SU978727A3 - Process for producing quinoline carbohylic acid derivatives or salts threreof - Google Patents

Abstract

Certain novel quinoline carboxylic acid derivatives, being the compounds of the general formula: <IMAGE> (wherein R2 is halogen; R3 is a 1- piperazinyl or 4-(C1-C5)alkyl- piperazinyl; and either R1 is (C1-C5) alkyl and R4 is halogen or (C1-C5) alkyl, or R1 and R4 are each alkylene and together form a 5 or 6 membered ring which may be substituted by a (C1-C5) alkyl radical) and the hydrates and salts thereof, possess good anti-bacterial activity against both gram-negative and gram-positive bacteria. They may be prepared by reacting a corresponding 7-halo quinoline carboxylic acid derivative with a compound of formula R3H. The 7-halo quinoline carboxylic acid derivatives employed as starting materials are novel compounds which may be prepared by processes analogous to known processes.

Description

3978 A mixture of 3 ethoxycarbonyl-β-oxy-6, 7,8-trifluoroquinoline (3.0 g), anhydrous potassium carbonate (7.6 g, ethyl iodide (8.8 ml) and N, M-dimethylformamide (DNL) (100 ml is heated by stirring at 90-100 ° for 10 hours. The reaction mixture is evaporated to dryness, water is added, the residue is collected, washed with water and dried. The residue is dissolved in dichlrmetane, filtered and evaporated. 18% - is added to the residue. hydrochloric acid (50 ml) and ethanol (25 ml). The mixture is boiled for 2.5 hours. After cooling, the residue is filtered, washed with water and dried. The residue is recrystallized Ate from a mixture of DMF and ethanol to obtain 2.1 g of 1-ethyl-1,4-dihydro- (-oxy-6,7,8-triLorquinolin-3-carboxylic acid in the form of colorless needles, etc., 239 -2b1 ° C. Found,%: C 53.30; H 2.88; NS.2k; Calculated,%: C 53.15; H 2.97; N5.16; Starting compound — 3-ethoxycarb, nyl-oxy -6,7,8-trifluoroquinoline - prepared as follows: / J A mixture of 2,3, -trifluoroaniline (, 9 g) and ethoxymeulenenmalonic acid diethyl ester (7.2 Vg; heated at 120-1 ° C for 1 h. After cooling, simple diphenyl ether (50 ml) is added to the mixture and boiled for 30 minutes. After cooling, benzene is added to the mixture, the precipitate is filtered, washed with benzene, dried and recrystallized from DMF to obtain 5.7 g of 3-ethoxycarbonyl-α-oxy-6,7,8-trifluoroquinoline as a colorless powder, mp 280- 283 C (decomposition). Found, I: C 52.83; H 2, N 5,10. Calculated,%: C 53.15; H 2.97; N 5.16. Example 2. 1-ethyl-6,8-difluoro 1, -dihydro-oxo-7, - {1-piperazinyl) quinoline-3-carbonoic acid hydroxychloride. A mixture of 1-ethyl-1, 4-dihydro-α-oxo-6, 7.0-trifluoroquinoline-3-carboxylic acid (1.35 g), piperazine (2.2 g) and pyridine (10 ml) is boiled within 6 hours. The reaction mixture is evaporated to dryness, dilute hydrochloric acid is added to the residue and the pH is adjusted to 1, and the precipitated axis 4 is filtered. The residue is recrystallized from water and 1.45 g of 1-ethyl-6,8-difluoro-1, ighydro-4-oxo-7 (1-piperazinyl) quinoline-3-carboxylic acid hydrochloride are obtained in the form of colorless crystals, mp. 300 C. Found,%: C .51, 07; H k, 73; N 11, 18, Calculated,%: C 51.1; H, 85; 11, Example 3. 1-Ethyl-6,8-difluoro-1, -dihydro-1-oxo-7 - (- methyl-1-piperazinyl) quinoline-3-carboxylic acid. 1-Ztil-6, -8-difluoro-1, 4-dihydro-oxo-7- (1-piperazinyl) 3-carboxylic acid hydrochloride mixture (0.75 g) sodium formate (0.27 g), of formic acid (A ml) and formaldehyde solution (4 ml) is boiled for 5 hours. The reaction mixture is evaporated. Water (10 ml) is added to the residue, the pH of the solution is adjusted to 7 with 10% sodium hydroxide solution and extracted with dichloromethane. The organic layer is washed with water, dried with anhydrous sodium sulfate and evaporated. The residue is recrystallized from a mixture of DMF and ethanol, resulting in a gram of 1-ethyl-6, 8-difluoro-1 ./13- dihydro-oxo-7-t 4-methyl-1-piperazinyl} quinoline-3-carboxylic acid in the form of colorless crystals, so pl. 2A5-2A6 ° C; Found,%: C 57.97; H 5, N 12.02. C 58.11; H 5, (5; Calculated, N 11.96, Example: 8,9-Difluoro-6, 7-dihydro-5-methyl-1-OXO-1H, 5H-benzo i, i quinolizin 2-carboxylic acid., A mixture of 5,6-difluoro-2-methyl-1,2,3, -tetrahydroquinoline (5.0 g) and ethoxymethylenemalonic acid diethyl ester (5.9 g) is heated at 120-130 ° C for 5 hours. After (polyphos is added to the mixture (hydrochloric acid, tO g) and heated with stirring to 120-13 ° C for 20 minutes. After cooling, water (80 ml), concentrated hydrochloric acid (30 ml) are added to the mixture and boil for 3 hours. The reaction mixture is cooled and diluted with water. the precipitate was filtered off, washed with water, and dried. The residue perekristallizopyvayut mixture of DMF and ethanol,

as a result, (5 g of 8,9-difluoro-6,7-dihydro-5-methyl-1-oxo-1I, 5H-benzo fi, j quinolysin-2-carboxylic acid are obtained in the form of colorless crystals, mp 287-288 ° C.

 Found,% C 60.38; H 3, N, 9.

 Calculated,% C 60.22; H 3.97; N 5.02.

The starting compound, 5,6-difluoro-2-methyl-1, 2,3, -tetrahydroquinoline, was prepared as follows.

Nitric acid (11.2 g) was added dropwise to the mixture of 1-bromo-3, -difluorobenzene (27 g) and concentrated sulfuric acid (30 ml) at 20-30 ° C and then stirred for 2 hours at 50-6P ° D, “The mixture is placed on ice, extracted with benzene, washed with water, dried with anhydrous sodium sulfate and evaporated, resulting in 32.7 g of 2-bromo-A, 5-difluoro-1-nitrobenzene as yellow oil dusta substance

2-Bromo-4,5-difluoro-1-nitrobenzene (32.7 g) with stirring was added to a mixture of powdered iron (6 g), concentrated hydrochloric acid (6.8 ml) and water (500 ml) at 80 - 90 ° C. Then stirred for 2 hours at 83-90 ° C. After cooling, the mixture is basified with potassium carbonate, extracted with benzene, washed with water, dried with anhydrous sodium sulfate, and evaporated.

The remaining oily residue is pergon- gated, resulting in a yield of 19.5 g of 2-bromo-, 5-difluoroaniline as an oily substance, t, bales. 120125 ° С (27 mm of mercury "st.)"

Under stirring, a mixture of 2-bromo-, 5 difluoroaniline (19.5 g) and polyphosphoric acid (100 g) is added to this complex ester acetoacetate ester (13 g) and stirred for 2 h. The mixture is cooled and neutralized with 10% sodium hydroxide solution. The precipitate formed is filtered, washed with water and dried. The residue is recrystallized from DMF and 11.3 g of 8-bromo-5,6-diphthorg-oxy-2-methylquinoline are obtained in the form of colorless needle crystals, mp. 278-279 C .;

A mixture of 8-bromo-5,6-difluoro-4-hydroxy-2-methylquinoline (11.3 g) and oxychloride. Phosphorus (100 ml) was boiled in 5 mg of anemia. Excess phosphorus oxychloride was evaporated and the residue was neutralized with an aqueous solution of potassium carbonate under ice cooling. The precipitate is extracted with dichloromethane., Washed with water, dried with anhydrous sodium sulfate and evaporated. The residue is recrystallized from ethanol and 9.3 g of 8-bromo-chloro-5,6-difluoro-2-methylquinoline are obtained in the form of colorless needle-like crystals, mp, ItOU2 ° c;

A mixture of 8-bromo-chloro-5,6-difluoro-2-methylquinoline (9.3 g), sodium acetate (5.2 g), acetic acid (100 ml and 100 palladium on activated carbon (3.0 g) The mixture is filtered, evaporated and basified with an aqueous solution of potassium carbonate, then extracted with dichloromethane, washed with water, dried with anhydrous sodium sulfate and evaporated to give 5.3 g. -2-methylquinoline.

A mixture of 5,6-difluoro-2-methylquinoline (5.3 g), platinum dioxide (0.3 g) and methanol (150 ml) is hydroenzymed at room temperature under pressure

LO atm until complete absorption of hydrogen. The mixture is filtered and evaporated, whereby 5.0 g of 5,6-difluoro-1,2,3, -tetrahydro-2-methy lhinolin are obtained,

Example 5 9-Fluoro-6, 7-dihydro-5 methyl-1-oxo (1-piperazinyl) -1H, 5H-6eH3o i, j Hinolisin-2-carboxylic acid hydrochloride.

A mixture of 8,9-difluoro-6,7-Dihydro - $ -methyl-1-oxo-1H-5H-benzo 1, j Chinolysin-2-carboxylic acid (1, g), piperazine (2.2 g) and N - picoline (5 ml) is boiled for 7.5 hours. The mixture is evaporated

dry and acidified with hydrochloric acid. The precipitate formed is filtered and recrystallized from a mixture of water and ethanol. As a result, 1.0 g of 9 FTor-6,7-dihydro-5-methyl-1-oxo-8 (.1-piperazinyl) -1 H, 5H-benzo

i, j quinolizin-2-carboxylic acid in the form of colorless crystals ;, so pl. 300 ° C. . Found,%: C 52.25; H 5,

-l ..

. calculated,%: C 52.30; H 5.97; N 10.17. 79 6. 9 Fluorine-6,7-dihydP p and mepero-5 methyl-1-oxo-8- (-methyl-1-piperazinyl) 1H, 5H-benzo P ,, quinolizin-2-carboxylic acid. A mixture of 9-fluoro-6,7 dihydro-5 methyl-1-oxo-8- (1-piperazinyl -1H, 5H-6eH3o i, j quinolizin-2-carboxylic acid hydrochloride (0.9 g), sodium formate (0 , 6A g), 87% formic acid (5 ml) and 37% solution of rmaldehyde (5 ml) are boiled for 5 hours. The mixture is evaporated to dryness and an aqueous solution of sodium hydroxide is added, the alkaline solution is neutralized acetic acid and extracted with dichloromethane. The organic layer is washed with water, dried with anhydrous sodium sulfate, and evaporated. The solid residue is recrystallized from a mixture of DMF and ethanol and get 0.70 g:) - fto p-6, 7-dihydro-5-methyl-1-oxo-8-li-methyl-1-piperazinyl) -1H, 5H-benzo 1, Zquinolizin-2-carboxylic acid in the form of colorless needles, so pl. 2b1-2bzs. Found,%: C 63.5; H 6.20; N 11.65. V l aNjF Calculated, g: C 63.50; H 6.17; N 11.69. Example 7. 8-Chloro-1-ethyl-6, 7-Aiftor-1,1-dihydro-oxy-quinoline-3-caronic acid. A mixture of 8-chloro-6,7-Difluoro-1,4-dihydro-oxoquinoline-3-carboxylic acid ethyl ester (12.0 g) of anhydrous potassium carbonate (29 g), ethyl iodide (33.6 ml) and DMF (300 ml) is stirred at 90-100 ° C for 12 hours. To the mixture is added without aqueous potassium carbonate (I, 5 g), iodine iodine (16.8 ml) and heated, stirring at -100 ° C. for 9.5 hours. The mixture is evaporated to dryness, water is added, the mixture is extracted with dichloromethane and evaporated. Hydrochloric acid (100 ml) was added to the residue and boiled for 4 hours. Water (200 ml) was added to the aqueous solution and extracted with: dichloromethane. The dichloromethane layer is washed and evaporated. The residue is recrystallized from a mixture of LMF and ethanol, resulting in 5.7 g of 8-chloro-1-ethyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid in the form of colorless needles m.p. 215-217 S. .. 7 Found, I: C 50.40; And 2.72; N 4.93. C, 2 8 h2C.8 C 50.11; H 2.80; Calculated N 4.87. The starting compound, 8-chloro-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester, was prepared as follows. 2-Chloro-3,4-difluoroaniline (9.6 g) and ethoxymethylenemalonic acid diethyl ester (12.8 g) are mixed and heated for 2 hours at 120-130 C. After cooling, the mixture is added to diphenyl ether ( 100 f-tn) and boil for 30 minutes. The reaction mixture is cooled, washed with benzene and dried. The residue is recrystallized from DMF, resulting in 13.3 g of 8-chloro-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester as a colorless powder, mp. 292-293 ° C (decomposition). Example 8. 8-chloro-1-ethyl-6-fluoro-1, 4-dihydro-4-oxo-7- (1-piperazinyl) quinoline 3-carboxylic acid hydrochloride. A mixture of 8-chloro-1-ethyl-6,7-difluoro-1, 4-dihydro-4-oxoquinoline-3-carbonic acid (0, b5 g), piperazine (1.0 g) and pyridine (5 ml) kip t for 30 min. The reaction mixture was evaporated and acidified with hydrochloric acid. The precipitated precipitate is collected and recrystallized from a mixture of water and ethanol, resulting in a yield of 0.60 g of 8-chloro-1-ethyl-6-fluoro-1, 4-dihydro-4 oxo-7- (1-piperazinyl) -quinoline hydrochloride -3-carboxylic acid in the form of a colorless powder, so pl. . Found,%: C 49.30; H 4.59} N 10.25. C H OjNjFCl-MCl 1 / 4С2Н OH. Calculated,%: C 49.33; And 4.89; N 10.46. Example 9. 8-Chloro-1-ethyl-b-fluoro-1, 4-dihydro-4-oxo-7 (1-piperazinyl) quinoline-3-carboxylic acid {P, 25 g), sodium formate (0.5 d) 87% formic acid (5 ml) and 37 h formaldehyde solution (5 ml are mixed and boiled for 6.5 h. The solution is evaporated and basified with an aqueous solution of sodium hydroxide. The solution is neutralized with acetic acid and extracted dichloromethane and evaporated. The residue is recrystallized from ethanol to give 0.21 g of 8-chloro-1-ethyl-6-0tor-1, -dihydro-oxo-7-M methyl-1-piperazinyl) -quinoline-3 carboxylic acids s in the form of a colorless powder, so pl. 213-216 ° C.

Found,%: C 5.98; H 5.20; N 11.1.

 J) 3N, FCM / fH20.

Calculated,%: C, 8ij; .H, 5.28; N 11.29.

Example 10. 1-Ethyl-6,8-difluoro-1, -dihydro-7- (methyl-1-piperazinyl) -oxoquinoline-3 carboxylic acid.

A mixture of 1.35 g of 1-ethyl-6,7,8-trifluoro-1, -dihydro 4-oxoquinoline-3 carboxylic acid, 2.5 rN -methylpiperazine i of pyridine. The mixture is boiled under reflux for 2 hours. The mixture is evaporated to dryness, neutralized with aqueous acetic acid and extracted with dichloromethane. The organic layer is dried over anhydrous sodium sulfate and evaporated. The residue is recrystallized from a mixture of dimethylformamide and ethanol to obtain 1.5 g of (86) 1-ETHYL-6, 8-di L-1-1, 4-dihydro 7- (-methyl-1-piperazinyl) -oxoxin-3-carboxylic acid in the form of colorless crystals, tp, 2A221 ° C.

Found,%: C 57, H 5.9; N 11.83.

OPN

Calculated,%: C 58.11; H 5, N 11.96.

Experiment 1. The antibacterial effect of the compounds obtained according to the present invention was evaluated using the standard agar dilution method against gram ples (Teln and gram negative bacteria. The results obtained in comparison with the data for the known compounds are shown in Table 1. The compounds of examples 2, 3, 5i 6 , 8 and 9 more

than nalidixin (MM) and pipemidinovy acids (PPA) against gram-positive and gram-negative bacteria.

Experiment 2, The antibacterial effect of the compounds of examples 2, 3 and 6 was determined by the method of systemic infections. The test results are presented in Table. 2 in comparison with the data for LM-71i, nalidixic (NA), pimemidinic acids (PPA) and miloxacin, (M1X). Systemic infections were carried out on mouse male with a weight of 20) by the intraperitoneal method, using suspensions of the following test strains; mov in 0.5 ml extract of the central part of the strain containing 5% mucin: Pseudonranas aeruginpsa 6N11187, .3.3 x X 10 cells, Settatla. marcescens 6N7377 2.2 X 10 cells and Stapbylococcus aureiis Smith 3.0 x 10 cells. The drugs are administered to the mice orally twice a day: immediately after and after f hours after infection. The therapeutic effect of drugs is estimated by survival. Comparison of the antibacterial action in vivo is carried out on the basis of the average effective dose (ED) calculated from the sample-analysis data. The antibacterial action .In vivo of compounds of examples 2, 3 and 6 is significantly greater than the activity of compounds AM-715, NA, PPA and miloxacin against systemic infections of mice with each type of bacteria.

In tab. 2 shows the comparative results of the action of the compounds of examples 2, 3 and 6, AM-715, NA, PPA and M2X against systemic infections (AN-715: 1-methyl-6-fluoro-1, -dihydro-7- (1-piperazinyl) -A-oxoquinolin-3-carboxylic acid; NA — nalidixin-in-acid; PPA (pimemidic acid).

Table 1

BacIHus subttUs PC1219 O.Y. 0.20 0.10 Staphytococcus aureus 209P 0.39 0.39 0.78 0.10 0.20 0.20 6.25 6.25-0, 20 0.78 0.78 100 25

11 Minimal Inga Organism ililll 1.56 0.783.13 S. aureus LTCC1 775 Escfierichla coli HIHJ. 0.05 0.050.025 E. coli ATCC10536 0.05 0.050.05 Proteus vulgaris 3167 0.025 0.050.025 P. vulgnris XK Denken 0.05 0.100.20 Klebsiella pneumoniae IFO 3512 0.025 0.025 0.025 Pseudomonas aeruginosa Vl 0.39 1.56 6.25 P .eruginosa fF012689 0.78 3.13 6.25 P. aeruqiriosa 11D1210 3.13 12.5 P. aerugtnosa 11D1130 0.78 3.13 Salmonella enterltidls 11D604 0.20 0.39 0.39 Shigella sonnet .11D969 0.05 0 , 05 0.05

Serratia (Tiarcescens 1106.8 0.10 0.20

0,200,39

0,100,20

0,100,20 0,39 0,39 0,20

0.780.20 0.78 0.20 0.39

dls

0.780.78 1.56 0.39 1.56

3,136.25

12,512,5

6,256,25

6,256,25

s

3,136.25

978727

12

Continued table. 1 Connection

0.39 0, -39 1.56

100 100 100 100

100 100 100 Test concentration, mg / ml as per example llll 0,391,56 1,56,100,100 0,106,05 0,653,131,56 0,053,131,56 0,050,05 0,053,13З, 13 0,050,05 0,393,136,25 0,200,10 1,561,56 0,025 0 , 05 0.05 3.13 1.56 6.25 10012.5 6.25 3.13 12.5 20025 20050 20025 1.56, 12.512.5 1.561.56 0.05

13 where or in general

978727

U Table 2 H - ethyl; R 2 Na - piperazinyl,, -methyl-1-pipa.-at boiling, with the release of the target razinil; 0 product in free form or. In R-fluorine, chlorine or R4, KOTO-form salt. Sources of Information, a six-membered ring taken into account in the examination of their salts, are different. 1. Elderfield R-Heterocyclic that conducts the reaction of compound 45, T. 6, M., Foreign Formula Literature, 1980, p. . 30 where R, Rj and R4 are defined above; X is fluorine; with piperazine of the general formula - 35R where R5 is hydrogen or methyl, in the medium of an organic solvent.

Claims (1)

Formula of the invention _; The method for producing derivatives of chiolinincarbric acid of the common morgue forde “2 ^R 3 SOON - ethyl; - fluorine; piperazinyl, 4 ~ methyl-1-piperazinyl; ⁴⁰ -`` fluorine, chlorine or R'H R4, which together can close the six-membered ring, salts, about t, or by the fact that they carry out the general formula a different reaction of compound 45 0 -J-L / Cooh _χ I r ₄ I R ¹ where R ₁ , R ₂ and R _{4 are as} defined above; X is fluorine; with piperazine total formulas r ₅ - ⁵ W where R ^ is hydrogen or methyl, in an organic solvent, when boiled, with the isolation of the target product in free form or in the form of salt.