Agent for inactivating dna viruses
SUBSTANCE: disclosed is an agent which is one of the derivatives of N-substituted 1,4-diazabicyclo[2.2.2.]octane, which exhibits antiviral activity on DNA viruses. The disclosed agent can be used in veterinary and healthcare.
EFFECT: higher antiviral activity towards DNA viruses.
6 dwg, 3 tbl, 7 ex
The invention relates to the field of chemistry and Biomedicine, namely by means of exhibiting antiviral activity against DNA viruses.
Viral diseases are a common threat to public health worldwide. Viruses containing gene in the DNA, causing a number of serious diseases of animals (domestic and wild) and are among the most dangerous to humans. DNA viruses have the ability to transform cells that they infect. So, papilloma viruses are the etiological factor in cervical tumors (Adams, M. et. al, Vaccine, 2007, 25(16), 3007-3013), hepatitis b virus is associated with liver tumors (Chu, CM., J Gastroenterol Hepatol., 2000, E25-30), Epstein-Barr associated with cancer of the nasopharynx and Burkitt's lymphoma (Moormann, AM. et al, Curr Opin Infect Dis., 2011, 24(5), 435-41), and herpes virus type 8 is associated with Kaposi's sarcoma (Cai Q, et al., Adv Virus Res. 2010, 78, 87-142).
The risk of diseases caused by DNA viruses, makes the development of new antiviral drugs and new tools and methods of inactivation of one of the most pressing problems of the day.
Currently, as a means of inactivation of viruses use physical methods (irradiation with UV light, ionizing radiation, heating at high pressure) and a number of chemical compounds (formaldehyde, β-propiolactone, e is elenkin, some detergents), which differ in the mechanism of action and, therefore, the scope of application, toxicity, efficacy of inactivation of the virus and value (De Benedictis, P. et al. Zoonoses Public Health. 2007, 54(2), 51-68).
Range of compounds, allowing to inactivate the virus, including to obtain televizionnyh vaccines, limited to a few compounds: formaldehyde, secondary ethylenimine (Hulskotte E.G.J., Vaccine, 1997, 15, 1839-1845), kaprilat (Korneyeva M et.al, Biologicals, 2002, 30, 153-162), oxidized polyamine (Bachrach U., Amino Acids, 2007, 33(2), 267-272), irradiation with long-wave UV light in the presence of compounds that increase the photosensitivity of the virus (C.V. Hanson, et.al., J. gen. Virol., 1978, 40, 345-358; Specht, K.G., Photochem Photobiol., 1994, 59, 506-514). It is known that the treatment of the virus such compounds leads to the partial destruction of viral antigenic determinants and thus to reduce immunogenic properties of the vaccine, and selective destruction of formalin antigenic determinants of the surface glycoproteins of viruses can induce the development of an unbalanced immune response (Kasermann F., et al., Antiviral Res., 2001,52, 33-41).
The most closest to the claimed means the prototype is a tool that represents 1,4-diazabicyclo[2.2.2.]octane General formula Dxn high ribonuclease activity (N.Koval'ov, et al., Nucleosides, Nucleotides and Nucleic Acids. 2004, 32, 981-985.) Figure 1 presents the structural forms of the La connection Dxn, where n=1, 4, 6, or 12 x - position in the benzene ring is an ortho, meta or para.
However, in the available literature there is no information about the antiviral activity of a known drug against DNA viruses.
The task of the invention to provide an effective, non-lethal means, which has antiviral activity against DNA viruses.
The problem is solved by application of the known derivatives of N-substituted 1,4-diazabicyclo[2.2.2.]octane General formula (I):
where n=3 for (1, 2), n=1 (3); AKm: histamine (1), histidine (2), decroly ether glutamyl-glycyl-lysyl-glycine (3), have identified a new biological activity, consisting in antiviral activity against DNA viruses.
The figure 2 shows the structural formulas of compounds(1), (2), (3).
Known compounds (1-3) of General formula (I) were obtained according to the General scheme presented in figure 3.
The process of obtaining the claimed known compounds involves the reaction of monosubstituted 1,4-diazabicyclo-[2.2.2]octane (4) with 4-nitrophenylamino esters bromocarbons acids with the formation of activated nitrophenylamino ether derivative of 1,4-diazabicyclo-[2.2.2]octane, which further reacts with either commercially available histamine and histidine (1 and 2)or decyl the new air tetrapeptide Glu-Gly-Lys-Gly (Konevets DA, et al. 1999, Tetrahedron, 55, 503-512). In the synthesis of the peptide Glu-Gly-Lys-GlyA2 use activated N-hydroxysuccinimide esters of amino acids. The introduction of tert-butyloxycarbonyl protection and synthesis of activated esters are conducted according to standard methods (Have, Accipere. The synthesis of peptides. Reagents and methods. Kiev: Naukova Dumka, 1987).
Comparative analysis of the proposed drug, representing derivatives of N-substituted 1,4-diazabicyclo[2.2.2.]octane General formula (I), and known compounds commonly used compounds, such as formaldehyde, UV light or Monomeric or secondary ethylenimine (Hulskotte E.G.J., Vaccine, 1997, 15, 1839-1845), showed that the proposed compounds have the following advantages:
1) the Inventive tool has antiviral activity against DNA viruses that can be considered as a promising disinfectant agent for use in veterinary medicine and healthcare.
2) the Claimed means allatoxin to humans and does not require special precautions (mask, gloves, work under the hood when working with him. In addition, the tool is stable when stored in the form of a concentrated aqueous solution or a solution in an aprotic solvents such as dimethyl sulfoxide.
3) the Claimed product has membranolytic activity, enabling the et to consider it as a promising agent against DNA viruses. Under "membranolytic" activity refers to the ability of the compounds to disintegrate lipid membranes, including membrane of the virion".
The search for sources of scientific-technical and patent literature showed that antiviral activity against DNA-containing viruses to derivatives of N-substituted 1,4-diazabicyclo[2.2.2.]octane General formula (I) in a known sources not described.
The invention is illustrated by the following examples.
Example 1. Getting 1-tetradecyl-4-γ-[N-(2-(imidazol-4-yl)-ethyl)-carbamyl]-propyl-1,4-diazoniabicyclo[2.2.2]octane dibromide (compound 1)
The scheme of synthesis of compound (1) is shown in figure 4. Bromide 1-tetradecyl-4-Aza-1-azoniabicyclo[2.2.2]octane (4) (1.95 g, 5 mmol) suspended in a solution of 1.51 g (5.25 mmol) of 4-nitrophenylamino ether γ-pamakani acid (5) in 10 ml of acetone. The mixture was shaken at 50°C for 70 hours, After cooling the precipitate othertable, washed with acetone and dried in vacuum. Output dibromide 1-tetradecyl-4-(4-nitrophenoxyacetic)propyl-1,4-diazoniabicyclo[2.2.2]octane 3.08 g (91%). A solution of 12 mg (0.11 mmol) of histamine and 11.1 mg (0.11 mmol) of triethylamine was added to a solution of 69.3 mg (0.1 mmol) dibromide 1-tetradecyl-4-(4-nitrophenoxyacetic)propyl-1,4-diazoniabicyclo[2.2.2]-octane in 1 ml of DMF. The mixture was stirred at 45°C for 12 h, evaporated in vacuum to a volume of 0.2 ml and precipitated cont the CT acetone. For purification of the compound (1) was perioadele acetone from ethanol, the precipitate was filtered, washed with acetone and dried in vacuum. The yield of the desired product (30 mg (45%).
ES-TOF-MS: m/z found 244.76 [M-2Br]2+calculated 244.72.
Example 2. Getting 1-tetradecyl-4-[N-(1-carboxy-2-(imidazol-4-yl)-ethyl)-carbamyl]-propyl-1,4-diazoniabicyclo[2.2.2]octane dibromide (2)
The compound (2) was obtained by the method described in example 1, using instead of histamine methyl ester of histidine (37 mg, 0.22 mmol) and 138 mg (0.2 mmol) of the activated ester (5). Yield 66 mg (47%).
Next, the resulting conjugate (2) was dissolved in a mixture of ethanol/water/triethylamine 4:5:1 (v/v/v) and kept at 50°C for 12 h the Solution was evaporated to dryness, the residue triturated with acetone. The quantitative output.
The total yield of 1-tetradecyl-4-[N-(1-carboxy-2-(imidazol-4-yl)-ethyl)-carbamyl]-propyl-1,4-diazoniabicyclo[2.2.2]octane dibromide was 47%.
ES-TOF-MS: m/z found 532.46 [M-2Br]+calculated 532.42.
Example 3. Obtaining n-delovogo ether (1-tetradecyl-1,4-diazoniabicyclo[2.2.2]Oct-4-yl)-acetyl glutamyl-glycyl-lysyl-glycine (3)
The scheme of synthesis of compound (3) is shown in figure 5. Nα-Boc-glycine (11) (28 mmol, 5 g) was dissolved in 15 ml of ethyl acetate, was added N-ethyldiethanolamine (34 mmol, 5.8 ml) and 1-bramdean (9) (28 mmol, 5.9 ml). The reaction mixture is boiling the or under reflux during the day. Fallen bromohydrin N-ethyldiethanolamine was filtered. The resulting solution was washed sequentially with 2%citric acid solution (20 ml), water (20 ml), a saturated solution of NaHCO3(20 ml) and water (20 ml). The organic layer was dried anhydrous Na2SO4. The solvent was removed in vacuum. The Nα-Boc-Gly-OC10H21was dissolved in a mixture of TFA:CH2Cl2=1:1 (5 ml) and kept the reaction mixture for 1.5 h at room temperature. The solvent and excess TFA was removed in vacuo, the residue was evaporated with ethanol (3×10 ml). The resulting oil triturated with diethyl ether. The resulting white precipitate was filtered, dried in vacuum. The output of triptoreline delovogo ester of glycine 4.41 g, 47%.
To a solution of triptoreline delovogo ester of glycine (3 mmol, 1 g) and N-ethyldiethanolamine (7.6 mmol, 1.3 ml) in 10 ml of ethyl acetate was added with stirring a solution of N-hydroxysuccinimide ether Nα-Boc-Lys(Z(2Cl)) (3.6 mmol, 1.9 g) in 5 ml of ethyl acetate. After 2 hours the reaction mixture was added N,N-dimethylethylenediamine (1 mmol, 110 μl) and stirred 30 minutes, the Reaction mixture was washed successively with 2%citric acid solution (20 ml), water (20 ml), a saturated solution of NaHCO3(20 ml) and water (20 ml). The organic layer was dried anhydrous Na2SO4. The solvent was removed in vacuum. The oil obtained is astoral in a mixture of TFA:CH 2Cl2=1:1 (5 ml) and kept the reaction mixture for 1 h at room temperature. The solvent and TFA were removed in vacuo, the residue was evaporated with ethanol (3×10 ml), was dissolved in ethyl acetate (15 ml) and washed with saturated solution of NaHCO3(10 ml) and water (10 ml), dried over anhydrous Na2SO4. The solvent was removed in vacuum. The resulting substance in the form of foam was dried in vacuum. Output delovogo ether Z(2Cl)-lysyl-glycine 1.47 g, 95.0%.
Then repeated the process of condensation. Consistently pursued the reaction delovogo ether Z(2Cl)-lysyl-glycine (0.78 mmol, 400 mg) with N-hydroxysuccinimide ester of Boc-β-alanine (0.86 mmol, 246 mg), then with N-hydroxysuccinimide ester of Nα-Boc-Glu(Bzl) (0.82 mmol, 356 mg). A solution of the protected tetrapeptide (12) in ethyl acetate (15 ml) after removal of the Boc-protection was washed with saturated solution of NaHCO3(10 ml) and water (10 ml), dried anhydrous Na2SO4. The solvent was removed in vacuum. The resulting foam was dried in vacuum. Output Glu(Bzl)-β-Ala-Lys(Z(2Cl))-Gly-OC10H21per decroly ether Nε-Z(2Cl)-lysyl-glycine 463 mg, 74%.
H-decroly ether tetrapeptide Glu(Bzl)-Gly-Lys(Z(2Cl))-Gly (0.1 mmol, 80.0 mg) was dissolved in 1 ml of dry DMF, was added triethylamine (0.1 mmol, 14.2 ml). In the reaction mixture was added a suspension dibromide 1-tetradecyl-4-(4-nitrophenoxyacetic)methyl-1,4-diazoniabicyclo[2.2.2]-octane (8) (0.1 mmol, 660 mg) in 1 ml DMF. The reaction mixture was stirred at room temperature for 48 hours Product besieged from the reaction mixture 10-fold excess of diethyl ether. Loose white flocculent precipitate was separated by centrifugation, washed with ether and dried in vacuum. The output is protected conjugate (13) in the condensation reaction 47 mg, 35.8%.
The protected conjugate (13) (0.036 mmol, 47 mg) was dissolved in 10 ml of methanol and subjected to hydrogenolysis in the presence of 40 mg of 5%Pd/C. Upon completion of the reaction the catalyst was filtered, the solvent was evaporated in vacuum. The yield in the reaction of hydrogenation of 29.5 mg, 78.4%.
The total yield of n-delovogo ether (1-tetradecyl-1,4-diazoniabicyclo[2.2.2]Octan-4-yl)-acetyl glutamyl-glycyl-lysyl-glycine (3) in the calculation of tetrapeptide (with protected functional groups without Sun-protection) 28.1%. Data1H NMR spectrum for n-delovogo ether (1-tetradecyl-1,4-diazoniabicyclo[2.2.2]Octan-4-yl)-acetyl glutamyl-glycyl-lysyl-glycine (3) (CD3OD) δ, ppm (J/Hz): 0.92 (t, 6N, 2 CH3, J=6.5); 1.33 (m, N, CH2(CH2)8CH3CH2(CH2)12CH3); 1.70 (m, 4H, [CHCH2CH2]Glu, [CHCH2CH2CH2CH2]Lys); 1.88 (m, 4H, [CHCH2CH2CH2CH2]Lys); 2.52 (t, 2H, [CHCH2CH2]Glu, J=7.5); 3.00 (m, 2H, [SN(CH2)3CH2]Lys); 3.64 (m, 2H, [CH2]Gly); 3.98 (m, 3H, Glu-HCH 2CH2, -CH2C(O)-OAlk); 4.08-4.50 (m, 16H, DABCO (N), OCH2(CH2)8CH3, NCH2(CH2)12CH3); 4.78 (m, 1H, [CH(CH2)4]Lys); 4.90 (m, 2H, N-CH2-C(O)-Glu). ESI-MS, m/z found 531.75 [M+Na]2+calculated 1037.51.
Example 4. Inactivation of vaccinia virus compounds(1), (2), (3).
Antiviral activity of compounds(1), (2), (3) studied on the model of vaccinia virus strain IF the EAP.
Used vaccinia virus (BOB) infectious titer of 105plaque-forming units (PFU) vaccinated material. Contagious virus was determined by counting the BATTLE of the cells CV-1 (kidney cells of monkeys). The method is based on the ability of the virus to form individual sites of lysed cells (plaques) on the cell monolayer after infection of a cell by a certain number of viral particles, the minimum required for infection of a single cell. When the infected cell monolayer serial dilutions of the virus and subsequent staining of living cells dye "gentianales purple" is rendered in the number of lysed platelets, which measure the amount of virus. Inactivation of vaccinia virus compounds(1), (2), (3) was carried out at 37°C in 50 mm Tris-HCl buffer, pH 7.0, containing 0.2 M KCl and 2 mm EDTA for 24 h at 37°C at concentrations of compounds(1), (2) (3) from 0.04 μm to 1 mm.
Table 1 presents data on antiviral activity of compounds(1), (2), (3).
|Connection name||Vaccinia virus|
|The concentration of connections||The titer of the virus, lg(PFU/ml)|
Connection(1), (2), (3) effectively inactivate WWII, and the level of virus inactivation increases with increasing concentration of the compounds, which were in the inactivation of the virus. Thus, incubation of the virus for 24 h at 37°C with compounds (1) at a concentration of 0.2 mm, (2) 0.2 mm, (3) - 0.25 mm reduces the titer of the virus by approximately 1 order compared with the control. By increasing the concentration of compounds(1), (2), (3) to 0.3, 0.4 and 0.5 mm, respectively, there is a complete inactivation of the great Patriotic war.
The results obtained clearly vidualistic about the high antiviral activity of compounds (1), (2), (3).
Example 5. The study membranolytic compounds(1), (2), (3).
Membranolytic activity of the compounds were investigated in experiments with sheep erythrocytes. The ability of compounds to cause lysis of erythrocytes was evaluated after incubation of sheep erythrocytes at a concentration of 15·106in the presence of one of the compounds(1), (2), (3) in the concentration range from 0.001 to 2 mm for 120 minutes at 37°C. After incubation, the efficiency of lysis was assessed by the change in staining phosphate buffer, measured on the spectrophotometer at a wavelength of 550 nm. As a positive control for 100% took membranolytic activity equal volume of distilled water. As a negative control was used 100 mm phosphate buffer, the efficiency of lysis of erythrocyte membranes in the presence of which in the indicated conditions did not exceed 2%.
Table 2 presents the values of the efficiency of lysis of erythrocytes connections(1), (2), (3).
|Connection name||Membranolytic active connections|
|The concentration of compounds in which there is lysis of the membranes at the hands of Eritrean is ozimov, mm||The efficiency of lysis by incubation 2 h at 37°C, %|
|The phosphate buffer||100||2|
Connection(1), (2), (3) cause lysis of erythrocytes, and its efficiency increases with increasing concentration of compounds in which carried out the incubation of a suspension of erythrocytes. Thus, incubation of the virus for 2 h at 37°C with compounds (1) and (2) at a concentration of 0.5 mm, (3) - 0.05 mm results in complete lysis of the erythrocyte membrane, comparable to the lysis of red blood cells, incubated in the presence of distilled water. The decrease in the concentration of the compounds to 0.05 mm in the case of (1) and (2), 0.01 mm - (3) resulted in complete loss of membranolytic activity of these compounds. Thus, it was demonstrated that the compounds(1), (2), (3) have high membranolytic activity.
Example 6. The study of morphology in the particles originate in the process of inactivation using compound (2)
The morphology of viral particles after incubation with compound (2) was performed using electron microscopy negative-contrast. The analyzed samples barbirolli on the reference electron microscope grid covered with formularovy film, within 30 seconds, the residual liquid was removed, the grid was dried and placed in a contrasting solution (2% solution of phosphorus-tungsten acid in distilled water) for 30 seconds, the remaining solution was removed, the grid was allowed to dry. Samples (4-6 mesh) was examined in a transmission electron microscope Jem 1400 when increases from 10000 to 200000.
Electron-microscopic investigation of the morphology of the virus particles inactivated compound (2), revealed virions with a damaged lipid membrane, a small proportion of viral particles was also observed by changing the thickness of the lipid layer (Figa), control is provided on figb. The degree of damage to the structure of the virion directly depended on the concentration of the compound (2). With increasing concentration of the compound from 0.05 to 0.5 mm were evolving damage their structure. Based on the results of electron microscopic studies it can be concluded that the compound (2) disintegrates the lipid membrane of the virion, i.e. has membranolytic activity, which leads to inactivation of the virus.
P the emer 7. The influence of compounds(1), (2), (3) the viability of cells CV-1
Cell line CV-1 (kidney cells of the African green monkey) were maintained in DMEM containing 5%fetal calf serum, antibiotics (100 units/ml penicillin and 0.1 mg/ml streptomycin) and antimycotic amphotericin (0.25 μg/ml) in an atmosphere of 5%CO2at 37°C.
Cell viability after incubation with compounds(1), (2), (3) was determined using the MTT test, which is based on the ability of living cells to make connections on the basis of tetrazole (MTT) in brightly colored crystals formazan that allows spectrophotometric estimate the number of living cells in the preparation. For this, cells were planted in 96-well plates (15×103cells per well cells per well). After 48 h in the wells was changed environment and to the cells was added an equal volume of an aqueous solution of the compound (1), (2) or (3) to the final concentration in the medium from 10-7up to 10-3M. Cells were incubated in the presence of compounds in the day in the same conditions. At the end of incubation without changing the environment to the cells was added a solution of MTT (5 mg/ml) in phosphate-buffered saline to a concentration of 0.5 mg/ml and incubated for 3 h in the same conditions. The medium was removed, cells were added to 100 μl of dimethyl sulfoxide in which the dissolution occurs resulting in the cells of the crystal form of the Ana, and measured the optical density for multi-channel spectrophotometer at wavelengths of 570 and 630 nm, where a570- absorption formosana, and A630- the background of the cell.
From the experimental data to calculate the value of the IC50the concentration of compounds in which there is a loss of 50% of the cells. The values of the IC50compounds(1), (2), (3) for cells CV-1 are shown in table 3.
The data show that treatment of cells with compounds(1), (2), (3) cause their effective death only at concentrations of compounds than 0.05 mm, which indicates the low toxicity of these compounds.
Thus, the above examples clearly indicate high membranolytic and antiviral activity against DNA viruses connections(1), (2), (3), so you can use them as promising components for the development of dosage forms of drugs intended for the treatment of viral diseases.
Tool, PR is dostavljaust one of the derivatives of N-substituted 1,4-diazabicyclo[2.2.2.]octane General formula (I):
where AKm choose from
for inactivation of DNA viruses.
SUBSTANCE: agent is an N- and C-substituted peptide selected from n-decyl ether (1-tetradecyl-1,4-diazoniabicyclo[2.2,2.]octan-4-yl)-acetyl-glutamyl-glycyl lysyl-glycine (1), n-decyl ether (1-tetradecyl-1,4-diazoniabicyclo[2.2,2.]octan-4-yl)-acetyl-glutamyl-β-alanyl-arginyl-glycine (2) and n-decyl ether glutamyl-β-alanyl-lysyl-glycine (3).
EFFECT: high antiviral activity of the agent.
3 dwg, 2 tbl, 6 ex
SUBSTANCE: invention relates to a compound of formula I or use thereof to prepare a medicine for treating depression, anxiety or both: or pharmaceutically acceptable salts thereof, where m is 0-3; n is 0-2; Ar is: optionally substituted indolyl; optionally substituted indazolyl; azaindolyl; 2,3-dihydro-indolyl; 1,3-dihydro-indol-2-one-yl; optionally substituted benzothiophenyl; benzothiazolyl; benzisothiazolyl; optionally substituted quinolinyl; 1,2,3,4-tetrahydroquinolinyl; quinolin-2-one-yl; optionally substituted naphthalenyl; optionally substituted pyridinyl; optionally substituted thiophenyl or optionally substituted phenyl; R1 is: C1-6alkyl; hetero-C1-6alkyl; halo-C1-6alkyl; halo-C2-6alkenyl; C3-7cycloalkyl; C3-7cycloalkyl-C1-6alkyl; C1-6alkyl-C3-6cycloalkyl-C1-6alkyl; C1-6alkoxy; C1-6alkylsulphonyl; phenyl; tetrahydropyranyl-C1-6alkyl; phenyl-C1-3alkyl, where the phenyl part is optionally substituted; heteroaryl-C1-3alkyl; R2 is: hydrogen or C1-6alkyl; and each Ra and Rb is independently: hydrogen; C1-6alkyl; C1-6alkoxy; halo; hydroxy or oxo; or Ra and Rb together form C1-2alkylene; under the condition that, when m is 1, n is 2, and Ar is an optionally substituted phenyl, then R1 is not methyl or ethyl, and where optionally substituted denotes 1-3 substitutes selected from alkyl, cycloalkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, amino, acylamino, monoalkylamino, dialkylamino, hydroxyalkyl, alkoxyalkyl, pyrazolyl, -(CH2)q-S(O)rRf; -(CH2)q-C(=O)-NRgRh; -(CH2)q-N(Rf)-C(=O)-Ri or -(CH2)q-C(=O)-Ri; where q is 0, r is 0 or 2, each Rf, Rg and Rh is independently hydrogen or alkyl, and each Ri is independently alkyl, and where "heteroaryl" denotes a monocyclic radical having 5-6 ring atoms, including 1-2 ring heteroatoms selected from N or S, wherein the rest of the ring atoms are C atoms, "heteroalkyl" denotes an alkyl radical, including a branched C4-C7-alkyl, where one hydrogen atom is substituted by substitutes selected from a group consisting of -ORa, -NRbH, based on the assumption that the bonding of heteroalkyl radical occurs through a carbon atom, where Ra is hydrogen or C1-6alkyl, Rb is C1-6alkyl. Pharmaceutical compositions based on said compound are also disclosed.
EFFECT: obtaining novel compounds which can be used in medicine to treat depression, anxiety or both.
14 cl, 1 tbl, 28 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to compounds of formula
possessing the protein kinase inhibitor property, their pharmaceutically acceptable salts, solvates and hydrates, as well as to the use thereof and a based pharmaceutical composition. In general formula (1) X1 represents N, CRt 1; X2 represents N, CRt 2, X3 represents N, CRt 3, X4 represents N, CH and wherein X1, X2, X3 and X4 are independently specified; Rt 1 represents -H, halogen, -COOH, -CH3, -CH2CH3, -OH, -OCH3, -OCH2CH3, -CN, -CH3OH; Rt 2 represents -H, halogen, -CH3, -CH2CH3, -OH, -OCH3, -OCH2CH3, -CN, CH2OH, -NH2; Rt 3 represents -H, -S(O)rR4, halogen, -CN, -COOH, -CONH2, -COOCH3, -COOCH2CH3; the cycle A represents phenyl or a 6-member heteroaryl cycle, wherein heteroaryl contains 1-2 heteroatoms specified in N optionally substituted by 1-4 groups R'; the cycle B represents phenyl or a 5- or 6-member heteroaryl cycle, wherein heteroaryl contains 1-2 heteroatoms specified in N, S optionally substituted by 1-5 groups Rb; Ra and Rb are independently specified and represent -H, halogen, -CN, -R6, -OR4, -NR4R5, -C(O)YR4, -S(O)rR4, -SO2NR4R5, -NR4SO2NR4R5 wherein Y is independently specified and represents a chemical bond, -O-, -S-, -NR3-; L1 represents NR3C(O) or C(O)NR3; R3, R4 and R5 are independently specified and represent H, C1-C6-alkyl, and also the group NR4 R5 may represent a 5- or 6-member saturated or aromatic cycle; in each case R6 is independently specified and represents C1-C6-alkyl optionally substituted by C1-C6- alkyl or 5-6 merous heterocyclyl which may be substituted by C1-C6-alkyl; r is equal to 0; In general formula (II) Z represents CH; X, represents CRt 1; X2 represents CRt 2, X3 represents CRt 3 X4 represents CH and wherein X1, X2, X3 and X4 are independently specified; Rt 1 represents -H; Rt 2 represents -H, -F; Rt 3 represents -H, -F; the cycle A represents phenyl or 6-member heteroaryl cycle wherein heteroaryl contains 1-2 heteroatoms specified in N optionally substituted by 1-4 groups R3; the cycle B represents phenyl or a 5- or 6-member heteroaryl cycle wherein heteroaryl contains 1-2 heteroatoms specified in N, S optionally substituted by 1-5 groups Rb, Ra and Rb are independently specified and represent -H, halogen, -CN, -R6, -OR4, -NR4R5, -C(O)YR4, -S(O)rR4, -SO2NR4R5 wherein Y is independently specified and represents a chemical bond, -NR3-; L represents NR3C(O) or C(O)NR3; R4 and R5 are independently specified and represent H, C1-C6-alkyl, also the group NR4R3 may represent a 6-member saturated cycle; in each case R6 is independently specified and represents, C1-C6-alkyl optionally substituted by C1-C6-alkyl or 5-6 member heterocyclyl which may be substituted by C1-C6-alkyl; r is equal to 0; m is equal to 1; p is equal to 1.2.
EFFECT: preparing the compounds possessing the protein kinase inhibitor property.
16 cl, 5 ex
SUBSTANCE: invention relates to substituted N-phenylpyrrolidinyl methylpyrrolidine amides of formula , where R, R1, R2 and R3 are identical or different and independently denote H, (C1-C4)alkyl, CF3; R4 denotes phenyl, cyclohexyl, pyridinyl, furanyl, isoxazolyl, quinolinyl, naphthyridinyl, indolyl, benzoimidazolyl, benzofuranyl, chromanyl, 4-oxo-4H-chromenyl, 2,3-dihydrobenzofuranyl, benzo[1,3]dioxolyl and 2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e]][1,4]diazepinyl; where said R4 is optionally substituted one to more times with a substitute selected from halogen, hydroxy, (C1-C4) alkyl, (C1-C4) alkoxy, CF3, hydroxymethyl, 2-hydroxyethylamino, methoxyethylamide, benzyloxymethyl, piperidinyl, N-acetylpiperidinyl, pyrrolyl, imidazolyl, 5-oxo-4,5-dihydropyrazolyl; or pharmaceutically acceptable salt thereof or enantiomer or diastereomer thereof.
EFFECT: compounds have modulating activity on histamine H3 receptor, which enables use thereof to prepare a pharmaceutical composition.
10 cl, 3 dwg, 29 ex
SUBSTANCE: described are symmetrical cyanine dyes with terminal nitrogen-containing groups in N-substitutes of heterocyclic residues of formula (I): where Q is a sulphur atom, CMe2 group; R1-R4 denote hydrogen, lower alkyl, lower alkoxyl group, R1 and R2 or R3 and R4 together form a C4H4 - benzo group; n=0-3; A is (CH2)mNH3 +E" or a phthalimidoalkyl group; E is Br, I, ClO4, PF6, BF4, TsO, MeSO3, CF3SO3, MeOSO3. Said compounds are obtained by reacting a quaternary salt of a 2-methyl derivative of a heterocyclic base with an electrophilic agent which is a donor in central fragments of a polymethine chain of high purity with output of up to 93%.
EFFECT: novel dyes have intense luminescence in the visible and near-infrared spectral regions in the 475-820 nm range.
3 cl, 1 dwg 1 tbl, 17 ex
SUBSTANCE: invention relates phenyl pyrrole derivatives formula (I) where: A denotes =NOR4, O; R4 denotes, C1-C6 alkyl; R1 denotes C1-C6 alkyl, C1-C6 alkoxy, halogen-C1-C6 alkyl, halogen-C1-C6 alkoxy, NH2, mono- C1-C6 alkylamino, halogen-mono-C1-C6 alkylamino, di(C1-C6 alkyl)amino, halogen-di-(C1-C6 alkyl)amino; or A and R1 together with the carbon atom with which they are bonded form a 5- or 6-member heterocyclic aromatic group or a heterocyclic group with partially or completely reduced saturation, which can be benzo-condensed, can contain 1-3 heteroatoms selected from N, O and S, which can be substituted and contain 1 or 2 α substitutes; R2 denotes phenyl which can be substituted with 1 or 2 α substitutes, or a 6-member heteroaryl group containing 1 or 2 N atoms, which can be substituted with 1 or 2 α substitutes; R3 denotes OH, C1-C6 alkoxy, values of α are given in claim 1, or a pharmaceutically acceptable salt thereof.
EFFECT: compounds exhibit glucokinase activating activity, which enables use thereof in treating diabetes.
51 cl, 1 tbl, 132 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention relates to novel dihydroindolone derivatives of formula I or its pharmaceutically acceptable salts: Formula I, where values of R1-R9,R16,R17,n1,n2,n3, m, are given in 1 of the formula. Described are methods of obtaining compounds.
EFFECT: compounds demonstrate anti-tumour activity, which makes it possible to use them in pharmaceutical compositions for treatment and/or prevention of diseases, associated with protein tyrosine kinases in organism, in particular for treatment and/or prevention of tumours and diseases, associated with proliferation of fibroblasts.
13 cl, 1 dwg, 5 tbl, 37 ex
SUBSTANCE: invention relates to a compound which is 4-[4-(2-adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]benzoic acid or a pharmaceutically acceptable salt thereof. The invention also relates to use thereof to inhibit 11βHSD1 (11-β-hydroxysteroid-dehydrogenase type 1), synthesis method thereof and a pharmaceutical composition containing said compounds.
EFFECT: improved method.
12 cl, 1 tbl, 47 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to new substituted heteroaryl derivatives of general formula I: , wherein: A means N, CR7-10, with A at the most twice meaning N; W means O, S or NR4, the values B, C, R7-10 are presented in clause 1 of the patent claim. The method for preparing the compound I is described.
EFFECT: compounds show analgesic activity that enables using them for a variety of diseases, especially acute pain, neuropathic, chronic or inflammatory pain.
16 cl, 2 tbl, 307 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: present invention refers to new imidazole derivatives of formula I wherein R1 represents a hydrogen atom or C1-7alkyl; R2 represents C1-7alkyl; R3 represents C1-7alkyl, C1-7alkoxy, phenyloxy, benzyloxy, a halogen atom or C1-7alkyl substituted by a halogen atom; R4 represents a hydrogen atom or C1-7alkyl; X represents -CH2-, -CHR2 - or -O; Y represents -CH2-, -CH2CH2- or a bond; provided X represents -O-, Y represents -CH2-; Z represents -CH2- or -CHR2-; provided R2 is found twice, simultaneously for X and Z which are CHR2 , then R2 can be identical alkyls or different; n has the value 0, 1 or 2; provided n has the value 2, R3 can be identical or different; and its pharmaceutically acceptable acid addition salts, except for the following compounds: 1-(1H-imidazol-4-ylmethyl)-1,2,3,4-tetrahydro-quinoline and 1-(3H-imidazol-4-ylmethyl)-2,3-dihydro-1H-indole. Also, the invention refers to a method for preparing the compounds of formula I, to a drug based on the compound of formula I and applying the compound of formula I in preparing the drug.
EFFECT: there are prepared new imidazole derivatives effective in treating such pathological conditions, as bipolar disorder, stress-induced disorder, psychotic disorders, schizophrenia, neurological conditions, Parkinson's disease, neurodegenerative disorders, Alzheimer's disease.
13 cl, 61 ex
SUBSTANCE: invention relates to novel substituted pyrimidine derivatives, having HIV replication inhibiting properties, or pharmaceutically acceptable salts thereof. In formula (1): R1 denotes hydrogen; R2 and R3 independently denote hydrogen; R7 and R8 denote C1-6alkyl; R4 denotes cyano; R9 denotes C1-6alkyl optionally substituted with cyano, C2-6alkenyl substituted with cyano, C2-6alkynyl optionally substituted with cyano; R5 denotes C1-6alkyl optionally substituted with Ar or Het; C2-6alkenyl optionally substituted with Ar or Het; C2-6alkynyl optionally substituted with Ar or Het; C3-7cycloalkyl; Ar; Het; R6 denotes H, Het; Y denotes -OR11, -NR12R13; R11 denotes hydrogen or C1-6alkyl optionally substituted with hydroxy, C1-6alkoxy or pyridyl; R12 denotes hydrogen or C1-6alkyl; R13 denotes hydrogen or C1-6alkyl; or R12 and R13 together with a nitrogen atom, which is substituted by said two substitutes, form a morpholinyl; imidazolyl; X denotes -NR1-; Het denotes 5- or 6-member completely saturated ring, where one or two ring members are heteroatoms, each independently selected from nitrogen and sulphur, and where the rest of the ring members are carbon atoms; and where any member of the heterocycle with a nitrogen heteroatom can optionally be substituted with C1-6alkyl; where the 5- or 6-member ring can optionally be annelated with a benzene or thiophene ring; each aryl independently denotes phenyl or phenyl substituted with one substitute selected from C1-6alkoxy.
EFFECT: high efficiency of using said compounds.
7 cl, 4 ex, 1 tbl
SUBSTANCE: invention relates to medicine, in particular to pediatrics, and relates to method of treating congenital hepatitis B treatment in children of first year of life. Continuous treatment is performed for 12-18 months, including introduction of viferon and additional introduction of zeffix in dose 3 mg/kg per day once daily after breakfast and ursodeoxycholic acid in day dose 20 mg/kg, divided into two takings.
EFFECT: application of invention makes it possible to increase efficiency of treatment of congenital hepatitis B.
FIELD: chemistry; pharmaceutics.
SUBSTANCE: present invention relates to 6-substituted isoquinoline and isoquinolinone derivatives of formula or stereoisomer and/or tautomer forms thereof, and/or pharmaceutically acceptable salts thereof, where R1 is H or OH; R2 is R', (C7-C8)alkyl, (C1-C6)alkylene-R', (C2-C6)alkenyl; or R2 is (C1-C6)alkyl, under the condition that in said alkyl residue, at least one hydrogen is substituted with OH or OCH3; or R2 is (C1-C6)alkylene, bonded with cycloalkylamine, where (C1-C4)alkylene forms a second bond with another carbon atom of the cycloalkylamine ring and, together with carbon atoms of the cycloalkyalmine, forms a second 5-8-member ring; R3, R5 and R8 denote H; R4 is H, (C1-C6)alkyl or (C1-C6)alkylene-R'; R6 and R6' independently denote H, (C1-C8)alkyl, (C1-C6)alkylene-R' or C(O)O-(C1-C6)alkyl; R7 is H, halogen or (C1-C6)alkyl; n equals 1; m equals 3 or 5; r equals 0 or 1 and L is O(CH2)p, where p=0; where R' is (C3-C8)cycloalkyl, (C6)aryl; where in residues R2-R8 (C6)aryl is unsubstituted or substituted with one or more suitable groups independently selected from halogen, (C1-C6)alkyl, O-(C1-C6)alkyl, where the alkyl group can be substituted with 1-3 halogen atoms. The invention also relates to use of the compound of formula (I) and a medicinal agent based on the compound of formula (I).
EFFECT: obtaining novel 6-substituted isoquinoline and isoquinolinone derivatives suitable for treating and/or preventing diseases associated with Rho-kinase and/or Rho-kinase-mediated myosin light chain phosphatase phosphorylation.
36 cl, 5 tbl
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to biotechnology, virology and medicine. What is disclosed is a recombinant protein containing one or more polypeptides carrying one or more epitopes of one or more human papilloma virus HPV antigens. Said polypeptides are embedded in one or various permissive sites of adenylatecyclase (CyaA) or its fragments. What is also disclosed is the polypeptide coding such protein and their use in expression systems for producing immunogenic compositions and drugs. The invention can be used in medicine.
EFFECT: CyaA fragment possesses the property of said adenylatecyclase protein for targeted interaction with antigen-presenting cells.
60 cl, 21 dwg, 1 tbl, 3 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: given invention refers to drugs containing compounds of specified structural formulae or to their pharmaceutically acceptable salts. Besides, the invention refers to pharmaceutical compositions for treating a host infected by hepatitis B virus, on the basis of each of said compounds separately (or their pharmaceutically acceptable salt), and also in their combination with an effective amount of a compound chosen from a group consisting of β-L-2-hydroxymethyl-5-(cytosine-1-yl)-1,3-oxathiolane (3TC), cys-2-hydroxymethyl-5-(5-fluorocytosine-5-yl)-1,3-oxathiolane (FTC), β-L-2'-fluor-5-methyl-arabinofuranosyl-uridine (L-FMAU), β-D-2,6-diaminopurindioxolane (DAPD), famciclovir, penciclovir, 2-amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)2-methylenecyclopentyl]-6H-purine-6-one (entecavir, BMS-200475), 9-[2-(phosphono-methoxy)ethyl]adenine (PMEA, adefovir, dipivoxyl), lobucavir, ganciclovir and ribavirin.
EFFECT: creation of the drug for treating a host infected by hepatitis B virus.
12 cl, 6 tbl, 4 dwg, 11 ex
SUBSTANCE: invention relates to pharmaceutical industry, in particular to application of skeleton of Nocardia rubra cell wall for preparation of medication against human papilloma virus (HPV).
EFFECT: application of skeleton of Nocardia rubra cell wall ensures increase of medication safety and efficiency, simplifies application, and also reduces therapy terms and increases spectrum of medication activity.
8 cl, 2 tbl
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to veterinary science and concerns applications of protein ORF-2 of porcine circovirus 2 for making a vaccine for protection of piglets from PCV-2 infection with positive maternal antibodies (MDA-positive). A minimal dose 20 mcg/dose of protein ORF-2 of porcine circovirus 2 (PCV-2) is able to induce a protective immune response to PCV-2 even if they have relatively high MDA titre to PCV-2. The vaccine under the invention can contain recombinant protein ORF-2 where said recombinant protein is preferentially prepared by expression in baculovirus express ion vector in insects cells, said baculovirus express ion vector contains sequence of gene ORF-2 PCV-2 under control of p10 promotor.
EFFECT: ensured protection against infection in MDA-positive piglets.
9 cl, 5 ex, 2 tbl
SUBSTANCE: invention relates to amidines of formula (I) and to their derivatives, methods for making thereof and pharmaceutical compositions containing amidines of formula (I). According to said invention, amidines are applicable for inhibition of IL-8 induced chemotactic factor, and can be applied to produce medicine agents for treating psoriasis, ulcerative colitis, melanoma, chronic obstructive pulmonary disease (COPD), bullous pemphigoid, rheumatoid arthritis, idiopathic fibrosis, glomerulonephritis and for preventing and treating injuries caused by ischemia and reperfusion.
EFFECT: higher clinical effectiveness.
7 cl, 6 ex, 1 tbl
SUBSTANCE: invention concerns medicine, namely immunology, and can be used for prevention of recurrence and treatment of herpes virus infections. Method is implemented as follows. In remission period, synthetic dipeptide gamma-D-glutamyl-L-tryptophan is introduced intranasally in a dose 50-100 mcg daily within 7-10 days. In exacerbation period, synthetic dipeptide gamma-D-glutamyl-L-tryptophan is introduced intranasally in a dose 100 mcg daily within 10 days within integrated antiviral therapy involving preparations valaciclovir 500 mg orally 1 tablet twice a day - 5-10 days, penciclovir for external application on affected areas 3-4 times a day within 5-7 days.
EFFECT: invention enables reductions of acute period and prolonged recurrence of herpes virus infection due to normalisation of amount of T-helpers, T-suppressors, NK cells and their relations, intensified formation of endogenous interferon.
3 tbl, 1 ex
FIELD: organic chemistry, medicine, pharmacy.
SUBSTANCE: invention relates to novel derivatives of tetrahydrocarbazole of the formula (I): wherein n = 0, 1 or 2; X represents -NH or oxygen atom (O); each R is a similar or different radical and chosen independently from group consisting of halogen atom, halogenalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, -R10-cycloalkyl, -OR2, -R10OR2, -R10C(O)R2, -C(O)R2, -CO2R2, -R10CO2R2, -R10SO2R2, -S(O)mR2, cyano- or nitro-group; each R1 is a similar or different radical and chosen independently from group consisting of halogen, halogenalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, -R10-cycloalkyl, -OR2, -R10OR2, -R10C(O)R2, -C(O)R2, -CO2R2, -R10CO2R2, -R10SO2R2, -S(O)mR2, cyano- or nitro-group and wherein each m means 2 independently; each R10 is a similar or different radical and chosen independently from alkylene; each p and q is chosen independently from 0, 1, 2, 3, 4 or 5; each R2 is a similar or different radical and chosen independently from group consisting of hydrogen atom (H), alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, -R10-cycloalkyl and -R10OH; ring A represents phenyl, naphthyl or heteroaryl wherein heteroaryl represents monocyclic 5-7-membered aromatic ring or condensed bicyclic aromatic ring system consisting of two such aromatic rings that comprise one or two nitrogen atoms and/or sulfur atoms, and to their pharmaceutically acceptable salts, solvates, esters and amides. Compounds of the formula (I) possess effect against disorders caused by HPV-infection and useful in treatment of human papilloma. Also, invention relates to a pharmaceutical composition based on compounds of the formula (I) and its using in preparing drugs for their using in treatment and prophylactic of states or disorders caused by HPV-infection.
EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.
FIELD: medicine immunobiological preparations.
SUBSTANCE: claimed method includes passivation of vaccine virus on 12-13-day hen embryos, lyophilization with 15 % of lactose, grinding, blending with recipient and pressing (palletizing) to produce preparation comprising up to 30 % of dry virus-containing material and recipient containing (%): lactose 87.8; sucrose 10; calcium stearate 2.0 and vanilla 0.2 %.
EFFECT: simplified method for production of pelletized embryonic variolar living vaccine.