2-methylsulphanyl-6-nitro-oxo-1,2,4-triazolo[5,1-c] [1,2,4]triazinide l-argininium dihydrate, possessing antiviral activity, method of its obtaining and application for prevention and treatment of west nile fever

FIELD: chemistry.

SUBSTANCE: described is novel biologically active compound 2-methylsulphanyl-6-nitro-7-oxo-1,2,4-triazolo[5,1-c][1,2,4]triazinide L-argininium dehydrate of formula , which has antiviral action, method of its obtaining and application for prevention and treatment of West Nile fever.

EFFECT: increased efficiency of compound application.

3 cl, 2 tbl, 2 ex

 

The invention relates to the field of biologically active compounds and relates to 2-methylsulfanyl-6-nitro-7-oxo-1,2,4-triazolo[5,1-C][1,2,4]triazine L-arginine dihydrate, which has antiviral action, intended for the treatment and prevention of viral diseases of humans and animals, mainly of West Nile Fever, and can be used in pharmaceutical industry, research laboratories, hospitals, and veterinary medicine.

The urgency of the problem of antiviral therapy, especially in conditions of rapid mutation of the virus, detection of new pathogens dangerous and slow virus infections, causes a constant need for new tools that would have high efficiency and stability when mutations of viruses, prolonged action, low toxicity and no side effects during treatment. In this regard, an important factor is the ability of synthetic drugs, as well as creating accessible technologies of their production.

Currently, the incidence of West Nile fever (hereinafter referred to West Nile virus in the world and, in particular, on the territory of the Russian Federation continues to grow.

For 10 months of 2012 in the European Union, the Russian Federation and the territory of the neighboring States registered 923 cases of West Nile virus, including: in Greece - 161, Hungary - 17, Italy - 50, Romania - 14, Algeria - 1, Croatia - 5, Republic of Macedonia - 6, Israel - 83, Kosovo - 4, Montenegro - 1, Russian Federation - 447, the Palestinian authority - 2, Serbia - 69, Tunisia - 63 (see www.edc.europa.eu/en/healthtopics/west_nile_fever/West-Nile-fever-maps/Pages/2012-table.aspx).

According to the centers for control and prevention of diseases of the United States only in September-October in 2012 in the U.S. 48 States registered 5674 cases of West Nile virus, including 2969 neuroinvasive cases (representing 51%), 3491 (62,0%) persons were hospitalized, of which 286 cases (5,0%) had fatal outcome (see West Nile virus and other Arboviral diseases - United States, 2012 // Morbidity and Mortality Weekly Report. - 2013. - 62(25); 513-517).

West Nile virus epidemic process has a number of features, both in epidemiological and clinical aspects: the early start and late finish epidsezona, marked seasonality of disease; differences in clinical manifestations and morbidity is determined by the number of cases, their age, the territory in which the recorded disease and so on, while in the territories of the "old" and "new" sources, an increase in the proportion of cases of West Nile virus rural residents, a significant increase in the proportion of cases age category 20-29 years (although the dominant group continues to age category of 60 and upper sec is"), the emergence of new clinical manifestations of infection, namely the changing structure of West Nile virus infection is a significant increase in the population infected during travel in recreational nature on the territory of the Russian Federation and foreign countries (see Information letter of the Chief sanitary doctor of the Russian Federation, G. Onishchenko from 22.02.2013, No. 01/1990-13-32 "Forecast epidemiological situation of West Nile virus for 2013").

The expansion of the distribution of West Nile virus and the increase in the incidence encourages researchers and developers to search for and production of effective nonspecific antiviral drugs against this infection. However, attempts to study the effectiveness of individual compounds in vitro and in vivo (see Odelola H. A. Antiviral activity of Virazole, on the replication of viruses isoleted in Nigeria. In: Siegenthaler W., Lathy R. editors. Current chemotherapy. Vol.1. Washington: American Society of Microbiology. - 1978. - Vol.1. - P. 3343-3345; I. Jordan, T. Briese, N. Fisher et al. Ribavirin inhibits West Nile virus replication and cytopathic effect in neural cells // J. Infect. Dis. - 2000. - Vol.182. - P. 1214-1217. Shahar, A., Lustig, S., y Akov et al. Different pathogenicity of encephalitic togaviruses in organotypic cultures of spinal cord slices // J. Neurosci. Res. - 1990. - Vol.25. - P. 345-352. Anderson J. F., J. J. Rahal. Efficacy of interferon alpha-2b and ribavirin against West Nile virus in vitro // Emerg. Inf. Dis. - 2002. - Vol.8, n.1. - P. 107-108; Loginov, S. I., Kovalchuk, A. C., Borisevich, S. W. and others; Antiviral efficacy of interferon inducer of Amiksin against experimental forms of Fever Reserves the Nile // Matters. virusol. - 2004. No. 2. - S. 14-17; Loginov, S. J., Borisevich, S. C., Pashchenko Y. I., B. N. Bondarev Prevention and therapy of experimental forms of West Nile Fever // Antibiot. and Himyar. - 2009. Tom. 54, No. 11-12. - S. 17-20, Loginov, S. J., Borisevich, S. C.; Maksimov, C. A., B. N. Bondarev toxicity Assessment of nonspecific antiviral medical funds intended for the prevention and treatment of dangerous and especially dangerous viral infections // Antibiot. and Himyar. - 2009. Tom. 54, No. 3-4. - S. 11-14.), has led to their use in the treatment of West Nile virus.

Considering the above, the search and development of new effective means for the prevention and treatment of West Nile virus, are relevant.

In a wide range of synthetic drugs exhibiting antiviral activity, a significant place is occupied isoleucine containing in the structure of the molecule bridging nitrogen atom.

The prior art thiadiazolidine active against hepatitis b virus, Coxsackie virus (see A. M. Demchenko, C. C. Sour, H. B. Vacheva, M. O. Lozinskii. Synthesis and antiviral activity of derivatives [1,3,4]thiadiazolo[2,3-C][1,2,4]triazine. Journal of the organic farmaceutyczny chemistry, 2003, T. 1, vol.1-2, PP 55-58; M. A. El-Badawi, A. A. El-Barbary, Y. M. Lokshaa, Mai El-Daly. Synthesis and biological evaluation of some novel N,N'-bis-(1,2,4-Triazin-4-yl)dicarboxylic acid amides and some fused rings with 1,2,4-triazine ring. Phosph., Sulfur, Silicon and the elated Elements, 2002, V. 177, pp.587-596).

Antiviral activity against herpes have pyrazolo[5,1-C][1,2,4]triazine (G. Bravi, A. Goretti Cheasty, J. A. Corfield, R. M. Grimes. 4-Carboxy pyrazole derivates as antiviral agents. WO 2007039146; F. A. Attaby, A. H. Elghandour, M. A. Ali, Y. M. Ibrahem. Synthesis, reactions, and antiviral activity of 1-(1h-pyrazolo[3,4-b]pyridin-5-yl)ethanone and pyrido[2',3':3,4]pyrazolo[5,1-c][1,2,4]triazine derivatives. Phosph., Sulfur, Silicon and Related Elements, 2006, v.181, No. 5, pp.1087-1102).

Antiviral activity against influenza and herpes have triazolo[5,1-C]-1,2,4-triazine (V. A. Plastunov, M. M. Kozlovs'kii, L. V. Benzel, G. V. Bilets'ka, I. M. Lozins'kii,; E. G. Rogochii, Sholomei, M. D. L viv. NDI Epidemiol. ta Gigieni. Mikrobiologichnii Zhurnal. 2001, 63, №2, 14-19; C. L. Rusinov, E. N. Ulanski, O. N. Chupakhin, M. M. Zubairov, A. B. Kapustin, N. And. Mitin and other Synthesis and antiviral activity of 6-nitro-7-oxo-4,7-dihydrooxazolo[5,1-C][1,2,4]triazines. Chemical and pharmaceutical journal. 1990, No. 9, S. 41-44).

Analysis of the known technical solutions showed that analogs of 1,2,4-triazolo[1,5-and]triazines-1,2,4-triazolo[1,5-and]pyrimidines are promising area of the search for new antiviral compounds.

The closest in structure and show antiviral activity of the claimed compound (prototype) is the sodium salt of 2-methylthio-6-nitro-7-oxo-[5,1-C]-1,2,4-triazine-7-(4H)-she, having the formula

(see RF patent №2294936 invention "Sodium salt of 2-methylthio-6-nitro-1,2,4-triazolo[5,1-C]-1,2,4-triazine-7(4H)-it, dehydrate, about laduma antiviral activity", filing date 29.06.2005, published 10.03.2007,).

The technical result, which is aimed by the invention is the creation of new effective tools esaleasing series with antiviral activity against a group of RNA-containing viruses, and reducing the dependence of active connections from cellular metabolism.

This technical result is achieved by the fact that the new drug 2-methylsulfanyl-6-nitro-7-oxo-1,2,4-triazolo[5,1-C][1,2,4]triazine L-arginine the dihydrate, which has antiviral activity and having the formula

This technical result is achieved in that a method of obtaining 2-methylsulfanyl-6-nitro-7-oxo-1,2,4-triazolo[5,1-c][1,2,4]triazine L-arginine dehydrate, including the mixing of dissolved arginine and dissolved in water-ethanol mixture (1:1) 2-methylthio-6-nitro-7-oxo-1,2,4 triazolo[5,1-C]triazine sodium dihydrate, after which the resulting mixture is boiled on a water bath, then cooled, precipitated precipitate is filtered off and dried.

Technical solutions, which coincides with the set of essential features of the claimed invention, is not revealed, which allows to make a conclusion on the compliance of the claimed invention to such a condition of patentability as "novelty".

The home is Jaimie essential features determining receipt of the indicated technical result that is explicitly not follow from the prior art, which allows to make a conclusion on the compliance of the claimed invention to such a condition of patentability as "inventive step".

The condition of patentability "industrial applicability" is confirmed by examples of specific applications.

The technical problem solved by modification of the molecules of the sodium salt of 2-methylthio-6-nitro-7-oxo-[5,1-c]-1,2,4-triazine-7-(4H)-it is, in particular, replacement of the cation sodium biogenic amino acid argeninian fragment.

Synthesis of 2-methylsulfanyl-6-nitro-7-oxo-1,2,4-triazolo[5,1-c][1,2,4]triazine-arginine dihydrate is as follows:

In a round bottom flask of 50 ml volume, equipped with a heating bath, stirrer and reverse ball refrigerator with water cooling, load 2.1 g (0.01 mol) of arginine, add 9 ml of water and at room temperature with stirring, bring the mixture until complete dissolution. Then in another round bottom flask of 50 ml volume, equipped with a heating bath, stirrer and reverse ball refrigerator with water cooling, loads of 2.53 g (0.01) mol 2-methylthio-6-nitro-7-oxo-1,2,4-triazolo[5,1-C]triazine sodium dihydrate, add 20 ml of water-ethanol mixture (1:1) and heated to t is mperature 20-25°C. the mixture is brought to dissolution.

The obtained solutions merge with each other and heated in a water bath for 10 minutes at a temperature of 90-95°C. the Reaction mass is then cooled, precipitated is filtered off the precipitate, which is then dried at room temperature for one day (24 hours).

The compound obtained 2-methylthio-6-nitro-7-oxo-1,2,4-triazolo[5,1-C][1,2,4]triazine L-arginine the dihydrate has the following physicochemical characteristics: TPL>300°C; Found C - 30,30%, N - 4,86%, N - 32,08%. Brutto-formula - C11H18N10O5S*2H2O. Calculated: 30,14%, N Of 5.06%, N - 31,95%. Range1H NMR (400 MHz, D2O), δ (ppm): 1.702 flats totally (m, 2H, CH2), 1.918 (m, 2H, CH2), 2.651 (C., 3H, SCH3), 3.245 (m, 2H, CH2), 3.786 (m, 1H, CH).

The claimed compound is a yellow amorphous substance, soluble in water, dimethylformamide, dimethylsulfoxide, and insoluble in chloroform, ethanol, benzene.

The implementation of the claimed invention is confirmed by examples of specific performance.

Example 1

Evaluation of the cytotoxicity of the compounds with the use of continuous cell culture GMK-AH (1D).

For the formation of a continuous monolayer tube was introduced into 1 ml of cell suspension with a density of 200 thousand/ml, incubated at a temperature of (37,0±0,5)°C, 5% CO2. Then the growth medium was removed and made fresh medium containing different the concentrations of the investigational product (from 1000 to 6.25 µg/ml). Then the tubes were incubated for 5 days at a temperature of (37,0±0,5)°C, 5% CO2. Using the light microscope, observed the state of the monolayer of cells: partial or complete destruction of the monolayer of cells, damage to individual cells, the formation of cell syncytium. Control samples were tubes monolayer, which was made supportive environment without the drug.

The results of the evaluation of the cytotoxicity of the compounds indicate that substance the active substance in a concentration of 500 μg/ml does not cause visible changes in cell cultures (see table 1).

Table 1
The study of the cytotoxicity of the claimed compounds in the cell culture GMK-AH (1D)
MedicationThe frequency of the cytopathic effect in the application of the claimed compounds in concentration, µg/mlCPD, ug/mlIPC mg/ml1/2 BMD, mg/ml
1000,0500,0250,0125,062,5 31,315,57,8
The claimed connection2/40/40/40/40/40/40/40/41000,0500,0250,0

Example 2

Study of the effectiveness of the substance in respect of West Nile virus in cell culture GMK-AH (1D).

The monolayer cell culture GMK-AH (1D) infected with the West Nile virus at a dose of 0.05 PFU/cell. The adsorption of the virus was carried out at 37°C, 5% CO2within 60 minutes after incubation, the monolayer washed three times supporting medium containing 100 units/ml penicillin and streptomycin, to remove not absorbirowawrzegosa virus and contributed tested compound concentration, part 1/2 of the IPC. The substance was dissolved in supporting nutrient medium to the desired concentration. For each connection used at least 10 tubes with a monolayer of cells. Incubation was carried out at 37°C, 5% CO2within 48 hours. Next were cryosurgery cells and combined samples. Infectious titers in pooled samples op is delali titration method for forming negative colonies under agar plated in cell culture GMK-AH (1D).

The results of the study of antiviral activity of the claimed compounds indicate that the drug suppresses the reproduction of the virus 3H on 2,31 g, while the ratio of inhibition was 99.5% (see table No. 2).

Table 2
To study the efficacy of the inventive compounds in the cell culture GMK-AH (1D) in respect of the West Nile virus
MedicationThe concentration of the claimed compounds, mg/mlThe level of accumulation of the virus, lg PFU/mlReducing the accumulation of virus, lg PFU/mlThe ratio of inhibition of virus reproduction, percentage
The claimed connection250,04,22,399,5
It dose-7,8--

Thus, the claimed chemical compound is not toxic in the concentrations used, has significant antiviral activity in vitro against virus West Nile is.

1. 2-Methylsulfanyl-6-nitro-7-oxo-1,2,4-triazolo[5,1-C][1,2,4]triazine L-arginine the dihydrate, which has antiviral activity and having the formula

2. The method of obtaining 2-methylsulfanyl-6-nitro-7-oxo-1,2,4-triazolo[5,1-C][1,2,4]triazine L-arginine dehydrate under item 1, comprising mixing the dissolved arginine and dissolved in water-ethanol mixture (1:1) 2-methylthio-6-nitro-7-oxo-1,2,4-triazolo[5,1-C]triazine sodium dihydrate, after which the resulting mixture is boiled, then cooled, precipitated precipitate is filtered off and dried.

3. Application 2-methylsulfanyl-6-nitro-7-oxo-1,2,4-triazolo[5,1-c][1,2,4]triazine L-arginine dehydrate under item 1 for the prevention and treatment of West Nile Fever.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of structural formula

possessing inhibitory activity on BTK, TEC, BMX, ITK, ErbB1, ErbB4 and/or JAK3 kinases. In formula (I-b), ring A and ring B represents phenyl; Ry represents -CN, -CF3, C1-4 aliphatic group, C1-4 halogenaliphatic group, -OR, -C(O)R or -C(O)N(R)2; each group R independently represents hydrogen or a group specified in C1-6 aliphatic group optionally containing a substitute presented by halogen, -(CH2)0-4R°, -(CH2)0-4OR°, -(CH2)0-4N(R°)2, -(CH2)0-4N(R°)C(O)OR°, -(CH2)0-4C(O)R°, -(CH2)0-4S(O)2R°, or 5-6-merous substituted or aryl ring containing 1-2 heteroatoms independently specified in nitrogen or oxygen optionally substituted by group =O, -(CH2)0-4R°, -(CH2)0-4N(R°)2 or -(CH2)0-4OR°; phenyl; 5-6-merous heterocyclic ring containing 1-2 heteroatoms independently specified in nitrogen, oxygen or sulphur optionally substituted by group -(CH2)0-4R°, -(CH2)0-4OR° or =O; or 6-merous monocyclic heteroaryl ring containing 1 nitrogen atom; W1 and W2 represent -NR2-; R2 represents hydrogen, C1-6aliphatic group or -C(O)R; m and p are independently equal to 0, 1, 2, 3 or 4; Rx is independently specified in -R, -OR, -O(CH2)qOR or halogen, wherein q=2; Rv is independently specified in -R or halogen; R1 and R° radical values are presented in the patent claim. The invention also refers to a pharmaceutical composition containing the above compounds.

EFFECT: preparing the compounds possessing the inhibitory activity on BTK, TEC, BMX, ITK, ErbB1, ErbB4 and/or JAK3 kinases.

17 cl, 25 dwg, 20 tbl, 286 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described new compounds of formula I or their pharmaceutically acceptable salts, wherein R1 means phenyl once or twice substituted by C1-6 alkyl, C1-6 alkoxy, halogen or 5-6-merous heteroaryl; R2 is phenyl once or twice substituted by C1-6 alkyl, C1-6 alkoxy, halogen, halogen-C1-6alkyl, halogen-C1-6alkoxy, C1-6 alkylsulphonyl, nitrile, etc. R3 means H or C1-6 alkyl; X - -O-, -NRa-,-S(O)m- or CRbRc, wherein Ra - H, C1-6 alkyl or C1-6 alkylcarbonyl; Rb and Rc mean H or together with the atom to which they are attached, form 5-merous cycle additionally containing 2 oxygen atoms; m is equal to 0-2; Y means -NRc-, wherein Rc - H or C1-6 alkyl.

EFFECT: compounds can find application in medicine for treating autoimmune and inflammatory diseases related to P2X7 purinoceptor.

15 cl, 1 tbl, 10 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I, possessing a modulating action with respect to the CC chemokine receptor 3 (CCR3), a based on them pharmaceutical composition, versions of treatment methods and a method of controlling the CCR3 activity. In the general formula I R1 and R2 represent halogen or C1-6alkyl; R3 represents cyano or nitro; R4 represents or ; R5 represents oxo; C1-6alkyl, optionally substituted with halogen atoms; or C(O)OR1a; X represents O or S; Y represents -O-, -S-, -N(R1a)-, -C(R1a)(R1d)- or -C(R1a)(NR1bR1c)-; m represents an integer number from 0 to 2; n represents 1; p represents an integer number from 0 to 2; r represents 1 or 2; and each R1a, R1b, R1c and R1d represents (a) hydrogen; (b) C3-7cycloalkyl; or (c) C1-6alkyl, optionally substituted with hydroxyl, or each pair R1b and R1c together with a N atom, which they are bound to, form imidazoimidazolyl, substituted with oxo, butyl or chlorine, or heterocycle, containing 5 or 6 atoms in a cycle.

EFFECT: improvement of the composition properties.

41 cl, 2 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the field of organic chemistry, namely to benzoimidazole derivatives of formula (I), as well as to their enantiomers, diastereoisomers, racemates and pharmaceutically acceptable salts, where n equals from 2 to 4, each of R1 substituents is independently selected from H, halogen, -C1-4alkyl, -C1-4pergaloalkyl, trifluoro-C1-4alkoxy, -NO2, -CN, CO2H, -OC1-4alkyl, -SC1-4alkyl, -S(C1-4alkyl)-Rc, -S(O)2(C1-4alkyl)-Rc, -S(O)-C1-4alkyl, -SO2-C1-4alkyl, -S-Rc, -S(O)-Rc, -SO2-Rc, -SO2-NH-Rc, -O-Rc, -CH2-O-Rc, -C(O)NH-Rc, -NRaRb, benzyloxy, phenyl, optionally substituted with one-two Rd, cyanobiphenyl-4-ylmethylsulpfanyl, cyanobiphenyl-4-ylmethanesulphonyl, or -S-(CH2)2-morpholine and two adjacent groups R1 can bind with formation of an aromatic 5-6-membered ring, optionally substituted with one methyl group or two atoms of halogen, optionally containing one or two S or N; Ra and Rb each independently represents C1-4alkyl, -C(O)C1-4alkyl, -C(O)-Rc, -C(O)CH2-Re, C1-4alkyl-Re, -SO2-Rc, -SO2-C1-4alkyl, phenyl, benzyl; or Ra and Rb together with a nitrogen atom, which they are bound with, form a monocyclic 5-6- membered heterocycloalkyl ring, optionally containing one heteroatom, selected from O; Rc represents -C3-8cycloalkyl, phenyl, optionally substituted with one-two Rd, benzyl, optionally substituted with one-three Rd; morpholine; Rd independently represents halogen, -OH, -C1-4alkyl or -C1-4perhalogenalkyl, trifluorine C1-4alcoxy, -OC1-4alkyl, or -O-benzyl optionally substituted with halogen, Re represents -C6heterocycloalkyl, optionally containing one or two of O or N atoms, optionally substituted with a methyl group; R2 and R3 both represent H, -CF3 or C1-3alkyl; each of Z represents a C or N atom, on condition that simultaneously not more than two Z represent N. The invention also relates to particular compounds, a pharmaceutical composition, based on formula (I) compound or a particular said compound, a method of treating diseases, mediated by propyl hydroxylase activity.

EFFECT: novel derivatives of benzimidazole, possessing an inhibiting activity with respect to PHD are obtained.

11 cl, 1 tbl, 186 ex

FIELD: chemistry.

SUBSTANCE: invention relates to (3aR,6aR)-N-(4-(3-ethylphenylamino)-7-methoxyquinazolin-6-yl)-1-methylhexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxamide or its pharmaceutically acceptable salt, as well as to a pharmaceutical composition for treatment of the cancer disease, sensible to inhibition of hyper-expression and/or hyperactivity of a receptor of an epidermal growth factor, which contains the claimed compound, a method of the cancer disease treatment, a method of inhibition and to the application of the claimed compound for a drug preparation.

EFFECT: (3aR,6aR)-N-(4-(3-ethylphenylamino)-7-methoxyquinazoline-6-yl)-1-methylhexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxamide, which shows an inhibition activity to hyperexpression and/or hyperactivity of the epidermal growth factor receptor.

12 cl, 4 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel 5-methyl-6-nitro-7-oxo-4,7-dihydro-1,2,4-triazolo[1,5-α]pyrimidinide l-argininium monohydrate of formula (1) The compound has antiviral activity with respect to group A and B strain viruses in in vitro and in vivo systems.

EFFECT: compound has low toxicity.

4 dwg, 3 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to quinazolinone compounds of formula (I) and its pharmaceutically acceptable salts, wherein n is equal to 0 to 3, and R1 is defined as stated in the patent claim. The above compounds are prolyl hydroxylase inhibitors and can be used in pharmaceutical compositions and methods of treating pathological conditions, disorders and conditions mediated by prolyl hydroxylase activity.

EFFECT: compounds can be administered into the patient for treating, eg anaemia, vascular diseases, metabolic disorders, as well as for wound healing.

22 cl, 2 tbl, 211 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I), wherein A means morpholinyl, 1,4-oxazepamyl, piperidinyl, pyrrolidinyl or azetidinyl which is bound to N; R1 means C1-C6-alkyl group; R2 means bicyclic aryl group specified in 1H-indolyl, 1H-pyrrolo[3,2-b]pyridyl, quinolyl, naphthyl, 1H-pyrrolo[2,3-b]pyridyl, 5H-pyrrolo[3,2-d]pyrimidinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, benzo[b]thiophenyl, imidazo[1,2-a]pyridyl, benzo[b]thiazolyl, 5H-pyrrolol[2,3-b]pyrazinyl and quinoxalinyl which can be substituted by R4; R3 means hydrogen or halogen atom; R4 means C1-C6-alkyl group, C1-C6-halogenalkyl group, OR1A, halogen, -(CH2)aOH, CN, NHCOR1A, SO2R1A or NHSO2R1A; R5 means C1-C6-alkyl group, -(CH2)aOH, -(CH2)aOR1B, halogen or CONH2; provided p is a plural number, R5 can be identical or different, or R5 can be combined with another R5; each of R1A and R1B independently means C1-C6-alkyl group; a is equal to 0, 1 or 2; n is equal to 1 or 2; p is equal to 0, 1, 2, 3, 4 or 5. Besides, the invention refers to intermediate compounds of formulas (IA) and (IB) for preparing the compounds of formula (I), to a preventive or therapeutic agent containing the compounds of formula (I), pharmaceutical compositions, using the compounds of formula (I) and to a method for preventing or treating diseases.

EFFECT: compounds of formula (I) as selective 5-HT2B receptor antagonists.

11 cl, 1 dwg, 18 tbl, 88 ex

FIELD: chemistry.

SUBSTANCE: there are described new derivatives of imidazo[1,2-b][1,2,4,5]tetrazines of general formula (I) wherein: Het=4-methylimidazol-1-yl, R=H or Het=3,5-dimethylpyrazol-1-yl, R=propylthio, and based anticancer agents for treating oncological patients.

EFFECT: higher clinical effectiveness.

2 cl, 1 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds or their pharmaceutically acceptable salts, where compound has formula 1-a, in which R1 and R3 are absent, m represents integer number from 1 to 2, n represents integer number from 1 to 3, A represents , B represents or , where X2 represents O or S, R4a is absent, R4b is selected from the group, consisting of: , , , , and ; Rk is selected from C1-6alkyl and C1-6halogenalkyl, L and E are such as given in i.1 of the invention formula; or compound is such as given in b) of i.1 of the invention formula. Invention also relates to pharmaceutical composition, which contains said compounds.

EFFECT: compounds by i1, possessing inhibiting activity with respect to anti-apoptosis protein Bcl-XL.

27 cl, 6 dwg, 2 tbl, 126 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula wherein each of R1 and R2 is independently selected from a group consisting of a hydrogen atom, nitro and NR6R7; R3 is C1-C8alkyl; each of R4 and R5 is independently selected from a group consisting of C1-C8alkoxy, phenoxy and phenyl(C1-C8alkylene)oxy; each of R6 and R7 is independently selected from a group consisting of a hydrogen atom, C1-C8alkyl, C(O)R8 and SO2R8;R8 is selected from a group consisting of a hydrogen atom, C1-C8alkyl, halogen-substituted C1-C8-alkyl, C1-C8-alkyl, substituted (C1-C8-alkylsubstituted amino), C1-C8-alkyl, substituted with piperidine and C1-C8-alkyl, substituted with morpholine.

EFFECT: reduced PDE4 enzyme activity and treating PDE4 enzyme mediated diseases or conditions.

21 cl, 2 tbl, 32 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel cocrystals of niflumic acid with isonicotinamide or caffeine, where molar ratio of niflumic acid with isonicotinamide or caffeine constitutes 1:1, and cocrystal of niflumic acid with isonicotinamide has entothermic peak from 152 to 162°C according to the data of measurement by means of differential scanning calorimetry and peaks at 2θ(°) 6.3, 7.4, 12.5, 14.5, 19.2, 23.2, 25.0 by the data of measurement of X-ray radiation difraction on powder, and cocrystal of niflumic acid with caffeine has endothermic peak from 155 to 165°C by the data of measurements by means of differential scanning calorimetry and peaks at 2θ(°) 9.7, 12.0, 13.26, 14.3, 17.0, 18.1, 22.5, 26.2 and 26.9 by the data of measurement of X-ray radiation diffraction on powder.

EFFECT: increase of solubility in water in comparison with indices of niflumic acid solubility in pure form.

12 dwg, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I) and (II), which possess the blocking activity on voltage-sensitive sodium channels, such as TTX-S channels, and their pharmaceutically salts. In general formula (I) and (II), R1 represents -CF3, -CHF2, -OCF3, -OCHF2, -OCH2CHF2/ -OCH2CF3, -OCF2CHF2; -OCF2CF3, -OCH2CH2CF3, -OCH(CH3)CF3, -OCH2C(CH3)F2, -OCH2CF2CHF2, -OCH2CF2CF3, OCH2CH2OCH2CF3, -NHCH2CF3, -SCF3, -SCH2CF3, -CH2CF3 -CH2CH2CF3, -CH2OCH2CF3 and -OCH2CH2OCF3; R2 is specified in (1) hydrogen, (2) halogen (3) -On-C1-6 alkyl, (4) -On-C3-6 cycloalkyl, (5) -On-phenyl, (6) -On-heterocyclic group, (7) -NR7 (C=O)R8; wherein n is equal to 0 or 1, p is equal to 1, 2; R3 and R4 represents hydrogen or C1-6 alkyl, X represents carbon atom; Y represents hydrogen or C1-6 alkyl; Ar represents 4-pyridyl, 4-pyrimidyl or 6-pyrimidyl, which is substituted in the 2nd position by a substitute, which is independently specified in (1) -(C=O)-NR7R8, (2) -NR7(C=O)R8; R9 is specified in: (1) hydrogen, (2) halogen, (3) -On-C1-6 alkyl, wherein alkyl is unsubstituted or substituted by hydroxyl; q is equal to 1, 2 or 3; R10 independently represents hydrogen, C1-6 alkyl, C2-6alkenyl, C3-7 cycloalkyl or phenyl, which is unsubstituted or substituted by one or substitutes independently specified in hydroxyl, -On-C1-6 alkyl and -C3-7 cycloalkyl.

EFFECT: preparing the compounds possessing the blocking activity on voltage-sensitive sodium channels.

7 cl, 2 tbl, 1281 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a new compound, namely to (S)-enantiomer of 1'-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxol-7,3'-indole]-2'(1'H)-one of formula (I), and a method for preparing it which is effective for treating diseases and conditions, such as pain, an intensity of which can be reduced or relieved by modulating potential-dependent sodium channel gatings.

EFFECT: invention refers to the pharmaceutical composition of the above compound, methods of treating and a method of relieving an ion flux through the potassium channel gating in a cell.

10 cl, 5 tbl, 6 dwg, 11 ex

FIELD: medicine.

SUBSTANCE: agent possessing the anti-inflammatory, antipyretic and antimicrobial action representing a dry extract of drug hedge hyssop leaves and blossom by grinding them, extracting in 96% alcohol on a water bath to a boil, and boiling, evaporating, diluting the evaporated residue by distilled water first, adding chloroform then, cooling to a room temperature and centrifuging, separating a water fraction and drying it in the certain environment.

EFFECT: agent possesses the pronounced anti-inflammatory, antipyretic and antimicrobial action.

5 dwg, 5 tbl, 2 ex

FIELD: biotechnology.

SUBSTANCE: invention is a composition having antibacterial, immunostimulating, anti-allergic and anti-inflammatory action, containing bacterial waste products useful for human body, in the form of exometabolites and fermentolysis products, characterised in that it is a culture medium of lactic acid bacteria, containing laxarane in an amount of 5-10 g/ml, caseicyne, isracydine or their mixture and lectins in an amount of 0.05-2.5 mol/l, histamine in an amount of 0.8-2.0 mmol/l and monocarboxylic fatty acid with an unbranched chain, namely, acetic acid, propionic acid, butyric acid and valeric acid - in an amount of 10-20 mg/ml.

EFFECT: expanding the range of agents having complementary antibacterial, immunomodulating, anti-allergic and anti-inflammatory action.

4 cl, 5 ex

FIELD: medicine.

SUBSTANCE: presented group of inventions refers to medicine. What is presented is a method of treating visceral pain and/or one or more symptoms of visceral pain, involving administering a therapeutically effective amount of an antagonist antibody against calcitonin gene-related peptide (CGRP) into an individual suffering visceral pain, or an individual suffering a risk of visceral pain, wherein the CGRP agonist antibody is applicable for peripheral administration. What is also presented is a pharmaceutical composition containing the CGRP agonist antibody and a pharmaceutically acceptable carrier, applicable for peripheral administration.

EFFECT: presented group of inventions provides the effective treatment of visceral pain with using no opiates.

18 cl, 3 dwg, 2 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to lambertianic acid amides of formula (Ia, b), which have expressed analgesic activity and stimulating action, manifested in increase of motor and investigation activity of animals, absence of anxiety, etc. In formula I ; (Ib).

EFFECT: improvement of compound properties.

6 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: in general formula

A represents optionally substituted aminocarbonyl group -N-C(O)-, in which amino group can be substituted and substituents can be selected from hydrogen, C1-C5alkyl, possibly substituted with C1-C3alkoxy, C3-C6cycloalkyl, 5-6-membered heteroaryl, in which heteroatoms are selected from oxygen or nitrogen; aryl, selected from phenyl, possibly substituted with hydroxy, C1-C5alkyl, C1-C5alkoxy, halogen, C1-C5acylamino group, or naphthyl; or amino group is selected from C3-C7heterocyclyl, containing 1-2 heteroatoms in cycle, selected from nitrogen, oxygen or sulphur, possibly substituted with hydroxy, C1-C3alkyl, benzyl, phenyl, which can be substituted with halogen, and said heterocyclyl can be condensed with benzene ring; acylamino group, in which acyl is selected from C1-C6alkylcarbonyl, where alkyl can be substituted with phenyl, substituted with phenyl, in which substituents are selected from C1-C5alkoxy; 5-membered heteroaryl with heteroatom, selected from atom of oxygen or sulphur; benzoyl, possibly substituted with C1-C5alkyl, C1-C5alkoxy, C1-C5alkylthio or halogen, methylenedioxy; heterocyclylcarbonyl, in which heterocyclyl is selected from 5-6-membered heterocyclyl, with 1-2 heteroatoms, selected from nitrogen, oxygen or sulphur, possibly condensed with benzene ring and possibly substituted with C1-C5alkyl, halogen; or ureido group, in which one of substituents of terminal amido group represents hydrogen, and the second substituent is selected from: C1-C3alkyl, substituted with phenyl, 5-membered saturated or aromatic heterocyclyl, in which heteroatoms are selected from oxygen or sulphur; C2-C6alkenyl; aryl, selected from phenyl, substituted with C1-C5alkyl, C1-C5alkoxy, ethylenedioxy, methylenedioxy, halogen, C1-C3alkylcarbonyl; 5-membered heterocyclyl, in which heteroatoms are selected from sulphur or oxygen atom, and possibly substituted with alkyloxycarbonyl group; B represents non-aromatic cyclic substituent, selected from C4-C6cycloalkyl; and has other values, given in the invention formula. Values R1a R1b R1c are given in the invention formula.

EFFECT: increased efficiency of application of compounds.

12 cl, 8 tbl, 13 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new crystalline forms of acid addition salts of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, wherein the acid is specified in methanesulphonic, maleic, fumaric, citric, orotic, 10-camphor sulphonic acids and fencifose. The salts possess the agonist properties of neuronal nicotine receptor (NNR) and can be used for managing or preventing pain, an inflammation or a CNS disorder. Each of the crystalline salts is characterised by an X-ray powder diffraction diagram. The invention also involves an amorphous form of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine monocitrate and polymorphic forms of the above crystalline salts.

EFFECT: invention refers to a pharmaceutical composition containing an effective amount of the presented salts.

19 cl, 8 dwg, 33 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

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