SU1627086A3 - Method of producing quinoline derivatives, their esters or salts used in pharmacy - Google Patents

Abstract

PURPOSE:To obtain a rice cake having good sense of eating and hardly sticking to teeth, by containing a polyglycerol ester of a fatty acid. CONSTITUTION:0.1-1.0wt% polyglycerol ester of a fatty acid is preferably contained in a rice cake. Since the ester is a surfactant having extremely high hydrophilicity and high HLB value, it is oriented in a rice cake dough to form a kind of protective film and suppress sticking and adhering to teeth. A polyglycerol ester having preferably >=6 average polymerization degree and <=970 OH value of polyglycerol and >=14C fatty acid is preferred for the above- mentioned ester.

Description

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This invention relates to a process for the preparation of quinoline derivatives or their pharmaceutically acceptable salts with very high bactericidal activity.

The purpose of the invention is the creation of new more active substances.

Example 1. 7- (3-Amino-3-methyl-1-pyrrolidinide) -1-cyclopropyl-5, 6,8-trifluoro-1,4-dihydro-4-oxocoquinoline-3-carboxylic acid.

A mixture of 0.8 g of 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 0.8 g of 3-amino-3-methylpyrrolidine and 35 ml of acetonitrile is stirred for 30 minutes at 5 and C. The precipitated crystals are separated by filtration and washed with water, dissolved in 10% aqueous ammonia, treated with activated carbon and concentrated under reduced pressure. The precipitated crystals are separated by filtration, washed with water and dried obtaining 0.81 g of 7- (3-amino-3-methyl-1-pyrrolidinyl) -1-cyclopropyl-6,6,8-trifluoro-1,4-dihydro-4-oxoquinoline-3- carboxylic acid, so pl. 280-2820С.

Example 2. 7- (cis-3-Amino-4-methyl-1-pyrrolidinyl) -1-cyclopropyl-5,6,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

According to the method of example 1, a mixture of 1-cyclopropyl-5,6,7 48-tetrafluoro-1,4-di-hydro-4-oxoquinoline-3-carboxylic acid, cis-3-amino-4-methylpyrrolidine and pyridine stirred for 30 minutes at 50 ° C to obtain 7- (cis-3-amino-4-methyl-1-pyrrolidinyl) -1-cyclopropyl-5,6,8-trifluoro-1,4-dihydro -4-oxoquinoline-3-carboxylic acid, so pl. 264-265 ° C.

Example 3.7- (trans-3-Amino-4-methyl-1-pyrrolidinyl) -1-cyclopropyl-5,6,8-trifluoro-1,4-dihydro-4-oxocoquinoline-3-carboxylic acid .

According to the procedure of Example 1, a mixture of 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-di-hydro-4-oxoquinoline-3-carboxylic acid, gran-3-amino-4-methylpyrrolidine and xylene is boiled for 3 hours to obtain 7- (trans-3-amino-4-methyl-1-pyrrolidinyl) -1-cyclopropyl-5,6,8-trifluoro-1,4-dihydro-4-oxoquinoline -3-carboxylic acid, t.p.255- 256 ° C.

Example 4. 7- (cis-3-Amino-4-β-fluoromethyl-1-pyrrolidinyl) -1-cyclopropyl-5, 6,8-trifluoro-1, 4-digi / tro-4-ok-co-quinolin-3- carboxylic acid.

A mixture of 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (1.3 g) and cis-3-trifluoroacetylamino-4-fluoromethylpyrro - lidine (1.41 g) and pyridine are boiled for 5 hours. The reaction mixture is concentrated to dryness under reduced pressure. Water was added to the residue and the precipitate formed was separated. Recrystallization from dimethylformamide gives 1-cyclopropyl-5,6,8-trifluoro-7- (cis-3-trifluoroacetylamino-4-fluoromethyl-1-pyr-olydinyl) -1,4-dihydr o-4-ca with oxy- nolin-3-carboxylic acid (1.25 g), so pl. 283-284 ° C.

A mixture of the obtained compound (1 g) and a 10% aqueous solution of sodium hydroxide (5 ml) is stirred for 1 hour at 80-90 ° C. By adding glacial acetic acid, the pH is adjusted to

reaction mixtures 8-9; and the precipitated crystals are separated by filtration. By recrystallization from dimethylformamide, 7- (cis-3-amino-4-fluoromethyl--1-pyrrolidinyl) -1-cyclopropyl-5,6,80-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid is obtained (0.52 g), m.p. 252-253 ° C.

Example 5. 7- (trans-3-Amino-4-fluoromethyl-3-methyl-1-pyrrolidinyl) -1-cyclopropyl-5, 6,8-trifluoro-1,4-di-hydro-4-oxoquinoline H-carboxylic acid.

According to the method of example 1, a mixture of 1-cyclopropyl-5, 6, 7,8-tetrafluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, trans-3-amino-4-fluoromethyl-3-methylpyrrolidine and dimethyl sulfoxide is stirred for 2 hours at 150 ° C to obtain 7- (trans-3-amino-4-fluoromethyl-3-methyl-1-pyrrolidinyl) -1-cyclopropyl-5, 6.8-trifluoro-1-, 4-DIHIDRO-4- -oxoquinoline-3-carboxylic acid, recrystallized from a mixture of chloroform - ethanol, mp. 300 C.

Example 6. 5-Amino-7- (3-amino-3-methyl-1-pyrrolidinyl) -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinolin-3 carboxylic acid and its salts.

5 A mixture of 5-amino-1-cyclopropyl-6,7,8-β-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (1.5 g), 3-amino-3-methylpyrrolidine ( 0.76 g), DBU (077 g) and acetonitrile (30 ml) were boiled down for 7 hours. The crystals which precipitated out after cooling were separated by filtration and washed with acetonitrile. The crystals are then suspended in water (50 ml) and dissolved by the addition of a 10% strength aqueous solution of acetic acid. The resulting solution is treated with activated carbon and the addition of 10% aqueous ammonia, the pH of the solution is adjusted to 7-8. Precipitated

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the crystals are separated by filtration, washed with water, then with ethanol, and dried to obtain 5-amino-7- (3-amino-3-methyl-1-pyrrolidinyl) -1-cyclo procl-6,8-difluoro-1,4 -dihydro-4-oxoquilin-3-carboxylic acid (1.15 g), so pl. 271-273 C (with decomposition).

The resulting compound (200 mg) is dissolved in 20% hydrochloric acid (5 ml) and the resulting solution is concentrated to dryness under reduced pressure. Ethanol is added to the residue and the resulting crystals are separated by filtration. Recrystallization from a mixture of water - ethanol gives 5-amino-7- (3-amino-3-methyl--1-pyrrolidinyl) -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4- chlorohydrate oxoquinoline-3-carboxylic acid (145 g), so pl. 293-297 ° С (with decomposition).

Salt with acetic acid (t, mp 272-274 ° C, with decomposition) and a mixture of methanesulfonic acid (mp. 300 ° C) were obtained by a known method.

Example 7. 5-amino-7- (3-amino-3-ethyl-1-pyrrolidinyl) -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-ox-co-quinolin-3 - carboxylic acid.

According to the procedure of Example 6, but using 3-ethyl-3-aminopyrrolidium instead of 3-amino-3-methylpyrrolidine, 5-amino 7- (H-amino-3-ethyl -1-pyrrolidinyl) -1-cyclopropyl-6 , 8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, recrystallized

Acetonitrile reform mixtures prepared from a mixture, m.p. 205-206 S.

Example 8. 5-Amino-7- (trans-3-amino-4-methyl-1-pyrrolinyl) -1-cyclopropyl-6,8-dLt or-1,4-digndro-4-oxoquinoline-j - carboxylic acid.

A mixture of 5-aminocyclopopropyl-6,7,8-β-trifluoro-1,4-dihydro-4-ocoxynolyn-3-carboxylic acid (1.5 g), trans-3-amino-4-methylpyrrolidine (0.76 g The DBU (0.77 g) and acetonitrile (30 ml) are boiled for 7 hours. The precipitated crystals after cooling are separated by filtration, washed with acetonitrile and dried. Recrystallization from a mixture of chloroform - ethanol gives 5-amino-7 - (trans-3-amino-4-methyl-3-pyrrolidinyl) -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4- oxoquinoline-3-carboxylic acid (1.05 g), so pl. 234-236 ° C.

Example 9. 5-Amino-7- (trans-3-amino-4-ethyl-1-pyrrolidinyl) -1-cyclopropyl-6,8-difluoro-1,4-dihyd0

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ro-4-oxoquinoline-H-carboxylic acid.

A mixture of 5-amino-1-cyclobuch-6,7,8-trifluoro-1,4-dngydro-4-oxoquinoline-3-carboxylic acid (1.36 g), trans-3-methoxycarbonylamino-4-ethnyl-pyro- lidine (0.94 g), diisopropyl ethyl amine (0.88 g) and acetonitrile (20 ml) are boiled for 15 h. The precipitated crystals are separated by filtration and dried to give 5-amino-1-cyclopropyl-7- - (trans-methoxycarbonylamino-4-ethyl--1-ethyl-5-pyrrolidinyl) -6,8-dnfluoro--1,4-dihydro-4-oxoquinoline-3-carboxylic acid (1.15 g), recrystallized from a mixture of chloroform - ethanol, so pl. 231-23 ° C.

A mixture of the resulting caric acid (750 mg), a 0% aqueous solution of sodium hydroxide (ml) and methanol (4 ml) was boiled for 10 hours, then concentrated under reduced pressure. The residue is diluted with water and the pF is brought to 8 by adding acetic acid. After cooling, the precipitated crystals are separated by filtration, washed successively with water and with a pollen, and after drying, 5-amino-7- (traps-3-α-amino-4 - ethyl-1-pyrpropane) -1-cyclopropyl-6, 8-difluoro-1,4-dngydro-4-oxoquinoly-3-carbonic acid (610 mg), i.e. 195-196 ° C.

Example 10. 5-Amino-7- (cis-3-amino-4-fluoromethyl-1-pyrrolidinyl) -1 -1 cyclo-chopropyl-6,8-difluoro-1, 4-digndro-4-oxoquinoline -carboxylic acid.

According to the method of example 9, a mixture of 5-ami-po-2-cyclopropyl-b, 7,8-trifluoro-1,4-dihydro-4-ca (oquinolip-H-clrboxylic acid, cis-H-triboroacetylamino-4- - fluoromethylphenolchidine, diisopropylztilamine and dioxanl are boiled for 12 hours to obtain 5-amino-7- (cis-3-trifluoroacetylamino-4-fluorotyl-1-pyrrolidinyl) -1-cyclopropyl-6,8-difluoro- 1,4-di-hydro-4-octoquinoline-3-carboxylic acid.

A mixture of the carboxylic acid obtained (1 g) and 10% aqueous sodium hydroxide (5 ml) is boiled in a boiling water bath. The resulting mixture is acidified with 10% aqueous acetic acid, after which it is made slightly alkaline by the addition of concentrated aqueous ammonia. The mixture is concentrated under reduced pressure and the precipitated

the crystals are separated by filtration, washed hollow and dried, and recrystallization from dimethylformamide gives 5-amino-7- (cis-3-amino-4-fluoro-methyl-1-pyrrolidinyl) -1-cycdopropyl-6,8-difluoro-1 , 4-dihydro-4-oxoquinoline-3-carboxylic acid (615 mg), mp 268-249 ° C.

Example 11. 5-Amino-7- (trans-3-amino-4-fluoromethyl-3-methyl-1-pyrrolidinyl) -1-cyclopropyl-6,8-difluoro--1,4-dihydro-4-oxoquinoline 3-carboxylic acid.

According to the method of example 9, a mixture of 5-ami-1-cyclopropyl-6,7,8-trifluoro-1,4-β-dngydro-4-oxoquinoline-3-carboxylic acid, trans-3-amino-4-fluoromethyl-3 -methylpyrrolidine, triethylamine and pyridine are boiled for 1.5 hours to obtain 3-amino-7- (trans-3-amino-4-fluoromethyl-3-methyl-1 -pyrrolidinyl) -1-cyclopropyl-6, 8-difluoro -1, 4-dngydro-4-oxoquinoline-3-carboxylic acid, recrystallized from chloroform-ethanol, m.p. 299-301 ° C.

Example 12. 5-Amino-7- (cis-3-aminomethyl-4-methyl-1-pyrrolidnyl) -1-cyclopropyl-6,8-difluoro-1, 4-dihydro-4-ocohicolin-3 carboxylic acid and its hydrochloride.

A mixture of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1, 4-DIHYDRO-4-OXOHSHYLIN- -3-carboxylic acid (1.22 g), pis-Z-aminomethyl-4-methylpyrrolidine ( 1.68 g) and acetonitrile (30 ml) are boiled for 4.5 hours. The reaction mixture is concentrated to dryness under reduced pressure. After recrystallization of the obtained crude crystals from ethanol, 5-amino 7- (cis-3-aminomethyl-4-methyl-1-pyrrolidinyl) -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4- is obtained. oceanokinolin-3-carboxylic acid (1.3 g) recrystallized from ethanol-chloroform, so pl. 221-223 ° C.

The resulting compound (0.5 g) is suspended in ethanol, after which concentrated hydrochloric acid (2 ml) is added. The resulting mixture is stirred, and agitated crystals are separated by fixing, washed with ethanol and dried. Recrystallization from aqueous ethanol gives 5-amino-7- (cis-3-amino-methyl-4-methyl-1-pyrrolidinyl) -1-cyclopropyl-6, 8-difluoro-1,4-dihydro-40 chloro-ethylt

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-oxoquinoline-3-carboxylic acid (0.59 g), so pl. 268-271 ° С (with decomposition).

Example 13. 5-Amino-7- (trans-3-aminomethyl-4-methyl-1-pyrrolidinyl) -1-cyclopropyl-6,8-difluoro-1, 4-dihydro-4-oxoquinoline-3-carbono - wa acid.

According to the procedure of Example 12, a mixture of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, trans-3-aminomethyl-4-methylpyrrolidine and dimethylformamide is stirred for 24 hours at room temperature to obtain 5-amino-7- (trans-3-aminomethyl-4-methyl-1-pyrrolidinyl) -cyclopropyl-6,8-difluoro-1, 4-dihydro-4- oxoquinols of n-3-carboxylic acid recrystallized from ethanol, m.p. 223-225 ° C.

Example 14. 5-Amino-7- (trans-3-aminomethyl-4-ethyl-1-pyrrolidinyl) -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-ocohicolin-3 - carboxylic acid and its hydrochloride.

A mixture of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (1.57 g), trans-3-aminomethyl-4- ethyl pyrrolidine (0.88 g), DBU (0.8 g) and acetonitrile (30 ml) were boiled for 4 hours. The crystals which had precipitated after cooling were separated by filtration, suspended in ethanol, concentrated hydrochloric acid (5 ml) was added and the mixture is stirred. The precipitated crystals are separated by filtration, and after recrystallization from aqueous ethanol, 5-amino-7- (trans-3-amino-methyl-4-ethyl-1-pyrrolidinyl) -1-cyclopropyl-6, 8-difluoro-1 is obtained. 4-dihydro-4-oxoxin-3-carboxylic acid in the form of hydrochloride (1.01 g), mp 183-184 ° C.

The resulting compound (300 mg) is suspended in water (20 ml) and the pH is adjusted to 8 by addition of 10% aqueous ammonia. The mixture is extracted with chloroform, the extracts are dried and concentrated. After recrystallization of the residue from ethanol, 5-amino-7- (trans-3-aminomethyl-4-ethyl--1-pyrrolidinyl) -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline is obtained 3-carboxylic acid (215 mg), so pl. 121-122 ° C.

Example 15 .. 5-Amino-7- (cis-3-aminomethyl-4-ethyl-1-pyrrolidinyl) -1-cyclopropyl-6, 8-difluoro-1,4-dihydro-4-oxoquinolin-3 - carboxylic acid.

According to the method of example 14, a mixture of 5-amino-1-cyclopropyl-6,7,8-trifluoro--1,4-dihydro-4-oxoquinoline-3-carboxylic acid, cis-3-aminomethyl-4-ethylpyrrolidine, LBU n-xylene is boiled for 3 hours and 5-amino-7-hydrochloride (cis-3-methylmethyl-4-ethyl--1-pyrrolidinyl) -1-cyclopropyl-6,8-difluoro-1,4-DNHYDRO is obtained -4-OXOHONOLIN- -3-carboxylic acid, mp, 252-256 ° C (with decomposition).

The resulting compound (200 mg) is suspended in water (20 ml) and the pH of the suspension is adjusted to 8 by addition of 10% aqueous ammonia. The crystals are separated by filtration and after recrystallization from ethanol-chloroform, 5-amino-7- is obtained (cis -3-aminomethyl-4-ethnl-1-pyrrolidinyl) - - -cyclopropyl-6, I-difluoro-1,4-dihydro-4-oxoquinone-3-carboxylic acid (114 mg), so pl. .0-222 ° С (with decomposition).

Example 16. 5-Amino-7- (cis-3-ethylminomethyl-4-ethyl-1-pyrrolidinyl) -cyclopropyl-6, 8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid .

According to the method of example 9, but using the PIS-3-trifluoroacetylamine 10

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hydro-4-ocohoquinoline-3-carboxylic acid, 3-amnno-3-methylpyrrolidine DV, and dimethylsulphoxy acids are stirred for 7 hours at 130 ° C to give 5-amnno-7- (3-amino-3-methi -1- ethyl ester) pyrrolidinyl) -1-cyclopropyl-6,8-difluoro-1,4-DIHIDRO-4-OXOHHNRLIN-carbonic acid.

Mix the mixture of the indicated ester and 15% hydrochloric acid at 90-100 ° G for 3 hours. The mixture is concentrated to dryness under reduced pressure. Ethanol is added to the residue and the resulting crystals are filtered off. When lane crystallization from water - ethanol, 5-amnno-7- (3-amino-3-methyl-pyrrolidinyl) -1-cyclopropyl-6, 9-d fluoro-1,4-DIHYDRO-4-OXOHINOLIN-3- is obtained. -carboxylic acid hydrochloride, t 293-297 ° C (with decomposition).

Example 18. 5-Amino-7- (tra -3-amino-4-methyl-1-pyrrolidinyl) - -cyclopropyl-6,8-difluoro-1,4-DNH-4-oxo-quinoline-3-carbyuca acids

A mixture of ethyl 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dng po-4-occo: inulin-3-carboxon-Ron acid, trans-3-amino-4-methylpyrrolne on, DRN1 and dimothylLoxnda is stirred for 7 h at 130 ° G, these elvir 5-amio-7- (transg-3-amine 4-methyl-1-pyrrhythmshl) -1-cyclopromethyl-4-ethylpyrrolidine are obtained instead of trans-35-lngidgo- 4-oxo-3-methoxycarbonylamino-4-ethylpyrrolidine gives 5-amino-7- (cyg-trifluoro-acetyl-ethylaminomethyl-4-ethyl-pyrrolidinyl) -1-cyclopropyl-6,8-difluoro-1.4 -dihydro-4-oxoquinochin-3-carboxylic acid, recrystallized from ethyl acetate-n- ek san, m.p. 145-1464,

According to the method of example 10 obtained

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quinoline-3-car Pop ass

The mixture is indicated with ester and 10% aqueous sodium hydroxide and heated to a water bath for 1 hour. The mixture is acidified with 10 aqueous acetic acid, then adjusted to pH 7-8 with 10% aqueous ammonia. The precipitated crystals are filtered, washed

the compound, a 5% aqueous solution of hydrodz in ° D ° and then ethanol, is dried, to obtain 5-amino-7- (trlns-3-amino-4-methyl-1-pyrrolidinyl) -1-cyclopropyl- 6, 8-trifluoro-T, 4-dihydro-4-oxo-quinolin-3-carGyunic acid, so pl.

sodium oxide and ethanol are heated for 15 minutes in a boiling water bath to give 5-amino-7- (cis-3-ethylaminomethyl-4-e-gil-1-pyrrolidinyl) -1-cyclopropyl-6, 8-difluoro- 1,4-dihydro-4-ox-co-quinoline-3-carboxylic acid, m.p. 171-172 ° C.

Example 17. 5-Amino-7-C3-α-amino-3-methyl-1-pyrrolidinyl) -1-cyclopropyl-6,8-difluoro-1,4-dihydro-3-oxoquinoline-3-carboxylic acid hydrochloride.

A mixture of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-di ethyl ester

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hydro-4-ocohicinol-3-carboxylic acid, 3-amnno-3-methylpyrrolidine, DVI and dimethitsulphoxy are stirred for 7 hours at 130 ° C, 5-amnno-7- (3-amino-3-methyl-1 -pyrrolidinyl) -1-cyclopropyl-6,8-difluoro-1,4-DIHYDRO-4-OXOHNNRLIN3-carbonic acid.

Stir the mixture of the indicated ester and 15% hydrochloric acid at 90-100 ° G for 3 hours. The reaction mixture is concentrated to dryness under reduced pressure. Ethanol is added to the residue and the resulting crystals are filtered off. By recrystallization from water - ethanol, 5-amnno-7- (3-amino-3-methyl-1-pyrrolidinyl) -1-cyclopropyl-6, 9-difluoro-1,4-DIHYDRO-4-OXOHINOLIN-3- is obtained. -carboxylic acid hydrochloride, so pl. 293-297 ° С (with decomposition).

Example 18. 5-Amino-7- (trans-3-amino-4-methyl-1-pyrrolidinyl) -β-cyclopropyl-6,8-difluoro-1,4-dngydro-4-oxoquinoly-3-carbytuic acid .

A mixture of ethyl 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dngid-po-4-occo: inulin-3-carboxonone acid, trans-3-amino-4-methylpyrroldine , DRN1 and dimothyl-Loxinda are stirred for 7 h at 130 ° G; ethyl eLir 5-amio-7- (transg-3-amino-4-methyl-1-pyrrone shlshl) -1-cyclopropyl 6 -lngidgo-4-oxo is obtained

quinoline-3-car Pop ass

The mixture is indicated with ester and 10% aqueous sodium hydroxide and heated to a water bath for 1 hour. The mixture is acidified with 10% aqueous acetic acid, then adjusted to pH 7-8 with 10% aqueous ammonia. . The precipitated crystals are filtered, washed

in ° D ° and then ethanol, dried, according to

5-amino-7- (trlns-3-amino-4-methyl-1-pyrrolidinyl) -1-cyclopropyl-6, 8-trifluoro-T, 4-dihydro-4-oxoquinoline-3-cargoyonic acid is obtained m.p.

234-236 ° C.

The bactericidal effect in vitro is shown in Table 1. The minimum inhibitory concentration was calculated in terms of the free base by the method of two-fold dilution of agar using Müller-Hinton agar. One loop of the test organism culture grown during the day in Muller-Hinton broth was applied to an elephant containing medicine in 10 ml of agar in Petri dishes. The bacterial inoculum contains approximately 10 colony forming units. Bacterial growth is observed after 20 hours of incubation at 37PC. The MIC is defined as the lowest concentration of drug that prevents visible growth of bacteria.

From the results in Table 1, it can be seen that the compounds 2-5 of the invention show very high bactericidal activity against gram positive and gram negative bacteria. In addition, the compounds of the invention show the best in. Vitro action against gram-positive and gram-negative bacteria compared with compound A.

The results of in vitro against common infections in mice are shown in Table 2.

Each compound is dissolved in deionized water. Each solution is administered orally to mice infected with the test organism under the conditions given and, based on the analysis of the samples, the mean effective dose (ED JQ) is calculated

Experimental conditions.

Mice - male individuals (ddy-S) weighing about 20 g.

Infection: Staphylococcus aureus 50774 (intravenous infection of cells per mouse suspended in saline), Streptococcus rougenes A 65 (infection intraperitoneally 3 10 cells per mouse suspended in heart-brain infusion broth); Pseudomonas aeruginosa 12 (infection of intraperitoneally cells per mouse suspended in tryptosoy broth with 4% mucin).

Medica Twice immediately after infection and after 6 h.

Observations For 14 days for Staphylococcus aureus 50774. for 7 days for other organisms

From the data in Table 2, it can be seen that compound 3 of the invention has a strong therapeutic effect on general infections caused by gram-positive and gram-negative bacteria, and a better therapeutic effect on common infections caused by gram-positive and

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Gram-negative bacteria, compared with compounds A and B. In particular, compounds 3 have a better effect on the general infection caused by P. aeruginosa, compared with compound A.

Male mice (ddy) are given an oral solution, each containing a compound of the invention in varying concentrations, at a dosage of 0.1 ml per 10 g of body weight. After 7 days, dead mice are counted and, in accordance with the Beirens-Kerber method, the mean lethal dose (DLu, mg / kg) is calculated. The results are shown in Table 3.

From the results in Table 3 it can be seen that compounds 2-5 of the invention show low toxicity when administered orally.

As can be seen in Tables 1-3, the compounds of the invention have a strong therapeutic effect on experimental infections caused by gram-positive and gram-negative bacteria, with low toxicity. The compounds also have good absorbability and metabolic stability. In addition, the compounds have low cytotoxicity and, when parenterally administered, cause low local irritation. Accordingly, these compounds are useful as bactericidal agents for oral administration or administration by injection.

Claims (1)

Invention Formula The method of obtaining quinoline derivatives of the general formula Z o F. 50 where Z is an amino group or a halogen atom; R (is a group of formula Rl Rs Ng R: / N- (Wn 3 131627086 - lower alkyl or haloalkyl, hydrogen or lower alkyl is the same or different and each is hydrogen or lower alkyl, 0 or 1, pharmaceutically acceptable complex or pharmaceutically acceptable, characterized by the dinene formula city state ten gd cc where and Known compounds. Note. ED values are given in terms of free state. U; where X is halogen; Y is hydrogen or lower alkyl; Z has the indicated meanings, provided that when Z is a g-loid, V is hydrogen, is reacted with a compound of the formula R, - N where Rf is as defined and the desired product is isolated in its free form or as a salt. T in l and and "I table 2 151627086 Table Compound in mg / kg