Antifungal preparation, based on methyl ether of 2-benzimidazolylcarbamic acid, or its derivatives

FIELD: chemistry.

SUBSTANCE: invention relates to antifungal preparation, containing effective quantity of methyl ether of 2-benzimidazolylcarbamic acid, or its salts with inorganic and organic acids, or their hydrates, or its complex compounds with organometallic and inorganic salts, containing transition metal. Claimed invention demonstrates antifungal activity with respect to causative agents of mycoses from the group, including Trichophyton mentagrophytes var. Interdigitale, Trichophyton rubrum, Microsporum canis, Trichophyton mentagrophytes var. granulosum, Candida albicans. Antifungal activity has been detected with respect to pathogenic and opportunistic fungi, causing mycoses of mucosa and skin in humans and animals.

EFFECT: increased activity of preparation.

9 cl, 4 tbl, 28 ex

 

The present invention relates to a new antifungal means on the basis of known compounds, namely methyl ester 2-benzimidazolecarbamic acid and its derivatives, which can be used for the prevention and treatment of diseases of man and animals caused by pathogenic and conditionally-pathogenic fungi.

Methyl ester 2-benzimidazolecarbamic acid (hereinafter - carbendazim, Madamin, BMC) - the simplest derivative of benzimidazole, which have found practical use as a systemic fungicide in agriculture. LD50for rats 6400, 8000 rabbits, dogs 8000 mg/kg. the Drug is used at a concentration of 0.03-0.06% on the active substance. In the concentrations applicable BMC not Fielden for most plants [Melnikov N. N. Chemistry and technology of pesticides. M.: Chemistry, 1974, p. 635].

Carbendasim is one of the first fungicides with systemic action, which is used currently. It is effective against a number of plant diseases and, primarily, against powdery mildew.

The disadvantage of this drug is relatively rapid acquisition of resistance to it of a number of phytopathogenic fungi. In addition, despite the low acute toxicity in high doses they can cause teratogenic effect [Melnikov N. N. The pesticides. Chemistry, technology � application. M.: Chemistry, 1987, p. 565].

Permitted for use on the territory of the Russian Federation in the form of a suspension concentrate of 200 g/l 500 g/l for wheat, barley, rye, sugar beet root and basal rot, cercosporella, snow mold, powdery mildew, loose smut and head smut, brown rust, from Apple scab and powdery mildew, potato Fusarium root rot and Rhizoctonia (List of pesticides and agrochemicals permitted for use on the territory of the Russian Federation. Appendix to the journal "Protection and quarantine of plants", No. 4, 2012, pp. 162-164).

Carbendasim (madmin) is also used as an antihelminthic drug that has activity against intestinal nematodes [Demidov N. In. The anthelmintic in veterinary medicine. M.: Kolos, 1982].

Carbendasim - commonly known as a fungicide and as a remedy for the treatment of parasitic infections caused by worms, offered by us for treatment of fungal infections of the skin.

The present invention is the use of methyl ester of 2-benzimidazolecarbamic acid, some of its derivatives and compositions on their basis as protivodiabeticheskih funds exhibiting antifungal activity against pathogens of diseases such as tinea, trichophytosis, microsporia and candidiasis.

The object of the invention is a new antifungal�diesel vehicle, containing the effective amount of methyl ester 2-benzimidazolecarbamic acid

or its salt with organic or inorganic acids, or their hydrates, or its complex compounds with ORGANOMETALLIC and inorganic salts containing transition metal, and possibly one or more acceptable auxiliary components.

Antifungal activity revealed against pathogenic and conditionally pathogenic fungi causing mycosis of mucous membranes, skin and its appendages in humans and animals.

Salts forming complex compounds with methyl ester of 2-benzo-imidazolecarboxamide acid selected from the group comprising chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formate, tartrate, maleate, malate, citrates, benzoates, salicylates, ascorbates, acetates, propionates, etc., and mixtures thereof.

These complex compounds can have one or two molecules of methyl ester of 2-benzimidazolecarbamic acid and one molecule of salt.

Inorganic acids, forming salts with methyl ester of 2-benzimidazolecarbamic acid selected from the group comprising chloride, sulfuric, nitric, phosphoric, bromoethanol, hydrofluoric, iodomethane acid, etc..

Organic acids, forming salts with methyl ether benzimidazolecarbamic acid, selected from the group comprising benzoic, sulfonic, alkylsulfonate, acetic, propionic, alkylbenzenesulfonate, salicylic, formic, succinic acid, etc..

Salt of methyl ester of 2-benzimidazolecarbamate with inorganic acids and organic acids can be in the form of hydrates.

Transition metals include zinc, copper, Nickel, manganese, cobalt, cadmium, iron, molybdenum, tungsten and chromium.

Antifungal activity identified against the following pathogens of fungal infections: Trichophyton mentagrophytes var. Interdigitale, Trichophyton rubrum, Microsporum canis, Trichophyton mentagrophytes var. granulosum, Aspergillus niger, Penicillium notatum, Candida albicans, Alternaria alternate, Fusarium graminearum.

The claimed compounds for the prevention and treatment of fungal infections is applicable with a minimum inhibitory concentration in the range of values 0.1 to 7 mg/ml.

As acceptable auxiliary components, the compound contains, in particular, substances that promote the penetration.

The proposed connection is applicable for the prevention and treatment of fungal infections of the mucous membranes, skin and its appendages in humans and animals.

Mycoses, which effectively declared the tool include: opportunistic fungi - Candida and fungal dermatoses, onychomycosis (nail infections), otomycosis (lesions of skin and mucous membranes of the ear canal), Zab�the indicated skin and its appendages (hair, the nail) caused by dermatophyte (dermatophytosis): zooantroponoznyh and antropos trichophytosis smooth skin, scalp, beard and mustache (parasitic sycosis), superficial, infiltrative and suppurative forms, onychomycosis, favus (ringworm) of the scalp, smooth skin, beard and mustache, superficial, infiltrative and suppurative forms, onychomycosis, zooantroponoznyh and antropos microsporia smooth skin, scalp, superficial, infiltrative and suppurative forms, onychomys, fungal infections of the feet and hands, rubromikoz smooth skin and onychomycosis, epidermofitia groin in the defeat of major folds of smooth skin, epidermofitia stop.

Synthesis of complex compounds methyl ester 2-benzimidazolecarbamate with inorganic acids and organic salts containing transition metal, is known and described in detail in the literature [US 3595870, publ. 29.01.1974, US 3789122, publ. 27.07.1971, JPS 4948433, publ. 21.12.1974, JPS 54145216, publ. 13.11.1979, AU 477616, publ. 07.10.1971, Novikov G. A., Molodkin, A. K., Chukalenko S. C. Coordinazione metal compounds with imidazolov and benzimidazoles. Russian journal of inorganic chemistry. Volume 33, issue.12, 1988, pp. 3111-3122, etc.].

Studied comparative antifungal activity of methyl ester 2-benzimidazolecarbamic acid and its derivatives in some respect �ito-, the anthropo-, topogenic mushrooms. The results are shown in table 1.

As can be seen from the materials of table 1, as phytopathogenic fungi (which can also be the causative agents of mycoses of man and animals), opportunistic fungal pathogens "opportunistic" mycosis of humans and animals characterized by almost the same resistance to the action of BMK and investigated its derivatives. Minimum inhibitory concentration (hereinafter IPC) BMC investigated in relation to phyto-and topogenic fungi was similar concentrations (1-5 mg/ml). Data on the fungicidal activity of BMK correspond to previously known data on the suppression of the growth of BMC and its similar derivatives (at concentrations of 3-5 mg/ml) other phytopathogenic fungi of the species Fusarium culmorum and Helminthosporium sativum [Pilyugin B. C. Nitrogen-containing heterocyclic compounds. Synthesis and biological activity of derivatives of 2-aminobenzimidazole and 1,3,5-SIM-triazine. Ufa: Gil, 2008]. According to our materials biological activity hydrochloride BMC and BMC complex with copper sulphate used against pathogenic and conditionally pathogenic fungi were superior to that of the actual BMK 1.5-2 times.

Yeast-like fungi, in particular, one of the leading causative agents of "opportunistic" mycosis in humans, the causative agent of candidiasis (Candida albians) showed significantly less resistance (up to 10 times) in comparison with molds zooantropopogenic mushrooms to act as BMC, and its derivatives. However, the studied derivatives BMC was superior for antifungal activity against Candida albicans source drug BMC 1.5-1.8 times.

The causative agents of dermatophytosis in respect of BMC and its derivatives studied in comparison with filamentous fungi showed significantly less resistance. IPC for BMC at action on all the dermatophytes was similar to the one in against yeasts and much lower (10 times or more) than fungal opportunistic pathogens "opportunistic" mycosis of humans and animals, we investigated derivatives BMC in comparison with the original drug was lower in 3-5 times.

Thus, the plant and its derivatives studied by us are capable to exhibit antifungal properties against zooantropopogenic fungi causing mycosis. As you know, the "opportunistic" infections are caused by various species of fungi, the occurrence of which is preceded by the presence of predisposing factors from the host organism (various disorders of certain mechanisms to protect it from fungi causing). Pathogens such "mold" of fungal infections (aspergillosis, penicillin, etc.) are mostly free-living inhabitants of environmental objects (soil, air, water, plants and others). While pathogens "opportu�oticheskih" mycoses can act and some phytopathogenic fungi. In General, the similarity of biological properties of free-living soil, pathogenic fungi and pathogens "opportunistic" mold mycoses, apparently, and determines their similar sensitivity to the antifungal action developed as a systemic fungicide BMC and its derivatives.

Yeast-like fungi that causes "opportunistic" infections, especially the main causative agents of candidiasis inherent in a different environment. Fungi of the genus Candida, including the most frequent causative agent of candidiasis Candida albicans, are the natural inhabitants of epithelial tissues (skin, mucous membranes) of humans and animals. In view of this, according to their physiological properties of these mushrooms are much closer to zooperstars mushrooms. The sensitivity of these fungi to the antifungal action of BMC and its derivatives is much higher IPC and for them similar to those for dermatophytes.

Dermatophytes - filamentous fungi of the genera Trichophyton, Microsporum and Epidermophyton. Dermatophytes cause dermatophytosis - contagious infection of the skin lesions of different depths (epidermis, dermis) and its appendages (hair, nails). Depending on the type of pathogen diseases - fungal infections in the feet and hands, antropos and zooantroponoznyh trichophytosis and microsporia; favus ("scab"), athlete - can occur acutely and/or chronically, with varying degrees virginnot� inflammation and or transmitted only from person to person, or from animals to humans. The causative agents of dermatophytosis are imperfect forms of soil keratinophilic fungi genera Arthroderma and Nannizzia, the pathogenicity of which is disputed. It is believed that during parasitic adaptation dermatophytes lost the ability to saprophytically existence. In view of the above antifungal activity of BMC and its derivatives against dermatophytes and other enteropathogenic fungi may be of interest in terms of prospects for their potential use for the treatment of fungal infections. In this regard it should be noted that the concentration of BMC and especially its derivatives studied, have a dampening effect on anthropophaginian mushrooms (0.1 to 7 mg/ml), slightly larger, but comparable in the fungicidal activity of therapeutic doses of drugs used for topical treatment of people, such as Miramistin (benzyldimethyl [3-(myristoylation)propyl]ammonium chloride monohydrate) - (0,015-0,5 mg/ml) [Pat. No. 3789122 USA, US C1. 260-299, 424-245, (A01n 9/22). Fungicidal cjmpositions of transition metal complexes and ecological feasibility study of substituted 2-benzimidazoltcarbamftic aside, alkyl esters].

Example 1.

Fungicidal activity was tested by accounting for the full delay of growth is the minimum inhibitory concentration (IPC) against the test cultures of fungi on a dense environment Saburo containing the studied drugs. The study of powdered drugs PR�varicella were dissolved in dimethylsulfoxide (hereinafter referred to DMSO) and stored in a molten medium Saburo (selective), contributed solutions BMC and its derivatives in 1 ml DMSO per 100 ml of the medium (to a final concentration of 0.1-10.0 mg/ml) were poured into 20 ml in a Petri dish and evenly stirred until the polymerization medium. After polymerization ("curing") to environments with drugs and control environment (environment without the addition of substances to the environment with a solvent and 1% DMSO) were sown in the culture test fungi and incubated at 28°C for 40 days. The results were recorded daily visually by the presence of growth of typical colonies of fungi [Kashkin PPT, Vladimir Lisin Practical guide to medical Mycology. L.: Medicine, 1983. - 190 p.].

To determine the fungicidal activity of compounds against phytopathogenic soil fungi causing diseases of plants, used test-cultures of phytopathogenic fungi Fusarium graminearum and Alternaria altemata.

As test objects for the assessment of antifungal action against the anthropo - and topogenic fungi used in the clinical culture (isolated from pathological material of patients and laboratory identified) strains of fungi: pathogens "opportunistic infections" - opportunistic fungi - Penicillium notatum and Aspergillus ninger, yeast-like fungi - Candida albicans, and "primary pathogenic" fungi causing de�of maturity: dermatophytes anthropophilic - the causative agents of fungal infections of feet and hands Trichophyton mentagrophytes var. interdigitale and Trichophyton rubrum, pathogens zooantroponoznyh trichophytosis and microsporia - Trichophyton mentagrophytes var. gypseum (seu granulosum) and Microsporum canis.

The IPC definition of the investigated compounds against all the test cultures of fungi were carried out not less than three times.

Example 2.

Obtaining salts of carbendazim with hydrochloric acid in hydrated form BMC·HCl·2H2O - hydrochloride carbendazim dihydrate (hereinafter GHMC). Suspension BMC 15 g (0,0785 moles) in 80 ml of N2Oh was heated with stirring to 60°C for 15 minutes metered 13,13 ml 11,96 N aqueous HCl (0,157 moles), maintained at this temperature for 15 minutes. The reaction mixture is cooled at room temperature for 3 hours. The resulting precipitate was filtered and dried under IR lamp. The weight of precipitate obtained - 18,451 G. Output in the calculation of the hydrochloride of carbendazim dihydrate - 89,17%. Based on mercurimetric analysis on the content of Cl-ions share GHMC in the obtained preparation is 86,88%, residue analysis according to UV spectroscopy of 86%, indicating the formation of GHMC·2H2O. Similarly receive the salt of carbendazim with other inorganic acids.

Example 3.

Synthesis of BMC complex with copper sulfate BMC2·CuSO4. To BMC 3,82 g (0,02 mol) pour 2.5 g (0.01 mol) of CuSO4·5H2O, dissolved in�revani in 6 ml of N 2Oh, and 2 ml of acetone. The suspension was stirred for 2 hours at 50°C. there is a change in color of the reaction mixture from blue to gray and purple. Gradually raise the temperature to 90-100°C and at this temperature, continue synthesis of 1 hour. When the distillation of acetone there is a change in color of the suspension from gray-purple to light green. Then cooled the reaction mass to room temperature, the precipitate was filtered off, washed on the filter with water and dried. After drying, the gain of 4.9 g (yield 90.4 percent) of sludge with a content of Cu2+9.7 percent, the estimated copper content - 11,72%. Maintenance of the complex in the sediment 83%.

Example 4.

Getting salt BMC with salicylic acid (BMK·ck). To 0.04 moles of acid poured 30-35 ml of acetone is poured of 7.64 g (0.04 moles) BMC, the resulting suspension was stirred for 15 minutes at 50°C, then the acetone is evaporated. The resulting crystalline precipitate is finally dried under an infrared lamp.

A salt is changing the nature of the IR spectra of the stretching vibrations. For BMC 3319(N-H); 1711(C=O); 1643(C=C+C-N); 1599(C-N+C-O); 1286, 1267(C-O-With Asim.); 1096(C-O-C SIM.) cm-1. For salt BMC with salicylic acid 3328, 3319(N-H); 1653, 1617(C-0); 1634(C=C+C=N); 1591(C-N+C-O); 1267(C-O-With Asim.); 1096(C-O-C SIM.) cm-1.

Example 5.

The synthesis of complex BMC copper chloride (BMC2·CuCl2): of 1.91 g (0.01 mol) BMC pour the solution 0,8526 g (0,005 mol) of CuCl2·2H About 6 ml of N2Oh and add 2 ml of acetone. The resulting suspension was heated with stirring at 55°C for 20 minutes and dried under an infrared lamp. For analysis the compound obtained is washed with water from the unreacted copper chloride, then with acetone and dried over CaCl2. In the obtained compound, the content of copper is 12,29%, calculation of 12.3%.

Example 6.

Getting the BMC complex copper chloride (BMK·CuCl2): in 10 ml of methanol was dissolved of 1.91 g (0.01 mol BMC) and 1,71 g (0.01 mol) of CuCl2·2H2Oh, after removal of the solvent receive approximately 3 g BMK·CuCl2. The synthesis was carried out as described in patent document JP 49-48433 (1974).

Example 7.

Getting the BMC complex with copper sulfate (BMK·CuSO4): 2.5 g (0.01 mol) of CuSO4·5H2O pour 60 ml of methanol, poured of 1.91 g (0.01 mol) BMC. Under vigorous stirring the synthesis goes for 4 hours at 50°C. the Resulting precipitate was filtered off and washed on the filter with methanol. After drying receive 3.11 g of sediment. The yield of 86.2%. Maintenance of the complex in the sediment 94-96%.

Example 8.

Getting the BMC complex with manganese chloride chetyrekhtomnym (BMC2·MnCl2): the synthesis is carried out by analogy with the example of obtaining BMC2·CuCl2.

Example 9.

Getting the BMC complex with zinc bromide (BMC2·ZnBr2): synthesis of p�control by analogy with the example of obtaining BMC 2·CuCl2.

Example 10.

Getting the BMC complex with ferric chloride hestevognen (BMC2·FeCl3): the synthesis is carried out by analogy with the example of obtaining BMC2·CuCl2.

Example 11.

Getting the BMC complex with nitrate of cobalt hestevognen (BMC2·CoNO3): the synthesis is carried out by analogy with the example of obtaining BMC2·CuCl2.

Example 12.

Salt BMC with alkylbenzenesulfonates (hereinafter - ABSC) (C8-18H17-37C6H5SO3H) is prepared according to the patent of Russian Federation №2497361.

Example 13.

Salt BMC with formic acid (hereinafter - HCO2H) and benzoic acid (hereinafter NOSE6N4COOH) is prepared analogously to example 4.

Example 14.

To BMC 3,82 g (0,02 mol) was added 2.5 g (0.01 mol) of CuSO4·5H2O, pour 6 ml of water and 2 ml of acetone, the suspension was stirred for 2 hours at 50°C, then the temperature was raised to 90°C and continue the synthesis of 1 hour. The solvent was distilled off. The precipitate is finally dried under an infrared lamp. For analysis a portion of the precipitate is washed with water from unreacted copper sulfate. In the washed sediment content of Cu2+is 9.6%, the estimated copper content - 11,72%. Maintenance of the complex in the sludge 82%.

Example 15.

Getting the BMC complex with cupric acetate (BMK·C(C2N3O2)2next BMK·Secib): to a solution of hydrate of acetamide 2.4 g (0,012 mole) in 80 ml of ethanol is added of 1.91 g (0.01 mol) BMC. The reaction is carried out under vigorous stirring at a temperature of about 50°C for 3 hours. The resulting suspension was cooled to room temperature and filtered. The filter cake was washed with water, alcohol and dried. Get 3.1 g of the complex green with access 83,42%. The copper content in the sediment is 17,02%, theoretical value 17,05%, theoretical value 17,05%. The ethanol filtrate can be used for further syntheses.

Suitable substances that promote penetration, are dimethyl sulfoxide, dimethylformamide, salicylic acid (alcohol or water-alcohol solution), dimethylacetamide, propylene glycol, isopropyl alcohol, surfactants (e.g. sodium lauryl sulphate). As auxiliary substances used inert ointment base is petrolatum, mineral oil, etc.

The present composition is obtained by mixing the components at ambient or elevated temperature.

Example 16.

Take 1 g of BMC complex with sulphate of copper, which is mixed with 99 g of vaseline as an ointment base at room temperature to form a homogeneous mass.

Example 17.

Take 1.6 g salt BMC with salicylic acid, is added to 98.4 g of dimethyl sulfoxide was stirred at room temperature for 0.5 h.

Example 18.

Analogously to example 17,except instead of dimethyl sulfoxide take dimethylformamide.

Example 19.

Take 0.5 g of salt BMC with hydrochloric acid in hydrated form, is added to 99.5 g of isopropyl alcohol was stirred at room temperature for 1.0 h.

Example 20.

Analogously to example 19, but instead of isopropyl alcohol is added the propylene glycol in the amount of 98 g, and salt BMC with hydrochloric acid in hydrated form, taken in an amount of 2.0 g

Example 21.

Take 1 g of BMC complex with cupric acetate, is added to 99 g of dimethylacetamide, stirred at room temperature for 1.5 h.

Example 22.

Analogously to example 21, only as the active ingredient take the BMC complex with the bromide of zinc.

Example 23.

Analogously to example 17, only the sulfoxide is taken in an amount to 95.3 g and further added 3 g of water and 0.1 ml of 36% hydrochloric acid to stabilize the composition.

Example 24.

Take 5 g of salt with BMC alkylbenzenesulfonates, add 95 g of propylene glycol and stirred for 1 h at room temperature.

Example 25.

Take 37 g of PEG 400, mixed with 17 g of PEG 15000, add dimethylsulfoxide in the amount of 19 g, BMC 1.7 g and water of 25.3 g. the Mixture was heated to 50-60°C and stirred until a homogeneous mass.

Check antifungal properties in vivo for therapeutic application was carried out in relation to the causative agents of dermatophytosis on the model zooantroponoses�th ringworm controlled for. Experimental zoonotic dermatophytosis were modeled in mice of the line BALB/C, are genetically sensitive to this dermatophytosis [Calderon R., Hay R. Cell-also been other ideas where immunity in experimental murine dermatohyytosis // Immunology. - 1984. - Vol. 53, No. 3. - P. 457-464. Calderon R., Hay R. Fungicidal activity of human neutrophyls and monocytes on dermatophyte fungi Trichophyton quinckeanum and Trichophyton rubrum // Immunology. - 1987. - Vol. 61, No. 3. - P. 289-295]. Controlled the intensity of mycotic skin lesions was provided, in addition to the use of linear animals dosed infection, which in the infective quality material used selected unicellular elements of cultures of the fungus - microconidia of Trichophyton. In the process of allocation of microconidia after receiving a 7-day culture of Trichophyton mentagrophytes variant granulosum strain 182 in a liquid medium Saburo was held for the release of the culture fluid from mycelial mushroom formations (centrifugation at 3000 rpm). Deposition of microconidia was carried out by centrifugation at 8000 rpm, followed by 3-fold laundering sterile isotonic with the addition of gentamycin sulfate (5 mg/ml). The resulting suspension of microconidia after the packing was preserved in frozen form. The determination of the concentration of microconidia to infection was performed microscopically (microscopy of native suspension in a dark field) and determining their viability by measuring seeding at �acidic environment Saburo followed (after 7 days) calculating the number of colony-forming units [Medvedev Y. A. Molecular and cellular mechanisms of immunogenesis in zoonotic ringworm: Dis. ...d-RA med. Sciences. - M., 1988. - 240 p.]. For modeling infection, the mice of the line BALB/C on a shaven surface of the skin of the back area of 4×2 cm caused a suspension of microconidia of the fungus (1-3×10×9 microconidia in a 0.05% solution of tween-80 in saline) at a volume of 0.05 ml/mouse. The efficiency of infection was monitored on day 5 after infection according to the results of seeding skin scales on a dense environment Saburo followed by identification of cultures by cultural and morphological properties [Kashkin P. N., Vladimir Lisin Practical guide to medical Mycology. - L.: Medicine, 1983. - 190 p.]. Clinically, the degree of skin lesions in the dynamics of the disease were scored according to the formula: diameter of the lesion × severity of hyperemia × severity of edema × severity of suppurative (the last three criteria in intensity from 1 to 3) [Calderon R., Hay R. Cell-also been other ideas where immunity in experimental murine dermatohyytosis // Immunology. - 1984. - Vol. 53, No. 3. - P. 457-464].

External therapy of infected animals was carried out by applying to initiated skin solutions (suspensions, slurries) test substances. Antifungal effect of derivative BMC during therapeutic use can be illustrated by the following examples.

Example 26. Treatment zooantroponoznyh ringworm salicylate BMK (BMK·ck).

In the experiments the zoonotic dermatophytosis was simulated for 20 inbred mice of the line BALB/C by the above procedure. All mice already on day 3 after infection marked by inflammation, similar in intensity in all groups of animals (Table. 2). Also, all mice on day 5 after infection as a result of seeding on Wednesday Saburo from skin flakes were selected retromolar Trichophyton mentagrophytes variant granulosum. The treatment was performed by external application on the affected areas of the BMC solution·SC in 5% aqueous-alcoholic solution of salicylic acid (hereinafter - SC) at a concentration of 2 mg/ml. Treatment was started from the third day after infection. As a control therapy used topically applied 5% aqueous-alcoholic solution BMK·ck-and-cream Nizoral" (hereinafter - cm) containing as the active ingredient ketoconazole. The treatment was performed, starting from the third day after infection until complete cure.

The effectiveness of antifungal therapy was controlled Ekologicheskie: conversion of results of microscopic examination and seeding skin scales from foci of infection in a dense environment Saburo [Kashkin P. N., Vladimir Lisin Practical guide to medical Mycology. - L.: Medicine, 1983. - 190 p] and disappearance of clinical signs of skin lesions in disease dynamics in points according to the formula: diameter of the lesion × severity of Hyper�AI × severity of edema × severity of suppurative (the last three criteria in intensity from 1 to 3) [R. Calderon, Hay R. Cell-also been other ideas where immunity in experimental murine dermatohyytosis // Immunology. - 1984. - Vol. 53, No. 3. - P. 457-464]. The negative results of mycological examination, the lesions were observed in groups of mice: ointment ketoconazole (MK) - on the 14th day of infection, BMC·SC - by the 21st day after infection, in the group without treatment" and IC causative agents of ringworm Ekologicheskie was determined up to 30 days after infection (end of observation). Changes in the foci of infection are shown in table. 2.

Thus, there was a complete cure when applied topically salt BMK·SC in aqueous-alcoholic solution of salicylic acid.

Example 27. Treatment zooantroponoznyh ringworm complex BMC copper chloride BMC2·CuCl2.

In the experiments the zoonotic dermatophytosis was simulated for 20 inbred mice of the line BALB/C by the above procedure. All mice already on day 3 after infection marked by inflammation, similar in intensity in all groups of animals (Table. 3). Also, all mice on day 5 after infection as a result of seeding on Wednesday Saburo from skin flakes were selected retromolar Trichophyton mentagrophytes variant granulosum. The treatment was performed by external application to the lesion suspension of BMC complex copper chloride (BMC2·CuCl2) at a concentration of 5 mg/ml in mineral oil (hereafter VM). Treatment was started from the third day pic�e infection. As a control therapy used topically applied vaseline oil (VMS). The treatment was performed, starting from the third day after infection until complete cure.

The effectiveness of antifungal therapy was controlled Ekologicheskie: conversion of results of microscopic examination and seeding skin scales from foci of infection in a dense environment Saburo [Kashkin P. N., Vladimir Lisin Practical guide to medical Mycology. L.: Medicine, 1983. - 190 p] and disappearance of clinical signs of skin lesions in disease dynamics in points according to the formula: diameter of the lesion × severity of hyperemia × severity of edema × severity of suppurative (the last three criteria in intensity from 1 to 3) [Calderon R., Hay R. Cell-also been other ideas where immunity in experimental murine dermatohyytosis // Immunology. - 1984. - Vol. 53, No. 3. - P. 457-464]. The negative results of mycological examination, the lesions were observed in groups of mice: ointment ketoconazole (MK) - on the 14th day of infection, WM-BMK2·CuCl2- by the 21st day after infection, in the group without treatment" VM and the causative agents of ringworm Ekologicheskie was determined up to 30 days after infection (end of observation). Changes in the foci of infection are shown in table. 3.

Thus, there was a complete cure when applied topically.�and BMC 2·CuCl2that was mixed with paraffin oil as an ointment base.

Example 28. Treatment zooantroponoznyh ringworm salt of carbendazim (BMC) with hydrochloric acid in hydrated form BMC·HCl·2H2O - hydrochloride of carbendazim dihydrate.

In the experiments the zoonotic dermatophytosis was simulated for 20 inbred mice of the line BALB/C by the above procedure. All mice already on day 3 after infection marked by inflammation, similar in intensity in all groups of animals (Table. 4). Also, all mice on day 5 after infection as a result of seeding on Wednesday Saburo from skin flakes were selected retromolar Trichophyton mentagrophytes variant granulosum. The treatment was performed by external application to the lesion suspension of salt carbendazim (BMC) with hydrochloric acid in hydrated form BMC·HCl·2H2O, at a concentration of 5 mg/ml in mineral oil (hereafter VM). Treatment was started from the third day after infection. As a control therapy used topically applied vaseline oil (VMS). The treatment was performed, starting from the third day after infection until complete cure.

The effectiveness of antifungal therapy was controlled Ekologicheskie: conversion of results of microscopic examination and seeding skin scales from foci of infection in a dense environment Saburo [Kashkin P. N., Vladimir Lisin Practical �owner's manual for medical Mycology. L.: Medicine, 1983. - 190 p] and disappearance of clinical signs of skin lesions in disease dynamics in points according to the formula: diameter of the lesion × severity of hyperemia × severity of edema × severity of suppurative (the last three criteria in intensity from 1 to 3) [Calderon R., Hay R. Cell-also been other ideas where immunity in experimental murine dermatohyytosis // Immunology. - 1984. - Vol. 53, No. 3. - P. 457-464]. The negative results of mycological examination, the lesions were observed in groups of mice: ointment ketoconazole (MK) - on the 14th day of infection, VM-GHMC - by the 21st day after infection, in the group without treatment" VM and the causative agents of ringworm Ekologicheskie was determined up to 30 days after infection (end of observation). Changes in the foci of infection are shown in table 4.

Thus, there was a complete cure when applied topically BMK·HCl·2H2O in mineral oil.

1. Antifungal agent containing an effective amount of methyl ester 2-benzimidazolecarbamic acid, or its salts with inorganic and organic acids, or their hydrates, or its complex compounds with ORGANOMETALLIC and inorganic salts containing transition metal, and possibly one or more acceptable auxiliary components exhibiting antifog�optimum activity against the causative agents of mycoses from the group including Trichophyton mentagrophytes var. Interdigitale, Trichophyton rubrum, Microsporum canis, Trichophyton mentagrophytes var. granulosum, Candida albicans.

2. A compound according to claim 1, wherein the salt forming complex compounds with methyl ester of 2-benzimidazolecarbamic acid selected from the group comprising chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, benzolsulfonat, formate, tartrate, maleate, malate, citrates, benzoates, salicylates, ascorbates, acetates, propionates, and mixtures thereof.

3. A compound according to claim 1, wherein the complex compound with methyl ether 2-benzimidazolecarbamic acid may have one or two molecules of methyl ester of 2-benzimidazolecarbamic acid and one molecule of salt.

4. A compound according to claim 1, wherein the inorganic acid, forming salts with carbendazim selected from the group comprising chloride, sulfuric, nitric, phosphoric, bromoethanol, hydrofluoric, iodomethane acid.

5. A compound according to claim 1, wherein the organic acid forming a salt with carbendazim selected from the group comprising benzoic, sulfonic, alkylsulfonate, acetic, propionic, alkylbenzenesulfonate, salicylic, formic acid.

6. A compound according to claim 1, in which transition metals include zinc, copper, Nickel, manganese, cobalt, cadmium, iron and chromium.

7. A compound according to claim 1, wherein an auxiliary� components it contains, in particular, substances that promote the penetration.

8. A compound according to claim 1, wherein the minimum inhibitory concentration specified in paras. 1-6 compounds is 0.1-7 mg/ml.

9. A compound according to claim 1, in which specified in s.1-7 compounds applicable for the prevention and treatment of fungal infections of mucous membranes, skin and its appendages in humans and animals.



 

Same patents:

FIELD: medicine.

SUBSTANCE: skin care compound possessing the antifungal properties, alcoholic extract of birch leaves, pine paste, tea tree, fir, lemon and eucalyptus essences, an emulsion base in certain proportions.

EFFECT: compound possesses the pronounced antifungal properties.

4 ex

FIELD: medicine.

SUBSTANCE: therapeutic agent contains recombinant interferon specified in a group of: recombinant interferon alpha, recombinant interferon beta, recombinant interferon gamma, metronidazole, fluconazole and/or voriconazole, and a pharmaceutically acceptable base in the following proportions, g per 1 ml of the mixture: recombinant interferon, international units 100-10,000,000; metronidazole 0.00001-0.5; fluconazole and/or voriconazole 0.00001-0.5; pharmaceutically acceptable base - the rest. Besides, the therapeutic agent contains boric acid in an amount of 0.00001-0.5 g and hypromellose in an amount of 0.00001-0.5 g. As a pharmaceutically acceptable base, it contains macrogol 400 or macrogol 1500, or macrogol 4000.

EFFECT: higher efficacy of the compound.

2 cl, 5 ex

FIELD: biotechnology.

SUBSTANCE: strain Trametes versicolor is proposed, used for production of antifungal agents against fungi of the genus Penicillium. The strain is deposited in the RCIM under the number F-1024.

EFFECT: strain has high chitinase and fungicidal activity.

4 dwg, 1 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: method of producing a carbon sorbent with antibacterial and antimycotic properties includes impregnating granules of a carbon hemosorbent with 10-50% aqueous solution of glycolic acid for 7-9 hours at room temperature. The ratio of the hemosorbent to the modifier solution of glycolic acid is 1:1. Further, drying is carried out for an hour at 100-110°C. Polycondensation of glycolic acid on the carbon hemosorbent is carried out in two steps: at 185-205°C for 1 hour, at 215-235°C for not less than 5 hours, on a sand bath. The disclosed modified carbon sorbent with antibacterial and antimycotic properties is granules with a round shape, contains not less than 5% polyglycolide, characterised by a specific adsorption surface area of less than 250 m2/g and total pore volume of less than 0.50 cm3/g.

EFFECT: improved properties of the sorbent.

2 cl, 2 tbl, 2 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to antifungal compounds based on 3,5,8-trioxabicyclo[5,1,0]octane derivatives, obtained by trans-opening of its epoxide cycle, namely 6-(arylthio)-1,3-dioxepan-5-ols in racemic and enantiopure form of the general formula Ia and Ib , where at R1=F, R2=H, R3=H; at R1=Br, R2=H, R3=H; at R1=H, R2=Br, R3=H; at R1=H, R2=H, R3=Br.

EFFECT: compounds of formula Ia and Ib possess low toxicity and high antifungal activity with respect to fungi Candida albicans, Aspergillus fumigatus, Epidermophyton floccosum, Mucor pusilos, Saccharomyces cerevisiae and can be applied in medicine and veterinary.

2 tbl, 13 ex

FIELD: medicine.

SUBSTANCE: as an active substance, the composition contains butoconazol, a base that is a combination of a hydrophobic ingredient, a hydrophilic ingredient and an emulsifier, and also a gel-forming polymer. Hydroxypropylstarch phosphate is preferentially used as the gel-forming polymer. A method for preparing the declared composition consists in the fact that a mixture of butoconazol with a portion of the hydrophilic ingredient, the hydrophobic ingredient and emulsifier is added with a dispersion of the gel-forming polymer in the rest of the hydrophilic ingredient; the produced mixture is agitated homogenously with a preserving agent added where it might be necessary.

EFFECT: new pharmaceutical composition is characterised by a high level of antifungal activity, stability both at a storage temperature, and at a use temperature, and good pack extrusion.

14 cl, 2 tbl, 10 ex

FIELD: medicine.

SUBSTANCE: invention represents an antifungal preparation in suppositories for children containing recombinant human interferon 2α and fluconazole, wherein lysozyme, Licopid and dimephosphone are additionally introduced.

EFFECT: preparation possesses the high clinical effectiveness in the fungal diseases in children that leads to reducing the length of treatment and prolonging the intercurrent period.

1 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to the field of medicine, namely to pharmacology, and describes a composition, containing fulvic acid or its salt and an antifungal compound, selected from fluconazole and amphotericin B. In accordance with the first version of the implementation the composition contains about 10 ml/kg of a solution of from about 0.25% to about 1% (wt/vol) fulvic acid or its salt and of about 10 mg/kg fluconazole. In accordance with the second version of the implementation the composition contains 0.25% (wt/vol) of the solution of fulvic acid or its salt and from about 0.06 mg/l to about 0.5 mg/l of amphotericin B.

EFFECT: invention can be used in a method of treating a fungal infection of the human or animal body, the method includes the introduction to an object, requiring it, of a therapeutically effective quantity of the composition.

11 cl, 1 dwg, 10 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: declared group of inventions refers to veterinary science and is applicable for treating the animals suffering from bacteriosis and yeast mycosis. A declared preparation contains oxytetracycline hydrochloride, sulphadimine, ampicillin sodium, nistatine, a solvent and the active substance conduit dimethyl sulphoxide, the quick-relief anaesthetic lidocaine in the following proportions, wt %: ampicillin sodium 4.0-8.0, oxytetracycline hydrochloride 2.0-4.0, nistatine 1.0-2.0, sulphadimine 2.0-4.0, novocaine 0.25-0.5, lidocaine 0.25-0.5, dimethyl sulphoxide 10.0-20.0, 1,2-propylene glycol - the rest. A method of treating the animals consists in administering the declared preparation in a dose of 0.1-0.2 cm3 per 1 kg of body weight.

EFFECT: using the declared group of inventions is high-efficiency for treating the animals suffering from bacteriosis and yeast mycosis and enables improving livestock farms with an unfavourable incidence of bacteriosis and yeast mycosis.

5 cl, 9 ex

FIELD: chemistry.

SUBSTANCE: preparation can be applied for elimination of fungi and in treatment of diseases, caused by fungi, as well as for the prevention of damage by fungi to different materials and agricultural products. The fungicidal preparation represents an associate of 5-[3,5-dichloro-2-hydroxybenzylidine)amino]-4-hydroxy-1H-pyrimidine-2-one with 1,2,3,4,5-pentahydroxy-6-methylaminohexane and corresponds to the following formula: . Compounds were obtained in the crystalline form, and their structure is proved by spectra of proton magnetic resonance in dimethylsulphoxide.

EFFECT: preparation has a wide spectrum of action and high solubility, which increases efficiency of its application in the form of solutions.

2 tbl, 6 ex

FIELD: medicine.

SUBSTANCE: pulmonary metastatic lesion in rats is simulated, and the Stellanin alcohol solution is administered intragastrically. After sarcoma 45 cells are introduced in the rats, Stellanin is applied according to a prevention schedule in a single dose of 0.4 mg/kg dissolved in water 0.5 ml, interruptedly - 5 days daily with a pause of 2 days. The length of exposure is 8 weeks. The absence of metastases is stated in 83.5% in animals of both genders in average.

EFFECT: invention enables limiting the development of pulmonary metastases.

1 tbl

FIELD: chemistry.

SUBSTANCE: claimed is the application of 5(6)-nitro-1-(1,1-dioxothietanyl-3)-2-chlorobenzimidazole of formula (I) , earlier known as the means with broncholytic and spasmolytic activity, as the means, inhibiting peroxide oxidation of lipids.

EFFECT: realisation of the claimed purpose.

1 dwg

FIELD: chemistry.

SUBSTANCE: claimed is the application of 5(6)-nitro-2-chloro-benzimidazole of formula (I) as the preparation, inhibiting peroxide oxidation of lipids.

EFFECT: achievement of the claimed purpose, activity of the said formula compound is higher than of the comparison medication dibazole.

1 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to chemical-pharmaceutical industry and represents method of medication encapsulation by precipitation with non-solvent, which is characterised by the fact that as medication used is fenbendazole, and as envelope - sodium carboxymethylcellulose, which is precipitated from solution in acetone by addition as non-solvent of methylcarbinol and water at 25°C.

EFFECT: invention ensures simplification and acceleration of process of obtaining microcapsules, reduction of loss in obtaining microcapsules (increase of output by weight).

3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to an albendazole-based composition. The claimed composition consists of a substance of albendazole and arabinogalactane polysaccharide from Siberian larch or Gmelin with weight ratios of the components albendazole : arabinogalactane 1:5-20.

EFFECT: invention possesses the higher anti-opisthorchosis pharmaceutical activity than albendazole, and does not cause the toxic injury of hepatocytes.

3 cl, 7 dwg, 2 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to encapsulation, particularly a method of producing fenbendazole microcapsules in a sodium carboxymethyl cellulose capsule. The method includes dissolving fenbendazole in dioxane or dimethyl sulphoxide or dimethyl formamide, adding the obtained fenbendazole solution to a solution of sodium carboxymethyl cellulose in tetrachloromethane in the presence of E472c while stirring at a rate of 1000 rps. Fenbendazole and sodium carboxymethyl cellulose are taken in weight ratio of 1:3. Methanol and distilled water, taken in ratio of 2:1 vol/vol, are then added. The obtained suspension of microcapsules is filtered and dried. The process is carried out at 25°C for 20 minutes.

EFFECT: invention simplifies and speeds up the process of producing microcapsules, reduces losses during production thereof (high mass output).

3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to chemical-pharmaceutical industry and represents method of medication encapsulation by precipitation with non-solvent, which is characterised by the fact that as medication used is fenbendazole, and as envelope - sodium carboxymethylcellulose, which is precipitated from solution in ethylacetate by addition as non-solvent of carbinol and water at 25°C.

EFFECT: invention ensures simplification and acceleration of process of obtaining microcapsules, reduction of loss in obtaining microcapsules (increase of output by weight).

3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to the chemical-pharmaceutical industry and represents a method of medication encapsulation by precipitation with a non-solvent, which is characterised by the fact that as the medication used is fenbendazole, and as an envelope - sodium carboxymethylcellulose, which is precipitated from a solution in diethyl ether by the addition as the non-solvent of carbinol and water at 25°C.

EFFECT: invention ensures the simplification and acceleration of the process of obtaining microcapsules, reduction of loss in obtaining the microcapsules (increase of output by weight).

3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to the field of encapsulation, in particular to a method of obtaining fenbendazole microcapsules in an envelope of sodium carboxymethylcellulose. In accordance with the method fenbendazole is dissolved in dioxane or dimethylsulphoxide, or dimethylformamide, the obtained fenbendazole solution is added to a solution of sodium carboxymethylcellulose in methanol in the presence of E472c with mixing at a rate of 1000 rev/s. Fenbendazole and sodium carboxymethylcellulose are taken in a weight ratio of 1:3. After that ethanol and distilled water, taken in a ratio of 2:1 vol/vol, are added. The obtained suspension of microcapsules is filtered and dried. The process is realised at 25°C for 20 minutes.

EFFECT: invention ensures the simplification and acceleration of the process of obtaining microcapsules, reduction of loss in their obtaining (increase of output by weight).

3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to the chemical-pharmaceutical industry and represents a method of medication encapsulation by precipitation with a non-solvent, which is characterised by the fact that as the medication used is fenbendazole, and as an envelope - sodium carboxymethylcellulose, which is precipitated from a solution in diethyl ether by the addition as the non-solvent of isopropanol and water at 25°C.

EFFECT: invention ensures the simplification and acceleration of the process of obtaining microcapsules, reduction of loss in obtaining the microcapsules (increase of output by weight).

3 ex

FIELD: medicine.

SUBSTANCE: there are presented drug derivatives wherein said derivatives contain a H2S-releasing fragment of 4-hydroxythiobenzamide which is either covalently bond with the drug, or forms a pharmaceutically acceptable salt with the antilipidemic drug.

EFFECT: compounds show higher activity, or reduced side effects.

5 cl, 26 ex, 22 dwg

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