Alkyl2-{[(2r,3s,5r)-5-(4-amino-2-oxo-2h-pyrimidine-1-yl)- -hydroxy- tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-proptonates, nucleoside inhibitors of rna-polymerase hcv ns5b, methods for producing and using them

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

 

The invention relates to new substituted alkyl 2-{[(2R,3S,5R)-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-3-hydroxy-tetrahydro-furan-2-ylethoxy]-phenoxy-phosphorylating}-propionate, nucleoside RNA polymerase of HCV NS5B, their use as a means to an inhibitor of RNA polymerase of HCV NS5B and the treatment of viral diseases. These compounds are inhibitors of RNA-dependent RNA viral replication and are useful as a nucleoside polymerase inhibitor of HCV NS5B inhibitors of the replication of hepatitis C virus (HCV) for the treatment of hepatitis C in mammals. The hepatitis C virus, along with other important human pathogens such as yellow fever virus, West Nile virus, the virus Dengue (Dengue) and hepatitis GBV-C), refers to Flaviviruses (genus Flaviviridae).

Examples of drug candidates can serve nucleoside inhibitors of the HCV polymerase NS5B: PSI-7977 firm Pharmasset, USA (US patents 07964580 B2 and US 8334270 B2) and NM283 (Valopicitabine) firm Idenix (USA) and others [M. J. Sofia, D. Bao, W. Chang, J. Du, D. Nagarathnam, S. Rachakonda, P. G. Reddy, B. S. Ross, P. Wang, H.-R. Zhang, S. Bansal, C. Espiritu, M. Keilman, A. M. Lam, H. M. M. Steuer, Congrong Niu, M. J. Otto, P. A. Furman. Discovery of a β-D-20-Deoxy-20-r-fluoro-20-β-C-methyluridme Nucleotide Prodrug (PSI-7977) for the Treatment of Hepatitis With Virus. J. Med. Chem. 2010, 53, 7202-7218].

The most advanced drug candidate is a nucleoside polymerase inhibitor of HCV NS5B (isopropyl (S)-2-{(S)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-PI is kidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylethoxy]-phenoxy-phosphorylating}-propanoate (PSI-7977). Gilead Sciences successfully conducts clinical research on treatment of HCV genotypes 1, 2 and 3 using PSI-7977 is a nucleotide analog polymerase inhibitor.

Experimental drug GS-7977 from Gilead Sciences, Inc, in conjunction with Galatasaray (Bristol-Myers Squibb Co) gave a successful result in 100% of cases in patients with viral hepatitis C, not previously held treatment, according to the intermediate data of the clinical studies presented at the European conference on liver diseases. It is important that the result was achieved without the use of interferon that causes a lot of side effects, which sometimes cause patients to interrupt or postpone treatment, and ribavirin, which is the most classical treatments.

Currently there are a limited number of approved therapeutic methods, which generally would be considered suitable for treatment of HCV infection. New and existing therapeutic approaches for the treatment of HCV and inhibition of HCV NS5B polymerase are described in the following works:

R. G. Gish, Sem. Liver. Dis., 1999 19: 5; Di Besceglie, A. M. And Bacon, B. R., Scientific American, October: 1999 80-85; G. Lake-Bakaarm Current and Future Therapy for Chronic Hepatitis With Virus Liver Disease, Curr. Drug Targ Infect Dis. 2003 3(3): 247-253; P. Hoffmann et al. Recent patents on experimental therapy for hepatitis With virus infection (1999-2002), Exp. Opin. Ther. Patents 2003 13(11): 1707-1723; F. Poordad et al. Developments in Hepatitis therapy drug during 2000-2002, Exp.Opin. Emerging Drugs 2003 8(1): 9-25; M. P. Walker et al. Promising Candidates for the treatment of chronic hepatitis C, Exp. Opin. Investig. Drugs 2003 12(8): 1269-1280; S. - L. Tan et al. Hepatitis With Therapeutics: Current Status and Emerging Strategies, Natire Rev. Drug Discov. 2002 1: 867-881; R. De Francesco et al. Approaching a new era for hepatitis With virus therapy: inhibitors of the NS3-4A serine protease and the NS5B RNA-dependent RNA polymerase. Antiviral Res. 2003 58: 1-16; Q. M. Wang et al. Hepatitis With virus encoded proteins: targets for antiviral therapy. Drugs of the Future 2000 25(9): 933-8-944; J. A. Wu and Z. Hong, Targeting NS5B-Dependent RNA Polymerase for Anti-HCV Chemotherapy Cur. Dmg Targ. - Inf. Dis. 2003 3: 207-219.

Nucleoside inhibitors of NS5B polymerase can act either as a non-natural substrate, which results in the termination circuit, or as a competitive inhibitor competes with the binding of the nucleotide to the polymerase. In order to function as a chain terminator, nucleoside analogue must be absorbed by the cell and converted in vivo triphosphate to compete for customers nucleotide binding to the polymerase. This conversion to the triphosphate is commonly by cellular kinases, which leads to additional structural requirements for the potential of the nucleoside polymerase inhibitor. Unfortunately, this limits the direct assessment of nucleosides as inhibitors of HCV replication in studies conducted on cells amenable to in situ phosphorylation.

B=adenine, thymidine, uracil, citizen, guanine and gipoksantin.

In WO 0190121, published on November 29, 2001, J.-P. Sommadossi and P. Lacolla described and gave examples of activity of anti-HCV polymerase in part 1'-alkyl - and 2'-alkynylamino formulas 2 and 3. In WO 01/92282 published on 6 December 2001, J.-P. Sommadossi and P. Lacolla disclosed and described examples of treating Flaviviruses and Pesti viruses 1'-alkyl - and 2'-alkynylamino formulas 2 and 3. In WO 03/026675, published April 3, 2003, G. Gosselin has described the use of 4'-alkynylamino formula 4 for treating Flaviviruses and Pestiviruses.

In WO 2004003000, published January 8, 2004, J.-P. Sommadossi et al. described 2'- and 3'-prodrugs based on 1'-, 2'-, 3'- and 4'-substituted β-D and β-L-nucleosides. In WO 2004/002422, published January 8, 2004, described 2'-C-methyl-3'-O-malinowy ether ribofuranosylthiazole for the treatment of Flaviviridae infection. Idenix reported clinical trials related compounds NM283, which I guess is the valine ester 5 and analogue 2 cytidine (B=cytosine). In WO 2004/002999, published January 8, 2004, J.-P. Sommadossi et al. he described a series of 2' or 3' prodrugs of 1', 2', 3' or 4'-branched nucleosides for the treatment of infections Flaviviridae, including HCV infections.

In WO 2004/046331, published June 3, 2004, J.-P. Sommadossi et al. described 2'-branched nucleosides and mutation Flaviviridae. In WO 03/026589, published April 3, 2003, G. Gosselin et al. described methods of treatment of viral hepatitis C using 4'-option is qualified nucleosides. In WO 2005009418, published February 3, 2005, R. Storer et al. described purine nucleoside analogues for the treatment of diseases caused by, including Flaviviridae.

Other patent applications disclose the use of certain nucleoside analogues for the treatment of viral hepatitis C. In WO 01/32153, published on 10 may 2001, R. Storer described derivatives of nucleosides for treatment of viral diseases. In WO 01/60315, published on 23 August 2001, H. Ismaili et al. described methods of treatment or prevention of infections caused by Flaviviruses, using derivatives of nucleosides. In WO 02/18404, published 7 March 2002, R. Devos et al. described 4'-substituted nucleosides for treatment of viral HCV. In WO 01/79246, published on 25 October 2001, K. A. Watanabe described derivatives of 2' or 3'-hydroxymethyl-nucleosides for treatment of viral diseases. In WO 02/32920, published April 25, 2002, and in WO 02/48165, published on 20 June 2002, L. Stuyver et al. described derivatives of nucleosides for treatment of viral diseases.

In WO 03/105770, published on 24 December 2003, C. Bhar et al. described a number of carbocyclic nucleoside derivatives which inhibit RNA-dependent RNA polymerase of the virus. Nucleosides disclosed in this publication are mainly 2'-methyl-2'-hydroxy-substituted nucleosides. In WO 2002/057425, published on 25 July 2002, S. S. Carroll et al. who wrote the derivatives of nucleosides, which inhibit RNA-dependent viral polymerases, and methods of treatment of HCV infections.

In WO 02/057287, published on 25 July 2002, S. S. Carroll et al. described related 2α-methyl and 2β-methylribose derivatives, in which the base is optional substituted 7H-pyrrolo[2,3-(1]pyrimidine radical 6. In the same application shows one example 3β-methyl-nuke. S. S. Cairoll et al. (J. Biol.Chem. 2003 278(14): 11979-11984) described the inhibition of HCV polymerase 2'-O-methylcytidine (6A). In WO 2004/009020, published on January 29, 2004, D. B. Olsen et al. described a number dinucleotide derivatives as inhibitors of RNA-dependent RNA polymerase of the virus.

PCT publication number WO 99/43691, in the name of Emory University, entitled "2'-Formulised", describes the use of certain 2'-pornological for treatment of HCV. US patent No. 6348587 issued by Emory University, entitled "2'-Formulised, shows the number of families 1'-pornological, useful in the treatment of hepatitis b, HCV, HIV and abnormal cell proliferation. Both configurations 1'-forsometimes disclosed.

Eldrup et al. (Oral Session V, Hepatitis With Vims, Flaviviridae; 16thInternational Conference on Antiviral Research (Apr. 27, 2003, Savannah, Ga.)) describe the relationship between structure and activity of 2'-modified nucleosides in terms of inhibition of HCV.

Br et al. (Oral Session V, Hepatitis C Virus, Flaviviridae; 16thInternational Conference on Antiviral Research (Apr. 27, 2003, Savannah, Ga.), p. A75) described the synthesis and pharmacoki eticheskie properties of nucleoside analogues as potential inhibitors of replication of HCV RNA. The authors reported that 2'-modified nucleosides show high inhibitory activity studies on cell replicons.

Olsen et al. (Oral Session V, Hepatitis C Virus, Flaviviridae; 16thInternational Conference on Antiviral Research (Apr. 27, 2003, Savannah, Ga.), p. A76) also showed the effect of 2'-modified nucleosides on the replication of HCV RNA.

Non-nucleoside allosteric inhibitors of HIV reverse transcriptase have proven to be an efficient therapeutic effect alone or in combination with nucleoside inhibitors and protease inhibitors. Several classes of non-nucleoside HCV NS5B inhibitors have already been described and are currently at the stage of testing, including benzimidazole (H. Hashimoto et al. WO 01/47833, H. Hashimoto et al. WO 03/000254, P. L. Beaulien et al. WO 03/020240: A2; P. L. Beaulien et al. US 6448281 B1, P. L. Beaulien et al. WO 03/007945 Al); indoles (P. L. Beaulien et al. WO 03/0010141 A2); benzothiadiazine, for example 7 (D. Dhanak et al. WO 01/85172 Al; D. Dhanak et al. WO 03/037262 A2; K. J. Duffy et al. WO 03/099801 Al; D. Chai et al. WO 2004052312, D. Chai et al. WO 2004052313, D. Chai et al. WO 02/098424, J. K. Pratt et al. WO 2004/041818 Al; J. K. Pratt et al. WO 2004/087577 A1), tifany, for example 8 (C. K. Chan et al. WO 02/100851)

Benzothiophene (D. S. Young and T. R. Bailey WO 00/18231); β-ketopropane (S. Attamura et al. US 6492423 B1, A. Attamura et al. WO 00/06529); pyrimidines (C Gardelli et al. WO 02/06246 A1); pyrimidinedione (T. R. Bailey and D. C. Young WO 00/13708); triazine (K.-H. Chung et al. WO 02/079187 A1); derivatives of rhodanine (T. R. Bailey and D. C. Young WO 00/1053, J. C. Jean et al. WO 01/77091 A2); 2,4-dioxopregna (R. A. Love et al. EP 256628 A2); derivatives of phenylalanine (M. Wang et al. J. Biol. Chem. 2003 278: 2489-2495).

Concomitant therapy that can be suppressed resistant mutant strains has become an accepted approach in antiviral chemotherapy. Described here nucleoside inhibitors can be combined with other nucleoside inhibitors of HCV polymerase, non-nucleoside inhibitors of HCV polymerase inhibitors and HCV protease. As it emerged and developed other classes of drug against HCV, such as inhibitors of virus entry inhibitors of helicase, IRES inhibitors, ribozymes and antisense oligonucleotides, they can also be excellent candidates for use in combination therapy. Derivatives of interferon has already been successfully combined with ribavirin and interferon or chemically modified interferon will be useful in combination with the described here nucleosides.

Derivatives of nucleosides are often effective anti-virus (such as HIV, HCV, Herpes simplex, CMV) and anti-cancer chemotherapeutic agents. Unfortunately, their practical use is often limited by two factors. First, poor pharmacokinetic properties often limit the absorption of nucleoside from the digestive tract and the intracellular concentration of the nucleoside is produced in the water, and secondly, suboptimal physical properties limit the choice of the drug compound, which could be used to increase the level of separation of the active ingredient.

Hepatitis C until the present time is a serious health problem. It leads to chronic liver disease, goes to liver cirrhosis and hepatocellular carcinoma.

In this regard, the search for new highly efficient protivovirusnyh drugs currently still is one of the main directions of development of new pharmacological agents for the treatment of a wide and diverse range of viral infections, including HCV. So up to the present time is the actual synthesis of new compounds and their use as antiviral active ingredients for pharmaceutical compositions and medicaments, including HCV.

Below are definitions of terms used in the description of this invention.

"Azaheterocycle" means an aromatic or non-aromatic monocyclic or polycyclic system containing a loop, at least one nitrogen atom.

"Alkyl" means an aliphatic hydrocarbon of linear or branched group with 1-12 carbon atoms in the chain. Branched means that the alkyl chain is one who does a few "lower alkyl" ( 1-C6)alkyl substituents. Preferred alkyl groups are lower (C1-C6)alkyl, or methyl, ethyl, n-propyl, ISO-propyl, n-butyl, ISO-butyl, sec-butyl, tert-butyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, n-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, n-hexyl, cyclohexyl. The alkyl may have substituents.

"Alkyloxy" or "Alkoxy" means Alkyla - group in which alkyl is defined in this section. The preferred alkoxygroup are methoxy, ethoxy, n-propoxy, ISO-propoxy, n-butoxy and tert-butoxy.

"Amino group" means R R"N - group, a substituted or unsubstituted not necessarily the same substituents R' and R". The amino group may have substituents.

"Aminocarbonyl" means C(=O)N RkaRk+1agroup, substituted or unsubstituted not necessarily the same substituents carbamaepine Rkaand Rk+1aincluding hydrogen, methyl, cycloalkyl, which with the nitrogen atom forms a pyrolidine cycle.

"Aryl" means an aromatic monocyclic or polycyclic system containing from 6 to 14 carbon atoms, predominantly from 6 to 10 carbon atoms. Aryl can contain one or more "cyclic system substituents"which may be the same or different.

"Aromatic cycle" (the romantic system) means a planar cyclic system, in which all the atoms of the cycle involved in the formation of a unified system of conjugation, including, according to the hückel rule, (4n+2) π-electrons (n is a nonnegative integer). Examples of aromatic cycles are benzene, naphthalene, anthracene, etc., In the case of heteroaromatic cycles in the system of pairing involves π-electrons and p-electrons of heteroatoms, their total number is also equal to (4n+2). Examples of such cycles include pyridine, thiophene, pyrrole, furan, thiazole, etc., Aromatic cycle can have one or more "cyclic system substituents" which may be annylirovan with non-aromatic cycle, heteroaromatic or heterocyclic system.

"Acyl group (Acyl) means R-C(=O) -, preferably C1-C6acyl), optionally substituted C1-C5alkyl-C(=O)-, C1-C5alkenyl-C(=O)-, C1-C5cycloalkyl-C(=O)- (preferably cyclopropyl-C(=O)-, cyclobutyl-C(=O)-); heterocyclyl-C(=O) -, preferably 2-methylfuran), aryl-C(=O)- (aroyl), aralkyl-C(=O) -, preferably 3-phenylpentane-C(=O)-), heteroaryl-C(=O)- (heteroaryl), heteroallyl-C(=O)- group, which1-C5alkyl, C1-C5alkenyl-, C1-C5cycloalkyl-, heterocyclyl-, aryl-, aralkyl, heteroaryl, heteroaromatic, methoxy group, these groups may have substituents, see "alternate C is Klionsky system", "substituted alkyl", "substituted alkenyl, the substituents of the heterocyclic system"is defined in this section.

"α-aminoaniline group (α-aminoacyl) means C(=O)CH(R2k)NR2k+1R2k+2,

where R2k, R2k+1and R2k+2can take is hydrogen, C1-C5alkyl-, aryl, heterocyclyl, or NR2kR2k+2is a 5-6 membered heterocycle, these groups may have substituents, see "cyclic system substituents", "substituted alkyl", "substituted alkenyl, the substituents of the heterocyclic system", "substituted aryl", as defined in this section.

"Active component" (drug substance, drug substance, drug-substance) means a physiologically active substance is synthetic or other (biotechnology, plant, animal, microbial or other origin, possessing pharmacological activity and which is the active beginning of the pharmaceutical composition used for the production and manufacture of the medicinal product (tools).

"Heteroaryl" (hetaryl) means an aromatic monocyclic or polycyclic system containing from 5 to 14 carbon atoms, preferably from 5 to 10, in which one or more carbon atoms Zam is shifted by a heteroatom or heteroatoms, such as nitrogen, sulfur or oxygen. The prefix "Aza", "oxa" or "thia" before "heteroaryl" means the presence in the cyclic system, nitrogen atom, oxygen atom or sulfur atom, respectively. The nitrogen atom located in heteroaryl, can be oxidized to N-oxide. Heteroaryl may have one or more "cyclic system substituents"which may be the same or different. Preferably pyrrolyl, furanyl, thienyl, pyridinyl, pyrrolidin, imidazolyl, oxazolyl, benzothiadiazole, indolyl, isoindolyl, benzimidazolyl, benzothiazolyl, chinoline, imidazolyl, cyanopyridyl, hintline, thienopyrimidines, pyrrolopyridine, imidazopyridine, ethenolysis, benzoxazinones, 1,2,4-triazinyl, thienopyrrole, properaly and other

"Heterocycle" means an aromatic or non-aromatic saturated or partially saturated monocyclic or polycyclic system containing from 3 to 10 carbon atoms, predominantly from 4 to 6 carbon atoms, in which one or more carbon atoms replaced by a heteroatom, such as nitrogen, oxygen, sulfur, phosphorus. The prefix "Aza", "oxa" or "thia" before heterocyclyl means the presence in the cyclic system of nitrogen atom, oxygen atom or sulfur atom, respectively. Heterocyclyl may have one or more substituents, which may be the same or different is mi. Atoms of nitrogen and sulfur, in heterocyclyl, can be oxidized to N-oxide, S-oxide or S-dioxide. Representatives heterocyclyl are piperidinyl, pyrrolidinyl, piperazinil, morpholinyl, thiomorpholine, thiazolidine, 1,4-dioxane-2-yl, tetrahydrofuryl, tetrahydrothieno and other

"Replaced alkenyl may also have one or more identical or different substituents including halogen, alkenylacyl, aroyl, heteroaryl, cyano, hydroxy, alkoxy, carboxy, alkyloxy, Alcoxy, aryloxy, aryloxyalkyl, alkylthio, heteroaromatic, Uralkali, arylsulfonyl, alkylsulfonyl, heteroarylboronic etc. Preferred alkenylamine groups are ethynyl, propenyl, n-butenyl, ISO-butenyl, 3-methylbut-2-enyl, n-pentenyl and n-hexenyl.

"Substituted alkyl" may have one or more identical or different substituents including halogen, alkenylacyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, aroyl, heteroaryl, cyano, hydroxy, alkoxy, carboxy, alkyloxy, Alcoxy, aryloxy, aryloxyalkyl, alkylthio, heteroaromatic, Uralkali, arylsulfonyl, alkylsulfonyl, heteroarylboronic RkaRk+1aN-, where Rkaand Rk+1aindependently from each other represent "amino substituents", which is defined in this section is, for example, a hydrogen atom, alkyl, aryl, aralkyl, heteroalkyl, heterocyclyl or heteroaryl, or Rkaand Rk+1atogether with the N atom to which they are bound, form a through Rkaand Rk+1a4-7 membered heterocyclyl or heterocyclyl. Predpochtitelnei "alkyl substituents are aryl, heteroaryl, heterocyclyl, hydroxy, C1-C5alkoxy, C1-C5alkoxycarbonyl, Alcoxy, aryloxy, alkylthio, heteroaromatic, Uralkali, alkylsulfonyl, arylsulfonyl, alkoxycarbonyl, arelaxation, heteroarylboronic or RkaRk+1aN, RkaRk+1aNC(=O)-, annelirovannymi arylheteroacetic, annelirovannymi arylheteroacetic. Namely, the hydroxy-group, substituted florfenicol oxygraph, mono - and dis1-C5alkylamino (dimethylaminopropyl, methylaminopropyl)1-C5allyloxycarbonyl group (ethoxycarbonyl), phenyl, chlorophenyl, forfinal,1-C5alkyl (methyl) substituted phenyl, With1-C5cycloalkyl (cyclopentyl) substituted phenyl, With1-C5alkoxy substituted phenyl (methoxyphenyl), thiophenyl, furanyl, pyrrolidin.

"Amino substituents R' and R" represent hydrogen, optionally substituted C1-C5alkyl, optionally substituted by the initial C 1-C5cycloalkyl (see Deputy cyclic system), optionally substituted aryl (see Deputy cyclic system), optionally substituted heteroaryl (see Deputy cyclic system), optionally substituted heterocyclyl (see Deputy cyclic systems)1-C5alkenyl, acyl, aroyl, heteroaryl, C1-C5alkylsulfonyl, arylsulfonyl, heteroarylboronic, alkoxycarbonyl, substituted linear or nelineinym1-C5by alkyl, halogen, heterocyclyl; aryloxyalkyl, arelaxation, alkylaminocarbonyl, allumination, heteroarylboronic, heterocyclization, alkylaminocarbonyl, allumination, heteroarylboronic, heterocyclization, optionally substituted aminosulfonyl. R R"N-group may represent nonaromatic azaheterocycle, preferably azetidin, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, homopiperazine, homopiperazin. Preferred substituents of the amino groups are hydrogen, C1-C5alkyl, C1-C5cycloalkyl, substituted C1-C5alkyl (the"substituted alkyl"), not necessarily simultaneously substituted by 1-3 radicals substituted phenyl (C1-C5by alkyl, halogen, C1-C5alkoxy group, a C1-C allyloxycarbonyl), pyridinyl, optionally substituted by titaniam, optionally substituted TuranAlem (see "cyclic system substituents").

"Cyclic system substituents" can represent aryl groups, preferably phenyl or naphthyl, substituted phenyl or substituted naphthyl. The aryl may be annylirovan with non-aromatic cyclic system or heterocycle. Preferably zamestitelyami cyclic system are hydrogen, halogen (chlorine, fluorine, bromine), optionally substituted C1-C5alkyl, optionally substituted ciclos1-C5alkyl, C1-C5alkene, hydroxygroups, C1-C5alkyloxy (methoxy, ethoxy, propoxy, fluids ethylene glycol fluids of methanediol), cyano, C1-C5allyloxycarbonyl (methyl, ethyl), allylthiourea (methylthio)carboxypropyl, aminocarbonyl (see "aminocarbonyl"), phenyl annelirovannymi with a 5-7 membered saturated cycle containing 1-3 heteroatoms (atoms nitrogen, oxygen and sulfur, preferably).

"Deputy" means a chemical moiety that is attached to the molecular core (scaffold, fragment), for example, Deputy alkyl", "Deputy amino group", "Deputy carbamoyl", "Deputy cyclic system", which is defined in this section.

"Substituted aminocarbonyl group" (aminocarbonyl) means R R N-C(=O)- group in which the substituents R' and R" can be represented optionally substituted by alkyl, alkenyl, quinil, cycloalkyl, aryl, hetaryl and heterocyclyl, the value of which is determined in this section. Preferred aminocarbonyl groups are optionally substituted C1-C5alkyl, C1-C5alkenyl,1-C5cycloalkyl, optionally substituted aryl (see Deputy cyclic system), optionally substituted hetaryl (see Deputy cyclic system), optionally substituted heterocyclyl (see Deputy heterocyclyl) or amino group, R R"n

"Substituted oxycarbonyl group" (oxycarbonyl) means R-O-C(=O)- group in which the substituent R can be represented optionally substituted by alkyl, alkenyl, cycloalkyl, aryl, hetaryl and heterocyclyl, the value of which is determined in this section. Preferred oxycarbonyl groups are methoxycarbonyl, etoxycarbonyl, tert-butyloxycarbonyl and benzyloxycarbonyl.

"Deputy carbamoyl" means the Deputy attached to aminocarbonyl group, the value of which is defined in this section. Deputy carbamoyl represents hydrogen, alkyl, cyclea the keel, aryl, heteroaryl, heterocyclyl, alkoxycarbonyl, alcoxycarboxylates, heteroarylboronic-carbonylethyl or RkaRk+1aN-, RkaRk+1aNC(=O)-alkyl, annelirovannymi heteroarylboronic, annelirovannymi heteroalicyclic, annelirovannymi heterooligomerization, annelirovannymi heteroalicyclic, annelirovannymi arylchloroalkanes, annelirovannymi aristically, annelirovannymi arylheteroacetic, annelirovannymi arylheteroacetic. Preferred substituents carbamaepine" are alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkoxycarbonyl, alcoxycarboxylates, heteroarylboronic or RkaRk+1aN-, RkaRk+1aNC(=O)-alkyl, annelirovannymi arylheteroacetic, annelirovannymi arylheteroacetic.

"Substituents of the heterocycle can be representatives of aryl groups, preferably phenyl or naphthyl, substituted phenyl or substituted naphthyl. The aryl may be annylirovan with non-aromatic cyclic system or heterocycle. Preferably zamestitelyami cyclic system are hydrogen, halogen (chlorine, fluorine, bromine), optionally substituted C1-C5alkyl, optionally substituted ciclos1-C5alkyl, C1-C alkene, hydroxygroups,1-C5alkyloxy (methoxy, ethoxy, propoxy, fluids, ethylene glycol fluids of methanediol), cyano, C1-C5allyloxycarbonyl (methyl, ethyl), allylthiourea (methylthio)carboxypropyl, aminocarbonyl (see "aminocarbonyl"), phenyl, annelirovannymi with a 5-7 membered saturated cycle containing 1-3 heteroatoms (atoms nitrogen, oxygen and sulfur, preferably).

"The drug (the drug), a substance (or mixture of substances in the form of pharmaceutical compositions in the form of tablets, capsules, injections, ointments and other fabricated forms intended for restoring, correcting or modifying physiological functions in humans and animals, as well as for treatment and prevention of diseases, diagnostics, anesthesia, contraception, cosmetology and others.

"Lower alkyl" means a linear or branched alkyl with 1-6 carbon atoms.

"Therapeutic cocktail" is simultaneously SKOLKOVO initiative combination of two or more drugs with different mechanisms of pharmacological action and aimed at different biological target involved in the pathogenesis of the disease.

"Pharmaceutical composition" means a composition comprising a compound of formula I and at least one component selected from the group consisting of farmacevtichesky acceptable and pharmacologically compatible excipients, solvents, diluents, carriers, auxiliary, distributing and perceiving means, means of delivery, such as preservatives, stabilizers, fillers, shredders, moisturizers, emulsifiers, suspendresume agents, thickeners, sweeteners, flavors, fragrances, antibacterial agents, fungicides, lubricants, regulators prolonged delivery, the choice and the value of which depends on the nature and mode of appointment and dosage. Examples suspendida agents are ethoxylated isostearoyl alcohol, polyoxyethylene, sorbitol and sorbitol ester, microcrystalline cellulose, Metagalaxy aluminum, bentonite, agar-agar and tragakant, as well as mixtures of these substances. Protection from the action of microorganisms can be ensured by various antibacterial and antifungal agents such as parabens, chlorobutanol, sorbic acid and similar compounds. The composition may also include isotonic agents such as sugars, sodium chloride and the like. Prolonged action of the composition can be achieved with agents that slow the absorption of the active principle, for example, aluminum monostearate and gelatin. Examples of suitable carriers, solvents, diluents and delivery vehicles include water, ethanol, polyalcohol, and the mixture vegetable oils (such as olive oil) and injectable organic esters (such as etiloleat). Examples of fillers are lactose, milk sugar, sodium citrate, calcium carbonate, calcium phosphate and the like. Examples of shredders and distributes funds are starch, aginova acid and its salts, silicates. Examples of lubricants are magnesium stearate, sodium lauryl sulphate, talc, and polyethylene with high molecular weight. Pharmaceutical composition for oral, sublingual, transdermal, intramuscular, intravenous, subcutaneous, local or rectal injection of the active principle, one or in combination with other active early, can be introduced animals and people in the standard form of administration, mixed with conventional pharmaceutical carriers. Usable standard form of introduction include oral forms such as tablets, gelatin capsules, pills, powders, granules, chewing gum and oral solutions or suspensions, sublingual and transbukkalno forms of administration, aerosols, implants, local, transdermal, subcutaneous, intramuscular, intravenous, intranasal or intraocular forms of administration and rectal forms of administration.

"Pharmaceutically acceptable salt" means in relation to detox cnie organic and inorganic salts of acids and bases, claimed in the present invention. These salts can be obtained in situ during the synthesis, separation, or purification of compounds or prepared. In particular, salts of bases can be obtained specifically on the basis of the purified free base of the claimed compounds and a suitable organic or inorganic acid. Examples of the thus obtained salts are hydrochloride, hydrobromide, sulphates, bisulfate, phosphates, nitrates, acetates, oxalates, valeriote, oleates, palmitate, stearates, laurate, borate, benzoate, lactates, tozilaty, citrates, maleate, fumarate, succinate, tartratami, mesylates, malonate, salicylates, propionate, econsultancy, bansilalpet, sulfamate and the like (for a detailed description of the properties of such salts are described in Berge S. M., et al., "Pharmaceutical Salts" J. Pharm. Sci. 1977, 66: 1-19). Salts of the stated acids can also be specially obtained by the reaction of purified acid with a suitable base, can be synthesized metal salts and amines. The metal include sodium, potassium, calcium, barium, zinc, magnesium, lithium and aluminum, the most desirable of which are sodium and potassium salts. Suitable inorganic bases which can be obtained metal salts are the hydroxide, carbonate, bicarbonate and sodium hydride, hydroxide and bicarbonate of potassium, potash, g is droxia lithium calcium hydroxide, magnesium hydroxide, zinc hydroxide. As organic bases, of which can be obtained salts of the stated acids, selected amines and amino acids with sufficient basicity to form a stable salt, and suitable for use in medical purposes (in particular, they should have a low toxicity). Such amines include ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, benzylamine, dibenzylamine, dicyclohexylamine, piperazine, ethylpiperidine, Tris(hydroxymethyl)aminomethane and the like. In addition, for the salt formation can be used tetraalkylammonium hydroxide, such as, choline, Tetramethylammonium, tetraethylammonium and the like. As amino acids can be used basic amino acids such as lysine, ornithine and arginine.

The purpose of the present invention is to provide new inhibitors of RNA polymerase.

This goal is achieved new nucleoside inhibitors of RNA polymerase General formula 1, their stereoisomers, salts, hydrate, solvate or crystalline form.

The subject of this invention are new substituted alkali 2-{[(2R,3S,5R)-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-3-hydroxy-tetrahydro-furan-2-ylethoxy]-phenoxy-phosphorylating}-propionate General formula is 1, their stereoisomers, salts, hydrate, solvate or crystalline form:

where

R1represent1-C4alkyl;

R2and R3represent fluorine, or

R2represents fluorine, and R3represents methyl;

R4and R5represent hydrogen, or

R4represents a C1-C6acyl, a R5represents hydrogen, or

R4represents hydrogen, and R5represents a C1-C6acyl, or

R4represents an optionally substituted α-aminoacyl, and R5represents hydrogen, or

R4represents hydrogen, and R5represent optionally substituted

α-aminoacyl;

R6represents hydrogen, methyl, methoxy or halogen atom.

Preferred is (S)-isopropyl 2-{[(2R,3S,5R)-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-3-hydroxy-tetrahydro-furan-2-ylethoxy]-phenoxy-phosphorylating}-propionate General formula 2 and (S)-isopropyl 2-{[(2R,3S,5R)-3-acetoxy-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-tetrahydro-furan-2-ylethoxy]-phenoxy-phosphorylating}-propionate General formula 3, their stereoisomers, salts, hydrate, solvate or crystalline form:

More p is impactfully are substituted by alkyl (S)-2-{[(2R,3S,5R)-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-4,4-debtor-3-hydroxy-tetrahydro-furan-2-ylethoxy]-phenoxy-phosphorylating}-propionate General formula 1.1 and substituted alkyl (S)-2-{[(2R,3S,4R,5R)-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-4,4-debtor-3-hydroxy-4-methyl-4-fluoro-tetrahydro-furan-2-ylethoxy]-phenoxy-phosphorylating}-propionate the General formula 1.2.

where R1, R4and R5have the above value.

More preferred are a substituted alkyl 2-{[(2R,3S,5R)-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-3-hydroxy-tetrahydro-furan-2-ylethoxy]-phenoxy-phosphorylating}-propionate, substituted alkyl (S)-2-{[(2R,3S,5R)-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-4,4-debtor-3-hydroxy-tetrahydro-furan-2-ylethoxy]-phenoxy-phosphorylating}-propionate General formula 1.1.1, 1.1.2 and substituted alkyl (S)-2-{[(2R,3S,4R,5R)-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-4,4-debtor-3-hydroxy-4-methyl-4-fluoro-tetrahydro-furan-2-ylethoxy]-phenoxy-phosphorylating}-propionate General formula 1.2.1, 1.2.2.

where R1, R4, R5and R6have the above value.

The most preferred substituted alkyl 2-{[(2R,3S,5R)-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-3-hydroxy-tetrahydro-furan-2-ylethoxy]-phenoxy-phosphorylating}-propionate are:

(S)-isopropyl 2-{[(2R,3S,5R)-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-3-(2-dimethylamino-acetoxy)-4,4-debtor-3-hydroxy-tetrahydro-furan-2-ylethoxy]-phenoxy-phosphorylating}-propionate (1.1.1(1));

(2R,3S,5R)-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-4,4-debtor-2-[((S)-1-isopropoxycarbonyl-ethylamino)-Fe is oxy phosphoramidates]-tetrahydro-furan-3-yl(S)-1-methyl-pyrrolidin-2-carboxylate (1.1.1(2));

(2R,3R)-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-4,4-debtor-2-[(S)-((S)-1-isopropoxycarbonyl-ethylamino)-phenoxy-phosphoramidates]-tetrahydro-furan-3-yl (S)-2-tert-butoxycarbonylamino-3-methyl-butanoate (1.1.1(3));

(2R,3R)-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-4,4-debtor-2-[(R)-((S)-1-isopropoxycarbonyl-ethylamino)-phenoxy-phosphoramidates]-tetrahydro-furan-3-yl (S)-2-tert-butoxycarbonylamino-3-methyl-butanoate (1.1.1(4));

isopropyl (S)-2-({(2R,3R,5R)-5-[4-(2-dimethylamino-acetylamino)-2-oxo-2H-pyrimidine-1-yl]-4,4-debtor-3-hydroxy-tetrahydro-furan-2-ylethoxy}-phenoxy-phosphorylating)-propionate (1.1.2(1));

isopropyl (S)-2-({(2R,3R,5R)-5-[4-((R)-2-tert-butoxycarbonylamino-3-methyl-Butylimino)-2-oxo-2H-pyrimidine-1-yl]-4,4-debtor-3-hydroxy-tetrahydro-furan-2-ylethoxy}-phenoxy-phosphorylating)-propionate (1.1.2(2));

isopropyl (S)-2-[((2R,3R,5R)-4,4-debtor-3-hydroxy-5-{4-[((S)-1-methylpyrrolidine-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(3));

methyl (S)-2-[((2R,3R,5R)-4,4-debtor-3-hydroxy-5-{4-[((S)-1-methylpyrrolidine-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(4));

isopropyl (R)-2-[((2R,3R,5R)-4,4-debtor-3-hydroxy-5-{4-[((S)-1-methylpyrrolidine-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(5));

isopropyl (S)-2-[(4-chlorphen the SR)-((2R,3R)-4,4-debtor-3-hydroxy-5-{4-[((S)-1-methylpyrrolidine-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(6));

isopropyl (S)-2-[(2,4-dichlorphenoxy)-((2R,3R)-4,4-debtor-3-hydroxy-5-{4-[((S)-1-methyl-pyrrolidin-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(7));

isopropyl (S)-2-[((2R,3R)-4,4-debtor-3-hydroxy-5-{4-[((S)-1-methyl-pyrrolidin-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-p-tolyl-phosphorylating)-propionate (1.1.2(8));

isopropyl (S)-2-((S)-{(2R,3R,5R)-5-[4-(2-dimethylaminoacetyl)-2-oxo-2H-pyrimidine-1-yl]-4,4-debtor-3-hydroxy-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(9));

isopropyl (S)-2-((R)-{(2R,3R,5R)-5-[4-(2-dimethylaminoacetyl)-2-oxo-2H-pyrimidine-1-yl]-4,4-debtor-3-hydroxy-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(10));

isopropyl (S)-2-[(S)-((2R,3R,5R)-4,4-debtor-3-hydroxy-5-{4-[((S)-1-methylpyrrolidine-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(11));

isopropyl (S)-2-[(R)-((2R,3R,5R)-4,4-debtor-3-hydroxy-5-{4-[((S)-1-methylpyrrolidine-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(12));

methyl (S)-2-{[((2R,3R,5R)-4,4-debtor-3-hydroxy-5-{4-[((S)-1-methylpyrrolidine-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(13));

isopropyl (S)-2-[((2R,3R,5R)-4,4-debtor-3-hydroxy-5-{4-[((S)-1-meth is pyrrolidin-3-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(14));

isopropyl (S)-2-[((2R,3R,5R)-4,4-debtor-3-hydroxy-5-{4-[((S)-1-methylpyrrolidine-4-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(5));

isopropyl (S)-2-({(2R,3R,4R,5R)-5-[4-(2-dimethylaminoacetyl)-2-oxo-2H-pyrimidine-1-yl]-4-methyl-4-fluoro-3-hydroxy-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.2.2(1));

isopropyl (R)-2-({(2R,3R,4R,5R)-5-[4-(2-dimethylaminoacetyl)-2-oxo-2H-pyrimidine-1-yl]-4-methyl-4-fluoro-3-hydroxy-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.2.2(2));

isopropyl (R)-2-[((2R,3R,4R,5R)-3-hydroxy-4-methyl-4-fluoro-5-{4-[((S)-1-methylpyrrolidine-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.2.2(3));

isopropyl (S)-2-((S)-{(2R,3R,4R,5R)-5-[4-(2-dimethylaminoacetyl)-2-oxo-2H-pyrimidine-1-yl]-4-methyl-4-fluoro-3-hydroxy-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.2.2(4));

isopropyl (S)-2-((R)-{(2R,3R,4R,5R)-5-[4-(2-dimethylaminoacetyl)-2-oxo-2H-pyrimidine-1-yl]-4-methyl-4-fluoro-3-hydroxy-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.2.2(5));

isopropyl (S)-2-[(S)-((2R,3R,4R,5R)-3-hydroxy-4-methyl-4-fluoro-5-{4-[((S)-1-methylpyrrolidine-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.2.2(6));

isopropyl (S)-2-[(R)-((2R,3R,4R,5R)-3-hydroxy-4-methyl-4-fluoro-5-{4-[((S)-1-m is tiliroside-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.2.2(7)).

The subject of this invention is a method of obtaining compounds of General formula 1 and General formula 2, their stereoisomers, pharmaceutically acceptable salt, hydrate, solvate or crystalline form by the interaction of the compounds of General formula 4 with a compound of General formula 5

where R1, R2, R3, R4, R5and R6have the above values.

The subject of this image is etenia is a method of obtaining compounds of General formula 2, their stereoisomer, salt, hydrate, MES or crystalline form, the interaction of compounds of General formula 4(1) with the compound of General formula 5(1).

where R2, R3have the above values.

The subject of this invention is a method of obtaining compounds of General formula 1, their stereoisomers, pharmaceutically acceptable salt, hydrate, solvate or crystalline form by the interaction of the compounds of General formula 6 with an anhydride of General formula 7 in the presence of 4-dimethylaminopyridine (DMAP) and triethylamine.

where R4represent an optionally substituted α-aminoacyl, R5represent hydrogen, and R1, R2, R3and R6have the above values.

The subject of this invention is a method of obtaining compounds of General formula 3, its stereoisomer, salt, hydrate, MES or crystalline form by the interaction of the compounds of General formula 2 with acetic anhydride in the presence of 4-dimethylaminopyridine (DMAP) and triethylamine.

The subject of this invention is a method of obtaining compounds of General formula 1, their stereoisomers, pharmaceutically acceptable salt, hydrate, solvate or crystalline form of the interaction of the compounds of General formula 6 with an α-amino acid of General formula 8 in the presence of 1,1'-carbodiimide.

where R4represents hydrogen, R5represents an optionally substituted α-aminoacyl, and R1, R2, R3and R6have the above values.

The subject of this invention is a method of obtaining compounds of General formula 1, its stereoisomers, salts, hydrates, solvate, crystalline or polycrystalline form by the interaction of the compounds of General formula 9 with an acid of General formula 10 in the presence of 1,1'-carbodiimide and subsequent debateroom formed product 11.

where R4represents an optionally substituted α-aminoacyl, R5represents hydrogen, and R1, R2, R3and R6have the above values.

Separation of compounds of General formula 1, 2 and 3 on their phosphorus stereoisomers carried out by crystallization and/or liquid chromatography high pressure (HPLC).

The parent compound, which are used to obtain new inhibitors of General formula 1, 2 and 3 are commercially available or obtained by the known methods described in the literature.

The object of this invention is the active component with the properties of NAA is osignage inhibitor of RNA polymerase of HCV NS5B, represents a substituted alkyl 2-{[(2R,3S,5R)-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-3-hydroxy-tetrahydro-furan-2-ylethoxy]-phenoxy-phosphorylating}-propionate General formula 1, its stereoisomer, salt, hydrate, MES or crystalline form, (S)-isopropyl 2-{[(2R,3S,5R)-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-3-hydroxy-tetrahydro-furan-2-ylethoxy]-phenoxy-phosphorylating}-propionate General formula 2 and (S)-isopropyl 2-{[(2R,3S,5R)-3-acetoxy-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-tetrahydro-furan-2-ylethoxy]-phenoxy-phosphorylating}-propionate General formula 3, their stereoisomers, salts, hydrates, solvate or crystalline form.

Preferred nucleoside inhibitor of RNA polymerase of HCV NS5B is substituted by alkyl (S)-2-{[(2R,3S,5R)-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-4,4-debtor-3-hydroxy-tetrahydro-furan-2-ylethoxy]-phenoxy-phosphorylating}-propionate General formula 1.1 and substituted alkyl (S)-2-{[(2R,3S,4R,5R)-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-4,4-debtor-3-hydroxy-4-methyl-4-fluoro-tetrahydro-furan-2-ylethoxy]-phenoxy-phosphorylating}-propionate General formula 1.2.

Preferred nucleoside inhibitor of RNA polymerase of HCV NS5B is also substituted by alkyl (S)-2-{[(2R,3S,5R)-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-4,4-debtor-3-hydroxy-tetrahydro-furan-2-ylethoxy]-phenoxy-phosphorylating}-propionate General formula 1.1.1, 1.1.2 and substituted alkyl (S)-2-{[(2R,3S,4R,5R)-5-(4-amino-2-oxo-2H-shall eremein-1-yl)-4,4-debtor-3-hydroxy-4-methyl-4-fluoro-tetrahydro-furan-2-ylethoxy]-phenoxy-phosphorylating}-propionate General formula 1.2.1, 1.2.2.

The most preferred nucleoside inhibitor of RNA polymerase of HCV NS5B is:

(S)-isopropyl 2-{{(2R,3S,5R)-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-3-(2-dimethylamino-acetoxy)-4,4-debtor-3-hydroxy-tetrahydro-furan-2-ylethoxy]-phenoxy-phosphorylating}-propionate (1.1.1(1));

(2R,3S,5R)-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-4,4-debtor-2-[((S)-1-isopropoxycarbonyl-ethylamino)-phenoxy-phosphoramidates]-tetrahydro-furan-3-yl (S)-1-methyl-pyrrolidin-2-carboxylate (1.1.1(2));

(2R,3R)-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-4,4-debtor-2-[(S)-((S)-1-isopropoxycarbonyl-ethylamino)-phenoxy-phosphoramidates]-tetrahydro-furan-3-yl (S)-2-tert-butoxycarbonylamino-3-methyl-butanoate (1.1.1(3));

(2R,3R)-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-4,4-debtor-2-[(R)-((S)-1-isopropoxycarbonyl-ethylamino)-phenoxy-phosphoramidates]-tetrahydro-furan-3-yl (S)-2-tert-butoxycarbonylamino-3-methyl-butanoate (1.1.1(4));

isopropyl (S)-2-({(2R,3R,5R)-5-[4-(2-dimethylamino-acetylamino)-2-oxo-2H-pyrimidine-1-yl]-4,4-debtor-3-hydroxy-tetrahydro-furan-2-ylethoxy}-phenoxy-phosphorylating)-propionate (1.1.2(1));

isopropyl (S)-2-({(2R,3R,5R)-5-[4-((R)-2-tert-butoxycarbonylamino-3-methyl-Butylimino)-2-oxo-2H-pyrimidine-1-yl]-4,4-debtor-3-hydroxy-tetrahydro-furan-2-ylethoxy}-phenoxy-phosphorylating)-propionate (1.1.2(2));

isopropyl (S)-2-[((2R,3R,5R)-4,4-debtor-3-hydroxy-5-{4-[((S)-1-methylpyrrolidine-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro is-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(3));

methyl (S)-2-[((2R,3R,5R)-4,4-debtor-3-hydroxy-5-{4-[((S)-1-methylpyrrolidine-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(4));

isopropyl (R)-2-[((2R,3R,5R)-4,4-debtor-3-hydroxy-5-{4-[((S)-1-methylpyrrolidine-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(5));

isopropyl (S)-2-[(4-chlorphenoxy)-((2R,3R)-4,4-debtor-3-hydroxy-5-{4-[((S)-1-methylpyrrolidine-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(6));

isopropyl (S)-2-[(2,4-dichlorphenoxy)-((2R,3R)-4,4-debtor-3-hydroxy-5-{4-[((5)-1-methyl-pyrrolidin-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(7));

isopropyl (S)-2-[((2R,3R)-4,4-debtor-3-hydroxy-5-{4-[((S)-1-methyl-pyrrolidin-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-p-tolyl-phosphorylating)-propionate (1.1.2(8));

isopropyl (S)-2-((S)-{(2R,3R,5R)-5-[4-(2-dimethylaminoacetyl)-2-oxo-2H-pyrimidine-1-yl]-4,4-debtor-3-hydroxy-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(9));

isopropyl (S)-2-((R)-{(2R,3R,5R)-5-[4-(2-dimethylaminoacetyl)-2-oxo-2H-pyrimidine-1-yl]-4,4-debtor-3-hydroxy-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(10));

isopropyl (S)-2-[(S)-((2R,3R,5R)-4,4-debtor-3-hydroxy-5-{4[((3)-1-methylpyrrolidine-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(11));

isopropyl (S)-2-[(R)-((2R,3R,5R)-4,4-debtor-3-hydroxy-5-{4-[((S)-1-methylpyrrolidine-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(12));

methyl (S)-2-{[((2R,3R,5R)-4,4-debtor-3-hydroxy-5-{4-[((S)-1-methylpyrrolidine-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(13));

isopropyl (S)-2-[((2R,3R,5R)-4,4-debtor-3-hydroxy-5-{4-[((S)-1-methylpyrrolidine-3-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(14));

isopropyl (S)-2-[((2R,3R,5R)-4,4-debtor-3-hydroxy-5-{4-[((S)-1-methylpyrrolidine-4-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(5));

isopropyl (S)-2-({(2R,3R,4R,5R)-5-[4-(2-dimethylaminoacetyl)-2-oxo-2H-pyrimidine-1-yl]-4-methyl-4-fluoro-3-hydroxy-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.2.2(1));

isopropyl (R)-2-({(2R,3R,4R,5R)-5-[4-(2-dimethylaminoacetyl)-2-oxo-2H-pyrimidine-1-yl]-4-methyl-4-fluoro-3-hydroxy-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.2.2(2));

isopropyl (R)-2-[((2R,3R,4R,5R)-3-hydroxy-4-methyl-4-fluoro-5-{4-[((S)-1-methylpyrrolidine-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.2.2(3));

isopropyl (S)-2-((S)-{(2R,3R,4R,5R)-5-[4-(2-dimethylaminoacetyl)-2-about the co-2H-pyrimidine-1-yl]-4-methyl-4-fluoro-3-hydroxy-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.2.2(4));

isopropyl (S)-2-((R)-{(2R,3R,4R,5R)-5-[4-(2-dimethylaminoacetyl)-2-oxo-2H-pyrimidine-1-yl]-4-methyl-4-fluoro-3-hydroxy-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.2.2(5));

isopropyl (S)-2-[(S)-((2R,3R,4R,5R)-3-hydroxy-4-methyl-4-fluoro-5-{4-[((S)-1-methylpyrrolidine-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.2.2(6));

isopropyl (S)-2-[(R)-((2R,3R,4R,5R)-3-hydroxy-4-methyl-4-fluoro-5-{4-[((S)-1-methylpyrrolidine-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.2.2(7)).

The subject of this invention is a method of inhibiting RNA polymerase of HCV NS5B, which consists in contacting RNA polymerase of HCV NS5B substituted with alkyl 2-{[(2R,3S,5R)-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-3-hydroxy-tetrahydro-furan-2-ylethoxy]-phenoxy-phosphorylating}-propionate General formula 1, or (S)-isopropyl 2-{[(2R,3S,5R)-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-3-hydroxy-tetrahydro-furan-2-ylethoxy]-phenoxy-phosphorylating}-propionate General formula 2, or (S)-isopropyl 2-{[(2R,3S,5R)-3-acetoxy-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-tetrahydro-furan-2-ylethoxy]-phenoxy-phosphorylating}-propionate General formula 3 or a stereoisomer, salt, hydrate, MES or crystalline form.

The preferred method of inhibiting RNA polymerase of HCV NS5B is the pic is b, which consists in contacting RNA polymerase of HCV NS5B substituted with alkyl (S)-2-{[(2R,3S,5R)-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-4,4-debtor-3-hydroxy-tetrahydro-furan-2-ylethoxy]-phenoxy-phosphorylating}-propionate General formula 1.1 or substituted alkyl (S)-2-{[(2R,3S,4R,5R)-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-4,4-debtor-3-hydroxy-4-methyl-4-fluoro-tetrahydro-furan-2-ylethoxy]-phenoxy-phosphorylating}-propionate General formula 1.2.

The preferred method of inhibiting RNA polymerase of HCV NS5B is also the method which consists in contacting RNA polymerase of HCV NS5B substituted with alkyl (S)-2-{[(2R,3S,5R)-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-4,4-debtor-3-hydroxy-tetrahydro-furan-2-ylethoxy]-phenoxy-phosphorylating}-propionate General formula 1.1.1, 1.1.2 or substituted alkyl (S)-2-{[(2R,3S,4R,5R)-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-4,4-debtor-3-hydroxy-4-methyl-4-fluoro-tetrahydro-furan-2-ylethoxy]-phenoxy-phosphorylating}-propionate General formula 1.2.1,1.2.2.

The most preferred method of inhibiting RNA polymerase of HCV NS5B is the method which consists in contacting RNA polymerase of HCV NS5B with a compound selected from the following:

(S)-isopropyl 2-{[(2R,3S,5R)-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-3-(2-dimethylamino-acetoxy)-4,4-debtor-3-hydroxy-tetrahydro-furan-2-ylethoxy]-phenoxy-phosphorylating}-propionate (1.1.1(1));

(2R,3S,5R)-5-(4-amino-2-oxo-2H-p is rimidine-1-yl)-4,4-debtor-2-[((S)-1-isopropoxycarbonyl-ethylamino)-phenoxy-phosphoramidates]-tetrahydro-furan-3-yl (S)-1-methyl-pyrrolidin-2-carboxylate (1.1.1(2));

(2R,3R)-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-4,4-debtor-2-[(S)-((S)-1-isopropoxycarbonyl-ethylamino)-phenoxy-phosphoramidates]-tetrahydro-furan-3-yl (S)-2-tert-butoxycarbonylamino-3-methyl-butanoate (1.1.1(3));

(2R,3R)-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-4,4-debtor-2-[(R)-((S)-1-isopropoxycarbonyl-ethylamino)-phenoxy-phosphoramidates]-tetrahydro-furan-3-yl (S)-2-tert-butoxycarbonylamino-3-methyl-butanoate (1.1.1(4));

isopropyl (S)-2-({(2R,3R,5R)-5-[4-(2-dimethylamino-acetylamino)-2-oxo-2H-pyrimidine-1-yl]-4,4-debtor-3-hydroxy-tetrahydro-furan-2-ylethoxy}-phenoxy-phosphorylating)-propionate (1.1.2(1));

isopropyl (S)-2-({(2R,3R,5R)-5-[4-((R)-2-tert-butoxycarbonylamino-3-methyl-Butylimino)-2-oxo-2H-pyrimidine-1-yl]-4,4-debtor-3-hydroxy-tetrahydro-furan-2-ylethoxy}-phenoxy-phosphorylating)-propionate (1.1.2(2));

isopropyl (S)-2-[((2R,3R,5R)-4,4-debtor-3-hydroxy-5-{4-[((8)-1-methylpyrrolidine-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(3));

methyl (S)-2-[((2R,3R,5R)-4,4-debtor-3-hydroxy-5-{4-[((8)-1-methylpyrrolidine-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(4));

isopropyl (R)-2-[((2R,3R,5R)-4,4-debtor-3-hydroxy-5-{4-[((S)-1-methylpyrrolidine-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(5));

isopropyl (S)-2-[(4-chlorphen the SR)-((2R,3R)-4,4-debtor-3-hydroxy-5-{4-[((S)-1-methylpyrrolidine-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(6));

isopropyl (S)-2-[(2,4-dichlorphenoxy)-((2R,3R)-4,4-debtor-3-hydroxy-5-{4-[((S)-1-methyl-pyrrolidin-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(7));

isopropyl (S)-2-[((2R,3R)-4,4-debtor-3-hydroxy-5-{4-[((S)-1-methyl-pyrrolidin-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-p-tolyl-phosphorylating)-propionate (1.1.2(8));

isopropyl (S)-2-((S)-{(2R,3R,5R)-5-[4-(2-dimethylaminoacetyl)-2-oxo-2H-pyrimidine-1-yl]-4,4-debtor-3-hydroxy-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(9));

isopropyl (S)-2-((R)-{(2R,3R,5R)-5-[4-(2-dimethylaminoacetyl)-2-oxo-2H-pyrimidine-1-yl]-4,4-debtor-3-hydroxy-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(10));

isopropyl (S)-2-[(S)-((2R,3R,5R)-4,4-debtor-3-hydroxy-5-{4-[((S)-1-methylpyrrolidine-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(11));

isopropyl (S)-2-[(R)-((2R,3R,5R)-4,4-debtor-3-hydroxy-5-{4-[((S)-1-methylpyrrolidine-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(12));

methyl (S)-2-{[((2R,3R,5R)-4,4-debtor-3-hydroxy-5-{4-[((S)-1-methylpyrrolidine-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(13));

isopropyl (S)-2-[((2R,3R,5R)-4,4-debtor-3-hydroxy-5-{4-[((S)-1-meth is pyrrolidin-3-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(14));

isopropyl (S)-2-[((2R,3R,5R)-4,4-debtor-3-hydroxy-5-{4-[((S)-1-methylpyrrolidine-4-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(5));

isopropyl (S)-2-({(2R,3R,4R,5R)-5-[4-(2-dimethylaminoacetyl)-2-oxo-2H-pyrimidine-1-yl]-4-methyl-4-fluoro-3-hydroxy-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.2.2(1));

isopropyl (R)-2-({(2R,3R,4R,5R)-5-[4-(2-dimethylaminoacetyl)-2-oxo-2H-pyrimidine-1-yl]-4-methyl-4-fluoro-3-hydroxy-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.2.2(2));

isopropyl (R)-2-[((2R,3R,4R,5R)-3-hydroxy-4-methyl-4-fluoro-5-{4-[((S)-1-methylpyrrolidine-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.2.2(3));

isopropyl (S)-2-((S)-{(2R,3R,4R,5R)-5-[4-(2-dimethylaminoacetyl)-2-oxo-2H-pyrimidine-1-yl]-4-methyl-4-fluoro-3-hydroxy-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.2.2(4));

isopropyl (S)-2-((R)-{(2R,3R,4R,5R)-5-[4-(2-dimethylaminoacetyl)-2-oxo-2H-pyrimidine-1-yl]-4-methyl-4-fluoro-3-hydroxy-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.2.2(5));

isopropyl (S)-2-[(S)-((2R,3R,4R,5R)-3-hydroxy-4-methyl-4-fluoro-5-{4-[((S)-1-methylpyrrolidine-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.2.2(6));

isopropyl (S)-2-[(R)-((2R,3R,4R,5R)-3-hydroxy-4-methyl-4-fluoro-5-{4-[((S)-1-m is tiliroside-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.2.2(7)).

The subject of this invention is a pharmaceutical composition for the treatment and prevention of viral infections, including hepatitis C, in the form of tablets, capsules, or injections, placed in pharmaceutically acceptable packing, not necessarily containing the inhibitor of inosine-5-monophosphate dehydrogenase, and/or protease inhibitors of hepatitis C NS3, and/or protease inhibitors of hepatitis C NS3/4A, and/or an inhibitor of RNA polymerase, NS5A, comprising a therapeutically effective amount of compounds of General formula 1, 2 or 3, or a stereoisomer, salt, hydrate, solvate or crystalline form.

More preferred is a pharmaceutical composition containing a therapeutically effective amount of substituted alkyl (S)-2-{[(2R,3S,5R)-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-4,4-debtor-3-hydroxy-tetrahydro-furan-2-ylethoxy]-phenoxy-phosphorylating}-propionate General formula 1.1 or substituted alkyl (S)-2-{[(2R,3S,4R,5R)-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-4,4-debtor-3-hydroxy-4-methyl-4-fluoro-tetrahydro-furan-2-ylethoxy]-phenoxy-phosphorylating}-propionate General formula 1.2.

More preferred is a pharmaceutical composition containing a therapeutically effective amount of substituted alkyl (S)-2-{[(2R,3S,5R)-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-4,4-debtor-3-hydroxy-tetrahydro-furan-2-ylethoxy]-phenoxy-phosphorylating}-propionate total formula.1.1, 1.1.2 or substituted alkyl (S)-2-{[(2R,3S,4R,5R)-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-4,4-debtor-3-hydroxy-4-methyl-4-fluoro-tetrahydro-furan-2-ylethoxy]-phenoxy-phosphorylating}-propionate General formula 1.2.1, 1.2.2.

Most preferred is a pharmaceutical composition containing a therapeutically effective amount of a compound selected from the following:

(S)-isopropyl 2-{[(2R,3S,5R)-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-3-(2-dimethylamino-acetoxy)-4,4-debtor-3-hydroxy-tetrahydro-furan-2-ylethoxy]-phenoxy-phosphorylating}-propionate (1.1.1(1));

(2R,3S,5R)-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-4,4-debtor-2-[((S)-1-isopropoxycarbonyl-ethylamino)-phenoxy-phosphoramidates]-tetrahydro-furan-3-yl (S)-1-methyl-pyrrolidin-2-carboxylate (1.1.1(2));

(2R,3R)-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-4,4-debtor-2-[(S)-((S)-1-isopropoxycarbonyl-ethylamino)-phenoxy-phosphoramidates]-tetrahydro-furan-3-yl (S)-2-tire-butoxycarbonylamino-3-methyl-butanoate (1.1.1(3));

(2R,3R)-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-4,4-debtor-2-[(R)-((S)-1-isopropoxycarbonyl-ethylamino)-phenoxy-phosphoramidates]-tetrahydro-furan-3-yl (S)-2-term-butoxycarbonylamino-3-methyl-butanoate (1.1.1(4));

isopropyl (S)-2-({(2R,3R,5R)-5-[4-(2-dimethylamino-acetylamino)-2-oxo-2H-pyrimidine-1-yl]-4,4-debtor-3-hydroxy-tetrahydro-furan-2-ylethoxy}-phenoxy-phosphorylating)-propionate (1.1.2(1));

isopropyl (S)-2-({(2R,3R,5R)-5-[4-((R)-2-tert-butoxycarbonyl the Ino-3-methyl-Butylimino)-2-oxo-2H-pyrimidine-1-yl]-4,4-debtor-3-hydroxy-tetrahydro-furan-2-ylethoxy}-phenoxy-phosphorylating)-propionate (1.1.2(2));

isopropyl (S)-2-[((2R,3R,5R)-4,4-debtor-3-hydroxy-5-{4-[((S)-1-methylpyrrolidine-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(3));

methyl (S)-2-[((2R,3R,5R)-4,4-debtor-3-hydroxy-5-{4-[((S)-1-methylpyrrolidine-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(4));

isopropyl (R)-2-[((2R,3R,5R)-4,4-debtor-3-hydroxy-5-{4-[((S)-1-methylpyrrolidine-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(5));

isopropyl (S)-2-[(4-chlorphenoxy)-((2R,3R)-4,4-debtor-3-hydroxy-5-{4-[((S)-1-methylpyrrolidine-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(6));

isopropyl (S)-2-[(2,4-dichlorphenoxy)-((2R,3R)-4,4-debtor-3-hydroxy-5-{4-[((S)-1-methyl-pyrrolidin-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(7));

isopropyl (S)-2-[((2R,3R)-4,4-debtor-3-hydroxy-5-{4-[((S)-1-methyl-pyrrolidin-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-p-tolyl-phosphorylating)-propionate (1.1.2(8));

isopropyl (S)-2-((S)-{(2R,3R,5R)-5-[4-(2-dimethylaminoacetyl)-2-oxo-2H-pyrimidine-1-yl]-4,4-debtor-3-hydroxy-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(9));

isopropyl (S)-2-((R)-{(2R,3R,5R)-5-[4-(2-dimethyl is invocationinfo)-2-oxo-2H-pyrimidine-1-yl]-4,4-debtor-3-hydroxy-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(10));

isopropyl (S)-2-[(S)-((2R,3R,5R)-4,4-debtor-3-hydroxy-5-{4-[((S)-1-methylpyrrolidine-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(11));

isopropyl (S)-2-[(R)-((2R,3R,5R)-4,4-debtor-3-hydroxy-5-{4-[((S)-1-methylpyrrolidine-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(12));

methyl (S)-2-{[((2R,3R,5R)-4,4-debtor-3-hydroxy-5-{4-[((S)-1-methylpyrrolidine-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(13));

isopropyl (S)-2-[((2R,3R,5R)-4,4-debtor-3-hydroxy-5-{4-[((S)-1-methylpyrrolidine-3-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(14));

isopropyl (S)-2-[((2R,3R,5R)-4,4-debtor-3-hydroxy-5-{4-[((S)-1-methylpyrrolidine-4-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(5));

isopropyl (S)-2-({(2R,3R,4R,5R)-5-[4-(2-dimethylaminoacetyl)-2-oxo-2H-pyrimidine-1-yl]-4-methyl-4-fluoro-3-hydroxy-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.2.2(1));

isopropyl (R)-2-({(2R,3R,4R,5R)-5-[4-(2-dimethylaminoacetyl)-2-oxo-2H-pyrimidine-1-yl]-4-methyl-4-fluoro-3-hydroxy-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.2.2(2));

isopropyl (R)-2-[((2R,3R,4R,5R)-3-hydroxy-4-methyl-4-fluoro-5-{4-[((3)-1-methylp Raiden-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.2.2(3));

isopropyl (S)-2-((S)-{(2R,3R,4R,5R)-5-[4-(2-dimethylaminoacetyl)-2-oxo-2H-pyrimidine-1-yl]-4-methyl-4-fluoro-3-hydroxy-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.2.2(4));

isopropyl (S)-2-((R)-{(2R,3R,4R,5R)-5-[4-(2-dimethylaminoacetyl)-2-oxo-2H-pyrimidine-1-yl]-4-methyl-4-fluoro-3-hydroxy-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.2.2(5));

isopropyl (S)-2-[(S)-((2R,3R,4R,5R)-3-hydroxy-4-methyl-4-fluoro-5-{4-[((R)-1-methylpyrrolidine-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.2.2(6));

isopropyl (S)-2-[(R)-((2R,3R,4R,5R)-3-hydroxy-4-methyl-4-fluoro-5-{4-[((S)-1-methylpyrrolidine-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.2.2(7)).

Most preferred is a pharmaceutical composition, in which as an inhibitor of inosine-5-monophosphate dehydrogenase used Ribamidil, as protease inhibitors of hepatitis C NS3 use Asunaprevir (BMS-650032), as protease inhibitors of hepatitis C NS3/4A use Sofosbuvir (TMC435), and as an inhibitor of RNA polymerase, NS5A use Daclatasvir (BMS-790052) or Declatasvir (GS-5885).

The subject of this invention is a medicinal product containing as active principle an effective amount of compounds of General formula 1, 2 or 3, their stereoisomers, salts, hydrates, with Iwata or crystalline form, for the treatment of any condition caused by hepatitis C.

More preferred is a pharmaceutical preparation containing as active principle an effective amount of substituted alkyl (S)-2-{[(2R,3S,5R)-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-4,4-debtor-3-hydroxy-tetrahydro-furan-2-ylethoxy]-phenoxy-phosphorylating}-propionate General formula 1.1 or substituted alkyl (S)-2-{[(2R,3S,4R,5R)-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-4,4-debtor-3-hydroxy-4-methyl-4-fluoro-tetrahydro-furan-2-ylethoxy-phenoxy-phosphorylating}-propionate General formula 1.2.

More preferred is a drug containing as active principle an effective amount of substituted alkyl (S)-2-{[(2R,3S,5R)-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-4,4-debtor-3-hydroxy-tetrahydro-furan-2-ylethoxy]-phenoxy-phosphorylating}-propionate General formula 1.1.1, 1.1.2 or substituted alkyl (S)-2-{[(2R,3S,4R,5R)-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-4,4-debtor-3-hydroxy-4-methyl-4-fluoro-tetrahydro-furan-2-ylethoxy]-phenoxy-phosphorylating}-propionate General formula 1.2.1, 1.2.2.

Most preferred is a pharmaceutical preparation containing as active principle an effective amount of the compounds selected from the following:

(S)-isopropyl 2-{[(2R,3S,5R)-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-3-(2-dimethylamino-acetoxy)-4,4-debtor-3-hydroxy-tetrahydro-furan-2-olmeto is C]-phenoxy-phosphorylating}-propionate (1.1.1(1));

(2R,3S,5R)-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-4,4-debtor-2-[((S)-1-isopropoxycarbonyl-ethylamino)-phenoxy-phosphoramidates]-tetrahydro-furan-3-yl (S)-1-methyl-pyrrolidin-2-carboxylate (1.1.1(2));

(2R,3R)-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-4,4-debtor-2-[(S)-((S)-1-isopropoxycarbonyl-ethylamino)-phenoxy-phosphoramidates]-tetrahydro-furan-3-yl (S)-2-tert-butoxycarbonylamino-3-methyl-butanoate (1.1.1(3));

(2R,3R)-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-4,4-debtor-2-[(R)-((S)-1-isopropoxycarbonyl-ethylamino)-phenoxy-phosphoramidates]-tetrahydro-furan-3-yl (S)-2-tert-butoxycarbonylamino-3-methyl-butanoate (1.1.1(4));

isopropyl (S)-2-({(2R,3R,5R)-5-[4-(2-dimethylamino-acetylamino)-2-oxo-2H-pyrimidine-1-yl]-4,4-debtor-3-hydroxy-tetrahydro-furan-2-ylethoxy}-phenoxy-phosphorylating)-propionate (1.1.2(1));

isopropyl (S)-2-({(2R,3R,5R)-5-[4-((R)-2-tert-butoxycarbonylamino-3-methyl-Butylimino)-2-oxo-2H-pyrimidine-1-yl]-4,4-debtor-3-hydroxy-tetrahydro-furan-2-ylethoxy}-phenoxy-phosphorylating)-propionate (1.1.2(2));

isopropyl (S)-2-[((2R,3R,5R)-4,4-debtor-3-hydroxy-5-{4-[((S)-1-methylpyrrolidine-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(3));

methyl (S)-2-[((2R,3R,5R)-4,4-debtor-3-hydroxy-5-{4-[((S)-1-methylpyrrolidine-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(4));

isopropyl (R)-2-[((2R,3R,5R)-4,4-iftar-3-hydroxy-5-{4-[((S)-1-methylpyrrolidine-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(5));

isopropyl (S)-2-[(4-chlorphenoxy)-((2R,3R)-4,4-debtor-3-hydroxy-5-{4-[((S)-1-methylpyrrolidine-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(6));

isopropyl (S)-2-[(2,4-dichlorphenoxy)-((2R,3R)-4,4-debtor-3-hydroxy-5-{4-[((S)-1-methyl-pyrrolidin-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(7));

isopropyl (S)-2-[((2R,3R)-4,4-debtor-3-hydroxy-5-{4-[((S)-1-methyl-pyrrolidin-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-p-tolyl-phosphorylating)-propionate (1.1.2(8));

isopropyl (S)-2-((S)-{(2R,3R,5R)-5-[4-(2-dimethylaminoacetyl)-2-oxo-2H-pyrimidine-1-yl]-4,4-debtor-3-hydroxy-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(9));

isopropyl (S)-2-((R)-{(2R,3R,5R)-5-[4-(2-dimethylaminoacetyl)-2-oxo-2H-pyrimidine-1-yl]-4,4-debtor-3-hydroxy-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(10));

isopropyl (S)-2-[(S)-((2R,3R,5R)-4,4-debtor-3-hydroxy-5-{4-[((S)-1-methylpyrrolidine-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(11));

isopropyl(S)-2-[(R)-((2R,3R,5R)-4,4-debtor-3-hydroxy-5-{4-[((3)-1-methylpyrrolidine-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(12));

methyl (S)-2-{[((2R,3R,5R)-4,4-debtor-3-hydrox�-5-{4-[((S)-1-methylpyrrolidine-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(13));

isopropyl (S)-2-[((2R,3R,5R)-4,4-debtor-3-hydroxy-5-{4-[((S)-1-methylpyrrolidine-3-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(14));

isopropyl (S)-2-[((2R,3R,5R)-4,4-debtor-3-hydroxy-5-{4-[((S)-1-methylpyrrolidine-4-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(5));

isopropyl (S)-2-({(2R,3R,4R,5R)-5-[4-(2-dimethylaminoacetyl)-2-oxo-2H-pyrimidine-1-yl]-4-methyl-4-fluoro-3-hydroxy-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.2.2(1));

isopropyl (R)-2-({(2R,3R,4R,5R)-5-[4-(2-dimethylaminoacetyl)-2-oxo-2H-pyrimidine-1-yl]-4-methyl-4-fluoro-3-hydroxy-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.2.2(2));

isopropyl (R)-2-[((2R,3R,4R,5R)-3-hydroxy-4-methyl-4-fluoro-5-{4-[((3)-1-methylpyrrolidine-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.2.2(3));

isopropyl (S)-2-((S)-{(2R,3R,4R,5R)-5-[4-(2-dimethylaminoacetyl)-2-oxo-2H-pyrimidine-1-yl]-4-methyl-4-fluoro-3-hydroxy-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.2.2(4));

isopropyl (S)-2-((R)-{(2R,3R,4R,5R)-5-[4-(2-dimethylaminoacetyl)-2-oxo-2H-pyrimidine-1-yl]-4-methyl-4-fluoro-3-hydroxy-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.2.2(5));

isopropyl (S)-2-[(S)-((2R,3R,4R,5R)-3-hydroxy-4-methyl-4-fluoro-5-{4-[((S)-1-metile Raiden-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.2.2(6));

isopropyl (S)-2-[(R)-((2R,3R,4R,5R)-3-hydroxy-4-methyl-4-fluoro-5-{4-[((S)-1-methylpyrrolidine-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.2.2(7)).

Drugs can be administered orally or parenterally (e.g. intravenously, subcutaneously, intraperitoneally, topically or rectally). The clinical dosage of the active ingredient (substance), pharmaceutical composition or drug combination tool, comprising pharmaceutically effective amount of the active component, patients may be adjusted depending on therapeutic efficacy and bioavailability of the active ingredients in the body, the speed of their metabolism and excretion from the body, and depending on age, gender and stage of disease of the patient, the daily dose in adults is usually 10~500 mg, preferably 50~300 mg. Therefore, during the preparation of pharmaceutical compositions of the present invention in the form of dosage units it is necessary to consider the above-mentioned effective dosage, each the unit dosage of the drug should contain 10~500 mg, preferably 50~300 mg. In accordance with the instructions of the doctor or pharmacist these medications can be taken several times during a defined time period (preferably the t one to six times).

The subject of this invention is a method of treating disease caused by the hepatitis C virus, which includes the introduction of therapeutically effective amounts of compounds of General formula 1, 2 or 3 or its stereoisomer, salt, hydrate, MES, crystalline forms or pharmaceutical compositions containing compounds of General formula 1, 2 or 3, or a stereoisomer, salt, hydrate, solvate, crystal form.

The preferred method of treatment of a disease caused by the hepatitis C virus, in subjects in need, is a method, which includes the introduction of a therapeutically effective amount of substituted alkyl (S)-2-{[(2R,3S,5R)-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-4,4-debtor-3-hydroxy-tetrahydro-furan-2-ylethoxy]-phenoxy-phosphorylating}-propionate General formula 1.1 or substituted alkyl (S)-2-{[(2R,3S,4R,5R)-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-4,4-debtor-3-hydroxy-4-methyl-4-fluoro-tetrahydro-furan-2-ylethoxy]-phenoxy-phosphorylating}-propionate General formula 1.2.

The preferred method of treatment of a disease caused by the hepatitis C virus, in subjects in need is also a method, which includes the introduction of a therapeutically effective amount of substituted alkyl (S)-2-{[(2R,3S,5R)-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-4,4-debtor-3-hydroxy-tetrahydro-furan-2-ylethoxy]-phenox the-phosphorylating}-propionate General formula 1.1.1, 1.1.2 or substituted alkyl (S)-2-{[(2R,3S,4R,5R)-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-4,4-debtor-3-hydroxy-4-methyl-4-fluoro-tetrahydro-furan-2-ylethoxy]-phenoxy-phosphorylating}-propionate General formula 1.2.1, 1.2.2.

The most preferred method of treating disease caused by the hepatitis C virus, in subjects in need, is a method, which includes the introduction of a therapeutically effective amount of compounds selected from the following:

(S)-isopropyl 2-{[(2R,3R,5R)-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-3-(2-dimethylamino-acetoxy)-4,4-debtor-3-hydroxy-tetrahydro-furan-2-ylethoxy]-phenoxy-phosphorylating}-propionate (1.1.1(1));

(2R,3S,5R)-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-4,4-debtor-2-[((S)-1-isopropoxycarbonyl-ethylamino)-phenoxy-phosphoramidates]-tetrahydro-furan-3-yl (S)-1-methyl-pyrrolidin-2-carboxylate (1.1.1(2));

(2R,3R)-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-4,4-debtor-2-[(S)-((S)-1-isopropoxycarbonyl-ethylamino)-phenoxy-phosphoramidates]-tetrahydro-furan-3-yl (S)-2-tert-butoxycarbonylamino-3-methyl-butanoate (1.1.1(3));

(2R,3R)-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-4,4-debtor-2-[(R)-((S)-1-isopropoxycarbonyl-ethylamino)-phenoxy-phosphoramidates]-tetrahydro-furan-3-yl (S)-2-tert-butoxycarbonylamino-3-methyl-butanoate (1.1.1(4));

isopropyl (5)-2-({(2R,3R,5R)-5-[4-(2-dimethylamino-acetylamino)-2-oxo-2H-pyrimidine-1-yl]-4,4-debtor-3-hydroxy-tetrahydro-furan-2-ylethoxy}-dryer is XI-phosphorylating)-propionate (1.1.2(1));

isopropyl (S)-2-({(2R,3R,5R)-5-[4-((R)-2-tert-butoxycarbonylamino-3-methyl-Butylimino)-2-oxo-2H-pyrimidine-1-yl]-4,4-debtor-3-hydroxy-tetrahydro-furan-2-ylethoxy}-phenoxy-phosphorylating)-propionate (1.1.2(2));

isopropyl (S)-2-[((2R,3R,5R)-4,4-debtor-3-hydroxy-5-{4-[((S)-1-methylpyrrolidine-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(3));

methyl (S)-2-[((2R,3R,5R)-4,4-debtor-3-hydroxy-5-{4-[((S)-1-methylpyrrolidine-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(4));

isopropyl (R)-2-[((2R,3R,5R)-4,4-debtor-3-hydroxy-5-{4-[((S)-1-methylpyrrolidine-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(5));

isopropyl (S)-2-[(4-chlorphenoxy)-((2R,3R)-4,4-debtor-3-hydroxy-5-{4-[((S)-1-methylpyrrolidine-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(6));

isopropyl (S)-2-[(2,4-dichlorphenoxy)-((2R,3R)-4,4-debtor-3-hydroxy-5-{4-[((S)-1-methyl-pyrrolidin-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(7));

isopropyl (S)-2-[((2R,3R)-4,4-debtor-3-hydroxy-5-{4-[((S)-1-methyl-pyrrolidin-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-p-tolyl-phosphorylating)-propionate (1.1.2(8));

isopropyl (S)-2-(S)-{(2R,3R,5R)-5-[4-(2-dimethylaminoacetyl)-2-oxo-2H-pyrimidine-1-yl]-4,4-debtor-3-hydroxy-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(9));

isopropyl (S)-2-((R)-{(2R,3R,5R)-5-[4-(2-dimethylaminoacetyl)-2-oxo-2H-pyrimidine-1-yl]-4,4-debtor-3-hydroxy-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(10));

isopropyl (S)-2-[(S)-((2R,3R,5R)-4,4-debtor-3-hydroxy-5-{4-[((S)-1-methylpyrrolidine-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(11));

isopropyl (S)-2-[(R)-((2R,3R,5R)-4,4-debtor-3-hydroxy-5-{4-[((S)-1-methylpyrrolidine-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(12));

methyl (S)-2-{[((2R,3R,5R)-4,4-debtor-3-hydroxy-5-{4-[((S)-1-methylpyrrolidine-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(13));

isopropyl (S)-2-[((2R,3R,5R)-4,4-debtor-3-hydroxy-5-{4-[((S)-1-methylpyrrolidine-3-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(14));

isopropyl (S)-2-[((2R,3R,5R)-4,4-debtor-3-hydroxy-5-{4-[((S)-1-methylpyrrolidine-4-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(5));

isopropyl (S)-2-({(2R,3R,4R,5R)-5-[4-(2-dimethylaminoacetyl)-2-oxo-2H-pyrimidine-1-yl]-4-methyl-4-fluoro-3-hydroxy-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.2.2(1));

isopropyl (R)-2-({(2R,3R,4R,5R)-5-[4-(2-dimethylaminoacetyl)-2-oxo-2H-p is rimidine-1-yl]-4-methyl-4-fluoro-3-hydroxy-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.2.2(2));

isopropyl(R)-2-[((2R,3R,4R,5R)-3-hydroxy-4-methyl-4-fluoro-5-{4-[((S)-1-methylpyrrolidine-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.2.2(3));

isopropyl (S)-2-((S)-{(2R,3R,4R,5R)-5-[4-(2-dimethylaminoacetyl)-2-oxo-2H-pyrimidine-1-yl]-4-methyl-4-fluoro-3-hydroxy-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.2.2(4));

isopropyl (S)-2-((R)-{(2R,3R,4R,5R)-5-[4-(2-dimethylaminoacetyl)-2-oxo-2H-pyrimidine-1-yl]-4-methyl-4-fluoro-3-hydroxy-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.2.2(5));

isopropyl (S)-2-[(S)-((2R,3R,4R,5R)-3-hydroxy-4-methyl-4-fluoro-5-{4-[((S)-1-methylpyrrolidine-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.2.2(6));

isopropyl (S)-2-[(R)-((2R,3R,4R,5R)-3-hydroxy-4-methyl-4-fluoro-5-{4-[((S)-1-methylpyrrolidine-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.2.2(7)).

The clinical dosage of the pharmaceutical composition for the treatment and prevention of viral infections, including hepatitis C, in the form of tablets, capsules, or injections, placed in pharmaceutically acceptable packing, not necessarily containing the inhibitor of inosine-5-monophosphate dehydrogenase, and/or protease inhibitors of hepatitis C NS3, and/or protease inhibitors of hepatitis C NS3/4A, and/or an inhibitor of RNA polymerase, NS5A, including the maintenance of the compounds of General formula 1, 2 or 3, or a stereoisomer, salt, hydrate, solvate or crystalline form, patients can be corrected depending on: therapeutic efficiency and bio-availability of active ingredients in the body, the speed of their metabolism and excretion from the body, and depending on age, gender and stage of disease of the patient, the daily dose in adults is usually 10~500 mg. Therefore, during the preparation of pharmaceutical compositions of the present invention in the form of dosage units it is necessary to consider the above-mentioned effective dosages, each unit dosage of the drug should contain 10~500 mg new nucleoside analog RNA polymerase of HCV NS5B General formula 1, 2 or 3, or its stereoisomer, pharmaceutically acceptable salt, hydrate, MES, crystalline or polycrystalline form. In accordance with the instructions of the doctor or pharmacist these medications can be taken several times during a defined time period (preferably from one to six times).

For combination therapy any classes of agents that can be useful when combined with the compounds of the present invention in the pharmaceutical composition, and which may involve, for example, nucleoside and non-nucleoside inhibitors of HCV polymerase inhibitors PR is easy, inhibitors of helicase and medical agents that are functionally inhibit internal ribosomal site of entry (IRES) and other drugs that inhibit attachment or entry of the virus into cells, the transcription of HCV RNA, replication, maturation or attenuation of the virus. Specific compounds in these classes and useful in this invention include, but are not limited macrocyclic, heterocyclic and linear HCV protease inhibitors such as telaprevir (VX-950), boceprevir (SCH-503034), narlaprevir (SCH-900518), ITMN-191 (R-7227), TMC-435350 (a.k.a. TMC-435), MK-7009, BI-201335, BI-2061 (ciluprevir), ACH-1625, ACH-1095 (HCV NS4A inhibitor connecting factor protease), VX-500, VX-813, PHX-1766, PHX2054, IDX-136, IDX-316, ABT-450 EP-013420 (and related) and VBY-376; nucleoside inhibitors of HCV polymerase (replicase), useful in this invention include, but are not limited to the following: R7128, IDX-184, IDX 102, R1479, UNX-08189, PSI-6130, PSI-938 and PSI-879 and various other nucleoside and nucleotide analogues and HCV inhibitors, including (but not limiting) derived from 2'-C-methyl modified nucleosides and nucleotides and 7'-deaza modified nucleosides and nucleotides. Inhibitors non-nucleoside HCV polymerase (replicase), useful in this invention include, but are not limited to: HCV-796, HCV-371, VCH-759, VCH-916, VCH-222, ANA-598, MK-3281, ABT-333, ABT-072, PF-00868554, BI-207127, GS-9190, A-837093, JKT-109, GL-59728 and GL-60667.

In addition, new nucleoside inhibitors of RNA polymerase the HCV NS5B General formula 1, 2 or 3 can be used in pharmaceutical compositions in combination with antagonists cyclophilin and immunophilin (for example, without limitation DEBIO connections, NM-811, as well as cyclosporine and its derivatives), kinase inhibitors, inhibitors of heat shock proteins (e.g., HSP90, HSP70), other immune modulating agents, which may include, without limitation, the interferons (alpha, beta, omega, gamma, lambda or synthetic), such as Intron A™, Roferon - A™, Canferon-A300™, Advaferon™, Infergen™, Humoferon™, Sumiferon MP™, Alfaferon™, IFN-P™, Feron ™ and similar interferon compounds, derivateservlet polyethylene glycol (pegylated), such as PEG interferon-α-2a (Pegasys™), PEG interferon-α-2b (PEGIntron™), pegylated IFN-α-con 1 and the like; prolonged formulas and derivatives of interferon compounds such as the albumin-condensed interferon, Albuferon™, Locteron™ and the like; interferons with different types of controlled delivery (e.g., ITCA-638, omega-interferon delivered DUROS subcutaneous delivery system); compounds that stimulate the synthesis of interferon in cells, such as resiquimod and the like; interleukins; compounds that enhance the development of the response of cells of type I helper T, such as SCV-07 and like; TOLL - like receptor agonists such as CpG-10101 (action), isotorabine, ANA773 and the like; thymosin α-1, ANA-245 and ANA-246, histamine dihydrochloride, propagermanium; tetrachlorodecaoxide; ampligen; IMP-321; KRN-7000; antibodies, such as civacir, XTL-6865 and the like, and prophylactic and therapeutic vaccines such as: Inno Vac, HCV E1E2/MF59 and the like. In addition, any of the methods described above, including the introduction of an NS5B inhibitor, agonist receptor interferon type I (e.g., IFN-α) and the agonist receptor interferon type II (e.g., IFN-γ) can be strengthened by the introduction of an effective amount of TNF-α antagonist. Typical non-limiting TNF-α antagonist, which is suitable for use in such combination therapy, - ENBREL™ and HUMIRA™.

In addition, a new nucleoside RNA polymerase of HCV NS5B General formula 1, 2 or 3 can be used in pharmaceutical compositions in combination with Antiprotozoal, and other anti-viruses are considered to be effective in the treatment of HCV infection, such as a prodrug nitazoxanide. Nitazoxanide can be used as an agent in combination with the compounds disclosed in this invention, as well as in combination with other agents useful in the treatment of HCV infection, such as peginterferon alfa-2a and ribavarin (e.g., Rossignol, JF and'keeffe, EB, Future Environ. 3: 539-545, 2008).

New nucleoside RNA polymerase of HCV NS5B General formula 1, 2 or 3 can also be used in pharmaceutical compositions with alternative forms of interferons and pegylated interferons, ribavirin or its analogs (e.g., Tarabavarin, levovirion), microRNA, little harmful RNA compounds (e.g., SIRPLEX-140-N and the like is), analogues of nucleotides or nucleosides, immunoglobulins, hepatoprotectors, anti-inflammatory agents and other inhibitors of NS5B. Inhibitors of other targets in the HCV life cycle include inhibitors of NS3 helicase; inhibitors NS4A co-factor inhibitors, antisense oligonucleotides, such as: ISIS-14803, AVI-4065 and the like; the vector-encoded short hairpin RNA (shRNA); HCV specific ribozymes, such as heptazyme, RPI, 139199 and the like; entry inhibitors such as: Nareh, HuMax-nurse and the like; alpha-glucosidase inhibitors, such as celgosivir, UT-231 and such; BAP 02003002 and BIVN 401 and IMPDH inhibitors. Other illustrative compounds inhibitors of HCV include inhibitors disclosed in the known scientific and patent publications.

Additionally, the combination of, for example, ribavirin and interferon can be entered as combination therapy with at least one new nucleoside inhibitor of RNA polymerase of HCV NS5B General formula 1, 2 or 3, or a stereoisomer, pharmaceutically acceptable salt, hydrate, MES, crystalline or polycrystalline form. The present invention is not limited to the above classes or compounds and considers known and new compounds and combinations of biologically active agents. Have in mind that the combined therapy of the present invention include any helices is their compatible combination of new nucleoside inhibitor of RNA polymerase of HCV NS5B General formula 1, 2 or 3 with other compounds in this patent group, or other connections outside of this patent group, and the combination does not eliminate the antiviral activity of the compounds of this patent group or antiviral activity of the pharmaceutical compositions.

Combination therapy can be sequential, i.e., the first treatment with one agent, and then another (for example, when each stage of treatment involves another connection of the present invention or when one stage of treatment involves the connection of the present invention, and the other involves one or more biologically active agents), or may be treated with both agents simultaneously. Sequential therapy can be a significant time after the first therapy and the second therapy. Treatment with both agents at the same time can be carried out in a single daily dose or in multiple doses. Combination therapy does not require the restriction of the two agents, and may include three or more agents. Doses for simultaneous and sequential combination therapy will depend on the absorption, distribution, speeds metabolism and excretion of the components of the combination therapy, as well as other factors well known to the specialist. The size of the dose will also vary depending on the severity of SOS is sustainability, want to facilitate. It should be understood that for any particular subject, specific regimen of doses and schedule can be adjusted over time in accordance with the needs of the individual and the professional judgment of the person who treats or supervises the treatment method of combination therapy.

Although the above invention has been described in some detail with illustrations and examples to facilitate the understanding, for the specialist in this area it is obvious that with the main idea of this invention, there may be some changes and modifications not departing from the purpose and scope of the invention as defined in the attached claims.

The following examples illustrate, but not limit the invention.

Example 1. A common way to obtain (S)-isopropyl 2-{[(2R,3S,5R)-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-3-(2-dimethylamino-acetoxy)-4,4-debtor-3-hydroxy-tetrahydro-furan-2-ylethoxy]-phenoxy-phosphorylating}-propionate (1.1.1(1)) and (2R,3S,5R)-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-4,4-debtor-2-[((S)-1-isopropoxycarbonyl-ethylamino)-phenoxy-phosphorylmethyl]-tetrahydro-furan-3-yl (S)-1-methyl-pyrrolidin-2-carboxylate (1.1.1(2)).

Dissolved 2.24 g in (11.2 mmol) of 4-amino-1-((2R,4R,5R)-3,3-debtor-4-hydroxy-5-hydroxymethyl-tetrahydro-furan-2-yl)1H-pyrimidine-2-it (5(1)) in 8 ml dimethylformamid the a and added to the resulting solution of 3.85 g (1.5 EQ), BOC-anhydride. Was heated at 50°C for 18 h To decompose the excess of Boc2O added 8 ml of water, cooled the reaction mass to room temperature, was added with stirring 16 ml of water. The suspension was filtered, the filter cake washed with water. The obtained tert-butyl [1-((2R,4R,5R)-3,3-debtor-4-hydroxy-5-hydroxymethyl-tetrahydro-furan-2-yl)-2-oxo-1,2-dihydro-pyrimidine-4-yl]-carbamate (5(2)) was dried in vacuum. Exit 365 g (86%). HPLC purity (UV254) was 98,3%. 1H-NMR (300 MHz, DMSO-d6) δ of 1.46 (s, 9H), 3,6-3,9 (m, 2H), 4,18 (m, 1H), from 5.29 (Shir. s, 1H), 6,16 (t, J=7.5 Hz, 1H), 6,30 (d, J=6,6 Hz, 1H), 7,06 (d, J=7,8, 1H), 8,18 (d, J=7.8 Hz, 1H), 10,52 (s, 1H).

A solution of 1.8 mmol of the obtained product 5(2) and 10,98 mmol (875 μl) of N-methylimidazole in 10 ml of THF is stirred 30 min at 0°C is added dropwise a solution 5,49 mmol (5)-isopropyl-2-(chloro(phenoxy)phosphorylating)propanoate(1) in 10 ml dichloromethane at 0°C and stirred for 16 hours at room temperature. To the reaction mass is added 0.3 ml of methanol, stirred for 10 min. Then the reaction mass is added 20 ml of ethyl acetate, washed with 5% hydrochloric acid, a saturated solution of NaHCO3, dried over Na2SO4and evaporated in vacuum. The remainder chromatographic on silica gel, eluent chloroform: methanol 9:1. Get (8)-isopropyl 2-{[(2R,3S,5R)-3-hydroxy-5-(4-tert-butoxycarbonylamino-2-oxo-2H-pyrimidine-1-yl)-tetrahydro-furan-2-illcox the]-phenoxy-phosphorylating}-propionate, (9(1)), LC-MS m/e 633 (M+l).

To a mixture of 0.2 mmol of the obtained compound 9(1), 115 mg (0.6 mmol) of the hydrochloride of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDAC) and 14 mg (0,115 mmol) of 4-dimethylaminopyridine (DMAP) in 3 ml of acetonitrile, add 0.5 mmol 2-dimethylaminoethanol acid or (S)-1-methylpyrrolidine-2-carboxylic acid and stir the mixture under argon for 12 hours the Mixture is diluted with 15 ml of chloroform and stirred for 3 h with a saturated solution of NaHCO3. The organic layer is dried over Na2SO4and evaporated in vacuum. The remainder chromatographic on silica gel with a mixture of chloroform: methanol: triethylamine (80:1:2) and are respectively of (S)-isopropyl 2-{[(2R,3R,5R)-5-(4-tert-butoxycarbonylamino-2-oxo-2H-pyrimidine-1-yl)-3-(2-dimethylamino-acetoxy)-4,4-debtor-tetrahydro-furan-2-ylethoxy]-phenoxy-phosphorylating}-propionate (10(1)), LC-MS m/e 718 (M+1), or 2-{[(2R,3R,5R)-5-(4-tert-butoxycarbonylamino-2-oxo-2H-pyrimidine-1-yl)-4,4-debtor-2-[((S)-1-isopropoxycarbonyl-ethylamino)-phenoxy-phosphorylmethyl]-tetrahydro-furan-3-yl] (S)-1-methyl-pyrrolidin-2-carboxylate 10(2) (R4=(8)-1 methylpyrrolidine-2-carbonyl), LC-MS m/e 744 (M+1).

Mix 0.2 mmol of the obtained compound 10(1,2) 30% triperoxonane acid in dichloromethane at room temperature until completion of the reaction. Control over the course of the reaction is carried out by the method LC-MS. actuarial drove in a vacuum, and the residue purified using high-performance liquid chromatography. Receive, respectively, isopropyl (S)-2-{[(2R,3S,5R)-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-3-(2-dimethylamino-acetoxy)-4,4-debtor-3-hydroxy-tetrahydro-furan-2-ylethoxy]-phenoxy-phosphorylating}-propionate (1.1.1(1)), LC-MS m/e 618 (M+1), or (2R,3S,5R)-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-4,4-debtor-2-[((S)-1-isopropoxycarbonyl-ethylamino)-phenoxy-phosphoramidates]-tetrahydro-furan-3-yl (S)-1-methyl-pyrrolidin-2-carboxylate (1.1.1(2)), LC-MS m/e 644 (M+1).

Example 2. A common way to obtain isopropyl (S)-2-({(2R,3R,5R)-5-[4-((R)-2-tert-butoxycarbonylamino-3-methyl-Butylimino)-2-oxo-2H-pyrimidine-1-yl]-4,4-debtor-3-hydroxy-tetrahydro-furan-2-ylethoxy}-phenoxy-phosphorylating)-propionate (1.1.2(2)) and isopropyl (S)-2-[((2R,3R,5R)-4,4-debtor-3-hydroxy-5-{4-[((S)-1-methylpyrrolidine-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(3)).

Dissolve 271 mg (1.25 mmol) of BOC-valine in 5 ml of dichloromethane, added 230 mg (1.37 mmol) of 1,1'-carbodiimides and stirred for 30 minutes at room temperature. The resulting solution imidazoline was added dropwise to a solution of 436 mg (0.82 mmol) of (S)-isopropyl 2-{[(2R,3S,5R)-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-3-hydroxy-tetrahydro-furan-2-ylethoxy]-phenoxy-phosphorylating}-propionate 2 in 10 ml of dichloromethane. The reaction mass is then boiled for 16 hours. RA the solvent is distilled off in vacuum, the residue LC-MS m/e 732 (M+1), is subjected to the primary purification on silica gel, eluent ethyl acetate: hexane 2:1, chloroform: methanol 9:1. Get two fractions, which are then individually cleaned using high-performance liquid chromatography. Get stereoisomer 1.1.2(2), LC-MS m/e 732 (M+1)and 1.1.2(3), LC-MS m/e 732 (M+1).

Example 3. A common way to obtain the alkyl 2-((((2R,3R)-5-(4-aminoantipyrine-1(2H)-yl)-3-hydroxy-2-4,4-debtor-tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylating)-propanoate General formula 1-3. A solution of 1.83 mmol of 2'-deoxy-2',2'-diversityin and 10,98 mmol (875 μl) of N-methylimidazole in 10 ml of THF is stirred 30 min at 0°C is added dropwise a solution 5,49 mmol (S)-alkyl-2-(chloro(phenoxy)phosphorylating)propanoate in 10 ml of dichloromethane at 0°C and stirred for 16 hours at room temperature. To the reaction mass is added 0.3 ml of methanol, stirred for 10 min. Then the reaction mass is added 20 ml of ethyl acetate, washed with 5% hydrochloric acid, us. a solution of NaHCO3, dried over Na2SO4and evaporated in vacuum. The remainder chromatographic on silica gel, eluent chloroform: methanol 9:1. If necessary, conduct additional purification using HPLC without acid. Get the target product, including: (S)-isopropyl 2-({(2R,3R,5R)-5-[4-(2-dimethylamino-acetylamino)-2-oxo-2H-pyrimidine-1-yl]-4,4-debtor-3-hydroxy-tetrahydro-furan-2-ylethoxy}-pheno is C-phosphorylating)-propionate (1.1.2(1)), LC-MS m/e 618 (M+1),1H NMR (DMSO-d6, 400 MHz) δ 10,51 (ush. s, 1H), 8,02 (m, 1H), 7,37 (m, 2H), 7,27 (m, 1H), 7,20 (m, 3H), 6,52 (ush. m, 1H), 6.22 per (K, J=8.0 Hz, 1H), 6,13 (m, 1H), a 4.86 (m, 1H), 4.26 deaths (m, 4H), 3,80 (m, 1H), 3,17 (s, 2H), and 2.27 (s, 6H), to 1.22 (t, J=6.8 Hz, 3H)and 1.15 (m, 6H); (S)-isopropyl 2-[((2R,3R,5R)-4,4-debtor-3-hydroxy-5-{4-[((S)-1-methylpyrrolidine-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(4)), LC-MS m/e 644 (M+1),1H NMR (DMSO-d6, 400 MHz) δ 10,31 (ush. s, 1H), 8,04 (doctor d, J1=14,8 Hz, J2=7,6 Hz, 1H), 7,33 (m, 3H), 7,20 (m, 3H), 6,54 (ush. m, 1H), 6,23 (K, J=8.0 Hz, 1H), 6,13 (m, 1H), a 4.86 (m, 1H), 4.26 deaths (m, 4H), 3,80 (m, 1H), is 3.08 (m, 3H), 2,90 (m, 1H), 2,35 (s, 3H), of 1.76 (m, 3H), of 1.23 (t, J=7.0 Hz, 3H)and 1.15 (m, 6H); (S)-isopropyl 2-((((2R,3R)-5-(4-aminoantipyrine-1(2H)-yl)-3-hydroxy-2-4,4-debtor-tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylating)propanoate (2), LC-MS m/e 533 (M+1),1H NMR (DMSO-d6, 400 MHz) δ: of 7.70 (d, J=9.6 Hz, 1H), 7,40 (m, 4H), 7,21 (m, 3H), 6.30-in (m, 1H), 6,20 (m, 1H), 5,80 (d, J=9.6 Hz, 1H), 5,20 (ush. s, 1H), free 5.01 (m, 1H), a 4.86 (m, 1H), of 4.05 (m, 1H), 3,78 (m, 2H), 3,61 (m, 1H), 1,25 (m, 3H), of 1.16 (m, 6H); (S)-isopropyl 2-((((2R,3R)-3-acetoxy-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4,4-debtor-tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylating)propanoate (3), LC-MS m/e 575 (M+1),1H NMR (DMSO-d6, 400 MHz) δ 7,49 (m, 3H), of 7.36 (m, 2H), 7,18 (m, 3H), of 6.26 (m, 1H), between 6.08 (m, 1H), 5,77 (m, 1H), lower than the 5.37 (ush. m, 1H), a 4.86 (m, 1H), 4,35 (m, 3H), 3,79 (m, 1H), 2,15 (s, 3H), 1,22 (t, J=6.8 Hz, 3H),1,15 (m, 6H).

Example 4. A common way to obtain (5)-isopropyl 2-({(2R,3R,5R)-5-[4-(2-dimethylamino-acetylamino)-2-oxo-2H-pyrimi the Jn-1-yl]-4,4-debtor-3-hydroxy-tetrahydro-furan-2-ylethoxy}-phenoxy-phosphorylating)-propionate (1.1.2(1)and (5)-isopropyl 2-[((2R,3R,5R)-4,4-debtor-3-hydroxy-5-{4-[((5)-1-methylpyrrolidine-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(4)).

To a mixture of 0.2 mmol of compound 6, 115 mg (0.6 mmol) of the hydrochloride of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDAC) and 14 mg (0,115 mmol) of 4-dimethylaminopyridine (DMAP) in 3 ml of acetonitrile added 0.5 mmol of the corresponding amino acids 8 and stirred the mixture under argon for 12 hours the Mixture is diluted with 15 ml of chloroform and stirred for 3 h with a saturated solution of NaHCO3. The organic layer is dried over Na2SO4and evaporated in vacuum. The remainder chromatographic on silica gel with a mixture of chloroform: methanol: triethylamine (80:1:2) and obtain the target product 1 (R6=N), including (S)-isopropyl 2-({(2R,3R,5R)-5-[4-(2-dimethylamino-acetylamino)-2-oxo-2H-pyrimidine-1-yl]-4,4-debtor-3-hydroxy-tetrahydro-furan-2-ylethoxy}-phenoxy-phosphorylating)-propionate (1.1.2(1)), LC-MS m/e 618 (M+1),1H NMR (DMSO-d6, 400 MHz) δ 10,51 (ush. s, 1H), 8,02 (m, 1H), 7,37 (m, 2H), 7,27 (m, 1H), 7,20 (m, 3H), 6,52 (ush. m, 1H), 6.22 per (K, J=8.0 Hz, 1H), 6,13 (m, 1H), a 4.86 (m, 1H), 4.26 deaths (m, 4H), 3,80 (m, 1H), 3,17 (s, 2H), and 2.27 (s, 6H), to 1.22 (t, J=6.8 Hz, 3H)and 1.15 (m, 6H); (S)-isopropyl 2-[((2R,3R,5R)-4,4-debtor-3-hydroxy-5-{4-[((S)-1-methylpyrrolidine-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydro-furan-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2(4)), LC-MS m/e 644 (M+1),1H NMR (DMSO-d6, 400 MHz) δ 10,31 (ush. s, 1H), 8,04 (doctor d, J1=14,8 Hz, J2=7,6 Hz, 1H), 7,33 (m, 3H), 7,20 (m, 3H), 6,54 (ush. m, 1H), 6,23 (K, J=8.0 Hz, 1H), 6,13 (m, 1H), a 4.86 (m, 1H), 4.26 deaths (m, 4H), 3,80 (m, 1H), is 3.08 (m, 3H), 2,90 (m, 1H), 2,35 (s, 3H), of 1.76 (m, 3H), of 1.23 (t, J=7,0 is C, 3H)and 1.15 (m, 6H)

where R4represents hydrogen, R5represents an optionally substituted α-aminoacyl, a R1, R2, R3and R4have the above value.

Example 5. (S)-Isopropyl 2-((((2R,3R)-3-acetoxy-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4,4-debtor-tetrahydrofuranyl)methoxy)(phenoxy)phosphorylating) propanoate General formula 3. To a mixture of 80 mg (0.15 mmol) of (S)-isopropyl 2-((((2R,3R)-3-hydroxy-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4,4-debtor-tetrahydrofuryl)methoxy)(phenoxy) phosphorylating)propanoate General formula 2, 1.4 mg (0.01 mmol) of 4-dimethylaminopyridine (DMAP) and 34.6 μl (0.25 mmol) of triethylamine in 2 ml of acetonitrile add 21,3 μl (0.23 mmol) of acetanhydride and the mixture is stirred under argon for 12 hours To the mixture is added 40 μl of methanol, stirred for 3 h and evaporated in vacuum. Target product produce by HPLC without adding in the eluent (gradient water-acetonitrile). Output (S)-isopropyl 2-((((2R,3R)-3-acetoxy-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4,4-debtor-tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylating)propanoate General formula 3 45 mg LC-MS m/e 575 (M+1),1H NMR (DMSO-d6, 400 MHz) δ 7,49 (m, 3H), of 7.36 (m, 2H), 7,18 (m, 3H), of 6.26 (m, 1H), between 6.08 (m, 1H), 5,77 (m, 1H), lower than the 5.37 (ush. m, 1H), a 4.86 (m, 1H), 4,35 (m, 3H), 3,79 (m, 1H), 2,15 (s, 3H), 1,22 (t, J=6.8 Hz, 3H)and 1.15 (m, 6H).

Example 6. Pharmaceutical composition in the form of tablets. With eshivot 1600 mg of starch, 1600 mg of powdered lactose, 400 mg of talc and 1000 mg (S)-isopropyl 2-((((2R,3R)-5-(4-aminoantipyrine-1(2H)-yl)-3-hydroxy-2-4,4-debtor-tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylating)propanoate. The resulting block is crushed into granules and sieved through a sieve, collecting the granules with a size 14-16 mesh. The obtained granules tabletirujut in a suitable form tablets weighing 560 mg each.

Example 7. Pharmaceutical composition in the form of capsules. Thoroughly mix (S)-isopropyl 2-((((2R,3R)-5-(4-aminoantipyrine-1(2H)-yl)-3-hydroxy-2-4,4-debtor-tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylating)propanoate with lactose powder in a 2:1 ratio. The obtained powder mixture is Packed 300 mg in gelatin capsules of suitable size.

Example 8. Pharmaceutical composition in the form of injectable compositions for intramuscular, intraperitoneal or subcutaneous injection. Mix 500 mg of (S)-isopropyl 2-((((2R,3R)-5-(4-aminoantipyrine-1(2H)-yl)-3-hydroxy-2-4,4-debtor-tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylating)propanoate with 300 mg of chlorobutanol, 2 ml of propylene glycol and 100 ml of injectable water. The resulting solution is filtered and placed in 1 ml ampoules which are sealed.

Example 9. Pharmaceutical composition in the form of tablets. Mix 1600 mg of starch, 1600 mg of powdered lactose, 400 mg of talc and 1000 mg (S)-isopropyl 2-((((2R,3R)-5-(4-aminoantipyrine-1(2)-yl)-3-hydroxy-2--4,4-debtor-tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylating)propanoate. The resulting block is crushed into granules and sieved through a sieve, collecting the granules with a size 14-16 mesh. The obtained granules tabletirujut in a suitable form tablets weighing 560 mg each, which is used in conjunction with the tablet Ribamidil.

Example 10. Pharmaceutical composition in the form of tablets. Mix 1600 mg of starch, 1600 mg of powdered lactose, 400 mg of talc and 1000 mg (S)-isopropyl 2-((((2R,3R)-5-(4-aminoantipyrine-1(2H)-yl)-3-hydroxy-2-4,4-debtor-tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylating)propanoate. The resulting block is crushed into granules and sieved through a sieve, collecting the granules with a size 14-16 mesh. The obtained granules tabletirujut in a suitable form tablets weighing 560 mg each, which is used in conjunction with tablet Asunaprevir (BMS-650032).

Example 11. Pharmaceutical composition in the form of tablets. Mix 1600 mg of starch, 1600 mg of powdered lactose, 400 mg of talc and 1000 mg (S)-isopropyl 2-((((2R,3R)-5-(4-aminoantipyrine-1(2H)-yl)-3-hydroxy-2-4,4-debtor-tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylating)propanoate. The resulting block is crushed into granules and sieved through a sieve, collecting the granules with a size 14-16 mesh. The obtained granules tabletirujut in a suitable form tablets weighing 560 mg each, which is used in conjunction with tablet Sofosbuvir (TMC435).

Example 12. Pharmaceutical composition in the form of tablets. Mix 1600 mg crash is Ala, 1600 mg of powdered lactose, 400 mg of talc and 1000 mg (S)-isopropyl 2-((((2R,3R)-5-(4-aminoantipyrine-1(2H)-yl)-3-hydroxy-2-4,4-debtor-tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylating)propanoate. The resulting block is crushed into granules and sieved through a sieve, collecting the granules with a size 14-16 mesh. The obtained granules tabletirujut in a suitable form tablets weighing 560 mg each, which is used in conjunction with tablet Daclatasvir (BMS-790052) or Declatasvir (GS-5885).

Example 13. Determination of antiviral activity (EC50) nucleoside RNA polymerase of HCV NS5B General formula 1, 2 and 3.

Antiviral activity (EC50) nucleoside RNA polymerase of HCV NS5B General formula 1, 2 and 3 (hereinafter - the test substance) was determined in cell line human hepatoma Huh7 containing subgenomic RNA replicon HCV (genotype 1b, 1a and 2A). For the quantitative determination of viral replication was used option immune test ELISA for virus core-antigen in 96-well format. Cytotoxicity (CC50) test substances were evaluated in parallel. As the comparison drug was used PSI-7977. The Huh7 cells were inoculated in 96-well plates (7.5×103 cells per well in 100 μl medium). Solutions of test compounds in the environment DMEM {DMEM) IX; source: Cellgro; directory: 10-013-CV} were prepared directly before used the eat. Just preparing eleven serial three-fold dilutions with concentrations ranging from 20 nm to 0.2 PM. 4 hours after sowing cells, the serial cultivation of drugs were added to the cells (100 μl per well). The final concentration of test compounds ranged from 10 nm to 0.1 PM, and DMSO-0.5%. If necessary, we investigated a higher concentration of the tested substance. Each drug dilution was tested on two identical holes. Next, cells were incubated for three days at 37°C/5% CO2. The cells were fixed by addition of 250 µl/well of a mixture of acetone/methanol (1:1). After 1 minute, the cells washed three times with a solution of PBS (Phosphate Buffered Saline). After that, the cells were blocked by adding 150 μl/well of 10% fetal calf serum in PBS solution for 1 hour at room temperature. Next, cells were incubated with mouse monoclonal antibodies to core-HCV antigen, clone C7-50 (Source: Affinity BioReagents; Directory: MA-080) (100 µl/well, working dilution is 1:500 in 10% fetal calf serum in PBS solution) for two hours at 37°C. Cells were washed 6 times with a solution of PBS/0.05% tween-20, then incubated for 1 hour with antibodies goat to mouse IgG (conjugated with horseradish peroxidase, 100 µl/well, working dilution is 1:2500 in 10% fetal calf serum in PBS solution). Cells were washed 6 times with a solution of PBS/0.05 tween-20, once the solution of PBS, after which was added 100 μl/well of substrate (1 tablet PDX + 12 ml citrate/phosphate buffer + 5 μl of 30% H2O2). The tablet was kept for 30 min in the dark at room temperature. The reaction was stopped by adding 100 μl/well of 2N H2SO4and measured the optical density (wavelength 490 nm) using a multichannel spectrophotometer Victor3 V 1420 (Perkin Elmer). Values IR50(the concentration of the test substance, decreasing the level of viral RNA replicon 50%) for each compound was calculated using XLfit 4. The results are presented in Table 1.

Example 14. Determination of cytotoxicity nucleoside RNA polymerase of HCV NS5B General formula 1, 2 and 3.

Cytotoxicity (CC50) of the test substances was studied in experiments on the culture of the cell line human hepatoma Huh7. Metabolic activity of cells was determined using the ATPLite kit (Perkin Elmer, Boston, USA) according to manufacturer's instructions. Cytotoxic effects were assessed, waseela cells in black microplate with a transparent bottom (96 cells, 104 cells per well). For each test substance used three independent repeat. The test substance was added after 18 hours, after which cells were incubated with the substances within 96 hours. Washed twice each well of phosphate-saline buffer 0.2 ml/LUN.) and then literally cells by adding cell buffer (50 μl/LUN.) (all these reagents included in the kit ATPLite). Microplate were incubated for 5 minutes on a rotating platform at 600 Rev/min, then was added to each well 50 µl of substrate solution (part of the ATPLite kit). Incubated for another 5 minutes on a rotating platform at 600 Rev/min, kept for 10 minutes in the dark and then measured the luminescence of the device TopCount NXT (Packard, Perkin Elmer). As a quantitative parameter for the assessment of cytotoxicity used the value of CC50that corresponds to the concentration of test substance that will kill 50% of cells. The calculation of the parameter CC50: to calculate the efficiency of inhibition (% Ing) used the formula: % Ing = [(LPOS- Lex)/LPOS- LRef)]* 100%, where LPOS- positive control, luminescence in cells with cells without substance; LRef- negative control, luminescence in cells with medium without cells; Lex- luminescence in cells with a substance in a certain concentration. Values of CC50then considered using XLfit 4. The results are presented in Table 1. In the following Table 1 presents data on the inhibitory activity of some of the new nucleoside.

RNA polymerase of HCV NS5B General formula 1, formula 2 and 3 and standard PSI-7977 in relation to subgenogroup RNA replicon HCV (genotype 1b, 1a and 2A), from which it follows that the new floor is meranie inhibitors 2-6 times more active than standard. The cytotoxicity of the new compounds above 10000 PM.

Table 1
Activity (EC50) and cytotoxicity (CC50) nucleoside polymerase inhibitor of HCV NS5B compounds of General formula 1 and formula 2 and 3.
No. inhibitorHCV genotypes (10% FBS)
1b1a2A
EC50CC50EC50EC50
PM
PSI-7977 (Standard)91,8>10000292,288,4
1.1.2(1)35,0>10000105,9115,6
1.1.2(2)60,6>1000095,678,9
1.1.2(3) 60,9>10000182,169,4
1.1.2(6)14.4V>10000123,579,3
213,9>10000113,657,2
315,7>10000141,061,0

The results of the testing of new inhibitors of General formula 1, 2, 3 testify to their high activity and low cytotoxicity. And suddenly the claimed compounds were more active nucleoside polymerase inhibitor of HCV NS5B than the most advanced inhibitor PSI-7977.

1. Compounds of General formula 1, or its stereoisomers, or a pharmaceutically acceptable salt

where R1represents a C1-C4alkyl;
R2and R3represent fluorine, or
R2represents fluorine, and R3represents methyl;
R4represents a C1-C6acyl, and R5represents hydrogen, or
R4 represents hydrogen, and R5represents a C1-C6acyl, or
R4represents an optionally substituted α-aminoacyl, selected from the group comprising (dimethylamino)acetyl, 1-tert-butoxycarbonylamino-2-methyl-propylboronic, 1 methylpyrrolidine-2-carbonyl, 1-methylpiperidin-3-carbonyl and 1-methylpiperidin-4-carbonyl, and R5represents hydrogen, or
R4represents hydrogen, and R5represents an optionally substituted α-aminoacyl, selected from the group comprising (dimethylamino)acetyl, 1-tert-butoxycarbonylamino-2-methyl-propylboronic, 1 methylpyrrolidine-2-carbonyl, 1-methyl-piperidine-3-carbonyl and 1-methylpiperidin-4-carbonyl;
R6represents hydrogen, methyl, methoxy or halogen.

2. Connection on p. 1 of the formula 3

3. Connection on p. 1 of General formula 1.1 or General formula 1.2


where R1, R4and R5have the above values.

4. Connection under item 3 of the General formula 1.1.1, 1.1.2 or General formula 1.2.1, 1.2.2




where R1, R4, R5and R6have the above values.

5. Connection under item 1, provide the Commissioner a
(S)-ISO-propyl 2-{[(2R,3S,5R)-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-3-(2-dimethylamino-acetoxy)-4,4-debtor-tetrahydro-furan-2-ylethoxy]-phenoxy-phosphorylating}-propionate (1.1.1 (1));
(2R,3S,5R)-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-4,4-debtor-2-[((S)-1-ISO-propoxycarbonyl-ethylamino)-phenoxy-phosphorylmethyl]-tetrahydrofuran-3-yl (S)-1-methylpyrrolidine-2-carboxylate (1.1.1 (2));
(2R,3R)-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-4,4-debtor-2-[(S)-((S)-1-ISO-propoxycarbonyl-ethylamino)-phenoxy-phosphorylmethyl]-tetrahydrofuran-3-yl (S)-2-tert-butoxycarbonylamino-3-methyl-butanoate (1.1.1 (3));
(2R,3R)-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-4,4-debtor-2-[(R)-((S)-1-ISO-propoxycarbonyl-ethylamino)-phenoxy-phosphorylmethyl]-tetrahydrofuran-3-yl (S)-2-tert-butoxycarbonylamino-3-methyl-butanoate (1.1.1 (4));
ISO-propyl (S)-2-({(2R,3R,5R)-5-[4-(2-dimethylamino-acetylamino)-2-oxo-2H-pyrimidine-1-yl]-4,4-debtor-3-hydroxy-tetrahydrofuran-2-ylethoxy}-phenoxy-phosphorylating)-propionate (1.1.2 (1));
ISO-propyl (S)-2-({(2R,3R,5R)-5-[4-((R)-2-tert-butoxycarbonylamino-3-methyl-Butylimino)-2-oxo-2H-pyrimidine-1-yl]-4,4-debtor-3-hydroxy-tetrahydrofuran-2-ylethoxy}-phenoxy-phosphorylating)-propionate (1.1.2 (2));
ISO-propyl (S)-2-[((2R,3R,5R)-4,4-debtor-3-hydroxy-5-{4-[((S)-1-methylpyrrolidine-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydrofuran-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2 (3));
methyl (S)-2-[((2R,3R,5R)-4,4-debtor-3-hydroxy-5-{4-[((S)-1-metile Raiden-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydrofuran-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2 (4));
ISO-propyl (R)-2-[((2R,3R,5R)-4,4-debtor-3-hydroxy-5-{4-[((S)-1-methylpyrrolidine-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydrofuran-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2 (5));
ISO-propyl (S)-2-((2R,3R)-4,4-debtor-3-hydroxy-5-{4-[((S)-1-methylpyrrolidine-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydrofuran-2-ylethoxy)-(4-chlorphenoxy)-phosphorylating)-propionate (1.1.2 (6));
ISO-propyl (S)-2-[((2R,3R)-4,4-debtor-3-hydroxy-5-{4-[((S)-1-methyl-pyrrolidin-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydrofuran-2-ylethoxy)-(2,4-dichlorphenoxy)-phosphorylating)-propionate (1.1.2 (7));
ISO-propyl (S)-2-[((2R,3R)-4,4-debtor-3-hydroxy-5-{4-[((S)-1-methylpyrrolidine-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydrofuran-2-ylethoxy)-p-tolyloxy-phosphorylating)-propionate (1.1.2 (8));
ISO-propyl (S)-2-((S)-{(2R,3R,5R)-5-[4-(2-dimethylaminoacetyl)-2-oxo-2H-pyrimidine-1-yl]-4,4-debtor-3-hydroxy-tetrahydrofuran-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2 (9));
ISO-propyl (S)-2-((R)-{(2R,3R,5R)-5-[4-(2-dimethylaminoacetyl)-2-oxo-2H-pyrimidine-1-yl]-4,4-debtor-3-hydroxy-tetrahydrofuran-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2 (10));
ISO-propyl (S)-2-[(S)-((2R,3R,5R)-4,4-debtor-3-hydroxy-5-{4-[((S)-1-methylpyrrolidine-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydrofuran-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2 (11));
ISO-propyl (S)-2-[(R)-((2R,3R,5R)-4,4-debtor-3-hydroxy-5-{4-[((S)-1-metier is lidin-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydrofuran-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2 (12));
methyl (S)-2-{[((2R,3R,5R)-4,4-debtor-3-hydroxy-5-{4-[((S)-1-methylpyrrolidine-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydrofuran-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2 (13));
ISO-propyl (S)-2-[((2R,3R,5R)-4,4-debtor-3-hydroxy-5-{4-[((S)-1-methylpyrrolidine-3-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydrofuran-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.1.2 (14));
ISO-propyl (S)-2-({(2R,3R,4R,5R)-5-[4-(2-dimethylaminoacetyl)-2-oxo-2H-pyrimidine-1-yl]-4-methyl-4-fluoro-3-hydroxy-tetrahydrofuran-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.2.2 (1));
methyl (R)-2-({(2R,3R,4R,5R)-5-[4-(2-dimethylaminoacetyl)-2-oxo-2H-pyrimidine-1-yl]-4-methyl-4-fluoro-3-hydroxy-tetrahydrofuran-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.2.2 (2));
ISO-propyl (R)-2-[((2R,3R,4R,5R)-3-hydroxy-4-methyl-4-fluoro-5-{4-[((S)-1-methylpyrrolidine-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydrofuran-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.2.2 (3));
ISO-propyl (S)-2-((S)-{(2R,3R,4R,5R)-5-[4-(2-dimethylaminoacetyl)-2-oxo-2H-pyrimidine-1-yl]-4-methyl-4-fluoro-3-hydroxy-tetrahydrofuran-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.2.2 (4));
ISO-propyl (S)-2-((R)-{(2R,3R,4R,5R)-5-[4-(2-dimethylaminoacetyl)-2-oxo-2H-pyrimidine-1-yl]-4-methyl-4-fluoro-3-hydroxy-tetrahydrofuran-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.2.2 (5));
ISO-propyl (S)-2-[(S)-((2R,3R,4R,5R)-3-hydroxy-4-methyl-4-fluoro-5-{4-[((S)-1-methylpyrrolidine-2-Carboni is)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydrofuran-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.2.2 (6));
ISO-propyl (S)-2-[(R)-((2R,3R,4R,5R)-3-hydroxy-4-methyl-4-fluoro-5-{4-[((S)-1-methylpyrrolidine-2-carbonyl)-amino]-2-oxo-2H-pyrimidine-1-yl}-tetrahydrofuran-2-ylethoxy)-phenoxy-phosphorylating)-propionate (1.2.2 (7)).

6. The method of obtaining compounds of General formula 1, their stereoisomers or pharmaceutically acceptable salts, which consists in the interaction of the compounds of General formula 4 with a compound of General formula 5

where R1, R2, R3, R4, R5and R6have the above values.

7. The method of obtaining compounds of General formula 1.1.1 or 1.2.1, their stereoisomers or pharmaceutically acceptable salts, which consists in the interaction of the compounds of General formula 6 with an anhydride of General formula 7 in the presence of 4-dimethylaminopyridine and triethylamine

where R1, R2, R3, R4and R6have the above value.

8. The method of obtaining the compounds of formula 3, its stereoisomers or salts, which consists in the interaction of compound 4(1) with compound 5(1) followed by acylation of the resulting product with acetic anhydride in the presence of 4-dimethylaminopyridine and triethylamine

9. The method of obtaining compounds of General formula 1.1.2 1.2.2 or, their stereoisomers or pharmaceutically acceptable salts, zakluchalos is in the interaction of compounds of General formula 6 with a compound of General formula 8 in the presence of 1,1'-carbonyldiimidazole

where R1, R2, R3, R5and R6have the above value.

10. The method of obtaining compounds of General formula 1.1.1 or 1.2.1, their stereoisomers or the salts, which consists in the interaction of the compounds of General formula 9 with an acid of General formula 10 in the presence of 1,1'-carbonyldiimidazole and the subsequent release of the formed product 11


where R1, R2, R3, R4and R6have the above value.

11. The active component with the properties of nucleoside RNA polymerase of HCV NS5B, which are compounds of General formula 1 according to any one of items 1 to 5, or a stereoisomer or pharmaceutically acceptable salt.

12. Method of inhibiting RNA polymerase of HCV NS5B contacts RNA polymerase of HCV NS5B with compounds of General formula 1 according to any one of items 1 to 5 or stereoisomers or pharmaceutically acceptable salts.

13. Pharmaceutical composition having the properties of an inhibitor of RNA polymerase of HCV NS5B suitable for the treatment and prevention of viral infections, including hepatitis C, containing a therapeutically effective amount of the active ingredient under item 11.

14. Pharmaceutical composition having the properties of an inhibitor of RNA polymerase of HCV NS5B, prigoda the th for the treatment and prevention of viral infections, including hepatitis C, containing a therapeutically effective amount of the active component on p. 11, and an active component selected from the group comprising an inhibitor of inosine-5-monophosphate dehydrogenase, an inhibitor of the protease of the hepatitis C NS3, protease inhibitor of HCV NS3/4A inhibitor of RNA polymerase, NS5A.

15. The pharmaceutical composition according to p. 14, which as an inhibitor of inosine-5-monophosphate dehydrogenase selected Ribamidil, as protease inhibitors of hepatitis C NS3 selected Asunaprevir (BMS-650032), as protease inhibitors of hepatitis C NS3/4A selected Sofosbuvir (TMC435), an inhibitor of RNA polymerase, NS5A selected Daclatasvir (BMS-790052) or Ledipasvir (GS-5885).

16. The pharmaceutical composition according to any one of paragraphs. 13-15 in the form of tablets, capsules, injections, ointments, rectal suspensions or gels, placed in pharmaceutically acceptable packing.

17. Drug for treatment and prophylaxis of viral infections, including hepatitis C, containing an effective quantity of the active component on p. 11, or the pharmaceutical composition according to any one of paragraphs. 13-16.

18. Method of prevention and treatment of disease caused by the hepatitis C virus, the introduction of a therapeutically effective amount of the active component on p. 11, or the pharmaceutical composition according to any one of paragraphs. 13-16, or medicines on p. 17.



 

Same patents:

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: organic chemistry, medicine, virology.

SUBSTANCE: invention relates to novel 5'-phosphonates of 3`-azido-3`-deoxythymidine of the general formula (I) possessing anti-HIV activity, and to using 5'-phosphonates of 3`-azido-3`-deoxythymidine as an active component for preparing drugs possessing anti-HIV activity. In compound of the general formula (I): at n = 0-2; R1 means (wherein X means -CH2, -NH, O); R2 means -NH-C(O)- (wherein R2 means H, (C1-C6)-alkyl, (C5-C7)-cycloalkyl), -HO(CH2)k- (wherein k = 2-4); at n = 0 R1 means -Cl3C; at n = 1-6 R1 means Cl-, Br-, J-, and at n = 2-6 R3 means -C(O)O- (wherein R3 means (C1-C6)-alkyl) at n = 2-6.

EFFECT: valuable medicinal properties of compounds.

3 cl, 2 tbl, 10 ex

FIELD: organic chemistry, virology.

SUBSTANCE: invention relates to a novel compound, namely 3'-azido-3'-deoxythymidine 5'-choline phosphate possessing antiviral activity. Indicated compound shows the enhanced penetration through cellular membranes.

EFFECT: improved and valuable property of agent.

1 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to 2-amino-1-((phosphonoxy)methyl)-3-(3-((4-((2-pyridinyloxy)methyl)phenyl)methyl)-5-isoxazolyl)pyridinium of formula: and salts thereof effective as an antimycotic agent, and to pharmaceutical compositions and therapeutic agents based on it and the use thereof in treating mycotic diseases.

EFFECT: what is presented is the new effective antimycotic agent with improved water solubility and safety.

6 cl, 16 dwg, 3 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to derivatives of Ice formula and the use thereof in treating the diseases associated with thrombocyte aggregation ICE', wherein P(O)R5R8 is specified in R1 is specified in phenyl; W is specified in a bond, -O-, -NR3-; R2 is specified in alkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, phenyl, heterocyclyl, or heteroaryl, alkoxycarbonyl alkyl, carboxyalkyl or phenyl alkyl; R3 is specified in hydrogen or alkyl; or R2 and R3 form a ring together with a nitrogen atom; Ra is specified in hydrogen or methyl; R4 is specified in alkoxy; n is from 0 to 3; m is from 0 to 1; V is specified in a bond and phenyl; R5 and R8 are specified in hydroxyl, phenyloxy, benzyloxy, -O-(CHR6)-O-C(=O)-R7, -O-(CHR6)-O-C(=O)-O-R7, -O-(CHR6)-C(=O)-O-R9, -NH-(CHR10)-C(=O)-O-R9, -NH-C(CH3)2-C(=O)-O-R9; q is equal to 2; R6 is specified in hydrogen and alkyl; R7 is specified in alkyl or cycloalkyl; R9 is specified in alkyl; R10 is specified in hydrogen, alkyl, phenyl or benzyl; and R11 is specified in hydrogen, alkyl or alkoxy.

EFFECT: new P2Y12 receptor antagonists are produced.

25 cl, 126 ex, 5 tbl

FIELD: chemistry.

SUBSTANCE: compounds under the present invention are characterised by properties of aurora-kinase-A and/or aurora-kinase-B inhibitor. In general formula (I) : A represents 5-merous heteroaryl containing two nitrogen atoms; X represents NR14; m represents 0, 1, 2 or 3; Z represents the group chosen from -NR1R2, and 4-7-merous saturated ring connected by carbon atom containing nitrogen atom and substituted at nitrogen atom with C1-C4alkyl substituted by phosphonoxy; R1 represents C1-C6-alkyl substituted by phosphonoxy; R2 represents the group chosen from hydrogen, C1-C6-alkyl where C1-C6-alkyl is optionally substituted with 1, 2 or 3 halogen or C1-C4-alkoxy groups, or R2 represents the group chosen from C2-C6-alkenyl, C2-C6-alkinyl, C3-C6-cycloalkyl and C3-C6-cycloalkyl-C1-C4alkyl; or R1 and R2 together with nitrogen atom whereto attached form 4-7-merous saturated ring substituted at carbon or nitrogen atom by the group chosen from phosphonoxy and C1-C4-alkyl where C1-C4alkyl is substituted by phosphonoxy; R3 represents the group chosen from hydrogen, halogen, C1-C6-alkoxy; R4 represents phenyl substituted with 1-2 halogens; R5, R6, R7 and R14 represent hydrogen. In addition, the invention concerns the pharmaceutical composition containing therapeutically active amount of the compound under the invention, to application of the compound for preparation of a medical product applied in therapy of disease wherefore inhibition of one or more aurora-kinases is efficient, to method treatment, as well as production of the compounds under the invention.

EFFECT: high-yield end product.

26 cl, 5 tbl, 50 ex

FIELD: medicine; pharmacology.

SUBSTANCE: subjects of invention are also pharmaceutical drugs or agents for prophylaxis and treatment of neuropathy, increase of production and treatment of the neurotrophic factor, for pain relief, for nerve protection, for prophylaxis and treatment of the neuropathic pain containing compound of the formula or of the formula . In the compounds of the formulas (I) and (II) symbols and radicals have the meanings mentioned in the invention formula. The specified agents have an excellent effect and low toxicity. There are also proposed ways of treatment and prophylaxis of the abovementioned conditions by means of the compounds of the formula (I) or (II) and application of these compounds for production of the abovementioned agents. Besides, one has proposed methods for production of the specified compounds and intermediate pyrazol compounds.

EFFECT: compound has an effect increasing production and secretion of the neurotrophic factor.

46 cl, 1 tbl, 233 ex

FIELD: chemistry.

SUBSTANCE: description is given of a hetero-aromatic compounds with a phosphonate group with formula (I) and their pharmaceutical salts, radicals of which are given in the formula of invention. The compounds are inhibitors of fructose-1,6-bisphosphotase. Description is also given of pharmaceutical compositions based on compounds with formula (I) and (X) and the method if inhibiting fructose-1,6-bisphosphotase, using the compound with formula (I).

EFFECT: obtaining of new biologically active substances.

184 cl, 52 tbl, 62 ex

FIELD: chemistry of organophosphorus compounds, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new bisamidate phosphonate compounds that are inhibitors of fructose 1,6-bis-phosphatase. Invention describes a compound of the formula (IA): wherein compound of the formula (IA) is converted in vivo or in vitro to compound of the formula M-PO3H2 that is inhibitor of fructose 1,6-bis-phosphatase and wherein M represents R5-X- wherein R5 is chosen from a group consisting of compounds of the formula or wherein each G is chosen from the group consisting of atoms C, N, O, S and Se and wherein only one G can mean atom O, S or Se and at most one G represents atom N; each G' is chosen independently from the group consisting of atoms C and N and wherein two G' groups, not above, represent atom N; A is chosen from the group consisting of -H, -NR42, -CONR42, -CO2R3, halide, -S(O)R3, -SO2R3, alkyl, alkenyl, alkynyl, perhaloidalkyl, haloidalkyl, aryl, -CH2OH, -CH2NR42, -CH2CN, -CN, -C(S)NH2, -OR2, -SR2, -N3, -NHC(S)NR42, -NHAc, or absent; each B and D is chosen independently from the group consisting of -H, alkyl, alkenyl, alkynyl, aryl, alicyclyl, aralkyl, alkoxyalkyl, -C(O)R11, -C(O)SR11, -SO2R11, -S(O)R3, -CN, -NR92, -OR3, -SR3, perhaloidalkyl, halide, -NO2, or absent and all groups except for -H, -CN, perhaloidalkyl, -NO2 and halide are substituted optionally; E is chosen from the group consisting of -H, alkyl, alkenyl, alkynyl, aryl, alicyclyl, alkoxyalkyl, -C(O)OR3, -CONR42, -CN, -NR92, -NO2, -OR3, -SR3, perhaloidalkyl, halide, or absent; all groups except for -H, -CN, perhaloidalkyl and halide are substituted optionally; J is chosen from the group consisting of -H, or absent; X represents optionally substituted binding group that binds R5 with phosphorus atom through 2-4 atoms comprising 0-1 heteroatom chosen from atoms N, O and S with exception that if X represents urea or carbamate then there are 2 heteroatoms that determine the shortest distance between R5 and phosphorus atom and wherein atom bound with phosphorus means carbon atom and wherein X is chosen from the group consisting of -alkyl(hydroxy)-, -alkynyl-, - heteroaryl-, -carbonylalkyl-, -1,1-dihaloidalkyl-, -alkoxyalkyl-, -alkyloxy-, -alkylthioalkyl-, -alkylthio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -alkoxycarbonyl-, -carbonyloxyalkyl-, -alkoxycarbonylamino- and -alkylaminocarbonylamino- and all groups are substituted optionally; under condition that X is not substituted with -COOR2, -SO3H or -PO3R22; n means a whole number from 1 to 3; R2 is taken among the group -R3 and -H; R3 is chosen from the group consisting of alkyl, aryl, alicyclyc and aralkyl; each R4 is chosen independently from the group consisting of -H and alkyl, or R4 and R4 form cycloalkyl group; each R9 is chosen independently from the group consisting of -H, alkyl, aryl, aralkyl and alicyclyl, or R9 and R9 form in common cycloalkyl group; R11 is chosen from the group consisting of alkyl, aryl, -NR22 and -OR2; each R12 and R13 is chosen independently from the group consisting of hydrogen atom (H), lower alkyl, lower aryl, lower aralkyl wherein all groups are substituted optionally, or R12 and R13 in common are bound through 2-5 atoms comprising optionally 1-2 heteroatoms chosen from the group consisting of atoms O, N and S to form cyclic group; each R14 is chosen independently from the group consisting of -OR17, -N(R17)2, -NHR17, -NR2OR19 and -SR17; R15 is chosen from the group consisting of -H, lower alkyl, lower aryl, lower aralkyl, or in common with R16 is bound through 2-6 atoms comprising optionally 1 heteroatom chosen from the group consisting of atoms O, N and S; R16 is chosen from the group consisting of -(CR12R13)n-C(O)-R14, -H, lower alkyl, lower aryl, lower aralkyl, or in common with R15 is bound through 2-6 atoms comprising optionally 1 heteroatom chosen from the group consisting of atoms O, N and S; each R17 is chosen independently from the group consisting of lower alkyl, lower aryl and lower aralkyl and all groups are substituted optionally, or R17 and R17 at atom N are bound in common through 2-6 atoms comprising optionally 1 heteroatom chosen from the group consisting of atoms O, N and S; R18 is chosen independently among the group consisting of hydrogen atom (H), lower alkyl, aryl, aralkyl, or in common with R12 is bound through 1-4 carbon atoms forming cyclic group; each R19 is chosen independently from the group consisting of -H, lower alkyl, lower aryl, lower alicyclyl, lower aralkyl and -COR3; and under condition that when G' represents nitrogen atom (N) then the corresponding A, B, D or E are absent; at least one from A and B, or A, B, D and E is chosen from the group consisting of -H, or absent; when G represents nitrogen atom (N) then the corresponding A or B is not halide or group bound directly with G through a heteroatom; and its pharmaceutically acceptable salts. Also, invention describes a method for treatment or prophylaxis of diabetes mellitus, a method for inhibition of activity 0f fructose 1,6-bis-phosphatase, a method for decreasing blood glucose in animals, a method for treatment of diseases associated with glycogen deposition, a method for inhibition of gluconeogenesis in animal and a pharmaceutical composition based on compounds of the formula (IA).

EFFECT: valuable medicinal and biochemical properties of compounds.

69 cl, 7 tbl, 64 ex

The invention relates to organic chemistry, specifically to methods of producing phosphoric esters of thiamine, which (namely fosfotiamina and cocarboxylase hydrochloride) is used in medicine as drugs

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound of formula (I) , where A is selected from -C(=O)-, -S(=O)2-, and -P(=O)(R5)-, where R5 is selected from C1-6-alkyl, C1-6-alkoxy and hydroxy; B is selected from single bond, -O-, and -C(=O)-NR6-, where R6 is selected from hydrogen; D is selected from single bond, -O-, and -NR9, where R7, R8 and R9 are independently selected from hydrogen; m equals integer number 0-12 and n equals integer number 0-12, where the sum m+n equals 1-20; p equals integer number 0-2; R1 is selected from optionally substituted heteroaryl, where heteroaryl represents aromatic carbocyclic ring, where one carbon atom is substituted with heteroatom; R2 is selected from hydrogen, optionally substituted C1-12-alkyl, and substituents are selected from phenyl, morpholine, halogen and pyridine; C3-12-cycloalkyl, -[CH2CH2O]1-10-C1-6-alkyl); and R3 is selected from optionally substituted C1-12-alkyl, and substituents are selected from morpholine, phenyl, dialkylamine and C3-12-cycloalkyl, optionally substituted with halogen aryl; or R2 and R3 together with adjacent atoms form optionally substituted with alkylcarbonyl or alkyl N-containing heterocyclic or heteroaromatic ring; each of R4 and R4* independently represents hydrogen; and their pharmaceutically acceptable salts, as well as to application of said compounds for treatment of diseases/states, induced by increased level of nicotinamide phosphoribosyltransferase (NAmPRTase).

EFFECT: obtaining novel compounds.

21 cl, 1 dwg, 2 tbl, 83 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compositions for surface purification, including detergent washing compositions, dish-washing compositions, compositions for textile softening, and solid surface cleaners. Invention, in particular, relates to composition, containing considerable quantity of surface-active agents in combination with additional quantity of compounds of phosphonic acids.

EFFECT: obtaining composition, providing better efficiency with significantly reduced side, for instance ecological, disadvantages.

12 cl, 2 ex

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