Antibacterial

 

(57) Abstract:

The invention relates to new antibacterial agent from the class of 4-oxo-quinoline-3-carboxylic acid, 1-cyclopropyl-6-nitro-7-(4-methylpiperazine)-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid or its hydrochloride. The aim of the invention is a new low-toxic derivative of 4-oxoindole-3-carboxylic acid containing no fluorine atom in the quinoline nucleus. This goal is achieved by the structure of the new antibacterial agents, namely 1-cyclopropyl-6-nitro-7-(4-methylpiperazine)-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid and its hydrochloride for oral administration (tablets, capsules), parenterally (intramuscularly, subcutaneously, intravenously), in the form of injection solutions, topically in the form of solutions, ointments and suppositories. 9 table.

The invention relates to new antibacterial agent from the class of derivatives of 4-oxo-quinoline-carboxylic acid, which is a 1-cyclopropyl-6-nitro-7-(4-methyl-piperazinil)-4-QA - with-1,4-dihydroquinoline-3-carboxylic acid (Ia) or its hydrochloride (IB).

H3C-N n HCl

n=0 (Ia)

n=1 (IB)

The search for new antibacterial drugs, despite the large number of already sintesio the territorial infections. Available at the doctor's drugs (antibiotics and synthetic antimicrobial agents) do not solve the problem of the treatment of severe generalized purulent bacterial infections, including those caused by Pseudomonas aeruginosa (Ps. aeruginosa). Difficulties associated with the treatment of sepsis and purulent processes in the membranes and tissues of the brain (meningitis, meningoencephalitis). A barrier to effective therapy known medications are cases of severe forms of bacterial infections caused by strains of bacteria that are resistant (acquired resistance) to apply tools, including strains with multiple drug resistance. Importance the search for highly soluble and toxic compounds that could be applied parenterally (subcutaneously, intravenously), when you need emergency effective therapy, including in pediatric practice.

Derivatives of 4-oxoindole-3-carboxylic acids are of considerable interest from the point of view of the search for new antibacterial agents, as active compounds in this series of substances do not have cross-resistance with antibiotics of different chemical groups and synthetic antibacterial drugs and the STU characterized by a number of adverse reactions and contraindications children under the age of 12-15 years. In this regard, particularly relevant search active low-toxic compounds that do not contain fluoride, which was the main purpose of the present invention.

The claimed compounds Ia and IB in connection with the established us for the first time their high antibacterial activity and low toxicity are of interest as new antibacterial drugs for administration (tablets, capsules), parenterally (intramuscularly, subcutaneously, intravenously, IB) in the form of injection solutions, local (IB) in the form of solutions, ointments and candles.

In the patent the Federal Republic of Germany, 1984 data are available about how to get some 6-nitro-derivatives of quinoline-carboxylic acid (described by General structural formula), which indicates that they have a weak fungistatic activity; among these substances, described General formula, mentioned compound Ia (base). No data on antibacterial activity neither in the description nor in the experimental part for this reason (Ia) is not given. Any indications on the possibility of obtaining soluble compounds of the number of substances with high antibacterial activity in the patent are also missing.

Instant inventive compound IB obtained at the pout investigated for antibacterial activity.

Compounds Ia and IB were first investigated for antibacterial activity:

in experiments in vitro against gram-negative and gram-positive bacteria (table. 1, 2, 3);

in experiments in vivo in infected white mice with infections caused by bacterial disease (table. 4, 5, 6, 7);

in model experiments in vitro the effect on the level of inhibition of DNA synthesis in Escherichia coli cells (PL. 8);

in model experiments in vitro using the method of electron microscopy to study the influence of substances on the ultrastructure of bacterial cells in experiments with Staphylococcus (table. 9);

in experiments on intact and infected animals were evaluated tolerability and toxicity Ia and IB with the inside (Ia and IB) and parenteral (IB).

When assessing activity and practical significance of the connections came primarily from the effectiveness of Ia and IB in experiments in vivo in models of generalized bacterial infections caused the "problem" agents of purulent processes (Escherichia coli, multidrug-resistant Staphylococcus) and the causative agent of typhoid fever (causes a person severe generalized infection, serious difficulties arise in the treatment of chronic br is ivali with oxolinic acid - known antibacterial drug from the group of derivatives of 4-oxoindole-3-carboxylic acid (5). The drug for more than 15 years, used in medical practice, primarily in urology for the treatment of urinary tract infections. In addition, in the experiments were compared with the activity of the drugs used to treat infections caused by Escherichia coli:

dioksidin (on the model of septicopyemia) and dioksidin and gentamicin (model meningoencephalitis), and in infections caused by Staphylococcus;

with the activity of the drugs used in staphylococcal infections;

erythromycin, oxacillin, penicillin.

Studying the activity of Ia and IB in experiments in vitro.

Activity in vitro has been studied in relation to II species of pathogenic bacteria; only used 55 strains, including reference strains (obtained from CT to them. L. A. Tarasevich) and a number of clinical strains, including highly active in experimental animals.

Evaluation of the activity of the claimed compounds in vitro carried out in respect of the five reference strains in experiments on liquid nutrient medium (broth of Hottinger, 120 mg.% amino nitrogen) method twofold serial dilutions in dimethylformamid the radio (BMD) was assessed after 18-20 h after cultivation at 35-37aboutC. As can be seen from the table. 1, the inventive compound is highly active against all five species of bacteria. The greatest interest represents the activity against B. aeruginosa, S. aureus, Bac. subtilis (IPC within 1-4 µg/ml); IB (soluble compound) more actively than Ia.

Action spectrum and the range of degree of activity of the claimed compounds in vitro was studied in experiments on solid agar medium in the ratio of 9 species of bacteria and 48 strains. Used agar AGV and method of serial twofold dilutions. Inoculation of bacteria was carried out using the stamp-Replicator (Steers); the concentration of microbial cells in the spot at sowing Replicator 104CFU/ml Crops were incubated at 35-37aboutWith 18-20 hours

As can be seen from the table. 2, the claimed compounds are characterized by high activity against the studied bacteria. For most species and strains IPC90no more than 4 μg/ml; Ia (insoluble compound) is somewhat less active than IB (soluble). Both substances have a high effect against most strains of Ps. aeruginosa: the most active soluble compound IB (IPC50- 2 µg/ml). Activity against Ps. aeruginosa is slightly inferior activity against other studied bacterial is colinmeloy acid - conducted experiments with highly virulent strains of bacteria that were used in the experiments in vivo (table. 3). Experiments on liquid nutrient medium when the amount of inoculum, 10 times greater (1x106CFU/ml) than in the first series of experiments (table. 1). In experiments with Staphylococcus experiments conducted with 4 strains, including three multiresistant (178, 191, 18b), including methicillin-resistant and oxacillin.

As can be seen from the table. 3, both the claimed compounds were highly active against all 6 highly virulent strains. The highest activity observed against S. typhi. Efficiency in experiments with S. aureus and Ps.aeruginosa was comparable. Ocalenia acid was less active than the claimed compounds; this difference was larger in the experiments with Staphylococcus and most significantly in the experiments with Ps.aeruginosa.

Studying the activity of the claimed compounds Ia and IB in the experiments in models of acute bacterial infection of white mice (table. 4, 5, 6, 7)

The experiments were conducted with Ps.aeruginosa 165, S. typhi 4446 and Saureus: 178 1750 outbred mice weighing 15-16 in models of acute bacterial infections with intraperitoneal infection of animals (Methods of experimental chemotherapy". M, "Medicine", 1971) and the infection intracerebral is 80-100% control untreated animals after 24-48 h after infection.

The claimed compound Ia (base) was administered per os IB (hydrochloride) - under the skin or per os; Ossolineum acid (insoluble compound) was administered per os. Studied the activity of substances in doses ranging from 6.25 to 600 mg/kg once provided injection 30 min after infection. The duration of observation of the animals 10 days. Assessment activity carried out on the basis of survival and life span of treated animals. In addition, in experiments with Ps. aeruginosa as Comparators used dioxidine and gentamicin (model meningoencephalitis), indicated for the treatment of generalized infections caused by this pathogen. In experiments with S. aureus were used for comparison benzylpenicillin, oxacillin and erythromycin.

As can be seen from the table. 4, the inventive compounds highly active when septicopyemia mice caused by Ps. aeruginosa. Soluble compound IB (hydrochloride) is more active than the base Ia and exhibits a high protective effect when introduced per os in doses of 200-400 mg/kg, with the introduction of under the skin in doses of 100 mg/kg and above (survival 80%); at the dose of 50 mg/kg survives 50% of treated animals. Both compounds significantly greater activity during the infection Ossolineum acid; IB (hydrochloride) suseo - 83% when using dioksidina in the same dose survival in case of introduction of the drug into or under the skin only 25-30%.

Very important is the fact that the compound IB (hydrochloride) is active when the infection caused by Ps. aeruginosa, and on the model of purulent meningoencephalitis mice (infection caused by intracerebral infection, PL. 5). On this model IB has the advantage of activity: 1) compared with oxolinic acid, which is practically not active in this experiment; 2) compared with gentamicin in the case of applying a high (400 mg/kg) doses of the drug due to better tolerability; IB is well tolerated at a dose of 400 mg/kg for gentamicin - this dose is toxic. When comparing the effects of IB activity dioksidina on this model should take into account that portable products has a significant advantage IB. Dioxidine, providing a dose of 400 mg/kg once, practically depends on survival. Effect of compound IB 10 days causes mice in this dose damaging effect on the adrenal gland, and, as a consequence, possible remote (on the 30th day) death of animals.

As can be seen from the table. 6, the claimed compounds were highly active on the model of septicemia the activity Ossolineum acid, which has a high chemotherapeutic effect in doses of 50-100 mg/kg of the Claimed compounds with abdominal typhoid infection, highly active, starting with a dose of 6.25 mg/kg (survival 80-100%).

As can be seen from the table. 7, the inventive compounds Ia and IB show chemotherapeutic activity in experimental staphylococcal infections when administered under the skin, IB, and with the introduction of per os Ia and IB.

In this model, the claimed compounds are significantly more active than ocalenia acid. From table. 7 also shows that Ia and IB active after a single dose in infection caused by a strain of staph that is resistant to benzylpenicillin, oxacillin and erythromycin. These antibiotics in the given conditions of the experiment do not show chemotherapeutic effect, despite the use of very high doses (400-500 mg/kg). The development of bacterial drug resistance is a major obstacle in the treatment of infectious processes. In our observations with Staphylococcus is very pointedly for example infections caused by multidrug-resistant strain (absence of effect of antibiotics, for which staphylococcal infection is one of the first indications.

Used culture of E. coli K-12 in the phase of logarithmic growth. The status of DNA biosynthesis was assessed by the incorporation of H3 thymidine into acid-insoluble fraction of E. coli cells. A culture of E. coli K-12 were grown on synthetic medium before the content 5x108CFU ml) was cooled to 0about(For stunting) was added NC-thymidine to a final concentration of 2 μg/ml, were incubated with Ia or IB, or oxolinic acid in concentrations of 0.1; 1; 10 and 100 µg or for 30 min at 37aboutWith shaking. After incubation samples were taken (1 ml) to which was added 1 ml of 10% trichloroacetic acid (THU). Samples were filtered (millionover the filters were dried, placed in vials with toluene scintillator. Radioactivity of samples was measured in a liquid scintillation counter (Delta (Tracor, USA) on the basis of specially developed liquid-scintillation method of measuring the radioactivity of the DNA in the presence of 6-nitro-derivatives of hinolan-carboxylic acid. The level of inhibition of DNA biosynthesis was determined by reduction enable NC-thymidine.

As can be seen from the table. 8 of the claimed compounds Ia (base) according to the degree of ingibirovaniya DNA synthesis correspond oxolinic acid, otnosiashikhsia Ia (base) and Ossolineum acid.

Study of the effect of the inventive compounds on the ultrastructure of bacterial cell.

Using electron microscopy were used to study the effect of the claimed compounds Ia and IB on the ultrastructure of cells of Staphylococcus compared with oxolinic acid.

The daily cell culture of Staphylococcus aureus (strain S. aureus 178, multidrug-resistant, highly virulent for mice) were subjected to Ia, IB and oxolinic acid at a concentration of microbial cells in the environment 1x106CFU ml investigated the influence of the above mentioned compounds in concentrations of 1.5 and 10 µg/ml Ultrastructural changes in cells of Staphylococcus studied in dynamics at exposure of 24, 48, 72 and 96 hours For electron microscopy of S. aureus cells were fixed in a 2.5% solution of glutaric aldehyde for 30 min in 1% solution of osmaboy acid for 15 min, then according to the standard technique (7) made in resin Epone-araldit. Were evaluated by the following structural changes in the microbial cell:

minor changes in the form of vacuolization cytoplasm;

thickening of the cell wall;

violation of the cell division process (chaining);

the formation of giant cells (unbalanced growth),

the formation of CL/BR> despiralization DNA and vacuolization of nucleoid;

lysis of the cells.

Expected frequency of development of these changes in % compared to 100 carried to the cells of S. aureus.

The claimed compounds Ia and IB caused some structural changes in the bacterial cell. These changes were particularly intensively expressed under the action of a soluble form - IB (hydrochloride). As can be seen from the table. 9, at 50-60% of the cells when exposed to IB was despiralization DNA with partial fragmentation and disintegration of matter nucleoid, 30-35% of the cells developed thickening of the cell wall, in 20-25% of cases were formed its unbroken chain of cells. In 30-45% of cases were observed scalloped shape with refined cell wall and destroyed by the membrane, in 30-40% met giant cells; when exposed to the maximum concentration in 30% of cases showed complete lysis of the cells. Insoluble form - Ia (base) less of an impact on the development of structural changes in the cells.

Scalloped cells, cells with unbalanced growth (huge), lysis of cells indicate rough irreversible changes in the cells of S. aureus under the action of compounds IB. This process is much less pronounced Realizacija DNA under the action of the IB is seen in 50-60% of the examined cells (the effective dose of 5-10 µg/ml), under the action of Ia and the comparison drug oxolinic acid in the dose of 30 to 40% of cases (table. 9). The difference in degree of effect is particularly defiantly when evaluating actions in this regard in the current dose of 5 mg.

The claimed compounds Ia and IB have low toxicity and are well tolerated intact white outbred mice weighing 15-16 g in doses up to 500 mg/kg once, Ia with the introduction of per os, IB with the introduction of per os and under the skin. The same dose of the compounds are well tolerated and infected animals.

For soluble compounds Ia LD50with the introduction of per os in mice is 2100 mg/kg (1858-2378), with the introduction of intraperitoneally - LD50580 mg/kg (517-649,6), which characterizes it as a substance of very low toxicity.

Drug comparison ocalenia acid - little toxicity, LD50when oral administration in mice - 10000 mg/kg, with the introduction of intraperitoneally (as a suspension in 1% starch solution) 3600 mg/kg (2400-5400).

Thus, studies show high antibacterial activity of the claimed compounds Ia and IB, and especially soluble form IB, in experiments on infected animals with generalized infections caused by Pseudomonas aeruginosa ploitical.

A very important property is the activity of compounds in infections caused by Escherichia coli when administered per os (Ia and IB), and parenteral (under the skin, IB). Note that the treatment of generalized infections caused by Ps. aeruginosa is one of the very difficult problems of chemotherapy. The effectiveness of the IB model of purulent meningitis says about the ability of IB to penetrate the blood-brain barrier, which is a necessary property of the drugs recommended for treatment of purulent meningitis.

No less important is the efficiency of Ia and IB in a generalized infection caused by a strain of staph that is resistant to antibiotics. Multiresistant strains and are often characterized by highly virulent properties, which further complicates the effectiveness of the treatment.

The high activity of the drug on the model of abdominal typhoid infection justifies the possibility of using the inventive compounds for the treatment of typhoid fever and Salmonella. therapeutic Arsenal for the treatment of these diseases is extremely small, and effective tools for radical treatment of chronic abdominal typeslogo bacteria carrier virtually absent.

The claimed compounds highly active in vitro. It is very important that they have expressed a damaging effect on the cells of bacteria, especially IB; this connection is also very highly active inhibitor of the synthesis of bacterial DNA. In this regard, the instant inventive compound may be very promising as a means for the local treatment of purulent-inflammatory processes caused by gram-positive and gram-negative bacteria.

Application 1-cyclopropyl-6-nitro-7-(4-methylpiperazine)-4-oxo 1,4-dihydroquinoline-3-carboxylic acid or its hydrochloride General formula

nHCl< / BR>
where n = 0 or 1,

as an antibacterial agent.

 

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