2,4-dioxo-5-(2-hydroxy-3,5-dichlorobenzylidene)imino-1,3-pyrimidine salts

FIELD: organic chemistry, microbiology.

SUBSTANCE: invention relates to new synthetic biologically active derivatives of pyrimidine, namely to 2,4-dioxo-5-(2-hydroxy-3,5-dichlorobenzylidene)imino-1,3-pyrimidine potassium, sodium or ammonium salt of the general formula: wherein X is taken among the group: Na+, K+, NH+4. The claimed substance shows expressed antibacterial activity directed mainly against different fungi, bacteria, protozoan and viruses.

EFFECT: valuable biological properties of compounds.

13 tbl, 13 ex

 

The invention relates to medicine, namely to pharmacology, specifically to synthetic biologically active derivative of pyrimidine.

The claimed substance has a pronounced antimicrobial activity directed mainly against various fungi, and some bacteria, protozoa and viruses, and also has anticancer and analgesic effect.

In addition, these compounds may be used for the same purposes in veterinary medicine, cosmetology, as preservatives in construction, food, leather, wood and other types of industry for the prevention and destruction of various microorganisms, mainly fungi.

As you know, one of the most serious problems of modern medicine are fungal, and bacterial and viral diseases, many of which are extremely difficult to treat, due to the lack of effectiveness of existing drugs and their rapid variability, leading to the emergence of resistant forms, Fidel P.L. Jr, J.A. Vazquez, Sobel J.D. Candida glabrata: review of epidemiology, pathogenesis and clinical disease with comparison to C. albicans 1999, 1:80-96. White T. Antifungal drug resistance in Candida albicans., ASM News 8:427-433.

Similar problems relevant to animal health and industry, with widespread damage to the product associated with the development and distribution of mi is croorganisms. The most common medications for treating fungal diseases are nystatin, fluconazole, terbinafine and some other (encyclopedia of drugs radar-2000, M., 2000, str). However, each drug has certain disadvantages. Fluconazole, despite the wide range of actions, is fungistatic and does not kill the fungi, but prevents their growth and reproduction. Terbinafine does not kill yeast-like fungi. This complicates the use of these drugs for treatment of people with a weakened immune system. Another common drug is nystatin. Its main disadvantages should be considered low activity against multicellular fungi and common thereto resistance in microbes. The most active antifungal drug is amphotericin b, which is extremely toxic and poorly tolerated by a large number of patients.

The closest in chemical nature to the claimed is -2,4-dioxo-5-arylidene-1,3-pyrimidines of General formula

where R is independently selected from the group: H, HE, lowest alkoxyl, halogen, nitro, di(lower)alkylamino; n=1-3, or two adjacent R along the benzene ring to which they are attached, for n=2,4, form a benzo, and dibenzo when n=2 form a 3,4-dioxolane ring, EN 2198166.

This prophetic who has selected us as a prototype. The disadvantage of this substance is low activity against some microorganisms, mycobacteria and chlamydia.

The objective of the invention is to develop a new antifungal drug with a wide spectrum of action, with pronounced activity against gram-positive and gram-negative bacteria, viruses, protozoa and tumor cells; it also aims to prevent damage to products.

The problem is solved by the synthesis of new substances, namely potassium, or sodium, or ammonium salts of 2,4-dioxo-5-(2-hydroxy-3,5-dichlorobenzamide)imino-1,3-pyrimidine of the General formula

where X is selected from the group of Na, K, NH4+.

The list of synthesized and the claimed compounds are given in table 1.

Table 1
The name of the substanceDesignationBrutto-formula
Sodium salt of 2,4-dioxo-5-(2-hydroxy-3,5-dichlorobenzamide)imino-1,3-pyrimidineIWith11H6Cl2N3NaO3
Potassium salt of 2,4-dioxo-5-(2-hydroxy-3,5-dichlorobenzamide)imino-1,3-pyrimidineIIWith11H6Cl2KN3About3
Ammonium salt of 2,4-dioxo-5-(2-hydroxy-3,5-dichlorobenzamide)imino-1,3-pyrimidineIIIC11H10Cl2N4O3

The stated substances are new, because they are not known from the available information sources. The availability of a wide range of effective biological activity of the newly synthesized stated substances is not obvious from the prior knowledge.

The invention is explained below:

a way of producing new derivatives of 2,4-dioxo-5-(2-hydroxy-3,5-dichlorobenzamide)imino-1,3-pyrimidine;

data PMR spectroscopy of compounds I-III (table 2);

- the experimental data for the determination of antifungal activity of the claimed compounds in comparison with the known effective date means the same purposes, namely:

experiment 1 - determination of the antifungal activity of the claimed compounds;

experiment 2 - the definition of a joint action of the claimed compounds and antifungal drug fluconazole;

experiment 3 - the definition of a joint action of the claimed compounds and antifungal drug nystatin;

experiment 4 - the definition of therapeutic action of the claimed compounds on experimental infection caused by fungi of the genus Candida;

experiment 5 - determine the antitumor activity of the claimed compounds;

experiment 6 - determination of analgesic activity of the claimed compounds;

experiment 7 - determination of the acute toxicity of the inventive compounds;

experiment 8 - determination of effects on herpes simplex virus;

experiment 9 - definition antimycobacterial actions;

experiment 10 - defining action of the compounds against gram-positive and gram-negative bacteria;

experiment 11 - determination of Antiprotozoal action of the compounds against trichomonads (Trichomonas vaginalis);

experiment 12 - determine the possibility of using the inventive compounds to fight with a mixed microbial infection;

experiment 13 - determine the possibility of using the inventive compounds to prevent spoilage.

The way to obtain new derivatives of 2,4-dioxo-5-(2-hydroxy-3,5-dichlorobenzamide)imino-1,3-pyrimidine (I, II, III).

The target salt of 2,4-dioxo-5-(2-hydroxy-3,5-dichlorobenzamide)imino-1,3-pyrimidine of the General formula

where X is selected from the group of K, Na, NH4+that obtained by the interaction of 5-aminouracil or its alkali metal salts with dichlorosalicylic aldehyde. The solvent used is a mixture of ethanol-water 1:1. roducti were obtained with yields above 90% of theoretical.

Synthesis of sodium salt of 2,4-dioxo-5-(2-hydroxy-3,5-dichlorobenzamide)imino-1,3-pyrimidine.

Into the flask was placed 0.04 g sodium hydroxide and 20 ml of water. To the resulting solution was added 1.27 g of 5-aminouracil; the resulting mass was stirred until complete dissolution of aminouracil. In parallel, in 50 ml of ethanol was dissolved at 1.91 g of 3,5-dichlorosalicylic aldehyde and the resulting solution is added dropwise with stirring was added to a solution of sodium salt of 5-aminouracil. Immediately fell sediment bright red color. The reaction mixture was stirred for half an hour. The precipitate was filtered, washed with alcohol, dried. The product yield was 98% of theoretical.

Compounds II and III were obtained in a similar way, but instead of caustic soda were used sodium hydroxide or ammonium hydroxide.

Compounds of General formula are colorless or light-colored crystalline substance, soluble in dimethyl sulfoxide, pyridine. The melting temperature of all substances exceed 300°C.

Individuality substances proven by thin layer chromatography on Silufol UV-254 plates, eluent carbon tetrachloride - isopropanol=9:1. The structure of synthesized compounds proved by the method of PMR spectroscopy. Data spectroscopic compounds I-III are presented in table 2.

Table 2
No. of connectionsCH-NNHCH(Ur)
I9,511,37,9
II9,511,27,9
III9,511,47,9

The experimental data for the determination of the biological effect of the claimed connection.

Experiment 1. Determination of antifungal activity of the claimed connection.

The activity of drugs against fungi was determined by the method of serial dilution (table 3). As the comparison drug was used fluconazole. Compounds were dissolved in dimethyl sulfoxide (DMSO) and was titrated in the environment N-1, RPMI, Saburo, so that the product contained in separate test tubes with the medium at concentrations from 200 to 0.025 mg/L. concentration of the drug in the environment of neighboring tubes (holes) differed in two times. The control used DMSO, which was bred as a drug. The results were taken into account after the cultivation of mushrooms when using the optimal time and temperature conditions for each type.

Table 3

The definition of the action of the claimed compounds on yeast
Fungus StrainThe minimum inhibitory concentration (MIC) (μg/ml)
FluconazoleIIIIII
S.cervisiaeVT-22111
G.candidumVT-061111

Data shown indicate a high activity of drugs against yeast.

Table 4

The definition of the action of the claimed compounds by fungi of the genus Candida
FungusStrainThe minimum inhibitory concentration (MIC) (μg/ml)
FluconazoleIIIIII
C.albicans212111
C.albicans3721111
C.albicans800,25111,0
C.glabrata382160,1250,1250,125
C.glabrata111640,250,250,25
C.glabrata160320,1250,1250,125
C.kruseiof 5,24832111

Data shown indicate a high activity of drugs against unicellular fungi of the genus Candida for the most part used strains exceeding that of the reference preparation of fluconazole.

Table 5

The definition of the action of the claimed compounds in multicellular fungi of the genus Aspergillus and Mucor
FungusStrainThe minimum inhibitory concentration (MIC) (μg/ml)
FluconazoleIIIIII
AspergillusVT-70>64222
MucorVT-12>64111

Data shown indicate a high activity of the claimed drugs, many times exceeding that of the reference product - FL is conazole, against fungi of the genera Aspergillus and Mucor.

Experiment 2. The definition of a joint action of the claimed compounds and antifungal drug fluconazole. The results of the experiment are shown in table 6.

Table 6

The combined use of fluconazole and the claimed compounds
FungusStrainThe minimum inhibitory concentration (MIC) (μg/ml)
FluconazoleIIIFluconazole +IFluconazole + II
AspergillusVT-70>642210,5
C. albicansVT-186110,50,5

The data obtained indicate the possibility of using the inventive compounds together with existing drugs.

Experiment 3. The definition of a joint action of the claimed compounds and antifungal drug nystatin. The results are shown in table 7.

Table 7

The combined use of nystatin and declare the response
FungusStrainThe minimum inhibitory concentration (MIC) (μg/ml)
NystatinIIINystatin + INystatin + II
C.kruseiVT-624110,250,5
C. albicansVT-182110,50,5

The data obtained indicate the possibility of using the inventive compounds together with nystatin.

Experiment 4. Determination of therapeutic action of the claimed compounds on experimental infection caused by fungi of the genus Candida.

The study was carried out on outbred white mice weighing 24-26, Animals intravenously drove pathogenic strain .albicans VT-18 in number 1×109the bacteria/animal. The substance I was injected intraperitoneally. In the control group on a similar scheme was introduced isotonic solution of sodium chloride or nystatin. Each group consisted of 10 animals. The introduction of the drug lasted until the death of the last animal in the control, untreated group. The test drug was administered in the dose of 5 mg/kg intraperitoneally. Fluconazole was administered in a similar way and the same amount. Effectiveness was assessed by the number of animals surviving after the death of the deceased in the control group. In the control group to 10 days killed all infected animals. Among the animals treated with the drug I survived all the animals. Protection was 100%. In the group treated with fluconazole, survived 8 animals. Protection was 80%. These findings indicate the feasibility and efficacy of drug use I for the treatment of infectious conditions caused by fungi.

Experiment 5. Determination of antitumor activity of the claimed compounds. The results are shown in table 8.

Table 8
SubstanceConcentrationThe percentage growth of tumor cells compared to control
Lung cancerBreast cancerCancer of the nervous system
I1002452
II1002052
III1004212-5

The study was performed according to the requirements of the National Institute of health, USA.

E is speriment 6. Determination of analgesic activity of the claimed compounds.

In groups of 3 rats were evaluated by the time required for otdergivanija tail, placed under directional thermal radiation. The lengthening of the reaction time by more than 50% after intraperitoneal administration of the drug (30 mg/kg) indicated the presence of analgesic activity. As the comparison drug used analgin (2 mg/kg). The results are shown in table 9.

Table 9

Evaluation of the analgesic action of the claimed compounds
MedicationThe lengthening of the latent period of reaction (%)
I79
II80
III82
Analgin83

These findings point to the existence of the claimed compounds analgesic activity.

Experiment 7. Determination of acute toxicity of the claimed compounds.

The test compound was administered orally using a stomach probe (1000 mg/kg) or intraperitoneally (300 mg/kg) nonlinear white mice weighing 20-25 g (5 males and 5 females in each of the tested groups), and then watched their condition for 14 days. The absence of symptoms characteristic of Toxics what their effects, and no animals died during a specified period of time allows to make a conclusion about the low toxicity of the studied compounds. In the presence of acute toxic effects the dose is reduced to identify the maximum tolerated dose.

Table 10

Acute toxicity
ConnectionThe concentration of the tested compounds (mg/l)
Introduction through the mouthIntroduction intraperitoneal
I1000300
II1000300
III1000300

Thus, studies have shown that within the used doses of substances do not exhibit acute toxicity used in the model.

Experiment 8. Determination of the effect on the herpes simplex virus.

Antiviral activity was studied against herpes simplex virus type I (HSV-I/Leningrad/248/88) by the conventional method [Gentry G.A., Lawrency N., Lushbaugh N. Isolation and differentiation of Herpes simplex virus and Trichomonas vaginalis in cell culture, J. of Clinical Microbiology 1985, Vol.22, No.2, P.199-204]. Viruses were grown on transplantable cell culture Vero obtained from the Bank of cell cultures at the Institute of Cytology of the Russian Academy of Sciences.

The result is evaluated by the presence cytopathogenic action of the virus on the cells after 36 hours of cultivation at 37° With CO2the incubator.

To assess the cytopathic effect of the virus was calculated the number of unmodified cells. The results are shown in table 11.

Table 11

The effect of the drug at a concentration of 100 µg/ml for herpes simplex
ConnectionThe number of unmodified cells (% protection)
Acyclovir8000*(30 μg/ml) (80%)
Control cells1000
DMSO10000
I9500 (95%)
II9500 (95%)
III9500 (95%)
the placeholder9000 (90%)
* the number of cells in 100 fields of accounting.

The obtained results indicate that given in the table of compounds have activity against herpes virus, comparable with that of the standard drug of acyclovir, and is superior to the activity of a substance is the prototype.

Experiment 9. Definition antimycobacterial actions.

To determine the activity was used a standard strain of Mycobacterium tuberculosis H37 RV, sensitive to all antimicrobial drugs. Assessment antimycobacterial actions performed by the serial dilution method.

Joint is dissolved in dimethyl sulfoxide (DMSO) and was titrated so, this preparation was kept in separate test tubes with the medium at concentrations from 200 to 0.025 mg/L. concentration of the drug in the environment of neighboring tubes differed in two times. The control used DMSO, which was bred as a drug. The result was taken into account after 72 hours of culturing bacteria at 37°C. the Results are shown in table 12.

Table 12

The minimum inhibitory concentration (MIC) against M. tuberculosis H37Rv (mg/l)
ConnectionIPC
I10
II50
III50
The placeholder100
Ethambutol5,0

The data show that the tested compounds have antimycobacterial activity in relation to the used strain of M. tuberculosis. The activity of the claimed compounds exceeds that in the matter of the prototype.

Experiment 10. The definition of the action of the compounds against gram-positive and gram-negative bacteria.

In the experiments used standard collection strains and bacteria isolated from patients. The estimation was performed by serial dilution method using nutrient medium suitable for the cultivation of the species of microorganisms.

Compounds were dissolved in dimethyl sulfoxide (DMSO) and was titrated at concentrations from 500 to 0.025 mg/L. concentration of the drug in the environment of neighboring tubes differed in two times. The result was taken into account after 72 hours of culturing bacteria at 37°C. the Results are shown in table 13.

Table 13
SubstanceThe minimum inhibitory concentration (mg/l)
E.coli

ATS
K.pneumoniaeP.aeruginosa ATCC27853S.typhimur. VT-191S.aureusB.cereusE.fecalis
I501503005025100150
II100150200100100100150
III501002505050100150

These data indicate that the studied compounds have a broad spectrum of antimicrobial activity against various bacteria, including vegetative forms of spore-forming bacilli (Bacillus cereus). The level of activity indicates the ability of IP is to alsowhat these substances as an antiseptic or in industry as preservatives in various materials.

Experiment 11. Definition Antiprotozoal action of the compounds against trichomonads (Trichomonas vaginalis).

In the experiments used strains isolated from patients. The estimation was performed by serial dilution method using nutrient medium suitable for the cultivation of the species of microorganisms.

Compounds were dissolved in dimethyl sulfoxide (DMSO) and was titrated at concentrations from 500 to 0.025 mg/L. concentration of the drug in the environment of neighboring tubes differed in two times. The result was taken into account after 72 hours of culturing bacteria at 37°C. it is Established that the drugs I-III inhibit reproduction used the simplest in concentrations from 50 to 0.1 mg/ml

Experiment 12. The determination of whether the use of the claimed compounds to fight with a mixed microbial infection.

In laboratory animals (Guinea pigs) shaved part of hair, applied surface scratches and rubbed microbial mixture consisting of fungi of the genus Candida, Staphylococcus, Escherichia coli and Enterococcus (strains see example 12). After 24 hours in all animals there was a local inflammatory process. To ensure used the ointment prepared from compounds I or II and lanolin. Substances were added in the amount of 300 mg/kg In the controls was applied pure lanolin or standard ointment fluc is natla. Each group consisted of 5 animals. Efficacy criterion was the time for full healing and recovery of the skin. Animals in groups treated with substances, recovery occurred after 5 days. In the groups treated with lanolin or fluconazole, after 6 days, all animals were sick and were further treated with drugs II and III.

The recovery of these groups came after another 7 days. Thus, the obtained data show that the inventive preparations can be used topically to combat with mixed infections caused by gram-positive and gram-negative bacteria and fungi.

Experiment 13. The determination of whether the use of the claimed compounds to prevent spoilage.

As the model was used butter, which were added microbes specified in example 12 in quantity of 105bacteria of each species in 1 gram of oil. In oil were added to the subjects of substance I, II, III (prepared in 10 samples for each substance). Substances are added in quantities of 200 or 300 mg/kg Samples were incubated at 37°With, every day making quantitative sowing on nutrient medium designed for the growth of appropriate bacteria and fungi. In the control oil was added, the solvent is DMSO used for cooking providethem drugs. After 24 hours of incubation in the control samples registered the increase of the number of introduced microbes in 10 times. Of the samples where substances were made in the amount of 300 mg/kg, the microorganisms were inoculated. When made of 200 mg/kg in sample II registered saves any number of Pseudomonas. Two weeks later (time of observation) in samples containing 300 µg/ml II and III substances, microbial growth was not observed.

The data obtained indicate the possibility of protection of food products from mixed microbial spoilage.

Industrial applicability

The above examples and practical results of the synthesis and analysis of the claimed compounds confirm the possibility of laboratory and industrial synthesis of the claimed compounds means mastered modern pharmaceutical and chemical industry, as well as their strict identification of common methods of control.

A series of experiments to determine the biological activity presented in the report showed that the claimed compounds have strong antifungal (against single and multicellular fungi), as well as antibacterial and antiviral, and anticancer and analgesic action. These facts prove the achievement of the objectives of the invention.

Salt 2,4-dioxo-5-(2-hydroc and-3,5-dichlorobenzamide)imino-1,3-pyrimidine of the General formula

where X is selected from the group of Na, K, NH4+.



 

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wherein R1 means one of radicals:

or ; R2 means -CH(CH3)-CH3, -CH(CH3)-C2H5, -C(CH3)=CH-CH(CH3)2 or cyclohexyl; R3 means hydrogen atom or hydroxy-group if a bond between atoms 22 and 23 represents a double bond, or it means hydrogen atom or group =N-O-CH3 if an ordinary bond presents between atoms 22 and 23; R4 means HO-, and the preparation can be in free form or in physiologically acceptable form. Invention provides preparing preparations with good tolerance and rapid effect and persistence with respect to different helminth-associated diseases, parasitiformous and acariformous mites being without adverse effect on normal behavior of animals.

EFFECT: valuable properties of compounds.

7 cl, 3 tbl, 8 ex

FIELD: organic chemistry, veterinary science.

SUBSTANCE: invention relates to a method for control over exto- and endoparasites taken among group including acariform mites, parasitoformous mites and nematodes parasitizing in animals, productive cattle and domestic animals. Method involves applying veterinary preparation comprising 1-[4-chloro-3-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenyl]-3-(2,6-difluoro)urea and compound of the formula (i):

wherein R1 means one of radicals:

or ; R2 means -CH(CH3)-CH3, -CH(CH3)-C2H5, -C(CH3)=CH-CH(CH3)2 or cyclohexyl; R3 means hydrogen atom or hydroxy-group if a bond between atoms 22 and 23 represents a double bond, or it means hydrogen atom or group =N-O-CH3 if an ordinary bond presents between atoms 22 and 23; R4 means HO-, and the preparation can be in free form or in physiologically acceptable form. Invention provides preparing preparations with good tolerance and rapid effect and persistence with respect to different helminth-associated diseases, parasitiformous and acariformous mites being without adverse effect on normal behavior of animals.

EFFECT: valuable properties of compounds.

7 cl, 3 tbl, 8 ex

FIELD: medicine, helminthology, chemical-pharmaceutical industry.

SUBSTANCE: invention relates to the creature of medicinal species used for treatment of helminthism of different etiology. Invention proposes the helminthicide species comprising dried fennel seeds, clove fruits, thyme herb, common wormwood herb, tansy flowers, walnut leaves, tumeric roots, valerian roots and licorice roots in the following ratio, mas. p. p.: fennel seeds, 0.8-1.2; clove fruits, 0.4-0.8; thyme herb, 0.4-0.8; common wormwood herb, 0.8-1.2; tansy flowers, 0.8-1.2; walnut leaves, 0.8-1.2; tumeric roots, 0.4-0.6; valerian roots, 0.24-0.36, and licorice roots, 0.4-0.6. Helmithicide species is used as a powder or a powder placed into a capsule. The species elicits high activity in treatment of different parasitic diseases, such as ascariasis, enterobiasis, lamblialis, infection with flat helminthes and this species shows normalizing effect on functional activity of gastroenteric tract.

EFFECT: valuable medicinal properties of species.

4 cl, 4 ex

FIELD: biochemistry, medicine, pharmacy.

SUBSTANCE: leaves of Mikania micrantha, Mikania scandens and Mikania cordata are milled and dries and a solvent - toluene, ethyl acetate, their mixture, mixture of toluene with acetone, mixture of ethyl acetate with heptane or mixture of heptane with acetone is added in the ratio (7:3)-(3:7), mixture is filtered and concentrated up to 2.5-10% as measure for dry extract. Then extract is contacted with a mixture containing 10-50% of methanol or ethanol in water, an aqueous-alcoholic phase is washed out with n-hexane or heptane and alcohol is removed. An aqueous phase is extracted with ethyl acetate, prepared phase is dried, solvents are evaporated and dry extracted is purified. Dry extract prepared from leaves is dissolved in ethyl acetate and hydrogenated at 10-35°C in the presence of hydrogenation catalyst under pressure 1-2 atm. After hydrogenation dihydromikanolid is crystallized. Mikanolid and dihydromikanolid are used for treatment proliferative diseases and parasitic diseases. Also, invention relates to a medicinal agent containing above indicated vegetable extract. Invention provides realization of indicated designation.

EFFECT: valuable properties of agents.

12 cl, 3 tbl, 3 ex

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