Method, inhibiting na+/h+-exchange, and dihydrochloride of 2-(3,4-methylenedioxyphenyl)-9-morpholinoethylimidazo[1,2-a]benzimidazole

FIELD: chemistry, pharmacology.

SUBSTANCE: invention relates to medications, capable of inhibiting Na+/H+-exchange (NHE-exchangers, NHE inhibitors).

EFFECT: increased efficiency of inhibitors.

3 cl, 1 tbl

 

The invention relates to possessing the ability to inhibit Na+/N+exchange (NHE inhibitors).

Na+/H+exchangers (NHE) are a group of integral membrane proteins expressed in all tissues of the body, which carry the transmembrane exchange of Na+at ions H+. Currently, nine different types of Na+/H+protein-exchangers have been cloned from mammalian tissue, and these isoforms are usually referred to as NHE-1, 2, 3, 4, 5, 6, 7, 8, 9 respectively. They vary in amino acid composition, tissue specificity, mechanisms of intracellular regulation. NHE-exchangers involved in many complex physiological and pathological processes, including regulation of cellular pH, cell migration, apoptosis, hypertrophy, damage associated with ischemia and reperfusion, protection of cells from acidification of the cytoplasm, regulation of cell volume [Malo ME, Fliegel L Physiological role and regulation of the Na+/H+exchanger./ Can. J. Physiol. Pharmacol. - 2006. No. 84 (11). - p.1081-1095], endothelial dysfunction, and diseases such as diabetes and its complications, heart failure, cerebrovascular disease, the development of malignant tumors [Fliegel L. Regulation of the Na(+)/H(+) exchanger in the healthy and diseased myocardium. / Expert. Opin. Ther. Targets. - 2009. No. 13 (1). - p.55-68; Karmazyn M.,

Kilic, A., S. Javaov The role of NHE-1 in myocardial hypertrophy and remodeling. / J. Mol. Cell Cardiol. - 2008. No. 44. - p.647-653; Provost JJ, Wallert MA. Inside Out: Targeting NHE1 as an Intracellular and increasing interest among Regulator of Cancer Progression. // Chem Biol Drug Des. - 2013. No. 81(1). - p.85-101].

There are various groups of NHE inhibitors: amiloride and its derivatives (DMA, EIPA, MIBA and intangible assets), benzylguanine derivatives, such as HOE-642 (cariporide), its derivative HOE-694 and eniporide (EMD-85131), cariporide (BIIB-722), bicyclic guanidine derivatives containing quinoline (MS 31038), indole (SM-20220, SM 20550, SMP-300), benzoxazine (KB-R9032), dihydrobenzofuran (BMS 284640), tetrahydronaphthalene (T-162559), cycloheptatrien (TY-12533) and others [Masereel Century, L. Pochet, Laeckmann D. An overview of inhibitors of Na+/H+ exchanger // Eur. J. Med. Chem. - 2003. No. 38. - R-554].

Known derivatives of benzimidazole containing acyclic guanidine group (benzimidazole-2-yl and benzimidazole-2-altimeter benzylguanine), able to inhibit Na+/H+currency [Zhang R et al. Benzimidazol-2-yl or benzimidazol-2-ylthiomethyl benzoylguanidines as novel Na+/H+exchanger inhibitors, synthesis and protection against ischemic-reperfiision injury. / Bioorg. Med. Chem. Lett. - 2007. - No. 17. - p.2430-2433].

The closest to the achieved result is Zoniporide (CP-597396) - [1-(quinoline-5-yl)-5-cyclopropyl-1H-pyrazole-4-carbonyl] guanidine hydrochloride monohydrate [A. Guzman-Perez et al. Discovery of zoniporide: A potent and selective sodium-hydrogen exchanger type 1 (NHE-1) inhibitor with high aqueous solubility. /Bioorganic & Medicinal Chemistry Letters. - 2001. No. 11 (6). - p.803-807]. In vitro studies on the platelet the rabbit has been shown this drug inhibits NHE-1 - dependent swelling of platelets (EC50=56 nm) [Tracey WR et al. Zoniporide: a potent and selective inhibitor of the human sodium-hydrogen exchanger isoform 1 (NHE-1) // Cardiovasc. Drug Rev. - 2003. - No. 21. - p.17-32].

However, its properties as an inhibitor of NHE are not sufficiently effective.

The technical result is to increase the efficiency of inhibitors of Na+/H+-exchange (NHE inhibitor).

The technical result is achieved by using as inhibitors of Na+/H+-exchange of tricyclic derivatives of imidazo[1,2-a]benzimidazole of General formula I:

where Ar=C6H5C6H4OCH3-4, C6H4OH-4, C6H3(O2CH2)-3,4

NR2=N(C2H5)2N(CH2CH2)2O

including Ia Ar=C6H5; NR2=N(C2H5)2

Ib Ar=C6H5; NR2=N(CH2CH2)2O

Ic Ar=C6H4OCH3-4; NR2=N(CH2CH2)2O

Id Ar=C6H4OH-4; NR2=N(CH2CH2)2O

Ie Ar=C6H3(O2CH2)-3,4; NR2=N(CH2CH2)2O.

Connections may be used, including, for the manufacture of tools, with the ability to inhibit Na+/H+-currency, as well as for inhibition of Na+/H+-sharing of living is Organismo.

Compound Ia is known as having anti-hypertensive and anti-inflammatory activities (Amimono, Alo, VAIDISOVA, Switanowski. Chem.-Pharm. journal, 1969, No. 1, p.7-10).

Compound Ib is known as exhibiting anti-diabetic and antiplatelet action (V.A.Anisimova, M.V.Levchenko, T.B.Korochina, A.A.Spasov, S.G.Kovalev, G.P.Dudchenko. New derives du benzimidazole, leur precede de preparation et les compositions pharmaceutiques que les contiennent. Fr. Pat. 2691462 (1995); Bull., 95/23. EP 0571253).

Compound Ic is known as having the ability to inhibit PDE camp and to reduce anxiety fibrillation (VAIDISOVA, Spa, Vahasalo, Afrocubanismo, Overstroke, Nperiod, Resibence. Pharmacological activity of 2-methoxyphenylalanine 9 dialkylaminoalkyl[1,2-a]benzimidazole. Chem.-Pharm. journal, 2005, t, No. 9, p.26-32), as well as exhibiting the properties of purine antagonist P2Y1receptors and antithrombotic activity [RF patent №2377990, IPC AC 31/5377, 2006)

The connection Id is antioxidant and antiplatelet activity, as well as weak antiserotonin and antipsoriaticescoe action (VAIDISOVA, Spa, Vahasalo, Mverno, Australia, Livelove, Nperiod, Resibence, Oesatanica. Synthesis and biological activity of 9-dialkylaminomethyl-2-hydroxy(deoxy)phenylimidazo[1,2-a]benzimidazole. Chem.-Pharm. journal, 2006, t, No. 10, p.23-26).

Those are the technical result is also new connections in the row imidazo[1,2-a]benzimidazole having the property of inhibiting Na+/H+-currency.

The technical result is achieved by the dihydrochloride of 2-(3,4-methylenedioxyphenyl)-9-morpholinosydnonimine[1,2-a]benzimidazole of the formula Ie:

The synthesis of the dihydrochloride of 2-(3,4-methylenedioxyphenyl)-9-morpholinosydnonimine[1,2-a]benzimidazole is in interaction 1-morpholinoethyl-2-aminobenzimidazole with 3,4-methylenedioxybenzyl-bromide and subsequent cyclization of the intermediate formed when bromide 1-morpholinoethyl-2-amino-3-(3,4-methylendioxyphenyl)benzimidazole (without allocation) in tricyclic basis, which translated in the usual way in the dihydrochloride Ie.

Example. Getting dihydrochloride Ie.

In a solution of 2.46 g (10 mmol) 1-morpholinoethyl-2-aminobenzimidazole in acetone contribute 2,43 g (10 mmol) of 3,4-methylenedioxyphenethylamine. The mixture is stirred. The solvent from the reaction mass with loose sediment bromide 1-morpholinoethyl-2-amino-3-(3,4-methylendioxy-phenacyl)-benzimidazole evaporated, to the residue was added 120 ml of water and the mixture is boiled until a complete reaction. The solution is cooled, alkalinized and the liberated base is 2-(3,4-methylenedioxyphenyl)-9-(2-morpholino-ethyl)imidazo[1,2-a]benzimidazole extracted with chloroform. The extract is purified on a chromatographic column, the Eluate evaporated, the residue is dissolved in acetone and acidified with HCl. The precipitation of the salt is filtered off, washed with acetone and dried. The output of 92.5-94,3%. TPL 183-184°C (decomposition).

Found, %: C 57,18; H Of 5.29; Cl 15,5; N 12,17.

C22H22N4O3·2HCl.

Calculated, %: C 57,03; H 5,22; Cl 15,30; N 12,09.

The infrared spectrum, λmaxcm-1: 1660 (C=N), 2360-2650 (wide band N+H).

An NMR spectrum1H (DMSO-d6), δ, ppm: 3.37-3.56 m (4H, N(CH2)2); 3.71 t (2H, J 6.5 Hz, CH2); 3.80-4.00 m (4H, O(CH2)2); 5.02 t (2H, J 6.5 Hz, CH2); 6.10 (2H, OCH2O); 7.06 (1H, J 9.0 Hz, HAr),7.39-7.58 (m 4H, HAr), 7.90-8.00 (m 2H, HAr), 8.48 (1H, H3Ar), 2H+in the exchange.

Below are the results of testing the properties of the compounds as inhibitors of Na+/H+exchange.

1. Materials and methods.

1.1. Research scheme.

stage 1 - study of the effect of compounds on the activity of Na+/H+-exchange of rabbit platelets. The calculation of the IC50.

stage 2 - study of acute toxicity.

1.2. Materials.

Compounds Ia-e, zoniporide (SIGMA, USA).

Reagents: sodium propionate (MP Biomedicals, Inc., France), HEPES (GERBU, Germany), calcium chloride-2-water (dihydrate) CaCI2·2H2O (LLC AGATE-MED, Russia), magnesium chloride 6-water "h" MgCI2·6H2O (CJSC UNICHEM", Russia), D-glucose (anhydrous) crystalline "h" C6H12O6OJSC "AGAT-HONEY", Russia), n is tri chloride "chemically pure" NaCl ("NPO ECROS", Russia), potassium chloride "analytical grade" KCl (LLC RAHIM", Russia), potassium phosphate one-deputizing KH2PO4"Analytical grade" (JSC "Petersburg Red chemist", Russia), magnesium sanitarily 7-water MgSO4·7H2O (LLC RAHIM", Russia), sodium bicarbonate NaHCO3(LLC RAHIM", Russia), ethylenediaminetetraacetic acid (EDTA) (MP Biomedicals, Inc., France).

1.3. Animals.

In experiments were used rabbits-males, weighing 2.5-3.5 kg, which was kept in vivarium conditions with natural light regime on a standard diet of laboratory animals in accordance with GOST R 50258-92 [1993]. The study was performed in accordance with the applicable requirements of GOST ISO/IEC 17025-2009, GOST R ISO 5725-2002 and "good laboratory practice", approved by order of the health Ministry of the Russian Federation dated 23 August 2010 No. 708n, in compliance with the "European Convention for the protection of vertebrate animals used for experimental and other scientific purposes" [Directive 2010/63/EU of the European Parliament and of the Council of 22 September 2010 on the protection of animals used for scientific purposes Official Journal L 276, 20.10.2010 p.33-79 (revising Directive 86/609/EEC)].

1.4. Methods.

The study to study the effect of compounds on the activity of Na+/H+-exchange of rabbit platelets were conducted in vitro in rabbit platelets (method Rosskopf D. et. al., Rapid determination of the elevated Na+/H+exchanger in platelets of patients with essential hypertension using an optical swelling assay / Journal of Hypertension. - 1991. No. 9. - p.231-238; Kusumoto K. et al., In vitro and in vivo pharmacology of a structurally novel Na+/H+exchanger inhibitor, T-162559 // British Journal of Pharmacology. - 2002. No. 135. - p.1995-2003).

As research material selected rabbit platelets, on the membrane which actively Express NHE-1. The method is based on the approaches based on the change in light transmission when changing the form of the platelet.

Blood samples were taken from the marginal ear vein of the rabbit in a test tube containing 3.8% sodium citrate in a ratio of 1:10. To obtain platelet-rich plasma (PBGC) the blood was centrifuged at 1000 revolutions/minute for 12 minutes.

For calibration used PBGC with EDTA and the Krebs solution (NaCl 120 mm, KCl : 4.8 mm, KH2PO4- 1.2 mm MgSO42.5 mm NaHCO3- 25 mm, CaCl2- 2.6 mm, glucose - 5,4 mm, pH 7,4.).

In the control series of experiments to 200 ál of Pbgt to reduce intracellular pH was added 600 μl of a solution of sodium propionate (mmol/l: Na propionate 135, HEPES 20, CaCl21, MgCl21, glucose 10; pH 6.7; t=37°C). This was accompanied by activation of Na+/H+exchanger, the flow of sodium associated with the release of cytosolic H+leading to edema (ferulacea) the platelet as a result of water accumulation in the cytoplasm. It was observed facilitate light transmission. To control the changes of transmittance in terms of the physical and the logical pH of the solution was used Krebs.

Changing the shape of the platelets was detected by changes in the level of light transmission using a laser aggregometry "BIOLA-220 LA", Russia.

In the study of new compounds and the comparison drug zoniporide (10 μl) of a substance added to a cuvette containing Pbgt (200 μl) for 3-5 minutes before adding a solution of sodium propionate, incubated at 37°C and constant stirring using a magnetic stirrer (1000 rpm).

The research was carried out in the concentration range 10-10-10-5M

Expected IC50the concentration of compounds that block Na+/H+-the exchange of rabbit platelets by 50%.

1.5. Study of acute toxicity

To calculate the latitude of therapeutic activity of a compound was determined acute toxicity of 50 mice male intraperitoneal injection. The calculation of the magnitude of LD-50performed graphically by Miller and Tataru [Belenky, M. elements of a quantitative evaluation of the pharmacological effect. - Leningrad, 1963. - 152 C.].

1.6. Methods of statistical processing

For the studied drug and drug compare experimentally determined values IC50using the method of regression analysis of the relationship between lg concentration and the percentage inhibition activity of the exchanger in Microsoft Excel (Office XP, Microsoft, USA).

2. The results of the investigated what I

The study of the effects of new compounds and zoniporide on the activity of Na+/H+exchange rabbit was shown dozozavisimoe increase inhibitory effect. Calculated IC50presented in table 1.

In the study of acute toxicity intraperitoneal injection to mice calculated LD50. To assess the breadth of therapeutic action on the isolated organs intended therapeutic index (table 1).

Thus, NHE-inhibitory effect of compound I a-e were more zoniporide and surpass it as the largest IC5019.7; 12,1; 2,1; 3,34 and 2.7 times, and therapeutic index - 34,7; 9,8; 1,7; 1.3 and 1.1 times, respectively.

Table 1
Calculate therapeutic index of the most active inhibitors of Na+/H+-sharing among the derivatives of IMBI
No.SubstanceInhibition of NHELD50mg/kgTherapeutic index
IC50MED50mg/l (kg)
1.of 1.37×10-90,001598,01002748,34
2.Icof 2.23×10-90,001282,8282252,71
3.Ie8,08×10-90,004182,348698,21
4.Ib1,28×10-80,005197,536798,68
5.Ia1,00×10-80,00395,031127,13
6.Zoniporideof 2.7×10-80,009250,028903,57

1. Use as inhibitors of Na+/H+-exchange of tricyclic derivatives of imidazo[1,2-a]benzimidazole of General formula I:

where Ar=C6Hsub> 5C6H4OCH3-4, C6H4OH-4, C6H3(O2CH2)-3,4
NR2=N(C2H5)2N(CH2CH2)2O
including Ia Ar=C6H5; NR2=N(C2H5)2
Ib Ar=C6H5; NR2=N(CH2CH2)2O
Ic Ar=C6H4OCH3-4; NR2=N(CH2CH2)2O
Id Ar=C6H4OH-4; NR2=N(CH2CH2)2O
Ie Ar=C6H3(O2CH2)-3,4; NR2=N(CH2CH2)2O.

2. Use .l for the manufacture of tools, with the ability to inhibit Na+/H+-currency, as well as for inhibition of Na+/H+-exchange in living organisms.

3. The dihydrochloride of 2-(3,4-methylenedioxyphenyl)-9-morpholinoethyl imidazo[1,2-a]benzimidazole of the formula Ie:



 

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14 cl, 824 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to compounds of formula or a pharmaceutically acceptable salt of such a compound, where - X is a carbon atom and R1a and R2a together form a bond; or - X is a carbon atom, R1a and R2a together form a bond, and R1 and R2 together form a moiety , where the asterisk shows the bonding site of R2; or - X is a carbon atom, R1a is hydrogen or (C1-4)alkoxy, and R2a is hydrogen; and R1 and R2, unless indicated otherwise, independently denote hydrogen; (C1-5)alkyl; aryl, where aryl denotes naphthyl or phenyl, where said aryl is unsubstituted or independently mono- or disubstituted, where the substitutes are independently selected from a group consisting of (C1-4)alkyl, (C1-4) alkoxy and halogen; or heteroaryl, selected from pyridyl, thienyl, oxazolyl or thiazolyl, where said heteroaryl is unsubstituted; under the condition that if R2 is aryl or heteroaryl, R1 cannot be aryl or heteroaryl, where the aryl and heteroaryl are independently unsubstituted or substituted as defined above; R3 is hydrogen or -CO-R31; R31 is (C1-5)alkyl, (C1-3)fluoroalkyl or (C3-6)cycloalkyl; n equals 1, 2, 3 or 4; B is a -(CH2)m- group, where m equals an integer from 1 to 3; A is-(CH2)P-, where p equals 2 or 3; R4 is (C1-5)alkyl; W is , where R5 is hydrogen or (C1-5)alkyl; R8, R9 and R10 is independently hydrogen, halogen, (C1-5)alkyl, hydroxy, -(C1-5)alkoxy, -O-CO-(C1-5)alkyl, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, -CO-(C1-5)alkoxy, (C1-2)alkoxy-(C1-4)alkoxy or -NH-CO-(C1-5)alkyl. The invention also relates to a pharmaceutical composition based on a compound of formula (I).

EFFECT: novel compounds which are useful as calcium channel blockers are obtained.

11 cl, 2 tbl, 166 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to organic chemistry, namely to new phenylimidazole derivatives of general formula , wherein R1 represents a hydrogen atom, a phenyl lower-alkyl group or a pyridyl lower-alkyl group with a benzene ring and a pyridine ring are optionally substituted by 1 or 2 substitutes specified in a group consisting of halogen atoms, cyano group and halogen-substituted lower-alkyl groups; one or R2 and R3 represents a hydrogen atom, and another one represents a lower alkoxy group; R4 represents a lower-alkyl group, a difurylglyoxal group, a thienyl group or a phenyl group optionally substituted by 1 or 2 substitutes specified in a group consisting of lower-alkyl groups, lower-alkoxy groups, halogen atoms, a carboxyl group, lower alkoxycarbonyl groups, and halogen-substituted lower-alkyl groups; R5 and R6 are identical or different, and represent a hydrogen atom or a lower alkyl group; R7 and R8 are identical or different, and represent a hydrogen atom or a lower alkoxy group; provided R1 represents an unsubstituted phenyl lower-alkyl group, R2 represents a lower alkoxy group, R3 represents a hydrogen atom, R4 represents an unsubstituted phenyl group or a phenyl group containing 1 or 2 halogen-substituted lower-alkyl groups, and R5 represents a hydrogen atom, then R6 is other than a hydrogen atom. Also, the invention refers to an LPL activator, an agent for preventing or treating hyperlipidaemia, an agent for treating arteriosclerosis, and an agent for treating obesity on the basis of the compound of formula (1).

EFFECT: there are prepared new phenylimidazole derivatives effective for LPL activation.

23 cl, 10 tbl, 7 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds being aspartyl protease inhibitors applicable for treating cardiovascular, neurodegenerative disorders and fungal infection of formula , wherein W represents -C(=O)-; X represents -NH-; U represents -C(R6)(R7)-; R1 represents methyl, R2, R3 and R6 represent H, R4 and R7 represent optionally substituted phenyl, as well as tautomers and pharmaceutically acceptable salts thereof.

EFFECT: there are presented new effective aspartyl protease inhibitors specified in rennin, cathepsin D, BACE-1, for treating cardiovascular diseases, cognitive and neurodegenerative diseases, as well as fungal infections.

67 cl, 1 tbl, 4393 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, and may be used for treating septic wounds and burns. A composition possessing antibacterial action contains active metal biocomplexes with 5-nitroimidazole and β-pyridine carboxylic acid and a base providing a soft dosage form. As a gelling agent, there may be used modified cellulose derivatives, additionally comprising methyl monosilane hydrogel (enterosgel) and/or polyvinylpyrrolidone, or an alloy of polyethylene oxide-400 and polyethylene oxide-1500. As a mixture of hydrophilic substances, the base contains substances specified in a group of: polyethylene oxides, dimexide, glycerol and aerosol, may comprise at least one target additive of: anaesthetic - trimecaine, pyrromecaine, lidocaine, or a mixture thereof, a repair process stimulator - methyluracil, acemine, solcoseryl, Spirulina microalgae (Spirulina platensis), or a mixture thereof, antiseptic - miramistine, chlorhexidine digluconate, dioxidine or a mixture thereof. The composition is presented in the form of an ointment or gel.

EFFECT: invention provides the improved microcirculation in wound tissues, as well as anti-inflammatory action, repair process stimulation.

5 cl, 6 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: described are novel substituted O-[ω-(azol-1-yl)alkyl]-N-phenylcarbamates of general formula I:

,

where Z and Y=CH, N or together form an annulated ring with a C-CH=CH-CH=CH-C chain; or Y=CH, Z denotes a nitrogen atom, m=1-3; R=Hal, alkyl, alkoxycarbonyl, sulphamoyl, nitro etc, n=0-2, and pharmaceutically acceptable salts thereof, which are obtained by acylating the corresponding ω-(azol-1-yl)-1-alkanol with phenyl isocyanates in polar aprotic solvents at temperature of 20-100°C, preferably in the presence of organic bases as catalysts.

EFFECT: antiaggregatory activity of certain O-[ω-(azol-1-yl)alkyl]-N-phenylcarbamates of general formula I, eg O-[2-(1H-imidazol-1-yl)ethyl]-N-(3-trifluoromethylphenyl)carbamate hydrochloride is higher than that of dazoxybene.

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel medication for treatment of purulent-inflammatory processes of skin and mucous membranes of different etiology. Medication is made in form of gel and contains the following ingredients with the following ratio of components in g per 100 g: biocomplex of cobalt (II) with metronidasole 0.20-0.50. biocomplex of cobalt (II) with ampicillin 0.20-0.50, trimecaine 3.00-5.00, methyluracyl 1.00-3.00, dimexide 10.00, glycerol 5.00-10.00, hydrophilic base 3.00-7.00, water 77.60-64.00.

EFFECT: extension of assortment of wound-healing medications.

3 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel medication for treatment of purulent-inflammatory processes of skin and mucous membranes of different etiology. Medication is made in form of gel and contains the following ingredients with the following ratio of components in g per 100 g: biocomplex of metronidazole with zinc 0.5-2.0, biocomplex of furacilinum with copper 0.1-0.2, trimecaine 3.0-5.0, vitamins (vitamin A, vitamin E, vitamin PP, vitamin C or their mixture) 0.1-1.0, dimexide 10.0, hydrogel of methylsiliconic acid 1.0-5.0, hydrophilic base 3.0-7.0, water 82.3-69.8.

EFFECT: extension of assortment of wound-healing medications.

2 tbl, 1 ex

FIELD: pharmaceutics.

SUBSTANCE: the present innovation deals with mixing water for injections, conservation agent, metronidasol till complete dissolving at 50-60 C, adding a buffer (NaOH solution) pH 4.5-6.5 at pre-estimated quantity of water, then one should sterilize the obtained medicinal form due to membranous filtration followed by sterile packaging. As a conservation agent one should apply sodium chloride at the quantity of 1.5-2.0 against metronidasol weight, then metronidasol solution should be supplemented with a half-volume of sodium chloride solution, after complete dissolving the obtained solution should be supplemented with the rest quantity of sodium chloride solution. As for membranous filtration it should be carried out by applying a capsule out of polypropylene with hydrophilic membrane of 1.2 mcm. The method provides no crystallization of an active substance during prolonged period of time.

EFFECT: higher therapeutic efficiency.

1 ex, 1 tbl

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