6-(2'-amino-2'-carboxyethylthio)-2-methylthio-4-pivaloyloxy-methyl-1,2,4-triazolo[5,1-c] 1,2,4-triazin-7(4h)-one

FIELD: chemistry.

SUBSTANCE: described is a novel compound - 6-(2'-amino-2'-carboxyethylthio)-2-methylthio-4-pivaloyloxy-methyl-1,2,4-triazolo[5,1-c] 1,2,4-triazin-7(4H)-one of formula having antiviral action and low toxicity.

EFFECT: compound can be used in medicine.

1 cl, 1 ex, 3 dwg

 

1. The technical field to which the invention relates.

The invention relates to the field of biologically active compounds and relates to 6-(2'-amino-2'-carboxymethylthio)-2-methylthio-4-pivaloyloxymethyl-1,2,4-triazolo[5,1-C]1,2,4-triazine-7(4H)-it is with antiviral action intended for the treatment and prevention of viral infectious diseases in animals and humans. The invention can be used in hospitals, research laboratories, as well as in livestock and poultry.

2. The level of technology

There is evidence of antiherpetic action 6-phenyl-4-hydroxybutyl-1,2,4-triazolo[5,1-C]-1,2,4-triazine-7(4H)-she (V.L. Rusinov, Onepager, Enhamce and others, patent RF №2345080 from 27.01.2009)and 4-((Z)-4'-Hydroxybutane-2'-yl)-2-R-6-phenyl-1,2,4-triazolo[5,1-C][1,2,4]triazine-7-ones (Onepager, Volturino, and other Enhamce, RF patent №2376307 from 20.12.2009,). Antiviral activity against influenza viruses types a and b have a 2-R-6-nitro-4-allyloxymethyl-1,2,4-triazolo[5,1-C]-1,2,4-triazine-7(4H)-ones, R=H, CH3, SCH3(Volturino, Enhamce, Sleep. And others, patent RF №2340614 from 10.12.2008; Volturino, Onepager, Sleep, Tschistjakowa, Enhamce, Liouciou, Oigusele, Aggeeva. Synthesis and antiviral activity of nucleoside analogues on the basis of 1,2,4-triazolo[3,2-C][1,2,4]triazine-7(4H)-ones. News of Academy of Sciences, Seri is chemical, 2010, No. 1, s-142). The most similar in structure to the claimed compound from this series 2-methylthio-6-nitro-4-allyloxymethyl-1,2,4-triazolo[5,1-C]-1,2,4-triazine-7(4H)-he (1) can be regarded as a prototype. When using compounds (1) at a concentration of 40 μg/ml in vitro infectious titer of influenza A/H3N2 And a/Hong Kong/1/68 and influenza A/H5N1 virus A/Duck/Singapore R/F119-3/97 reduced by 0,5-3,0 lg. However, this compound at higher concentrations showed cytotoxicity. The concentration at which killed 50% of cells (CC50), 80 µg/ml

3. The invention

The invention is 6-(2'-amino-2'-carboxymethylthio)-2-methylthio-4-pivaloyloxymethyl-1,2,4-triazolo[5,1-C]1,2,4-triazine-7(4H)-he of the formula (2)

possessing antiviral effect.

4. Information confirming the possibility of carrying out the invention.

4.1. Synthesis of 6-(2'-amino-2'-carboxymethylthio)-2-methylthio-4-pivaloyloxymethyl-1,2,4-triazolo[5,1-C]1,2,4-triazine-7(4H)-it

Example 1. To 2-methylthio-6-nitro-4-pivaloyloxymethyl-1,2,4-triazolo[5,1-C]1,2,4-triazine-7(4H)-ONU received from 0.05 mol of sodium salt of 2-methylthio-6-nitro-1,2,4-triazolo[5,1-C]1,2,4-triazine-7-she dihydrate effect of 0.05 mol climaterealists using dimethylformamide as a solvent, was added a solution of 1 equivalent of the cyst is on in ethanol. Upon completion of the reaction the solvent is removed in vacuo and the resulting residue purified by chromatographic column (eluent - acetonitrile: water = 8:1).

Output connections (2) is 51%.

The chemical scheme for the synthesis of the claimed compounds 6-(2'-amino-2'-carboxymethylthio)-2-methylthio-4-pivaloyloxymethyl-1,2,4-triazolo[5,1-C]1,2,4-triazine-7(4H)-he (2) has the following physicochemical characteristics: TPL=204°C;1H NMR spectrum in D2O δ, ppm: 5,18 (D., 1H, CH2), to 5.13 (d, 1H, CH2), 4,19 (m, 1H, CH), 3,91 (m, 1H, SCH2), 3,39 (m, 1H, SCH2), 2,69 (C., 3H, CH3), 1,18 (D., 9H, C(CH3)3). Found: 40,56, H - 4,77, N - 20,32. Brutto-formula - C14H20N6O5S2. Calculated: C - 40,38, H - 4,84, N - 20,18%.

The inventive compound is a light yellow crystalline substance, soluble in water, methanol, dimethylsulfoxide, and insoluble in benzene, ether and most other solvents.

4.2. Antiviral properties 6(2'-amino-2'-carboxymethylthio)-2-methylthio-4-pivaloyloxymethyl-4,7-dihydro-1,2,4-triazolo[5,1-C]1,2,4-triazine-7-it (2)

Example 2. Determination of toxicity and antiviral activity of compounds against influenza virus

Cells. Used one monoclonal epithelial cell culture MDCK (dog kidney).

The viruses. To assess protivovirusny the th activity used the reference virus A/Puerto Rico/8/34, and pandemic influenza a H1N1v A/St. Petersburg/2/09 (similar to the so-called virus of swine influenza A/California/7/09).

The maximum tolerated concentration of compounds was determined using the MTT-test in the culture of MDCK cells.

The toxicity testing was carried out according to the following scheme: sample weight of 5 mg was otvalivalas in a sterile tube with a volume of 5 ml and was diluted growth medium for MDCK cells (α-MEM, Biolot, St. Petersburg) to a concentration of 1 mg/ml, thus obtaining a basic solution. Further, this environment did 8 consecutive binary breeding(500; 250; 125; 62,5; 31,25; 15,13; 7,56 and of 3.78 μg/ml, respectively), which was used to test toxicity. The experience put in 4 matches for each concentration. One-day culture of MDCK cells grown on 96-well plates (Costar)were examined visually in the inverted microscope on the integrity of the monolayer. Tablets twice washed with medium containing no serum, after which he made the test compound at the appropriate concentration in a volume of 100 μl in each well. The plates were incubated 72 hours at 37°C in the presence of 5% CO2after which recorded the results of the experiment visually assessing the integrity of the monolayer compared with control cells, and the method of MTT (quantitatively confirming the viability of the cells) using tablet reed is RA Hydex Chameleon. Statistical analysis was performed using Statistica 6.0.

Evaluation of the antiviral activity was performed for 2 concentrations: maximum concentration (from binary dilution)at which survived 100% of the cell monolayer, and the concentration equal to half of the previous one. To assess the antiviral activity used the reference virus A/Puerto Rico/8/34. One-day culture of MDCK cells grown on 96-well plates (Costar)were examined visually in the inverted microscope on the integrity of the monolayer. Next was preparing tenfold viral cultivation on supporting the growth medium with the addition of trypsin (-1 through -6). Tablets with monolayer cells were twice washed with medium containing no serum, after which he made a virus cultivation in appropriate wells in a volume of 50 μl. Control wells were filled with growth medium in equal volume. The plates were incubated 60 min at 37°C in the presence of 5% CO2, then washed with medium to remove not bind to the cells of the virus particle. Then brought the drug into the wells with virus dilutions of 100 μl in the appropriate concentration. Each concentration of tested compound was placed in four parallel for each viral dilution. Control wells were filled with growth medium in the same amount. Also the wells were returned to re-test the toxicity of the used concentrations. The plates were incubated 72 hours at 37°C, and then recorded the results of the experiment visually assessing the integrity of the monolayer compared with the control cells and the degree of cytopathic effect of the virus on cell culture, staged reaction of haemagglutination and used the MTT method for quantitative assessment of cell viability using a tablet reader Hydex Chameleon.

Statistical analysis was performed using Statistica 6.0 [Borovikov VP, Borovikov I.P. Statistica. Statistical analysis and data processing in the Windows environment. - M., 1997. - Pp.33-34], using regression analysis [Rokicki PF Biological statistics. - Minsk, 1967. - S]. The results are presented using graphs derived from the linear regression equation having the General form of y=k+b*x, where the variable y is expressed by the constant k and the angular coefficient of b, multiplied by the variable X. In this case, the graph indicates the coefficient of determination, denoted as r2and expressing the dispersion of the values around the regression line relative to the total variation. The closer the value of r2to 1, the better the model explains the variability of the corresponding variables. The confidence interval for all of the regression equations was equal to 95%.

Toxicity assessment of the claimed compounds

Toxicity assessment, the AK and evaluation of antiviral drugs, produced by three methods:

1) Observation and assessment of the integrity of the monolayer of cells under an inverted microscope. Means comparison of the morphology of the cells in the control wells with experienced and registering changes under the influence of an agent (drug, virus, etc). The change in morphology may include violation of the integrity of the monolayer, changing the shape of the cells, expression of the cytopathic effect in viral infection.

2) Check the presence of the virus in the reaction of haemagglutination with suspension of chicken erythrocytes (0,75%). The reaction of haemagglutination (DSA) allows to assess the qualitative presence of the virus in the sample.

3) the Method of MTT. The method used in the evaluation of drug sensitivity based on the ability of the dehydrogenases of living cells to restore unpainted form 3-4,5-dimethylthiazol-2-yl-2,5-diphenylthiazole (MTT reagent) to blue crystalline parmesana, soluble in dimethyl sulfoxide or 96% alcohol. The saturation of the color indicates the intensity of metabolic processes in cells, i.e. a normal level of viability. The colour intensity is recorded with a spectrophotometer, and the obtained values of optical density can be used for statistical data processing.

It is established that the concentration of the drug which killed 50% of ketoconozole in testing conditions on MDCK cells, amounted to 177 ág/ml concentration of the drug at which survive all cells in the monolayer, was 62.5 µg/ml, which was used to test the antiviral activity of the drug.

In terms of this test cell viability in the control was 0,571±0,044. Thus, the optical densities at which survives 50% of the cell monolayer is 0,286. If you put this value on the ordinate axis of the graph presented in figure 1, to hold through it line parallel to the x-axis, and then from the point of intersection of this line with the schedule of viability to draw a perpendicular on the x-axis, we get the value corresponding to the concentration of the inventive compound, which killed 50% of the cell monolayer (see Fig.2).

Evaluation of antiviral activity

The claimed connection for all three estimation methods (concentration = 62,5 µg/ml) had a pronounced antiviral activity, reducing viral titers at 3 lg regarding the control of infectious virus activity.

When building the graph, corresponding to the action of the claimed compounds, the coefficient of determination r2was equal 0,86, indicating that this model explains well the variability of the tested variables, namely the effect of the test compounds on cells infected with the influenza virus. PR is constructing perpendiculars through the points appropriate optical density, at which survive 50% of the cell monolayer, on the y axis and through the point of intersection of this perpendicular with the straight line corresponding to the viability of the cells under the conditions of use of the drug, have the following schedule is presented on Fig.3.

From figure 3 it follows that the point of intersection of the perpendicular with the x-axis corresponds to the value of lg viral cultivation, equal is 3.5. Considering the fact that the virus in the absence of the drug infects the cell monolayer to a value equal to

10-6,5(contagious virus, found in a separate testing when testing the biological properties of the virus A/PR/8/34), we can say that the use of this drug in vitro reduces contagious virus on 3lg.

From the data above shows that the connection-prototype (1) is more toxic than the claimed connection (for connection (1) SS50=80 μg/ml, and for the claimed compounds CC50=177 µg/ml). The compound (1) is practically not active against pandemic influenza A/H1N1v strain - A/St. Petersburg/2/09 (A/California/7/09-like). At the same time, the inventive compound (2) in much smaller concentrations, in comparison with toxic, has a pronounced antiviral activity, reducing the titers of virus A/Puerto Rico/8/34 virus and pandemic DOF is and H1N1v A/St. Petersburg/2/09 (A/California/7/09-like) 3.0 lg at concentrations of 62.5 and 125 μg/ml, respectively, that is more active antiviral compound compared with the connection of the prototype.

6-(2'-Amino-2'-carboxymethylthio)-2-methylthio-4-pivaloyloxymethyl-1,2,4-triazolo[5,1-C]1,2,4-triazine-7(4H)-he of the formula (2)



 

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FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and synthesis of heterocyclic compounds - 5,6-dihydro-7H-pyrrolo[1,2-d][1,4]benzodiazepin-6-one derivatives of formula 1a-e by boiling 2-amino-N-(2-furan-2-yl-phenyl)-acetamides in a mixture of glacial acetic acid and concentrated hydrochloric acid with subsequent treatment with sodium bicarbonate while boiling.

EFFECT: method is characterised by simple execution.

2 tbl, 5 ex

Polycyclic compound // 2451685

FIELD: medicine, pharmaceutics.

SUBSTANCE: described is a new polycyclic compound with general formula (I-1) and (1-3) or a pharmaceutically acceptable salt thereof where X1- -CR1 =CR2 - where R1 and R2 independently stand for hydrogen or C1-6 alkyl while Het stands for a radical of the following formulae: that may be substituted 1-3 times additionally described is a pharmaceutical composition containing such compound and intended for prevention or treatment of diseases caused by β-amyloid.

EFFECT: production of a pharmaceutical composition prevention or treatment of diseases caused by β-amyloid.

7 cl, 392 ex, 12 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: this invention relates to compounds that may be applied for HIV infection treatment or prevention or for AIDS or AIDS-associated complex treatment. According to the invention, the compounds represent compounds with formula I, where A stands for A1 , A2 , A3 or A4 and R1, R2, R3, R4a, R4b, R5, R6, Ar, X1, X2, X4, X4 and X5 having values specified in the patent claim. Additionally, this invention relates to a pharmaceutical composition containing the said compounds.

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SUBSTANCE: invention refers to an amorphous form of N-{2- fluorine-5-[3-(thiophen-2-carbonyl)-pyrazolo[1,5-a]-pyrimidin-7-yl]-phenyl}-N-methyl-acetamide, methods for preparing it.

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12 cl, 4 dwg

FIELD: medicine, pharmaceutics.

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21 cl, 2 tbl, 274 ex

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11 cl, 30 ex, 7 tbl

FIELD: chemistry.

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21 cl, 645 ex

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10 cl, 10 dwg, 6 tbl, 5 ex

FIELD: chemistry.

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11 cl, 25 ex

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18 cl, 2 ex, 10 dwg

FIELD: medicine, pharmaceutics.

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2 cl, 4 tbl

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14 cl, 1 ex

FIELD: medicine, pharmaceutics.

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2 ex

FIELD: chemistry.

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19 cl, 2 tbl, 2 ex

FIELD: chemistry.

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11 cl, 1 tbl, 69 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine and is intended for treatment of lingering versions of jaundice course in newborn babies. UDCA preparations are administered in dose 20-30 mg/kg per day, therapy is carried out for not less than 3 months. Viferon suppositories are administered rectally. Day dose is 50 thousand units/kg. Scheme of introduction is 10 days-daily, after that every second day from 3 to 9-12 months. Cytomegalovirus is suppressed with application of medication aciclovir-akri and its analogues zovirax, valtrex for 21-30 days. To suppress causing agents of mycoplasmosis, ureaplasmosis and chlamidiosis, preparations from group of macrolids rovamicin and sumamed are administered. Scheme is: rovamicin in dose 100 thousand units/kg for 7 days, after that, sumamed with a single dose 10 mg/kg once, according to discontinuous scheme 1 time per week, for 3 weeks. Additionally applied are medications, enhancing phagocytocis: licopid, polyoxydonium, solution of dimephosphone in age doses.

EFFECT: method makes it possible to reduce treatment terms and avoid complications.

2 ex

FIELD: medicine.

SUBSTANCE: for treating urogenital clamidiosis, cytomegalovirus, herpes simplex, Helicobacter pylori, polyethylene oxide 1500 and polyethylene oxide 400 are melted in the ratio 9:1; the liquid melt is added with a design amount of the preservative sodium chloride; further a design amount of sodium deoxyribonucleate is added in mixing. A melted paste is mould to prepare Derinat suppositories of 1.3-2.5 g.

EFFECT: prepared suppositories provide high bioavailability and prolonged action of the active agent.

3 cl, 7 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: method involves introduction in a period of premonitory signs, not later than after the first 6 hours of the symptoms of genital and urogenital herpetic infection, a combination of two antiviral preparations: allokin-alpha 1 mg, once a day, every second day, a therapeutic course of 3 subcutaneous injections and oral single dose of famciclovir 1500 mg, and also external therapy of infagel 2 times a day for 5 days.

EFFECT: use of the invention enables reducing formation of vesicles and urogenital mucosal erosions, decreasing length of recurrences and a prolonged intercurrent period.

2 ex

FIELD: chemistry.

SUBSTANCE: compound of formula (I) has antiviral activity toward the human cytomegalovirus (HCMV) or some other representative of the Herpes virida group. In formula (I)

, R1 is a group of formula , where * denotes the point of bonding to a carbonyl group, R3 denotes a pyridyl which can be substituted with a substitute independently selected from a group comprising C1-C6alkyl or a cyano group, R5 and R6 independently denote hydrogen, R2 denotes a phenyl which can be substituted with a substitute selected from a group comprising a trifluoromethoxy group, a difluoromethoxy group and a monofluoromethoxy group, A is a group of formula

or , where * denotes the point of bonding to the carbonyl group, # denotes the point of bonding to the nitrogen atom of urea, R7 denotes C1-C6alkyl which can be substituted with a substitute selected from a group comprising C3-C6cycloalkyl, R8 and R9 independently denote hydrogen, halogen or C1-C6alkyl. The invention also relates to a method of producing a compound of formula (I) from a compound of formula , a method of producing a compound of formula (V), a medicinal agent containing the disclosed compound, use of the compound in preparing a medicinal agent and a method of fighting viral infections, among them human cytomegalovirus (HCMV) or some other representative of the Herpes viridae group.

EFFECT: high antiviral activity.

9 cl, 1 tbl, 39 ex

FIELD: organic synthesis.

SUBSTANCE: invention provides group of novel antiviral nitrogen-containing compounds, in particular adamantane derivatives having general formula:

, wherein R represents chlorine or ethyl.

EFFECT: increased choice of biologically active compounds suitable for use in medicine as antiherpetic agents.

2 cl, 6 tbl, 3 ex

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