Urethane azt derivatives - potential antiviral agents
SUBSTANCE: invention relates to 5'-urethane AZT derivatives of general formula
where X = -NH2, -NHMe, -NHEt, .
EFFECT: compounds have low toxicity, can efficiently inhibit reproduction of the immunodeficiency virus type 1 virus in a CEM SS cell culture.
1 cl, 2 tbl, 7 ex
The invention relates to the field of molecular biology, Virology and medicine, namely to new derivatives of nucleoside - urethane derivatives of AZT. These compounds have antiviral activity and can be used to suppress the reproduction of the human immunodeficiency virus.
Currently, in clinical practice, a number of compounds with antiviral activity against HIV. Among them distinguish between nucleoside and non-nucleoside inhibitors. Among the derivatives of nucleosides most commonly used 3'-azido-3'-deoxythymidine (AZT, Zidovudine®), 2',3'-dideoxycytidine (ddC, Zalcitabine®), 2',3'-dideoxyinosine (ddI, Didanosine®), 2',3'-dideoxy-2',3'-didehydrothymidine (d4T, Stavudine®) and 2',3'-dideoxy-3'-thiacytidine (3TC, Lamivudine®) [De Clercq, E., 2002. New development in anti-HIV chemotherapy. Biochim. Biophys. Acta, 1587, 258-275].
The mechanism of action of the above compounds is that after penetration into infected cells, they are triphosphorylated and specific blocking DNA synthesis catalyzed by reverse transcriptase of HIV. The high variability of HIV leads to a rapid emergence of resistant virus strains [Groschel, Century, Cinatl, J. H., and J. Cinatl Jr., 1997. Viral and cellular factors for resistance against antiretroviral agents. Intervirology, 40, 400-407; Antonelli, G, Turriziani, O., Verri, A., Narciso, P., Ferri, F., D Offizi, G.; and Dianzini, F., 1996. Long-term exposure to zidovudine affects in vitro and in vivo the efficiency of thymidine kinase. AIDS Res Hum Retrovir., 12, 223-228] and, consequently, to the need to change medication. Moreover, due to the low efficiency of intracellular transformations used drugs require higher doses that cause significant toxic effects.
The effects of the toxicity of AZT are suppressing the activity of cells of the spinal cord, the liver and myopathy [Chariot, P., Drogou, I., De Lacroix-Szmania, I., Eliezer-Vanerot, M.C., Chazaud, C., Lombes, A., Schaeffer, A., arid Zafrani, E.S., 1999. Zidovudine-induced mitochondrial disorder with massive liver steanosis, myopathy, lactic acidosis, and mitochondial DNA depletion. J. Hepatol. 30, 156 to 160; Kellam, P., Boucher, C.A., and Larder, B.A., 1992. Fifth mutations in HIV reverse transcriptase contributes to the development of high level resistance to zidovudine. Proc. Natl. Acad. Sci. USA, 89, 1934-1938; Ren, J., Esnouf, R., Hopkins, A.L., Jones, DURING, Kirby, I., Keeling, J., Ross, C.K., Larder, B.A., Stuart, D.I., and Stammers, D.K., 1998. 3'-Azido-3'-deoxythymidine drug resistance mutations in HIV-1 reverse transcriptase can induce long range conformational changes. Proc. Natl. Acad. Sci. USA, 95, 9518-9523]. Rapid elimination of AZT from the body requires frequent administration of the drug. In addition, with long-term use of AZT quickly formed of resistant strains of the virus and the treatment loses its effectiveness. Despite all of the above disadvantages, AZT remains the most widely used anti-HIV drug.
Known H-phosphonate AZT (Nikavir®), approved in Russia for the treatment of AIDS, less toxic than AZT [Skoblov Yu., Karpenko I. Shirokova, E., Popov K., Andronova V., Galegov G., Kukhanova M., 2004. Intracellularmetabolism and pharmacokinetics of 5'-hydrohenphosphonate of 3'-azido-2',3'-dideoxythymidine, a prodrug of 3'-azido-2',3'-dideoxythymidine. Antiviral Reserch, 63, 107-113]. The action of Nikavir based on the ability to release AZT, which after intracellular conversion to AZT-5'-triphosphate inhibits HIV replication. According to pharmacokinetic studies clinical advantages of Nikavir explained in more slow and gradual increasing concentrations of AZT in the blood than when you actually receive AZT;maxAZT from Nievera<maxAZT from Zidovudine, and T1/2AZT from Nievera>T1/2AZT from Zidovudine. However, the toxicity of Nikavir remains quite high. Another disadvantage is the occurrence of resistance to Nikavir.
To date, described many potential depot-forms AZT, in particular 5'-ester and 5'-carbonate derivatives [Parang, K., Weibe L.I., E.E. Knaus Current Medical Chemistry. 2000. V.7. P.995-1039]. The closest analogue of the claimed compounds is 5'-diethylaminocoumarin-3'-azido-3'-deoxythymidin [Hammer, Hatlelid J, Gritli M, Arukwe J, Klaveness J, Rise F, K. Undheim Ether, carbonate and urethane deoxynucleoside derivatives as prodrugs. Acta Chem Scand. 1996. 50(7):609-22], which was shown marked anti-HIV activity in the cellular system. It should be noted that pharmacokinetic studies have not been conducted.
This invention solves the problem of creating a non-lethal derivatives of AZT, with the ability to penetrate into the cell and p is gradually release the active nucleoside AZT. This will allow you to maintain the intracellular concentration of the drug sufficient for the manifestation of therapeutic action for a long time and, thus, reduce the frequency of administration and to reduce side effects.
Problem solved by creating connections, 5'-urethane derivatives of 3'-azido-3'-deoxythymidine, of General formula:
where X = the residue of ammonia or amine (methylamine, ethylamine, research, piperazine):
X=-NH2, -NHMe, -NHEt,,.
The new compounds inhibit the reproduction of human immunodeficiency virus 1-th type in the cell culture SEM SS (lymphoblastoid T-cell line), protect cells from cytopathogenic steps of the virus and not show toxicity to the host cells up to very high concentrations (table). From the obtained experimental data shows that the compounds without exerting toxic effects on the cells in the effective concentration (50% toxic dose by 3-4 orders of magnitude in excess of 50%inhibiting dose) highly inhibit the reproduction of human immunodeficiency virus type 1 in cell culture SEM SS. therapeutic index of the compounds under study (IS), defined as the ratio of toxic dose to the effective dose, comparable with those of the La H-phosphonate AZT. Virological tests conducted in accordance with standard protocols.
Our compounds have good solubility in water, which makes them differ from the previously described 5'-diethylaminocoumarin-3'-azido-3'-deoxythymidine [Hammer, Hatlelid J, Graitli M, Arukwe J, Klaveness J, Rise F, K. Undheim Ether, carbonate and urethane deoxynucleoside derivatives as prodrugs. Acta Chem Scand. 1996. 50(7):609-22]. It is also shown that the claimed 5'-urethanes AZT well absorbed after oral administration and are metabolicheskie predecessors AZT in the organism of laboratory animals (dogs).
Target urethane derivative was obtained according to the following scheme:
First 3'-azido-3'-deoxythymidin treated with 1,1'-carbonyl diimidazol, then add aqueous ammonia or amine (methylamine, ethylamine, morpholine, piperazine, and others). The reaction is carried out in an environment aprotic solvent is dimethylformamide, dioxane, acetonitrile, etc.
The following are specific examples that reveal the essence of the invention.
To a solution of 3'-azido-3'-deoxythymidine (0.8 g, 3 mmol) in dimethylformamide (10 ml) was added 1,1'-carbonyldiimidazole the (0,81 g, 5 mmol). The mixture was stirred 2 hours at 18°C, was added morpholine (1.5 ml, 17 mmol), stirred for 18 hours. The reaction was evaporated mass and chromatographically on a column of silica gel (2×15 cm). Was suirable in a gradient of methanol in chloroform (from 3% to 10% methanol). The target fractions were evaporated, dissolved in water and was liofilizovane, got 0,91 g (82%) of the urethane (Ia).1H NMR (DMSO-d6): 11,23 with (3-NH) 7,40 (1H, H-6), 6,10 DD (1H, J=6.2 Hz and 6.9 Hz, H-1'), 4.45 m (1H, H-3'), 4,27 m (2H, H-5'), 3.98 (1H, H-4'), 3.55 m 3,36 m (8H, morpholine), 2,39 m (2H, H-2'), 1,79 d (3H), 5-CH3).13With NMR (DMSO-d6): 163,6 with (C4), 154,2 C (NC(O)O), 150,3 with (C2), 135,9 (C6), 109,9 with (C5), 83,9 with (C1'), 80,9 (C4'), 65,7 with (two-O (morpholine)), 64,2 (C3'), 60,1 (C5'), 43,8 (two C-N (morpholine)), 35,7 with (C2'), 11,9 (5-Me).
To a solution of 3'-azido-3'-deoxythymidine (1 g, 3.7 mmol) in dioxane (10 ml) was added 1,1'-carbonyldiimidazole (97%1 g, 6 mmol). The mixture was stirred for 1 hour at 18°C, was added piperazine (0.95 g, 11 mmol) in dioxane (5 ml)was stirred 18 hours. The reaction was evaporated mass and chromatographically on obremenitve column (RP-8) with silica gel (2,5×25 cm). Was suirable in a gradient of acetonitrile in water (from 0% to 40%). The target fractions were evaporated, dissolved in water and was liofilizovane, got 0.84 g (60%) of the urethane (Ib).1H NMR (D2O): 7,53 (1H, H-6), 6,24 t (1H, J=6,4 Hz, H-1'), 4.52 (2H, H-3' and H-5 a), 4,42 DD (1H, J=12 and 4.3 Hz, H-5'b), the 4.29 (1H, J=44 Hz, H-4'), 3,55 USS (4H, 2 CH2-NCO), 2,90 USS (4H, 2 CH2-NH), 2,59 m (2H, H-2'), 1,99 (3H, 5-CH3).
To a solution of 3'-azido-3'-deoxythymidine (0.8 g, 3 mmol) in dimethylformamide (10 ml) was added 1,1'-carbonyldiimidazole (0,81 g, 5 mmol). The mixture was stirred 3 hours at 18°C, was added 32% aqueous ammonia (7 ml)was stirred 18 hours. The reaction was evaporated mass and chromatographically on a column of silica gel (2×15 cm). Was suirable in a gradient of methanol in chloroform (from 3% to 10% methanol). The target fractions were evaporated, dissolved in water and was liofilizovane, received 0.76 g (78%) of the urethane (Ic).1H NMR (DMSO-d6): 11,3 (1H, 3-NH), the 7.43 (1H, H-6), 6,62 USS (2H, NH2), 6,12 t (1H, J=6,5 Hz, H-1'), 4,40 m (1H, H-3'), 4,21 DD (1H, J=11.8 and of 3.4 Hz, H-5 a), 4,08 DD (1H, J=11.8 and 5.2 Hz, H-5'b), 3.98 (1H, H-4'), 2,47 m (1H, H-2 a), 2.30 m (1H, H-2'b), 1,79 with (3H, 5-CH3).13With NMR (DMSO-d6): 163,8 with (C4), 156,4 C (NC(O)O), 150,5 with (C2), 135,9 (C6), 110,0 (C5), 83,8 with (C1'), 81,4 (C4'), 63,5 (C3'), 60,9 (C5'), 35,8 (C2'), 12,2 (5-Me).
To a solution of 3'-azido-3'-deoxythymidine (0.8 g, 3 mmol) in dioxane (15 ml) was added 1,1'-carbonyldiimidazole (0,81 g, 5 mmol). The mixture was stirred 4 hours at 18°C, was added 40% aqueous methylamine (5 ml)was stirred 18 hours. The reaction was evaporated mass and chromatographically on a column of silica gel (2×15 cm). Was suirable in gra is iente methanol in chloroform (from 3% to 7% methanol). The target fractions were evaporated, dissolved in water and was liofilizovane received 0.66 g (65%) of the urethane (Id).1H NMR (DMSO-d6): 11,34 (1H, 3-NH), 7,43 d (1H, J=0.9 Hz, H-6), 7,20 sq (2H, J=4,7 Hz, MeNH), 6,12 t (1H, J=6,8 Hz, H-1'), 4,42 m (1H, H-3'), 4,24 DD (1H, J=11.8 and of 3.4 Hz, H-5 a), 4,10 DD (1H, J=11.8 and 5.2 Hz, H-5'b), 3.98 (1H, H-4'), 2,59 d (2H, J=4.4 Hz, MeN), 2.45 m (1H, H-2 a), 2.29 m (1H, H-2'b), 1,78 D. (3H, J=0.9 Hz, 5-CH3).13With NMR (DMSO-d6): of 163.7 (C4), 156, 3mm C (NC(O)O), 150,4 with (C2), 135,9 (C6), 109,9 with (C5), 83,6 with (C1'), 81,2 (C4'), 63,8 with (C3'), 60,8 (C5'), 35,8 (C2'), 27,0 with (Me-N)to 12.1 (5-Me).
To a solution of 3'-azido-3'-deoxythymidine (0.8 g, 3 mmol) in dimethylformamide (15 ml) was added 1,1'-carbonyldiimidazole (0,81 g, 5 mmol). The mixture was stirred 4 hours at 18°C, was added 70% aqueous ethylamine (5 ml)was stirred 18 hours. The reaction was evaporated mass and chromatographically on a column of silica gel (2×15 cm). Was suirable in a gradient of ethanol in chloroform (from 0% to 10% ethanol). The target fractions were evaporated, dissolved in water and was liofilizovane, received 0.76 g (72%) of the urethane (Ie).1H NMR (DMSO-d6): of 11.29 (1H, 3-NH), the 7.43 (1H, H-6), 7.24 to t (2N, J=5.3 Hz, EtNH), 6,12 DD (1H, J=6.9 and 6.5 Hz, H-1'), to 4.41 m (1H, H-3'), 4,23 DD (1H, J=11.8 in and 3.7 Hz, H-5 a), 4,10 DD (1H, J=11.8 and 5.0 Hz, H-5'b), 3,99 m (1H, H-4'), 3,03 m (2H, CH2CH3), 2,48 m (1H, H-2 a), 2.30 m (1H, H-2'b), to 1.79 (3H, 5-CH3), 1,02 t (3H, J=7.2 Hz, CH2CH3).13With NMR (DMSO-d6): 163,6 with (C4), 155,6 C (NC(O)O)10,4 (C2), br135.8 with (C6), 109,8 with (C5), 83,7 with (C1'), 81,3 (C4'), 63,7 with (C3'), 60,8 (C5'), 35,6 with (C2'); 35,1 C (CH2(Et), and 14.9 (CH3(Et), to 12.1 (5-Me).
The study of inhibition of reproduction of HIV includes the cultivation initially infected lymphoblastoid T cells SEM SS in the presence of investigated compounds, the final concentration of which in the culture medium amount of 0.001-100 μg/ml, for one passage within 4 days.
Inhibition of reproduction of HIV in culture sensitive cells determined to reduce the accumulation virousspecificakih protein P24 (according to enzyme-linked immunosorbent assay), as well as to increase the viability of the cells in the presence of the drug compared with control defined on the 4th day of cultivation at colouring bromide 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT).
Evaluation of the cytotoxicity of the compounds.
The cytotoxicity of the drug is assessed by adding its dilutions in serum-free medium RPMI-1640 cell suspension SEM SS placed in the wells of 96-hole tablet ("Cel-Cult", England), to a final concentration of 0.001-100 µg/ml (three wells for each dose), followed by cultivation at 37°C for 4 days. The seeding concentration of 0.5×106 cell particles per milliliter. The controls are cells without addition of the drug, instead of which make this W is the number of serum-free medium. Cell viability count on 4 days of culture, using formosanum method (in vivo staining of cells MTT). The toxicity of different doses of the drug to determine cell viability relative to control, according to the obtained results build dose-dependent curve and determine the concentration by 50% reduce cell viability (CD50). The compounds do not exert toxic effects on cells of the CEM SS in effective concentrations. It should also be noted that 50% of the toxic dose to 3-4 orders higher than the effective dose in HIV-1 dose (table).
The influence of the studied compounds on the reproduction of HIV-1 in cell culture SEM SS investigated by well-known methods.
Therapeutic index, or index of selectivity (IS) is considered as the ratio of the 50%toxic concentration of the compound to its 50%effective dose (results are presented in the table). On the basis of these quantitative indicators of inhibition can be judged on the effectiveness of antiviral action of the claimed compounds, consisting in a high degree of suppression of HIV-1 replication in culture cells SEM SS comparable with the effectiveness of Nikavir.
|About iloverussia activity urethane derivatives of AZT against HIV-1:|
Dog weighing 12 kg was injected analyte orally (mixed with cottage cheese). After a certain period of time, taking blood samples (1 ml) from the femoral vein. Samples were centrifuged (10 min, 2000 rpm), the supernatant was separated. Of the supernatant was collected aliquots (0.25 ml), was added oxetan (0.25 microgram, as internal standard) and methanol (0.75 ml). The resulting mixture was centrifuged for 3 minutes at 5000 rpm, the Supernatant was separated and evaporated in a stream of air at 40°C. to the residue was added water (1 ml). Aliquots (20 μl) were analyzed by HPLC on a liquid chromatograph Gynkotec, Germany; analytical column Ultrasphere ODC "Beckman" USA. Eluent: 6% acetonitrile in 0.1% N3RHO4(pH 2,1) in the presence of 0.15% of triethylamine. Detection at λmax265 nm, a temperature of 30°C. Pharmacokinetics the settings, the resulting analysis of the data given in table 2.
|Pharmacokinetic parameters of azidothymidine after the introduction of the dog inside 250 mg AZT, 250 mg of Nikavir, 630 mg 1A.|
|connection||The main pharmacokinetic parameters observed in plasma AZT|
Thus, it is shown that the claimed compounds have low toxicity, SP is able to effectively inhibit the reproduction of human immunodeficiency virus type 1 in cell culture SEM SS and generate AZT in mammals, providing a smooth increase of its concentration in the blood.
5'-Urethane derivatives of AZT, having the General formula
where X=-NH2, -NHMe, -NHEt,,.
FIELD: medicine, pharmaceutics.
SUBSTANCE: present invention refers to compounds of formula (I) where R1 is chosen from ethyl, n-propyl, isopropyl or isobutyl, and to its pharmaceutically acceptable salts. Besides, the invention refers to a pharmaceutical composition on the basis of said compounds used for treating a hepatitis C virus (HCV) mediated disease, and also to a method of treating the hepatitis C virus (HCV) mediated disease, and to the method of selective O-acylation nucleoside II for producing O-acyl nucleoside I in an alkaline reaction medium including the stages: (i) dissolution of II and DMAP in a heterogeneous mixture of water and a solvent and addition of a water base for pH control between approximately 7.5 to approximately 12; (ii) optional addition of a sufficient amount of saturated aqueous NaCl for preparing a diphase reaction mixture; (iii) addition of an acidating agent and an accessory base sufficient for pH preservation between approximately 7.5 to approximately 12; (iv) reaction monitoring and interruption of adding said acidating agent and said base after sufficient conversion provided; (v) optional contact of O-acylnucleoside with the pharmaceutically acceptable acid to produce a pharmaceutically acceptable salt.
EFFECT: production of the pharmaceutical composition for treating the hepatitis C virus (HCV) mediated disease.
9 cl, 2 tbl, 8 ex
SUBSTANCE: invention relates to a pyrimidine nucleoside compound of general formula (1) , in which one of X and Y is a cyano group and the other is hydrogen; R1 is hydrogen, (R3)(R4)(R5)Si- or a carbonyl group which includes an alkyl monosubstituted with an amino group; R2 is hydrogen or (R6)(R7)(R8)Si-, provided that at least one of R1 and R2 is not hydrogen; or R1 and R2 together form a 6-member cyclic group -Si(R9)(R10)-, where each of R9 and R10 is a straight or branched alkyl; R3, R4 and R5 denote a straight or branched alkyl optionally substituted alkoxy, or cycloalkyl; R6, R7 and R8 denote a straight or branched alkyl optionally substituted alkoxy, cycloalkyl or phenyl, or to pharmacologically acceptable salts thereof. The invention also relates to a range of specific compounds of formula (1) or to their pharmacologically acceptable salts: 5'-O-triisopropylsilyl-2'-cyano-2'-desoxy-1-β-D-arabinofuranosylcytosine; 5'-O-diethylisopropylsilyl-2'-cyano-2,-desoxy-1-β-D-arabinofuranosylcytosine; 5'-O-dimethylthexylsilyl-2'-cyano-2'-desoxy-1-β-D-arabinofuranosylcytosine; 5'-O-(dimethyl-n-octylsilyl)-2'-cyano-2'-desoxy-1-β-D-arabinofuranosylcytosine; 3'-O-dimethylthexylsilyl-2'-cyano-2'-desoxy-1-β-D-arabinofuranosylcytosine; 3'-O-diethylisopropylsilyl -2'-cyano-2'-desoxy-1-β-D-arabinofuranosylcytosine; 3'-O-(tert-butyldimethylsily)-2'-cyano-2'-desoxy-1-β-O-arabinofuranosylcytosine; 3'-O-triisopropylsilyl-2'-cyano-2'-desoxy-1-β-D-arabinofuranosylcytosine; 3'-O-dimethylthexylsilyl-5'-O-(L-valyl)-2'-cyano-2'-desoxy-1-β-D-arabinofuranosylcytosine; 5'-O-(L-valyl)-3'-O-(tert-butyldimethylsilyl)-2'-cyano-2'-desoxy-1-β-D-arabinofuranosylcytosine; and 3'-O-cyclopropyl-diisopropylsilyl-2'-cyano-2'-desoxy-1-β-D- arabinofuranosylcytosine.
EFFECT: obtaining formula (1) compounds or their pharmacologically acceptable salts for preparing a medicinal agent for treating tumours.
9 cl, 20 tbl, 1 dwg, 73 ex
SUBSTANCE: invention relates to the method of producing 2'-desoxy-β-L-thymidine, which involves reacting 5'-O-trityl- or 5'-O-dimethoxytrityl- substituted 2,2' -anhydro-1 -β-L- arabinofuranosylthymine with a reducing agent RedAl and a complexing agent 15-crown-5-ether in a polar solvent 1,2-dimethoxyethane (DME) or tetrahydrofuran, obtaining 5'-O-trityl- or 5'-O-dimethoxytrityl- substituted 2,2'-desoxy-β-L-thymidine, subjected to protection removal if necessary. The invention also relates to the method of producing 2'-desoxy-β-L-thymidine, which involves reacting L-arabinose with cyanamide with subsequent reaction of the intermediate product - L-arabinofuranosylaminooxazoline - with a cycling or condensing agent, forming 2,2' -anhydro-1-β-L-arabinofuranosylthymine; reaction of the latter with a reducing agent RedAl and a complexing agent 15-crown-5-ether in a polar solvent 1,2-dimethoxyethane (DME) or tetrahydrofuran, obtaining 2'-desoxy-β-L-thymidine, where L-arabinofuranosylaminooxazoline can be protected by trityl or dimethoxytrityl in position 5' before or after reaction with the cycling or condensing agent; and protection removal of optionally protected 2'-desoxy-β-L-thymidine, if this is necessary or desired. Use in the given methods of such a reducing agent as Red-Al, and such a complexing agent as 15-crown -5-ether, causes a reaction of intramolecular protection and production of the required nucleoside product with good output.
EFFECT: compound is of great importance as an antiviral or antineoplastic preparation.
13 cl, 29 dwg, 28 ex
SUBSTANCE: invention relates to method of obtaining enriched with β-anomer 2'-desoxy-2',2'-difluorocytidine of formula (I)
, which includes stages: (i) interaction of enriched with α-anomer compound of 1-halogenribofuranose of formula (III) with nucleic base of formula (IV) in solvent obtaining enriched with β-anomer nucleoside of formula (II) , with constant removal of formed in reaction process silylhalogenide of formula R3SiX (V) by distillation using carrier or running inert gas through reaction mixture; and (ii) removal of protective group from enriched with β-anomer nucleoside of formula (II). Invention also relates to method of obtaining hydrate of enriched with β-anomer 2'-desoxy-2',2'-difluorocytidine of formula (I), which at stage (ii) after removal of protective group additionally includes stages of dissolving formula (I) nucleoside in water; heating of obtained solution to temperature from 40 to 60°C; cooling of solution to temperature ranging from 10 to 25°C with or without mixing and without changing pH; and filtering of deposited solid substances.
EFFECT: method improvement.
17 cl, 2 tbl, 7 ex
SUBSTANCE: present invention relates to (2'R)-2'-dezoxy-2'-fluoro-2'-C-methylnucleoside (β-D or (β-L) , where X represents O; R1 and R7 independently represent H; R3 represents hydrogen and R4 represents NH2; or its pharmaceutically acceptable salt. The invention also pertains to the method of producing the said compounds, which involves glycosylation of N4-benzoylcytosine with a compound of formula 1-4, where R represents methyl, Pg is chosen from C(O)Ph, CH2Ph or both Pg groups can be included in 1,3-(1,1,3,3-tetraisopropyldisiloxanylidene); with further removal of protection of 3'-OPg and 5'-OPg and N-benzoyl of the obtained product.
EFFECT: invented compounds or their pharmaceutically acceptable salts are used as active ingredients against Flaviviridae family viruses in pharmaceutical compositions and liposomal pharmaceutical compositions.
4 cl, 9 tbl, 5 ex, 4 dwg
SUBSTANCE: claimed invention relates to method of gemcitabine hydrochloride purification, which includes enriching gemcitabine hydrochloride with its p-anomer, according to which solution of gemcitabine hydrochloride in water is taken with ratio of water to gemcitabine hydrochloride from 3:1 to 12:1 (wt/vol); solution is processed with activated coal, activated coal being taken in amount from 0.1 to 10 wt % of gemcitabine hydrochloride amount in solution; activated coal is removed from solution with formation of filtered solution; concentration of gemcitabine hydrochloride in filtered solution is increased until ratio of filtered solution to gemcitabine hydrochloride equals from 1:1 to 1:5 (wt/vol), efficient for gemcitabine hydrochloride sedimentation; deposited gemcitabine hydrochloride is isolated; and in case admixture content in deposited gemcitabine hydrochloride is not reduced to required level, stages (a)-(e) are repeated. Claimed invention also relates to method of obtaining gemcitabine hydrochloride using claimed purification method.
EFFECT: creation of efficient method of gemcitabine hydrochloride purification.
5 cl, 1 tbl, 5 dwg, 8 ex
FIELD: medicine, pharmacology, bioorganic chemistry, pharmacy.
SUBSTANCE: invention relates to the effective using amount of β-L-2'-deoxynucleoside of the formula (I) or (II) used in manufacturing a medicinal agent used in treatment of hepatitis B, pharmaceutical compositions containing thereof, and methods for treatment of hepatitis B. Proposed agent shows the enhanced effectiveness in treatment of hepatitis B.
EFFECT: enhanced and valuable medicinal properties of agent.
83 cl, 6 tbl, 11 ex
FIELD: organic chemistry, biochemistry, medicine, virology.
SUBSTANCE: invention relates to derivatives of 2'=amino-2'-deoxynucleosides of the formula:
wherein R means hydrogen atom (H), alkyl, aminoalkyl; R1 means -(R2NR3) wherein R2 and/or R3 means H, -OH, -NH2, alkyl, benzyl under condition that R doesn't represent H or methyl when R2 and R3 mean H. Compounds elicit an antiviral activity with respect to measles and Marburg viruses exceeding that of ribavirin.
EFFECT: valuable properties of compounds.
4 tbl, 2 dwg, 18 ex
SUBSTANCE: composition for treating a HIV-infected patient contains eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and arachidonic acid (ARA), and at least two different oligosaccharides (OL1 and OL2) having monosaccharide unit homology 90 % and lower. In EPA, DHA and ARA, the long-chain polyunsaturated fatty acid content with 20 and 22 carbon atoms does not exceed 85 wt % of total fat content. The offered food composition contains EPA, DHA and ARA, at least two different oligosaccharides having monosaccharide unit homology 90 % and lower, and sour oligosaccharides, preferentially uronic acid polymer of degree of polymerisation 2 to 60. The food composition is also used for making a drug for diarrhoeia treatment or prevention in the HIV-infected patient.
EFFECT: barrier integrity improvement in HIV patients.
11 cl, 7 dwg, 4 tbl, 6 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to new compounds of general formula (I) or to their pharmaceutically acceptable salts exhibiting CCR2B antagonist activity, and to a based pharmaceutical composition. (I) where P represents phenyl optionally substituted by 1 or 2 substitutes independently selected from halogen, C1-4alkyl, cyano, trifluoromethyl, C1-4alkoxy and trifluormethylthio, and R2 has the values specified in the patent claim.
EFFECT: preparation of new compounds of general formula (I) or their pharmaceutically acceptable salts exhibiting CCR2B antagonist activity.
16 cl, 340 ex
SUBSTANCE: invention is related to a food product for AIDS patients. Proposed is a food composition containing one or more acidic oligosaccharide(s) and one or more neutral oligosaccharide(s) and cysteine and/or a cysteine source. The acidic oligosaccharides are produced from pectin, pectate, alginate, chondroitin, hyaluronic acids, heparin, heparan, sialoglycanes, fucoidan, fucooligosaccharides or carageenan. The neutral oligosaccharides are selected from a group consisting of galactooligosaccharide, fructooligosaccharide, transgalactooligosaccharide, xylooligosaccharide, lactosucrose and arabinooligosaccharide where the said cysteine source is represented by N-acetylcysteine and/or diacetylcysteine, whey, beestings, egg whites or combination thereof.
EFFECT: invention enables preclusion and prevention of AIDS-related disfunctions.
12 cl, 1 tbl, 7 ex
SUBSTANCE: invention relates to (5H-pyrazolo[1,5-c][1,3]benzoxazin-5-yl)phenylmethanone derivatives (I), useful as HIV viral replication inhibitors, as well as pharmaceutical compositions, use thereof as medicinal agents.
EFFECT: disclosed compounds are meant for preventing or treating HIV infection and treating AIDS.
7 cl, 2 tbl, 4 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to compounds described by a structural formula wherein: R1 is chosen from a group including R9-phenyl, and R2 is chosen from a group including H and (C1-C6)-alkyl; R3 is chosen from a group including (C1-C6)-alkyl, (C1-C6)-alkoxy-(C1-C6)-alkyl- and R9-(C6-C10)-aryl; R4, R5, R6 and R7 are independently chosen from a group including H and (C1-C6)-alkyl; R8 is chosen from a group including и ; R9 means 1, 2 or 3 substitutes independently chosen from a group, including H, halogen and -CF3; R10 is chosen from a group including H and (C1-C6)-alkyl; R11 is (C3-C10)-cycloalkyl-S (O2)-; R15 and R16 are independently (C1-C6)-alkyl; R17 is R20O-; R20 is chosen from a group including H, and (C1-C6)-alkyl-(C6-C10)-aryl; Q is N; Z is CH; n is equal to 0; s is equal to 2; and t is equal to 2. Also, the invention concerns a pharmaceutical composition exhibiting properties of a chemokine receptor inhibitor, based on these compounds.
EFFECT: produced are the new compounds and based pharmaceutical composition can find application in medicine for treating human immunodeficiency virus (HIV) infection.
8 cl, 2 tbl, 1 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention relates to novel 5-substituted pyrimidines of general formula (I), their pharmaceutically acceptable additive salts probably in form of their stereochemically isomeric form. In general formula (I), A represents -CH2-CH2-, -CH=CH-; each of R1 independently represents hydrogen; R2 represents cyano; X1 represents -NR1-; R3 represents H, C1-6-alkyl, halogen; R4 represents H, C1-6-alkyl, halogen; R5 represents nitro, amino, mono- and di(C1-4-alkyl)amino, phenyl, probably substituted by halogen, halogen, -CO-H-, -COOR7, -NH-C(=O)H, -NH-C(=O)R6, -CH=N-O-R8; R6 represents C1-4-alkyl, amino, mono- or di(C1-4-alkyl)amino or polyhalogen-C1-6-alkyl; R7represents hydrogen, C1-6-alkyl; R8 represents hydrogen, C1-6-alkyl. Invention also relates to pharmaceutical composition based on novel compounds.
EFFECT: elaborated are compounds which possess antiviral activity with respect to HIV infection.
7 cl, 2 tbl, 33 ex
SUBSTANCE: compounds have formula (lb) in which R1 denotes (1) -N(R1A)SO2-R1B, (2) -SO2NR1CR1D, (3) -COOR1E, (4) -OR1F, (5) -S(O)mR1G; (6) -CONR1HR1J, (7) -NR1K COR1L, or (8) cyano, where m equals 0, 1 or 2;X denote a bond or a spacer which contains 1-3 atoms as the backbone chain; ; R1A, R1B, R1C, R1D, R1E, R1F, R1G, R1H, R1J, R1K and R1L each independently denotes (1) a hydrogen atom, (2) a C1-8alkyl group which can have a substitute (substitutes) selected from a group comprising  a hydroxy group,  a carboxy group,  a C1-6alkoxy group which can be substituted with a halogen and  a mono- or disubstituted amino substituted C1-8alkyl group or (3) tetrahydropyran, piperazine, piperidine, azetidine, pyrrolidine or morpholine, each of which can have a substitute (substitutes) selected from a group comprising hydroxy, halogen, C1-8alkanoyl and C1-10halogenalkyl, and where R1C and R1D, or R1H and R1J together with a nitrogen atom to which they are bonded can form piperazine, piperidine, azetidine, pyrrolidine or morpholine, each of which can have a substitute (substitutes) selected from a group comprising hydroxy, halogen, C1-8alkanoyl and C1-10halogenalkyl; ring A is a benzene ring or a pyridine ring, each of which can have a substitute (substitutes) selected from a group comprising C1-8alkyl, nitro, C1-6alkoxy and halogen; ring B is a benzene ring, a pyridine ring or a pyrazine ring, each of which can have a substitute (substitutes) selected from a group comprising C1-8alkyl; R51 denotes (1) C1-8alkyl, C2-8alkenyl or C2-8alkynyl, each of which can have a benzene substitute (substitutes) or (2) benzene, pyrazole, pyridine, isoxazole, thiophene, benzothiazole, each of which can have a substitute (substitutes) selected from a group comprising C1-4alkokyl, C1-6alkoxy, C1-6alkylthio, C1-6alkylthionyl, C1-6alkylsulphonyl and halogen; R52 denotes a hydrogen atom; R53 denotes (1) C1-8alkyl, C2-8alkenyl or C2-8alkynyl, each of which can have a benzene substitute (substitutes) or (3) benzene, pyrazole, pyridine, thiophene, benzodioxane, cyclohexan or tetrahydropyran, each of which can have a substitute (substitutes) selected from a group comprising  hydroxy group,  cyano,  carbamoyl,  aminocarbonyl, substituted with one or two substitutes selected from (a) hydroxy group, (b) amino, (c) C1-4alkoxy, (d) mono or disubstituted amine, substituted with a C1-8 hydrocarbon group, (e) carboxyl and (f) C1-6alkoxycarbonyl,  carboxy,  halogen,  C1-6alkoxy,  C1-6alkylsulphonyl,  amino,  C1-6acylamino,  alkyl-sulphonylamino,  cyclic aminocarbonyl and  C1-8 hydrocarbon group substituted with 1 or 2 substitutes selected from (a) hydroxy, (b) amino, (c) C1-4alkoxy, (d) mono or disubstituted amine, substituted with a C1-8 hydrocarbon group and (e) aminocarbonyl, substituted with a C1-8 hydrocarbon group; to salts thereof, N-oxide thereof and solvate thereof. The invention also relates to a pharmaceutical composition based on said compound, having antagonistic activity towards CCR5, to use of formula (1b) compound to produce an agent for preventing or treating CCR5 related diseases. Novel compounds which have anti CCR5 activity are obtained and described. Said compounds are therefore useful in preventing and/or treating CCR5 related diseases, for example various inflammatory diseases, immunological diseases etc.
EFFECT: wider field of use of the compounds.
7 cl, 11 ex, 1 tbl
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention discloses pharmaceutical composition for controlled release regarding toxic active compounds, in particular, bioactive proteins from class of interferons. Composition contains bio-degradable block-copolymer made of poly(ethyleneglycol)terephthalate (PEGT) in amount from 50 to 95%, and poly(butyleneterephthalate) (PBT). Agent may be represented as injection microparticles, injection liquid, capable of independent gel or solid implant formation. Besides, invention provides a pharmaceutical set, including specified composition, methods of composition making and pharmaceutical versions of its application.
EFFECT: invention provides for initial release within 4 hours of not more than approximately 10% of included amount of one or more alpha-interferons and at least 80% of one or more alpha-interferons are released in monomer non-aggregated form.
31 cl, 8 ex, 2 dwg
SUBSTANCE: present invention refers to a spray drying production process of a solid pharmaceutical powder containing microcrystalline cellulose in a solid dispersion of the anti-HIV compound etravirine (TMC125) in a water-soluble polymer. In a parent mixture, the relation of the water-soluble polymer to TMC 125 makes 10:1 to 1:1, and of microcrystalline cellulose to TMC 125 - 1:1 to 1:3. Said parent mixture of microcrystalline cellulose, a solution of the water-soluble polymer and etravirine is sprayed in the form of drops into a drying chamber by atomisers to form a solid dispersion of TMC 125 powder.
EFFECT: better solubility and bioavailability of the antiviral compound etravirine.
10 cl, 9 dwg, 2 tbl, 1 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to new compounds of formula (I) and to its pharmaceutically acceptable additive salts, optionally in the form of stereochemical isomer and exhibiting anti-HIV antiviral activity, particularly having HIV inhibitor properties and applied as a drug. In formula , -a1=a2-a3=a4- represents a bivalent radical of formula -CH=CH-CH=CH-(a-1); -b1=b2-b3-b4 - represents a bivalent radical of formula -CH=CH-CH=CH- (b-1); n is equal to 0, 1, 2, 3, 4; m is equal to 0, 1, 2; each R1 independently represents hydrogen; each R2 represents hydrogen; R2a represents cyano; X1 represents -NR1-; R3 represents C1-6alkyl, substituted cyano; C2-6alkrnyl, substituted cyano; R4 represents halogen; C1-6alkyl; R5 represents 5 or 6-member completely unsaturated cyclic system where one, two or three members of the cycle represent heteroatoms, each independently specified from the group consisting of nitrogen, oxygen and sulphur and where the rest members of the cycle represent carbon atoms; and where 6-member cyclic system can be optionally annelated with a benzene cycle; and where any carbon atom in the cycle can be independently optionally substituted with a substitute specified from C1-6alkyl, amino, mono- and diC1-4alkylamino, aminocarbonyl, mono-and diC1-4alkylcarbonylamino, phenyl and Het; where Het represents pyridyl, thienyl, furanyl; Q represents hydrogen The invention also concerns a pharmaceutical composition.
EFFECT: preparation of the new anti-HIV antiviral compounds.
4 cl, 2 tbl, 22 ex
SUBSTANCE: invention represents oral pharmaceutical preparative form for treatment and/or prevention of cancer, which includes (i) capsule, and (ii) core, including crystalline 2'-cyano-2'-deoxy-N4-palmitoyl-1-β-D- arabinofuranosylcytosine and liquid carrier, selected from triglyceride oil with average chain length and polyglycolised glyceride.
EFFECT: improvement of stability.
22 cl, 4 ex