BG60537B2 - 6,8-difluoro-1,4-dihydro-1- (2-fluoroethyl) -4-oxo-7- PRACTICAL INFECTIONS AND INTERMEDIATE PRODUCTS - Google Patents

Abstract

The fluorinated derivative of 4-oxoquinoline-3-carboxylic acid named fleroxacin, especially 6,8-difluoro-1,4-dihydro-1- (2fluoroethyl) -4-oxo- 7- ) -quinoline-3-carboxylic acid, its hydrates and salts and the intermediates for its preparation can be used in the pharmaceutical industry. The drug has good antibacterial properties and reduced toxicity. Fleroxacin has the following formula

Description

TECHNICAL FIELD

The invention relates to 6,8-difluoro-1,4-dihydro-1- (2-fluoroethyl) -4-oxo-7- (4methyl-1-piperazinyl) -quinoline-3-carboxylic acid, its hydrates and pharmaceutically acceptable salts which have antibacterial properties and are particularly useful as medicaments for the treatment of bacterial infections. The invention also relates to the preparation of intermediates for the above compound, which is known in the art as fleroxacin.

BACKGROUND OF THE INVENTION

From (1) the compound which is 6,8-difluoro-1,4-dihydro-1-ethyl is known

4-Oxo-7- (4-methyl-1-piperazinyl) -quinoline-3-carboxylic acid, designated cipher AM 805, its hydrates and salts. The compound has good antibiotic properties and is active against Gram-positive and Gram-negative bacteria. The compound maintained a relatively high acute toxicity / its _LD10 was established by oral administration to mice in an amount of 985 mg / kg and cytotoxicity. The compound also showed moderate test activity in infected mice as well as moderate oral absorption.

The invention relates to a 6,8-difluoro-1,4-dihydro-4-oxo-7- (4-methyl-1-piperazinyl) -quinoline-3-carboxylic acid derivative, which has a particularly high activity as against Gram-positive and anti-Gram-negative bacteria, including 'Pseudomonas aeruginosa', and also have minor acute toxicity and cytotoxicity and high absorption by oral administration.

The present invention also relates to 6,8-difluoro-1,4-dihydro-1- (2-fluoroethyl) -4-oxo-7- (4-methyl-1-piperazinyl) -quinoline-3-carboxylic acid (denoted by cipher AM

833), as well as its hydrates and salts. Its pharmacologically acceptable salts are preferred.

The invention also relates to the use of these compounds for the treatment of bacterial infections. It also relates to 6,7,8-trifluoro-1,4-dihydro-1- (2-fluoroethyl) -

4-Oxo-quinoline-3-carboxylic acid and its ethyl ester as well as to the intermediates necessary for the preparation of the above carboxylic acid.

Acute toxicity (III ₅₀ in mice tested by oral administration) of the compound designated AM 833 is greater than 4000 mg / kg, absorption in humans by oral administration is at least 80%. The main indications of AM 833 are bacterial infections of the respiratory system and of the urinary tract.

The compound of the invention, designated AM 833 or phleroxacin, may be prepared by the substitution reaction of intermediates of the formula:

with N-methylpiperazine in an inert solvent medium such as water, alcohol, pyridine, picoline, N, N-dimethylformamide or dimethyl sulfoxide, or in the absence of a solvent at a temperature of from 60 to 180 ° C.

Such salts of the compounds of the present invention as sodium, potassium, calcium, magnesium, aluminum, cerium, chromium, cobalt, copper, iron, with silver, zinc and salts with organic bases or hydrochlorides, sulfates, phosphates, acetates, acetates, acetates other such are known. These salts can be prepared by known methods.

EXAMPLES FOR THE IMPLEMENTATION OF THE INVENTION

Example 1. Preparation of 6,8-difluoro-

1,4-Dihydro-1- (2-fluoroethyl) -4-oxo-7- (4-methyl-1-piperazinyl) -quinoline-3-carboxylic acid (AM 833).

A mixture of 0.34 g of 1-methylpiperazine, 3 ml of pyridine and 0.12 g of 6,7,8-trifluoro-1,4-dihydro2

- (2-Fluoroethyl) -4-oxoquinoline-3-carboxylic acid was refluxed for 6 hours. The solvent was then distilled off and the residue cooled and adjusted to pH 1 with aqueous hydrochloric acid. The mixture was then cooled and the resulting crystals were filtered off and recrystallized from water. 0.08 g of 6,8-difluoro-1,4-dihydro-1- (2-fluoroethyl) -4-oxo-7- (4-methyl-1-piperazinyl) -quinoline-3-carboxylic acid hydrochloride are obtained with mp 269-271 ° C (with decomposition).

C ₇ H ₁₈ F ₃ N ₃ O ₃ HCl calculated: C 50.32, H 4.72, N 10.36 found: C 50.12, H 4.97, N 10.24 Example 2. Preparation of the intermediate 6,7,8-Trifluoro-1,4-dihydro-1- (2-fluoroethyl) -4-oxo-quinoline-carboxylic acid product.

A mixture of 2.2 g of anhydrous potassium carbonate, 0.8 g of 6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid, 3.8 g of 1-bromo-2fluoroethane, 4 , 5 g of sodium iodide and 30 ml of dimethylformamide (DMF) are heated for 10 h with stirring at 90-100 ° C. The solvent was then distilled off and the residue was cooled, diluted with water and extracted with dichloromethane. The dichloromethane extract was washed with water, dried over anhydrous sodium sulfate and evaporated. The resulting solid was mixed with 14 ml of 18% hydrochloric acid and 7 ml of 5 ethanol and this acidic mixture was refluxed for 2.5 h. Then 14 ml of water and 14 ml of ethanol were added to the reaction mixture and cools. The resulting precipitate was filtered off and recrystallized from a mixture of IQ N, N-dimethylformamide and ethanol. They are obtained

0.34 g of 6,7,8-trifluoro-1,4-dihydro-1- (2-fluoroethyl) -4-oxo-quinoline-3-carboxylic acid, m.p. 208 - 210 ° C.

C ₁₂ H ₇ F ₄ NO ₃ calculated: C 49.84, H 2.44, N 4.84 found: C 49.86, H 2.37, N 5.01 Example 3. Investigation of antibacterial activity. The antibacterial activity of the compound AM 833 according to the present invention established by a standard agar dilution method performed against Gram-positive and Gram-negative bacteria by a known method. (Chemotherapy, 1974, 22, 1126).

The test results are shown in Tables 1, 2 and 3.

Table 1

Microorganisms tested / Minimum inhibitory concentration AM 833 g / ml Bacillus subtilis PCI 219 0.10 Staphylococcus aureus 209p 0.78 S. aureus Terajima 0.78 S. epidermidis IID 866 0.78 Escherichia coli NIHJ JC-2 <0.05 E.coli ATCC 10536 0.10 Proteus vulgaris 3167 <0.05 P. mirabilis IID 994 <0.05 P. morganii IID 602 0.10 Klebsiella pneumoniae 1FO 3512 <0.05 Enterobacter Cloacae IID 977 0.10 Citrobacter freundii IID 976 <0.05 Serratia marcescens IID 618 0.10 Shigella sonnei IID 969 <0.05 Salmonella enteritidis IID 604 0.10 Yersinia enterocolitica IID 918 0.10 Pseudomonas aeruginosa V-l 3.13 P. aeruginosa IFO 12689 3.13 Acinetobacter anitratus IID 876 0.39 Alcaligenes faecalis 0104002 0.78

Table 2

Cytotoxicity against CHL cells

Tested Concentration Growth retention compound (Hg / ml) (%) AM-833 50 27.3 AM-805 50 66,7

Table 3

MUSCLE ACTIVITY

Microorganism tested / Doses (cells / mice) AM 833 AM 805 minimum inhibitory concentration (pg / ml) ed ₅₀ (mg / ml) minimum inhibitory concentration (pg / ml) ^ED 50 (mg / ml) E.coli ML 4707 1.4 x 10 ¹ 0.10 0.81 0.10 1.5 P.aeruginosa IID 1210 5.0 x 10 ⁵ 3.13 8.2 6.25 10.7 S.marcescens GM 7577 2,4 x 10 ^s 1.56 6,3 1.56 18.6 S.aureus Smith 3.3 x 10 ⁵ 0.39 4.3 0.39 14.6

Claims

Claims (3)

Claims 1. 6,8-Difluoro-1,4-dihydro-1- (2-fluoroethyl) -4-oxo-7- (4-methyl-1-piperazinyl) -quinoline-3-carboxylic acid, its hydrates and 40 salts . Use of the compounds of claim 1 for the treatment of bacterial infections. 3. 6,7,8-Trifluoro-1,4-dihydro-1- (2-fluoroethyl) -4-oxoquinoline-3-carboxylic acid and its ethyl ester.