Prodrug of polymerase ns5b hcv inhibitor, method for its preparation and application

FIELD: medicine; pharmaceuticals.

SUBSTANCE: present invention relates to a novel prodrug which is cyclobutyl (S)-2-{[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydrofuran-2-ylmethoxy]phenoxy-phosphorylamino}-propanoate of general formula 1, its stereoisomer, or polycrystalline form. Stereoisomers of this compound are cyclobutyl (S)-2-{(S)-[(2R,3R,4R,5R)-5-(3,4-dihydro-2,4-dioxo-2H-pyrimidin-1-yl)-3-hydroxy-4-methyl-4-fluoro-tetrahydrofuran-2-ylmethoxy]-phenoxy-phosphorylamino}-propanoate of formula 1.1 or cyclobutyl (S)-2-{(R)-[(2R,3R,4R,5R)-5-(3,4-dihydro-2,4-dioxo-2H-pyrimidin-1-yl)-3-hydroxy-4-methyl-4-fluoro-tetrahydrofuran-2-ylmethoxy]-phenoxy-phosphorylamino}-propanoate of formula 1.2. Polycrystalline form of these compounds is a mixture of rhombic and monoclinic forms. Crystalline form is a rhombic form. Method for preparation of the prodrug of formulas 1, 1.1 and 1.2 is the reaction of cyclobutyl (S)-2-(pentafluorophenyloxy-phenoxy-phosphorylamino)-propionate of formula 2 or cyclobutyl (S)-2-((S)-pentafluorophenyloxy-phenoxy-phosphorylamino)-propionate of formula 2.1 or cyclobutyl (S)-2-((R)-pentafluorophenyloxy-phenoxy-phosphorylamino)-propionate of formula 2.2 with tert-butyl(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidine-1(2H)-yl)-2-(hydroxymethyl)-4-methyl-4-fluoro-tetrahydrofuran-3-yl carbonate of formula 7 in the presence of an alkyl magnesium halide, followed by deprotection.

EFFECT: prodrug has the properties of a polymerase NS5B HCV inhibitor and can be used in treatment of hepatitis C.

10 cl, 10 ex, 3 tbl



Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds intended for treatment of hepatitis C of formula


its stereoisomeric forms, pharmaceutically acceptable salts or solvates, where R1 represents hydrogen; R2 represents hydrogen, napthyl or phenyl, optionally substituted with 1, 2 or 3 substituents, selected from halogen and C1-C6alkyl; R3 and R4 represent hydrogen or C1-C6alkyl; R5 represents C1-C10alkyl, optionally substituted with C1-C6alkoxygroup, C3-C7cycloalkyl or benzyl; R8 represents hydrogen.

EFFECT: claimed are novel compounds and composition on their base, effective against hepatitis C.

12 cl, 4 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of general formula 1 or their stereoisomers or pharmaceutically acceptable salts possessing the properties of inhibitors of RNA polymerase HCV NS5B, and to methods for producing them. In general formula 1 R1 represents C1-C4alkyl; R2 and R3 represents fluorine, or R2 represents fluorine, while R3 represents methyl; one of R4 and R5 represents hydrogen, and the other of R4 and R5 represents C1-C6acyl optionally substituted by α-aminoacyl specified in a group containing (dimethylamino)acetyl, 1-tert-butoxycarbonylamino-2-methyl-propylcarbonyl, 1-methylpyrrolidine-2-carbonyl, 1-methylpiperidine-3-carbonyl and 1-methylpiperidine-4-carbonyl, R6 represents hydrogen, methyl, methoxy and halogen.

EFFECT: compounds can be used for treating and preventing viral infections, including hepatitis C, optionally with additional agents specified in an inhibitor of inosin-5-monophosphate dehydrogenase, eg Ribamidine, an inhibitor of hepatitis C protease C NS3, eg Asunaprevir (BMS-650032), an inhibitor of hepatitis C protease C NS3/4A, eg Sofosbuvir (TMC435), an inhibitor of RNA-polymerase NS5A, eg Daclatasvir (BMS-790052) or Ledipasvir (GS-5885).

18 cl, 1 tbl, 14 ex

FIELD: medicine.

SUBSTANCE: invention refers to isopropyl ester of (S)-2-{[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-ftor-3-hydroxy-4-methyl-tetrahydrofuran-2-ylmethoxy]-phenoxy-phosphorylamino}-propionic acid and its stereoisomer which may be used for treating viral infections in mammals, a method for preparing it, based compositions and the use thereof for treating viral diseases. The prepared method involves a reaction of the compounds

and ,

wherein X' represents a leaving group.

EFFECT: what is presented is the new effective agent for treating the diseases caused by hepatitis A and C, West Nile encephalitis, yellow fever, Aden fever, bovine diarrhoea, Japanese encephalitis viruses, rhinovirus, poliovirus, and an effective method for preparing it.

14 cl, 82 ex, 32 tbl

FIELD: medicine.

SUBSTANCE: invention refers to compounds for treating hepatitis of formulae or wherein Ry represents alkyl or hydroxyalkyl; each Ra and Rb independently represents hydrogen, alkyl, arylalkyl or cycloalkyl; or together with nitrogen atom whereby substituted, form morpholine, piperidine or pyrrolidine; and each R2 and R3 are independently H, or R2 and R3 are bound, thereby forming a cyclic group by an alkyl, ester or carbamate bind. There are presented new biologically active compounds.

EFFECT: higher efficacy of the composition.

20 cl, 28 ex, 2 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to 5'-aminocarbonylphosphonate 3'-azido-3'-deoxythimidine salts showing anti-HIV-1 activity of general formula

where R is an alkaline and alkaline earth metal ion, or an ammonium ion with various substitutes.

EFFECT: preparing new compounds showing the ability to inhibit the human immunodeficiency virus selectively and being stable substances that facilitates preparing based drugs.

1 cl, 12 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to dinucleoside forms of phosphonic acids which can be used as antiviral agents, having formula where Azt is a 3'-azido-3'-deoxythymidine residue, ZTS - 2',3'-dideoxy-3'-thiacitidine residue, R is an electron acceptor group, for example ClCH2-, CH3C(O)CH2-, H2NCO-, PhCH2CH2HNCO-, PhOCH2-, CH3OCH2-, N3CH2-.

EFFECT: obtaining novel antiviral agents.

1 cl, 3 ex, 2 tbl

FIELD: medicine.

SUBSTANCE: invention refers to polymer conjugates of formula (I) comprising nucleotide or oligonucleotide residue, which can be applied for treatment of cancer and methods for their obtaining. where R1 and R2 independently represent H or polyalkylenoxyde, not necessarily having capping group selected from OH, NH2, SH, CO2N, C1-6 alkyls, compounds of formula (II) X2-(L2)n-(L1)o- and the formula (III) -(L4)p-(L3)m-X3, and when (o+n)≥2 each of n and o is a positive integer, each p and m are equal to zero, and R2 represents H, and when (p+m)≥2 each p and m is a positive integer, each n and o are equal to zero and R1 represents H; X1, X2, X3 are independently selected from a single-stranded or double-stranded oligonucleotide residue; L1 and L4 independently represent released link fragments; L2 and L3 are independently selected from bifunctional spacer groups.

EFFECT: developing of new nucleotide conjugates with antitumor activity.

21 cl, 25 ex, 7 tbl, 12 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to 5'-phosphorus-containing derivatives of 2',3'-dideoxy-3'-thiacytidine with general structural formula given below , where R=H, NH2-C(O)-. The invented compounds can be used for inhibiting reproduction of the human immunodeficiency virus type 1 in an MT-4 cell culture.

EFFECT: increased antiviral activity of the compounds.

1 cl, 2 tbl, 4 ex

FIELD: medicine.

SUBSTANCE: invention refers to new compounds of formula (IX) or to their pharmaceutically acceptable salts having inhibitory activity to hepatitis C, to the related pharmaceutical composition and to their application for making a medical product. In compound of formula (IX) , R1 and R2 independently represent H, phosphate or acyl; X represents O; base* represents pyrimidine base; R12 represents C(Y3)3; Y3 represents H and R13 represents fluorine.

EFFECT: higher efficiency of the composition and treatment method.

31 cl, 14 dwg, 26 ex

FIELD: biology.

SUBSTANCE: present invention relates to biotechnology, more specifically to obtaining nucleoside-5'-triphosphates, labelled with phosphorous-32 (phosphorous-33) in the alpha-position, and can be used for analysis in molecular biology, genetics and medical biochemistry. The method is realised through treatment of labelled nucleosidephosphate in a buffer solution with a mixture of deoxyribonucleoside monophosphate kinase of bacteriophage T5 and pyruvate kinase with subsequent chromatographic purification of the target product.

EFFECT: simple method of obtaining nucleoside-5'-triphosphates and stable output of the target product.

4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a crystalline compound effective for treating hyperproliferative diseases and having formula (I) ,

wherein A+ represents a conjugated acid of tris(hydroxymethyl)aminomethane (Tris); X and Y independently represent chlorine having a fusion point of 103.37°C-105.77°C, and an X-ray powder diffraction spectrum is presented in Fig. 2, as well as to using it for treating various oncological diseases.

EFFECT: what is presented is a new crystalline compound possessing high stability, effective for treating hyperproliferative diseases.

15 cl, 32 dwg, 2 tbl, 16 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of formulas: wherein Ry represents hydoxy(C1-C10)alkyl; Ra and Rb independently represent hydrogen, optionally substituted C1-C10 alkyl, aryl, aryl(C1-C10)alkyl or (C1-C10)cycloalkyl, or Ra and Rb together with a nitrogen atom form a heterocyclic or a heteroaryl ring having 3 to 7 members; R1 is specified in ribavirin, viramidine, valopicitabine, PSI-6130, MK-0608, resiquimod, celgosivir, lamivudine, entecavir, telbivudine, racivir, emtricitabine, clevudine, amdoxovir and valtorcitabine; as well as to compositions based thereon for treating hepatitis B or C.

EFFECT: there are presented new effective compounds for hepatitis B or C.

13 cl, 2 dwg, 28 ex

FIELD: chemistry.

SUBSTANCE: claimed invention is aimed at novel method of obtaining triamides from ammonia and amidodichlorides, in which initial substances are mixed with each other in absence of reverse mixing and are introduced into reaction, and concentration of amidodichloride in mixing device all the time constitutes less than 0.2 (mole/mole)% of reaction mixture, in terms of volume of said reaction mixture.

EFFECT: development of novel method of obtaining triamides from ammonia and amidodichlorides.

10 cl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compositions with improved urease inhibiting action, which contain at least two different triamides of (thio)phosphoric acid, as well as urea-containing fertilisers which contain said compositions. The invention also relates to a method of producing said compositions and use of said compositions when using urea-containing fertilisers in agriculture or horticulture. The composition contains triamide of (thio)phosphoric acid with structures according to the following formula (I), R1R2N-P(X)(NH2)2 (I), in which X denotes oxygen or sulphur, R1 denotes an alkyl group having 1-10 carbon atoms, cycloalkyl having 3-10 carbon atoms, aryl having 6-10 carbon atoms or dialkyl aminocarbonyl and R2 denotes hydrogen, or R1 and R2 together the nitrogen atom with which they are bonded form a 5- or 6-member saturated or unsaturated heterocyclic residue which, if necessary, can contain an additional 1 or 2 other heteroatoms selected from a group comprising nitrogen, oxygen and sulphur.

EFFECT: invention improves utilisation of nitrogen and reduces the required amount of urease inhibitors.

10 cl, 12 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a method of extracting acids from reaction mixtures containing at least one desired product with insignificant solubility in water using at least one nonpolar amine as an auxiliary base, involving steps a) reaction of the auxiliary base with acid to form a salt; b) reacting the salt formed at step (a) with another base which absorbs acid when freeing the auxiliary base; c) extraction of the mixture obtained at step (b) with water or aqueous medium, where the salt of another base dissolves in the aqueous phase and the desired product or solution of the desired product in a suitable solvent and the auxiliary base form at least one separate non-aqueous phase; and d) distillation of at least a portion of the inert solvent from at least one non-aqueous phase obtained at step (c), thereby forming two immiscible liquid phases. The invention also relates to a method of producing triamides of thiophosphoric acid involving the steps given above.

EFFECT: extracting acids from chemical reaction mixtures; producing triamides of thiophosphonic acid.

7 cl, 2 ex

FIELD: medicine.

SUBSTANCE: invention refers to A pharmaceutical composition including of one or more compounds specified from the group given in the patent claim and having an evident cytotoxic action and an antineoplastic effect provided by their ability to block a phosphor acceptor site on casein kinase 2 substrata by direct or indirect action, as well as to application of the compounds for preparation of medical products to inhibit malignant cell proliferation.

EFFECT: improved clinical effectiveness.

2 cl, 45 ex, 4 tbl, 1 dwg

FIELD: pharmacology.

SUBSTANCE: invention concerns N-phenylphosphoric acid triamides of general formula (I), method of their obtainment and application as inhibition agents in enzymic hydrolysis of carbamide , where X is oxygen or sulphur; R1, R2, R3, R4 are selected out of hydrogen, C1-C8 alkyl, alcoxy, fluorine, chlorine, bromine, iodine, trifluoromethyl.

EFFECT: obtaining novel efficient urease inhibitors.

12 cl, 4 ex, 1 tbl

The invention relates to the technology of composite wood and cellulosic materials

The invention relates to a technology for halogen-substituted derivatives of the amides postnasal acid

The invention relates to pharmacology, in particular ORGANOMETALLIC compounds possessing biological activity, which can find application in drug development for the prevention and treatment of coronary heart disease

FIELD: chemistry.

SUBSTANCE: method for production of crystalline iodine of reactive qualifications, which includes extraction of iodine from solutions to produce an iodine plaste, dehydration of iodine paste and sublimation of iodine. Dehydration of iodine-paste is carried out by evaporation of water at the first stage of the process of iodine sublimation, prior to sublimation sodium carbonate is added into the iodine-paste in the amount providing for pH of water condensate of at least 4.0, the process of sublimation of dehydrated iodine is carried out at the temperature of iodine vapours of 114-184°C, and partial pressure of iodine vapours in the iodine-water mixture prior to desublimation is reduced by dissolution with air to the pressure of saturated vapours of iodine in a triple point. The device for production of crystalline iodine of reactive qualifications includes an iodine evaporator, an iodine condenser with a receiver of finished product, a trap for off-gases and a tail fan. The iodine condenser is made from elastic film stretched onto a carcass, the inner space of the condenser is under vacuum, which prevents release of iodine vapours, at the same time iodine receiver is simultaneously a container for finished product.

EFFECT: increased quality of finished product, simplified and cheaper technological process and increased efficiency of the device.