SU1075976A3 - Process for preparing derivatives of 1,8-naphthyridine or their salts - Google Patents

Abstract

NEW MATERIAL:A 1,8-naphthylidine derivative of formula I (X is halogen; R is amino; R1 is lower alkyl, lower alkenyl, lower alkynyl; R2 is H, lower alkyl), and its salt. EXAMPLE:6 -Chloro-1-ethyl-1, 4-dihydro-4-oxo-7-pyrrolidino-1, 8-naphthylidine-3- carboxylic acid. USE:Antibacterial agent especially effective to gram negative bacteria including Pseudomonas aeruginosa. Medicine, animal drug, fish drug, food preservative, intermediate of various compounds, etc. PROCESS:The title compound I is prepared, e.g. by reacting a compound II (Y is a functional group which can be replaced with amine group) with an amine R-H in an inert solvent such as ethanol, etc., at 20-180 deg.C, pref. 50-150 deg.C, for 20-60 minutes. The compound II is also novel.

Description

This invention relates to a process for the preparation of new 1,8 naphthyridine derivatives with antibacterial properties that can be used in medicine.  The hydrolysis of carboxylic acid derivatives such as nitrile esters, nitrides, amidines, imino ether into the corresponding free acid C is known.  The purpose of the invention is to obtain derivatives of 1,8-naphthioyline, possessing valuable pharmacological properties.  This goal is achieved based on the known reaction of producing derivatives of 1,8 naphthyridine of the general formula ITU nt to R where ethyl is ethyl or vinyl, or their salts, which means that in the compound of general formula k. EDG where R has the indicated meanings; 2 C —C alkoxycarbonyl, carboxyl, cyano, carbamoylamidino or —C (NH) OAIk group, where Alk is C-alkyl; RJ - hydrogen or a protecting group hydrolyzes the group Rjj when it is not carboxyl, and / or removing the protecting group RJ, followed by isolating the desired product as a base or salt.  It is preferable to conduct hydrolysis using an aqueous solvent in the presence of an acid or base at 30-100 ° C.  The initial products receive according to standard methods.  Standard method 1.  2.18 g of diethyl-N-C6- (4-acetyl) -1-piperazinyl) -5-fluoro-2-pyridyl-H-ethylaminomethylenemalonate is added to 10 g of polyphosphoric acid, and the mixture is heated at 110120 ° C and stirred in for 15 minutes  After cooling, the syrup product is mixed with ice water, adjusted to pH 620 with an aqueous solution of sodium hydroxide and extracted with chloroform.  After drying, the extract is evaporated to dryness.  Occa is crystallized by the addition of ethyl acetate, recrystallization from ethyl acetate from the ethyl acetate gives 1.3 g of ethyl 7- {4-acetyl-1-piperazinyl) -1-ethyl-b-fluoro-1, 4-dihydro-4-oxo-1,8- naphthyridine-3-carboxylate, t. square  195197 ° C.  Standard Method 2.  When heated ethyl-S-Sat- (4-acetyl-1-piperazinyl) -5-fluoro-2-pyridylZaminomethylene cyanoacetate (3.3 g) obtained from 6- (4-acetyl-1-piperazinyl) -5-fluoro- 2-aminopyridine and ethyl ethoxymethylene cyanoacetate, up to 255 C, 2.3 g of 7- (4-acetyl-1g-piperazinyl) -6-fluoro-1,4-dihydro-4-oxo-1, 8-naphthyridine-3-carbonitrile are obtained.  The obtained nitrile without further purification is treated with ethyl iodide and potassium carbonate in dimethylformamide.  The reaction mixture is evaporated to dryness under reduced pressure.  The residue is extracted with chloroform, the extract is washed with water and dried.  The resulting solid is recrystallized from a mixture of ethanol and xjoprop.  2.2 g of 7- (4-acetyl-1-piperazinyl) -1-ethyl-6-fluoro-1,4-dihydro-4-oKco-1, 8-naphthyridine-3-carbonitrile are obtained, t. square  289-290 s.  Standard Method 3.  A mixture of 1-ethyl-6-fluoro-1,4-dihydro-4-OXO-1, 8-naphthyridine-3-carboxylic acid (3.25 g) and phosphoryl chloride (30 ml) is boiled for 5 minutes.  After distilling off the excess phosphoryl chloride, 30 g of ice-cold water is added to the residue with stirring and the mixture is left at room temperature overnight.  The precipitate is separated by filtration, washed with water and recrystallized from acetonitrile.  Obtain 3.2 g of 7-chloro-1-ethyl-6-fluoro-1,4-DIGIDRO-4-oxo-1, 8-naphthyridine-3-carboxylic acid, t. square  265-267С.  Standard method 4.  The reaction of 2,6-dichloro-3-nitropyridine with N-ethoxycarbonylpiperazinsm produces b-chloro-2- (4-ethoxycarbonyl-1-piperazinyl) -3-nitropyridine.  When the product is heated (without pre-treatment) with a solution of ammonia in ethyl alcohol in a sealed tube at 120-125s, 6-amino-2- (4-ethoxycarbonyl-1-piperazini) -3-nitropyridine (t. square  132-134 c), treatment with acetic anhydride in acetic acid leads to 6-acetylamino-2- (4-ethoxycarbonyl-1-piperazinyl) -3-nitropyridine (t. square  168-169 C) With the catalytic hydrogenation of this compound in acetic acid in the presence of 5% palladium on charcoal, 3'1ino-b-acetylamino-2- (4-ethoxycarbonyl-1-piperazinyl) pyridine is obtained.  This 3-amino derivative is dissolved without purification in a mixture of ethyl alcohol and 42% boron fluorosorbic acid, and a solution of isoamylnitrite in ethanol is added to this solution at a lower temperature.  After 20 minutes, ether was added to the solution.  The resulting residue of b-acetylamino-2- (4-ethoxycarone-onyl-1-piperazinyl-3-pyridinediazonium tetrafluoroborate) is filtered and washed with a mixture of methanol and ether and then with chloroform (m. square  117-117, with decomp. ), The suspension of the indium salt in toluene is slowly heated to 120 ° C (bath temperature) and maintained at this temperature with constant stirring for 30 minutes. After removing the solvent under reduced pressure, the residue is basified with 10% sodium carbonate solution and then extracted with chloroform .  The chloroform extract is dried with anhydrous sodium carbonate. After evaporation of the solvent, the crystalline residue is recrystallized from ethyl acetate.  6-acetylamino-2- (4-ethoxycarbonyl-1-piperazinyl) -3-fluoropyridine (m. square  132-133C).  The 3-fluoro derivative is hydrolyzed with a mixture of 15% hydrochloric acid and methanol (1: 2 by volume).  6-amino-2- (4-ethoxycarbonyl-1-piperazinyl) -3-fluoropyridine is obtained.  This compound is treated with diethyl ether; methylene malonate at 13 O – 140 C; (4-ethoxycarbonyl-1-piperazinyl) -3-fluoro-6-pyridinyl-aminomethylene malonate (t. square  144145 ° C), then the product is cyclized by heating with ethyl-7- (4-ethoxycarbonyl-1-piperazinyl) -6-fluoro-1, 4 dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (t . square  279-281 Standard Method 5.  A mixture of ethyl 7- (4-ethoxycarbonyl-1-piperazinyl) -6-fluoro-1,4-dihydro-4-6xo-1, 8 naphthyridine-3-carboxyl that (10.5 g), dimethylformamide (100 ml ) and carbonate.  potassium (7.4 g) is heated for 15 minutes. A solution of 10.1 g of ethylene bromohydrin in dimethylformamide is added to the solution and the mixture is heated at 100 ° C and stirred for 45 minutes.  After removing the resulting inorganic compound by filtration, the filtrate is evaporated to dryness under reduced pressure.  VO ml of water is added to the residue, and the resulting crystals are separated by filtration and recrystallized from ethyl alcohol.  10.2 g of ethyl-7- (4 ethoxycarboxy-1-1-piperazinyl) -6-fluoro-1- (2-hydroxyethyl) -1,4-dihydro-4-oxo-1, 8 naphthyridine-3-carboxylate ( t. pl, 215-217 O.  To a solution of this hydroxyethylproduced (4.6 g) c chlo. Rof01 4e (50 ml) was added 5.0 g of thionyl chloride, and the mixture was boiled under reflux for 30 minutes.  After cooling, the solution is treated with 30 ml of water and neutralized with a saturated sodium bicarbonate solution.  The chloroform layer is separated, washed with water and dried with anhydrous sodium sulfate.  After removal of the solvent, the residue is chromatographed on silica gel (eluent: chloroform), and the crystals obtained by evaporation of the main fraction are recrystallized from eth. ylacetate.  Obtain 4.7 g of ethyl-1- (2-chloroethyl) -7- (4-ethoxycarbonyl-1-piperazinsh1) -b-F1: op-1, 4-dihydro-4-occo-1, 8-oil readin- 3-cartridges (m. square  143144С).  Standard method 6.  To a well stirred mixture of ethyl-7- (4-acetyl-1-piperazinyl) -1,4-dihydro-6-nitro-4-oxo-1, 8-naphthyridine-3-carboxylate (4.7 g) and potassium carbonate (3.77 g) in 40 ml of dimethylformamide was added 3.6 g of ethyl iodide.  The mixture is stirred for 80 minutes at the same temperature ().  After removing the insoluble residue, the filtrate is evaporated to dryness under reduced pressure.  The residue is dissolved in water and extracted with chloroform. After evaporation of the chloroform and addition of ether to the residue, 4.5 g of ethyl 7- (4 acetyl-1-piperazinyl) -1-ethyl-1, 4-dihydro-6-nitro-4-oxo-1, 8-on: ftiyridine are obtained. - 3-carboxylate, t. square  211-212c.   To a solution of this product (8.0 g) in 200 ml of acetic acid at 7080c, 16 g of reduced iron are added in portions.  After stirring for 0.5 h at the same temperature, ethyl alcohol is added to the mixture.  After filtration, the filtrate is evaporated to dryness under reduced pressure.  300 ml of water is added to the residue and the mixture is cooled in an ice bath.  The resulting solid grade is collected and recrystallized from ethyl alcohol.  5.8 g of ethyl-7- (4-acetyl-1-piperazinyl) -6-amino-1-ethyl-1, 4-DIGIDRO-4-OXO-1, 8-naphthyridine-3-carboxylate are obtained, t. square  265-270 C.  i Example 1.  Ethyl 1-ethyl-b-fluoro-1, 4-DIHYDRO-4-OXO-7- (4-piperazinyl) -1, L-naphthyridine-3-carboxylate (3.48 g) is heated with 30 ml of aqueous 5% sodium hydroxide in a water bath for 30 minutes.  After cooling with acetic acid, the pH is adjusted to 7.  The resulting solid is collected and distilled from a mixture of ethyl alcohol and chloroform.  Obtain 3.0 g of 1-ethyl-6-fluoro-1, 4-DIHYDRO-4-OXO-7- (l-nHne-razinil) -1,8-naphthyridine-3-carboxylic acid, t. square  220-224 ° C.  Example 2  A mixture of ethyl 7- (4-acetyl-1-piperazinyl) -1-ethyl-6-fluoro-1, 4-DIHIDRO-4-OXO-1,8-naphthyridine-3-carboxylate (20 g) and 20% hydrochloric acid is refluxed for 3.5 hours and then 100 ml of water and 200 ml of ethyl alcohol are added to the reaction mixture.  The resulting solid is collected and dissolved in 300 ml of hot water. 5 activated carbon is added to the solution and filtered.  To the filtrate, 25.5 ml of concentrated hydrochloric acid are added and while cooling in an ice bath, 15.2 g of 1-ethyl-b-fluoro-1, 4-DIHYDRO-4-OXO-7- {1- pip razinyl) -1,8-naphthyridine-3-carboxylic acid, m. square  above 200s.  14.2 g of the hydrochloride salt is dissolved in 100 ml of aqueous 4% sodium hydroxide and diluted acetic acid to pH 7.5.  The precipitate is collected, washed and recrystallized from a mixture of ethyl alcohol and chloroform.  11.7 g of 1-ethyl-6-fluoro-1, 4-dihydro-4-oxy-7- (1-piperazinyl) -1, b-naphthyridine-3-carbonic acid are obtained.  Example 3  7- (4-Acetyl-1-piperazinyl) -1-ethyl-6-fluoro-1,4-di-Dro-4-oxo-1,. 8-naphthyridine-b-carbonitrile (3.43 g) is dissolved by heating in 10 ml of concentrated sulfuric acid.  The solution is heated for 15 minutes in a steam bath and then poured into ice water.  The plant is adjusted to pH 8 with aqueous 10% sodium hydroxide and extracted with chloroform.  The extract is washed with water,. dried and evaporated with chloroform.  The precipitate obtained is crystallized by the addition of ethyl alcohol and chloroform.  3.35 g of 7- (4-acetyl-1-piperazinyl) -1-ethyl-6-flu-1,4-DIHIDRO-4-OXO-1,8-naphthyridine- are obtained. 3-k arb oxy amide, t. square  282-283 ° C.  A mixture of 7- (4-acetyl-1-piperazinyl) -1-: 9-ethyl-6-fluoro-1,4-DIHIDRO-4-OXO71, B-naphthyridine-3-carboxamide (3.3 g) acetic acid (20 ml ) and concentrated hydrochloric acid (20 ml) is refluxed for 4 hours.  The mixture was evaporated to one third the volume and adjusted to pH 7 with aqueous 10% sodium hydroxide.  The resulting solid is collected, washed with water and recrystallized from a mixture of ethyl alcohol and chloroform.  2.92 1-ethyl-b-fluoro-1,4-dihydrr-4-oxo-7- (1-piperazinyl) -1,8-naphthyridine-3-carboxylic acid is obtained.  P. Example 4.  To a stirred solution of ethyl 1-ethyl-6-fluoro-1,4-dihydro-4-oxy-7- (4-trifluoroacetyl-1-piperazin-yl) -1,8-naphthyridine-3-carboxylate (2.66 g) in a mixture of chloroform (20 ml) -d and methanol (30 ml) a solution of sodium carbonate (4.14 g) in 60 ml of water is added.  The mixture is stirred for 5 hours at room temperature, neutralized with acetic acid and extracted with chloroform.  The extract is dried and the chloroform is evaporated.  A crystalline product is obtained.  The crude product is recrystallized from ethyl acetate, thus obtaining 2.0 g of ethyl 1-ethyl-6-fluoro-1, 4-DIHYDRO-4-OXO-7- (1-piperazinyl) -1,8-naphthyridine-3-carboxylate , t square  150-15lc.  The carboxylate (1.74 g) is heated with 15 ml of a 5% aqueous solution of sodium hydroxide in a water bath for 20 minutes.  After cooling with acetic acid, m.  .  pH of the reaction mixture to 7.  The resulting solid is collected and recrystallized from a mixture of ethanol and chloroform.  1.5 g of 1-ethyl-6-fluoro-1 are recovered. , 4-DIHIDRO-4-OXO-7- (1-piperazinyl) -1,8-naphthyridine-3-carboxylic acid.  Example 5  6-Fluoro-1,4-dihydro-4-OXO-7- (1-piperazinyl) -1-vinyl-1, B-naphthyridine-3-carboxylic acid (m. square  256-260 ° C) is obtained from ethyl-6-fluoro-1,4-DIHIDRO-4-OXO-7- (1-piperazinyl) -1-vinyl-1,8-naphthyrig din-3-carboxylate by the method of Example 4 .  Example 6   sodium hydroxide solution (30 ml) is added to 1.5 g of 7- (4-ethoxycarbonyl-1-piperazinyl) -b-fluoro-1,4-DIGIDRO-4-OXO-1-VINIL-1, 8-naphthyridine- 3-carboxylic acid.  The mixture was heated under reflux with stirring for 5 hours.  After cooling, the solution is adjusted to pH 7 with acetic acid. The resulting precipitate is separated by filtration.  The precipitate was dissolved in aqueous 10% acetic acid with heating, and the pH of the solution was adjusted to 7 with ammonia solution.  The resulting precipitate was separated by filtration, and 0.98 g of b-fluoro-1,4-DIGIDRO-4-OXO-7- (1-piperazinyl) -1-vinyl-1,8-naphthyridine-3-carboxylic acid was isolated.  Example 7  A mixture of ethyl 1-ethyl-7- (4-ethoxycarbonyl-1-piperazinyl) -b-fluoro-1, 4-DIHYDRO-4-OXO-1,8-naphthyridine-3-carboxylate (10 g), 15% hydrochloric acid (50 ml) and ethyl alcohol (50 ml) are heated under reflux for 45 minutes.  After evaporation of ethanol, the mixture is cooled.  The resulting solid is separated, washed with water and recrystallized from a mixture of dichloromethane and ethyl alcohol.  Obtain 7.5 g of 1-ethyl-7- (4-ethoxycarbonyl-1-piperazinyl) -6-fluoro-1,4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid, t. square  246-247 C.  A solution of 7.5 g of 1-ethyl-7- (4-ethoxy carbonyl-l-piperazinyl) -6-fluoro-1, 4-dihydro-4-oxo-1, 8 naphthyridine-3-carboxylic acid. 75 ml of aqueous 10% sodium hydroxide are boiled under reflux for 3 hours. The mixture is cooled and adjusted to pH 7 with acetic acid.  The resulting solid is collected, washed with water and recrystallized from a mixture of ethyl alcohol and chloroform.  5.45 g of 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl) -1,8-naphthyridine-3-carboxylic acid are obtained.  PRI me R 8.  A stirred solution of 1-ETHIL-6. -Fluoro-1,4-dihydro-4-oxo-7- (4-trifluoroacetyl-1-piperazinyl) -1/8 naphthyridine-3-carboxylic acid (1.12 g) in 30 ml of acetic acid is left overnight at room temperature.  After evaporation of the acetic acid under reduced pressure, the pH of the residue is adjusted to 8-9 with dilute ammonia solution.  The precipitate is collected, washed with water and recrystallized from a mixture of ethyl alcohol and chloroform.  0.6 g of 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl) -1,8-naphthyridine-3-carboxylic acid is obtained.  Example 9  To a solution of 7- (4-benzyloxycarbonyl-1-piperazinyl) -1-ztil-6-fluoro-1, 4-DIHIDRO-4-OXO-1, 8-naphthyridine-3-carboxylic acid (1.4 g, t. square  232-234 c) in a mixture of ethyl alcohol 20 ml), water (8 ml) and pyridine (2 ml), 140 mg of 5% palladium on carbon is added.  The mixture was hydrogenated at room temperature with shaking.  After uptake of 84 ml of hydrogen, the mixture is filtered to remove the catcher and the filtrate is concentrated to dryness under reduced pressure.  16 ml of water are added to the residue and the pH of the solution is adjusted to 7, and a precipitate is formed.  The precipitate is separated, washed with water and recrystallized from a mixture of ethyl alcohol and chloroform.  Obtain 0.82 g of 1-ethylg-6-fluoro-1,4-DIHIDRO-4-OXO-7- (1-piperazinyl) 1-1, 8-naphthyridine-3-carboxylic acid. Example 10.  1-Ethyl-6-fluoro-1, 4-dihydro-4-oxo-7- (4- (/ 1, (L, y-trichloroethoxycarbonyl) -1-piperazinyl) -1, 8-naphthyridine-3-carboxylic acid (500 mg) is treated with 500 mg of zinc dust and 5 ml of acetic acid at a temperature of 2-4 hours.  After filtering, the filtrate is evaporated under reduced pressure.  The residue is dissolved in water and neutralized with ammonia solution.  The resulting precipitate is collected and recrystallized from a mixture of ethyl alcohol and chloroform.  290 mg of 1-ethnp-6-fluoro -1,4-dngydro-4-oxo-7- (1-piperazinyl) -1,8-naphthyridine-3-carboxylic acid are obtained.  PRI me R 11.  A mixture of ethyl 1-6-fluoro-1, 4-dihydro-4-oxo-7- (4-ethoxycaronyl-1-piperazinyl) -1,8-naphthyridine-3-carboxylate (t. square  171173c) (0.8 g), 10% sodium hydroxide (b ml) and ethyl alcohol (2 ml) are refluxed for 3 hours.  After cooling, the pH of the solution is adjusted to 7.0-7.5 with 10% acetic acid.  The precipitate is separated by filtration, washed with ethyl alcohol and recrystallized from a mixture of dimethylformamide and ethyl alcohol.  0.57 g of 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl) -1,8-naphthyridine-3-carboxylic acid is obtained.  The resulting carboxylic acid (0.2 g) is dissolved in 5% hydrochloric acid, and the solution is evaporated to dryness under reduced pressure.  The residue is crystallized from water.  Get the hydrochloride of this acid (0.21 g).  0.2 g of this carboxylic acid is dissolved in a 7% solution of methanesulfonic acid by heating.  After cooling, the precipitate is recrystallized from aqueous methanol.  An adduct of methanesulfonic acid with this carboxylic acid (0.22 g) and tons is obtained. square  above (with dec. ).  The carboxylic acid (1.0 g) is dissolved in ethyl alcohol with heating, then acetic acid (1 ml) is added to the solution.  After cooling the mixture, the resulting crystals are separated ,.  recrystallized from ethyl alcohol.  Get the adduct of acetic acid and carboxylic acid (0.93 g) with t. square  228-229c.  Standard method 7.  To a mixture of 37% phymalin (12 ml) and formic acid (18 ml) was added 6.0 g of 1-ethyl-6-fluoro-1,4-dihydro-4-ox-7- (1-piperazinyl) - 1,8-naphthyridine-3-carboxylic acid.  The mixture is heated at 120-125 C for 4 hours with stirring.  The mixture is then evaporated to dryness under reduced pressure, and the residue is adjusted to pH 8 by the addition of aqueous 7% sodium bicarbonate.  Extracted with chloroform.  The extract is dried and the solvent is evaporated.  The precipitate is recrystallized from a mixture of methylene chloride and ethyl alcohol.  5.0 g of 1-ethyl-6-fluoro-1,4-dihydro-7- (1-methyl-1-piperazinyl) -4-OXO-1, 8-naphthyridine-3-carboxylic acid are obtained, t. square  228-230 ° C.  Connection- 1.  1-Ethyl-6-fluoro-1, 4-dihydro-4-oxo-7- (1-piperazinyl) -1,8-naphthyridine-3-carboxylic acid.  910759 Compound 1.  1-Ethyl-6-fluoro-1, 4-dihydro-4-oxo-7- (1-piperaoinyl) -1,8-naphthyridine methanesulfonate, ° Compound 2.  6-Fluoro-1, 4-dihydro-4-oxo-7- (1-pi-naprazine-5-nyl) -1-vinyl-1,8 naphthyridine-3-carboxylic acid, Compound A (izvest.  nre).  1-Ethyl-1,4-Dihydro-4-ox-7- (1-piperazinyl) -1,8-naphthyridine-10 -3-carboxylic acid (unsubstituted 6-naphthyriline).  C D E N E N B (obtained by the standard method).  1-Ethyl-6-fluoro-1, 4-dihydro-7- (4-methyl-1-piperaz-5wil) -4-OXO-1,8-naphthyridine-3-carboxylic acid.  Compound C (known).  b-Chloro-1-ethyl-1,4-dihydro-4-oxo-7-q - (1-piperazinyl) -quinoline-3-carboxylic acid. , 7610 Compound D (known), 1-Ethyl-6-fluoro-1,4-dihydro-4-oxo-7- (1-piperaoinyl) quinoline-3-carboxylic acid.  CONCERNED E. (known)  1-Ethyl-1,4-dihydro-7-methyl-4-oxo-1, 8-naphthyridine-3-carboxylic acid.  Connection (known).  8-Ethyl-5,8-dihydro-5-oxo-2- (1-piperazinyl) pyrido (2, 3-o1) pyrimidine-6-carboxylic acid.  Compound G (known).  Sodium salt of dt - (5-indanyloxycarbonyl) benzylpenicillin.  Compound H (known).  D-Aminobenzylpenicillin.  Compound (known).  7- (ito-Aminophenylacetamido). deacetoxycephallosporic acid.  Antibacterial activity in vitro at the minimum inhibitory concentrations of the proposed compounds is given in Table.  1 and 2.  .  b l and c a 1

table 2

Streptococcus faecalis Pt2473

Streptococcus pyogenes 65 A

ICorynebacterium pyogenes C 21

200

1.56

50

200

0.2 0.025 0.78

200

25

3.13 1.56 l., 56 It follows from the results of tabs 1 and 2 that compounds 1, l and 2 have a very high antibacterial activity against gram-positive and gram-negative bacteria, including Pseudomonas aeruglnosa; Compound A (6-indispensable 1,8-naphthyridine) is inferior in antibacterial activity with respect to gram-positive and gram-negative | L111 bacteria by the proposed compounds.

Continued table. 2 Therapeutic efficacy in vivo. Compounds 1, 1 and 2, as well as compounds A - G (each), are dissolved in deionized water or suspended in a 2.0% -HOh4 aqueous solution of CWIC. Each solution was orally administered. Pre-infected with test microbes. The average effective dose () is presented in Table. 3. Tables in 3

Calculated for free carboxylic acid. Male mice (ddy) weighing 1 g are infected with Staphylococcus aureus No. 50774 infection intravenously with a dose of 5 x 10 LD50 (about 9 x HO cells / mouse) of the bacterial suspension in saline. Escherichia coli P-5101. Intraperitoneal infection with a dose of 5 - 10 LDso (about Eh 10 cells / mouse) of bacterial suspension in tryptosoy broth. Preudomonas aeruginosa No. 12. Internal infection with a dose of 50,100 LDjo (about 9 X 10 cells / mea) of bacterial suspension in tryptosoy broth with 4% mucin. Treatment: the drug is administered twice (5 minutes and 6 hours after infection). Observation: Staphylococcus aureu 50774 - 14 days; Escherichia coli P-5101 - 7 days; Pseudomonas aeruginosa I 12 - 7 days. From the results table. 3, it follows that compounds 1 and l exhibit a high therapeutic efficacy in the general infection with gram-positive and gram-negative bacteria; The therapeutic efficacy of Compound 2 for Gram-positive bacteria is lower than for Compounds 1 and 1, but for Gram-negative bacteria, its therapeutic efficacy is higher. In this way,

Continued table. 3 Compound 2 is particularly useful for the treatment of a common infection caused by jPseudomonas aeruginosa; Compounds 1, L and 2 demonstrate better therapeutic efficacy in the common infection of Gras 1 positive bacteria, especially Pseudomonas aeruginosa, than Compounds A and C, Compounds E and F, which are industrial synthetic antibacterial agents, and Compounds G, H, and are industrial antibiotics; Compounds 1 .and 1 have greater therapeutic efficacy than | Compound D against gram-positive bacteria in vivo. Therapeutic efficacy in vivo. The therapeutic efficacy of compounds 1 and 2 was determined in mice with an upcoming kidney infection caused by Pseudomonas aeruginosa No. 12. The results obtained (mg / kg) are presented in table. 4. Test method. In female mice (ddY) weighing 22-30 grams under intravenous pentobarbital anesthesia (50 mg / kg), a bladder is opened with a small suprapubic incision and 0.1 ml diluted in a ratio of 1: 10,000 Pseudomonas aeruginosa 12 culture grown in 20 hours, using a 0.25 ml syringe and a 0.25 mm needle. Mice are restrained in drinking for 1–3 days and on the first day after infection for three days after infection, the tested preparations are administered twice a day. Detection of bacteria on the fifth day after infection of the kidney is removed, the transverse media are prepared, pledged into King A agar and incubated for 10 months. At the same time, no bacteria of an upcoming kidney infection are detected in the soil. The values of BD are calculated with averaged analyzes. The efficacy of in vivo compounds during uptake of kidney infection with Pseud monas aeruginosa No. 12 in mice is given in Table 4. Ta be tsa 4 From the results table. 4, it follows that the therapeutic efficacy of compounds 1 and 2 with an upcoming infection of the kidney caused by Pseudomonas aeruginosa is much higher than that of compound D. / Acute toxicity. Solutions proposed and known compounds in various concentrations are orally administered to male mice (udY (groups of 4 to 8 individuals) with a dose of 0.1 ml for every 10 g of mouse weight. Count on the number of dead mice after 7 days, and in accordance with The mean lethal dose is calculated by a known method; (ID, mg / kg). The results obtained are presented in Table 5. -Tablice 514000 Continued Table 5. Values calculated for caribonic acid. Table 5 concludes that | the proposed compounds have very low toxic toxicity; Compound B obtained by introducing the methyl group at position 4 in the 1-piperazinyl group of Compound 1 shows the same or higher antibacterial activity than the proposed compounds (see Table 1-3), but it has very high toxicity. toxicity. Compound 1 was orally administered once to six male mice (3CL-ICR lines), having an average weight of 20 g, in an amount of 2 mg / kg in one of 14 days. During the test period, each of the M1L11s was weighed. On the 15th day a hematological examination was performed. After a hematological examination, the mice are sacrificed and each of the organs is scooped up, and histopathological examination is also carried out. There were no abnormalities in the body and organs in the group of mice administered with compound 1. Hematological examinations and his; topological observation also showed no deviations compared with the control group of mice. Plasma level .. Dogs (males) weighing 12 Kic, as oy-orally administered capsules containing one of compounds 1 and 2, a dose of 25 mg / kg of body weight with 200 ml milk. Blood samples are taken from the vein of each of the dogs after 0.5; 1, 2, 3, 6, 8 and 10 hours after administration and plasma were separated by centrifuging each sample. The level of the drug in the blood is determined by thin layer chromatography using Escherichia coil Kp as an indicator. The results obtained here are shown in Table 6.

From the results of Table 6, it can be seen that compounds 1 and 2 are well absorbed by the body when administered orally, and the plasma level of the drug remains high for quite a long time, in particular, compound 1 shows a higher plasma level than the MIC values (see Table 1), for most bacteria for 1–10 hours after administration. Thus, for example, plasma 1 (5.9 mg / ml) is 8 times higher than the MIC against Pseudomonas aeruginosa 12 and Staphylococcus aureus 507704, and 60 more than the MIC against Escherichia coli P-5101.

Compounds 1 and 2 demonstrate a rather high plasma level and, thus, high antibacterial activity of the drug is observed at low doses in the treatment of general infection caused by various bacteria.

Excretion with urine.

The urine of the dogs used in the previous example is collected within 24 hours, and the content of compounds 1 and 2

From the results table. 7 it follows that the excretion of compounds 1 and 2 with urine is quite good and is

0 in 24 hours 30-40% of the drug administered orally; the level of preparations 1 and 2 (326–205 mg / ml) in urine 1 exceeds by 13–6000 times the MIC (0.1–25 mg / ml) for various

5 bacteria (Table 1); Compounds 1 and 2 demonstrate higher efficacy at low doses in the treatment of urinary tract infection caused by various bacteria.

As follows from the table. 1-7, the proposed compounds, especially compounds 1, 1, and 2, exhibit high therapeutic efficacy in severe infections with gram-positive and cis-negative bacteria. After oral administration, they remain high in plasma and urine for a long time. They are low toxic and effective at low doses in the treatment of urinary tract infections and general infections caused by various bacteria.

Claims (2)

METHOD FOR PRODUCING DERIVATIVES 1,8-NAFTIRIDINE OR THEIR SALTS. (57) 1, Method for the preparation of 1,8-naphthyridine derivatives of the general formula 'xA ”i V To | where is ethyl or vinyl, or their salts, characterized in that in the compound of the general formula where R ₁ has the indicated meanings; R ₂ is alkoxycarbonyl, carboxy, cyano, carbamoyl, amidino or C (= NH) OAIk where Aik is C ^ -C ^ -alkyl; R ₃ is hydrogen or a “protecting group, hydrolyzes the R ^ group when it is not carboxyl, and / or the R ^ protecting group is removed, followed by isolation of the target product as a base or salt. 2. The method of pop. 1, characterized in that the hydrolysis is carried out with an aqueous solvent in the presence of an acid or a base at 30100 ° C.