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

Description

The subject of the invention is a method for preparing new 1,8-naphthyridine derivatives of the general formula I, wherein X is a halogen atom, especially fluorine, and R is a hydrogen atom or a lower alkali metal, as well as pharmacologically acceptable salts of these compounds. The compounds prepared by the method according to the invention have a strong bactericidal effect on Gram-positive and Gram-negative bacteria, including Pseudomonas aeruginosa bacteria. The term "lower" used in the description and claims in relation to alkyl radicals and groups containing alkyl radicals denotes radicals with 1-6 carbon atoms. The compounds of the formula I form salts with acids and bases. Various inorganic or organic acids can be used as acids, for example hydrochloric acid, acetic acid, lactic acid, succinic acid, lactobionic acid and methanesulfonic acid, and inorganic or organic bases which give salts with a carboxyl group in the compounds of formula 1 can also be used as bases. Examples of such bases are hydroxides and carbonates of metals such as sodium and potassium. Salts of compounds of formula I with hydrochloric acid or methanesulfonic acid have particularly advantageous properties. Under certain conditions, compounds of formula I exist in the form of hydrates and the preparation of such hydrates is also within the scope of the invention. Examples of compounds prepared by the process of 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 formula U, the ethyl ester of the acid of formula I, as well as 1-ethyl-6-chloro-1,4-dihydro-4-keto-7-(1-piperazinyl)-1,8-naphthyridine-3-carboxylic acid of formula U. -7-(1-piperazinyl)-1,8-naphthyridine-3-carboxylic acid of formula 12. Of the compounds produced by the method according to the invention, the above-mentioned acid of formula U and its salts have the most valuable antibacterial properties. As shown in the following description, this compound is highly effective against bacteria in vitro and in vivo, and because it has negligible toxicity, it can be used to combat urinary tract infections caused by Gram-positive and Gram-negative bacteria, as well as to combat infections of other systems. Compounds of formula I, in which X has the meanings given above and R is a lower alkyl radical, also exhibit quite strong antibacterial activity in vivo and are furthermore useful as intermediates in the preparation of other compounds of formula I. Structures similar to those of compounds of formulas I and I are known from U.S. Patent No. 120,1543. No. 4 017 622 piperazine derivatives of formula 2, in which Rx is 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 with 1-4 carbon atoms, a benzyl radical or a vinyl radical, and R3 is a hydrogen atom or an alkyl radical with 1-6 carbon atoms. As can be seen from formula 2, these compounds do not have a substituent in position 6 of the naphthyridine ring. In the tests described below, it was shown that the compounds produced by the method according to the invention act against Gram-negative bacteria, including Pseudornonas aeruginosa, and also against Gram-positive bacteria, surprisingly much more effectively than T^w^KT^zlazKrifAzorze 2.1 From the Japanese published act no. 83 590/77, and a summary of which is given in the list of publishers - | «sfl*f! by Derwent Fublications Ltd. (Derwent No. Official No. 11111) are 6-nitro-1,8-naphthyridine derivatives of the formula 3, wherein the group of the formula -N(R)(R') represents an amino group, a substituted anilino group, an alkylamino group, a cycloalkylamino group, a dialkylamino group, a dialkylamino group, an alkylallylamino group, an alkylcycloalkylamino group, a dihydroxyalkylamino group, a pyrblidine group, a piperidine group, a morpholine group and a piperazine group, and Rx and R2 represent lower alkyl radicals. However, this description only mentions that these compounds are effective against trichomonas and there is no mention of antibacterial activity. In the report of the 98th Congress of the Japanese Pharmaceutical Society (JIA), published on March 10, 1978, page 223, there is information on compounds of formula 4, in which Rx is an ethyl radical or its corresponding radical, R2 is a hydrogen atom, R3 and R3 are electron-attracting groups, and R4 is an electron-donating group. According to this information, compounds of formula 4, in which R3 and R5 are chlorine or fluorine atoms, and R4 is a piperazine group, optionally substituted, were tested to determine the relationship between their structure and properties. It was found that compounds in which R2 is an ethyl radical, R2 is a hydrogen atom, R3 or R5 is a chlorine atom or fluorine, and R4 is a piperazine group, have stronger antibacterial properties than 1-ethyl-1,4-dihydro-7-methyl-4-keto-1,8-naphthyridinecarboxylic acid. From the U.S. Patent No. 4,147,719, corresponding to Belgian Patent No. 863,429, quinoline derivatives of the formula V are known, and from the published Japanese Patent No. 65,887/78 (Derwent No. 52,436 A/29) quinoline derivatives of the formula 6 are known. However, the test results given below in Tables 2 and 3 prove that the compounds prepared by the process according to the invention have antibacterial activity. Gram-negative bacteria, including Pseudornonas aeruginosa bacteria, significantly more potent than the compounds of formulae 5-6. #5 0154 4 According to the invention, compounds of formula 1, wherein X and R are as defined above, are prepared by ethylation of compounds of formula 7, wherein X is as defined above, •~5- ' Rg- -ozrra'czH**"Htcrm"""wTKtoru or a protecting group, an amino group, and R4 is a carboxyl group; a lower alkoxycarbonyl group or a group of formula -R^, wherein R'4 is a cyano group, a carbamoyl group or a group of formula 8, wherein Alk is a lower alkyl radical. In the ethylation process, known agents are used. ethylating agents, such as ethyl halides, e.g. ethyl iodide, or ethyl esters, e.g. diethyl sulfate, ethyl p-toluenesulfonate, or triethyl phosphate. The reaction components are usually used in stoichiometric amounts and the reaction is carried out in an inert solvent at a temperature of 25°-150°C. If R3 is a protecting group in the compound of formula (II), an excess of the ethylating agent is preferably used. Suitable solvents include, for example, ethanol, methylethylene glycol, dimethylformamide, dimethyl sulfoxide, and water. The reaction can be accelerated by adding an acid-binding agent, e.g. a base, such as an alkali metal carbonate, hydroxide, or alkanoate, sodium hydride, pyridine, triethylamine or benzyltrimethylammonium hydroxide. The resulting product, in which R4 is a group of the formula -R'4, is then hydrolyzed and/or the product, in which R3 is a protecting group, is subjected to a reaction to cleave this protecting group. Hydrolysis of the group: R4 is carried out with water, wherein a catalyst in the form of an acid or a base is added to accelerate the reaction. Inorganic or organic acids or bases can be used, e.g. acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, formic acid and toluenesulfonic acid, and e.g. bases such as alkali metal or alkaline earth metal hydroxides, e.g. sodium hydroxide or barium hydroxide, alkali metal carbonates, e.g. sodium carbonate. Sodium or potassium, and also sodium acetate. These reactions are preferably carried out by heating the compound to be hydrolyzed in a solvent medium and with the addition of water. Water is usually used as the solvent, but depending on the properties of the compound, solvents such as ethanol, dioxane, ethylene glycol dimethyl ether, benzene or acetic acid mixed with water can be used. The reactions are usually carried out at a temperature of 0° to 150° C, preferably 30° to 100° C. The protecting group R3 is preferably cleaved off by solvolysis or hydrogenolysis, depending on the nature of this group. Examples of groups R3 which can be cleaved off by solvolysis, including hydrolysis, are groups such as formyl, acetyl, trifluoroacetyl, benzyloxycarbonyl, in-tert.(butoxycarbonyl, p-methoxybenzyloxycarbonyl, vinyloxycarbonyl, ethoxycarbonyl, β-/p-toluene, sulfonyl-120, 134, sulfonyl-134, ethoxycarbonyl, o-nitrophenylsulfenyl, trimethylsilyl, triphenylmethyl, tetrapyranyl and diphenylsulfinyl. The solvation reactions are carried out in a solvent, optionally in the presence of an acid or a base, e.g. such as those given above in the discussion of the hydrolysis reactions of the R4 group. Water is usually used as the solvent, but a mixture of water with solvents such as ethanol, dioxane, ethylene glycol dimethyl ether, benzene or ethylene glycol acid can also be used. acetic acid. The reaction is carried out at a temperature of 0°-150°C, preferably 30°-100°C. Examples of groups Rs which can be cleaved by reduction are arylsulfonyl groups, such as p-toluenesulfonyl, methyl groups substituted by a benzyl or benzyloxy group, such as benzyl, triphenylmethyl or benzyloxymethyl, or arylmethoxycarbonyl groups, such as benzyloxycarbonyl or p-methoxybenzyloxycarbonyl. ' """' When cleaving the protecting group K3, the conditions of the hydrogenolysis process are adapted to the nature of this 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. Reduction can also be performed using sodium metal in liquid ammonia, or using a metal such as zinc in acetic acid or in an alcohol, e.g. methanol. Catalytic hydrogenolysis is carried out at room temperature or at temperatures elevated to 60°C. Solvents used include ethylene glycol, dioxane, dimethylformamide, ethanol, or acetic acid. If the protecting group is a benzyl, triphenylmethyl, or p-toluenesulfonyl group, the group can be cleaved using sodium metal in liquid ammonia, usually at a temperature of -50°C to -20°C. The starting compounds of formula 7 are new compounds. An example of their preparation is shown in the diagram in the figure, where in the formulas appearing in this diagram, Et denotes a radical. ethyl and A— denotes the anion of fluoroboric acid HBF4. In the first stage of the process, the compound of formula 12 is reacted in a known manner with carbonic acid monoethyl ester piperidide, and the resulting compound of formula 13 is aminated in the 2-position in a known manner with ammonia in ethanol, and then acetylated in the same position also in a known manner, to obtain the compound of formula 14. The nitro group in the 5-position of this compound is diazotized, reduced, and the amino group in the resulting compound of formula 15 is reduced in the presence of fluoroboric acid, and the resulting compound of formula 16 is heated, to obtain 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 1,1-diethyl 2-ethoxyethylenedicarboxylate, to obtain 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 of suitable boiling point, such as, for example, diphenyl ether, diphenyl phthalate, dibutyl phthalate, o-dichlorobenzene, diphenylene oxide or mixtures thereof. It is also possible to use the addition of known cyclization accelerators, such as polyphosphoric acid, lower alkyl polyphosphate, concentrated sulfuric acid, phosphoryl chloride or phosphorus pentoxide. If polyphosphoric acid, alkyl polyphosphate or phosphorus pentoxide is used, the reaction is carried out in in a solvent such as benzene, dioxane or dimethylformamide, while when sulfuric acid is used, the solvent is usually acetic anhydride or acetic acid. If the cyclizing additive has suitable properties, it can also be used 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 process according to the invention are isolated and purified by known methods. Depending on the nature of the starting products and the reaction conditions, compounds of formula I are obtained in the free state or in the form of salts, and the free compounds can be converted into pharmacologically active salts with pharmaceutically acceptable acids or bases. For this purpose, various inorganic or organic acids, e.g., hydrochloric, acetic, lactic, succinic, lactobionic, oxalic, and methanesulfonic acids. As stated above and demonstrated in the tests described below, the compounds prepared by the method according to the invention have very good properties with low toxicity, and therefore can be used for the prevention and 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 administration, etc. The daily dose for adults is 0.1-7 g, preferably 0.2-5 g, of the compound of formula I or its salts. These compounds are used in the form of preparations also containing solid or liquid pharmacologically acceptable additives that do not react with the compounds of formula I. 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. The preparations may be in the form of powder, grains, tablets, ointments, suppositories, creams, capsules, etc. They may be sterile and/or contain preservatives, stabilizers and wetting agents. They may also contain other biologically active substances. Tests comparing the properties of the compounds prepared by the method according to the invention with the properties of known compounds and the compounds of formula 10, which is also a derivative, are described below. 1,8-Naphthyridine is not covered by formula 1. Since the method of preparation of this compound has not been published so far, it is illustrated below. To a mixture of 12 ml of 37% formaldehyde and 18 ml of formic acid, 6.0 g of 1-ethyl-6-fluoro-1,4-dihydro-4-(1-(piperazyl)-11,8-naphthyridine-3-carboxylic acid) are added and the mixture is kept under stirring at 120-125°C for 4 hours. The mixture is then evaporated to dryness under reduced pressure, and the residue is made alkaline with an aqueous solution of sodium bicarbonate to a pH of 120-125°C. 8 and extracted with chloroform. The extract was dried, the solvent was evaporated and the residue was recrystallized from a mixture of dichloromethane and ethanol, yielding 5.0 g of 1-ethyl-6-fluoro-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-1,8-naphthyridinecarboxylic acid of the formula (XI) and melting point 228-230°C. Test 1. Using the method given in Chemotherapy, 22(6), p. 1128, (1974), the minimum concentration of the compounds prepared by the process according to the invention and known compounds in vitro against 19 different bacterial strains was determined. The values of this minimum MIC concentration are given in Tables J, 1a and 1b in µg/ml. In this Table, As in the following tables, the tested compounds covered by the general formula I are designated by numerical symbols, and the known compounds by letter symbols. The meaning of these symbols is as follows: compound 1 — compound of formula Ii, compound 1' — compound of formula I', compound 2' — compound of formula I2', compound A — compound of formula IIa, known from U.S. Patent No. 4,017,622, compound B — compound of formula IO, compound C — compound of formula VI, known from Japanese Patent No. 65887/78, compound D — compound of formula V, known from Belgian Patent No. 863 4)29, compound E — acid 1-ethyl-1,4-dihydro-7-methyl-4-keto-1,8-naphthyridinecarboxylic acid-3 (U.S. Patent No. 3,149,104), compound F - 8-ethyl-5,3-dihydro-5-ke-acid to-2-(1-piperazinyl)-pyrido[2,3-d]pyrimidinecarboxyl-6 (US Pat. No. 3,887,557), compound G - α-(5-indenyloxycarbonyl)-benzylpenicillin sodium salt (Carindacillin) (US Pat. No. 3 557 090), compound H - D-a-aminobenzylpenicillin (am¬ picillin) (U.S. Patent No. 2,985,648), compound J — 7-(D-α-aminophenylacetamido)-dezoacetoxycephalosporanic acid (Cephalexin) (U.S. Patent No. 3,507,861). The results given in Table 1, 1a, 1b prove that the compounds prepared by the method according to the invention, and especially the compounds of formulae 1i, 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 Antibacterial activity in vitro 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 0.2 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 of the invention.' Test 2. In vivo treatment efficacy. The compounds of the invention and known compounds were dissolved in deionized water or suspended in a 0.2% aqueous solution of carboxymethylcellulose and administered orally to mice infected with the test bacteria. Table 1a Bacteria 1 Gram-positive bacteria 1 Staphylococcus aureus 209P JC-1 Staphylococcus 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 - Blackboard Ib Bactenc- 1 and Gram-positive bacteria 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 continued 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 Salmonella 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, denoting the dose value ** EDg0. The tests were carried out with male mice (ddY) weighing approximately 20 g. The test compounds were administered twice, namely 5 minutes and 6 hours after infection. Infection was carried out as follows: 53 1. Stephylococcus aureus no. 50774. Infection was carried out intravenously with a suspension of bacteria in saline, using 5-10 LDFQ, i.e., approximately 5-108 bacterial cells per mouse. Observations were carried out for 14 days. 55 2. Escherichia coli P-5101. Infection was carried out intraperitoneally with a suspension of bacteria in soybean extract with 4% mucin, using 5-10 LD50, i.e., approximately 9-106 bacterial cells per mouse. Observations were carried out for 7 days. 60 3. Pseudomonas aeruginosa No. 12. The bacteria were infected intraperitoneally with a suspension of soy extract containing 410 µg of mucin, using 50-100 LD50, i.e. approximately 5110s of bacterial cells, for each mouse. Observations were carried out for 7 days. 65 The test results are given in Table 2. These are ED50 values in mg/kg, calculated by the Behrens-Kärber method (Arch. Exp. Patj. Phem. 162, p. 480, 1931). The values in the table are marked with the symbol x and expressed as free carboxylic acid. The results given in Table 2 allow the following conclusions to be drawn: 1. The compounds of formulae I1 and I' show a strong therapeutic effect at systemic infections with Gram-positive and Gram-negative bacteria, 2. The compounds of formulae I1 and I' produced according to the invention show a stronger effect in systemic infections with Gram-negative bacteria, especially Pseudomones aeruginosa, than compounds A, C, E and F, known as antibacterial agents, and compounds G, H and J, which are known antibiotics. 3. The compounds of formulae I1 and I' are much more effective in vivo against Gram-positive bacteria than the known compound D, and the compounds of formulae I3. Table 2 In vivo effectiveness in systemic infection in mice Tested compound Compound 1 Compound 1' Compound 2' Ethyl ester of compound 1 Compound A Compound B Compound C Compound D Compound E Compound F Compound G Compound H Compound J Bacteria Staphylococci 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 Pseudomonas aeruginosa No. 12. 9.0 9.0* 58.6* 21.0 200 10.6 100 15.5 200 99.5 201.6 400 400 l1 and r are much more effective in vivo against Gram-negative bacteria, including Pseudomonas aeruginosa bacteria, than the known compound D. 4. The ethyl ester of the compound of formula I1, prepared by the method according to the invention, which is an intermediate product in the preparation of compounds of formulae I1 and I', is also potent in vivo against Gram-positive and Gram-negative bacteria. Test 3. In vivo therapeutic efficacy. Compound 1 and the known compound D were also tested to compare their efficacy against progressive Pseudomonas aeruginosa infections of mice. aeruginosa No. 12. Female mice (ddY-s) weighing 2-30 g were anaesthetized with an intravenous dose of pentobarbital sodium 50 mg/kg, then the urinary bladder was exposed through a small incision in the lower abdomen and, using a 0.25 ml syringe with a 0.25 mm needle, they were infected with 0.1 ml of a 1:10,000 solution of Pseudomonas aeruginosa No. 12 culture, prepared within 20 hours in soy extract. For 1 day before and 1 day after infection, the mice were deprived of drinking water and, starting from the day of infection, they were administered the test compounds twice a day for 3 days. On the fifth day after In the case of infection, the kidneys were removed, cut crosswise and cultured overnight at 37°C on King A agar. If no bacteria were found, the compound was considered to protect against kidney infection. The test results are given in Table 3. Table 3 In vivo efficacy in mouse kidney infection with Pseudomonas aeruginosa bacteria No. 12 Test compound Compound 1 Compound D Administration Oral Oral ED50 mg/kg 2.4 16.1 The results given in Table 3 show that the efficacy of the compound produced by the method according to the invention, namely compound 1, in the case of an increasing kidney infection with Pseudomonas aeruginosa bacteria No. 12 is significantly higher than that of the known compound D. Test 4. Acute toxicity. Solutions containing individual compounds produced by the method according to the invention or known compounds were administered orally in various concentrations to groups of 4-8 male mice (ddY) in doses of 0.1 ml per 10 g of body weight and after 7 days the number of dead mice was determined by calculating the lethal dose LD50 in mg/kg using the Dehreus-Kaerbar method. ,ft The results are given in Table 4, where the values marked with the symbol x denote the values expressed as the free carboxylic acid. Table 4 33 Acute toxicity in mice Test compound [Compound 1 Compound 1' Compound 2' Compound B Compound C Compound D Compound E Compound F Compound G Compound H Compound J LD50 mg/kg above 4000 above 4000* above 2000* 210 above 2000 above 2000 1516 above 5000 above 4000 above 5000 3000 The results given in Table 4 show that the toxicity of the compounds prepared by the method according to the invention is negligible, and compound B, °o prepared by introducing a methyl radical into position 4 of the piperazinyl group of compound 1, prepared by the method according to the invention, although having the same or even higher antibacterial efficacy than the compounds prepared by the method according to the invention (see Table 1, 1a, 1b 12), has 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, at a dose of 2 g/kg for 14 days. During this period, each mouse was weighed and after 15 days, hematological examination was performed. After the examination, necropsies were performed, the organs were weighed and examined to determine the presence of any tissue disease. In the mice treated with compound 1, no disturbances in body weight gain or any signs of disease were observed, compared to the control group of mice that were not treated with this compound. This indicates that this compound can be administered without causing harmful effects. Table 6. Plasma concentration. Male Great Dane JBeagle weighing 12 kg was administered orally a capsule containing one of the compounds 1 and 2 at doses of 25 mg/kg with 200 ml of milk. After 0.5, 1, 2, 3, 6, 8, and 10 hours, blood samples were collected by venipuncture and centrifuged to separate the plasma. The content of the tested compounds in the plasma was determined by the thin-layer cylinder-plate method, using Escherichia coli Kp as an indicator microorganism. The results are given in Table 5 in µg/ml. Table 5 Plasma content in µg/ml Test compound Compound 1 Number of hours after administration of the tested 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 allow 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 1-10 hours after administration is higher than the lowest MIC concentration at which this compound is effective against most bacteria (see Table 1, 1a, 1b). For example, the plasma concentration of compound 1, 5.9 µg/ml, is about 8 times higher than the lowest concentration at which this compound is effective against Pseudomonas aeruginosa No. 12 and Sptahylococcus aureus no. 50774, and about 60 times higher in relation to the Escherichia coli P = 5101 bacteria. The results given in Table 5 prove that compound 1 produced by the method according to the invention has a high concentration in plasma and even at low doses is effective in combating systemic infections with various bacteria. Test 7. Excretion of compounds in urine. The urine of the dogs subjected to the tests described in test 6 was collected over 24 hours and the urine content was determined using the method given in test 6. The test results are given in Table 6. Table 6 Excretion of compounds in urine tested 10 Test compound Compound 1 Concentration Compound in urine ng/ml 606 Amount of compound excreted % 40.7 The data in Table 6 allow drawing the following conclusions: 1. Compound 1 is quite well excreted in urine and within 24 hours after oral administration about 40.0% of the given compound is excreted in urine. 2. The concentration of compound 1 is about 51-6000 times higher than the lowest concentration at which this compound is effective against various bacteria (04-1(2.15 [Ag/ml according to Table 1, 1a, 1b). 3. Compound 1 is even at low doses highly effective against urinary tract infections caused by various bacteria. As given in Tables 1-6, the compounds produced by the method The compounds of the invention, and especially the compounds of formulae I1 and I', have a strong therapeutic effect in artificially induced infections with Gram-positive and Gram-negative bacteria and, after oral administration, remain at high concentrations in the plasma and urinary tract for a long time. Furthermore, their toxicity is low, so they can be used, even in small doses, to combat urinary tract infections and systemic infections caused by various bacteria. In contrast, the known compounds A and C have significantly poorer antibacterial activity in vitro and in vivo against Gram-positive and Gram-negative bacteria, as shown in Tables 1, 1a, 1b, and 2. The known compound D has a significantly poorer effect in the case of combating an increasing kidney infection with Pseudomonas aeruginosa bacteria. Therapeutic activity is clearly worse than that of compounds of formulae I1 and I'. Compounds E and F, which are known synthetic antibacterial agents, and compounds G, H and J, which are known antibiotics, have a therapeutic activity in vivo in the case of infections with Gram-negative bacteria, especially Pseudomonas aeruginosa bacteria, which is significantly worse than that of compounds of formulae I1 and I' prepared by the method according to the invention. The method for preparing compounds of formula I is illustrated below. Example I. Preparation of compound of formula I1 and its addition salts. To a suspension of 1 g of 7-(4-ethoxycarbonyl-1-piperazinyl)-6-fluoro-1,4-di-ethyl ester, 0.53 g of sodium carbonate is added to a mixture of 4-hydroxy-1,8-methyl-1-carboxylic acid and 10 ml of dimethylformamide and stirred at 60°C for 10 minutes. 1.2 g of ethyl iodide and sodium iodide are added at 60-70°C for 2 hours. The mixture is then evaporated to a liquid under reduced pressure, water is added to the residue, the solution is extracted with chloroform, the extract is dried over anhydrous potassium carbonate and the chloroform is evaporated. The residue is recrystallized from a mixture of dichloromethane and n-hexane, yielding 0.89 g of 1-ethyl-6-fluoro-1,4-methyl-1-carboxylic acid ethyl ester. 7-Dihydro-4-oxo-7-(4-ethoxycarbonyl-1-piperazinyl)-1,8-naphthyridine-3-carboxylic acid, melting point 171°-173°C. A mixture of 0.8 g of this ester, 6 l of 103% sodium hydroxide and 2 ml of ethanol is boiled under reflux for 3 hours, then cooled, 10% acetic acid is added to obtain a pI of 7.0-7.5, the 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-carboxylic acid is obtained. -dihydro-4-oxo-7-(1-piprazinyl)-1,8-naphthyridinecarboxylic acid of formula I1. The product melts at 220-224°C. 0.2 g of the acid obtained is dissolved in 5% hydrochloric acid and the solution is evaporated to dryness under reduced pressure. The residue is recrystallized from water, obtaining 0.21 g of the hydrochloride of the acid of formula I1. The product melts at a temperature above 300°C. In a second test, 0.2 g of the acid of formula I1 is dissolved in 7% water at an elevated temperature, then cooled, the precipitate is filtered off and recrystallized from dilute methanol, obtaining 0.22 g of the methanesulfonic acid salt of the acid of formula I1, i.e. the compound of formula I'. The product melts with signs of 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, the mixture is cooled and the crystalline precipitate is filtered off. This product is recrystallized from ethanol to give 0.93 g of the acetic acid addition salt of the acid of formula I1. The product melts at 228-229°C. The ethyl ester of 7-(4-ethoxycarbonyl-1-piperazinyl)-6-fluoro-1,4-dihydro-4-methyl-3 ... -keto-1,8-naphthyridinecarboxylic acid-3 of formula 11 is prepared as follows: 2,u-dichloro-3-nitropiperidine is reacted with N-ethoxycarbonylpiperazine and 6-chloro-2-(4-ethoxycartonyl-1-piperazinyl)-3-mtropiperidine is obtained, without purifying it, heating it with an ethanolic ammonia solution in a soldered pipe at a temperature of 120-125°C, obtaining 6-amino-2-(4-ethoxycarbonyl-1-piperazinyl)-3-nitropiperidine with a melting point of 132-134°C. This product is treated with acetic anhydride in acetic acid to obtain 6-Acetylamino-2-(4-ethoxycarbonyl-1-piperazinyl)-3-nitropiperidine, m.p. 168-169°C. This compound is catalytically hydrogenated with C10 palladium on carbon to give 3-amino- & 18-6-acetylamino-2-(4-ethoxycarbonyl-1-piperazinyl)-pyridine, which is dissolved without purification in a mixture of ethanol and 42% tetrafluoroboric acid, and to the resulting solution is added, with stirring at a temperature below 0°C, a solution of isoamyl nitrite in ethanol. After 20 minutes, ether is added to the solution, the precipitate is filtered off, and the precipitate is washed with a mixture of methanol and ether and then with chloroform. mem. 6-acetylamino-2-(4-ethoxycarbonyl-1-piperazinyl)-3-pyridine diazonium tetrafluoroborate is obtained, melting at 117-117.5°C (decomposition symptoms). A suspension of the obtained diazonium salt in toluene is heated with 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 10% sodium carbonate solution 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, m.p. 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-ylfluoropyridine. This product is treated at 130-140°C with ethoxymethylenemalonic acid diethyl ester to give N-[2-(4-ethoxycarbonyl-1-piperazinyl)-3-fluoro-6-pyridyl]aminomethylenemalonic acid ethyl ester, m.p. 144-145°C. This compound is cyclized by heating at 255°C to give 7-(4-ethoxycarbonyl-1-piperazinyl)-6-fluoro-1,4-dihydro-4-keto-1,8-naphthyridine-3-carboxylic acid ethyl ester, melting at 279-281°C. Example 11. Preparation of the compound of formula I2. Following a procedure analogous to that described in Example 1, but starting from 7-(4-ethoxycarbonyl-1-piperazinyl)-1,4-dihydro-4-keto-1,8-naphthyridine-3-carboxylic acid ethyl ester, the hydrochloride is prepared. G-chloro-1-ethyl-1,4-dihydro-4-keto-7-(1Hpiperazinyl]-1;8-naphthyridinecarboxyl-3 acid. The product melts at a temperature above 30°C. Example 111. Preparation of the ethyl ester of the compound of formula I1. In a similar manner as described in Example 1, by reacting the ethyl ester of 6-fluoro-1,4-dihydro-4-keto-7-/4-trifluoroace- tyl-1-piperazinyl-1,8-naphthyridinecarboxylic acid-3 with ethyl iodide and potassium carbonate in dimethylformamide to prepare 1-ethyl-6-fluoro-1,4-dihydro-4-ke-acid ethyl ester 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(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 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,α-naphthyridine-3-carboxylic acid ethyl ester, melting at 150-151°C. Example 4. Preparation of the propyl ester and butyl ester of the acid of formula 11. In a manner analogous to that described in Example 3, 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,α-naphthyridine-3-carboxylic acid propyl ester is prepared. 3. A method for preparing new 1,8-naphthyridine derivatives of the general formula I, wherein X is a halogen atom and R is a lower alkyl radical, and when X is a halogen atom, R is a lower alkyl radical, R is a lower alkoxycarbonyl group, R is a lower alkoxycarbonyl group, and ... characterized in that the compound of formula 7, in which X has the above-mentioned meaning, R3 is a hydrogen atom, or pharmacologically acceptable salts of 1,8-naphthyridine of general formula 1, in which X is a fluorine atom and R is a hydrogen atom, or pharmacologically acceptable salts of these compounds, characterized in that the compound of formula 7, in which X is a fluorine atom, R3 is a hydrogen atom or a protecting group such as an acyl group, an o-nitrophenylsulfenyl group, an arylsulfonyl group or a methyl group substituted with a phenyl or benzyloxy group, and R4 is a carboxyl group or a lower alkoxycarbonyl group, is reacted with an ethylating agent and if in the resulting compound R4 is an alkoxycarbonyl group, then this compound is reacted with an ethylating agent and if in the resulting product R4 is a cyano group, an amine group or a lower alkoxycarbonyl group, then the compound is reacted with an ethylating agent and if in the resulting product R4 is a cyano group, the amine group or a lower alkoxycarbonyl group is hydrolyzed ... 2. A method according to claim 1, characterized in that the compound of formula 7, in which X is a carbon atom, and then if in the product R3 is a protective group, then this group is cleaved off by hydrolysis or hydrogenolysis, and then the obtained compound of formula 1 is optionally converted into its pharmacologically acceptable salt. COOR HN N/^t* CoH 2n5 COOH Formula and 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 N N <\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^ -c s H F NH ^OAlk O Y* °z*U CK Kl N EtOCO-l^ JN IY IY Wcrfr /O - H h'zór 14 reciuko/a A N 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 Formula 7a cukuzagcL Scheme H Formula g LZGraf. Z-d No. 2 — 418/83 90 copies A-4 Price 100 zl PL PL PL PL PL PL PL PL PL

Claims (1)

1.