -4-keto-1,8-naphthyridine carboxylic acid of formula 10, mp 228-230 ° C., Test 1. Method given in Chemotherapy, 22 (6), p. 1128, (1974) the minimum concentration of the compounds according to the invention and the compounds known in vitro against 19 different strains of bacteria was determined. The values of this minimum MIC concentration are given in Tables J, Ia and Ib in g / ml. In this table, as well as in the following tables, tested compounds covered by the general formula 1 are marked with numerical symbols, and known compounds - with letter symbols. The meaning of these symbols is as follows: compound 1 - compound of formula li, compound 1 '- compound of formula 1', compound 2 '- compound of formula 12', compound A - compound of formula 2a, known from the description U.S. Patent US Am. No. 4,017,622, compound B - compound of formula 10, compound C - compound of formula 6, known from Japanese Laid-open Patent No. 65887/78, compound D - compound of formula 5, known from Belgian Patent No. 863 4) 29, Compound E - 1-Ethyl-1,4-dihydro-7-methyl-4-keto-1,8-naphthyridine-3-carboxylic acid (U.S. Patent No. 3,149,104 ), compound F - 8-ethyl-5,3-dihydro-5-ke-to-2- (1-piperazinyl) -pyrido [2,3-d] pyrimidinecarboxylic acid-6 (US Patent No. No. 3,887,557), compound G - α- (5-indenyloxycarbonyl) -benzylpenicillin sodium salt (Carindacillin) (U.S. Patent No. 3,557,090), compound H - Da-aminobenzylpenicillin (am ¬ picillin) (U.S. Patent No. 2,985,648), Compound J - 7- (Da-aminophenylacetamino) -desoacetoxycephalosporanic acid (Cephalexin) (U.S. Patent No. 3,507,861) The results given in Tables 1, la, Ib show that the compounds produced by the method according to the invention, and in particular The compounds of formula I, 1 'and 12' are highly effective against gram-positive and gram-negative bacteria, including Pseudomonas aeruginosa. The known compound of formula 2a is active against gram-positive and gram-negative bacteria. S Table 1 Activity against bacteria in vitro 20 25 30 35 53 eo Bacteria 1 Gram-positive bacteria Staphylococcus aureus 209F JG-1 Staphylococcus aureus No. 50774 Streptococcus faecalis | P-2473 Streptococcus pyogenes 65A Corynebacterium pyogenes | c "21 Gram-negative bacteria Escherichia coli NIHJ JG-2 Escherichia coli P-5101 Escherichia coli P-140a Salmonella typhimurium | S-9 Salmonella enteriridis 1 No. 1291 Tested compounds | 1 2 0.78 0.78 12.5 12 , 5 1.56 0.2 0.1 0.2 0.1 0.1 Shigella flexneri 2a 1 0.2 Shigella flexnari 4a P-330 Klebsiella pneumoniae No. 13 | Enterobacter cloacae P-2540 Pseudomonas aeruginosa 1 Tsuchijima Pseudomonas aeruginosa No. 12 "| , Serratia marcescens IFO 3736 Proteus morgenii Kono Proteus mirabilis P-2381 0.39 0.2 0.2 0.39 0.78 0.39 0.2 0.39 1 '3 0.78 0.78 12.5 12 , 5 1.56 0.2 0.1 0.2 0.1 0.1 0.2 0.39 0.2 0.2. 0.39 0.78 0.39 0.2 0.39 2 '1 4 3.13 6.25 25 12.5 6.25 0.78 0.39 1 0.39 0.39 1 0.39 0 , 78 1.56 1.56 0.78 6.25 6.25 1.56 | 1.56 3.13 in total less than the compounds according to the invention. Trial 2. In vivo treatment efficacy. The compounds of the invention and the known compounds were dissolved in deionized water or suspended in 0.2% aqueous carboxymethylcellulose solution and administered orally to infected mice under study 121154 Table 1 Bacteria 1 Gram-positive bacteria 1 Staphylococcus aureus 209Poc-1 Staphylococcus aureus 209Poc aureus No. 50774 Streptotocuccus faecalis P-2473 Streptococcus pyogenes 65A | Corynebacterium pyogenes C-21 and Gram-negative bacteria and Escherichia coli N1HJ JC-2 Escherichia coli P-5101 Escherichia coli P-14Ca Salmonella typhimurium S-9 Salmonella enteritidis No. 1891 Shigella flexneri 2a Shigella flexnari 4a P-330 Klebsiella pneumoniae No. 13 Enterobacter cloacae P-2540 Pseudomonas aeruginosa Tauchijima 1 Pscudomonas aeruginosa No. 12 Serratia mercascens IFO 3736 Proteus morganii Kono Proteus mirabilis P-2381 Tested compounds 1 • A 1 2 ¦2 "5 50 ¦ 100 50 50 6.25 3.13 6.25 6.25 1.56 6.25 12.5 12.5 6.25 25 25 12.5 6.25 25 • 1 B 1 3 | 1.56 1.56 12.5 6.25 1.56 0.39 0.2 0.39 0.2 0, 1 0.39 0.78 0.39 0.39 1.56 3.13 1.56 0.78 1.56 1 C 1 4 0.78 1.56 6.25 6.25 1.56 0.39 0.2 0.2 0.2 0.2 0.39 0.2 0.78 0.2 3.13 3.13 0.78 0.39 0.39 D 1 5 0.39 0.78 3, 13 1 - 0.78 0.1 0.05 0.1 0.05 0.05 0.1 0.2 0.2 0.1 0.39 1 1 0.78 0.2 0.1 0.2 E 1 6 100 1 50 200 200 200 r2.5 3.13 - 3.13 3.13 6.25 - 12.5 6.25 200 200 6.25 6.25 - Table Ib Bacteria- 1 and Gram bacteria -positive Staphylococcus aureus 209P JC-1 Staphylococcus aureus No. 50774 Streptococcus faecalis P-2473 Tested compounds F 2 12.5 25 200 G 3 0.39 0.78 ¥ H 4 0.05 0.1 1.56 J 5 1 , 56 I 1.56. 20011 120 154 12 table Ib cd Bacteria 1 1 Streptoeoccus pyogenes 65A Corynebacterium pyogenes C-21 Gram-negative bacteria Escherichia coli NIHJ JC-2 Escherichia coli P-5101 Escherichia coli P-140a Salmone lla typhimurium S-9 Salmonella enteritidis No. 1891 Shigella flexneri 2a Shigella flexnari 4a P-330 Klebsiella pneumoniae No. 13 and Enterobacter cloacae P-2540 Pseudomonas aeruginosa Tsuchijima Pseudomonas aeruginosa No. 12 Serrabia marcescens IFO 3736 Proteus morganii Kono Proteus mirabilis P-2381 Test compounds | • F 1 2 200 25 1.56 1.56 1.56 1.56 1.56 3.13 1.56 6.25 1.56 12.5 25 3.13 3.13 3.13 1 G 1 3 0.2 3.13 6.25 6.25 50 0.78 0.78 12.5 6.25 200 3.13 6.25 50 3.13 0.78 0.78 1 H 1 4 0.025 1 1, 56 6.25 6.25 200 0.39 0.2 3.13 6.25 100 200 200 200 25 100 3.13 1 J 1 1 5 0.78 1.56 12.5 12.5 200 6.25 3.13 12.5 200 6.25 200 200 200 200 1 200 12.5 microorganisms, indicating the dose value ** EDg0. The studies were carried out with male mice (ddY) weighing about 20 g. The test compounds were administered twice, 5 minutes and 6 hours after the infection. It was infected as follows: 1. Stephylococcus aureus No. 50774. It was forbidden to suspend the bacteria intravenously in saline using 5-10 LDFQ, which is approximately 5-108 bacterial cells for each mouse. The observations were made during 14 days. 2. Escherichia coli P-5101. It was forbidden to suspend the bacteria in soybean extract with 4% of mucin, using 5-10 LD50, that is, about 9-106 bacterial cells for each mouse. Observations were carried out for 7 days. 60 3. Pseudomonas aeruginosa No. 12. The bacterial suspension from soybean extract of 410 µmin was forbidden intraperitoneally using 50-100 LD50, that is, about 5.110 bacterial cells per mouse. Observations were made for 7 days. The test results are given in Table 2. These are ED50 values in mg / kg, calculated by the Behrens-Kaerber method (Arch. Exp. Pat. Phem. 162, p. 480, 1931). The values in the table are marked with the symbol x given in terms of free carboxylic acid. The results given in Table 2 allow the following conclusions to be drawn: 1. Compounds of formulas l1 and 1 'show a strong therapeutic effect in systemic infections with Gram-positive bacteria and Gram-negative, 2. Compounds of the formula II and I 'prepared according to the invention show, in systemic infections with gram-negative bacteria, in particular Pseudomones aeruginosa, a stronger action than compounds A, C, E and F known as anti-bacterial agents. antibacterial agents and compounds G, H and J, which are known antibiotics. 3. Compounds of formulas l1 1 'have a much stronger effect in vivo against gram-positive bacteria than the known compound D, and compounds of formulas13 Table 2 In vivo efficacy against systemic infection in mice Test compound Compound 1 Compound ¦ 1' Compound 2 ' Compound 1 ethyl ester Compound A Compound B Compound C Compound D Compound E Compound F Compound G Compound H Compound J Bacteria Staphylococeus aureus No. 50774 10 10 * about 90 * about 20 100 4.8 about 100 21.9 800 215 10-40 2.2 12.1 and Escherichia coli P-5101 1.8 1.8 * 6.5 * 1.2 about 15 4.7 29.2, 21.2 100 43.5 22.6 Pseudo- monas aeruginosa Nr 12. 9.0 9.0 * 58.6 * 21.0 200 10.6 100 15.5 200 99.5 201.6 400 400 l1 ir are significantly more effective in vivo against gram-negative bacteria, These against Pseudomonas aeruginosa bacteria than the known compound D. 4. The ethyl ester of the compound of formula I1 produced by the process of the invention, being an intermediate in the preparation of compounds of the formulas I1 and I ', also has a strong effect in vivo against bakte Gram-positive and Gram-negative rioms. Trial 3. In vivo therapeutic efficacy. Compound 1 and the known compound D were also tested in order to compare their efficacy against the increasing kidney infections in mice with the bacteria Pseudomonas aeruginosa No. 12. Female mice (ddY-s) weighing 2 (2 - 30 g anesthesia with intravenous 50 mg / kg of pentobarbital sodium was used, then the bladder was exposed through a small incision in the abdomen, and the bladder was exposed with a 0.25 ml syringe with a 0.25 mm needle, 0.1 ml of a 1: 10,000 culture solution was forbidden. Pseudomonas aeruginosa No. 12, prepared for 20 hours in a soybean extract. The mice were not given water to drink during the 1 day before the infection and 1 day after the order, and from the day of the infection they were given 2 times a day for 3 days. The kidneys were excised transversely on the day after infection, and overnight the bacteria were cultured at 37 ° C on King A agar. If no bacteria was subsequently found, the compound was considered to protect against kidney infection. pr Table 3: In vivo efficacy against mouse kidney infection with Pseudomonas aeruginosa No. 12 Test compound Compound 1 Compound D Administration Oral Oral ED50 mg / kg 2.4 16.1 The results in Table 3 show that that the effectiveness of the compound according to the invention, namely the compound 1, in increasing kidney infection with the bacteria Pse-udomonas aeruginosa No. 12, is significantly higher than that of the known compound D. Test 4. Acute toxicity. Solutions containing the individual compounds according to the invention or known compounds were administered orally at various concentrations to groups of 4-8 male mice (ddY) in doses of 0.1 ml per 10 g of body weight, and the number of dead mice was determined after 7 days. calculating the lethal dose LD50 in mg / kg by the method of Dehreus-Kaerbar. , ft The results are given in Table 4, where the values denoted by x represent values converted to free carboxylic acid. Table 4 33 Acute toxicity in mice Test compound [Compound I 1 Compound 1 'Compound 2' Compound B Compound C Compound D Compound E Compound F Compound G Compound H Compound J LD50 mg / kg over 4000 over 4000 * over 2000 * 210 over 2000 over 2000 1516 over 5000 over 4000 over 5000 3000 The results given in Table 4 show that the toxicity of the compounds produced according to the method according to of the invention is negligible, and the compound B is produced by introducing a methyl radical at the 4-position of the piperazinyl group of compound 1, produced by the method of the invention, although having the same or even greater efficacy against bacteria than the compounds of the invention. However, 12B154 15 (see Tables 1, 1a, Ib 1 2), however, has a very high toxicity. Test 5. Subacute toxicity. Compound 1 was administered orally to 6 female mice (JOL-L.CE strain, with an average body weight of 20 g, using a dose of 2 g / kg over 14 days. During this period, each mouse was weighed and waited. Fifteen days were examined hematologically, and after examination, necropsy was performed, organs were weighed and examined for possible tissue disease. Mice treated with Compound 1 showed no disturbance in weight gain or signs of disease compared to mice in the control group that were not treated with this compound, indicating that the compound can be administered without causing any harmful effects. Erófca 6. Plasma concentration. A male dog JBeagle weighing 12 kg was administered orally a capsule containing one of compounds 1 and 2 in doses of 25 mg / kg with 200 ml of milk, and after 0.5, 1, 2, 3, 6, 8 and 10 hours, a blood sample was taken by venipuncture and then the blood was centrifuged in order to separate the plasma. The concentration of the tested compounds in the plasma was determined cylinder-plate thin film method, using Escherichia coli Kp as indicator microorganism. The results are given in Table 5 in µg / ml. Table 5 Plasma concentration in µg / ml Test compound Compound 1 Number of hours after administration of test compound 0.5 0.6 1. 2.4 2 5.5 3 5, 9 6 4.2 8 3.7 10 2'4 The results given in Table 5 give the following conclusions: Compound 1 prepared by the method according to the invention is well absorbed by the body when administered orally and its high plasma concentration is maintained for quite a long time. In particular, the plasma concentration of Compound 1 within 1 to 10 hours of administration is above the lowest MIC concentration at which the compound is effective against most bacteria (see Table 1, la, Ib). For example, the plasma concentration of Compound 1, 5.9 µg / mL, is about 8 times the lowest concentration at which it is effective against Pseudomonas aeruginosa No. 12 and Sptahylococcus aureus No. 50774, and about 60 times greater for the bacteria Escherichia coli P = 5101. The results given in Table 5 show that the compound 1 produced by the method according to the invention has a high concentration in plasma and even at low doses it is effective in combating systemic infections with various bacteria. riami.Trial 7. Urinary excretion. The match of the dogs subjected to the test described in trial 6 was collected over 24 hours and its urine content was determined using the method given in trial 6. The results of the trials are given in Table 6. Table 6 Tested excretion of compounds with urine 10 Test compound Compound 1 Concentration of compound in urine ng / ml 606 Amount of compound excreted% 40.7 The data in Table 6 allows the following conclusions to be drawn: 1. Compound 1 is fairly well excreted with urine and within About 40% of the compound is excreted in the urine 24 hours after oral administration. 2. The concentration of compound 1 is approximately 51-6000 times the lowest concentration at which this compound is effective against a variety of bacteria (04l (2, 15 [Ag / ml according to Table 1, la, lib). Compound 1 is highly effective even at low doses against infections of the urinary tract by various bacteria. As shown in Tables 1-6, the compounds of the invention, especially the compounds of the formulas I1 and 1 ', have a strong therapeutic effect against Artificially induced infections with Gram-positive and Gram-negative bacteria, and after oral administration, remain in high concentrations in the plasma and in the urinary tract for a long time. Moreover, their toxicity is low, so they can be used even in small In contrast to this, the known compounds A and C have antibacterial activity in vitro and in vivo against gram-positive and gram-negative bacteria from Compoundingly worse, as shown in Tables 1, 1a, Ib and 2. The known compound D, in the case of combating the increasing kidney infection with Pseudomonas aeruginosa bacteria, has a therapeutic effect that is worse than the compounds of the formulas I1 and 1 '. Compounds E and F, known synthetic antibacterial agents, and compounds G, H and J, known antibiotics, have an in vivo therapeutic effect against bacterial infections. Gram-negative bacteria, especially Pseudomonas aeruginosa bacteria, are significantly inferior to the compounds of the formulas I1 and I according to the invention. The method of producing the compounds of formula I is illustrated below. Example I. Preparation of the compound of formula I1 and its To a suspension of 1 g of ethyl 7- / 4-ethoxycarbonyl-1-piperazinyl) -6-fluoro-1,4-dihydroTO-4-keto-1,8-naithyridine carboxylic acid in 10 ml of dimethylformamide, add 0 53 g of sodium carbonate and stirred at 60 ° C 2 O 1 17 for 10 minutes, then 1.2 g of ethyl iodide and sword are added at 60-70 ° C for 2 hours. . The mixture is then evaporated to Luolia in vacuo, the residue is added with water, the solution is extracted with chloroform, the extract is dried over anhydrous potassium carbonate and the chloroform is evaporated off. The residue is recrystallized from a mixture of dichloromethane and n-hexane to give 0.89 g of ester. 1-ethyl-6-fluoro-1,4-10,7-dihydro-4-keto-7- (4-ethoxycarbonyl-1-piperazinyl) -1,8-naphthyridine-3-carboxylic acid ethyl, mp 171-173 ° C. A mixture of 0.8 g of this ester, 6 lvl 103% of sodium hydroxide and 2 ml of ethanol is boiled under reflux for 3 hours, then cooled, and 10% acetic acid is added until the value of p 7 is obtained. 0-7.5, the separated precipitate is filtered off, washed with ethanol and recrystallized from a mixture of dimethylformamide and ethanol. 0.57 g of 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7- (1-pip-3razinyl) -1,8-naphthyridinecarboxylic acid-3 is obtained in the formula II. The product melts at 220 ° C to 224 ° C. 0.2 g of the acid obtained was dissolved in 5% hydrochloric acid and the solution was evaporated to dryness under reduced pressure. The residue was recrystallized from water to give 0.21 g of the hydrochloride of the acid of formula II. The product melts above 300 ° C. 30 In the second test, 0.2 g of the acid of formula I1 is dissolved in 7N at elevated temperature, and then cooled, the precipitate formed is filtered off and recrystallized from dilute methanol to give 0.22 g of the acid salt. of Formula I1 with methanesulfonic acid, ie the compound of Formula I '. The product melts with decomposition at temperatures above 300 ° C. In the third test, 1.0 g of the acid of formula I1 is dissolved in hot ethanol, 1.0 ml of acetic acid is added, it is cooled and the crystalline precipitate is filtered off. This product was recrystallized from ethanol to give 0.93 g of the acid addition salt of formula I with acetic acid. The product melts at 228 ° -229 ° C. The 7- (4-ethoxycarbonyl-1-piperazinyl) -6-fluoro-1,4-dihydro-4-keto-1 acid ethyl ester used in this example is used as a starting product. The 8-naphthyridine-3-carboxyl-3 of formula 11 is prepared as follows: Reacted with N-ethoxycarbonyl-piperazine 2, u-dichloro-3-nitropiperazine to give 6-chloro-2- (4-ethoxycartonyl-1-piperazine) Without purification, it is heated with ethanolic ammonia in a sealed tube at 120 ° -125 ° C. to give 6-amino-2- (4-ethoxycarbonyl-1-piperazine). 1H-3-nitropiperidine, m.p. 132-134 ° C. This product was treated with acetic anhydride in acetic acid to give 6-acetylamino-2- (4-ethoxycarbonyl-1-piperazinyl) -3-nitropiperidine, mp 168-169 ° C. This compound is hydrogenated catalytically with C.sub.6 palladium on carbon to give 3-amino- &lt; 18 -6-acetylamino-2- (4-ethoxycaronyl-l-piperase-l-pyridine) which dissolves without purification. in a mixture of ethanol with 42% of tetrafluoroboric acid and to the resulting solution is added a solution of isoamyl nitrite in ethanol with stirring at a temperature below 0 ° C. After 20 minutes, ether is added to the solution, the precipitate formed is filtered off and washed with a mixture of methanol and ether and then with chlorophyll. There is obtained 6-acetylamino-2- (4-ethoxycarbonyl-1-pipazinyl) -3-pyridine diazonium tetrafluoroborate, mp 117-117.5 ° C (signs of decomposition). Suspension of the obtained diazonium salt in The slush is heated with stirring in a bath at 120 ° C. for 30 minutes, the solvent is evaporated under reduced pressure and the residue is made alkaline with a 10% solution of sodium carbonate and then extracted with chloroform. The extract is dried over anhydrous potassium carbonate, the solvent is evaporated, and the residue is recrystallized from ethyl acetate to give 6-acetylamino-2- (4-ethoxycarbonyl--1-piperazinyl) -3-fluoropyridine, mp 132-133 ° C. This product is hydrolyzed with a 15% mixture of hydrochloric acid and methanol (1: 2 by volume) to give 6-amino-2- (4-ethoxycarbonyl-1-piperazinyl) -3-yluoropyridine. This product is treated at 130 ° -140 ° C. with ethoxymethylene malonic acid diethyl ester to give N- [2- (4-ethoxycarbonyl-1-piperazinyl) -3-fluoro-6-pyridyl acid ethyl ester. j] -aminomethylene malonic, mp 144-145 ° C. This compound is cyclized by heating at 255 ° C to give 7- (4-ethoxycarbonyl-1-piperazinyl) -6 acid ethyl ester. -fluoro-1,4-dihydro-4-keto-1,8-naphthyridinecarboxylic-3 with a melting point of 279-281 ° C. Example 11. Preparation of the compound of formula I2 Proceed in an analogous manner to that described in the example I, but starting from 7- [4-ethoxycarbonyl-1-piperazinyl) -1,4-dihydro-4-keto-1,8-naphthyridine-3-carboxylic acid as starting product, G-chloro-l-ethyl-l, 4-dihydrogen-4-keto-7- (lH-piperazinyl] -l; 8-naphthyridine-3-carboxylic acid hydride. The product melts at a temperature above 30 ° C. Example 111. Preparation of the ethyl ester of the compound of formula II. In a similar manner to that described in Example I, by reacting the ethyl ester of 6-fluoro-1,4-dihydro-4-keto acid. 7- (4-trifluoroacetyl-1-piperazinyl) -1,8-naphthyridine-3-carboxylic acid with ethyl iodide and potassium carbonate in dimethylformamide is prepared 1-ethyl-6-fluoro-1,4-acid ethyl ester. dihydro-4-keto-7- (4-trifluoroacetyl-1-piperazinyl) -1,8-naphthyridine-3 carboxylic acid. This ester is hydroxylated with an aqueous solution of potassium carbonate in a mixture of chloroform and methanol to give the ethyl ester of 1-ethyl-6-fluoro-19m4 -1,4-dihydro-4-keto-7- (1-piperazinyl). -1, α-naphthyridine-3 carboxylic acid having a melting point of 150-151 ° C. Example IV. Preparation of propyl ester and acid butyl ester of formula I. 1-Ethyl-6-fluoro-1,4-dihydro-4-keto-7- / 1-propyl ester is prepared analogously to that described in Example III. - piperazinyl (-1,8-naphthyridine-3-carboxylic-3), R3 is lower alkoxyifoonyl and R4 is lower alkoxycarbonyl, reacted with an ethylating agent, and then hydrolyzes the reaction product to obtain optionally converting the compound of the formula I into a pharmacologically acceptable salt. 3. Process for the preparation of the new 1,8-naphthyridine derivatives of the general formula I, in which X is a halogen atom and R is a lower melting point of 133-135 ° C and a butyl ester is an alkyl radical, and X is a chlorine atom of the acid 119-120 ° C. having a non-fluorine groove melting point, then R is also a hydrogen atom, or a pharmacologically acceptable salt of these compounds, characterized in that the compound of formula 7, wherein X has a new derivative production method, as defined above, R3 is hydrogen-Z a; S tx and ez eze of patent 1,8-naphthyridine of general formula I, in which X is fluorine and R is hydrogen, or the pharmacologically acceptable salts of these compounds, characterized in that the compound of formula VII wherein X is fluoro, R3 is hydrogen or a protecting group such as an acyl group, o-nitrophenylsulfenyl group, arylsulfonyl group, or a substituted phenyl or benzyloxy methyl group, and R4 is a carboxyl group or a lower alkoxycarbonyl group, is reacted with an ethylating agent, and if the resulting compound R4 is an alkoxycarbonyl group, the compound is subjected to a ru or protecting group such as ak acyl group, o-nitrophenylsulfenyl group, lower trialkylsilyl group, tetrahydropyranyl group, diphenylphosphinyl group, aryl-sulfonyl or methyl group substituted phenyl or benzyloxy group and R4 is cyam, dine group, or Alk is a lower alkyl radical, and when X is a halogen atom other than fluorine, then R4 is also a carboxyl group or a lower alkoxycarbonyl group, is reacted with an ethylating agent and if in the obtained product R4 is a cyano group, the amino group is hydrolysis, and if in the obtained product 30 a carbamate group or a group of formula 3, then this product is subjected to the hydrolysis of R3 as a protecting group, then these groups are split off by hydrolysis or hydrolysis, and then the obtained compound is the formula I is optionally converted to a pharmacologically acceptable salt. 2. The method according to claim The compound according to claim 1, characterized in that the compound of formula 7, in which X is a nitrogen atom, and then, if R3 in the product is a protecting group, then this group is cleaved by hydrolysis or hydrogenolysis, and then the obtained compound of formula 1, optionally is not converted to its pharmacologically acceptable salt ../ COOR HN N / ^ t * CoH 2n5 COOH Formula i Hr (_N ^ N ^ N- CZH8 YlzocP Cl Hl V 0 li • a ~ N _v v ^ rvC00H HlOl ^ N ^ C2H5 o I CZH5 Formula I * COOH COOH HN NN <\ Y 'CH2S05H mtorl'120154 T2. ,, O / Yztfr 2a- Formula 3 F Viitr 5 JCOOH ^ / ^ COOH * s Ri C ^ 5 O Clv ^ móre ^ JCOOH C, H 2n5 O o /^.An^n^ -cs HF NH ^ OAlk OY * XOOH C2H5: f 9 ^ ¦isPco-OArW w 'H Formula 10120154 ciAn-ci Etoco-N ^ i) QrnitlOtVCin8 ¦ ^.' in-f.-iljwani? ° z * U CK Kl N EtOCO-l ^ JN IY IY Wcrfr / O - H h'zór 14 reciuko / a AN 2 / - \ EtOCO-N fo ^ N'vN- v ¦ 'H. to * ^ CK EtOCO -h (_N "H Scticmat cci Scheme cont. i ^ hydrolysis Et0C0-ti N ^ NXN / C0 EtOCON N- ^ N ^ NH. w? H £ 00Et Formula Ib condensation IF EtOCO-N N ^ N ^ N COOEt fCOOEt Etoco -i ^ i ^ isnisr ^ H Pattern 7a cukuzagcL Scheme H Pattern g LZGraf. Zd No. 2 - 418/83 90 copies A-4 Price PLN 100 PL

Claims (2)

In the following claims, the term "lower" in connection with alkyl radicals and groups containing alkyl radicals denotes radicals with 1-6 carbon atoms. The compounds of formula I form salts with acids and bases. Acids may be various inorganic or organic acids, e.g. such as hydrochloric, acetic, lactic, succinic, lactobionic and methanesulfonic acid, and as bases also inorganic or organic bases are used which give salts with a carboxyl group in the compounds of formula 1. Examples of such bases are the hydroxides and carbonates of such metals such as sodium and potassium, salts of compounds of formula 1 with hydrochloric acid or methanesulfonic acid have particularly preferred properties. Under certain conditions the compounds of formula 1 exist in the form of hydrates and the preparation of such hydrates is also within the scope of the invention. according to the invention are the following compounds and their pharmacologically acceptable salts: 1-ethyl-6-fluoro-1,4-dihydro-4-keto-7- / 1 -piperazinyl -1,8-naphthyridine-3-carboxylic acid of the formula U, ethyl ester of the acid of formula I, as well as 1-ethyl-6-chloro-1,4-dihydro-4-keto acid The 7- (1-piperazinyl) -1,8-naphthyridine-3-carboxylic acid of the formula 12. Of the compounds according to the invention, the most valuable antimicrobial properties have the above-mentioned acid of formula U and its salts. As shown later in the description, this compound is highly effective against bacteria in vitro and in vivo, and because at the same time it has negligible toxicity, it can be used in the control of urinary tract infections by Gram-positive and Gram-positive bacteria. negative, as well as to combat the prohibitions of other systems. The compounds of formula I, in which X is as defined above and R is a lower alkyl radical, also exhibit a fairly strong antimicrobial activity in vivo and are also useful as intermediate products in the preparation of other compounds of formula 1. similar to the structure of compounds of the formula and on May 12, known from US Pat. No. 120 1543 US Am. No. 4,017,622 piperazine derivatives of the formula 2, in which Rx represents a hydrogen atom, an alkyl radical with 1-4 carbon atoms, a benzyl radical or an acetyl group, R2 is a hydrogen atom, an alkali radical containing 1-4 carbon atoms, • the radical benzyl or vinyl, and R3 represents a hydrogen atom or an alkyl radical of 1-6 carbon atoms. As can be seen from formula 2, these compounds do not have a substituent at position 6 of the naphthyridine ring. In the tests described below, it has been shown that the compounds of the invention are active against gram-negative bacteria, including Pseudornonas aeruginosa, as well as against gram-positive bacteria, surprisingly much more effectively than T ^ in ^ KT ^ in KrifAzor 2. MA of the printed Japanese manuscript No. 83 590/77, a summary of which was given in the publishing list. «Sfl * f! by Derwent Fublications Ltd. (Der. No. OffiLfiS ^ fSSl ^^ zriaaiiJsa 6-nitro-1,8-naphthyridine derivatives of formula 3 wherein the group of formula -N (R) (R ') is an amino group, substituted anilino, alkylamino, cycloalkylamino, dialkylaminoalkylamino, hydroxyalkylamino, dialkylamino, alkylallylamino, alkylcycloalkylamino, dihydroxyalkylamino, pyrblidine, piperidine, morpholdnine, and the same description as R 2 and rhodium alkyl. However, the only point is that these compounds are effective against Trichinella and there is no mention of any antibacterial activity. In the report of the 98th Congress of the Japanese Pharmaceutical Society Jia, p. 223, published on March 10, 1978, there is an information ¬ation of p compounds of formula IV in which R x is ethyl or its corresponding radical, R2 is hydrogen, R3 and R3 are electron-attracting groups and R4 is electron donating. For information, the compounds of formula IV in which R3 and R5 are chlorine or fluorine and R4 is a piperazine group, optionally substituted, were investigated to establish a relationship between their structure and properties. It has been found that compounds in which R2 is an ethyl radical, R2 is a hydrogen atom, R3 or. R5 is chlorine or fluorine and R4 is piperazine, they have antimicrobial properties stronger than l-ethyl-1,4-dihydro-7-methyl-4-keto-1,8-naphthyridine carboxylic acid. 3. From US patent specification US Am. No. 4, 14, 719, corresponding to Belgian Patent Specification No. 863,429, quinoline derivatives of formula 5 are known, and the Japanese Patent Publication No. 65,887/78 (Derwent No. 52,436 A / 29) discloses quinoline derivatives of the formula On day 6. The results of the tests given in Tables 2 and 3 below show, however, that the compounds produced by the method according to the invention have an activity against gram-negative bacteria, including Pseudornonas aeruginosa bacteria, much stronger than the compounds of the present invention. formulas 5-6. According to the invention, compounds of formula I in which X and R are as defined above are prepared by ethylation of compounds of formula 7 in which X is as defined above, the symbol H ** "Htcrm" "" wTK2 or an amino protecting group, and R4 is a carboxyl group; a lower alkoxycarbonyl group or a group of the formula -R4 in which R'4 is a cyano group, a carbamoyl group or a group of the formula 8 in which Alk is a lower alkyl radical. In the ethylation process, known ethylating agents are used, such as ethyl halides, for example ethyl iodide or ethyl esters, for example diethyl sulfate, ethyl p-toluenesulfonate or triethyl phosphate. The reaction components are usually used in stoichiometrically calculated amounts and the reactions are carried out in an inert solvent at a temperature of 25 ° -150 ° C. If R3 is a protecting group in the compound of Formula 7, then an excess of ethylating agent is preferably used. Solvents used are, for example, ethanol, methyl ethylene glycol, dimethylformamide, dimethyl sulfoxide and water. The course of the reaction can be accelerated by adding an acid binding agent, for example a base such as an alkali metal carbonate, hydroxide or alkanolate, sodium hydride, pyridine, triethylamine or benzyltrimethylammonium hydroxide. The obtained product, in which R4 represents a group of the formula -R'4, is then hydrolyzed and / or the product in which R3 is a protecting group is subjected to cleavage of this protecting group. Hydrolysis of the R4 group is carried out with water, the addition of an acid or base catalyst to accelerate the reaction. Inorganic or organic acids or bases may be used, for example acids such as hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, trifluoroacetic, formic and toluenesulfonic acids, and, for example, bases such as alkali metal or alkaline earth metal hydroxides. carbonates, for example sodium or barium hydroxide, alkali metal carbonates, for example sodium or potassium carbonate, and also sodium acetate. These reactions are preferably carried out by heating the compound to be hydrolyzed in a solvent and with the addition of water. Water is usually used as the solvent, but depending on the nature of the compound, solvents such as ethanol, dioxane, ethylene glycol dimethyl ether, benzene or acetic acid mixed with water may be used. The reactions are usually carried out at temperatures between 0 ° and 150 ° C, preferably between 30 ° and 100 ° C. The protecting group R3 is cleaved preferably by solvolysis or hydrogenolysis, depending on the nature of the group. Examples of R3 groups that can be cleaved by solvolysis, including hydrolysis, are formyl, acetyl, trifluoroacetyl, benzyloxycarbonyl, and indi- vidual (butotascarbonyl, p-methoxybenzyloxycarbonyl, vinyloxycarbonyl, vinyloxycarbonyl, - / p-toluene Q-120 134 sulfonylAethoxycarbonyl, "o-nitrophenylsulfenyl, trimethylsilyl, triphenylmethyl, tetrahydropyranyl and diphenylsulfinyl. Solvent reactions are carried out in the environment of a solvent or base, possibly in the presence of such an acid or in the presence of such an acid. When discussing the hydrolysis of the R4 group, water is usually used as a solvent, but it is also possible to use a mixture of water with solvents such as ethanol, dioxane, ethylene glycol dimethyl ether, benzene or acetic acid. The reaction is carried out at temperatures between 0 ° and 150 ° C. ° C, preferably 30-100 ° C. Examples of Rs groups which can be cleaved by reduction are arylsulfonyl groups such as the p-to group luenesulfonyl, methyl substituted groups such as benzyl or benzyloxy groups such as benzyl, triphenylmethyl or benzyloxymethyl groups, or arylmethoxycarbonyl groups such as benzyloxycarbonyl or p-methoxybenzyloxycarbonyl. "" "" In the cleavage of the protecting group K3, the conditions of the hydrogenolysis process are adapted to the nature of the group. Usually, the product to be reacted is treated with hydrogen in the presence of a catalyst such as platinum, palladium, Raney nickel, etc., in an inert solvent. It is also possible to use reductions with metallic sodium in liquid ammonia or with a metal such as zinc in acetic acid or in an alcohol, for example methanol Catalytic hydrogenolysis is carried out at room temperature or elevated to 60 ° C. Solvents used are, for example, ethylene glycol, dioxane, dimethylformamide, ethanol or acetic acid. If the protecting group is a benzyl, triphenylmethyl or p-toluenesulfonyl group, this group can be cleaved with sodium metal in liquid ammonia, usually at -50 ° C to -20 ° C. Starting compounds of formula 7 are novel compounds. An example of their preparation is shown in the diagram given in the figure. In the formula used in this scheme, Et is the ethyl radical and A- is the anion of the fluoroboric acid HBF4. In the first stage of the process, the compound of formula 12 is reacted in a known manner with the piperidide of the monoethyl ester of carbonic acid, and the compound of formula 13 obtained is ammoniumated in the 2-position in a known manner with ammonia in ethanol and then acetylated in of this position also in a known manner, producing the compound of formula 14. The nitro group in the 5-position of this compound is diazotized, the amino group is reduced in the obtained compound of formula 15 in the presence of fluoroboric acid, and the obtained compound of formula 16 is heated to give the compound of formula 15. Formula 17. From this compound, by hydrolysis with hydrochloric acid in ethanol, the compound of formula 18 is prepared, which is condensed with diethyl 2-ethoxyethylene dicarboxylate to give the compound 6 10 20 29 30 33 40 45 50 55 mp of formula 9, which is cyclized by heating at 140 ° -260 ° C. in a solvent having a suitable boiling point, such as, for example, diphenyl ether, diphenyl, phthalate, dibutyl, o-dichlorobiene enzene, diphenylene oxide, or mixtures thereof. The addition of known cyclization accelerators such as polyphosphoric acid, lower alkyl polyphosphate, concentrated sulfuric acid, phosphoryl chloride, or phosphorus pentoxide may also be used. If the addition of polyphosphoric acid, alkyl polyphosphate or phosphorus pentoxide is used, the reactions are carried out in a solvent such as benzene, dioxane, or dimethylformamide, and with sulfuric acid the solvent is usually acetic anhydride or acetic acid. If the cyclizing additive has the appropriate properties, it can also act as a solvent. When using a cyclising agent, the reactions are usually carried out at a temperature lower than the above-mentioned temperature, preferably between 100 and 160 ° C. The compounds produced by the method according to the invention are isolated and purified by known methods. Depending on the nature of the starting products and the reaction conditions, the compounds of formula I are obtained in the free state or in the form of a salt, and the compounds in the free state can be converted into salts which act with pharmacologically acceptable acids or bases. For this purpose, various inorganic or organic acids should be used, for example hydrochloric, acetic, lactic, succinic, lactobionic, oxalic and methanesulfonic acids. As mentioned above and demonstrated in the tests described below, the compounds according to the invention have very good properties with low toxicity, and can also be used preventively and in the treatment of bacterial infections in warm-blooded animals, including humans. The dose of these compounds depends on the age, body weight and condition of the patient, the method of drug administration, etc. The daily dose for adults is 0.1-7 g, preferably 0.2-5 g of the compound of formula I or the same. salt. These compounds are used in the form of preparations containing also solids or - liquid pharmacologically acceptable additives, not reactive with the compounds of formula 1. Examples of such additives are: water, gelatin, lactose, starch, cellulose (preferably microcrystalline) , carboxymethylcellulose, methylcellulose, sorbitol, talc, magnesium stearate, vegetable oils, benzyl alcohol, resins, propylene glycol, polyalkylene glycols, and methyl paraben. The preparations may take the form of powders, grains, tablets, ointments, suppositories, creams, capsules, etc. They may be brightened and / or contain preservatives, stabilizing and wetting agents. They may also contain other biologically active substances. The following describes tests which compare the properties of the compounds according to the invention with those of the known compounds, and the compounds of formula 10, which is an rcw-derivative of no 1,8-naphthytidine not covered by formula 1. Because the method of producing this compound is not has been published heretofore, so the method is illustrated below. To a mixture of 12 ml of 37% formaldehyde and 18 ml of formic acid are added 6.0 g of 1-ethyl-6-fluoro-1,4-dihydro-4-, catate-7- / 1- (piperizitinyl) acid. (-1, 8-naphthyridine-3-carboxylic acid) and, under stirring, is kept at a temperature of 120-125 ° C for 4 hours. The mixture is then evaporated to dryness under reduced pressure, the residue made alkaline with an aqueous solution of hydrogen carbonate. sodium chloride to pH 8 and extracted with chloroform, the extract was dried, the solvent evaporated and the residue recrystallized from a mixture of dichloromethane and ethanol to give 5.0 g of l-ethyl-6-fluoro-1,4-fluoro acid. dihydro-7- (4-methyl-1-piperazinyl) -4-keto-1,8-naphthyridine carboxylic acid of formula 10, mp 228-230 ° C., Test 1 The method given in Chemotherapy, 22 (6 ), p. 1128, (1974), the minimum concentration of the compounds according to the invention and the compounds known in vitro against 19 different bacterial strains was determined. and a MIC are given in Tables J, Ia and Ib in g / ml. In this table, as well as in the following tables, tested compounds covered by the general formula 1 are marked with numerical symbols, and known compounds - with letter symbols. The meaning of these symbols is as follows: compound 1 - compound of formula li, compound 1 '- compound of formula 1', compound 2 '- compound of formula 12', compound A - compound of formula 2a, known from the description U.S. Patent US Am. No. 4,017,622, compound B - compound of formula 10, compound C - compound of formula 6, known from Japanese Laid-open Patent No. 65887/78, compound D - compound of formula 5, known from Belgian Patent No. 863 4) 29, Compound E - 1-Ethyl-1,4-dihydro-7-methyl-4-keto-1,8-naphthyridine-3-carboxylic acid (U.S. Patent No. 3,149,104 ), compound F - 8-ethyl-5,3-dihydro-5-ke-to-2- (1-piperazinyl) -pyrido [2,3-d] pyrimidinecarboxylic acid-6 (US Patent No. No. 3,887,557), compound G - α- (5-indenyloxycarbonyl) -benzylpenicillin sodium salt (Carindacillin) (U.S. Patent No. 3,557,090), compound H - Da-aminobenzylpenicillin (am ¬ picillin) (U.S. Patent No. 2,985,648), Compound J - 7- (Da-aminophenylacetamino) -desoacetoxycephalosporanic acid (Cephalexin) (U.S. Patent No. 3,507,861) . The results given in Tables 1, la, and Ib show that the compounds of the invention, in particular the compounds of the formulas I, 1 'and 12', are highly effective against gram-positive and gram-negative bacteria, including Pseudomonas aeruginosa. The known compound of formula 2a is active against Gram-positive and Gram-negative bacteria. Table 1 Activity against bacteria in vitro 20 25 30 35 53 eo Bacteria 1 Gram-positive bacteria Staphylococcus aureus 209F JG-1 Staphylococcus aureus No. 50774 Streptococcus faecalis | P-2473 Streptococcus pyogenes 65A Corynebacterium pyogenes | c "21 Gram-negative bacteria Escherichia coli NIHJ JG-2 Escherichia coli P-5101 Escherichia coli P-140a Salmonella typhimurium | S-9 Salmonella enteriridis 1 No. 1291 Tested compounds | 1 2 0.78 0.78 12.5 12 , 5 1.56 0.2 0.1 0.2 0.1 0.1 Shigella flexneri 2a 1 0.2 Shigella flexnari 4a P-330 Klebsiella pneumoniae No. 13 | Enterobacter cloacae P-2540 Pseudomonas aeruginosa 1 Tsuchijima Pseudomonas aeruginosa No. 12 "| , Serratia marcescens IFO 3736 Proteus morgenii Kono Proteus mirabilis P-2381 0.39 0.2 0.2 0.39 0.78 0.39 0.2 0.39 1 '3 0.78 0.78 12.5 12 , 5 1.56 0.2 0.1 0.2 0.1 0.1 0.2 0.39 0.2 0.2. 0.39 0.78 0.39 0.2 0.39 2 '1 4 3.13 6.25 25 12.5 6.25 0.78 0.39 1 0.39 0.39 1 0.39 0 , 78 1.56 1.56 0.78 6.25 6.25 1.56 | 1.56 3.13 in total weaker than the compounds according to the invention. 'Trial 2. Effectiveness of in vivo treatment. The compounds of the invention and the known compounds were dissolved in deionized water or suspended in 0.2% aqueous carboxymethylcellulose solution and administered orally to infected mice under study 121154 Table 1 Bacteria 1 Gram-positive bacteria 1 Staphylococcus aureus 209Poc-1 Staphylococcus aureus 209Poc aureus No. 50774 Streptotocuccus faecalis P-2473 Streptococcus pyogenes 65A | Corynebacterium pyogenes C-21 and Gram-negative bacteria and Escherichia coli N1HJ JC-2 Escherichia coli P-5101 Escherichia coli P-14Ca Salmonella typhimurium S-9 Salmonella enteritidis No. 1891 Shigella flexneri 2a Shigella flexnari 4a P-330 Klebsiella pneumoniae No. 13 Enterobacter cloacae P-2540 Pseudomonas aeruginosa Tauchijima 1 Pscudomonas aeruginosa No. 12 Serratia mercascens IFO 3736 Proteus morganii Kono Proteus mirabilis P-2381 Tested compounds 1 • A 1 2 ¦2 "5 50 ¦ 100 50 50 6.25 3.13 6.25 6.25 1.56 6.25 12.5 12.5 6.25 25 25 12.5 6.25 25 • 1 B 1 3 | 1.56 1.56 12.5 6.25 1.56 0.39 0.2 0.39 0.2 0, 1 0.39 0.78 0.39 0.39 1.56 3.13 1.56 0.78 1.56 1 C 1 4 0.78 1.56 6.25 6.25 1.56 0.39 0.2 0.2 0.2 0.2 0.39 0.2 0.78 0.2 3.13 3.13 0.78 0.39 0.39 D 1 5 0.39 0.78 3, 13 1 - 0.78 0.1 0.05 0.1 0.05 0.05 0.1 0.2 0.2 0.1 0.39 1 1 0.78 0.2 0.1 0.2 E 1 6 100 1 50 200 200 200 r2.5 3.13 - 3.13 3.13 6.25 - 12.5 6.25 200 200 6.25 6.25 - Table Ib Bacteria- 1 and Gram bacteria -positive Staphylococcus aureus 209P JC-1 Staphylococcus aureus No. 50774 Streptococcus faecalis P-2473 Tested compounds F 2 12.5 25 200 G 3 0.39 0.78 ¥ H 4 0.05 0.1 1.56 J 5 1 , 56 I 1.56. 20011 120 154 12 table Ib cd Bacteria 1 1 Streptoeoccus pyogenes 65A Corynebacterium pyogenes C-21 Gram-negative bacteria Escherichia coli NIHJ JC-2 Escherichia coli P-5101 Escherichia coli P-140a Salmon ella typhimurium S-9 Salmonella enteritidis No. 1891 Shigella flexneri 2a Shigella flexnari 4a P-330 Klebsiella pneumoniae No. 13 and Enterobacter cloacae P-2540 Pseudomonas aeruginosa Tsuchijima Pseudomonas aeruginosa No. 12 Serrabia marcescens IFO 3736 Proteus morganii Kono Proteus mirabilis P-2381 Test compounds | • F 1 2 200 25 1.56 1.56 1.56 1.56 1.56 3.13 1.56 6.25 1.56 12.5 25 3.13 3.13 3.13 1 G 1 3 0.2 3.13 6.25 6.25 50 0.78 0.78 12.5 6.25 200 3.13 6.25 50 3.13 0.78 0.78 1 H 1 4 0.025 1 1, 56 6.25 6.25 200 0.39 0.2 3.13 6.25 100 200 200 200 25 100 3.13 1 J 1 1 5 0.78 1.56 12.5 12.5 200 6.25 3.13 12.5 200 6.25 200 200 200 200 1 200 12.5 microorganisms, indicating the dose value ** EDg0. The studies were carried out with male mice (ddY) weighing about 20 g. The test compounds were administered twice, 5 minutes and 6 hours after the infection. It was infected as follows: 1. Stephylococcus aureus No. 50774. It was forbidden to suspend the bacteria intravenously in saline using 5-10 LDFQ, which is approximately 5-108 bacterial cells for each mouse. The observations were made during 14 days. 2. Escherichia coli P-5101. It was forbidden to suspend the bacteria in soybean extract with 4% of mucin, using 5-10 LD50, that is, about 9-106 bacterial cells for each mouse. Observations were carried out for 7 days. 60 3. Pseudomonas aeruginosa No. 12. The bacterial suspension of soybean extract of 410% mucin was forbidden intraperitoneally using 50-100 LD50, that is, approximately 5,110 bacterial cells per mouse. The observations were made during 7 days. The test results are given in Table 2. These are ED50 values in mg / kg, calculated by the Behrens-Kaerber method (Arch. Exp. Pat. Phem. 162, p. 480, 1931). Table values are given by the symbol x expressed as free carboxylic acid. The results given in Table 2 allow the following conclusions to be drawn: 1. Compounds of formulas I1 and 1 'show a strong healing effect in systemic infections with gram-positive and gram-negative bacteria, 2. Compounds of formula I1 produced according to the invention and 1 ', in systemic infections with gram-negative bacteria, in particular Pseudomones aeruginosa, show a stronger activity than compounds A, C, E and F known as antibacterial agents and compounds G, H and J, which are known antibiotics. 3. Compounds of formulas l1 1 'have a much stronger effect in vivo against gram-positive bacteria than the known compound D, and compounds of formulas13 Table 2 In vivo efficacy against systemic infection in mice Test compound Compound 1 Compound ¦ 1' Compound 2 ' Compound 1 ethyl ester Compound A Compound B Compound C Compound D Compound E Compound F Compound G Compound H Compound J Bacteria Staphylococeus aureus No. 50774 10 10 * about 90 * about 20 100 4.8 about 100 21.9 800 215 10-40 2.2 12.1 and Escherichia coli P-5101 1.8 1.8 * 6.5 * 1.2 about 15 4.7 29.2, 21.2 100 43.5 22.6 Pseudo- monas aeruginosa Nr 12. 9.0 9.0 * 58.6 * 21.0 200 10.6 100 15.5 200 99.5 201.6 400 400 l1 ir are significantly more effective in vivo against gram-negative bacteria, These against Pseudomonas aeruginosa bacteria than the known compound D. 4. The ethyl ester of the compound of formula I1 produced by the process of the invention, being an intermediate in the preparation of compounds of the formulas I1 and I ', also has a strong effect in vivo against bakte Gram-positive and Gram-negative riom. Trial 3. Therapeutic efficacy in vivo. Compound 1 and the known compound D were also tested in order to compare their efficacy against the increasing kidney infections in mice with the bacteria Pseudomonas aeruginosa No. 12. Female mice (ddY-s) weighing 2 (2 - 30 g anesthesia with intravenous 50 mg / kg of pentobarbital sodium was used, then the bladder was exposed through a small incision in the abdomen, and the bladder was exposed with a 0.25 ml syringe with a 0.25 mm needle, 0.1 ml of a 1: 10,000 culture solution was forbidden. Pseudomonas aeruginosa No. 12, prepared for 20 hours in a soybean extract During 1 day before the infection and 1 day after the command, the mice were not given water to drink, and from the day of the infection they were given 2 times a day for 3 days. On the fifth day after infection, the kidneys were excised transversely and overnight the bacteria were cultured at 37 ° C on King A agar. If no further bacteria were found, the compound was considered to protect against kidney infection.of the trials are given in Table 3. Table 3 In vivo efficacy against infection of the kidneys of mice with Pseudomonas aeruginosa No. 12 Test compound Compound 1 Compound D Administration Orally Oral ED50 mg / kg 2.4 16.1 The results in Table 3 show that that the effectiveness of the compound according to the invention, namely compound 1, in increasing kidney infection with the bacteria Pseodomonas aeruginosa No. 12, is much higher than that of the known compound D. Test 4. Acute toxicity. Solutions containing the individual compounds according to the invention or known compounds were administered orally at various concentrations to groups of 4-8 male mice (ddY) in doses of 0.1 ml per 10 g of body weight, and the number of dead mice was determined after 7 days. calculating the lethal dose LD50 in mg / kg by the method of Dehreus-Kaerbar. , ft The results are given in Table 4, in which the values denoted by x represent values expressed as free carboxylic acid. Table 4 33 Acute toxicity in mice Test compound [Compound l 1 Compound 1 'Compound 2' Compound B Compound C Compound D Compound E Compound F Compound G Compound H Compound J LD50 mg / kg over 4000 over 4000 * over 2000 * 210 over 2000 more than 2000 1516 more than 5000 more than 4000 more than 5000 3000 The results given in Table 4 show that the toxicity of the compounds according to the invention is negligible, and the compound B, ° produced by introducing a methyl radical in position 4 of the piperazinyl group of compound 1, by the method according to the invention, although having an efficacy against bacteria equal to or even higher than the compounds according to the invention (see Tables 1, la, Ib and 2), however, has a very high toxicity. Trial 5. Subacute toxicity. Compound 1 was administered orally to 6 female mice (JOL-L.CE strain, with an average body weight of 20 g, using a dose of 2 g / kg over 14 days. During this period, each mouse was weighed and waited. Fifteen days were examined hematologically, and after examination, the organs were dissected, the organs were weighed and examined for possible tissue disease. The mice treated with Compound 1 showed no disturbance in body weight gain or any signs of disease compared to mice in the control group that were not treated with this compound, which indicates that the compound can be administered without causing any harmful effects. Erófca 6. Plasma concentration A male dog JBeagle weighing 12 kg was administered orally a capsule containing one of compounds 1 and 2 in doses of 25 mg / kg with 200 ml of milk, and after 0.5, 1, 2, 3, 6, 8 and 10 hours, a blood sample was taken by venipuncture and then The blood was centrifuged in order to separate the plasma. The content of the tested compounds in the plasma was determined by ano the cylinder-plate thin-layer method, using Escherichia coli Kp as an indicator microorganism. The results are given in Table 5 w / µg / ml. Table 5 Plasma content in µg / ml Test compound Compound 1 Hours after administration of test compound 0.5 0.6 1. 2.4 2 5.5 3 5.9 6 4.2 8 3.7 10 2 The results given in Table 5 lead to the following conclusions: Compound 1 prepared according to the invention is well absorbed by the body when administered orally and its high plasma concentration is maintained for quite a long time. In particular, the plasma concentration of Compound 1 within 1 to 10 hours of administration is above the lowest MIC concentration at which the compound is effective against most bacteria (see Table 1, la, Ib). For example, the plasma concentration of Compound 1, 5.9 µg / mL, is about 8 times the lowest concentration at which it is effective against Pseudomonas aeruginosa No. 12 and Sptahylococcus aureus No. 50774, and about 60 times greater in relation to the bacteria Escherichia coli P = 5101. The results given in Table 5 show that the compound 1 produced according to the invention has a high concentration in plasma and even at low doses it is effective in combating systemic infections with various bacteria. riami. Trial 7. Urinary excretion. The match of the dogs subjected to the test described in trial 6 was collected over 24 hours and its urine content was determined using the method given in trial 6. The results of the trials are given in Table 6. Table 6 Tested excretion of compounds with urine 10 Test compound Compound 1 Concentration of compound in urine ng / ml 606 Amount of compound excreted% 40.7 The data in Table 6 allows the following conclusions to be drawn: 1. Compound 1 is fairly well excreted with urine and within About 40% of the compound is excreted in the urine 24 hours after oral administration. 2. The concentration of compound 1 is approximately 51-6000 times the lowest concentration at which this compound is effective against a variety of bacteria (04l (2, 15 [Ag / ml according to Table 1, la, lib). Compound 1 is highly effective even at low doses against urinary tract infections with various bacteria.As shown in Tables 1-6, the compounds of the invention, especially the compounds of the formulas I1 and I ', have a strong therapeutic effect against Artificially induced infections with Gram-positive and Gram-negative bacteria, and after oral administration, remain in high concentrations in the plasma and in the urinary tract for a long time. Moreover, their toxicity is low, so they can be used even in small in doses to combat urinary tract infections and systemic infections caused by various bacteria. In contrast, the known compounds A and C have an in vitro and in vivo antibacterial activity against gram-positive and gram-negative bacteria. much worse, as shown in Tables 1, 1a, Ib and 2. The known compound D has a therapeutic effect, in the control of the increasing kidney infection with the bacteria Pseudomonas aeruginosa, much worse than the compounds of the formulas I1 and 1 '. Compounds E and F, known synthetic antibacterial agents, and compounds G, H and J, known antibiotics, have an in vivo therapeutic effect against bacterial infections. Gram-negative bacteria, especially Pseudomonas aeruginosa bacteria, are significantly inferior to the compounds of the formulas I1 and 1 'prepared by the method according to the invention. The preparation of the compounds of formula I is illustrated below. Example 1 Preparation of the compound of formula I and its addition salts. To a suspension of 1 g of 7- (4-ethoxycarbonyl-1-piperazinyl) -6-fluoro-1,4-dihydroTO-4-keto-1,8-naithyridine carboxylic acid in 10 ml of dimethylformamide is added 0.53 g sodium carbonate and stirred at 60 ° C.sub.120.117 for 10 minutes, then 1.2 g of ethyl iodide and sword are added at 60-70 ° C. for 2 hours. The mixture is then evaporated to Luolia under reduced pressure, the residue is added with water, the solution is extracted with chloroform, the extract is dried over anhydrous potassium carbonate and the chloroform is evaporated off. The residue is recrystallized from a mixture of dichloromethane and n-hexane to give 0.89 g of ethyl-6-fluoro-1,4-dihydrogen-4-keto-7- (4-ethoxycarbonyl-1-piperazinyl) ethyl ester. -1,8-naphthyridine-3-carboxylic acid, m.p. 171-173 ° C. A mixture of 0.8 g of this ester, 6 lvl 103% of sodium hydroxide and 2 ml of ethanol is boiled under reflux for 3 hours, then cooled, and 10% acetic acid is added until the value of p 7 is obtained. 0-7.5, the separated precipitate is filtered off, washed with ethanol and recrystallized from a mixture of dimethylformamide and ethanol. 0.57 g of 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7- (1-pip-3razinyl) -1,8-naphthyridinecarboxylic acid-3 is obtained in the formula II. The product melts at 220 ° C to 224 ° C. 0.2 g of the acid obtained was dissolved in 5% hydrochloric acid and the solution was evaporated to dryness under reduced pressure. The residue was recrystallized from water to give 0.21 g of the hydrochloride of the acid of formula II. The product melts above 300 ° C. 30 In the second test, 0.2 g of the acid of formula I1 is dissolved in 7N at elevated temperature, and then cooled, the precipitate formed is filtered off and recrystallized from dilute methanol to give 0.22 g of the acid salt. of Formula I1 with methanesulfonic acid, ie the compound of Formula I '. The product melts with decomposition at temperatures above 300 ° C. In the third test, 1.0 g of the acid of formula I1 is dissolved in hot ethanol, 1.0 ml of acetic acid is added, it is cooled and the crystalline precipitate is filtered off. This product was recrystallized from ethanol to give 0.93 g of the acid addition salt of formula I with acetic acid. The product melts at 228 ° -229 ° C. The 7- (4-ethoxycarbonyl-1-piperazinyl) -6-fluoro-1,4-dihydro-4-keto-1,8-naphthyridine-3-carboxylic acid ethyl ester of formula 11 used in this example as a starting product produces is reacted as follows: 2, u-dichloro-3-nitropiperidine is reacted with N-ethoxycarbonylpiperazine to give 6-chloro-2- (4-ethoxycartonyl-1-piperazin-1) -3-mtropiperidine without purification She is heated with ethanolic ammonia in a sealed tube at 120 ° -125 ° C. to give 6-amino-2- (4-ethoxycarbonyl-1-piperazinyl) -3-nitropiperidine, mp 132 —134 ° C. This product was treated with acetic anhydride in acetic acid to give 6-acetylamino-2- (4-ethoxycarbonyl-1-piperazinyl) -3-nitropiperidine, mp 168-169 ° C. This compound is hydrogenated catalytically with C.sub.6 palladium on carbon to give 3-amino- &lt; 18 -6-acetylamino-2- (4-ethoxycaronyl-l-piperase-l-pyridine) which dissolves without purification. in a mixture of ethanol with 42% of tetrafluoroboric acid and to the resulting solution is added a solution of isoamyl nitrite in ethanol with stirring at a temperature below 0 ° C. After 20 minutes, ether is added to the solution, the precipitate formed is filtered off and washed with a mixture of methanol and ether and then with chlorophyll. This gives 6-acetylamino-2- (4-ethoxycarbonyl-1-pyrazinyl) -3-pyridine diazonium tetrafluoroborate, mp 117-117.5 ° C (signs of decomposition). The suspension of the obtained diazonium salt in toluene is heated by stirring in a bath at 120 ° C for 30 minutes, then the solvent is evaporated under reduced pressure and the residue is made alkaline with a 10% solution of sodium carbonate and then it is extracted with chloroform. The extract is dried over anhydrous potassium carbonate, the solvent is evaporated, and the residue is recrystallized from ethyl acetate to give 6-acetylamino-2- (4-ethoxycarbonyl--1-piperazinyl) -3-fluoropyridine, mp 132-133 ° C. This product is hydrolyzed with a 15% mixture of hydrochloric acid and methanol (1: 2 by volume) to give 6-amino-2- (4-ethoxycarbonyl-1-piperazinyl) -3-yluoropyridine. This product is treated at 130 ° -140 ° C. with ethoxymethylene malonic acid diethyl ester to give N- [2- (4-ethoxycarbonyl-1-piperazinyl) -3-fluoro-6-pyridyl acid ethyl ester. j] -aminomethylene malonic, m.p. 144-145 ° C. This compound is cyclized by heating at 255 ° C to give 7- (4-ethoxycarbonyl-1-piperazin-1-piperazin-1) -6-fluoro-1,4-dihydro-4-keto-1 acid ethyl ester. 8-naphthyridinecarboxylic acid-3, mp 279-281 ° C. Example 11. Preparation of the compound of formula I2. Proceeding in a manner analogous to that described in Example 1, but starting from 7- [4-ethoxycarbonyl-1-piperazinyl] -1,4-dihydro-4-keto-1,8-naphthyl ester 3-chloro-1-ethyl-1,4-dihydrogen-4-keto-7- (1H-piperazinyl] -1: 8-naphthyridine-3-carboxylic acid hydrochloride) is prepared. The product melts at temperatures above 30 ° e. Example 111. Preparation of ethyl ester of compound of formula I1. In an analogous manner to that described in Example I, by reacting 6-fluoro-1,4-dihydro-4-keto-7- (4-trifluoroacetyl-1-piperazinyl) -1,8-naphthyridine carboxylic acid ethyl ester - go-3 with ethyl iodide and potassium carbonate in dimethylformamide, the ethyl ester of 1-ethyl-6-fluoro-1,4-dihydro-4-keto-7- (4-trifluoroacetyl-1-piperazinyl) is prepared. 1,8-naphthyridine-3 carboxylic acid. This ester is hydroxylated with an aqueous solution of potassium carbonate in a mixture of chloroform and methanol to give the ethyl ester of 1-ethyl-6-fluoro-19m4 -1,4-dihydro-4-keto-7- (1-piperazinyl). -1, α-naphthyridine-3 carboxylic acid, mp 150-151 ° C. Example IV. Preparation of propyl ester and butyl acid ester of formula I1. 1-ethyl-6-fluoro-1,4-dihydro-4-keto-7- (1-piperazinyl) -1,8-naphthyridine-3-carboxylic acid propyl ester is prepared analogously to that described in Example III. at the rate of fluorine, R3 is the lower alkoxycarbonyl group and R4 is the lower alkoxycarbonyl group, is reacted with an ethylating agent, and then the reaction product is hydrolyzed and the resulting compound of formula I is optionally converted into a pharmacologically acceptable salt . 3. Process for the preparation of the new 1,8-naphthyridine derivatives of the general formula I, in which X is a halogen atom and R is a lower melting point of 133-135 ° C and a butyl ester is an alkyl radical, and X is a chlorine atom of the acid 119-120 ° C. having a non-fluorine groove melting point, then R is also a hydrogen atom, or a pharmacologically acceptable salt of these compounds, characterized in that the compound of formula 7, wherein X has a new derivative production method, as defined above, R3 is hydrogen-Z a; S tx and ez eze of patent 1,8-naphthyridine of general formula I, in which X is fluorine and R is hydrogen, or the pharmacologically acceptable salts of these compounds, characterized in that the compound of formula VII wherein X is fluoro, R3 is hydrogen or a protecting group such as an acyl group, o-nitrophenylsulfenyl group, arylsulfonyl group, or a substituted phenyl or benzyloxy methyl group, and R4 is a carboxyl group or a lower alkoxycarbonyl group, is reacted with an ethylating agent, and if the resulting compound R4 is an alkoxycarbonyl group, the compound is subjected to a ru or protecting group such as ak acyl group, o-nitrophenylsulfenyl group, lower trialkylsilyl group, tetrahydropyranyl group, diphenylphosphinyl group, aryl-sulfonyl or methyl group substituted phenyl or benzyloxy group and R4 is cyam, dine group, or Alk is a lower alkyl radical, and when X is a halogen atom other than fluorine, then R4 is also a carboxyl group or a lower alkoxycarbonyl group, is reacted with an ethylating agent and if in the obtained product R4 is a cyano group, the amino group is hydrolysis, and if in the obtained product 30 a carbamate group or a group of formula 3, then this product is subjected to the hydrolysis of R3 as a protecting group, then these groups are split off by hydrolysis or hydrolysis, and then the obtained compound is the formula I is optionally converted to a pharmacologically acceptable salt. 2. The method according to claim The compound according to claim 1, characterized in that the compound of formula 7, in which X is a nitrogen atom, and then, if R3 in the product is a protecting group, then this group is cleaved by hydrolysis or hydrogenolysis, and then the obtained compound of formula 1, optionally it is not converted into its pharmacologically acceptable salt. ./ COOR HN N / ^ t * CoH 2n5 COOH Formula i Hr (_N ^ N ^ N- CZH8 YlzócP Cl Hl V 0 li • a ~ N _v v ^ rvC00H HlOl ^ N ^ C2H5 o I CZH5 Formula I * COOH COOH HN NN <\ Y 'CH2SO5H mtorl'120154 T2. ,, O / Yztfr 2a- Formula 3F Viitr 5 JCOOH ^ / ^ COOH * s Ri C ^ 5 O Clv ^ Mine ^ JCOOH C, H 2n5 Oo / ^. An ^ n ^ -cs HF NH ^ OAlk OY * XOOH C2H5: f 9 ^ ¦isPco-OArW w 'H Formula 10120154 CiAn-ci Etoco-N ^ i) QrnitlOtVCin8 ¦ ^.' In-f.-iljwani? ° z * U CK Kl N EtOCO-l ^ JN IY IY Wcrfr / O - H h'zór 14 reciuko / a AN 2 / - \ EtOCO-N fo ^ N'vN- v ¦ 'H. to * ^ CK EtOCO -h (_N "H Scticmat cci Scheme cont. i ^ hydrolysis Et0C0-ti N ^ NXN / C0 EtOCON N- ^ N ^ NH. w? H £ 00Et Formula Ib condensation IF EtOCO-N N ^ N ^ N COOEt fCOOEt Etoco -i ^ i ^ isnisr ^ H Pattern 7a cukuzagcL Scheme H Pattern g LZGraf. Zd No. 2 - 418/83 90 copies A-4 Price PLN 100 PL