Modified 2- and 3-nucleosides and use thereof to produce medicinal agent, having hepatitis c inhibiting activity

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula or pharmaceutically acceptable salts thereof, having hepatitis C inhibiting activity, pharmaceutical composition based on said compounds and use thereof to produce a medicinal agent. In compounds of formula (IX) R1 and R2 independently denote H, phosphate or acyl; X denotes O; the base* is a purine base; R12 denotes C(Y3)3; Y3 denotes H and R13 denotes fluorine.

EFFECT: improved properties of the compound.

30 cl, 4 dwg, 26 ex

 

Cross-reference to related applications

In this application claims the priority of provisional patent application U.S. No. 60/392350 filed June 28, 2002, provisional application for U.S. patent No. 60/466194 filed April 28, 2003, and provisional application for U.S. patent No. 60/470949, filed may 14, 2003, the contents of each of which is incorporated herein by reference.

The scope of the invention

This invention relates to the field of pharmaceutical chemistry, in particular to the 2'-and/or 3'-prodrug of 6-modified 1', 2', 3' or 4'-branched pyrimidine nucleoside or 8-modified 1', 2', 3' or 4'-branched purine nucleoside, intended for the treatment of Flaviviridae infection, such as viral infection hepatitis C.

Background of invention

The virus Flaviviridae

The family of Flaviviridae viruses contains at least three distinct kinds: pestivirus that cause disease in cattle and pigs; flavivirus, which are the main cause of diseases such as dengue fever and yellow fever, and hepacivirus, the only member which is HCV (hepatitis C virus). Kind of flaviviruses includes more than 68 members, divided into groups on the basis of serological relatedness (Calisher et al., J. Gen. Virol, 1993, 70, 37-43). Clinical symptoms vary and include SEB is fever, encephalitis and haemorrhagic fever (Fields Virology, Editors: Fields, B.N., Knipe, D.M. and Howley, P.M., Lippincott-Raven Publishers, Philadelphia, PA, 1996, Chapter 31, 931-959). Flavivirus global values that are associated with human disease include viruses of dengue haemorrhagic fever (DHF), yellow fever virus, shock syndrome and Japanese encephalitis virus (Halstead, S.B., Rev. Infect. Dis., 1984, 6, 251-264; Halstead, S.B., Science, 239:476-481, 1988; Monath, T.P., New Eng. J. Med., 1988, 319, 641-643).

Kind of pestiviruses includes virus bovine viral diarrhea (BVDV), the virus of classical swine fever (CSFV, also called the virus of hog cholera) virus border disease (BDV) of sheep (Moennig, V., et al. Adv. Vir. Res. 1992,41,53-98). Pestivirus infection of domesticated animals (cattle, pigs and sheep) are the cause of significant economic losses worldwide. BVDV causes a disease of the mucosa in cattle and has considerable economic importance in industry growing livestock (Meyers, G. and Thiel, H.-J., Advances in Virus Research, 1996, 47, 53-118; Moennig V., et al., Adv. Vir. Res. 1992, 41, 53-98). Pestivirus man had not been so extensively characterized, as pestivirus animals. However, serological studies indicate a significant impact of pestiviruses per person.

Pestivirus and hepacivirus are closely related group of viruses in the family Flaviviridae. The other is their closely related viruses in this family include GB virus A, agents, such GB-virus And GB virus and GB virus (also called hepatitis G, HGV). Group hepacivirus (hepatitis C virus; HCV) consists of a series of closely related, but distinct genotypic viruses that infect humans. There are about 6 HCV genotypes and more than 50 subtypes. Due to the similarities between pestiviruses and hepaciviruses in combination with a weak ability hepaciviruses grow efficiently in cell culture virus bovine viral diarrhea (BVDV) is often used as a substitute for studying HCV virus.

Genetic organization of pestiviruses and hepaciviruses is very similar. These RNA viruses with positive strand of RNA have a single large open reading frame (ORF), encoding all viral proteins necessary for viral replication. These proteins are expressed as polyprotein, which is co - and pokeronline processed as cell and virusdataname proteases, with the formation of Mature viral proteins. Viral proteins responsible for replication of the viral RNA genome are approximately carboxy-terminal position. Two-thirds of the ORF are called non-structural (NS) proteins. Genetic organization and polyprotein processing nonstructural protein part of the ORF for pestiviruses and hepaciviruses are very similar. As d is I pestiviruses, and hepaciviruses Mature non-structural (NS) proteins in sequential order from aminobenzoyl group region that encodes a nonstructural protein, to carboxybenzoyl group ORF consist of P7, NS2, NS3, NS4A, NS4B, NS5A and NS5B.

NS-proteins pestiviruses and hepaciviruses together have domain sequences that are characteristic of the specific functions of proteins. For example, proteins NS3 viruses in both groups have the amino acid sequence motifs characteristic of semipretioase and helices (Gorbalenya et al. (1988) Nature 333:32; Bazan and Fletterick (1989) Virology 171:637-639; Gorbalenya et al. (1989) Nuckeic Acid Res. 17.3889-3897). Similarly NS5B proteins of pestiviruses and hepaciviruses have motifs characteristic of RNA-guided RNA polymerase (Koonin, E.V. and Dolja, V.V. (1993) Crit. Rev. Biochim. Molec. Biol. 28:375-430).

The actual roles and functions of proteins NS pestiviruses and hepaciviruses in the life cycle of viruses are directly similar. In both cases, semipretioase NS3 is responsible for the entire proteolytic processing polyproteins predecessors to the right from its position in the ORF (Wiskerchen and Collett (1991) Virology 184:341-350; Bartenschlager et al. (1993) J. Virol. 67:3835-3844; Eckart et al. (1993) Biochem. Biophys. Res. Comm. 192:399-406; Grakoui et al. (1993) J. Virol. 67:2832-2843; Grakoui et al. (1993) Proc. Natl. Acad. Sci. USA 90:10583-10587; Hijikata on et al. (1993) J. Virol. 67:4665-4675; Tome et al. (1993) J. Virol. 67:4017-4026). Protein NS4F in both cases, acts as a cofactor with serinproteaza NS3 (Batenschlager et al. (1994) J. Virol. 68:5045-5055; Failla et al. (1994) J. Virol. 68: 3753-3760; Lin et al. (1994) 68:8147-8157; Xu et al. (1997) J. Virol. 71:5312-5322). Protein NS3 both viruses also acts as a helicase (Kim. et al. (1995) Biochem. Biophys. Res. Comm. 215: 160-166; Jin and Peterson (1995) Arch. Biochem. Biophys., 323: 47-53; Warrener and Collett (1995) J. Virol. 69: 1720-1726). Finally, NS5B proteins of pestiviruses and hepaciviruses have predicted the activity of RNA-guided RNA polymerase (Behrens et al. (1996) EMBO J. 15:12-22; Lchmannet al. (1997) J. Virol. 71:8416-8428; Yuan et al. (1997) Biochem. Biophys. Res. Comm. 232:231-235; Hagedorn, PCT WO 97/12033; Zhong et al. (1988) J. Virol. 72.9365-ID 9369).

Hepatitis C virus

Hepatitis C virus (HCV) is a major cause of chronic liver disease worldwide (Boyer, N. et al. J. Hepatol. 32: 98-112, 2000). HCV causes a slowly developing a viral infection and is a major cause of cirrhosis and hepatocellular carcinoma (Di Besceglie, A.M. and Bacon, B.R., Scientific American, Oct.: 80-85, (1999); Boyer, N. et al. J. Hepatol. 32:98-112, 2000). It is estimated that worldwide, 170 million people are infected with HCV (Boyer, N. et al. J. Hepatol. 32:98-112, 2000). Cirrhosis caused by chronic hepatitis C infection is a cause of 8000-12000 deaths per year in the United States, HCV infection is the main indication for liver transplantation.

It is known that HCV causes at least 80% polytransfused hepatitis and significant part of accidental acute hepatitis. Preliminary data also imply the involvement of HCV in many cases of "idiopathic" chronic the CSOs hepatitis, "cryptogenic" cirrhosis and possibly hepatocellular carcinoma not associated with other hepatitis viruses such as hepatitis b virus (HBV). It turned out that a small portion of healthy people are chronic carriers of HCV, and this part varies depending on the geographical place of residence and other epidemiological factors. A number of them can essentially exceed the number of patients with HBV, although information is still preliminary; how many of these people have subclinical chronic liver disease is unclear (The Merck Manual. ch. 69, p. 901, 16thed., (1992)).

HCV is a virus with the envelope containing the genome of positive sense single-stranded RNA of approximately 9.4 TPN the Viral genome consists of a 5'-netransliruemoi region (UTR), a long open reading frame that encodes a precursor of polyprotein approximately 3011 amino acids, and a short 3'-UTR. 5'-UTR is the most conserved part of the genome of HCV and important for the initiation and regulation of broadcast polyprotein. Translation of the HCV genome is initiated by a cap-independent mechanism, known as the internal ribosome entry. This mechanism involves the binding of ribosomes to the RNA sequence known as the site of entrance of the internal ribosome (IRES). Recently it was found that the structure of pseudouser RNA is essential to nocturnum element of the HCV IRES. Viral structural proteins include nucleocapsid cow protein (C) and two glycoprotein shell, E1 and E2. HCV encodes two proteases, zinc-dependent the metalloproteinases encoded region of the NS2-NS3, and semipretioase encoded in the region of NS3. These proteinase required for cleavage of specific areas of polyprotein predecessor with the formation of the Mature peptides. Carboxyl half of the non-structural protein 5, NS5B, contains RNA-dependent RNA polymerase. The function of the remaining nonstructural proteins NS4A and NS4B, and NS5A function (aminobenzene half of the non-structural protein 5) remains unknown.

A significant part of the modern anti-virus research focuses on the development of improved methods of treatment of chronic HCV infections in humans (Di Besceglie, A.M. and Bacon, B.R. Scientific American, Oct.: 80-85 (1999)).

Treatment of HCV infection with interferon

Interferons (IFNs) have been commercially available for the treatment of chronic hepatitis b for almost a decade. IFNs are glycoproteins produced by immune cells in response to viral infection. IFNs inhibit the replication of several viruses, including HCV, and when used as the sole means for the treatment of hepatitis b infection With IFN may in some cases to suppress the contents of HCV-RNA in serum to levels not measurable. In addition to t the th, IFN can normalize the levels of aminotransferases in serum. Unfortunately, the effect of IFN is temporary, and long reaction takes place only at 8%-9% of patients chronically infected with HCV (Gary L. Davis. Gastroenterology 118:S104-S114, 2000). Most patients, however, treatment with interferon is difficult tolerated, it causes a severe, flu-like symptoms, weight loss and the decline of energy and vitality.

In a number of patents describe the treatment of Flaviviridae, including HCV, using therapies based on consensus interferon. For example, in U.S. patent No. 5980884, Blatt et al., describes how re-treatment patients infected HCV, using interferon consistency. In U.S. patent No. 5942223, Bazer et al., described therapy against HCV using sheep or bovine interferon-Tau. In U.S. patent No. 5928636, Alber et al., described combination therapy with interleukin-12 and interferon alpha for the treatment of infectious diseases, including those caused by HCV. In U.S. patent No. 5849696, Chretien et al., describes the use of thymosin, alone or in combination with interferon for the treatment of HCV infection. In U.S. patent No. 5830455, Valtuena et al., described combination therapy for treatment of HCV infection in which the use of interferon and catcher of free radicals. In U.S. patent No. 5738845, Imakawa, described the use of proteins, interferon Tau man to treat the Peccei HCV. Other ways of treatment of HCV infection on the basis of interferon are described in U.S. patent No. 5676942, Testa et al., U.S. patent No. 5372808, Blatt et al., and U.S. patent No. 5849696. In a number of patents also described paglierani forms of interferon, for example in U.S. patent No. 5747646, 5792834 and 5834594, Hoffmann-La Roche Inc.; the PCT publication no WO 99/32139 and WO 99/32140, Enzon; WO 95/13090 and U.S. patent No. 5738846 and 5711944, Schering, and U.S. patent No. 5908621, Glue et al.

Interferon Alfa-2A and interferon Alfa-2b is currently approved as monotherapy for the treatment of HCV infection. Roferon® (Roche) is a recombinant form of interferon Alfa-2A. Pegasis® (Roche) is paglierani (i.e. modified polyethylene glycol) form of interferon Alfa-2A. Intron® A (Schering Corporation) is a recombinant form of interferon alpha-2b and PEG-intron® (Schering Corporation) is paglierani form of interferon alpha-2b.

Other forms of interferon alpha and interferon beta, gamma, Tau and omega are currently in clinical development for the treatment of HCV infection. For example, at the development stage are infergen (interferon of alfacon-1), developed by InterMune, Omniture (natural interferon), developed by Viragen, Albuferon developed by Human Genome Sciences, Rebif (interferon beta-1A), developed by Ares-Serono, omega interferon, developed by BioMedicine, oral interferon alpha, developed AmarilloBiosciences, and interferon gamma, interferon Tau, and interferon gamma-1b, developed by InterMune.

Ribavirin

Ribavirin (1-β-D-ribofuranosyl-1-1,2,4-triazole-3-carboxamide) is a synthetic, pendulous interferon, antiviral nucleoside analogue broad-spectrum, sold under the trade name Virazole, (The Merck Index, 11thedition, Editor: Budavari, S., the Merck & Co., Inc., Rahway, NJ, p.1304, 1989). In the patent of the United States No. 3798209 and RE 29835 described and claimed ribavirin. Ribavirin is structurally similar to guanosine and has in vitro activity against several DNA and RNA viruses, including Flaviviridae (Gary L. Davis. Gastroenterology 118:S104-S114, 2000).

Ribavirin reduces the levels of aminotransferases in serum to normal levels in 40% of patients, but it does not reduces the level of HCV-RNA (Gary L. Davis. Gastroenterology 118:S104-S114, 2000). Thus, taken separately ribavirin is not effective in reducing the levels of viral RNA. In addition, ribavirin has significant toxicity and known to cause anemia.

Ribavirin is not approved for monotherapy against HCV. It is approved in combination with interferon Alfa-2A or interferon Alfa-2b for the treatment of HCV infection.

The combination of interferon and ribavirin

The current standard for the treatment of chronic hepatitis C is combination therapy with alpha interferon and ribavirin. Described that the combination and is of terferon and ribavirin for treatment of HCV infection is effective in the treatment of patients not subjected to treatment with interferon (Battaglia, A.M. et al., Ann. Pharmacother. 34:487-494, 2000), as well as to treat patients when there is histological disease (Berenguer, M. et al. Antivir. Ther. 3 (Suppl. 3): 125-136, 1998). Studies have shown that a larger number of patients with hepatitis C are susceptible to combination therapy with a combination of targeted interferon-alpha/ribavirin than combination therapy with naegeliana interferon-alpha. However, as in the case of monotherapy during combination therapy develop significant side effects, including hemolysis, flu-like symptoms, anemia and fatigue (Gary L. Davis. Gastroenterology 118:S104-S114, 2000).

For combination therapy with PEG-Intron® (peginterferon Alfa-2b) and Rebetron® (Ribavirin, USP) use capsules, available from the company Schering Corporation. Rebetol® (Schering Corporation) was also approved in combination with Intron® A (interferon Alfa-2b, recombinant, Schering Corporation). Pegasis® (targeted interferon Alfa-2A) of the companies Roche and Copegus® (ribavirin) is also approved for the treatment of HCV infection.

In PCT publications no WO 99/59621, WO 00/37110, WO 01/81359, WO 02/32414 and WO 03/024461, Schering Corporation, described the use of combination therapy with paglierani interferon-alpha and ribavirin for treatment of HCV infection. In PCT publications no WO 99/15194, WO 99/64016 and WO 00/24355, Hoffmann-La Roche Inc., also described using paglinawan interfere is and Alfa and ribavirin in combination therapy for the treatment of HCV infection.

Additional ways to treat infections Flaviviridae

Now is the development of new antiviral agents for infections Flaviviridae, especially hepatitis C. Develop specific inhibitors originating from HCV enzymes, such as protease inhibitors, helicase and polymerase. Developed drugs that inhibit other stages of the replication of HCV, for example, drugs that block the production of antigens of HCV RNA (IRES inhibitors), medicines that prevent normal processing of HCV proteins (glycosylation inhibitors), drugs that block the entry of HCV into cells (by blocking its receptor), and nonspecific chitosamine agents that block cell damage caused by viral infection. In addition, developed molecular approaches for the treatment of hepatitis C, such as ribozymes, which are enzymes that break down specific viral RNA molecules, and investigated the antisense oligonucleotides, which are small complementary segments of DNA that are associated with the viral RNA and inhibit viral replication. Several methods of treatment of HCV infection is indicated in the overview Bymock et al. in Antiviral Chemistry &Chemotherapy, 11:2; 79-95 (2000) and De Francesco et al. in Antiviral Research, 58: 1-16 (2003).

the reamers classes of drugs, being developed for the treatment of infections Flaviviridae include:

(1) protease Inhibitors

Examines the NS3 protease inhibitor-based substrate (Attwood et al., Antiviral peptide derivatives, PCT WO 98/22496, 1998; Attwood et al, Antiviral Chemistry and Chemotherapy 1999, 10, 259-273; Attwood et al, Preparation and use of amino acid derivatives as anti-viral agents, German Patent Pub. DE 19914474; Tung et al. Inhibitors of serine proteases, particularly hepatitis With virus NS3 protease, PCT WO 98/17679), including alpha-ketoamide and hydrazinoacetate, and inhibitors, which have in the limit position of the electrophile, such as boranova acid or phosphonate (Llinas-Brunet et al, Hepatitis C inhibitor peptide analogues, PCT WO 99/07734).

We also study the NS3 protease inhibitors are not based substrate, such as derivatives of 2,4,6-trihydroxy-3-nitrobenzamide (Sudo K. et al., Biochemical and Biophysical Research Communications, 1997, 238, 643-647; Sudo K. et al. Antiviral Chemistry and Chemotherapy, 1998, 9, 186), including RD3-4082 and RD3-4078, the former substituted at the amide chain of 14 carbon atoms and the latter has a pair of phenoxyphenyl group.

Sch 68631, phenanthridine, an inhibitor of HCV protease (Chu M. et al., Tetrahedron Letters 37: 7229-7232, 1996). In another example, the same authors Sch 351633, isolated from the fungi Penicillium griseofulvum, was identified as a protease inhibitor (Chu M. et al., Bioorganic and Medicinal Chemistry Letters 9:1949-1952). Nanomolar activity against the enzyme protease NS3 HCV was achieved by the development of selective inhibitors on the basis of macromolecular Eglin with. Eg is in isolated from leeches, is a potent inhibitor of several semiprotect, such as protease and S. griseus, α-chymotrypsin, chymase and subtilisin. Qasim M.A. et al., Biochemistry 36:1598-1607, 1997.

Several U.S. patents describe the protease inhibitors for the treatment of HCV infection. In U.S. patent No. 6004933, Spruce et al., describes a class of inhibitors cysteinate for inhibiting endopeptidase 2 HCV. In U.S. patent No. 5990276, Zhang et al., described synthetic inhibitors of the NS3 protease of hepatitis C. the Inhibitor is a sequence of the substrate of the protease NS3 or substrate cofactor NS4A. The use of enzymes for the treatment of HCV infection are described in U.S. patent No. 5538865, Reyes at al. Peptides as inhibitors semipretioase HCV NS3 described in WO 02/008251, Corvas International, Inc. and WO 02/08187 and WO 02/008256, Schering Corporation. Tripeptide inhibitors of HCV are described in U.S. patent No. 6534523, 6410531 and 6420380, Boehringer Ingelheim, and WO 02/060926, Bristol Myers Squibb. Varilite as inhibitors semipretioase HCV NS3 described in WO 02/48172, Schering Corporation. Imidazolidinone as inhibitors semipretioase HCV NS3 described in WO 02/08198, Schering Corporation, and WO 02/48157, Bristol Myers Squibb. In WO 98/17679, Vertex Pharmaceuticals, and WO 02/48116, Bristol Myers Squibb, also described the HCV protease inhibitors.

(2) Derivatives of thiazolidine that are acceptable inhibition in the analysis of HPLC with reversed-phase fused protein NS3/4A and the substrate NS5A/5B (Sudo K. et al., AntiviralResearch, 1996, 32, 9-18), especially compound RD-1-6250 with condensed cinnamoyloxy part, replaced by a long alkyl chain, RD4 6205 and RD4 6193.

(3) Thiazolidine and benzanilide identified Kakiuchi N. et al., J. EBS Letters 421, 217 to 220; N. Takeshita et al. Analytical Biochemistry, 1997, 247, 242-246.

(4) Phenanthridinone, possessing activity against protease in a SDS-PAGE and autoradiographical analysis, isolated from broth culture fermentation of Streptomyces sp., Sch 68631 (Chu M. et al., Tetrahedron Letters, 1996, 37, 7229-7232), and Sch 351633, isolated from fungi Penucillium griseofulvum, which demonstrates activity in a scintillation approximate assay (Chu M. et al., Bioorganic and Medicinal Chemistry Letters, 9, 1949-1952).

(5) Inhibitors of helicase (for example, Diana G.D. et al, Compounds, compositions and methods for treatment of hepatitis C, U.S. Pat. No. 5,633,358; Diana G.D. et al., Piperidine derivatives, pharmaceutical compositions thereof and their use in the treatment of hepatitis C, PCT WO 97/36554).

(6) a Nucleotide polymerase inhibitors and gliotoxin (Ferrari R. et al. Journal of Virilogy, 1999, 73, 1649-1654) and natural product cerulenin (Lohmann V. et al., Virology, 1998, 249, 108-118).

(7) Antisense phosphorothioate oligodeoxynucleotides (S-one), complementary to regions of the sequence in the 5'-noncoding region (NRC) of the virus (Alt M. et al., Hepatology, 1995, 22, 707-717), or nucleotides 326-348, containing the 3'end of the NCR and nucleotides 371-388 located in the cow coding region of HCV RNA (Alt M. et al., Archives of Virology, 1997, 142, 589-599; Galderisi U. et al., Journal of Cellular discrimination, 1999, 181, 251-257).

(8) Inhibitors of IRES-for what esimai broadcast (Ikeda N et al., Agent for the prevention and treatment of hepatitis C, the publication of the Japan patent JP-08268890; Kai Y. et al. Prevention and treatment of viral diseases, a publication of the Japan patent, JP-10101591).

(9) Ribozymes such as nuclease-resistant ribozymes (Maccjak, D.J. et al., Hepatology, 1999, 30, abstract 995), and ribozymes described in U.S. patent No. 6043077, Barber et al., and U.S. patent No. 5869253 and 5610054, Draper et al.

(10) nucleoside Analogues, which were also developed for the treatment of infections with Flaviviridae.

Idenix Pharmaceutical describe the use of branched nucleosides in the treatment of flaviviruses (including HCV) and pestiviruses in the publication of International patent number WO 01/90121 and WO 01/92282. Specifically, the method of treatment of hepatitis C infection (and flaviviruses and pestiviruses) in humans and other host animals is described in the publications Idenix, which include the introduction of an effective amount of a biologically active 1',2',3' or 4'-branched β-D or β-L-nucleosides or their pharmaceutically acceptable salts or derivatives thereof, administered either alone or in combination with another antiviral agent, optionally in a pharmaceutically acceptable carrier.

Other patents describing the use of certain nucleoside analogues for the treatment of infection of hepatitis C virus include PCT/SA/01316 (WO 01/32153, filed November 3, 2000) and PCT/SA/00197 (WO 01/60315, filed February 19, 2001)filed by BioChem Pharma, Inc. (now Shire Biochem, Inc.); PCT/US02/01531 (WO 02/057424 filed the th 18 January 2002) and PCT/US02/03086 (WO 02/057287; filed January 18, 2002)filed by Merck & Co., Inc., PCT/EP01/09633 (WO 02/18404; published August 21, 2001)filed by Roche, and PCT publication no WO 01/79246 (filed April 13, 2001), WO 02/32920 (filed October 18, 2001) and WO 02/48165, Pharmasset, Ltd.

In PCT publication no WO 99/43691, Emory University, entitled "2'-formulised", describes the use of certain 2'-pornological for the treatment of HCV infection.

Eldrup et al. (Oral Session V. Hepatitis C Virus, Flaviviridae; 16thInternational Conference on Antiviral Research (April 27, 2003, Savannah, Ga.)) described the relationship of structures of 2'-modified nucleosides activity for inhibition of HCV.

Br et al. (Orall Session V. Hepatitis C Virus, Flaviviridae, (Oral Session V, Hepatitis C Virus, Flaviviridae; 16thInternational Conference on Antiviral Research (April 27, 2003, Savannah, Ga.) p.A75) described the synthesis and pharmacokinetic properties of nucleoside analogues as potential inhibitors replicas HCV RNA. The authors indicated that the 2'-modified nucleosides exhibit strong inhibitory activity in replicon assays on a cellular basis.

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

(11) a variety of Other compounds, including 1-aminoalkylsilane (U.S. patent No. 6034134, Gold et al.), alkaliphile (U.S. patent No. 5922757, Chojkier et al.), vitamin E and other antioxidants (U.S. patent No. 5992757, Chojkier et al.), squalene, amantadine, W is lonie acid (U.S. patent No. 5846964, Ozeki et al.), N-(phosphonacetyl)-L-aspartic acid (U.S. patent No. 5830905, Diana et al.), benzodioxane (U.S. patent No. 5633388, Diana et al.), derivatives polyadenylic acid (U.S. patent No. 5496546, Wang et al.), 2',3'-dideoxyinosine (U.S. patent No. 5026687, Yarchoan et al.), the benzimidazole (U.S. patent No. 5891874, Colacino et al.), extracts of plants (U.S. patent No. 5837257, Tsai et al, U.S. patent No. 5725869, Omer et al, and U.S. patent No. 6056961) and piperidine (U.S. patent No. 5830905, Diana et al.).

(12) Other compounds currently in preclinical or clinical development for treatment, caused by the hepatitis C virus include: interleukin-10 firm Schering-Plough, IP-501 company Interneuron, merimepodib (VX-497) by Vertex, amantadine® (Symmetrel) by Endo Labs Solvay, heptazyme® company RPI, IDN-6556 company Idun Pharma., XTL-002 firm XTL., HCV/MF59 Chiron, civacir® (immune globulin hepatitis C) by NABI, levovirin® company ICN/Ribapharm, viramidine® company ICN/Ribapharm, zadaxin® (thymosin alpha-1) firms Sci Clone, thymosin plus targeted interferon firms Sci Clone, zeplin® (histamine dihydrochloride) company Maxim, VX 950/LY 570310 firm Vertex/Eli Lilly, ISIS 14803 firm Isis Pharmaceutical/Elan, IDN-6556 company Idun Pharmaceuticals, Inc., JTK 003 firm AKROS Pharma, BILN-2061 company Boehringer Ingelheim, CellCept (mycophenolate mofetil) company Roche, T67, an inhibitor of β-tubulin company Tularik, a therapeutic vaccine directed to E2 company Innogenetics, FK788 company Fujisawa Healthcare, Inc., IdB 1016 (siliphos, oral silybin-phosphatidylcholine picocom), inhib the Torah replication RNA (VP50406) firm ViroPharma/Wyeth, therapeutic vaccine company Intercell, a therapeutic vaccine company Epimmune/Genencor, an inhibitor of IRES company Anadys, ANA 245 and ANA 246 firms Anadys, immunotherapy (tarapor firms Avant, protease inhibitor firm Corvas/Schering, inhibitor of helicase firm Vertex fusion inhibitor company Trimeris, therapy T-cell company CellExSys, the polymerase inhibitor of the company Biocryst, chemical compounds targeting the RNA company PTC Therapeutics, dication company Immtech, Int., protease inhibitor firm Agouron, protease inhibitor Chiron/Medivir, antisense therapy company AVI BioPharma, antisense therapy company Hybridon, hemopurifier company Aethlon Medical, therapeutic vaccine company Merix, protease inhibitor firm Bristol-Myers Squibb/Axys, ChronVacC, therapeutic vaccine company Tripep, UT 231B company United Therapeutics, protease inhibitors, helicase and polymerase firm Genelabs Technologies, IRES inhibitors firm Immusol, R803 company Rigel Pharmaceuticals, infergen® (interferon of alphacon-1) by InterMune, Omniture (natural interferon) by Viragen, Albuferon® company Human Genome Sciences, Rebif® (interferon beta-1A) by Ares-Serono, omega interferon firm BioMedicine, oral interferon alpha company Amarillo Biosciences, and interferon gamma, interferon Tau, and interferon gamma-1b company InterMune.

Prodrugs of nucleosides that have been previously described for the treatment of other forms of hepatitis. In WO 00/09531 (filed August 10, 1999) and WO 01/96353 (filed June 15, 2001), Idenix Pharmaceuticals, described 2'-deoxy-β-L-nucleosides and their 3'-proletar the VA for treatment of HCV infection. In U.S. patent No. 4957924, Beauchamp described various therapeutic esters of acyclovir.

In light of the fact that HCV infection has reached epidemic levels worldwide, and causes the tragic consequences of the infected patient, there remains an acute need to provide new effective pharmaceutical for the treatment of hepatitis C, which would have low toxicity to the host.

In addition, when the existence of increasing threats other infections flaviviridae remains an acute need to provide new effective pharmaceutical agents who have low toxicity to the host.

Thus, the aim of the present invention to provide compounds, methods and compositions for the treatment of a host infected with hepatitis C.

Another objective of the present invention is to develop a method and composition suitable for treatment of patients infected with pestiviruses, flaviviruses or hepacivirus.

The invention

2'- and 3'-prodrugs of 1', 2', 3' or 4'-branched β-D or β-L-nucleoside or its pharmaceutically acceptable salt or pharmaceutically acceptable preparations containing these compounds, can be used for the prevention and treatment of infections Flaviviridae and other related conditions such as the state who were positive for antibodies against Flaviviridae and Flaviviridae-positive status, chronic inflammation of the liver caused by HCV, cirrhosis, acute hepatitis, fulminant hepatitis, chronic persistent hepatitis, and fatigue. These compounds or drugs may also be used prophylactically to prevent or retard the development of clinical disorders in patients who have antibodies against Flaviviridae, or have a positive reaction to the antigen Flaviviridae, or who have been exposed to Flaviviridae.

Also described is a method of treatment of viral infections Flaviviridae by host, including humans, which comprises introducing an effective amount of 2'- or 3'-prodrug of a biologically active 1', 2', 3' or 4'-branched β-D or β-L-nucleoside or its pharmaceutically acceptable salt, administered either separately, or in combination or sequentially with another agent against Flaviviridae, optionally, in a pharmaceutically acceptable carrier. The term 2'-prodrug used here, refers to the 1', 2', 3' or 4'-branched β-D or β-L-nucleoside, which is biologically tsepliaeva part in the 2'-position, including, but not limited to, specified, acyl, and in one embodiment, natural or synthetic D or L-amino acid, preferably L-amino acid. The term 3'-prodrug used here, refers to the 1', 2', 3' or 4'-branched β-D or β-L-nucleoside is, which is biologically tsepliaeva part of the 3'-position, including, but not limited to, specified, acyl, and in one embodiment, natural or synthetic D or L-amino acid, preferably L-amino acid.

Pharmaceutically acceptable salts include tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, α-Ketoglutarate, and α-glycerol, formate, fumarate, propionate, glycolate, lactate, pyruvate, oxalate, maleate, salicylate, sulfate, sulfonate, nitrate, bicarbonate, Hydrobromic, hydrobromide, hydroiodide, carbonate and salts of phosphoric acid. Especially preferred embodiment is a mono - or dihydrochloride salt.

In one embodiment, 1', 2', 3' or 4'-branched β-D or β-L-nucleoside includes biologically otsepleniya residues at the 2'- and/or 5'-positions. Preferred residues are esters of natural or synthetic D or L-amino acids, including D - or L-poured, more preferred are the esters of L-amino acids such as L-poured, and alkalemia esters, including acetyl. Thus, this invention, in particular, includes a 2'-ester of D - or L-amino acids and 2',5'-ester of D - or L-diaminoanisole, preferably, the ester of L-amino acids, 1', 2', 3' or 4'-branched β-D or β-L-nucleosides with any desired purine is m or pyrimidine base, where the original medicinal product has optional EC50less than 15 micromol, and even more preferably less than 10 micromol; 2'-(Elgiloy or arrowy) ether or 2',5'-di(Elgiloy or arrowy) ester of 1', 2', 3' or 4'-branched β-D or β-L-nucleosides with any desired purine or pyrimidine base, where the original medicinal product has optional EC50less than 10 or 15 micromol, and prodrugs of 2',5'-diesters of 1', 2', 3' or 4'-branched β-D or β-L-nucleosides, where (i) the 2'ester is an ester of natural or synthetic D or L-amino acids, more preferably, the ester of L-amino acids, 5'-ester is alkilany or allowin ether; (ii) both ether are, independently, esters of natural or synthetic D or L-amino acids, more preferably both are esters of L-amino acids; (iii) both ether are independently alkylamine or akrilovye esters and (iv) the 2'ester is independently alkilany or allowin ether and 5'-ester is an ester of natural or synthetic D or L-amino acids, more preferably the ester of L-amino acids, where the original medicinal product has optional EC50less than 10 or 15 micromol.

Examples of prodrugs included in the scope of the invention are 2'-D - or L-malinowy ester of β-D-2',6-dimethylethylene; 2'-L-malinowy ester of β-D-2',6-dim is miltimedia; 2'-L-malinowy ester of β-D-2',8-dimethylbenzene, 2'-L-malinowy ester of β-D-2',8-dimethylguanosine; 2'-L-malinowy ester of β-D-2',6-dimethyl-5-fortitudine; 2'-L-malinowy ester of β-D-2',6-dimethylaniline; 2'-acetyloxy ester of β-D-2',6-dimethylethylene; 2'-acetyloxy ether β-D-2',6-dimethylimidazo; 2'-acetyloxy ester of β-D-2',8-dimethylbenzene, 2'-acetyloxy ester of β-D-2',8-dimethylguanosine; 2'-acetyloxy ester of β-D-2',6-dimethyl-5-fortitudine; and complex 2'-esters of β-D-2',6-dimethyl(cytidine, 5-fluorouracil, uridine or thymidine) or complex 2'-esters of β-D-2',8-dimethyl(guanosine, adenosine or inosine), where (i) the 2'ester is an ester of the amino acids, or (ii) the 2'ester is alkilany or allowin ether.

Additional examples of prodrugs included in the scope of the invention are 2',5'-L-gialinovym ester of β-D-2',6-dimethylcathinone (dival-2',6-diMe-L-dC); 2',5'-L-gialinovym ester of β-D-2',6-dimethylimidazo; 2',5'-L-gialinovym ester of β-D-2',8-dimethylbenzene; 2',5'-L-gialinovym ether β-D-2',8-dimethylguanosine; 2',5'-L-gialinovym ester of β-D-2',6-dimethyl-5-fortitudine; 2',5'-L-gialinovym ester of β-D-2',6-dimethylaniline; 2',5'-diazotrophy broadcast D-2',6-dimethylethylene; 2',5'-diazotrophy ester of β-D-2',6-dimethylimidazo; 2',5'-diacetylenic ether β-D-2',8-dimethylbenzene; 2',5'-diazotrophy ester of β-D-2',8-dimethylguanosine; 2',5'-diazotrophy ester of β-D-2',6-dimethyl-5-fortitudine and complex 2',5'-diesters of β-D-2',6-dimethyl(cytidine, 5-fortitudine, uridine or thymidine) is the complex 2',5'-diesters of β-D-2',8-dimethyl(guanosine, adenosine or inosine), where (i) the 2'ester is an ester of the amino acids and 5'-ester is alkilany or allowin ether; (ii) both ester are esters of amino acids, (iii) both ether are independently alkylamine or akrilovye esters or (iv) the 2'ester is alkilany or allowin ether and 5'-ester is an ester of the amino acids.

In another embodiment, the 3'-prodrug 1', 2', 3' or 4'-branched β-D or β-L-nucleoside includes biologically otsepleniya residues in the 3'and/or 5'-positions. Preferred residues are esters of natural or synthetic D or L-amino acids, such as poured, the preferred esters of L-amino acids such as L-poured, and alkalemia esters, including acetyl. Thus, this invention, in particular, includes ether 3'-L-amino acids and ether 3',5'-L-diaminoanisole 1', 2', 3' or 4'-branched β-D or β-L-nucleosides with any desired purine or pyrimidine base, where the original medicinal product has optional EC50less than 15 micromol, and even more preferably less than 10 micromol; 3'-(Elgiloy or arrowy) ether or 3',5'-L-di(Elgiloy or arrowy) ester of 1', 2', 3' or 4'-branched β-D or β-L-nucleosides with any desired purine or pyrimidine base, where the original medicinal product has optional EC50

D - or L-amino acids; (iii) both ether are independently alkylamine or akrilovye esters and (iv) the 3'ester is independently alkilany or allowin ether and 5'-ester is an ester of natural or synthetic D or L-amino acids, where the original medicinal product has optional EC50less than 10 or 15 micromol.

Examples of prodrugs that are within the invention are 3'-L-malinowy ester of β-D-2',6-dimethylethylene; 3'-L-malinowy ester of β-D-2',6-dimethylimidazo; 3'-L-malinowy ester of β-D-2',8-dimethylbenzene, 3'-L-malinowy ester of β-D-2',8-dimethylguanosine; 3'-L-malinowy ester of β-D-2',6-dimethyl-5-fortitudine; 3'-L-malinowy ester of β-D-2',6-dimethylaniline; 3'-acetyloxy ester of β-D-2',6-dimethylethylene; 3'-acetyloxy ester of β-D-2',6-dimethylimidazo; 3'-acetyloxy ester of β-D-2',8-dimethylbenzene, 3'-acetyloxy ester of β-D-2',8-dimethylguanosine; 3'-acetyloxy ester of β-D-2',6-dimethyl-5-fortitudine; and a complex of 3'-ester of β-D-2',6-dimethyl(cytidine, 5-forwritten, uridine or thymidine) or complex 3'-ester of β-D-2',8-dimethyl(guanosine, adenosine or inosine), where (i) the 3'ester is the ester of the amino acids, or (ii) the 3'ester is alkilany or allowin complex ether.

Additional examples of prodrugs included in the scope of the invention are 3',5'-L-gialinovym ester of β-D-2',6-dimethylcathinone (dival-2',6-diMe-L-dC); 3',5'-L-gialinovym ester of β-D-2',6-dimethylimidazo; 3',5'-L-gialinovym ester of β-D-2',8-dimethylbenzene; 3',5'-L-gialinovym ether β-D-2',8-dimethylguanosine; 3',5'-L-gialinovym ester of β-D-2',6-dimethyl-5-fortitudine; 3',5'-L-gialinovym ester of β-D-2',6-dimethylaniline; 3',5'-diazotrophy broadcast D-2',6-dimethylethylene; 3',5'-diazotrophy ester of β-D-2',6-dimethylimidazo; 3',5'-diacetylenic ether β-D-2',8-dimethylbenzene; 3',5'-diazotrophy ester of β-D-2',8-dimethylguanosine; 3',5'-diazotrophy ester of β-D-2',6-dimethyl-5-fortitudine and complex 3',5'-diesters of β-D-2',6-dimethyl(cytidine, 5-fortitudine, uridine or thymidine) or complex 3',5'-diesters of β-D-2',8-dimethyl(guanosine, adenosine or inosine), where (i) the 3'ester is an ester of the amino acids and 5'-ester is alkilany or allowin ether; (ii) both ester are esters of amino acids, (iii) both ether independently are alkylamine or akrilovye esters or (iv) the 3'ester is alkilany or allowin ether and 5'-ester is an ester of the amino acids.

In another embodiment, the prodrug 1', 2', 3' or 4'-branched β-D or β-L-nucleoside includes biologically otsepleniya residues at the 2'-, 3'- and/or 5'-positions. Preferred residues are esters of natural or synthetic D or amino acids, including D - or L-poured, more preferred are the esters of L-amino acids such as L-poured, and alkalemia esters, including acetyl. Thus, this invention, in particular, includes the ester of 2',3'-L - or D-amino acid and the ester of 2',3',5'-L - or D-trainability 1', 2', 3' or 4'-branched β-D or β-L-nucleosides, preferably L-amino acids, with any desired purine or pyrimidine base, where the original medicinal product has optional EC50less than 15 micromol, and even more preferably less than 10 micromol; 2',3'-di(Elgiloy or arrowy) ether or 2',3',5'-L-three(Elgiloy or arrowy) ester of 1', 2', 3' or 4'-branched β-D or β-L-nucleosides with any desired purine or pyrimidine base, where the original medicinal product has optional EC50less than 10 or 15 micromol, and prodrugs of 2',3'-diesters of 1', 2', 3' or 4'-branched β-D or β-L-nucleosides, where (i) the 2'ester is an ester of the amino acid and the 3'ester is alkilany or allowin ether; (ii) both ester are esters of amino acids; (iii) both ether are independently alkylamine or akrilovye esters and (iv) the 2'ester is independently alkilany or allowin ether and 3'-ester is the ester of the amino acids, where the original medicinal product has optional EC50less than 10 or 15 micromol. In addition to t the th, the invention includes compound 2',3',5'-truefire 1', 2', 3' or 4'-branched β-D or β-L-nucleosides, where (i) all three ester are esters of amino acids; (ii) all three of ether are independently alkylamine or akrilovye esters; (iii) 2'-ester is an ester of the amino acid, the 3'ester is an ester of the amino acids and 5'-ester is alkilany or allowin ether; (iv) the 2'ester is ether amino acids, the 3'ester is alkilany or allowin ether and 5'-ester is alkilany or allowin ether; (v) the 2'ester is alkilany or allowin ether, 3'-ester is alkilany or allowin ether and 5'-ester is an ester of the amino acids; (vi) the 2'ester is alkilany or allowin ether, 3'-ester is an ester of the amino acids and 5'-ester is an ester of the amino acid; (vii) the 2'ester is alkilany or allowin ether, 3'-ester is ether amino acids and 5'-ester is alkilany or allowin ether and (viii) the 2'ester is an ester of the amino acid, the 3'ester is alkilany or allowin ether and 5'-ester is an ester of the amino acids, where the original medicinal product has optional EC50less than 10 or 15 micromol.

Examples of prodrugs that are included in the scope of the invention include 2',3'-L-gialinovym ester of β-D-2',6-dimethylcathinone (dival-2',6-diMe-L-dC); 2',3'-L-gialinovym ester of β-D-2',6-dimethylimidazo; 2',3'-L-gialinovym ester of β-D-2',8-dimethyl what denosine, 2',3'-L-gialinovym ester of β-D-2',8-dimethylguanosine; 2',3'-L-gialinovym ester of β-D-2',6-dimethyl-5-fortitudine; 2',3'-L-gialinovym ester of β-D-2',6-dimethylaniline; 2',3'-diazotrophy ester of β-D-2',6-dimethylethylene; 2',3'-diazotrophy ester of β-D-2'A 6-dimethylimidazo; 2',3'-diazotrophy ester of β-D-2',8-dimethylbenzene; 2',3'-diazotrophy ester of β-D-2',8-dimethylguanosine; 2',3'-diazotrophy ester of β-D-2',6-dimethyl-5-fortitudine; and a complex of 2',3'-diesters of β-D-2',6-dimethyl(cytidine, 5-fortitudine, uridine or thymidine) or complex 2',3'-diesters of β-D-2',8-dimethyl(guanosine, adenosine or inosine), where (i) the 2'ester is an ester of the amino acid and the 3'ester is alkilany or allowin ether; (ii) both ester are esters of amino acids; (iii) both ether are independently alkylamine or akrilovye esters or (iv) the 2'ester is alkilany or allowin ether and 3'-ester is an ester of the amino acids.

Additional examples of prodrugs that are included in the scope of the invention include 2',3',5'-L-trivalency ester of β-D-2',6-dimethylcathinone (trival-2',6-diMe-L-dC); 2',3',5'-L-trivalency ester of β-D-2',6-dimethylimidazo; 2',3',5'-L-trivalency ester of β-D-2',8-dimethylbenzene; 2',3',5'-L-trivalency ester of β-D-2',8-dimethylguanosine; 2',3',5'-L-trivalency ester of β-D-2',6-dimethyl-5-fortitudine; 2',3',5'-L-trivalency ester of β-D-2',6-dimethylaniline; 2',3',5'-triacetoxy broadcast D-2',6-dimethylethylene; 2',3',5'-triacetoxy ester of β-D-2',6-dimethylimidazo; 2',3',5'-�razmilovic ester of β-D-2',8-dimethylbenzene; 2',3',5'-triacetoxy ester of β-D-2',8-dimethylguanosine; 2',3',5'-triacetoxy ester of β-D-2',6-dimethyl-5-fortitudine and complex 2',3',5'-truefire β-D-2',6-dimethyl(cytidine, 5-fortitudine, uridine or thymidine) and compound 2',3',5'-truefire β-D-2',8-dimethyl(guanosine, adenosine or inosine), where (i) all three ester are esters of amino acids; (ii) all three of ether are independently alkylamine or akrilovye esters, (iii) 2'-ester is an ester of the amino acid, the 3'ester is an ester of the amino acids and 5'-ester is alkilany or allowin ether; (iv) the 2'ester is an ester of the amino acid, the 3'ester is alkilany or allowin ether and 5'-ester is alkilany or allowin ether; (v) 2'-the ether is alkilany or allowin ether, 3'-ester is alkilany or allowin ether and 5'-ester is an ester of the amino acids; (vi) the 2'ester is alkilany or allowin ether, 3'-ester is an ester of the amino acids and 5'-ester is an ester of the amino acid; (vii) the 2'ester is alkilany or allowin ether, 3'-ester is an ester of the amino acids and 5'-ester is alkilany or allowin ether and (viii) the 2'ester is an ester of the amino acid, 3'-ester is alkilany or allowin ether and 5'-ester is an ester of the amino acids.

In the first main embodiment, the proposed compound of formula (I)or its pharmaceutically acceptable salt, or prodrug, or CTE is eoysmena, tautomeric or polymorphic form, as well as a method of treatment of a host infected with Flaviviridae that includes the introduction of effective treatment amount of compound of formula (I):

or its pharmaceutically acceptable salt or prodrug, or a stereoisomeric, tautomeric or polymorphic form, where

R1, R2and R3are independently H, phosphate (including mono-, di - or triphosphate and a stabilized phosphate); alkyl with an unbranched, branched or cyclic chain (including lower alkyl); acyl (including lower acyl); CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, a sulphonate ester, including alkyl or aralkylamines, including methanesulfonyl and benzyl, where the phenyl group is optionally substituted by one or more substituents as described in this definition here aryl; alkylsulfonyl, arylsulfonyl, aralkylamines; a lipid, including a phospholipid; an amino acid and amino acid residue; carbohydrate; a peptide; a cholesterol, or other pharmaceutically acceptable, remove the group, which is capable of formation of the compound, in which R1, R2and/or R3are independently H, phosphate (including mono-, di - or triphosphate), for example, with the introduction of in vivo; where in one embodiment, the wasp is estline R 2and/or R3is not a phosphate (including mono-, di - or triphosphate or a stabilized phosphate prodrug);

where at least one of R2and R3is not hydrogen, and where

Y1represents hydrogen, bromine, chlorine, fluorine, iodine, CN, OH, OR4, NH2, Other4, NR4R5, SH or SR4;

X1represents an optionally substituted alkyl with an unbranched, branched or cyclic chain, CH3, CF3C(Y3)3, 2-Br-ethyl, - CH2F, CH2Cl, CH2CF3, CF2CF3C(Y3)2C(Y3)3CH2OH, optionally substituted of alkenyl, optionally substituted quinil, COOH, COOR4, COO-alkyl, COO-aryl, COO-alkoxyalkyl, CONH2, CONHR4, CON(R4)2, chlorine, bromine, fluorine, iodine, CN, N3, OH, OR4, NH2, Other4, NR4R5, SH or SR5and

X2represents hydrogen, optionally substituted alkyl with an unbranched, branched or cyclic chain, CH3, CF3C(Y3)3, 2-Br-ethyl, - CH2F, CH2Cl, CH2CF3, CF2CF3C(Y3)2C(Y3)3CH2OH, optionally substituted of alkenyl, optionally substituted quinil, COOH, COOR4, COO-alkyl, COO-aryl, COO-alkoxyalkyl, CONH2, CONHR4, CON(R 4)2, chlorine, bromine, fluorine, iodine, CN, N3, OH, OR4, NH2, Other4, NR4R5, SH or SR5and

where each Y3represents independently H, F, Cl, Br or I;

each R4and R5represents independently hydrogen, acyl (including lower acyl), alkyl (including, but not limited to, methyl, ethyl, propyl and cyclopropyl), lower alkyl, alkenyl, quinil or cycloalkyl.

In embodiments described herein implement R1, R2and/or R3may be pharmaceutically acceptable, removable group which is capable of formation of the compound, in which R1, R2and/or R3are independently H or phosphate (including mono-, di - or triphosphate), for example, when introduced in vivo.

In the second main embodiment, the proposed compound of formula (II), or its pharmaceutically acceptable salt, or prodrug, or a stereoisomeric, tautomeric or polymorphic form, as well as a method of treatment of a host infected with Flaviviridae that includes the introduction of effective treatment amount of compound of formula (II):

or its pharmaceutically acceptable salt or prodrug, or a stereoisomeric, tautomeric or polymorphic form, where R1, R2, R3, R4, R5, Y1, Y3X and X2have the values specified above.

In the third main embodiment, the proposed compound of formula (III), (IV) or (V)or its pharmaceutically acceptable salt, or prodrug, or a stereoisomeric, tautomeric or polymorphic form, as well as a method of treatment of a host infected with Flaviviridae that includes the introduction of effective treatment amount of compound of formula (III), (IV) or (V):

or its pharmaceutically acceptable salt or prodrug, or a stereoisomeric, tautomeric or polymorphic form, where

base selected from the group consisting of

R1, R2, R3, R4and R5have the values specified above;

each W1, W2, W3and W4represents independently N, CH, CF, CI, CBr, CCl, CCN, CCH3, CCF3, CCH2CH3CC(O)NH2CC(O)other4CC(O)N(R4)2CC(O)OH, CC(O)OR4or CX3;

each W represents independently O, S, NH or NR4;

X represents O, S, SO2CH2CH2OH, CHF, CF2C(Y3 2, CHCN, C(CN)2, CHR4or C(R4)2;

X* represents CH, CF, CY3or CR4;

X2represents H, optionally substituted alkyl with an unbranched, branched or cyclic chain, CH3, CF3C(Y3)3, 2-Br-ethyl, - CH2F, CH2Cl, CH2CF3, CF2CF3C(Y3)2C(Y3)3CH2OH, optionally substituted of alkenyl, optionally substituted quinil, COOH, COOR4, COO-alkyl, COO-aryl, COO-alkoxyalkyl, CONH2, CONHR4, CON(R4)2, chlorine, bromine, fluorine, iodine, CN, N3, OH, OR4, NH2, Other4, NR4R5, SH or SR5;

each X3represents an optionally substituted alkyl with an unbranched, branched or cyclic chain (including lower alkyl), CH3CH2CN, CH2N3CH2NH2CH2NHCH3CH2N(CH3)2CH2OH, halogenated alkyl (including halogenated lower alkyl), CF3C(Y3)3, 2-Br-ethyl, - CH2F, CH2Cl GH2CF3, CF2CF3C(Y3)2C(Y3)3not necessarily replaced alkenyl, halogenoalkanes, Br-vinyl, optionally substituted quinil, halogenoalkanes, N3CN, -C(O)OH, -C(O)OR4, -C(O)O(lower alkyl), -C(O)NH2, -C(O)other4, -C(O)NH(lower alkyl), -C(O)N(R4 )2, -C(O)N(lower alkyl)2, OH, OR4, -O(acyl), -O(lower acyl), -O(alkyl), -O(lower alkyl), -O(alkenyl), -O(quinil), -O(aralkyl), -O(cycloalkyl), -S(acyl), -S(lower acyl), -S(R4), -S(lower alkyl), -S(alkenyl), -S(quinil), -S(aralkyl), -S(cycloalkyl), chlorine, bromine, fluorine, iodine, NH2, -NH(lower alkyl), -other4, -NR4R5, -NH(acyl), -N(lower alkyl)2, -NH(alkenyl), -NH(quinil), -NH(aralkyl), -NH(cycloalkyl), -N(acyl)2;

each Y is independently selected from the group consisting of H, optionally substituted lower alkyl, cycloalkyl, alkenyl, quinil, CH2OH, CH2NH2CH2NHCH3CH2N(CH3)2CH2F, CH2Cl, CH2N3CH2CN, CH2CF3, CF3, CF2CF3CH2CO2R, (CH2)mCOOH, (CH2)mCOOR, (CH2)mCONH2, (CH2)mCONR2and (CH2)mCONHR;

where R represents H, alkyl or acyl;

Y1represents hydrogen, bromine, chlorine, fluorine, iodine, CN, OH, OR4, NH2, Other4, NR4R5, SH or SR4;

each Y2represents independently O, S, NH or NR4; each Y3represents independently H, F, Cl, Br or I;

where for reasons (B) W4cannot be CH if W1, W2and W3represent N;

where to base (E), (F), (K), (L), (W) and (X) W4 cannot be CH if W1represents N;

each R6represents independently optionally substituted alkyl (including lower alkyl), CH3CH2CN, CH2N3CH2NH2CH2NHCH3CH2N(CH3)2CH2OH, halogenated alkyl (including halogenated lower alkyl), CF3C(Y3)3, 2-Br-ethyl, - CH2F, CH2Cl, CH2CF3, CF2CF3C(Y3)2C(Y3)3not necessarily replaced alkenyl, halogenoalkanes, Br-vinyl, optionally substituted quinil, halogenoalkanes, -CH2C(O)OH, -CH2C(O)OR4, -CH2C(O)O(lower alkyl), -CH2C(O)NH2, -CH2C(O)other4, -CH2C(O)NH(lower alkyl), -CH2C(O)N(R4)2, -CH2C(O)N(lower alkyl)2, -(CH2)mC(O)OH, -(CH2)mC(O)OR4, -(CH2)mC(O)O(lower alkyl), -(CH2)mC(O)NH2, -(CH2)mC(O)other4, -(CH2)mC(O)NH(lower alkyl), -(CH2)mC(O)N(R4)2, -(CH2)mC(O)N(lower alkyl)2, -C(O)OH, -C(O)OR4, -C(O)O(lower alkyl), -C(O)NH2, -C(O)other4, -C(O)NH(lower alkyl), -C(O)N(R4)2, -C(O)N(lower alkyl)2or cyano;

each R7represents independently OH, OR2, optionally substituted alkyl (including lower alkyl), CH3, CH2CN, CH2N3CH2NH2CH2NHCH3CH2N(CH3)2CH2OH, halogenated alkyl (including halogenated lower alkyl), CF3C(Y3)3, 2-Br-ethyl, - CH2F, CH2Cl, CH2CF3, CF2CF3C(Y3)2C(Y3)3not necessarily replaced alkenyl, halogenoalkanes, Br-vinyl, optionally substituted quinil, halogenoalkanes, optionally substituted carbocycle (preferably, 3 to 7-membered carbocyclic ring, optionally substituted heterocycle (preferably a 3-7 membered heterocyclic ring having one or more O, S and/or N), optionally substituted heteroaryl (preferably 3-7-membered heteroaromatic ring having one or more O, S and/or N), -CH2C(O)OH, -CH2C(O)OR4, -CH2C(O)O(lower alkyl), -CH2C(O)SH, -CH2C(O)SR4, -CH2C(O)S(lower alkyl), -CH2C(O)NH2, -CH2C(O)other4, -CH2C(O)NH(lower alkyl), -CH2C(O)N(R4)2, -CH2C(O)N(lower alkyl)2, -(CH2)mC(O)OH, -(CH2)mC(O)OR4, -(CH2)mC(O)O(lower alkyl), -(CH2)mC(O)SH, -(CH2)mC(O)SR4, -(CH2)mC(O)S(lower alkyl), -(CH2)mC(O)NH2, -(CH2)mC(O)other4, -(CH2)mC(O)NH(lower alkyl), -(CH2) mC(O)N(R4)2, -(CH2)mC(O)N(lower alkyl)2, -C(O)OH, -C(O)OR4, -C(O)O(lower alkyl), -C(O)SH, -C(O)SR4, -C(O)S(lower alkyl), -C(O)NH2, -C(O)other4, -C(O)NH(lower alkyl), -C(O)N(R4)2, -C(O)N(lower alkyl)2, -O(acyl), -O(lower acyl), -O(R4), -O(alkyl), -O(lower alkyl), -O(alkenyl), -O(quinil), -O(aralkyl), -O(cycloalkyl), -S(acyl), -S(lower acyl), -S(R4), -S(lower alkyl), -S(alkenyl), -S(quinil), -S(aralkyl), -S(cycloalkyl), NO2, NH2, -NH(lower alkyl), -other4, -NR4R5, -NH(acyl), -N(lower alkyl)2, -NH(alkenyl), -NH(quinil), -NH(aralkyl), -NH(cycloalkyl), -N(acyl)2azido, cyano, SCN, OCN, NCO, or

halogen (fluorine, chlorine, bromine, iodine);

in the alternative case, R6and R7may together form spirochaetaceae selected from the group consisting of optionally substituted carbocycle (preferably a 3-7 membered carbocyclic ring) or optionally substituted heterocycle (preferably a 3-7 membered heterocyclic ring having one or more O, S and/or N); and

each m independently is 0, 1 or 2.

In the fourth embodiment, the proposed compound of formula (VI) or (VII), or its pharmaceutically acceptable salt, or prodrug, or a stereoisomeric, tautomeric or polymorphic form, as well as a method of treatment of a host infected with Flavivirida, including the introduction of effective treatment amount of compound of formula (VI) or (VII):

or its pharmaceutically acceptable salt or prodrug, or a stereoisomeric, tautomeric or polymorphic form, where

base, R, R1, R2, R3, R4, R5, R6, R7Y, Y1, Y2, Y3, W1, W2, W3, W4, W*, X, X*, X1X2and X3have the values specified above;

where in one embodiment, R8in the formula (VI) represents-OH or-NH2only when X is a carbon atom; and where the

each R8and R11represents independently hydrogen, optionally substituted alkyl (including lower alkyl), CH3CH2CN, CH2N3CH2NH2CH2NHCH3CH2N(CH3)2CH2OH, halogenated alkyl (including halogenated lower alkyl), CF3C(Y3)3, 2-Br-ethyl, - CH2F, CH2Cl, CH2CF3, CF2CF3C(Y3)2C(Y3)3not necessarily replaced alkenyl, halogenoalkanes, Br-vinyl, optionally substituted quinil, halogenoalkanes, -CH2C(O)OH, -CH2C(O)OR4, -CH2C(O)O(lower alkyl), -CH2C(O)NH2, -CH2C(O)other4, -CH2C(O)NH(lower alkyl), -CH2C(O)N(R4 )2, -CH2C(O)N(lower alkyl)2, -CH2)mC(O)OH, -(CH2)mC(O)OR4, -(CH2)mC(O)O(lower alkyl), -(CH2)mC(O)NH2, -(CH2)mC(O)other4, -(CH2)mC(O)NH(lower alkyl), -(CH2)mC(O)N(R4)2, -(CH2)mC(O)N(lower alkyl)2, -C(O)OH, -C(O)OR4, -C(O)O(lower alkyl), -C(O)NH2, -C(O)other4, -C(O)NH(lower alkyl), -C(O)N(R4)2, -C(O)N(lower alkyl)2, cyano, NH-acyl or N(acyl)2;

each R9and R10independently represents hydrogen, OH, OR2, optionally substituted alkyl (including lower alkyl), CH3CH2CN, CH2N3CH2NH2CH2NHCH3CH2N(CH3)2CH2OH, halogenated alkyl (including halogenated lower alkyl), CF3C(Y3)3, 2-Br-ethyl, - CH2F, CH2Cl, CH2CF3, CF2CF3C(Y3)2C(Y3)3not necessarily replaced alkenyl, halogenoalkanes, Br-vinyl, optionally substituted quinil, halogenoalkanes, optionally substituted carbocycle (preferably, 3 to 7-membered carbocyclic ring, optionally substituted heterocycle (preferably a 3-7 membered heterocyclic ring having one or more O, S and/or N), optionally substituted heteroaryl (preferably 3-7-the Lenna heteroaromatic ring, having one or more O, S and/or N), -CH2C(O)OH, -CH2C(O)OR4, -CH2C(O)O(lower alkyl), -CH2C(O)SH, -CH2C(O)SR4, -CH2C(O)S(lower alkyl), -CH2C(O)NH2, -CH2C(O)other4, -CH2C(O)NH(lower alkyl), -CH2C(O)N(R4)2, -CH2C(O)N(lower alkyl)2, -(CH2)mC(O)OH, -(CH2)mC(O)OR4, -(CH2)mC(O)O(lower alkyl), -(CH2)mC(O)SH, -(CH2)mC(O)SR4, -(CH2)mC(O)S(lower alkyl), -(CH2)mC(O)NH2, -(CH2)mC(O)other4, -(CH2)mC(O)NH(lower alkyl), -(CH2)mC(O)N(R4)2, -(CH2)mC(O)N(lower alkyl)2, -C(O)OH, -C(O)OR4, -C(O)O(lower alkyl), -C(O)SH, -C(O)SR4, -C(O)S(lower alkyl), -C(O)NH2, -C(O)other4, -C(O)NH(lower alkyl), -C(O)N(R4)2, -C(O)N(lower alkyl)2, -O(acyl), -O(lower acyl), -O(R4), -O(alkyl), -O(lower alkyl), -O(alkenyl), -O(quinil), -O(aralkyl), -O(cycloalkyl), -S(acyl), -S(lower acyl), -S(R4), -S(lower alkyl), -S(alkenyl), -S(quinil), -S(aralkyl), -S(cycloalkyl), NO2, NH2, -NH(lower alkyl), -other4, -NR4R5, -NH(acyl), -N(lower alkyl)2, -NH(alkenyl), -NH(quinil), -NH(aralkyl), -NH(cycloalkyl), -N(acyl)2azido, cyano, SCN, OCN, NCO, or

halogen (fluorine, chlorine, bromine, iodine);

each m independently is 0, 1 or 2 and

in the alternative case, the 6and R10, R7and R9, R8and R7or R9and R11may together form a bridged compound selected from the group consisting of optionally substituted carbocycle (preferably a 3-7 membered carbocyclic ring) or optionally substituted heterocycle (preferably a 3-7 membered heterocyclic ring having one or more O, S and/or N); or

in the alternative case, R6and R7or R9and R10may together form spirochaetaceae selected from the group consisting of optionally substituted carbocycle (preferably a 3-7 membered carbocyclic ring) or optionally substituted heterocycle (preferably a 3-7 membered heterocyclic ring having one or more O, S and/or N).

In the fifth main embodiment, the proposed compound of formula (VIII), (IX) or (X), or its pharmaceutically acceptable salt, or prodrug, or a stereoisomeric, tautomeric or polymorphic form, as well as a method of treatment of a host infected with Flaviviridae that includes the introduction of effective treatment amount of compound of formula (VIII), (IX) or (X):

or its pharmaceutically acceptable salt or prodrug, or a stereoisomeric, tautomeric or polymorphic form, where

R1, Rsup> 2, R3, R4, R5X, Y3and X* have the meanings indicated above;

base* is a purine or pyrimidine base as defined above;

each R12represents independently substituted alkyl (including lower alkyl), CH2CN, CH2N3CH2NH2CH2NHCH3CH2N(CH3)2CH2OH, halogenated alkyl (including halogenated lower alkyl), CF3C(Y3)3, 2-Br-ethyl, - CH2F, CH2Cl, CH2CF3, CF2CF3C(Y3)2C(Y3)3replaced alkenyl, halogenoalkanes (but not Br-vinyl), substituted quinil, halogenoalkanes, -CH2C(O)OH, -CH2C(O)OR4, -CH2C(O)O(lower alkyl), -CH2C(O)NH2, -CH2C(O)other4, -CH2C(O)NH(lower alkyl), -CH2C(O)N(R4)2, -CH2C(O)N(lower alkyl)2, -(CH2)mC(O)OH, -(CH2)mC(O)OR4, -(CH2)mC(O)O(lower alkyl), -(CH2)mC(O)NH2, -(CH2)mC(O)other4, -(CH2)mC(O)NH(lower alkyl), -(CH2)mC(O)N(R4)2, -(CH2)mC(O)N(lower alkyl)2, -C(O)OH, -C(O)OR4, -C(O)NH2, -C(O)other4, -C(O)NH(lower alkyl), -C(O)N(R4)2, -C(O)N(lower alkyl)2;

each R13represents independently substituted alkyl (including lower alkyl), CH 2CN, CH2N3CH2NH2CH2NHCH3CH2N(CH3)2CH2OH, halogenated alkyl (including halogenated lower alkyl), CF3C(Y3)3, 2-Br-ethyl, - CH2F, CH2Cl, CH2CF3, CF2CF3C(Y3)2C(Y3)3replaced alkenyl, halogenoalkanes (but not Br-vinyl), substituted quinil, halogenoalkanes, optionally substituted carbocycle (preferably, 3 to 7-membered carbocyclic ring, optionally substituted heterocycle (preferably a 3-7 membered heterocyclic ring having one or more O, S and/or N), optionally substituted heteroaryl (preferably 3-7-membered heteroaromatic ring having one or more O, S and/or N), -CH2C(O)OH, -CH2C(O)OR4, -CH2C(O)O(lower alkyl), -CH2C(O)SH, -CH2C(O)SR4, -CH2C(O)S(lower alkyl), -CH2C(O)NH2, -CH2C(O)other4, -CH2C(O)NH(lower alkyl), -CH2C(O)N(R4)2, -CH2C(O)N(lower alkyl)2, -(CH2)mC(O)OH, -(CH2)mC(O)OR4, -(CH2)mC(O)O(lower alkyl), -(CH2)mC(O)SH, -(CH2)mC(O)SR4, -(CH2)mC(O)S(lower alkyl), -(CH2)mC(O)NH2, -(CH2)mC(O)other4, -(CH2)mC(O)NH(lower alkyl), -(CH2)mC(O)N(R4)22)mC(O)N(lower alkyl)2, -C(O)OH, -C(O)OR4, -C(O)SH, -C(O)SR4, -C(O)S(lower alkyl), -C(O)NH2, -C(O)other4, -C(O)NH(lower alkyl), -C(O)N(R4)2, -C(O)N(lower alkyl)2, -O(R4), -O(quinil), -O(aralkyl), -O(cycloalkyl), -S(acyl), -S(lower acyl), -S(R4), -S(lower alkyl), -S(alkenyl), -S(quinil), -S(aralkyl), -S(cycloalkyl), -other4, -NR4R5, -NH(alkenyl), -NH(quinil), -NH(aralkyl), -NH(cycloalkyl), SCN, OCN, NCO, or fluorine;

in the alternative case, R12and R13together form spirochaetaceae selected from the group consisting of optionally substituted carbocycle (preferably a 3-7 membered carbocyclic ring) or optionally substituted heterocycle (preferably a 3-7 membered heterocyclic ring having one or more O, S and/or N), and

each m independently is 0, 1 or 2.

In the sixth basic version of the proposed compound of formula (XI) or (XII), or its pharmaceutically acceptable salt, or prodrug, or a stereoisomeric, tautomeric or polymorphic form, as well as a method of treatment of a host infected with Flaviviridae that includes the introduction of effective treatment amount of compound of formula (XI) or (XII):

or its pharmaceutically acceptable salt or prodrug, or a stereoisomeric, tautomeric or polio pneu form, where

in the alternative case basis* replaced on the basis of formulas (XI) and (XII) and

base, base*, R, R1, R2, R3, R4, R5, R12, R13Y, Y1, Y2, Y3, W*, W1, W2, W3, W4X, X*, X1X2and X3have the values specified above;

and where in one embodiment, R8in the formula (XI) is-HE-or-NH2only when X is a carbon atom, and where

each R8and R11represents independently hydrogen, optionally substituted alkyl (including lower alkyl), CH3CH2CN, CH2N3CH2NH2CH2NHCH3CH2N(CH3)2CH2OH, halogenated alkyl (including halogenated lower alkyl), CF3C(Y3)3, 2-Br-ethyl, - CH2F, CH2Cl, CH2CF3, CF2CF3C(Y3)2C(Y3)3not necessarily replaced alkenyl, halogenoalkanes, Br-vinyl, optionally substituted quinil, halogenoalkanes, -CH2C(O)OH, -CH2C(O)OR4, -CH2C(O)O(lower alkyl), -CH2C(O)NH2, -CH2C(O)other4, -CH2C(O)NH(lower alkyl), -CH2C(O)N(R4)2, -CH2C(O)N(lower alkyl)2, -(CH2)mC(O)OH, -(CH2)mC(O)OR4, -(CH2)mC(O)O(lower alkyl), -(CH )mC(O)NH2, -(CH2)mC(O)other4, -(CH2)mC(O)NH(lower alkyl), -(CH2)mC(O)N(R4)2, -(CH2)mC(O)N(lower alkyl)2, -C(O)OH, -C(O)OR4, -C(O)O(lower alkyl), -C(O)NH2, -C(O)other4, -C(O)NH(lower alkyl), -C(O)N(R4)2, -C(O)N(lower alkyl)2, cyano, NH-acyl or N(acyl)2;

each R9and R10represents independently hydrogen, OH, OR2, optionally substituted alkyl (including lower alkyl), CH3CH2CN, CH2N3CH2NH2CH2NHCH3CH2N(CH3)2CH2OH, halogenated alkyl (including halogenated lower alkyl), CF3C(Y3)3, 2-Br-ethyl, - CH2F, CH2Cl, CH2CF3, CF2CF3C(Y3)2C(Y3)3not necessarily replaced alkenyl, halogenoalkanes, Br-vinyl, optionally substituted quinil, halogenoalkanes, optionally substituted carbocycle (preferably, 3 to 7-membered carbocyclic ring, optionally substituted heterocycle (preferably a 3-7 membered heterocyclic ring having one or more O, S and/or N), optionally substituted heteroaryl (preferably 3-7-membered heteroaromatic ring having one or more O, S and/or N), -CH2C(O)OH, -CH2C(O)OR4, -CH2C(O)O(lower alkyl), -CH2 C(O)SH, -CH2C(O)SR4, -CH2C(O)S(lower alkyl), -CH2C(O)NH2, -CH2C(O)other4, -CH2C(O)NH(lower alkyl), -CH2C(O)N(R4)2, -CH2C(O)N(lower alkyl)2, -(CH2)mC(O)OH, -(CH2)mC(O)OR4, -(CH2)mC(O)O(lower alkyl), -(CH2)mC(O)SH, -(CH2)mC(O)SR4, -(CH2)mC(O)S(lower alkyl), -(CH2)mC(O)NH2, -(CH2)mC(O)other4, -(CH2)mC(O)NH(lower alkyl), -(CH2)mC(O)N(R4)2, -(CH2)mC(O)N(lower alkyl)2, -C(O)OH, -C(O)OR4, -C(O)O(lower alkyl), -C(O)SH, -C(O)SR4, -C(O)S(lower alkyl), -C(O)NH2, -C(O)other4, -C(O)NH(lower alkyl), -C(O)N(R4)2, -C(O)N(lower alkyl)2, -O(acyl), -O(lower acyl), -O(R4), -O(alkyl), -O(lower alkyl), -O(alkenyl), -O(quinil), -O(aralkyl), -O(cycloalkyl), -S(acyl), -S(lower acyl), -S(R4), -S(lower alkyl), -S(alkenyl), -S(quinil), -S(aralkyl), -S(cycloalkyl), NO2, NH2, -NH(lower alkyl), -other4, -NR4R5, -NH(acyl), -N(lower alkyl)2, -NH(alkenyl), -NH(quinil), -NH(aralkyl), -NH(cycloalkyl), -N(acyl)2azido, cyano, SCN, OCN, NCO, or halogen (fluorine, chlorine, bromine, iodine);

each m independently is 0, 1 or 2; and

in the alternative case, R8and R13, R9and R13, R9and R11or R10and R12may together form m is tikovoi connection, selected from the group consisting of optionally substituted carbocycle (preferably a 3-7 membered carbocyclic ring) or optionally substituted heterocycle (preferably a 3-7 membered heterocyclic ring having one or more O, S and/or N); or

in the alternative case, R12and R13or R9and R10may together form spirochaetaceae selected from the group consisting of optionally substituted carbocycle (preferably a 3-7 membered carbocyclic ring) or optionally substituted heterocycle (preferably a 3-7 membered heterocyclic ring having one or more O, S and/or N).

In a particular aspect of the invention proposed compound of formula (XI) or (XII), or its pharmaceutically acceptable salt, or prodrug, or a stereoisomeric, tautomeric or polymorphic form, as well as a method of treatment of a host infected with Flaviviridae that includes the introduction of effective treatment amount of compound of formula (XI) or (XII):

or its pharmaceutically acceptable salt or prodrug, or a stereoisomeric, tautomeric or polymorphic form, where

R3selected from the group consisting of H, mono-, di - or triphosphate or a stabilized phosphate prodrug; acyl; sulphonate ester; optional is tion substituted alkylsulfonyl; optionally substituted arylsulfonyl; lipid; amino acid; carbohydrate; peptide, cholesterol and pharmaceutically acceptable removed group, which when introduced in vivo are capable of forming a compound, which R3represents independently H or mono-, di - or triphosphate;

X is selected from the group consisting of one or more of the groups O, S, SO, SO2, N, NH, NR and CH2where any of the above groups may be optionally substituted, and can be located in different positions so as to form a 3-7-membered ring;

R represents H, alkyl or acyl, and

In denotes spirochaetaceae selected from the group consisting of optionally substituted carbocycle (preferably a 3-7 membered carbocyclic ring) or optionally substituted heterocycle (preferably a 3-7 membered heterocyclic ring having one or more O, S and/or N);

base selected from the group consisting of groups:

where

each of R', R", R"' and R"" are independently selected from the group consisting of H, HE, substituted or unsubstituted alkyl, substituted or unsubstituted, alkenyl, substituted or unsubstituted quinil, cycloalkyl, Br-vinyl, -O-alkyl, -O-alkenyl, -O-quinil, -O-aryl, -O-aralkyl, -O-acyl, O-cycloalkyl, NH2, NH-alkyl, N-dialkyl, NH-acyl, N-aryl, N-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-acyl, S-aryl, S-cycloalkyl, S-aralkyl, F, Cl, Br, I, CN, COOH, CONH2, CO2-alkyl, CONH-alkyl, CON-dialkyl, HE, CF3CH2OH, (CH2)mOH, (CH2)mNH2, (CH2)mCOOH, (CH2)mCN, (CH2)mNO2and (CH2)mCONH2;

m is 0 or 1;

W represents C-R or N;

T and V independently represent CH or N;

Q represents CH, -CCl-CBr, -CF, -Cl, -CCN-C-COOH, -C,-CONH2or N;

Q1and Q2independently represent N or C-R;

Q3, Q4, Q5and Q6independently represent N or CH, and

their tautomeric forms.

In the second aspect of the invention proposed compound of formula (XV), (XVI or XVII, or its pharmaceutically acceptable salt, or prodrug, or a stereoisomeric, tautomeric or polymorphic form, as well as a method of treatment of a host infected with Flaviviridae that includes the introduction of effective treatment amount of compound of formula (XV), (XVI) or (XVII):

or its pharmaceutically acceptable salt or prodrug, or a stereoisomeric, tautomeric or polymorphic form, where

G and E are independently selected from the group consisting of CH3CH2HE, CH2F, CH2N3CH 2CN, (CH2)mCOOH, (CH2)mCOOR, (CH2)mCONH2, (CH2)mCONR2, (CH2)mCONHR and N-acyl;

m is 0 or 1;

R represents H, alkyl or acyl, and

R', R", R"', R"and R3and the Foundation shall have the meanings indicated in the formula (XIII).

In the alternative case, the compound of formula (XVII) at most one of G and E may additionally be hydrogen.

In the third specific aspect of the invention proposed compound of formula (XVIII), or its pharmaceutically acceptable salt, or prodrug, or a stereoisomeric, tautomeric or polymorphic form, as well as a method of treatment of a host infected with Flaviviridae that includes the introduction of effective treatment amount of compound of formula (XVIII):

or its pharmaceutically acceptable salt or prodrug, or a stereoisomeric, tautomeric or polymorphic form, where

M is selected from the group consisting of S, SO and SO2and

R', R", R"', R"and R3and the Foundation shall have the meanings specified for formula (XIII).

In the fourth aspect of the invention proposed compound of formula (XIX), (XX), (XXI), (XXII) or (XXIII), or its pharmaceutically acceptable salt, or prodrug, or a stereoisomeric, tautomeric or polymorphic form, as well as a method of treatment of a host infected with Faviviridae, including the introduction of effective treatment amount of compound of formula (XIX), (XX), (XXI), (XXII) or (XXIII):

or its pharmaceutically acceptable salt or prodrug, or a stereoisomeric, tautomeric or polymorphic form, where

A is selected from the group consisting of optionally substituted lower alkyl, cycloalkyl, alkenyl, quinil, CH2OH, CH2NH2CH2NHCH3CH2N(CH3)2CH2F, CH2Cl, CH2N3CH2CN, CH2CF3, CF3, CF2CF3CH2CO2R, (CH2)mCOOH, (CH2)mCOOR, (CH2)mCO-NH2, (CH2)mCONR2and (CH2)mCONHR;

Y is selected from the group consisting of H, optionally substituted lower alkyl, cycloalkyl, alkenyl, quinil, CH2OH, CH2NH2CH2NHCH3CH2N(CH3)2CH2F, CH2Cl, CH2N3CH2CN, CH2CF3, CF3, CF2CF3CH2CO2R, (CH2)mCOOH, (CH2)mCOOR, (CH2)mCONH2, (CH2)mCONR2and (CH2)mCONHR;

X is selected from the group consisting of HE, optionally substituted alkyl, cycloalkyl, alkenyl, quinil, -O-alkyl, -O-alkenyl, -O-quinil, -O-aryl, -O-aralkyl, -O-cycloalkyl-, O-acyl, F, Cl, Br, I, CN, NC, SCN, ON, NCO, NO2, NH2N3, NH-acyl, NH-alkyl, N-dialkyl, NH-alkenyl, NH-quinil, NH-aryl, NH-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-alkenyl, S-quinil, S-aryl, S-aralkyl, S-acyl, S-cycloalkyl, CO2-alkyl, CONH-alkyl, CON-dialkyl, CONH-alkenyl, CONH-quinil, CONH-aralkyl, CONH-cycloalkyl, CH2OH, CH2NH2CH2NHCH3CH2N(CH3)2CH2F, CH2Cl, CH2N3CH2CN, CH2CF3, CF3, CF2CF3CH2CO2R, (CH2)mCOOH, (CH2)mCOOR, (CH2)mCONH2, (CH2)mCONR2, (CH2)mCONHR, optionally substituted 3-7-membered carbocyclic and optionally substituted 3-7-membered heterocyclic ring having independently O, S and/or N as a heteroatom taken alone or in combination;

m is 0 or 1;

R represents H, alkyl or acyl;

R3selected from the group consisting of H; mono-, di - or triphosphate or a stabilized phosphate prodrug; a substituted or unsubstituted alkyl; acyl; sulphonate ester; optionally substituted alkylsulfonyl; optionally substituted arylsulfonyl; lipid; amino acid; carbohydrate; peptide, cholesterol and pharmaceutically acceptable removed group, which when introduced in vivo are capable of forming a compound, is vtorogo R 3represents independently H or mono-, di - or triphosphate; and

the Foundation is a non-natural base selected from the group:

where

each R', R", R'" and R"" are independently selected from the group consisting of H, OH, substituted or unsubstituted alkyl, substituted or unsubstituted, alkenyl, substituted or unsubstituted, alkenyl, cycloalkyl, Br-vinyl, -O-alkyl, O-alkenyl, O-quinil, O-aryl, O-aralkyl, -O-acyl, O-cycloalkyl, NH2, NH-alkyl, N-dialkyl, NH-acyl, N-aryl, N-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-acyl, S-aryl, S-cycloalkyl, S-aralkyl, F, Cl, Br, I, CN, COOH, CONH2, CO2-alkyl, CONH-alkyl, CON-dialkyl, OH, CF3CH2OH, (CH2)mOH, (CH2)mNH2, (CH2)mCOOH, (CH2)mCN, CH2)mNO2and (CH2)mCONH2;

m is 0 or 1;

W represents C-R or N;

T and V independently represent CH or N;

Q represents CH, -CCl-CBr, -CF, -Cl, -CCN-C-COOH, -C,-CONH2or N;

Q1and Q2independently represent N or C-R”” and

Q3, Q4, Q5and Q6independently represent N or CH;

with the proviso that in (g) and (i) R', R”” is H, HE or NH2and Q, T, V, Q2, Q5and Q6is not n

In one embodiment, the amino acid is the STATCOM is a residue of the formula C(O)C(R 11)(R12)(NR13R14), where

R11represents the side chain of amino acids, and where, as in Proline, R11may not necessarily be attached to R13with the formation of a cyclic structure, or in the alternative case, R11represents alkyl, aryl, heteroaryl or heterocyclic residue;

R12represents hydrogen, alkyl (including lower alkyl) or aryl, and

R13and R14independently represent hydrogen, acyl ( including acyl derivative attached to R11) or alkyl (including but not limited to the above, methyl, ethyl, propyl and cyclopropyl).

In another preferred embodiment, at least one of R2and R3is amino acid residue, preferably L-validolum.

β-D and β-L-nucleosides of the present invention may inhibit the activity of the polymerase Flaviviridae. Nucleosides can be subjected to screening for their ability to inhibit the activity of the polymerase Flaviviridae in vitro in accordance with the methods of screening described here in more detail. Spectrum of activity can be easily determined by evaluation of compounds in the assays described herein, or other test analysis.

In one embodiment, the effectiveness of the compounds against Flaviviridae measured concentration with the organisations, necessary to reduce the number of virus plaques in vitro according to the methods described here are more detailed, 50% (i.e. EU50connection). In preferred embodiments, the initial connection procarcinogen connection has EU50less than 25, 15, 10, 5 or 1 micromole. In preferred embodiments, the implementation of connection is EU50less than 15 or 10 micromol when measuring on the analysis of the polymerase, as described in Ferrari et al., Jnl. Of Vir., 73:1649-1654,1999; Ishii et al., Hepatology, 29:1227-1235, 1999; Lohmann et al., Jnl. of Bio. Chem., 274:10807-10815, 1999; or Yamashita et al., Jnl. of Bio. Chem., 273:15479-15486, 1998.

In another embodiment, the proposed combinational and/or alternativna therapy. In combination therapy effective dose of two or more agents are administered together, whereas in alternativnoe therapy effective dose of each agent are administered sequentially. The dose will depend on absorption, inactivation, the rate of excretion of the drug, as well as other factors known to the person skilled in the art. It should be noted that the magnitude of the doses will also vary depending on the severity of the condition, which should be eased. In addition, it should be clear that for any particular subject charts and graphs of certain drugs must be adjusted in accordance with the needs of the patient and the professional assessment of the person, misleading or overseeing the introduction of songs.

The invention relates to a combination of at least two prodrugs described herein. The invention further provides at least one of the described 2'- and 3'-prodrugs in combination or alteration with a second nucleoside, which shows activity against Flaviviridae and includes, but is not limited to the original drug, any of the prodrugs listed here, i.e. β-D-2',6-dimerization, β-D-2',6-dimethylamide, β-D-2',8-dimetilbenzin, β-D-2',8-dimethylguanosine, β-D-2',6-dimethyl-5-perltidy and/or β-D-2',6-dimethylaniline. In the alternative case, the 2'- or 3'-prodrug can be introduced in combination or alteration with another agent against Flaviviridae, with EU50less than 10 or 15 micromol, or its prodrugs, or pharmaceutically acceptable salts.

Non-limiting examples of antiviral agents that can be used in combination with compounds described herein include 1) the interferon and/or ribavirin; 2) inhibitors of the NS3 protease-based substrate; 3) inhibitors are not based on the substrate; 4) derivatives of thiazolidine; 5) thiazolidine and benzanilide; (6) phenanthridine; 7) inhibitors of NS3; 8) inhibitors of helicase HCV, (9) polymerase inhibitors, including inhibitors of RNA-dependent RNA polymerase; (10) the antisense oligodeoxynucleotide the Chida; (11) inhibitors of IRES-dependent translation; (12) nuclease-resistant ribozymes and (13) other compounds that show activity against Flaviviridae. The invention further includes the introduction of the prodrug in combination or alteration with the immune modulator or other pharmaceutically active modifier of viral replication, including biological material, such as a protein, peptide, oligonucleotide, or gamma globulin, which includes, but is not limited to the above, interferon, interleukin, or oligonucleotides, which are antimuslim for genes expressing or regulating the replication of Flaviviridae.

The invention further includes the introduction of the prodrug in combination or alteration with the immune modulator or other pharmaceutically active modifier of viral replication, including biological material, such as a protein, peptide, oligonucleotide, or gamma globulin, which includes, but is not limited to the above, interferon, interleukin, or oligonucleotides, which are antimuslim for genes expressing or regulating the replication of Flaviviridae.

In particular, the present invention relates to the following:

(a) compound of formula (XIII)to(XXIII), or its pharmaceutically acceptable salt, or prodrug;

(b) pharmaceutical is oppozitsii, containing the compound of the formula (XIII)to(XXIII), or its pharmaceutically acceptable salt, or prodrug together with a pharmaceutically acceptable carrier or diluent;

(C) pharmaceutical compositions containing a compound of the formula (XIII)to(XXIII), or its pharmaceutically acceptable salt, or prodrug with one or more other effective antiviral agents, optionally, with a pharmaceutically acceptable carrier or diluent;

(d) a pharmaceutical composition for the treatment of a Flaviviridae infection in a host containing the compound of formula (I)-(XXIII), or its pharmaceutically acceptable salt, or prodrug together with a pharmaceutically acceptable carrier or diluent;

(e) a pharmaceutical composition for the treatment of a Flaviviridae infection in a host containing the compound of formula (I)-(XXIII), or its pharmaceutically acceptable salt, or prodrug with one or more other effective antiviral agents, optionally with a pharmaceutically acceptable carrier or diluent;

(f) methods of treating a Flaviviridae infection in a host, introducing the compounds of formula (I)-(XXIII), or its pharmaceutically acceptable salt or prodrug, optionally with a pharmaceutically acceptable carrier or diluent;

(g) methods of treating a Flaviviridae infection in a host containing centuries the definition of the compounds of formula (I)-(XXIII), or its pharmaceutically acceptable salts, or prodrugs, with one or more other effective antiviral agents, optionally with a pharmaceutically acceptable carrier or diluent;

(h) the use of the compounds of formula (I)-(XXIII), or its pharmaceutically acceptable salt or prodrug, optionally with a pharmaceutically acceptable carrier or diluent for the treatment of a Flaviviridae infection in a host;

(i) the use of the compounds of formula (I)-(XXIII), or its pharmaceutically acceptable salts, or prodrugs with one or more other effective antiviral agents, optionally with a pharmaceutically acceptable carrier or diluent for the treatment of a Flaviviridae infection in a host;

(j) the use of the compounds of formula (I)-(XXIII), or its pharmaceutically acceptable salt or prodrug, optionally with a pharmaceutically acceptable carrier or diluent in the manufacture of drugs for the treatment of a Flaviviridae infection in a host, and

(k) the use of the compounds of formula (I)-(XXIII), or its pharmaceutically acceptable salts, or prodrugs with one or more other effective antiviral agents, optionally with a pharmaceutically acceptable carrier or diluent in the manufacture of drugs for the treatment of infections Flaviviidae the owner.

In an alternative embodiment, the source nucleoside compound of any of the 2'- or 3'-prodrugs (i.e. without nucleosides 2'- or 3'- tseplyaesh parts) proposed for treatment of Flaviviridae infection, especially infection of hepatitis C.

Brief description of drawings

Figure 1 represents the structure of the various non-limiting examples of nucleosides of the present invention, as well as other well-known nucleosides, in particular IFAU and ribavirin.

Figure 2 represents a non-limiting example of the stages consisting in the esterification of 1',2',3' or 4'-branched β-D or β-L-nucleoside to obtain a 2'-prodrugs. The same General procedure can be used to obtain the 3'-prodrugs of selective protection of the 2'- and 5'-hydroxyl group or a protected 2'-, 3'- and 5'-hydroxyl groups and the selective removal of protecting the 3'-hydroxyl.

Figure 3 represents a non-limiting example of the stages consisting in the esterification of 1', 2', 3' or 4'-branched β-D or β-L-nucleoside to obtain 3'-prodrugs.

Figure 4 represents a non-limiting example of the stages consisting in the esterification of 1', 2', 3' or 4'-branched β-D or β-L-nucleoside to obtain 2',3'-prodrugs.

Detailed description of the invention

The invention described herein is a compound, method and composition for treating infection Flviviridae in humans and other animal hosts. The method includes introducing effective against Flaviviridae number of 2'- and/or 3'-prodrugs of 1', 2', 3' or 4'-branched β-D or β-L-nucleoside, as described herein, or its pharmaceutically acceptable salt or prodrug, optionally in a pharmaceutically acceptable carrier. The compounds of this invention either possess antiviral (i.e. anti-HCV) activity, or metabolize the compound that exhibits such activity. HCV is a member of the family Flaviviridae. HCV is placed in a new monotypic genus, hepacivirus. Thus, in one embodiment, Flaviviridae is HCV. In an alternative embodiment, Flaviviridae is flaviviruses or pestiviruses.

2'- and/or 3'-prodrugs of 1', 2', 3' or 4'-branched β-D or β-L-nucleoside is acylphosphatase secondary or tertiary alpha-alcohol secondary or tertiary carbon atom. Due to the steric hindrance of these prodrugs compared to the 5'-prodrugs, acylphosphatase primary alcohol, these prodrugs differently modulate biological properties of the molecule in vivo. Found that 2'- and/or 3'-prodrugs of 1', 2', 3' or 4'-branched β-D or β-L-nucleoside can provide a drug with a high half-period of existence in the body and improved pharmacokinetic profile.

2'- or 3'-prole the arstvo in the preferred embodiment, has tsepliaeva acyl group, and most definitely, amino acid residue derived from any natural or synthetic α-, β-, γ - or δ-amino acids, including but not limited to the above, glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, Proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartate, glutamate, lysine, arginine and histidine. In a preferred embodiment, the amino acid has the L-configuration. Alternatively derived amino acids can be alanyl, valinol, Latini, isoleucine, Proline, phenylalaninol, tryptophanyl, methionine, glycinyl, serinol, threonine, cysteine, tyrosine, asparagine, glutamine, aspartyl, glutaryl, lisini, arginine, histidine, β-alanyl, β-valinol, β-leucinol, β-isoleucine, β-Proline, β-phenylalanine, β-tryptophanyl, β-methionine, β-glycinin, β-serenil, β-threonine, β-cysteine, β-tyrosine, β-asparaginyl, β-glutamine, β-aspartyl, β-glutaryl, β-lisini, β-argininel or β-histidinol. In one specific embodiment, the residue is malinowy ether. Especially preferred compound is 3'-malinowy ester of 2',6-dimethylpiperidine.

Oral bioavailability of 1', 2', 3' or 4'-branched β-D or β-L-nucleoside in the form of a neutral base and as a salt with HCl is low for rodents and primates, but the people. It was found that there is significant competition 1', 2', 3' or 4'-branched β-D or β-L-nucleoside with other nucleosides or nucleoside analogues for the absorption or transfer of the gastrointestinal tract and the competition of other nucleosides or nucleoside analogues for the absorption of 1', 2', 3' or 4'-branched β-D or β-L-nucleoside. To improve oral bioavailability and reduced interaction potential drug-drug were obtained 2'- and 3'-prodrugs of 1', 2', 3' or 4'-branched β-D or β-L-nucleoside with a higher bioavailability than the parent molecule, and a reduced effect on the bioavailability of other nucleosides or nucleoside analogues used in combination.

2'-, 3'- and/or 5'-mono-, -di - or-trivalency ester of 1', 2', 3' or 4'-branched β-D or β-L-nucleoside has a higher oral bioavailability than the original 1', 2', 3' or 4'-branched β-D or β-L-nucleoside, and reduced interaction with other nucleosides or nucleoside analogues, when used in combination, compared with 1', 2', 3' or 4'-branched β-D or β-L-nucleoside.

2'-, 3'- and/or 5'-mono-, -di - or-trivalency ester of 1', 2', 3' or 4'-branched β-D or β-L-nucleoside can be converted to the original 1', 2', 3' or 4'-branched β-D or β-L-nucleoside through deesterification in SL is sistei the membrane of the gastro-intestinal tract, blood or liver. 2'-, 3'- and/or 5'-mono-, -di - or-trivalency ester of 1', 2', 3' or 4'-branched β-D or β-L-nucleoside can be actively transferred from the cavity of the gastrointestinal tract after oral delivery into the bloodstream function amino acid carrier in the mucosa of the gastrointestinal tract. This explains the increase in oral bioavailability compared to the original 1', 2', 3' or 4'-branched β-D or β-L-nucleoside, which is transferred primarily a function of the nucleoside carrier. There is also reduced competition for the uptake of 2'-, 3'- and/or 5'-mono-, -di - or-travelingwave ether 1', 2', 3' or 4'-branched β-D or β-L-nucleoside with other nucleosides or nucleoside analogues, which are transferred by the function nucleoside Transporter, and not a function of amino acid carrier. When there is partial deesterification di - or-travelingwave ether 1', 2', 3' or 4'-branched β-D or β-L-nucleoside before competing absorption, mono - and gialinovym ether continues to be adsorbed using amino acid carrier. Thus, it can be maintained the desired result of better absorption, or bioavailability, and reduced competition with other nucleosides or nucleoside analogues for absorption into the bloodstream.

In conclusion, the present invention includes the following distinctive features:

(a) 2'- and/or 3'-prodrug 1', 2', 3' or 4'-branched β-D or β-L-nucleoside, described here, and its pharmaceutically acceptable salts, and compositions;

(b) 2'- and/or 3'-prodrug 1'-, 2'-, 3'- or 4'-branched β-D or β-L-nucleoside, described here, and its pharmaceutically acceptable salts and compositions for use in the treatment and/or prophylaxis of a Flaviviridae infection, especially in patients diagnosed as having a Flaviviridae infection or having the risk of becoming infected With hepatitis C;

(C) 2'- and/or 3'-prodrug 1', 2', 3' or 4'-branched β-D or β-L-nucleoside, described here, and its pharmaceutically acceptable salts and compositions described here, essentially in the absence of the opposite enantiomers of the described nucleoside or being separated from a mixture with other chemical enantiomers;

(d) the method of obtaining 2'- and/or 3'-prodrugs of 1', 2', 3' or 4'-branched β-D or β-L-nucleoside, described in more detail below;

(e) pharmaceutical preparations containing 2'- and/or 3'-prodrug 1', 2', 3' or 4'-branched β-D or β-L-nucleoside or its pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier or diluent;

(f) pharmaceutical preparations containing 2'- and/or 3'-prodrug 1'-, 2'-, 3'- or 4'-branched β-D or β-L-nucleoside or its pharmaceutical is acceptable salt, together with one or more other effective against HCV agents, optionally in a pharmaceutically acceptable carrier or diluent;

(g) pharmaceutical preparations containing 2'- and/or 3'-prodrug 1', 2', 3' or 4'-branched β-D or β-L-nucleoside or its pharmaceutically acceptable salt together with other source 1', 2', 3' or 4'-branched β-D or β-L-nucleoside, optional, pharmaceutically acceptable carrier or diluent;

(h) the method of treatment and/or prevention of a host infected with Flaviviridae that includes the introduction of an effective amount of 2'- and/or 3'-prodrugs of 1', 2', 3' or 4'-branched β-D or β-L-nucleoside, its pharmaceutically acceptable salt or composition;

(i) a method of treatment and/or prevention of a host infected with Flaviviridae that includes the introduction of an effective amount of 2'- and/or 3'-prodrugs of 1', 2', 3' or 4'-branched β-D or β-L-nucleoside, its pharmaceutically acceptable salt or composition in combination and/or alteration of one or more effective agents against HCV;

(j) the method of treatment and/or prevention of a host infected with Flaviviridae that includes the introduction of an effective amount of 2'- and/or 3'-prodrugs of 1', 2', 3' or 4'-branched β-D or β-L-nucleoside, its pharmaceutical is Eski acceptable salt or composition with other source 1', 2', 3' or 4'-branched β-D or β-L-nucleoside;

(k) the method of treatment and/or prevention of a host infected with Flaviviridae that includes the introduction of an effective amount of 2'- and/or 3'-prodrug of β-D-2'-methylcytidine, or its pharmaceutically acceptable salt, or composition;

(l) the method of treatment and/or prevention of a host infected with Flaviviridae that includes the introduction of an effective amount of 2'-valovogo or acetylator ester of β-D-2'-methylcytidine, or its pharmaceutically acceptable salt or composition thereof;

(m) the use of 2'- and/or 3'-prodrugs of 1', 2', 3' or 4'-branched β-D or β-L-nucleoside and its pharmaceutically acceptable salts or compositions for the treatment and/or prophylaxis of a Flaviviridae infection in a host;

(n) the use of 2'- and/or 3'-prodrugs of 1', 2', 3' or 4'-branched β-D or β-L-nucleoside, its pharmaceutically acceptable salt or composition in combination and/or alteration of one or more effective agents against HCV for the treatment and/or prophylaxis of a Flaviviridae infection in a host;

(o) the use of 2'- and/or 3'-prodrugs of 1', 2', 3' or 4'-branched β-D or β-L-nucleoside or its pharmaceutically acceptable salt or composition with another source 1'-, 2'-, 3'- or 4'-branched β-D or β-L-nucleoside for the treatment and/or prevention of infection Flaiviridae the owner;

(p) the use of 2'- and/or 3'-prodrug of β-D-2'-methylcytidine, or its pharmaceutically acceptable salt or composition thereof for the treatment and/or prophylaxis of a Flaviviridae infection in a host;

(q) using 3'-valovogo or acetylator ester of β-D-2'-methylcytidine, or its pharmaceutically acceptable salt, or composition for the treatment and/or prophylaxis of a Flaviviridae infection in a host;

(r) the use of 2'- and/or 3'-prodrugs of 1', 2', 3' or 4'-branched β-D or β-L-nucleoside or its pharmaceutically acceptable salts and compositions in the manufacture of medicinal products for the treatment and/or prophylaxis of a Flaviviridae infection;

(s) the use of 2'- and/or 3'-prodrugs of 1', 2', 3' or 4'-branched β-D or β-L-nucleoside, its pharmaceutically acceptable salts or compositions in combination and/or alteration of one or more effective against HCV agents in the manufacture of medicinal products for the treatment and/or prophylaxis of a Flaviviridae infection in a host;

(t) the use of 2'- and/or 3'-prodrugs of 1', 2', 3' or 4'-branched β-D or β-L-nucleoside or its pharmaceutically acceptable salt or composition with other source 1', 2', 3' or 4'-branched β-D or β-L-nucleoside in the manufacture of medicinal products for the treatment and/or prophylaxis of a Flaviviridae infection in a host;

(u) the use of 2'- and/or 3'-prodrug of β-D-'-methylcytidine, or its pharmaceutically acceptable salt or composition in the manufacture of medicinal products for the treatment and/or prophylaxis of a Flaviviridae infection in a host, and

(v) the use of 3'-valovogo or acetylator ester of β-D-2'-methylcytidine, or its pharmaceutically acceptable salt or composition in the manufacture of medicinal products for the treatment and/or prophylaxis of a Flaviviridae infection in a host.

Flaviviridae, is included in the scope of the present invention, are discussed in General in Fields Virology, Editors: Fields, B.N., Knipe, D.M. and Howley, P.M., Lippincott-Raven Publishers, Philadelphia, PA, Chapter 31, 1996. In a specific embodiment, Flaviviridae is HCV. In an alternative embodiment of the invention Flaviviridae is flavivirus or pestivirus. Specific Flavius include, without limitation: Absettarov, Alfuy, Apoi, Aroa, Bagaza, Banzi, Bouboui, Bussuquara, Cacipacore, Carey Island, Dakar bat, dengue virus 1, dengue virus 2, dengue virus 3, dengue virus 4, Edge Hill, Entebbe bat, Gadgets Gully, Hanzalova, Hypr, Ilheus virus meningoencephalitis Israeli turkeys, virus Japanese encephalitis type, Jugra, Jutiapa, Kadam, Karshi, Kedougou, Kokobera, Koutango, Kumlinge, Kunjin virus kasanari fever, Langat virus diseases Lopinga, Meaban, Modoc virus leukoencephalitis Montana Myotis, encephalitis Murray valley, Naranjal, Negishi, Ntaya, Omsk hemorrhagic fever, Phnom-Penh bat, Powassan, Rio Bravo, Rocio, Royal Farm virus, spring-summer encephalitis, Saboya virus encephalitis CE the t-Luis, Sal Vieja, San Perlita, Saumares Reef, Sepik, Sokuluk, Spondweni, Statford, Tembusu, Tyuleniy, Uganda S, Usutu, Wesselsborn, West Nile, Yaounde, yellow fever virus and Zika.

Pestivirus included in the scope of the present invention, are discussed in General in Fields Virology, Editors: Fields, B.N., Knipe, D.M. and Howley, P.M. Lippincott-Raven Publishers, Philadelphia, PA, Chapter 31, 1996. Specific pestivirus include, without limitation: virus bovine viral diarrhea (“BVDV“), the virus of classical swine fever (“CSFV, also called virus hog cholera) virus border disease of sheep (“BDV”).

I. Active connections

In the first main embodiment, the proposed compound of formula (I)or its pharmaceutically acceptable salt, or prodrug, or a stereoisomeric, tautomeric or polymorphic form, as well as a method of treatment of a host infected with Flaviviridae that includes the introduction of effective treatment amount of compound of formula (I):

or its pharmaceutically acceptable salt or prodrug, or a stereoisomeric, tautomeric or polymorphic form, where

R1, R2and R3independently represents H, phosphate (including mono-, di - or triphosphate and a stabilized phosphate); alkyl with an unbranched, branched or cyclic chain (including lower alkyl); acyl (including lower acyl); CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl,CO-substituted aryl, sulphonate ester, including alkyl or aralkylamines, including methanesulfonyl and benzyl, where the phenyl group is optionally substituted by one or more substituents as described in this here the definition of aryl; alkylsulfonyl, arylsulfonyl, aralkylamines; a lipid, including a phospholipid; an amino acid and amino acid residue; carbohydrate; a peptide; a cholesterol, or other pharmaceutically acceptable, remove the group, which is capable of formation of the compound, in which R1, R2and/or R3are independently H, phosphate (including mono-, di - or triphosphate), for example, with the introduction of in vivo; where in one embodiment, R2and/or R3is not a phosphate (including mono-, di - or triphosphate or a stabilized phosphate prodrug);

where at least one of R2and R3is not hydrogen;

Y1represents hydrogen, bromine, chlorine, fluorine, iodine, CN, OH, OR4, NH2, Other4, NR4R5, SH or SR4;

X1represents an optionally substituted alkyl with an unbranched, branched or cyclic chain, CH3, CF3C(Y3)3, 2-Br-ethyl, - CH2F, CH2Cl, CH2CF3, CF2CF3C(Y3)2C(Y3)3CH2OH, optionally substituted of alkenyl, obazatelno substituted quinil, COOH, COOR4, COO-alkyl, COO-aryl, COO-alkoxyalkyl, CONH2, CONHR4, CON(R4)2, chlorine, bromine, fluorine, iodine, CN, N3, OH, OR4, NH2, Other4, NR4R5, SH or SR5;

X2represents hydrogen, optionally substituted alkyl with an unbranched, branched or cyclic chain, CH3, CF3C(Y3)3, 2-Br-ethyl, - CH2F, CH2Cl, CH2CF3, CF2CF3C(Y3)2C(Y3)3CH2OH, optionally substituted of alkenyl, optionally substituted quinil, COOH, COOR4, COO-alkyl, COO-aryl, COO-alkoxyalkyl, CONH2, CONHR4, CON(R4)2, chlorine, bromine, fluorine, iodine, CN, N3, OH, OR4, NH2, Other4, NR4R5, SH or SR5and

where each Y3represents independently H, F, Cl, Br or I;

each R4and R5represents independently hydrogen, acyl (including lower acyl), alkyl (including, but not limited to, methyl, ethyl, propyl and cyclopropyl), lower alkyl, alkenyl, quinil or cycloalkyl.

In the preferred sub-option of implementing the compound of formula (I)or its pharmaceutically acceptable salt, or prodrug, or a stereoisomeric, tautomeric or polymorphic form, as well as a method of treatment of a host infected with Flaviviridae, including the introduction of effective treatment amount of compound of formula I, or its pharmaceutically acceptable salt or prodrug, or a stereoisomeric, tautomeric or polymorphic form, where

R1represents H or phosphate (preferably, N);

R2and R3independently represent H, phosphate, acyl or amino acid residue, where at least one of R2and R3represents acyl or amino acid residue;

X1represents CH3, CF3or CH2CH3;

X2represents N or NH2and

Y represents hydrogen, bromine, chlorine, fluorine, iodine, NH2or HE.

In the second main embodiment, the proposed compound of formula (II), or its pharmaceutically acceptable salt, or prodrug, or a stereoisomeric, tautomeric or polymorphic form, as well as a method of treatment of a host infected with Flaviviridae that includes the introduction of effective treatment amount of compound of formula (II):

or its pharmaceutically acceptable salt or prodrug, or a stereoisomeric, tautomeric or polymorphic form, where

R1, R2, R3, R4, R5, Y1, Y3X1and X2have the values specified above.

In the preferred sub-option of implementing the compound of formula (II), or its pharmaceutically pickup is acceptable salt, or a prodrug, or a stereoisomeric, tautomeric or polymorphic form, as well as a method of treatment of a host infected with Flaviviridae that includes the introduction of effective treatment amount of compound of formula (II), or its pharmaceutically acceptable salt or prodrug, or a stereoisomeric, tautomeric or polymorphic form, where:

R1represents H or phosphate (preferably, N);

R2and R3independently represent H, phosphate, acyl or amino acid residue, where at least one of R2and R3represents acyl or amino acid residue;

X1represents CH3, CF3or CH2CH3;

X2represents H, F, Cl, Br, I or CH3and

Y represents hydrogen, bromine, chlorine, fluorine, iodine, NH2or HE.

In the third main embodiment, the proposed compound of formula (III), (IV) or (V)or its pharmaceutically acceptable salt, or prodrug, or a stereoisomeric, tautomeric or polymorphic form, as well as a method of treatment of a host infected with Flaviviridae that includes the introduction of effective treatment amount of compound of formula (III), (IV) or (V):

or its pharmaceutically acceptable salt or prodrug, or a stereoisomeric, tautomeric or polymorphic form, the de R 1, R2, R3, R4, R5Y, Y1and X2have the values specified above;

base selected from the group consisting of:

each W1, W2, W3and W4independently represents N, CH, CF, CI, CBr, CCl, CCN, CCH3, CCF3, CCH2CH3CC(O)NH2CC(O)other4CC(O)N(R4)2CC(O)OH, CC(O)OR4or CX3;

each W independently represents O, S, NH or NR4;

where for reasons (B) W4cannot be CH if W1, W2and W3represent N;

where to base (E), (F), (K), (L), (W) and (X) W4cannot be CH if W1represents N;

X represents O, S, SO2CH2CH2OH, CHF, CF2C(Y3)2, CHCN, C(CN)2, CHR4or C(R4)2;

X* represents CH, CF, CY3or CR4;

each X3independently represents an optionally substituted alkyl with an unbranched, branched or cyclic chain (including lower alkyl), CH3CH2CN, CH2N3CH2NH2CH2NCH 3CH2N(CH3)2CH2OH, halogenated alkyl (including halogenated lower alkyl), CF3C(Y3)3, 2-Br-ethyl, - CH2F, CH2Cl, CH2CF3, CF2CF3C(Y3)2C(Y3)3not necessarily replaced alkenyl, halogenoalkanes, Br-vinyl, optionally substituted quinil, halogenoalkanes, N3CN, -C(O)OH, -C(O)OR4, -C(O)O(lower alkyl), -C(O)NH2, -C(O)other4, -C(O)NH(lower alkyl), -C(O)N(R4)2, -C(O)N(lower alkyl)2, OH, OR4, -O(acyl), -O(lower acyl), -O(alkyl), -O(lower alkyl), -O(alkenyl), -O(quinil), -O(aralkyl), -O(cycloalkyl), -S(acyl), -S(lower acyl), -S(R4), -S(lower alkyl), -S(alkenyl), -S(quinil), -S(aralkyl), -S(cycloalkyl), chlorine, bromine, fluorine, iodine, NH2, -NH(lower alkyl), -other4, -NR4R5, -NH(acyl), -N(lower alkyl)2, -NH(alkenyl), -NH(quinil), -NH(aralkyl), -NH(cycloalkyl), -N(acyl)2;

each Y2independently represents O, S, NH or NR4;

each Y3independently represents H, F, Cl, Br or I;

each R6independently represents an optionally substituted alkyl (including lower alkyl), CH3CH2CN, CH2N3CH2NH2CH2NHCH3CH2N(CH3)2CH2OH, halogenated alkyl (including halogenated lower alkyl), CF3C(Y3 3, 2-Br-ethyl, - CH2F, CH2Cl, CH2CF3, CF2CF3C(Y3)2C(Y3)3not necessarily replaced alkenyl, halogenoalkanes, Br-vinyl, optionally substituted or unsubstituted quinil, halogenoalkanes, -CH2C(O)OH, -CH2C(O)OR4, -CH2C(O)O(lower alkyl), -CH2C(O)NH2, -CH2C(O)other4, -CH2C(O)NH(lower alkyl), -CH2C(O)N(R4)2, -CH2C(O)N(lower alkyl)2, (CH2)mC(O)OH, -(CH2)mC(O)OR4, -(CH2)mC(O)O(lower alkyl), -(CH2)mC(O)NH2, -(CH2)mC(O)other4, -(CH2)mC(O)NH(lower alkyl), -(CH2)mC(O)N(R4)2, -(CH2)mC(O)N(lower alkyl)2, -C(O)OH, -C(O)OR4, -C(O)O(lower alkyl), -C(O)NH2, -C(O)other4, -C(O)NH(lower alkyl), -C(O)N(R4)2, -C(O)N(lower alkyl)2or cyano;

each R7independently represents OH, OR2, optionally substituted alkyl (including lower alkyl), CH3CH2CN, CH2N3CH2NH2CH2NHCH3CH2N(CH3)2CH2OH, halogenated alkyl (including halogenated lower alkyl), CF3C(Y3)3, 2-Br-ethyl, - CH2F, CH2Cl, CH2CF3, CF2CF3C(Y3)2C(Y3)3not necessarily replaced alkenyl, ha is hohenecken, Br-vinyl, optionally substituted quinil, halogenoalkanes, optionally substituted carbocycle (preferably, 3 to 7-membered carbocyclic ring, optionally substituted heterocycle (preferably a 3-7 membered heterocyclic ring having one or more O, S and/or N), optionally substituted heteroaryl (preferably a 3-7-membered heteroaromatic ring having one or more O, S and/or N), -CH2C(O)OH, -CH2C(O)OR4, -CH2C(O)O(lower alkyl), -CH2C(O)SH, -CH2C(O)SR4, -CH2C(O)S(lower alkyl), -CH2C(O)NH2, -CH2C(O)other4, -CH2C(O)NH(lower alkyl), -CH2C(O)N(R4)2, -CH2C(O)N(lower alkyl)2, -(CH2)mC(O)OH, -(CH2)mC(O)OR4, -(CH2)mC(O)O(lower alkyl), -(CH2)mC(O)SH, -(CH2)mC(O)SR4, -(CH2)mC(O)S(lower alkyl), -CH2)mC(O)NH2, -(CH2)mC(O)other4, -(CH2)mC(O)NH(lower alkyl), -(CH2)mC(O)N(R4)2, -(CH2)mC(O)N(lower alkyl)2-C(O)OH, -C(O)OR4, -C(O)O(lower alkyl), -C(O)SH, -C(O)SR4, -C(O)S(lower alkyl), -C(O)NH2, -C(O)other4, -C(O)NH(lower alkyl), -C(O)N(R4)2, -C(O)N(lower alkyl)2, -O(acyl), -O(lower acyl), -O(R4), -O(alkyl), -O(lower alkyl), -O(alkenyl), -O(quinil), -O(aralkyl), -O(cycloalkyl), -S(acyl), -S(NCDs is s acyl), -S(R4), -S(lower alkyl), -S(alkenyl), -S(quinil), -S(aralkyl), -S(cycloalkyl), NO2, NH2, -NH(lower alkyl), -other4, -NR4R5, -NH(acyl), -N(lower alkyl)2, -NH(alkenyl), -NH(quinil), -NH(aralkyl), -NH(cycloalkyl), -N(acyl)2azido, cyano, SCN, OCN, NCO, or halogen (fluorine, chlorine, bromine, iodine);

in the alternative case, R6and R7may together form spirochaetaceae selected from the group consisting of optionally substituted carbocycle (preferably a 3-7 membered carbocyclic ring) or optionally substituted heterocycle (preferably a 3-7 membered heterocyclic ring having one or more atoms O, S and/or N), and

each m independently is 0, 1 or 2.

In the first sub-option of implementing the compound of formula (III), (IV) or (V)or its pharmaceutically acceptable salt, or prodrug, or a stereoisomeric, tautomeric or polymorphic form, as well as a method of treatment of a host infected with Flaviviridae that includes the introduction of effective treatment amount of compound of formula (III), (IV) or (V)or its pharmaceutically acceptable salt or prodrug, or a stereoisomeric, tautomeric or polymorphic form, where

R1represents H or phosphate (preferably, N);

R2and R3represent, independently, H, phosphate, acyl or AMI is kislotnyi residue, where at least one of R2and R3represents acyl or amino acid residue;

W4is a CX3;

X3represents CH3, CF3or CH2CH3;

R6represents alkyl and

X represents O, S, SO2or CH2.

In the second sub-option of implementing the compound of formula (III), (IV) or (V)or its pharmaceutically acceptable salt, or prodrug, or a stereoisomeric, tautomeric or polymorphic form or a method of treatment of a host infected with Flaviviridae that includes the introduction of effective treatment amount of compound of formula (III), (IV) or (V)or its pharmaceutically acceptable salt or prodrug, or a stereoisomeric, tautomeric or polymorphic form, where:

R1represents H or phosphate (preferably, N);

R2and R3represent, independently, H, phosphate, acyl or amino acid residue, where at least one of R2and R3represents an amino acid residue;

W4is a CX3;

X3represents CH3, CF3or CH2CH3;

R6represents alkyl and

X represents O, S, SO2or CH2.

In the third sub-option of implementing the connection the General formula (III), (IV) or (V)or its pharmaceutically acceptable salt, or prodrug, or a stereoisomeric, tautomeric or polymorphic form or a method of treatment of a host infected with Flaviviridae that includes the introduction of effective treatment amount of compound of formula (III), (IV) or (V)or its pharmaceutically acceptable salt or prodrug, or a stereoisomeric, tautomeric or polymorphic form, where:

R1represents H or phosphate (preferably, N);

R2and R3represent, independently, H, phosphate, acyl or amino acid residue, where at least one of R2and R3represents acyl or amino acid residue;

W4is a CX3;

X3represents CH3, CF3or CH2CH3;

R6represents alkyl and

X represents O.

In a more preferred sub-option of implementing the compound of formula (IV), or its pharmaceutically acceptable salt, or prodrug, or a stereoisomeric, tautomeric or polymorphic form or a method of treatment of a host infected with Flaviviridae that includes the introduction of effective treatment amount of compound of formula (IV):

or its pharmaceutically acceptable salt or prodrug, or a stereoisomeric, Automoney or polymorphic forms, where

the basement has a specified value, and optionally substituted with amine or cyclopropyl (for example, 2-amino, 2,6-diamino - or cyclopropylamino);

R7represents a halogen (F, Cl, Br or I), although preferably represents F;

R1represents H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulphonate ester, including alkyl or arylalkylamines, including methanesulfonyl and benzyl, where the phenyl group is optionally substituted by one or more substituents as described in the definition of aryl; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol, or other pharmaceutically acceptable delete the group, which when introduced in vivo is capable of providing the education connection which R1or R2independently represents H or phosphate. In one embodiment, R2is not a phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug), and

R2is a phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower and the keel); sulphonate ester, including alkyl or arylalkylamines, including methanesulfonyl and benzyl, where the phenyl group is optionally substituted by one or more substituents as described in the definition of aryl; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol, or other pharmaceutically acceptable delete the group, which when introduced in vivo is able to provide the formation of the compound, in which R1or R2independently represents H or phosphate. In one embodiment, R2is not a phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug).

In the fourth main embodiment, the proposed compound of formula (VI) or (VII), or its pharmaceutically acceptable salt, or prodrug, or a stereoisomeric, tautomeric or polymorphic form or a method of treatment of a host infected with Flaviviridae that includes the introduction of effective treatment amount of compound of formula (VI) or (VII):

or its pharmaceutically acceptable salt or prodrug, or a stereoisomeric, tautomeric or polymorphic form, where

base, R, R1, R4, R5, R6, R7Y, Y1, Y2, Y3, W*, W1, W2, W3, W4 X, X*, X1X2and X3have the values specified above;

where in one embodiment, R8in the formula (VI) is-HE-or-NH2only when X is a carbon atom; and

where each of R8and R11independently represents hydrogen, optionally substituted alkyl (including lower alkyl), CH3CH2CN, CH2N3CH2NH2CH2NHCH3CH2N(CH3)2CH2OH, halogenated alkyl (including halogenated lower alkyl), CF3C(Y3)3, 2-Br-ethyl, - CH2F, CH2Cl, CH2CF3, CF2CF3C(Y3)2C(Y3)3not necessarily replaced alkenyl, halogenoalkanes, Br-vinyl, optionally substituted quinil, halogenoalkanes, -CH2C(O)OH, -CH2C(O)OR4, -CH2C(O)O(lower alkyl), -CH2C(O)NH2, -CH2C(O)other4, -CH2C(O)NH(lower alkyl), -CH2C(O)N(R4)2, -CH2C(O)N(lower alkyl)2, -(CH2)mC(O)HE, -(CH2)mC(O)OR4, -(CH2)mC(O)O(lower alkyl), -(CH2)mC(O)NH2, -(CH2)mC(O)other4, -(CH2)mC(O)NH(lower alkyl), -(CH2)mC(O)N(R4)2, -(CH2)mC(O)N(lower alkyl)2, -C(O)OH, -C(O)OR4, -C(O)O(lower alkyl), -C(O)NH2, -C(O)other4, -C(O)NH(Nissi is alkyl), -C(O)N(R4)2, -C(O)N(lower alkyl)2, cyano, NH-acyl or N(acyl)2;

each R9and R10independently represents hydrogen, OH, OR2, optionally substituted alkyl (including lower alkyl), CH3CH2CN, CH2N3CH2NH2CH2NHCH3CH2N(CH3)2CH2OH, halogenated alkyl (including halogenated lower alkyl), CF3C(Y3)3, 2-Br-ethyl, - CH2F, CH2Cl, CH2CF3, CF2CF3C(Y3)2C(Y3)3not necessarily replaced alkenyl, halogenoalkanes, Br-vinyl, optionally substituted quinil, halogenoalkanes, optionally substituted carbocycle (preferably, 3 to 7-membered carbocyclic ring, optionally substituted heterocycle (preferably a 3-7 membered heterocyclic ring having one or more O, S and/or N), optionally substituted heteroaryl (preferably 3-7-membered heteroaromatic ring having one or more O, S and/or N), -CH2C(O)OH, -CH2C(O)OR4, -CH2C(O)O(lower alkyl), -CH2C(O)SH, -CH2C(O)SR4, -CH2C(O)S(lower alkyl), -CH2C(O)NH2, -CH2C(O)other4, -CH2C(O)NH(lower alkyl), -CH2C(O)N(R4)2, -CH2C(O)N(lower alkyl)2, -(CH2)mC(O)OH, -(CH2)mC(O)OR4, -(CH 2)mC(O)O(lower alkyl), -(CH2)mC(O)SH, -(CH2)mC(O)SR4, -(CH2)mC(O)S(lower alkyl), -(CH2)mC(O)NH2, -(CH2)mC(O)other4CH2)mC(O)NH(lower alkyl), -(CH2)mC(O)N(R4)2, -(CH2)mC(O)N(lower alkyl)2, -C(O)OH, -C(O)OR4, -C(O)O(lower alkyl), -C(O)SH, -C(O)SR4, -C(O)S(lower alkyl), -C(O)NH2, -C(O)other4, -C(O)NH(lower alkyl), -C(O)N(R4)2, -C(O)N(lower alkyl)2, -O(acyl), -O(lower acyl), -O(R4), -O(alkyl), -O(lower alkyl), -O(alkenyl), -O(quinil), -O(aralkyl), -O(cycloalkyl), -S(acyl), -S(lower acyl), -S(R4), -S(lower alkyl), -S(alkenyl), -S(quinil), -S(aralkyl), -S(cycloalkyl), NO2, NH2, -NH(lower alkyl), -other4, -NR4R5, -NH(acyl), -N(lower alkyl)2, -NH(alkenyl), -NH(quinil), -NH(aralkyl), -NH(cycloalkyl), -N(acyl)2azido, cyano, SCN, OCN, NCO, or halogen (fluorine, chlorine, bromine, iodine);

each m independently is 0, 1 or 2 and

in the alternative case, R6and R10, R7and R9, R8and R7or R9and R11may together form a bridged compound selected from the group consisting of optionally substituted carbocycle (preferably a 3-7 membered carbocyclic ring) or optionally substituted heterocycle (preferably a 3-7 membered carbocyclic ring having one or more O atoms, S and/or N), or

in the alternative case, R6and R7or R9and R10may together form spirochaetaceae selected from the group consisting of optionally substituted carbocycle (preferably a 3-7 membered carbocyclic ring) or optionally substituted heterocycle (preferably a 3-7 membered carbocyclic ring having one or more atoms O, S and/or N).

In a particularly preferred embodiment, the proposed compound of formula (VI), or its pharmaceutically acceptable salt, or prodrug, or a stereoisomeric, tautomeric or polymorphic form, as well as a method of treatment of a host infected with Flaviviridae that includes the introduction of effective treatment amount of compound of formula (VI), or its pharmaceutically acceptable salt or prodrug, or a stereoisomeric, tautomeric or polymorphic form, in which

X represents O, S, SO or SO2;

each R6independently represents an optionally substituted lower alkyl, optionally substituted of alkenyl, optionally substituted quinil, optionally substituted cycloalkyl, CH2HE, CH2NH2CH2NHCH3CH2N(CH3)2CH2F, CH2Cl, CH2N3CH2CN, CH2CF3, CF3, CF2CF3CH2CO2 R4, (CH2)mCOOH, (CH2)mCOOR4, (CH2)mCONH2, (CH2)mCON(R4)2or (CH2)mCONHR4;

each R7independently represents-HE, optionally substituted lower alkyl, optionally substituted of alkenyl, optionally substituted quinil, optionally substituted cycloalkyl, -O-alkyl, -O-alkenyl, -O-quinil, -O-aralkyl, -O-cycloalkyl, -O-acyl, F, Cl, Br, I, CN, NC, SCN, OCN, NCO, NO2, NH2N3, NH-acyl, NH-alkyl, N-dialkyl, NH-alkenyl, NH-quinil, NH-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-alkenyl, S-quinil, S-aralkyl, S-acyl, S-cycloalkyl, CO2-alkyl, CONH-alkyl, CON-dialkyl, CONH-alkenyl, CONH-quinil, CONH-aralkyl, CONH-cycloalkyl, CH2HE, CH2NH2CH2NHCH3CH2N(CH3)2CH2F, CH2Cl, CH2N3CH2CN, CH2CF3, CF3, CF2CF3CH2CO2R4, (CH2)mCOOH, (CH2)mCOOR4, (CH2)mCONH2, (CH2)mCON(R4)2, (CH2)mCONHR4, optionally substituted 3-7-membered carbocyclic and optionally substituted 3-7-membered heterocyclic ring having independently O, S and/or N as a heteroatom taken alone or in combination, and/or

each R9represents independently hydrogen, n is necessarily substituted lower alkyl, optionally substituted of alkenyl, optionally substituted quinil, optionally substituted cycloalkyl, -OH, -O-alkyl, -O-alkenyl, -O-quinil, -O-aralkyl, -O-cycloalkyl, -O-acyl, F, Cl, Br, I, CN, NC, SCN, OCN, NCO, NO2, NH2N3, NH-acyl, NH-alkyl, N-dialkyl, NH-alkenyl, NH-quinil, NH-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-alkenyl, S-quinil, S-aralkyl, S-acyl, S-cycloalkyl, CO2-alkyl, CONH-alkyl, CON-dialkyl, CONH-alkenyl, CONH-quinil, CONH-aralkyl, CONH-cycloalkyl, CH2HE, CH2NH2CH2NHCH3CH2N(CH3)2CH2F, CH2Cl, CH2N3CH2CN, CH2CF3, CF3, CF2CF3CH2CO2R4, (CH2)mCOOH, (CH2)mCOOR4, (CH2)mCONH2, (CH2)mCON(R4)2, (CH2)mCONHR4, optionally substituted 3-7-membered carbocyclic and optionally substituted 3-7-membered heterocyclic ring having independently O, S and/or N as a heteroatom taken alone or in combination, and/or

each R10represents independently hydrogen, optionally substituted lower alkyl, optionally substituted of alkenyl, optionally substituted quinil, optionally substituted cycloalkyl, CH2HE, CH2NH2CH2NHCH3CH2N(CH3)2CH2F, CH2Cl, CHsub> 2N3CH2CN, CH2CF3, CF3, CF2CF3CH2CO2R4, (CH2)mCOOH, (CH2)mCOOR4, (CH2)mCONH2, (CH2)mCON(R4)2, (CH2)mCONHR4and/or

- each of R8and R11represents independently N, CH3CH2HE, CH2F, CH2N3, (CH2)mCOOH, (CH2)mCOOR4, (CH2)mCONH2, (CH2)mCON(R4)2, (CH2)mCONHR4and N-acyl and/or

each m independently is 0 or 1, and/or

- the base is selected from one of the following reasons:

and where

each of R', R", R"' and R"" are independently selected from the group consisting of H, HE, substituted or unsubstituted alkyl, substituted or unsubstituted, alkenyl, substituted or unsubstituted quinil, cycloalkyl, Br-vinyl, -O-alkyl, -O-alkenyl, -O-quinil, O-aryl, O-aralkyl, O-acyl, O-cycloalkyl, NH2, NH-alkyl, N-dialkyl, NH-acyl, N-aryl, -N aralkyl, -NH-cycloalkyl, SH, -S-alkyl, S-acyl, S-aryl, -S-cycloalkyl, S-aralkyl, F, Cl, Br, I, CN, COOH, CONH2, CO2-alkyl, CONH-alkyl, CON-dialkyl, HE, CF3CH2OH, (CH2)mOH, (CH2)mNH2, (CH2)mCOOH, (CH2)mCN, (CH2)mNO2and (CH2 mCONH2;

W represents C-R or N;

T and V independently represent CH or N;

Q represents CH, -CCl-CBr, -CF, -CI, -CCN-C-COOH, -C,-CONH2or N;

Q1and Q2independently represent N or C-R;

where R represents H, alkyl or acyl;

Q3, Q4, Q5and Q6independently represent N or CH, and

its tautomeric forms.

In a particularly preferred alternative embodiment, the proposed compound of formula (VI), or its pharmaceutically acceptable salt, or prodrug, or a stereoisomeric, tautomeric or polymorphic form, as well as a method of treatment of a host infected with Flaviviridae that includes the introduction of effective treatment amount of compound of formula (VI), or its pharmaceutically acceptable salt or prodrug, or a stereoisomeric, tautomeric or polymorphic form, where

X represents O, S, SO or SO2; and/or

- R6and R7together form spirochaetaceae selected from the group consisting of optionally substituted 3-7-membered spinocerebellum or heterocyclic compounds having one or more atoms of N, O and/or S, and these heteroatoms taken separately or in combination with each other; and/or

each R9represents independently hydrogen, long is Ino substituted lower alkyl, optionally substituted of alkenyl, optionally substituted quinil, optionally substituted cycloalkyl, -OH, -O-alkyl, -O-alkenyl, -O-quinil, -O-aralkyl, -O-cycloalkyl, -O-acyl, F, Cl, Br, I, CN, NC, SCN, OCN, NCO, NO2, NH2N3, NH-acyl, NH-alkyl, N-dialkyl, NH-alkenyl, NH-quinil, NH-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-alkenyl, S-quinil, S-aralkyl, S-acyl, S-cycloalkyl, CO2-alkyl, CONH-alkyl, CON-dialkyl, CONH-alkenyl, CONH-quinil, CONH-aralkyl, CONH-cycloalkyl, CH2HE, CH2NH2CH2NHCH3CH2N(CH3)2CH2F, CH2Cl, CH2N3CH2CN, CH2CF3, CF3, CF2CF3CH2CO2R4, (CH2)mCOOH, (CH2)mCOOR4, (CH2)mCONH2, (CH2)mCON(R4)2, (CH2)mCONHR4, optionally substituted 3-7-membered carbocyclic and optionally substituted 3-7-membered heterocyclic ring having independently O, S and/or N as a heteroatom taken alone or in combination, and/or

each R10represents independently hydrogen, optionally substituted lower alkyl, optionally substituted of alkenyl, optionally substituted quinil, optionally substituted cycloalkyl, CH2HE, CH2NH2CH2NHCH3CH2N(CH3)2CH2F, CH2Cl, CHsub> 2N3CH2CN, CH2CF3, CF3, CF2CF3CH2CO2R4, (CH2)mCOOH, (CH2)mCOOR4, (CH2)mCONH2, (CH2)mCON(R4)2, (CH2)mCONHR4and/or

- each of R8and R11represents independently N, CH3CH2HE, CH2F, CH2N3, (CH2)mCOOH, (CH2)mCOOR4, (CH2)mCONH2, (CH2)mCON(R4)2, (CH2)mCONHR4and N-acyl and/or

each m independently is 0 or 1, and/or

- the base is selected from one of the following reasons:

and where

each of R', R", R"' and R"" are independently selected from the group consisting of H, HE, substituted or unsubstituted alkyl, substituted or unsubstituted, alkenyl, substituted or unsubstituted quinil, cycloalkyl, Br-vinyl, -O-alkyl, -O-alkenyl, O-quinil, O-aryl, O-aralkyl, -O-acyl, O-cycloalkyl, NH2, NH-alkyl, N-dialkyl, NH-acyl, N-aryl, -N aralkyl,-NH-cycloalkyl, SH, -S-alkyl, S-acyl, S-aryl, -S-cycloalkyl, S-aralkyl, F, Cl, Br, I, CN, COOH, CONH2, CO2-alkyl, CONH-alkyl, CON-dialkyl, HE, CF3CH2OH, (CH2)mOH, (CH2)mNH2, (CH2)mCOOH, (CH2)mCN, (CH2)mNO2, (CH2) mCONH2;

W represents C-R or N;

T and V independently represent CH or N;

Q represents CH, -CCl-CBr, -CF, -Cl, -CCN-C-COOH, -C,-CONH2or N;

Q1and Q2independently represent N or C-R;

where R represents H, alkyl or acyl;

Q3, Q4, Q5and Q6independently represent N or CH, and

its tautomeric forms.

In another particularly preferred embodiment, the proposed compound of formula (VI), or its pharmaceutically acceptable salt, or prodrug, and a method of treatment of a host infected with Flaviviridae that includes the introduction of effective treatment amount of compound of formula (VI), or its pharmaceutically acceptable salt or prodrug, or a stereoisomeric, tautomeric or polymorphic form, in which

X represents O, S, SO or SO2and/or

each R6independently represents an optionally substituted lower alkyl, optionally substituted of alkenyl, optionally substituted quinil, optionally substituted cycloalkyl, CH2HE, CH2NH2CH2NHCH3CH2N(CH3)2CH2F, CH2Cl, CH2N3CH2CN, CH2CF3, CF3, CF2CF3CH2CO2R4, (CH2)mCOOH, (CH2)mCOOR4, (CH )mCONH2, (CH2)mCON(R4)2or (CH2)mCONHR4and/or

each R7independently represents-HE, optionally substituted lower alkyl, optionally substituted of alkenyl, optionally substituted quinil, optionally substituted cycloalkyl, -O-alkyl, -O-alkenyl, -O-quinil, -O-aralkyl, -O-cycloalkyl, -O-acyl, F, Cl, Br, I, CN, NC, SCN, OCN, NCO, NO2, NH2N3, NH-acyl, NH-alkyl, N-dialkyl, NH-alkenyl, NH-quinil, NH-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-alkenyl, S-quinil, S-aralkyl, S-acyl, S-cycloalkyl, CO2-alkyl, CONH-alkyl, CON-dialkyl, CONH-alkenyl, CONH-quinil, CONH-aralkyl, CONH-cycloalkyl, CH2HE, CH2NH2CH2NHCH3CH2N(CH3)2CH2F, CH2Cl, CH2N3CH2CN, CH2CF3, CF3, CF2CF3CH2CO2R4, (CH2)mCOOH, (CH2)mCOOR4, (CH2)mCONH2, (CH2)mCON(R4)2, (CH2)mCONHR4, optionally substituted 3-7-membered carbocyclic and optionally substituted 3-7-membered heterocyclic ring having independently O, S and/or N as a heteroatom taken alone or in combination, and/or

- R9and R10together form spirochaetaceae selected from the group consisting of optionally substituted 3-7-member of the frame spinocerebellum or heterocyclic compounds, having one or more atoms of N, O and/or S, and these heteroatoms taken separately or in combination with each other; and/or

- each of R8and R11represents independently N, CH3CH2HE, CH2F, CH2N3, (CH2)mCOOH, (CH2)mCOOR4, (CH2)mCONH2, (CH2)mCON(R4)2, (CH2)mCONHR4and N-acyl and/or

each m is 0 or 1, and/or

- the base is selected from one of the following reasons:

and where

each of R', R", R"' and R"" are independently selected from the group consisting of H, HE, substituted or unsubstituted alkyl, substituted or unsubstituted, alkenyl, substituted or unsubstituted quinil, cycloalkyl, Br-vinyl, -O-alkyl, -O-alkenyl, O-quinil, O-aryl, O-aralkyl, O-acyl, O-cycloalkyl, NH2, NH-alkyl, N-dialkyl, NH-acyl, N-aryl, -N aralkyl, -NH-cycloalkyl, SH, -S-alkyl, S-acyl, S-aryl, -S-cycloalkyl, S-aralkyl, F, Cl, Br, I, CN, COOH, CONH2, CO2-alkyl, CONH-alkyl, CON-dialkyl, HE, CF3CH2OH, (CH2)mOH, (CH2)mNH2, (CH2)mCOOH, (CH2)mCN, (CH2)mNO2, (CH2)mCONH2;

W represents C-R or N;

T and V independently represent CH or N;

Q represents the N, -CCl-CBr, -CF, -CI, -CCN-C-COOH, -C,-CONH2or N;

Q1and Q2independently represent N or C-R;

where R represents H, alkyl or acyl;

Q3, Q4, Q5and Q6independently represent N or CH, and

its tautomeric forms.

In another particularly preferred embodiment, the proposed compound of formula (VI), or its pharmaceutically acceptable salt, or prodrug, or a stereoisomeric, tautomeric or polymorphic form, as well as a method of treatment of a host infected with Flaviviridae that includes the introduction of effective treatment amount of compound of formula (VI), or its pharmaceutically acceptable salt or prodrug, or a stereoisomeric, tautomeric or polymorphic form, in which

X represents O, S, SO or SO2; and/or

- R6and R7together form spirochaetaceae selected from the group consisting of optionally substituted 3-7-membered spinocerebellum or heterocyclic compounds having one or more atoms of N, O and/or S, and these heteroatoms independently taken separately or in combination with each other; and/or

- R9and R10together form spirochaetaceae selected from the group consisting of optionally substituted 3-7-membered spinocerebellum or heterocyclic connect the tion, having one or more atoms of N, O and/or S, and these heteroatoms taken separately or in combination with each other; and/or

- each of R8and R11represents, independently, N, CH3CH2HE, CH2F, CH2N3, (CH2)mCOOH, (CH2)mCOOR4, (CH2)mCONH2, (CH2)mCON(R4)2, (CH2)mCONHR4and N-acyl and/or

each m independently is 0 or 1, and/or

- the base is selected from one of the following reasons:

and where

each of R', R", R"' and R"" are independently selected from the group consisting of H, HE, substituted or unsubstituted alkyl, substituted or unsubstituted, alkenyl, optionally substituted or unsubstituted quinil, cycloalkyl, Br-vinyl, -O-alkyl, -O-alkenyl, O-quinil, O-aryl, O-aralkyl, O-acyl, O-cycloalkyl, NH2, NH-alkyl, N-dialkyl, NH-acyl, N-aryl, -N aralkyl, -NH-cycloalkyl, SH, S-alkyl, S-acyl, S-aryl, -S-cycloalkyl, S-aralkyl, F, Cl, Br, I, CN, COOH, CONH2, CO2-alkyl, CONH-alkyl, CON-dialkyl, HE, CF3CH2OH, (CH2)mOH, (CH2)mNH2, (CH2)mCOOH, (CH2)mCN, (CH2)mNO2and (CH2)mCONH2;

W represents C-R or N;

T and V independently represent CH Il is N;

Q represents CH, -CCl-CBr, -CF, -CI, -CCN-C-COOH, -C,-CONH2or N;

Q1and Q2independently represent N or C-R;

where R represents H, alkyl or acyl;

Q3, Q4, Q5and Q6independently represent N or CH, and

its tautomeric forms.

In a particularly preferred embodiment, the proposed compound of formula (VI), or its pharmaceutically acceptable salt, or prodrug, or a stereoisomeric, tautomeric or polymorphic form, as well as a method of treatment of a host infected with Flaviviridae that includes the introduction of effective treatment amount of compound of formula (VI), or its pharmaceutically acceptable salt or prodrug, or a stereoisomeric, tautomeric or polymorphic form, in which

- X represents CH2CH2HE, CHF, CF2C(Y3)2, CHCN, C(CN)2, CHR4or C(R4)2and/or

each R6independently represents an optionally substituted lower alkyl, optionally substituted of alkenyl, optionally substituted quinil, optionally substituted cycloalkyl, CH2HE, CH2NH2CH2NHCH3CH2N(CH3)2CH2F, CH2Cl, CH2N3CH2CN, CH2CF3, CF3, CF2CF3CH2CO2R4, (CH2)m COOH, (CH2)mCOOR4, (CH2)mCONH2, (CH2)mCON(R4)2or (CH2)mCONHR4and/or

each R7independently represents-HE, optionally substituted lower alkyl, optionally substituted of alkenyl, optionally substituted quinil, optionally substituted cycloalkyl, -O-alkyl, -O-alkenyl, -O-quinil, -O-aralkyl, -O-cycloalkyl, -O-acyl, F, Cl, Br, I, CN, NC, SCN, OCN, NCO, NO2, NH2N3, NH-acyl, NH-alkyl, N-dialkyl, NH-alkenyl, NH-quinil, NH-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-alkenyl, S-quinil, S-aralkyl, S-acyl, S-cycloalkyl, CO2-alkyl, CONH-alkyl, CON-dialkyl, CONH-alkenyl, CONH-quinil, CONH-aralkyl, CONH-cycloalkyl, CH2HE, CH2NH2CH2NHCH3CH2N(CH3)2CH2F, CH2Cl, CH2N3CH2CN, CH2CF3, CF3, CF2CF3CH2CO2R4, (CH2)mCOOH, (CH2)mCOOR4, (CH2)mCONH2, (CH2)mCON(R4)2, (CH2)mCONHR4, optionally substituted 3-7-membered carbocyclic and optionally substituted 3-7-membered heterocyclic ring having, independently, O, S and/or N as a heteroatom taken alone or in combination, and/or

each R9represents independently hydrogen, optionally substituted by the first lower alkyl, optionally substituted of alkenyl, optionally substituted quinil, optionally substituted cycloalkyl, -OH, -O-alkyl, -O-alkenyl, -O-quinil, -O-aralkyl, -O-cycloalkyl, -O-acyl, F, Cl, Br, I, CN, NC, SCN, OCN, NCO, NO2, NH2N3, NH-acyl, NH-alkyl, N-dialkyl, NH-alkenyl, NH-quinil, NH-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-alkenyl, S-quinil, S-aralkyl, S-acyl, S-cycloalkyl, CO2-alkyl, CONH-alkyl, CON-dialkyl, CONH-alkenyl, CONH-quinil, CONH-aralkyl, CONH-cycloalkyl, CH2HE, CH2NH2CH2NHCH3CH2N(CH3)2CH2F, CH2Cl, CH2N3CH2CN, CH2CF3, CF3, CF2CF3CH2CO2R4, (CH2)mCOOH, (CH2)mCOOR4, (CH2)mCONH2, (CH2)mCON(R4)2, (CH2)mCONHR4, optionally substituted 3-7-membered carbocyclic and optionally substituted 3-7-membered heterocyclic ring having independently O, S and/or N as a heteroatom taken alone or in combination, and/or

each R10represents independently hydrogen, optionally substituted lower alkyl, optionally substituted of alkenyl, optionally substituted quinil, optionally substituted cycloalkyl, CH2HE, CH2NH2CH2NHCH3CH2N(CH3)2CH2F, CH2Cl, CHsub> 2N3CH2CN, CH2CF3, CF3, CF2CF3CH2CO2R4, (CH2)mCOOH, (CH2)mCOOR4, (CH2)mCONH2, (CH2)mCON(R4)2or(CH2)mCONHR4and/or

- each of R8and R11represents independently N, CH3CH2HE, CH2F, CH2N3, (CH2)mCOOH, (CH2)mCOOR4, (CH2)mCONH2, (CH2)mCON(R4)2, (CH2)mCONHR4and N-acyl and/or

each m independently is 0 or 1, and/or

- the base is selected from one of the following reasons:

and where

each of R', R", R"' and R"" are independently selected from the group consisting of H, HE, substituted or unsubstituted alkyl, substituted or unsubstituted, alkenyl, substituted or unsubstituted quinil, cycloalkyl, Br-vinyl, -O-alkyl, -O-alkenyl, O-quinil, O-aryl, O-aralkyl, O-acyl, O-cycloalkyl, NH2, NH-alkyl, N-dialkyl, NH-acyl, N-aryl, -N aralkyl,-NH-cycloalkyl, SH, -S-alkyl, S-acyl, S-aryl, -S-cycloalkyl, S-aralkyl, F, Cl, Br, I, CN, COOH, CONH2, CO2-alkyl, CONH-alkyl, CON-dialkyl, HE, CF3CH2OH, (CH2)mOH, (CH2)mNH2, (CH2)mCOOH, (CH2)mCN, (CH2)mNO2and (CH2/sub> )mCONH2;

W represents C-R or N;

T and V independently represent CH or N;

Q represents CH, -CCl-CBr, -CF, -CI, -CCN-C-COOH, -C,-CONH2or N;

Q1and Q2independently represent N or C-R;

Q3, Q4, Q5and Q6independently represent N or CH, and

its tautomeric forms.

In a particularly preferred alternative embodiment, the proposed compound of formula (VI), or its pharmaceutically acceptable salt, or prodrug, or a stereoisomeric, tautomeric or polymorphic form, as well as a method of treatment of a host infected with Flaviviridae that includes the introduction of effective treatment amount of compound of formula (VI), or its pharmaceutically acceptable salt or prodrug, or a stereoisomeric, tautomeric or polymorphic form, in which

- X represents CH2CH2HE, CHF, CF2C(Y3)2, CHCN, C(CN)2, CHR4or C(R4)2; and/or

- R6and R7together form spirochaetaceae selected from the group consisting of optionally substituted 3-7-membered spinocerebellum or heterocyclic compounds having one or more atoms of N, O and/or S, and these heteroatoms taken separately or in combination with each other; and/or

each R9PR is dstanley an independently hydrogen, optionally substituted lower alkyl, optionally substituted of alkenyl, optionally substituted quinil, optionally substituted cycloalkyl, -OH, -O-alkyl, -O-alkenyl, -O-quinil, -O-aralkyl, -O-cycloalkyl, -O-acyl, F, Cl, Br, I, CN, NC, SCN, OCN, NCO, NO2, NH2N3, NH-acyl, NH-alkyl, N-dialkyl, NH-alkenyl, NH-quinil, NH-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-alkenyl, S-quinil, S-aralkyl, S-acyl, S-cycloalkyl, CO2-alkyl, CONH-alkyl, CON-dialkyl, CONH-alkenyl, CONH-quinil, CONH-aralkyl, CONH-cycloalkyl, CH2HE, CH2NH2CH2NHCH3CH2N(CH3)2CH2F, CH2Cl, CH2N3CH2CN, CH2CF3, CF3, CF2CF3CH2CO2R4, (CH2)mCOOH, (CH2)mCOOR4, (CH2)mCONH2, (CH2)mCON(R4)2, (CH2)mCONHR4, optionally substituted 3-7-membered carbocyclic and optionally substituted 3-7-membered heterocyclic ring having independently O, S and/or N as a heteroatom taken alone or in combination, and/or

each R10represents independently hydrogen, optionally substituted lower alkyl, optionally substituted of alkenyl, optionally substituted quinil, optionally substituted cycloalkyl, CH2HE, CH2NH2CH2NHCH3CH2N(C 3)2CH2F, CH2Cl, CH2N3CH2CN, CH2CF3, CF3, CF2CF3CH2CO2R4, (CH2)mCOOH, (CH2)mCOOR4, (CH2)mCONH2, (CH2)mCON(R4)2, (CH2)mCONHR4and/or

- each of R8and R11represents independently N, CH3CH2HE, CH2F, CH2N3, (CH2)mCOOH, (CH2)mCOOR4, (CH2)mCONH2, (CH2)mCON(R4)2, (CH2)mCONHR4and N-acyl and/or

each m independently is 0 or 1, and/or

- the base is selected from one of the following reasons:

and where

each of R', R", R"' and R"" are independently selected from the group consisting of H, HE, substituted or unsubstituted alkyl, substituted or unsubstituted, alkenyl, substituted or unsubstituted quinil, cycloalkyl, Br-vinyl, -O-alkyl, -O-alkenyl, O-quinil, O-aryl, O-aralkyl, -O-acyl, O-cycloalkyl, NH2, NH-alkyl, N-dialkyl, NH-acyl, N-aryl, -N aralkyl,-NH-cycloalkyl, SH, -S-alkyl, S-acyl, S-aryl, -S-cycloalkyl, S-aralkyl, F, Cl, Br, I, CN, COOH, CONH2, CO2-alkyl, CONH-alkyl, CON-dialkyl, HE, CF3CH2OH, (CH2)mOH, (CH2)mNH2, (CH2)mCOOH, (CH2)m2)mNO2and (CH2)mCONH2;

W represents C-R or N;

T and V independently represent CH or N;

Q represents CH, -CCl-CBr, -CF, -CI, -CCN-C-COOH, -C,-CONH2or N;

Q1and Q2independently represent N or C-R;

where R represents H, alkyl or acyl;

Q3, Q4, Q5and Q6independently represent N or CH, and

its tautomeric forms.

In another particularly preferred embodiment, the proposed compound of formula (VI), or its pharmaceutically acceptable salt, or prodrug, or a stereoisomeric, tautomeric or polymorphic form, as well as a method of treatment of a host infected with Flaviviridae that includes the introduction of effective treatment amount of compound of formula (VI), or its pharmaceutically acceptable salt or prodrug, or a stereoisomeric, tautomeric or polymorphic form, in which

- X represents CH2CH2HE, CHF, CF2C(Y3)2, CHCN, C(CN)2, CHR4or C(R4)2and/or

each R6independently represents an optionally substituted lower alkyl, optionally substituted of alkenyl, optionally substituted quinil, optionally substituted cycloalkyl, CH2HE, CH2NH2CH2NHCH3CH2N(CH3) CH2F, CH2Cl, CH2N3CH2CN, CH2CF3, CF3, CF2CF3CH2CO2R4, (CH2)mCOOH, (CH2)mCOOR4, (CH2)mCONH2, (CH2)mCON(R4)2or (CH2)mCONHR4and/or

each R7independently represents-HE, optionally substituted lower alkyl, optionally substituted of alkenyl, optionally substituted quinil, optionally substituted cycloalkyl, -O-alkyl, -O-alkenyl, -O-quinil, -O-aralkyl, -O-cycloalkyl, -O-acyl, F, Cl, Br, I, CN, NC, SCN, OCN, NCO, NO2, NH2N3, NH-acyl, NH-alkyl, N-dialkyl, NH-alkenyl, NH-quinil, NH-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-alkenyl, S-quinil, S-aralkyl, S-acyl, S-cycloalkyl, CO2-alkyl, CONH-alkyl, CON-dialkyl, CONH-alkenyl, CONH-quinil, CONH-aralkyl, CONH-cycloalkyl, CH2HE, CH2NH2CH2NHCH3CH2N(CH3)2CH2F, CH2Cl, CH2N3CH2CN, CH2CF3, CF3, CF2CF3CH2CO2R4, (CH2)mCOOH, (CH2)mCOOR4, (CH2)mCONH2, (CH2)mCON(R4)2, (CH2)mCONHR4, optionally substituted 3-7-membered carbocyclic and optionally substituted 3-7-membered heterocyclic ring having independently O, S and/or N in Kacha is TBE heteroatoms, taken separately or in combination, and/or

- R9and R10together form spirochaetaceae selected from the group consisting of optionally substituted 3-7-membered spinocerebellum or heterocyclic compounds having one or more atoms of N, O and/or S, and these heteroatoms taken separately or in combination with each other; and/or

- each of R8and R11represents, independently, N, CH3CH2HE, CH2F, CH2N3, (CH2)mCOOH, (CH2)mCOOR4, (CH2)mCONH2, (CH2)mCON(R4)2, (CH2)mCONHR4and N-acyl and/or

each m independently is 0 or 1, and/or

- the base is selected from one of the following reasons:

and where

each of R', R", R"' and R"" are independently selected from the group consisting of H, HE, substituted or unsubstituted alkyl, substituted or unsubstituted, alkenyl, substituted or unsubstituted quinil, cycloalkyl, Br-vinyl, -O-alkyl, -O-alkenyl, O-quinil, O-aryl, O-aralkyl, -O-acyl, O-cycloalkyl, NH2, NH-alkyl, N-dialkyl, NH-acyl, N-aryl, -N aralkyl, -NH-cycloalkyl, SH, -S-alkyl, S-acyl, S-aryl, -S-cycloalkyl, S-aralkyl, F, Cl, Br, I, CN, COOH, CONH2, CO2-alkyl, CONH-alkyl, CON-di is Lila, HE, CF3CH2OH, (CH2)mOH, (CH2)mNH2, (CH2)mCOOH, (CH2)mCN, (CH2)mNO2and (CH2)mCONH2;

W represents C-R or N;

T and V independently represent CH or N;

Q represents CH, -CCl-CBr, -CF, -CI, -CCN-C-COOH, -C,-CONH2or N;

Q1and Q2independently represent N or C-R;

where R represents H, alkyl or acyl;

Q3, Q4, Q5and Q6independently represent N or CH, and

its tautomeric forms.

In another particularly preferred alternative embodiment, the proposed compound of formula (VI), or its pharmaceutically acceptable salt, or prodrug, or a stereoisomeric, tautomeric or polymorphic form, as well as a method of treatment of a host infected with Flaviviridae that includes the introduction of effective treatment amount of compound of formula (VI), or its pharmaceutically acceptable salt or prodrug, or a stereoisomeric, tautomeric or polymorphic form, in which

- X represents CH2CH2HE, CHF, CF2C(Y3)2, CHCN, C(CN)2, CHR4or C(R4)2; and/or

- R6and R7together form spirochaetaceae selected from the group consisting of optionally substituted 3-7-membered pyrocarbonic the ical or heterocyclic compounds, having one or more atoms of N, O and/or S, and these heteroatoms independently taken separately or in combination with each other; and/or

- R9and R10together form spirochaetaceae selected from the group consisting of optionally substituted 3-7-membered spinocerebellum or heterocyclic compounds having one or more atoms of N, O and/or S, and these heteroatoms taken separately or in combination with each other; and/or

- each of R8and R11represents, independently, N, CH3CH2HE, CH2F, CH2N3, (CH2)mCOOH, (CH2)mCOOR4, (CH2)mCONH2, (CH2)mCON(R4)2, (CH2)mCONHR4and N-acyl and/or

each m independently is 0 or 1, and/or

- the base is selected from one of the following reasons:

and where

each of R', R", R"' and R"" are independently selected from the group consisting of H, HE, substituted or unsubstituted alkyl, substituted or unsubstituted, alkenyl, substituted or unsubstituted quinil, cycloalkyl, Br-vinyl, -O-alkyl, -O-alkenyl, O-quinil, O-aryl, O-aralkyl, O-acyl, O-cycloalkyl, NH2, NH-alkyl, N-dialkyl, NH-acyl, N-aryl, -N aralkyl,-NH-cycloalkyl, SH, S-alkyl, S-acyl, S-aryl, -S-cycloalkyl-aralkyl, F, Cl, Br, I, CN, COOH, CONH2, CO2-alkyl, CONH-alkyl, CON-dialkyl, HE, CF3CH2OH, (CH2)mOH, (CH2)mNH2, (CH2)mCOOH, (CH2)mCN, (CH2)mNO2and (CH2)mCONH2;

W represents C-R or N;

T and V independently represent CH or N;

Q represents CH, -CCl-CBr, -CF, -CI, -CCN-C-COOH, -C,-CONH2or N;

Q1and Q2independently represent N or C-R;

where R represents H, alkyl or acyl;

Q3, Q4, Q5and Q6independently represent N or CH, and

its tautomeric forms.

In a particularly preferred embodiment, the proposed compound of formula (VII), or its pharmaceutically acceptable salt, or prodrug, or a stereoisomeric, tautomeric or polymorphic form, as well as a method of treatment of a host infected with Flaviviridae that includes the introduction of effective treatment amount of compound of formula (VII), or its pharmaceutically acceptable salt or prodrug, or a stereoisomeric, tautomeric or polymorphic form, in which

X* represents CH, CF, CY3or CR4and/or

each R6independently represents an optionally substituted lower alkyl, optionally substituted of alkenyl, optionally substituted quinil, not necessarily alseny cycloalkyl, CH2HE, CH2NH2CH2NHCH3CH2N(CH3)2CH2F, CH2Cl, CH2N3CH2CN, CH2CF3, CF3, CF2CF3CH2CO2R4, (CH2)mCOOH, (CH2)mCOOR4, (CH2)mCONH2, (CH2)mCON(R4)2or (CH2)mCONHR4and/or

each R7independently represents-HE, optionally substituted lower alkyl, optionally substituted of alkenyl, optionally substituted quinil, optionally substituted cycloalkyl, -O-alkyl, -O-alkenyl, -O-quinil, -O-aralkyl, -O-cycloalkyl, -O-acyl, F, Cl, Br, I, CN, NC, SCN, OCN, NCO, NO2, NH2N3, NH-acyl, NH-alkyl, N-dialkyl, NH-alkenyl, NH-quinil, NH-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-alkenyl, S-quinil, S-aralkyl, S-acyl, S-cycloalkyl, CO2-alkyl, CONH-alkyl, CON-dialkyl, CONH-alkenyl, CONH-quinil, CONH-aralkyl, CONH-cycloalkyl, CH2HE, CH2NH2CH2NHCH3CH2N(CH3)2CH2F, CH2Cl, CH2N3CH2CN, CH2CF3, CF3, CF2CF3CH2CO2R4, (CH2)mCOOH, (CH2)mCOOR4, (CH2)mCONH2, (CH2)mCON(R4)2, (CH2)mCONHR4, optionally substituted 3-7-membered carbocyclic and not necessarily Sames the TES 3-7-membered heterocyclic ring, having independently O, S and/or N as a heteroatom taken alone or in combination, and/or

each R9represents independently hydrogen, optionally substituted lower alkyl, optionally substituted of alkenyl, optionally substituted quinil, optionally substituted cycloalkyl, -OH, -O-alkyl, -O-alkenyl, -O-quinil, -O-aralkyl, -O-cycloalkyl, -O-acyl, F, Cl, Br, I, CN, NC, SCN, OCN, NCO, NO2, NH2N3, NH-acyl, NH-alkyl, N-dialkyl, NH-alkenyl, NH-quinil, NH-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-alkenyl, S-quinil, S-aralkyl, S-acyl, S-cycloalkyl, CO2-alkyl, CONH-alkyl, CON-dialkyl, CONH-alkenyl, CONH-quinil, CONH-aralkyl, CONH-cycloalkyl, CH2HE, CH2NH2CH2NHCH3CH2N(CH3)2CH2F, CH2Cl, CH2N3CH2CN, CH2CF3, CF3, CF2CF3CH2CO2R4, (CH2)mCOOH, (CH2)mCOOR4, (CH2)mCONH2, (CH2)mCON(R4)2, (CH2)mCONHR4, optionally substituted 3-7-membered carbocyclic and optionally substituted 3-7-membered heterocyclic ring having independently O, S and/or N as a heteroatom taken alone or in combination, and/or

each R10represents independently hydrogen, optionally substituted lower alkyl, optionally alseny of alkenyl, optionally substituted quinil, optionally substituted cycloalkyl, CH2HE, CH2NH2CH2NHCH3CH2N(CH3)2CH2F, CH2Cl, CH2N3CH2CN, CH2CF3, CF3, CF2CF3CH2CO2R4, (CH2)mCOOH, (CH2)mCOOR4, (CH2)mCONH2, (CH2)mCON(R4)2, (CH2)mCONHR4and/or

- each of R8and R11represents independently N, CH3CH2HE, CH2F, CH2N3, (CH2)mCOOH, (CH2)mCOOR4, (CH2)mCONH2, (CH2)mCON(R4)2, (CH2)mCONHR4and N-acyl and/or

each m independently is 0 or 1, and/or

- the base is selected from one of the following reasons:

and where

each of R', R", R"' and R"" are independently selected from the group consisting of H, HE, substituted or unsubstituted alkyl, substituted or unsubstituted, alkenyl, substituted or unsubstituted quinil, cycloalkyl, Br-vinyl, -O-alkyl, -O-alkenyl, O-quinil, O-aryl, O-aralkyl, O-acyl, O-cycloalkyl, NH2, NH-alkyl, N-dialkyl, NH-acyl, N-aryl, N-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-acyl, S-aryl, -S-cycloalkyl, S-aralkyl, F, Cl, Br, I, CN, COOH, CONH2, CO2and the Qila, CONH-alkyl, CON-dialkyl, HE, CF3CH2OH, (CH2)mOH, (CH2)mNH2, (CH2)mCOOH, (CH2)mCN, (CH2)mNO2and (CH2)mCONH2;

W represents C-R or N;

T and V independently represent CH or N;

Q represents CH, -CCl-CBr, -CF, -CI, -CCN-C-COOH, -C,-CONH2or N;

Q1and Q2independently represent N or C-R;

where R represents H, alkyl or acyl;

Q3, Q4, Q5and Q6independently represent N or CH, and

its tautomeric forms.

In a particularly preferred alternative embodiment, the proposed compound of formula (VII), or its pharmaceutically acceptable salt, or prodrug, or a stereoisomeric, tautomeric or polymorphic form, as well as a method of treatment of a host infected with Flaviviridae that includes the introduction of effective treatment amount of compound of formula (VII), or its pharmaceutically acceptable salt or prodrug, or a stereoisomeric, tautomeric or polymorphic form, in which

X* represents CH, CF, CY3or CR4; and/or

- R6and R7together form spirochaetaceae selected from the group consisting of optionally substituted 3-7-membered spinocerebellum or heterocyclic compounds having od is n or more N atoms, O and/or S, and these heteroatoms independently taken separately or in combination with each other; and/or

each R9represents independently hydrogen, optionally substituted lower alkyl, optionally substituted of alkenyl, optionally substituted quinil, optionally substituted cycloalkyl, -OH, -O-alkyl, -O-alkenyl, -O-quinil, -O-aralkyl, -O-cycloalkyl, -O-acyl, F, Cl, Br, I, CN, NC, SCN, OCN, NCO, NO2, NH2N3, NH-acyl, NH-alkyl, N-dialkyl, NH-alkenyl, NH-quinil, NH-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-alkenyl, S-quinil, S-aralkyl, S-acyl, S-cycloalkyl, CO2-alkyl, CONH-alkyl, CON-dialkyl, CONH-alkenyl, CONH-quinil, CONH-aralkyl, CONH-cycloalkyl, CH2HE, CH2NH2CH2NHCH3CH2N(CH3)2CH2F, CH2Cl, CH2N3CH2CN, CH2CF3, CF3, CF2CF3CH2CO2R4, (CH2)mCOOH, (CH2)mCOOR4, (CH2)mCONH2, (CH2)mCON(R4)2, (CH2)mCONHR4, optionally substituted 3-7-membered carbocyclic and optionally substituted 3-7-membered heterocyclic ring having independently O, S and/or N as a heteroatom taken alone or in combination, and/or

each R10represents independently hydrogen, optionally substituted lower alkyl, n is necessarily replaced by alkenyl, optionally substituted quinil, optionally substituted cycloalkyl, CH2HE, CH2NH2CH2NHCH3CH2N(CH3)2CH2F, CH2Cl, CH2N3CH2CN, CH2CF3, CF3, CF2CF3CH2CO2R4, (CH2)mCOOH, (CH2)mCOOR4, (CH2)mCONH2, (CH2)mCON(R4)2, (CH2)mCONHR4and/or

- each of R8and R11represents independently N, CH3CH2HE, CH2F, CH2N3, (CH2)mCOOH, (CH2)mCOOR4, (CH2)mCONH2, (CH2)mCON(R4)2, (CH2)mCONHR4and N-acyl and/or

each m independently is 0 or 1, and/or

- the base is selected from one of the following reasons:

and where

each of R', R", R"' and R"" are independently selected from the group consisting of H, HE, substituted or unsubstituted alkyl, substituted or unsubstituted, alkenyl, substituted or unsubstituted quinil, cycloalkyl, Br-vinyl, -O-alkyl, -O-alkenyl, O-quinil, O-aryl, O-aralkyl, O-acyl, O-cycloalkyl, NH2, NH-alkyl, N-dialkyl, NH-acyl, N-aryl, -N aralkyl, -NH-cycloalkyl, SH, -S-alkyl, S-acyl, S-aryl, -S-cycloalkyl, S-aralkyl, F,Cl, Br, I, CN, COOH, CONH2, CO2-alkyl, CONH-alkyl, CON-dialkyl, HE, CF3CH2OH, (CH2)mOH, (CH2)mNH2, (CH2)mCOOH, (CH2)mCN, (CH2)mNO2and (CH2)mCONH2;

W represents C-R or N;

T and V independently represent CH or N;

Q represents CH, -CCl-CBr, -CF, -CI, -CCN-C-COOH, -C,-CONH2or N;

Q1and Q2independently represent N or C-R;

R represents H, alkyl or acyl;

Q3, Q4, Q5and Q6independently represent N or CH, and

its tautomeric forms.

In another particularly preferred embodiment, the proposed compound of formula (VII), or its pharmaceutically acceptable salt, or prodrug, or a stereoisomeric, tautomeric or polymorphic form, as well as a method of treatment of a host infected with Flaviviridae that includes the introduction of effective treatment amount of compound of formula (VII), or its pharmaceutically acceptable salt or prodrug, or a stereoisomeric, tautomeric or polymorphic form, in which

X* represents CH, CF, CY3or CR4and/or

each R6independently represents an optionally substituted lower alkyl, optionally substituted of alkenyl, optionally substituted quinil, not necessarily alseny cycloalkyl, CH2HE, CH2NH2CH2NHCH3CH2N(CH3)2CH2F, CH2Cl, CH2N3CH2CN, CH2CF3, CF3, CF2CF3CH2CO2R4, (CH2)mCOOH, (CH2)mCOOR4, (CH2)mCONH2, (CH2)mCON(R4)2or (CH2)mCONHR4and/or

each R7independently represents-HE, optionally substituted lower alkyl, optionally substituted of alkenyl, optionally substituted quinil, optionally substituted cycloalkyl, -O-alkyl, -O-alkenyl, -O-quinil, -O-aralkyl, -O-cycloalkyl, -O-acyl, F, Cl, Br, I, CN, NC, SCN, OCN, NCO, NO2, NH2N3, NH-acyl, NH-alkyl, N-dialkyl, NH-alkenyl, NH-quinil, NH-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-alkenyl, S-quinil, S-aralkyl, S-acyl, S-cycloalkyl, CO2-alkyl, CONH-alkyl, CON-dialkyl, CONH-alkenyl, CONH-quinil, CONH-aralkyl, CONH-cycloalkyl, CH2HE, CH2NH2CH2NHCH3CH2N(CH3)2CH2F, CH2Cl, CH2N3CH2CN, CH2CF3, CF3, CF2CF3CH2CO2R4, (CH2)mCOOH, (CH2)mCOOR4, (CH2)mCONH2, (CH2)mCON(R4)2, (CH2)mCONHR4, optionally substituted 3-7-membered carbocyclic and not necessarily Sames the TES 3-7-membered heterocyclic ring, having independently O, S and/or N as a heteroatom taken alone or in combination, and/or

- R9and R10together form spirochaetaceae selected from the group consisting of optionally substituted 3-7-membered spinocerebellum or heterocyclic compounds having one or more atoms of N, O and/or S, and these heteroatoms taken separately or in combination with each other; and/or

- each of R8and R11represents, independently, N, CH3CH2HE, CH2F, CH2N3, (CH2)mCOOH, (CH2)mCOOR4, (CH2)mCONH2, (CH2)mCON(R4)2, (CH2)mCONHR4and N-acyl and/or

each m independently is 0 or 1, and/or

- the base is selected from one of the following reasons:

and where

each of R', R", R"' and R"" are independently selected from the group consisting of H, HE, substituted or unsubstituted alkyl, substituted or unsubstituted, alkenyl, substituted or unsubstituted quinil, cycloalkyl, Br-vinyl, -O-alkyl, -O-alkenyl, O-quinil, O-aryl, O-aralkyl, -O-acyl, NH-cycloalkyl, NH2, NH-alkyl, N-dialkyl, NH-acyl, N-aryl, -N aralkyl,-NH-cycloalkyl, SH, -S-alkyl, S-acyl, S-aryl, -S-cycloalkyl, S-aralkyl, F, Cl, Br, I, CN, COOH, CONH2, CO2-Ala is La, CONH-alkyl, CON-dialkyl, HE, CF3CH2OH, (CH2)mOH, (CH2)mNH2, (CH2)mCOOH, (CH2)mCN, (CH2)mNO2and (CH2)mCONH2;

W represents C-R or N;

T and V independently represent CH or N;

Q represents CH, -CCl-CBr, -CF, -CI, -CCN-C-COOH, -C,-CONH2or N;

Q1and Q2independently represent N or C-R;

R represents H, alkyl or acyl;

Q3, Q4, Q5and Q6independently represent N or CH, and

its tautomeric forms.

In another particularly preferred embodiment, the proposed compound of formula (VII), or its pharmaceutically acceptable salt, or prodrug, or a stereoisomeric, tautomeric or polymorphic form, as well as a method of treatment of a host infected with Flaviviridae that includes the introduction of effective treatment amount of compound of formula (VII), or its pharmaceutically acceptable salt or prodrug, or a stereoisomeric, tautomeric or polymorphic form, in which

X* represents CH, CF, CY3or CR4; and/or

- R6and R7together form spirochaetaceae selected from the group consisting of optionally substituted 3-7-membered spinocerebellum or heterocyclic compounds having one or a few m is to N atoms, O and/or S, and these heteroatoms taken separately or in combination with each other; and/or

- R9and R10together form spirochaetaceae selected from the group consisting of optionally substituted 3-7-membered spinocerebellum or heterocyclic compounds having one or more atoms of N, O and/or S, and these heteroatoms taken separately or in combination with each other; and/or

- each of R8and R11represents, independently, N, CH3CH2HE, CH2F, CH2N3, (CH2)mCOOH, (CH2)mCOOR4, (CH2)mCONH2, (CH2)mCON(R4)2, (CH2)mCONHR4and N-acyl and/or

each m independently is 0 or 1, and/or

- the base is selected from one of the following reasons:

and where

each of R', R", R"' and R"" are independently selected from the group consisting of H, HE, substituted or unsubstituted alkyl, substituted or unsubstituted, alkenyl, substituted or unsubstituted quinil, cycloalkyl, Br-vinyl, -O-alkyl, -O-alkenyl, O-quinil, O-aryl, O-aralkyl, O-acyl, O-cycloalkyl, NH2, NH-alkyl, N-dialkyl, NH-acyl, N-aryl, -N aralkyl, -NH-cycloalkyl, SH, -S-alkyl, S-acyl, S-aryl, -S-cycloalkyl, S-aralkyl, F, Cl, Br, I, CN, COOH, CONH2, CO2-is Lila, CONH-alkyl, CON-dialkyl, HE, CF3CH2OH, (CH2)mOH, (CH2)mNH2, (CH2)mCOOH, (CH2)mCN, (CH2)mNO2, (CH2)mCONH2;

W represents C-R or N;

T and V independently represent CH or N;

Q represents CH, -CCl-CBr, -CF, -CI, -CCN-C-COOH, -C,-CONH2or N;

Q1and Q2independently represent N or C-R;

R represents H, alkyl or acyl;

Q3, Q4, Q5and Q6independently represent N or CH, and its tautomeric forms.

In the first sub-option of implementing the compound of formula (VI), or its pharmaceutically acceptable salt, or prodrug, or a stereoisomeric, tautomeric or polymorphic form and a method of treatment of a host infected with Flaviviridae that includes the introduction of effective treatment amount of compound of formula (VI), or its pharmaceutically acceptable salt or prodrug, or a stereoisomeric, tautomeric or polymorphic form, in which (1) R1independently represents H or phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulphonate ester, including alkyl or arylalkylamines, including methanesulfonyl and benzyl, where f is nilina group optionally substituted by one or more substituents, as described in the definition of aryl; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol, or other pharmaceutically acceptable delete the group, which when introduced in vivo is able to provide the formation of the compound in which R1independently represents H or phosphate, (2) R6represents alkyl; (3) R7and R9represent independently OR2, alkyl, alkenyl, quinil, Br-vinyl, O-alkenyl, chlorine, bromine, iodine, NO2, amino, lower alkylamino or di(lower alkyl)amino; (4) R8and R10independently represent H, alkyl (including lower alkyl), chlorine, bromine or iodine; (5) X represents O, S, SO2or CH2; (6) W4is a CX3and (7) X3represents CH3, CF3or CH2CH3.

In the second sub-option of implementing the compound of formula (VI), or its pharmaceutically acceptable salt, or prodrug, or a stereoisomeric, tautomeric or polymorphic form and a method of treatment of a host infected with Flaviviridae that includes the introduction of effective treatment amount of compound of formula (VI), or its pharmaceutically acceptable salt or prodrug, or a stereoisomeric, tautomeric or polymorphic form, in which (1) R1independently represents H or phosphate (including the th monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulphonate ester, including alkyl or arylalkylamines, including methanesulfonyl and benzyl, where the phenyl group is optionally substituted by one or more substituents as described in the definition of aryl; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol, or other pharmaceutically acceptable delete the group, which when introduced in vivo is able to provide the formation of the compound in which R1represents independently H or phosphate, (2) R6represents alkyl, alkenyl, quinil, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chlorine, bromine, fluorine, iodine, NO2, amino, lower alkylamino or di(lower alkyl)amino; (3) R7and R9represent independently OR2; (4) R8and R10independently represent H, alkyl (including lower alkyl), chlorine, bromine or iodine; (5) X represents O, S, SO2or CH2; (6) W4is a CX3and (7) X3represents CH3, CF3or CH2CH3.

In the third sub-option of implementing the compound of formula (VI), or its pharmaceutically acceptable salt, or prodrug, or a stereoisomeric, tautomeric or alimehra form and method of treatment of a host, infected with Flaviviridae that includes the introduction of effective treatment amount of compound of formula (VI), or its pharmaceutically acceptable salt or prodrug, or a stereoisomeric, tautomeric or polymorphic form, in which (1) R1independently represents H or phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulphonate ester, including alkyl or arylalkylamines, including methanesulfonyl and benzyl, where the phenyl group is optionally substituted by one or more substituents as described in the definition of aryl; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol, or other pharmaceutically acceptable delete the group, which when introduced in vivo is capable of providing education compounds in which R1independently represents H or phosphate, (2) R6represents alkyl, alkenyl, quinil, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chlorine, bromine, fluorine, iodine, NO2, amino, lower alkylamino or di(lower alkyl)amino; (3) R7and R9represent independently OR2, alkyl, alkenyl, quinil, Br-vinyl, O-alkenyl, chlorine, bromine, iodine, NO2, amino, lower alkylamino or di(lower alkyl)amino; (4) R8and R10 represent H; (5) X represents O, S, SO2or CH2; (6) W4is a CX3and (7) X3represents CH3, CF3or CH2CH3.

In the fourth sub-option of implementing the compound of formula (VI), or its pharmaceutically acceptable salt, or prodrug, or a stereoisomeric, tautomeric or polymorphic form and a method of treatment of a host infected with Flaviviridae that includes the introduction of effective treatment amount of compound of formula (VI), or its pharmaceutically acceptable salt or prodrug, or a stereoisomeric, tautomeric or polymorphic form, in which (1) R1independently represents H or phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulphonate ester, including alkyl or arylalkylamines, including methanesulfonyl and benzyl, where the phenyl group is optionally substituted by one or more substituents as described in the definition of aryl; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol, or other pharmaceutically acceptable delete the group, which when introduced in vivo is capable of providing education compounds in which R1the independence of the IMO represents H or phosphate, (2) R6represents alkyl, alkenyl, quinil, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chlorine, bromine, fluorine, iodine, NO2, amino, lower alkylamino or di(lower alkyl)amino; (3) R7and R9represent independently OR2, alkyl, alkenyl, quinil, Br-vinyl, O-alkenyl, chlorine, bromine, iodine, NO2, amino, lower alkylamino or di(lower alkyl)amino; (4) R8and R10independently represent H, alkyl (including lower alkyl), chlorine, bromine or iodine; (5) X represents O; (6) W4is a CX3and (7) X3represents CH3, CF3or CH2CH3.

In the fifth sub-option of implementing the compound of formula (VI), or its pharmaceutically acceptable salt, or prodrug, or a stereoisomeric, tautomeric or polymorphic form and a method of treatment of a host infected with Flaviviridae that includes the introduction of effective treatment amount of compound of formula (VI), or its pharmaceutically acceptable salt or prodrug, or a stereoisomeric, tautomeric or polymorphic form, in which (1) R1independently represents H or phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulphonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, where the phenyl group is optionally substituted by one or more substituents as described in the definition of aryl; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol, or other pharmaceutically acceptable delete the group, which when introduced in vivo is able to provide the formation of the compound in which R1represents H or phosphate, (2) R6represents alkyl; (3) R7and R9represent independently OR1; (4) R8and R10independently represent H, alkyl (including lower alkyl), chlorine, bromine or iodine; (5) X represents O, S, SO2or CH2; (6) W4is a CX3and (7) X3represents CH3, CF3or CH2CH3.

In the sixth sub-option of implementing the compound of formula (VI), or its pharmaceutically acceptable salt, or prodrug, or a stereoisomeric, tautomeric or polymorphic form and a method of treatment of a host infected with Flaviviridae that includes the introduction of effective treatment amount of compound of formula (VI), or its pharmaceutically acceptable salt or prodrug, or a stereoisomeric, tautomeric or polymorphic form, in which (1) R1independently represents H or phosphate (including monophos is at, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulphonate ester, including alkyl or arylalkylamines, including methanesulfonyl and benzyl, where the phenyl group is optionally substituted by one or more substituents as described in the definition of aryl; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol, or other pharmaceutically acceptable delete the group, which when introduced in vivo is able to provide the formation of the compound in which R1independently represents H or phosphate, (2) R6represents alkyl; (3) R7and R9represent independently OR2, alkyl (including lower alkyl), alkenyl, quinil, Br-vinyl, O-alkenyl, chlorine, bromine, iodine, NO2, amino, lower alkylamino or di(lower alkyl)amino; (4) R8and R10represent H; (5) X represents O, S, SO2or CH2; (6) W4is a CX3and (7) X3represents CH3, CF3or CH2CH3.

In the seventh sub-option of implementing the compound of formula (VI), or its pharmaceutically acceptable salt, or prodrug, or a stereoisomeric, tautomeric or polymorphic form and a method of treatment of a host infected with the data Flaviviridae, including the introduction of effective treatment amount of compound of formula (VI), or its pharmaceutically acceptable salt or prodrug, or a stereoisomeric, tautomeric or polymorphic form, in which (1) R1independently represents H or phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulphonate ester, including alkyl or arylalkylamines, including methanesulfonyl and benzyl, where the phenyl group is optionally substituted by one or more substituents as described in the definition of aryl; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol, or other pharmaceutically acceptable delete the group, which when introduced in vivo is capable of providing education compounds in which R1independently represents H or phosphate; (2) R6represents alkyl; (3) R7and R9represent independently OR2, alkyl (including lower alkyl), alkenyl, quinil, Br-vinyl, O-alkenyl, chlorine, bromine, iodine, NO2, amino, lower alkylamino or di(lower alkyl)amino; (4) R8and R10represent H, alkyl (including lower alkyl), chlorine, bromine or iodine; (5) X represents O; (6) W4is a CX 3and (7) X3represents CH3, CF3or CH2CH3.

In the eighth sub-option of implementing the compound of formula (VI), or its pharmaceutically acceptable salt, or prodrug, or a stereoisomeric, tautomeric or polymorphic form and a method of treatment of a host infected with Flaviviridae that includes the introduction of effective treatment amount of compound of formula (VI), or its pharmaceutically acceptable salt or prodrug, or a stereoisomeric, tautomeric or polymorphic form, in which (1) R1independently represents H or phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulphonate ester, including alkyl or arylalkylamines, including methanesulfonyl and benzyl, where the phenyl group is optionally substituted by one or more substituents as described in the definition of aryl; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol, or other pharmaceutically acceptable delete the group, which when introduced in vivo is capable of providing education compounds in which R1independently represents H or phosphate; (2) R6represents alkyl (including lower alkyl), alkenyl, al is inil, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chlorine, bromine, fluorine, iodine, NO2, amino, lower alkylamino or di(lower alkyl)amino; (3) R7and R9represent independently OR2; (4) R8and R10represent hydrogen; (5) X represents O, S, SO2or CH2; (6) W4is a CX3and (7) X3represents CH3, CF3or CH2CH3.

In the ninth modification of implementing the compound of formula (VI), or its pharmaceutically acceptable salt, or prodrug, or a stereoisomeric, tautomeric or polymorphic form and a method of treatment of a host infected with Flaviviridae that includes the introduction of effective treatment amount of compound of formula (VI), or its pharmaceutically acceptable salt or prodrug, or a stereoisomeric, tautomeric or polymorphic form, in which (1) R1independently represents H or phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulphonate ester, including alkyl or arylalkylamines, including methanesulfonyl and benzyl, where the phenyl group is optionally substituted by one or more substituents as described in the definition of aryl; a lipid, including F. spolied; amino acid; a carbohydrate; a peptide; a cholesterol, or other pharmaceutically acceptable delete the group, which when introduced in vivo is able to provide the formation of the compound in which R1represents H or phosphate; (2) R6represents alkyl (including lower alkyl), alkenyl, quinil, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chlorine, bromine, fluorine, iodine, NO2, amino, lower alkylamino or di(lower alkyl)amino; (3) R7and R9represent independently OR2; (4) R8and R10are independently H, alkyl (including lower alkyl), chlorine, bromine or iodine; (5) X represents O; (6) W4is a CX3and (7) X3represents CH3, CF3or CH2CH3.

In the tenth sub-option of implementing the compound of formula (VI), or its pharmaceutically acceptable salt, or prodrug, or a stereoisomeric, tautomeric or polymorphic form and a method of treatment of a host infected with Flaviviridae that includes the introduction of effective treatment amount of compound of formula (VI), or its pharmaceutically acceptable salt or prodrug, or a stereoisomeric, tautomeric or polymorphic form, in which (1) R1independently represents H or phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized potatoespolar); acyl (including lower acyl); alkyl (including lower alkyl); sulphonate ester, including alkyl or arylalkylamines, including methanesulfonyl and benzyl, where the phenyl group is optionally substituted by one or more substituents as described in the definition of aryl; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol, or other pharmaceutically acceptable delete the group, which when introduced in vivo is able to provide the formation of the compound in which R1independently represents H or phosphate; (2) R6represents alkyl (including lower alkyl), alkenyl, quinil, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chlorine, bromine, fluorine, iodine, NO2, amino, lower alkylamino or di(lower alkyl)amino; (3) R7and R9represent independently OR2, alkyl (including lower alkyl), alkenyl, quinil, Br-vinyl, O-alkenyl, chlorine, bromine, iodine, NO2, amino, lower alkylamino or di(lower alkyl)amino; (4) R8and R10represent hydrogen; (5) X represents O; (6) W4is a CX3and (7) X3represents CH3, CF3or CH2CH3.

In the eleventh sub-option of implementing the compound of formula (VI), or its pharmaceutically acceptable salt, or prodrug, or CTE is eoysmena, tautomeric or polymorphic form and a method of treatment of a host infected with Flaviviridae that includes the introduction of effective treatment amount of compound of formula (VI), or its pharmaceutically acceptable salt or prodrug, or a stereoisomeric, tautomeric or polymorphic form, in which (1) R1independently represents H or phosphate; (2) R6represents alkyl (including lower alkyl), alkenyl, quinil, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chlorine, bromine, fluorine, iodine, NO2, amino, lower alkylamino or di(lower alkyl)amino; (3) R7and R9represent independently OR2; (4) R8and R10represent hydrogen; (5) X represents O, S, SO2or CH2; (6) W4is a CX3and (7) X3represents CH3, CF3or CH2CH3.

In the twelfth sub-option of implementing the compound of formula (VI), or its pharmaceutically acceptable salt, or prodrug, or a stereoisomeric, tautomeric or polymorphic form and a method of treatment of a host infected with Flaviviridae that includes the introduction of effective treatment amount of compound of formula (VI), or its pharmaceutically acceptable salt or prodrug, or a stereoisomeric, tautomeric or polymorphic form, in which (1) R1independently of t is made by a H or phosphate; (2) R6represents alkyl; (3) R7and R9represent independently OR2; (4) R8and R10represent hydrogen; (5) X represents O, S, SO2or CH2; (6) W4is a CX3and (7) X3represents CH3, CF3or CH2CH3.

In the thirteenth sub-option of implementing the compound of formula (VI), or its pharmaceutically acceptable salt, or prodrug, or a stereoisomeric, tautomeric or polymorphic form and a method of treatment of a host infected with Flaviviridae that includes the introduction of effective treatment amount of compound of formula (VI), or its pharmaceutically acceptable salt or prodrug, or a stereoisomeric, tautomeric or polymorphic form, in which (1) R1independently represents H or phosphate; (2) R6represents alkyl; (3) R7and R9represent independently OR2; (4) R8and R10independently represent H, alkyl (including lower alkyl), chlorine, bromine or iodine; (5) X represents O; (6) W4is a CX3and (7) X3represents CH3, CF3or CH2CH3.

In the fourteenth sub-option of implementing the compound of formula (VI), or its pharmaceutically acceptable salt, or poleca the STV, or a stereoisomeric, tautomeric or polymorphic form and a method of treatment of a host infected with Flaviviridae that includes the introduction of effective treatment amount of compound of formula (VI), or its pharmaceutically acceptable salt or prodrug, or a stereoisomeric, tautomeric or polymorphic form, in which (1) R1independently represents H or phosphate; (2) R6represents alkyl; (3) R7and R9represent independently OR2, alkyl (including lower alkyl), alkenyl, quinil, Br-vinyl, O-alkenyl, chlorine, bromine, iodine, NO2, amino, lower alkylamino or di(lower alkyl)amino (4) R8and R10represent hydrogen; (5) X represents O; (6) W4is a CX3and (7) X3represents CH3, CF3or CH2CH3.

In even more preferred embodiments of implementing the compound of formula (VI), or its pharmaceutically acceptable salt, or prodrug, or a stereoisomeric, tautomeric or polymorphic form and a method of treatment of a host infected with Flaviviridae that includes the introduction of effective treatment amount of compound of formula (VI), or its pharmaceutically acceptable salt or prodrug, or a stereoisomeric, tautomeric or polymorphic form, in which

(1) the base is an 8-is lilageni; (2) R1represents hydrogen; (3) R6represents methyl; (4) R7and R9are hydroxyl; (5) R8and R10represent hydrogen and (6), X represents O;

(1) the base is an 8-methylguanine; (2) R1represents hydrogen; (3) R6represents methyl; (4) R7and R9are hydroxyl; (5) R8and R10represent hydrogen and (6), X represents O;

(1) base is a 6-methylcytosine; (2) R1represents hydrogen; (3) R6represents methyl; (4) R7and R9are hydroxyl; (5) R8and R10represent hydrogen and (6), X represents O;

(1) base is a 6-methylthymidine; (2) R1represents hydrogen; (3) R6represents methyl; (4) R7and R9are hydroxyl; (5) R8and R10represent hydrogen and (6), X represents O;

(1) base is a 6-methyluracil; (2) R1represents hydrogen; (3) R6represents methyl; (4) R7and R9are hydroxyl; (5) R8and R10represent hydrogen and (6), X represents O;

(1) the base is an 8-methyladenine; (2) R1is the th phosphate; (3) R6represents methyl; (4) R7and R9are hydroxyl; (5) R8and R10represent hydrogen and (6), X represents O;

(1) the base is an 8-methyladenine; (2) R1represents hydrogen; (3) R6represents ethyl; (4) R7and R9are hydroxyl; (5) R8and R10represent hydrogen and (6), X represents O;

(1) the base is an 8-methyladenine; (2) R1represents hydrogen; (3) R6represents propyl; (4) R7and R9are hydroxyl; (5) R8and R10represent hydrogen and (6), X represents O;

(1) the base is an 8-methyladenine; (2) R1represents hydrogen; (3) R6represents a butyl; (4) R7and R9are hydroxyl; (5) R8and R10represent hydrogen and (6), X represents O;

(1) the base is an 8-methyladenine; (2) R1represents hydrogen; (3) R6represents methyl; (4) R7represents hydrogen and R9represents a hydroxyl; (5) R8and R10represent hydrogen and (6), X represents O;

(1) the base is an 8-methyladenine; (2) R1represents hydrogen; (3)R 6represents methyl; (4) R7and R9are hydroxyl; (5) R8and R10represent hydrogen and (6) X represents S;

(1) the base is an 8-methyladenine; (2) R1represents hydrogen; (3) R6represents methyl; (4) R7and R9are hydroxyl; (5) R8and R10represent hydrogen and (6) X is a SO2;

(1) the base is an 8-methyladenine; (2) R1represents hydrogen; (3) R6represents methyl; (4) R7and R9are hydroxyl; (5) R8and R10represent hydrogen and (6) X represents CH2.

In the fifth main embodiment, the proposed compound of formula (VIII), (IX) or (X), or its pharmaceutically acceptable salt, or prodrug, or a stereoisomeric, tautomeric or polymorphic form, as well as a method of treatment of a host infected with Flaviviridae that includes the introduction of effective treatment amount of compound of formula (VIII), (IX) or (X):

or its pharmaceutically acceptable salt or prodrug, or a stereoisomeric, tautomeric or polymorphic form, where:

R1, R2, R3, R4, R5, Y3X and X* are the values specified above;

base defined here is a purine or pyrimidine base;

each R12independently represents a substituted alkyl (including lower alkyl), CH2CN, CH2N3CH2NH2CH2NHCH3CH2N(CH3)2CH2OH, halogenated alkyl (including halogenated lower alkyl), CF3C(Y3)3, 2-Br-ethyl, - CH2F, CH2Cl, CH2CF3, CF2CF3C(Y3)2C(Y3)3replaced alkenyl, halogenoalkanes (but not Br-vinyl), substituted quinil, halogenoalkanes, -CH2C(O)OH, -CH2C(O)OR4, -CH2C(O)O(lower alkyl), -CH2C(O)NH2, -CH2C(O)other4, -CH2C(O)NH(lower alkyl), -CH2C(O)N(R4)2, -CH2C(O)N(lower alkyl)2, (CH2)mC(O)OH, -(CH2)mC(O)OR4, -(CH2)mC(O)O(lower alkyl), -(CH2)mC(O)NH2, -(CH2)mC(O)other4, -(CH2)mC(O)NH(lower alkyl), -(CH2)mC(O)N(R4)2, -(CH2)mC(O)N(lower alkyl)2, -C(O)OH, -C(O)OR4, -C(O)NH2, -C(O)other4, -C(O)NH(lower alkyl), -C(O)N(R4)2, -C(O)N(lower alkyl)2;

each R13independently represents a substituted alkyl (including lower alkyl), CH2CN, CH2N3CH2NH2CH2NHCH3CH2N(CH3)2CH2OH, halogenated alkyl (including halogenerator the th lower alkyl), CF3C(Y3)3, 2-Br-ethyl, - CH2F, CH2Cl, CH2CF3, CF2CF3C(Y3)2C(Y3)3replaced alkenyl, halogenoalkanes (but not Br-vinyl), substituted quinil, halogenoalkanes, optionally substituted carbocycle (preferably, 3 to 7-membered carbocyclic ring, optionally substituted heterocycle (preferably a 3-7 membered heterocyclic ring having one or more O, S and/or N), optionally substituted heteroaryl (preferably 3-7-membered heteroaromatic ring having one or more O, S and/or N), -CH2C(O)OH, -CH2C(O)OR4, -CH2C(O)O(lower alkyl), -CH2C(O)SH, -CH2C(O)SR4, -CH2C(O)S(lower alkyl), -CH2C(O)NH2, -CH2C(O)other4, -CH2C(O)NH(lower alkyl), -CH2C(O)N(R4)2, -CH2C(O)N(lower alkyl)2, (CH2)mC(O)OH, -(CH2)mC(O)OR4, -(CH2)mC(O)O(lower alkyl), -(CH2)mC(O)SH, -(CH2)mC(O)SR4, -(CH2)mC(O)S(lower alkyl), -(CH2)mC(O)NH2, -(CH2)mC(O)other4, -(CH2)mC(O)NH(lower alkyl), -(CH2)mC(O)N(R4)2, -(CH2)mC(O)N(lower alkyl)2, -C(O)OH, -C(O)OR4, -C(O)SH, -C(O)SR4, -C(O)S(lower alkyl), -C(O)NH2, -C(O)other4, -C(O)NH(lower alkyl), -C(O)N(R4)2,-C(O)N(lower alkyl) 2, -On(R4), -O(quinil), -O(aralkyl), -O(cycloalkyl), -S(acyl), -S(lower acyl), -S(R4), -S(lower alkyl), -S(alkenyl), -S(quinil), -S(aralkyl), -S(cycloalkyl), -other4, -NR4R5, -NH(alkenyl), -NH(quinil), -NH(aralkyl), -NH(cycloalkyl), SCN, OCN, NCO, or fluorine;

in the alternative case, R12and R13can place to form spirochaetaceae selected from the group consisting of optionally substituted carbocycle (preferably a 3-7 membered carbocyclic ring) or optionally substituted heterocycle (preferably a 3-7 membered heterocyclic ring having one or more atoms O, S and/or N), and

each m independently is 0, 1 or 2.

In the sixth basic version of the proposed compound of formula (XI) or (XII), or its pharmaceutically acceptable salt, or prodrug, or a stereoisomeric, tautomeric or polymorphic form, as well as a method of treatment of a host infected with Flaviviridae that includes the introduction of effective treatment amount of compound of formula (XI) or (XII):

or its pharmaceutically acceptable salt or prodrug, or a stereoisomeric, tautomeric or polymorphic form, where:

base*, R, R1, R2, R3, R4, R5, R12, R13Y, Y1, Y2, Y3, W*, W1, W2, W3, W4 X, X*, X2and X3have the values specified above;

where in one embodiment, R8in the formula (XI) is-HE-or-NH2only when X is a carbon atom; and where the

each R8and R11independently represents hydrogen, optionally substituted alkyl (including lower alkyl), CH3CH2CN, CH2N3CH2NH2CH2NHCH3CH2N(CH3)2CH2OH, halogenated alkyl (including halogenated lower alkyl), CF3C(Y3)3, 2-Br-ethyl, - CH2F, CH2Cl, CH2CF3, CF2CF3C(Y3)2C(Y3)3not necessarily replaced alkenyl, halogenoalkanes, Br-vinyl, optionally substituted quinil, halogenoalkanes, -CH2C(O)OH, -CH2C(O)OR4, -CH2C(O)O(lower alkyl), -CH2C(O)NH2, -CH2C(O)other4, -CH2C(O)NH(lower alkyl), -CH2C(O)N(R4)2, -CH2C(O)N(lower alkyl)2, (CH2)mC(O)OH, -(CH2)mC(O)OR4, -(CH2)mC(O)O(lower alkyl), -(CH2)mC(O)NH2, -(CH2)mC(O)other4, -(CH2)mC(O)NH(lower alkyl), -(CH2)mC(O)N(R4)2, -(CH2)mC(O)N(lower alkyl)2, -C(O)OH, -C(O)OR4-C(O)O(lower alkyl), -C(O)NH2, -C(O)other4, -C(O)NH(lower alkyl), C(O)N(R 4)2, -C(O)N(lower alkyl)2, cyano, NH-acyl or N(acyl)2;

each R9and R10independently represents hydrogen, HE, OR2, optionally substituted alkyl (including lower alkyl), CH3CH2CN, CH2N3CH2NH2CH2NHCH3CH2N(CH3)2CH2OH, halogenated alkyl (including halogenated lower alkyl), CF3C(Y3)3, 2-Br-ethyl, - CH2F, CH2Cl, CH2CF3, CF2CF3C(Y3)2C(Y3)3not necessarily replaced alkenyl, halogenoalkanes, Br-vinyl, optionally substituted quinil, halogenoalkanes, optionally substituted carbocycle (preferably, 3 to 7-membered carbocyclic ring, optionally substituted heterocycle (preferably a 3-7 membered heterocyclic ring having one or more atoms O, S and/or N), optionally substituted heteroaryl (preferably 3-7-membered heteroaromatic ring having one or more atoms O, S and/or N), -CH2C(O)OH, -CH2C(O)OR4, -CH2C(O)O(lower alkyl), -CH2C(O)SH, -CH2C(O)SR4, -CH2C(O)S(lower alkyl), -CH2C(O)NH2, -CH2C(O)other4, -CH2C(O)NH(lower alkyl), -CH2C(O)N(R4)2, -CH2C(O)N(lower alkyl)2, (CH2)mC(O)OH, -(CH2)mC(O)OR 4, -(CH2)mC(O)O(lower alkyl), -(CH2)mC(O)SH, -(CH2)mC(O)SR4, -(CH2)mC(O)S(lower alkyl), -(CH2)mC(O)NH2, -(CH2)mC(O)other4, -(CH2)mC(O)NH(lower alkyl), -(CH2)mC(O)N(R4)2, -(CH2)mC(O)N(lower alkyl)2, -C(O)OH, -C(O)OR4-C(O)O(lower alkyl), -C(O)SH, -C(O)SR4, -C(O)S(lower alkyl), -C(O)NH2, -C(O)other4, -C(O)NH(lower alkyl), -C(O)N(R4)2, -C(O)N(lower alkyl)2, -O(acyl), -O(lower acyl), -O(R4), -O(alkyl), -O(lower alkyl), -O(alkenyl), -O(quinil), -O(aralkyl), -O(cycloalkyl), -S(acyl), -S(lower acyl), -S(R4), -S(lower alkyl), -S(alkenyl), -S(quinil), -S(aralkyl), -S(cycloalkyl), -NO2, NH2, -NH(lower alkyl), -other4, -NR4R5, -NH(acyl), -N(lower alkyl)2, -NH(alkenyl), -NH(quinil), -NH(aralkyl), -NH(cycloalkyl), -N(acyl)2azido, cyano, SCN, OCN, NCO, or halogen (fluorine, chlorine, bromine, iodine);

each m independently is 0, 1 or 2 and

in the alternative case, R8and R13and R9and R13, R9and R11or R10and R12may together form a bridged compound selected from the group consisting of optionally substituted carbocycle (preferably a 3-7 membered carbocyclic ring) or optionally substituted heterocycle (preferably a 3-7-membered gets aziklicescoe ring, having one or more O, S and/or N); or

in the alternative case, R12and R13or R9and R10may together form spirochaetaceae selected from the group consisting of optionally substituted carbocycle (preferably a 3-7 membered carbocyclic ring) or optionally substituted heterocycle (preferably a 3-7 membered heterocyclic ring having one or more O, S and/or N).

In a particular aspect of the invention proposed compound of formula (XIII) or (XIV), or its pharmaceutically acceptable salt, or prodrug, or a stereoisomeric, tautomeric or polymorphic form, as well as a method of treatment of a host infected with Flaviviridae that includes the introduction of effective treatment amount of compound of formula (XIII) or (XIV):

or its pharmaceutically acceptable salt or prodrug, or a stereoisomeric, tautomeric or polymorphic form, where:

R3selected from the group consisting of H; mono-, di - or triphosphate or a stabilized phosphate prodrug; acyl; sulphonate ester, optionally substituted alkylsulfonyl; optionally substituted arylsulfonyl; lipid; amino acid; carbohydrate; peptide; cholesterol and pharmaceutically acceptable removed group, which when introduced in vivo is able to provide the education connection in which R3independently represents H or mono-, di - or triphosphate;

X is selected from the group consisting of one or more of the groups O, S, SO, SO2, N, NH, NR and CH2where any of the above groups may be optionally substituted and may be in various positions, to form a 3-7-membered ring;

R represents H, alkyl or acyl;

In denotes spirochaetaceae selected from the group consisting of optionally substituted carbocycle (preferably a 3-7 membered carbocyclic ring) or optionally substituted heterocycle (preferably a 3-7 membered heterocyclic ring having one or more O, S and/or N), and

base selected from the group consisting of grounds:

where

each of R', R", R"' and R"" are independently selected from the group consisting of H, HE, substituted or unsubstituted alkyl, substituted or unsubstituted, alkenyl, substituted or unsubstituted quinil, cycloalkyl, Br-vinyl, -O-alkyl, O-alkenyl, O-quinil, O-aryl, O-aralkyl, O-acyl, O-cycloalkyl, NH2, NH-alkyl, N-dialkyl, NH-acyl, N-aryl, N-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-acyl, S-aryl, S-cycloalkyl, S-aralkyl, F, Cl, Br, I, CN, COOH, CONH2, CO2-alkyl, CONH-alkyl, CON-dialkyl, HE, CF3CH 2OH, (CH2)mOH, (CH2)mNH2, (CH2)mCOOH, (CH2)mCN, (CH2)mNO2and (CH2)mCONH2;

m is 0 or 1;

W represents C-R or N;

T and V independently represent CH or N;

Q represents CH, -CCl-CBr, -CF, -CI, -CCN-C-COOH, -C,-CONH2or N;

Q1and Q2independently represent N or C-R;

R represents H, alkyl or acyl;

Q3, Q4, Q5and Q6independently represent N or CH, and

its tautomeric forms.

In the second aspect of the invention proposed compound of formula (XV), (XVI) or (XVII), or its pharmaceutically acceptable salt, or prodrug, or a stereoisomeric, tautomeric or polymorphic form, as well as a method of treatment of a host infected with Flaviviridae that includes the introduction of effective treatment amount of compound of formula (XV), (XVI) or (XVII):

or its pharmaceutically acceptable salt or prodrug, or a stereoisomeric, tautomeric or polymorphic form, where:

G and E are independently selected from the group consisting of N, CH3CH2OH, CH2F, CH2N3CH2CN, (CH2)mCOOH, (CH2)mCOOR, (CH2)mCONH2, (CH2)mCONR2, (CH2)mCONHR or N-acyl;

R isone N, alkyl or acyl;

m is 0 or 1, and

R3and the Foundation shall have the meanings specified for formula (XIII).

In an alternative case for the compounds of formula (XVII) at most one of G and E may be, in addition, hydrogen.

In the third specific aspect of the invention proposed compound of formula (XVIII), or its pharmaceutically acceptable salt, or prodrug, or a stereoisomeric, tautomeric or polymorphic form, as well as a method of treatment of a host infected with Flaviviridae that includes the introduction of effective treatment amount of compound of formula (XVIII):

or its pharmaceutically acceptable salt or prodrug, or a stereoisomeric, tautomeric or polymorphic form, where

M is selected from the group consisting of S, SO and SO2and

R3and the Foundation shall have the meanings specified for formula (XIII).

In the fourth aspect of the invention proposed compound of formula (XIX), (XX), (XXI), (XXII) or (XXIII), or its pharmaceutically acceptable salt, or prodrug, or a stereoisomeric, tautomeric or polymorphic form, as well as a method of treatment of a host infected with Flaviviridae that includes the introduction of effective treatment amount of compound of formula (XIX), (XX), (XXI), (XXII) or (XXIII):

or its pharmaceutically acceptable salts, or prodrugs, or stereoisomers, tautomeric or polymorphic form, where

And selected from the group consisting of optionally substituted lower alkyl, cycloalkyl, alkenyl, quinil, CH2OH, CH2NH2CH2NHCH3CH2N(CH3)2CH2F, CH2Cl, CH2N3CH2CN, CH2CF3, CF3, CF2CF3CH2CO2R, (CH2)mCOOH, (CH2)mCOOR, (CH2)mCONH2, (CH2)mCONR2and (CH2)mCONHR;

Y is selected from the group consisting of H, optionally substituted lower alkyl, cycloalkyl, alkenyl, quinil, CH2OH, CH2NH2CH2NHCH3CH2N(CH3)2CH2F, CH2Cl, CH2N3CH2CN, CH2CF3, CF3, CF2CF3CH2CO2R, (CH2)mCOOH, (CH2)mCOOR, (CH2)mCONH2, (CH2)mCONR2and (CH2)mCONHR;

R represents H, alkyl or acyl;

X is selected from the group consisting of HE, optionally substituted alkyl, cycloalkyl, alkenyl, quinil, -O-alkyl, -O-alkenyl, -O-quinil, -O-aryl, -O-aralkyl, -O-cycloalkyl, -O-acyl, F, Cl, Br, I, CN, NC, SCN, OCN, NCO, NO2, NH2N3, NH-acyl, NH-alkyl, N-dialkyl, NH-alkenyl, NH-quinil, NH-aryl, NH-aralkyl,-NH-cycloalkyl, SH, S-alkyl, S-alkenyl, S-quinil, S-aryl, S-aralkyl, S, S-cycloalkyl, CO2-alkyl, CONH-alkyl, CON-dialkyl, CONH-alkenyl, CONH-quinil, CONH-aralkyl, CONH-cycloalkyl, CH2OH, CH2NH2CH2NHCH3CH2N(CH3)2CH2F, CH2Cl, CH2N3CH2CN, CH2CF3, CF3, CF2CF3CH2CO2R, (CH2)mCOOH, (CH2)mCOOR, (CH2)mCONH2, (CH2)mCONR2and (CH2)mCONHR, optionally substituted 3-7-membered carbocycle and optionally substituted 3-7-membered heterocyclic ring having O, S and/or N as heteroatoms present as a single atom or in combination;

m is 0 or 1;

R3selected from the group consisting of H; mono-, di - or triphosphate or a stabilized phosphate prodrug; a substituted or unsubstituted alkyl; acyl; sulphonate ester, optionally substituted alkylsulfonyl; optionally substituted arylsulfonyl; lipid; amino acid; carbohydrate; peptide; cholesterol and pharmaceutically acceptable removed group, which when introduced in vivo is able to provide the formation of the compound, in which R1independently represents H or mono-, di - or triphosphate, and

the Foundation is a non-natural base selected from the group:

p> where:

each R', R", R"' and R"" are independently selected from the group consisting of H, HE, substituted or unsubstituted alkyl, substituted or unsubstituted, alkenyl, substituted or unsubstituted quinil, cycloalkyl, Br-vinyl, -O-alkyl, O-alkenyl, O-quinil, O-aryl, O-aralkyl, O-acyl, O-cycloalkyl, NH2, NH-alkyl, N-dialkyl, NH-acyl, N-aryl, N-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-acyl, S-aryl, S-cycloalkyl, S-aralkyl, F, Cl, Br, I, CN, COOH, CONH2, CO2-alkyl, CONH-alkyl, CON-dialkyl, HE, CF3CH2OH, (CH2)mOH, (CH2)mNH2, (CH2)mCOOH, (CH2)mCN, (CH2)mNO2and (CH2)mCONH2;

m is 0 or 1;

W represents C-R or N;

T and V independently represent CH or N;

Q represents CH, -CCl-CBr, -CF, -CI, -CCN-C-COOH, -C,-CONH2or N;

Q1and Q2independently represent N or C-R"" and

Q3, Q4, Q5and Q6independently represent N or CH, with the proviso that in (g) and (i) R', R"" are H, HE or NH2and Q, T, V, Q2, Q5and Q6can't be N.

In another preferred embodiment, the proposed compound of formula (IX), or its pharmaceutically acceptable salt, or prodrug, or a stereoisomeric, tautomeric or polymorphic form, is also a method of treatment of a host, infected with Flaviviridae that includes the introduction of effective treatment amount of compound of formula (IX):

or its stereoisomeric, tautomeric or polymorphic form, or its pharmaceutically acceptable salts, where:

R1, R2and R3independently represent H; phosphate; alkyl with an unbranched, branched or cyclic chain; acyl; CO-alkyl; CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl; sulphonate ester; benzyl, which phenyl group is optionally substituted by one or more substituents; alkylsulfonyl; arylsulfonyl; aralkylamines; a lipid; an amino acid; a carbohydrate; a peptide; a cholesterol or a pharmaceutically acceptable delete the group, which when introduced in vivo is able to provide the formation of the compound in which R1, R2and/or R3independently represent H or phosphate

X represents O, S, SO2or CH2;

base* is a purine or pyrimidine base;

R12is(Y3)3;

Y3independently represents H, F, Cl, Br or I and

R13represents fluorine.

In one sub-option implementation X is a and Y3represents N. In another sub-option implementation, when X presented yet a and Y 3represents H, R1, R2and R3also represent N.

II. Stereochemistry

Obviously, the nucleosides of the present invention have several chiral centers and may exist in the form of a dedicated optically active and racemic forms. Some compounds may exhibit polymorphism. It should be clear that the present invention includes any racemic, optically active, diastereomers, polymorphic or stereoisomeric form, or mixtures of such forms of the compounds of the invention, which are described here are applicable properties. In this field it is well known how to obtain optically active forms (for example, separation of the racemic form by means of recrystallization, by synthesis from optically active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase).

In particular, since the 1'- and 4'-carbon atoms of the nucleoside are chiral, non-hydrogen substituents (groups base and CHOR, respectively) can be either CIS (on the same side) or TRANS-position (on opposite sides) with respect to the system of the sugar ring. Therefore, four optical isomers represented by the following configurations (when orienting the sugar residue in the horizontal plane, t is to the oxygen atom is on the back): CIS (with both groups "up", that corresponds to the configuration existing in nature, β-D-nucleosides), CIS (with both groups "down", which is not existing in nature, β-L-configuration), TRANS (C2'-Vice is "above" and C4'-the Deputy is at the bottom) and TRANS (C2'-Vice is "down" and C4'-the Deputy is at the top). "D-nucleosides" are CIS-nucleosides with existing in nature, configuration and L-nucleosides" are CIS-nucleosides with not existing in the nature of the configuration.

Similarly, most amino acids are chiral (named as L and D, where L-enantiomer has an existing in nature, configuration) and can exist as individual enantiomers.

Examples of methods for obtaining optically active materials are known in this area and include at least the following ways.

i)physical separation of crystals- the way in which macroscopic crystals of the individual enantiomers separated by hand. This method can be used if there are crystals of the individual enantiomers, i.e. the material is a conglomerate and the crystals are visually distinct;

ii)simultaneous crystallization- the way in which individual enantiomers separately crystallized from a solution of the rat is and, this way is possible only if the latter is a conglomerate in the solid state;

iii)enzymatic separation- the way in which partial or complete separation of the racemate is achieved due to the different speeds of reaction for the enantiomers with an enzyme;

iv)enzymatic asymmetric synthesis- the method of synthesis, which, in at least one stage of the synthesis uses an enzymatic reaction to obtain enantiomerically pure or enantiomerically enriched synthetic precursor of the desired enantiomer;

v)chemical asymmetric synthesis- synthetic method by which the desired enantiomer is synthesized from an achiral precursor under conditions in which there is asymmetry (i.e. chirality) in the product, which can be achieved using chiral catalysts or chiral auxiliaries;

vi)separation of the diastereomers- the method by which the racemic compound is subjected to interaction with an enantiomerically pure reagent (the chiral auxiliary substance)that converts the individual enantiomers to diastereomers. The resulting diastereomers are then separated by chromatography or crystallization due to their new, more distinct structural differences and chiral vspomogate the aspects of the matter later removed to obtain the desired enantiomer;

vii)asymmetric transformations of the first and second order- the way in which the diastereomers of the racemate is brought to an equilibrium state with a predominance in the solution of diastereoisomer of the desired enantiomer or in which the predominant crystallization of the desired diastereoisomer enantiomer violates the equilibrium state, so that subsequent equilibria essentially all of the material becomes crystalline diastereoisomer of the desired enantiomer. The desired enantiomer is then separated from the diastereoisomer;

viii)kinetic separation- this method refers to the achievement of partial or complete separation of the racemate (or further separation of the partially separated compounds) due to different speeds of reaction for the enantiomers with a chiral, deracemization reagent or catalyst under kinetic conditions;

ix)enantiospecific synthesis of narramissic predecessors- synthetic method by which the desired enantiomer is obtained from the organization of the achiral starting materials and where the stereochemical integrity is not impaired or deteriorating only minimally throughout the conduct of synthesis;

x)chiral liquid chromatography- the way in which the enantiomers of a racemate are separated in a liquid mobile phase full satisfaction is their different interactions with the stationary phase. The stationary phase can be made of a chiral material, or the mobile phase can contain additional chiral material to cause different interactions;

xi)chiral gas chromatography- the way in which the racemate is evaporated and the enantiomers separated due to their different interactions in the gaseous mobile phase with a column containing a stationary prizemistuyu chiral phase-absorbent;

xii)extraction of chiral solvents- the way in which the enantiomers separated due to the prevalent dissolution of one enantiomer in this chiral solvent;

xiii)transfer through chiral membrane- the way in which the racemate is in contact with a thin membrane barrier. Barrier normally separate two miscible liquids, one contains the racemate, and the driving force, such as the difference in the concentration or pressure, causes the preferred transfer through the membrane barrier. Separation occurs as a result prizemistoj chiral nature of the membrane, which allows only one enantiomer of the racemate to pass through it.

III. Definitions

Used herein, the term "alkyl", unless otherwise stated, refers to a saturated unbranched, branched or cyclic primary, secondary isotretinon hydrocarbon, typically the composition With1-C10and specifically includes methyl, CF3, CCl3, CFCl2, CF2Cl, ethyl, CH2CF3, CF2CF3, propyl, isopropyl, cyclopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, cyclohexylmethyl, 3-methylpentyl, 2,2-dimethylbutyl and 2,3-dimethylbutyl. The term includes both substituted and unsubstituted alkyl groups, and specifically includes a halogenated alkyl group, and still more specifically fluorinated alkyl groups. Non-limiting examples of residues that may be substituted by an alkyl group selected from the group consisting of halogen (fluorine, chlorine, bromine or iodine), hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected, or protected, if necessary, as known to the person skilled in the art, for example, as indicated in the publication Greene, et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, included this image as a reference.

The term "lower alkyl", as used here, unless otherwise noted, refers to a1-C4saturated unbranched, branched, or, if appropriate, a cyclic (for example, cyclopropyl) alkyl group, including both substituted, and unsubstituted residues.

The term "alkylamino" or "arylamino" refers to the amino group, which has one or two alkyl or aryl substituent, respectively. If this application is not mentioned specifically, when the alkyl is a suitable balance, preferred is lower alkyl. Similarly, when the alkyl or lower alkyl is a suitable balance, preferred is unsubstituted alkyl or lower alkyl.

Used herein, the term "protected", if not specified otherwise, refers to a group that is attached to the oxygen atom of nitrogen or phosphorus to prevent further interaction or for other purposes. Specialist in the field of organic synthesis known to a large number of protective groups for the atoms of oxygen and nitrogen.

Used herein, the term "aryl", unless otherwise stated, refers to phenyl, biphenyl or naphthyl, preferably, phenyl. The term includes both substituted and unsubstituted residues. Aryl group may be substituted by any desired residue, including but limited to the above, one or more residues selected from the group consisting of halogen (fluorine, chlorine, bromine or iodine), hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic to the slots, phosphate or phosphonate, either unprotected, or protected, if necessary, as known to the person skilled in the art, for example, as indicated in the publication Greene, et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, included this image as a reference.

The term "alkaryl" or "alkylaryl" refers to an alkyl group, aryl Deputy. The term aralkyl or arylalkyl refers to an aryl group with an alkyl substituent.

Used herein, the term "halogen" includes chlorine, bromine, iodine and fluorine.

The term "purine" or "pyrimidine" basis includes, but is not limited to, adenine, N6-alkylphenyl, N6-acylpyrin (where acyl represents C(O)(alkyl, aryl, alkylaryl or arylalkyl), N6-benzylurea, N6-halogenfree, N6-vinluan, N6-acetaminiphen, N6-acylpyrin, N6-hydroxyalkylated, N6-alkylamines, N6-dialkylphenol, N2-alkylphenyl, N2-alkyl-6-thiopurine, thymine, cytosine, 5-fertilizin, 5-methylcytosine, 6-etherimide, including 6-azacytosine, 2 - and/or 4-mercaptopyrimidine, uracil, 5-halogenerator, including 5-fluorouracil, With5-alkylpyridine, With5-benzylpyrimidines, With5-halogenopyrimidines, With5-vinylpyridin, With5-acetylenylanyline, With5-arylpyrimidine, With5-hydrox acylpyrin, With5-aminopyrimidine, With5-cyanopyrimidine, With5-iterkeys, With6-iterkeys, With5-Br-vinylpyridin, With6-Br-vinylpyridin, With5-nitropyrimidin, With5-aminopyrimidine, N2-alkylphenyl, N2-alkyl-6-thiopurine, 5-azacitidine, 5-azauracil, triazolopyridines, imidazopyridines, pyrrolopyrimidine and pyrazolopyrimidines. Purine bases include, but are not limited to, guanine, adenine, gipoksantin, 2,6-diaminopurine and 6-globulin. When necessary or desirable, functional oxygen and nitrogen groups on the basis of can be protected. Suitable protective groups are well known to the person skilled in the art, and include trimethylsilyl, dimethylhexylamine, tert-butyldimethylsilyl and tert-butyldiphenylsilyl, trityl, alkyl groups and acyl groups such as acetyl and propionyl, methanesulfonyl and p-toluensulfonyl.

The term "acyl" or "O-linked ester" refers to a group of formula S(O)R', where R' represents an unbranched, branched or cyclic alkyl (including lower alkyl), amino acid, aryl including phenyl, alkaryl, aralkyl, including benzyl, alkoxyalkyl, including methoxymethyl, aryloxyalkyl, such as phenoxymethyl, or substituted alkyl (including lower alkyl), aryl including a Hairdryer is l, optionally substituted by chlorine, bromine, fluorine, iodine,1-C4-alkyl or C1-C4-alkoxy, sulphonate esters such as alkyl - or aralkylamines, including methanesulfonyl, mono -, di - or trifosfatnogo ether, trityl or monomethacrylate, substituted benzyl, alkaryl, aralkyl, including benzyl, alkoxyalkyl, including methoxymethyl, aryloxyalkyl, such as phenoxymethyl. Aryl groups in esters optimally contain a phenyl group. In particular, the acyl group include acetyl, TRIFLUOROACETYL, methylacyl, cyclopropylacetic, cyclopropylmethoxy, propionyl, butyryl, hexanoyl, heptanoyl, octanoyl, neuleptil, phenylacetyl, 2-acetoxy-2-phenylacetyl, diphenylacetyl, α-methoxy-α-cryptomaterial, bromoacetyl, 2-nitrobenzoate, 4-chlorobenzoate, 2-chloro-2,2-diphenylacetyl, 2-chloro-2-phenylacetyl, trimethylacetyl, chlorodifluoroacetic, perforated, peracetyl, bromodifluoromethyl, methoxyacetyl, 2-thiopheneacetyl, chlorosulfonated, 3-methoxyphenylacetyl, phenoxyacetyl, tert-butylacetyl, trichloroacetyl, monochloracetic, dichloracetyl, 7H-dodecafluoroheptyl, perforation, 7H-dodecafluoroheptyl, 7-chloroderivatives, 7-chloroderivatives, 7H-dodecafluoroheptyl, 7H-dodecafluoroheptyl, nonfor-3,6-dioxaheptyl, nonfor-3,6-dioxaheptyl, perf olatunji, methoxybenzoyl, methyl-3-amino-5-phenylthiophene-2-carboxyl, 3,6-dichloro-2-methoxybenzoyl, 4-(1,1,2,2-tetrafluoroethoxy)benzoyl, 2-bromopropionyl, omega-aminocaproyl, decanoyl, n-pentadecanol, stearyl, 3-cyclopentylpropionyl, 1-benzopyrrole, acetylindole, pivaloate, 1-adamantanecarbonyl, cyclohexanecarbonyl, 2,6-pyridinedicarboxylic, cyclopropanecarbonyl, cyclobutanecarbonyl, perforceconfiguration, 4-methylbenzoyl, chloromethylisothiazolinone, perforceconfiguration, crotonyl, 1-methyl-1H-indazol-3-carbonyl 2-propenyl, isovaleryl, 1-pyrrolidinecarbonyl, 4-vinylbenzoic. When using the term acyl, this means that it is specific and independent description of acetyl, TRIFLUOROACETYL, methylacetyle, cyclopropylethyl, propionyl, butyryl, hexanoyl, heptanoyl, octanoyl, neuleptil, phenylacetyl, diphenylacetyl, α-cryptomaterial, bromoacetyl, 4-chlorobenzonitrile, 2-chloro-2,2-diphenylacetyl, 2-chloro-2-phenylacetyl, trimethylacetyl, chlortetracycline, perforate, peracetyl, bromodifluoromethyl, 2-thiopheneacetyl, tert-butylacetyl, trichloroacetyl, monochloracetic, dichloracetyl, methoxybenzoyl, 2-bromopropionyl, decanoyl, n-pentadecanol, sterile, 3-cyclopentylpropionyl, 1-benzoperoxide, pivaloate, 1-adamantanecarboxylic, cyclohexanecarboxylic, 2,6-pyridi is dicarboxyl, cyclopropanecarboxylic, cyclobutanecarboxylic, 4-methylbenzoyl, crotonyl, 1-methyl-1H-indazol-3-carbonyl, 2-propenyl, isovaleryl, 4-phenylbenzyl.

The term "amino acid" includes natural and synthetic α-, β-, γ - or δ-amino acids and includes, but is not limited to, amino acids found in proteins, i.e. glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, Proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartate, glutamate, lysine, arginine and histidine. In a preferred embodiment, the amino acid has the L-configuration. In the alternative case, the remaining amino acids can be alanyl, valinol, Latini, isoleucine, Proline, phenylalanine, tryptophanyl, methionine, glycinyl, serinol, threonine, cysteine, tyrosine, asparagine, glutamine, aspartyl, glutaryl, lisini, arginine, histidine, β-alanyl, β-valinol, β-leucinol, β-isoleucine, β-Proline, β-phenylalanine, β-tryptophanyl, β-methionine, β-glycinin, β-serenil, β-threonine, β-cysteine, β-tyrosine, β-asparaginyl, β-glutamine, β-aspartyl, β-glutaryl, β-lisini, β-argininel or β-histidinol. In tables 1-24 presents examples of the types of amino acids present invention. When using the term amino acid, it is believed that it is specific and independent description of what each of the esters of α, β-, γ - or δ-glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, Proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartate, glutamate, lysine, arginine and histidine, D - and L-configurations.

Used herein, the term "essentially containing no or essentially in the absence" refers to a nucleoside composition that includes at least 85 or 90 wt.%, preferably, 95%, 98%, 99% or 100 wt.% a particular enantiomer of a specified nuke. In a preferred embodiment, the methods and compounds of the present invention compounds are essentially the enantiomers, does not contain opposite enantiomers.

Similarly, the term "isolated" refers to a nucleoside composition that includes at least, 85%, 90%, 95%, 98%, 99% or 100 wt.% nucleoside, with the rest being other chemical species or enantiomers.

The term "owner"as used here, refers to a unicellular or multicellular organism that can replicate the virus, including cell lines and animals, preferably humans. In the alternative case, the owner can be part of a Flaviviridae viral genome replication or function which can be changed by the compounds of the present invention. The term host specifically the relative is raised to the infected cells, cells transfitsirovannykh the whole genome or a part of genome Flaviviridae, and animals, in particular, primates (including chimpanzees) and humans. In most applications of the present invention to the animal host is a patient man. In some indications, however, undoubtedly expected to apply the present invention in veterinary medicine (e.g., in the treatment of chimpanzees).

The term "pharmaceutically acceptable salt or prodrug" is used throughout the description to describe any pharmaceutically acceptable form (such as an ester, phosphate ester, salt of an ester or a related group) nucleoside compounds that when administered to a patient provides education nucleoside compounds. Pharmaceutically acceptable salts include salts formed from pharmaceutically acceptable inorganic or organic bases and acids. Suitable salts include salts formed from alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium, as well as numerous other acids well known in the pharmaceutical field. Pharmaceutically acceptable prodrugs refer to a compound that is metabolized, for example hydrolyzed or oxidized, in the host organism with the formation of compounds of the present invention. Typical p is emery prodrugs include compounds which have biologically labile protective group on the functional balance of active compounds. Prodrugs include compounds that can be oxidized, restored, laminirowany, diaminononane, gidroksilirovanii, dehydrosilybin, hydrolyzed, digitalizovane, alkylated, dialkylamide, etilirovany, diallylamine, phosphorylated, the dephosphorylated to obtain active compounds. Compounds of the present invention possess antiviral activity against Flaviviridae or are metabolized to a compound that possesses such activity.

IV. Prodrugs and derivatives

The active compound may be introduced in the form of any salt or prodrug, which when administered to the recipient is able to provide education directly or indirectly the parent compound or which itself has activity. Non-limiting examples are the pharmaceutically acceptable salts (alternatively called "physiologically acceptable salts"), and the connection, which was alkylated, allyawan or otherwise modified at the 5'-position of the purine or pyrimidine base (type "pharmaceutically acceptable prodrugs"). In addition, modifications can act on the biological activity of compounds, in some cases, increasing aktivnosti relative to the original connection. This can be easily estimated by obtaining salt or prodrug and a challenge to its antiviral activity by methods described herein or other methods known in this field.

A. Pharmaceutically acceptable salt

In cases where compounds are sufficiently basic or acidic to formation of stable non-toxic salts of acids or bases, may be an appropriate introduction connection in the form of pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts are acid additive salts with organic acids formed by the addition of acids which form a physiological acceptable anion, for example tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, α-Ketoglutarate, α-glycerol, formate, fumarate, propionate, glycolate, lactate, pyruvate, oxalate, maleate and salicylate. Can also be obtained suitable inorganic salts, including sulfate, nitrate, bicarbonate, carbonate salts, Hydrobromic and salts of phosphoric acid. In a preferred embodiment, the salt is a mono - or dihydrochloride salt.

Pharmaceutically acceptable salts may be obtained using standard procedures well known in the field, such as the interaction sufficiently basic compound such as amine, with a suitable acid, providing a physiologically acceptable anion. Can be also obtained salt of an alkali metal (e.g. sodium, potassium or lithium) or alkaline earth metal (e.g. calcium) carboxylic acids. In one embodiment, the salt is cleaners containing hydrochloride salt of the compound. In another embodiment, pharmaceutically acceptable salt is dihydrochloride salt.

Century Drugs nucleotide prodrugs

Described here nucleosides can be introduced in the form of nucleotide prodrug to increase the activity, bioavailability, stability or otherwise change the properties of the nucleoside. Famous is the number of ligands nucleotide prodrugs. In General, alkylation, acylation or other lipophilic modification of mono-, di - or triphosphate of the nucleoside reduces the polarity and allows you to place him in the cell. Examples of the groups of substituents, which can replace one or more hydrogen atoms on the phosphate residue, are alkyl, aryl, steroids, carbohydrates, including sugars, 1,2-diacylglycerol and alcohols. Many of them are described in R. Jones and N. Bischoferger, Antiviral Research, 1995, 27:1-17. Any of them may be used in combination with the described nucleoside to achieve the desired action.

In an alternative embodiment, the nucleoside is delivered in VI is e phosphonate or derived SATE.

The active nucleoside can also be provided in the form of a simple 2'-, 3'- and/or 5'-pastefire with lipid or simple 2'-, 3'- and/or 5'-ester with lipid. Described non-limiting examples here include the following links: Kucera, L.S., N. Iyer, E. Leake, A. Raben, Modest E.K., D.L.W., and Piantadosi. 1990. "Novel membrane-interactive ether lipid analogs that inhibit infectious HTV-1 production and induce defective virus formation." AIDS Res. Hum. Retro Viruses. 6:491-501; Piantadosi, C, J. Marasco C.J., S.L. Morris-Natschke, K.L. Meyer, F. Gumus, J.R. Surles, for K.S. Ishaq, L.S. Kucera, N. Iyer, C.A. Wallen, S. Piantadosi, and E.J. Modest. 1991. "Synthesis and evaluation of novel ether lipid nucleoside conjugates for anti-HIV activity." J. Med. Chem. 34:1408.1414; Hosteller, K.Y., D.D. Richman, D.A. Carson, L.M. Stuhmiller, G.M. T. van Wijk and H. van den Bosch. 1992. "Greatly enhanced inhibition of human immunodeficiency virus type 1 replication in CEM and HT4-6C cells by 3'-deoxythymine diphosphate dimyristoylglycerol, a lipid prodrug of 3,-deoxythymine." Antimicrob. Agents Chemother. 36:2025. 2029; Hosetler, K.Y., L.M. Stuhmiller, H.B. Lenting, H. van den Bosch, and D.D. Richman, 1990. "Synthesis and antiretroviral activity of phospholipid analogs of azidothymine and other antiviral nucleosides." J.Biol. Chem. 265:61127.

Non-limiting examples of U.S. patents which describe suitable lipophilic substituents that can be covalently incorporated into the nucleoside, preferably in position 2'-, 3'- and/or 5'-OH of the nucleoside or lipophilic preparations, include U.S. patent No. 5149794 (September 22, 1992, Yatvin et al.); 5194654 (March 16, 1993, Hostetler et al.), 5223263 (June 29, 1993, Hostetler et al.); 5256641 (October 26, 1993, Yatvin et al.); 5411947 (may 2, 1995, Hostetler et al.); 5463092 (October 31, 1995, Hostetler et al.); 5543389 (August 6, 1996, Yatvin et al.); 5543390 (August 6, Yatvin et al.); 543391 (August 6, 1996, Yatvin et al.) and 5554728 (September 10, 1996; Basava et al.), all of which is incorporated herein by reference. Applications for foreign patents, which describe lipophilic substituents that can be attached to the nucleosides of the present invention, or lipophilic preparations, include WO 89/02733, WO 90/00555, WO 91/16920, WO 91/18914, WO 93/00910, WO 94/26273, WO 96/15132, EP 0350287, EP 93917054.4 and WO 91/19721.

Also proposed akrilovye esters, especially phenyl esters. Non-limiting examples are described in DeLambert et al., J. Med. Chem. 37: 498 (1994). Also proposed phenyl esters containing ether carboxylic acid in ortho-position to the phosphate. Khamnei and Torrence, J. Med. Chem.; 39:4109-4115 (1996). In particular, the proposed benzyl esters, which generate the original connection, in some cases, using the substituents in the ortho - or para-position to accelerate the hydrolysis. Examples of this class of prodrugs described by Mitchell et al., J. Chem. Soc. Perkin Trans. I 2345 (1992); Brook, et al. WO/91/19721, and Glazier et al. WO 91/19721.

Also proposed cyclic and acyclic phosphonate esters. Non-limiting examples are described in Hunston et al., J. Med. Chem. 27:440-444 (1984) and Starrett et al. J. Med. Chem. 37: 1857-1864 (1994). In addition, the proposed cyclic 3',5'-phosphate esters. Non-limiting examples are described in Meier et al. J. Med. Chem. 22: 811-815 (1979). Also proposed cyclic 1',3'-propylphosphonate and phosphate esters, such as esters containing con is inspirowane aryl ring, i.e. cyclosaligenyl ether (Meier et al., Bioorg. Med. Chem. Lett. 7: 99-104 (1997)). Also proposed unsubstituted cyclic 1',3'-propanolamine esters of monophosphate (Farquhar et al., J. Med. Chem. 26: 1153 (1983); Farquhar et al., J. Med. Chem. 28: 1358 (1985)). In addition, the proposed cyclic 1',3'-propanolamine esters, substituted pivaloyloxymethyl at C-1' (Freed et al., Biochem. Pharmac. 38: 3193 (1989); Biller et al., U.S. patent No. 5157027).

It is known that phosphoramidate are oxidized in vivo by oxidative mechanism. Thus, in one embodiment of the present invention proposed a variety of substituted 1',3'-propanolamine circular phosphoramidate. Non-limiting examples of proposed Zon, Progress in Med. Chem. 19, 1205 (1982). In addition, proposed a number of 2'- and 3'-substituted profirov. 2'-Substituents include methyl, dimethyl, bromine, trifluoromethyl, chlorine, hydroxy and methoxy; 3'-substituents include phenyl, methyl, trifluoromethyl, ethyl, propyl, isopropyl and cyclohexyl. Also proposed a variety of 1'-substituted analogues.

Also proposed cyclic esters of phosphorus-containing compounds. Non-limiting examples are described in the following publications:

- [1] di - and treatery phosphoric acid, as described in Nifantyev et al., Phosphorus, Sulfur Silicon and Related Elements, 113: 1 (1996); Wijnberg et al., EP-180276 A1;

- [2] the esters of acids of phosphorus (III). Kryuchkov et al., Izv. Akad. Nauk SSSR, Ser. Khim. 6: 1244 (1987). Stated that some compounds are the Xia applicable for the asymmetric synthesis of the precursor L-Dopa. Sylvain et al., DE 3512781 A1;

- [3] phosphoramidate. Shih et al., Bull. Inst. Chem. Acad. Sin, 41: 9 (1994); Edmundson et al., J. Chem. Res. Synop. 5: 122 (1989), and

- [4] phosphonates. Neidlein et al., Heterocycles 35: 1185 (1993).

In addition, non-limiting examples of applications for U.S. patents and international patents, which describe suitable cyclic phosphoramidate prodrugs include U.S. patent No. 6312662; WO 99/45016; WO 00/52015; WO 01/47935 and WO 01/18013, Erion et al. from Metabasis Therapeutics, Inc. Specifically, the proposed prodrugs following formula

where

- V and Z are connected via an additional 3-5 atoms with the formation of a cyclic group containing 5-7 atoms, optionally 1 heteroatom, substituted hydroxy, acyloxy, alkoxycarbonyl or aryloxypropanolamine attached to the carbon atom, which is the third atom from both groups attached to the phosphorus atom; or

- V and Z are connected via an additional 3-5 atoms with the formation of a cyclic group, optionally containing 1 heteroatom, which is condensed with an aryl group at the beta and gamma position to the O attached to the phosphorus atom;

V and W are connected via an additional 3 carbon atoms, with formation of an optionally substituted cyclic group containing 6 carbon atoms and substituted by one Deputy, selected from the group status is the present from hydroxy, acyloxy, alkoxycarbonyl, alkyldiethanolamine, aryloxypropanolamine attached to one of the specified carbon atoms, which is the third atom from both groups attached to the phosphorus atom;

Z and W are connected via an additional 3-5 atoms with the formation of a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl or substituted by heteroaryl;

- W and W' are connected via an additional 2-5 atoms with the formation of a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl or substituted by heteroaryl;

Z is selected from the group consisting of CHR2OH, -CHR2OC(O)R3,

-CHR2OC(S)R3, -CHR2OC(S)OR3, CHR2OC(O)SR3, -CHR2OCO2R3, -OR2, -SR2, -CHR2N3, -CH2-aryl, -CH(aryl)HE, -CH(CH=CR22)OH, -CH(C. .CR2)OH, -R2, -NR22, -OCOR3, -OCO2R3, -SCOR3, -SCO2R3, -NHCOR3, -NHCO2R3, -CH2NH, -(CH2)p-OR12and -(CH2)p-SR12;

- p is an integer 2 or 3;

provided that:

- a) V, Z, W, W' are not all-H and

- (b) when Z represents-R2then, at least one of V, W W' are not-H, the alkyl, aralkyl or alicyclic radical;

- R2selected from the group consisting of R3and-N;

- R3selected from the group consisting of alkyl, aryl, alicyclic radical and aralkyl;

- R12selected from the group consisting of-h, and lower acyl;

- M is a biologically active agent, which is attached to the phosphorus atom in formula I via a 2'-, 3'- and/or 5'-hydroxyl.

V. Raman or alternativna therapy

Active compounds of the present invention can be introduced in combination or alteration with another agent against flavivirus or pestivirus or, in particular, with the agent against HCV for the treatment of any of these States. In combination therapy effective dose of two or more agents are administered together, whereas alteration or therapy with sequential stages of an effective dose of each agent administered in stages or sequentially. Input dose will depend on absorption, inactivation and rate of excretion of the drug, as well as other factors known to the person skilled in the art. It should be noted that the magnitude of the doses will also vary depending on the severity of the condition, which should be facilitated. In addition, it should be clear that for any particular subject certain modes and graphics receive karstenii funds should be adjusted within the limits of time in accordance with the needs of the patient and the professional assessment of the person misleading or controlling the introduction of the compositions. In preferred embodiments, the implementation is desirable connection against HCV (or against pestivirus, or against flavivirus)that manifests EC5010-15 microns or preferably less than 1-5 μm.

Found that drug-resistant tool options flavorwave, pestivirus or HCV may occur after prolonged treatment with antiviral agent. Resistance to drug most commonly occurs because of a mutation of the gene that encodes the enzyme used in viral replication. The effectiveness of drugs against viral infection can be prolonged, enhanced or restored by introducing the compound in combination or alteration with the second and maybe third antiviral compound that induces a mutation other than mutation, which caused the main drug. In the alternative case of the biodistribution and pharmacokinetics, or other parameter of a medicinal product may be modified such fluid or alternativnoe therapy. In General, combination therapy is usually preferred to alternativnoe therapy because it induces multiple simultaneous stresses on the virus.

Any of the treatments for viral is olivani, described in the present invention "Background of invention", can be used in combination or alteration with compounds described in this description. Non-limiting examples include:

1) protease Inhibitors

Examples include inhibitors of the NS3 protease-based substrate (Attwood et al., Antiviral peptide derivatives, PCT WO 98/22496, 1998; Attwood et al., Antiviral Chemistry and Chemotherapy 1999, 10, 259-273; Attwood et al., Preparation and use of amino acid derivatives as anti-viral agents, publication of German patent DE 19914474; Tung et al. Inhibitor of serine proteases, particularly hepatits C virus NS3 protease, PCT WO 98/17679), including alpha-ketoamide and hydrazinoacetate, and inhibitors, which have in the limit position of the electrophile, such as boranova acid or phosphonate (Llinas-Brunet et al, Hepatitis C inhibitor peptide analogues, PCT WO 99/07734); inhibitors of the NS3 protease is not based substrate, such as derivatives of 2,4,6-trihydroxy-3-nitrobenzamide (Sudo K. et al., Biochemical and Biophysical Research Communications, 1997, 238, 643-647, Sudo K. et al. Antiviral Chemistry and Chemotherapy, 1998, 9, 186), including RD3-4082 and RD3-4078, the first, replaced the chain amide with a 14 carbon atoms, and the latter having a pair of phenoxyphenyl group; and Sch 68631, phenanthridine, the HCV protease inhibitor (M. Chi et al., Tetrahedron Letters 37: 7229-7232, 1996).

Sch 351633, isolated from the fungi Penicillium griseofulvum, identified as the protease inhibitor (Chu M. et al., Bioorganic and Medicinal Chemistry Letters 9: 1949-1952). Eglin C, isolated from leech, is potent in what ibition several semiprotect, such as protease and S. griseus, α-chymotrypsin, chymase and subtilisin. Qasim M.A. et al., Biochemistry 36: 1598-1607, 1997.

U.S. patents describing the protease inhibitors for the treatment of HCV include, for example, U.S. patent No. 6004933, Spruce et al., which describes a class of inhibitors cysteinate for inhibiting endopeptidase 2 HCV; U.S. patent No. 5990276, Zhang et al., which describes synthetic inhibitors of the NS3 protease of hepatitis C virus; U.S. patent No. 5538865, Reyes et al.; WO 02/008251, Corvas International, Inc. and WO 02/08187 and WO 02/008256, Schering Corporation. The tripeptides as inhibitors of HCV are described in U.S. patent No. 6534523, 6410531 and 6420380, Boehringer Ingelheim, and WO 02/060926, Bristol Myers Squibb. Varilite as inhibitors semipretioase HCV NS3 described in WO 02/48172, Schering Corporation. Imidazolidinone as inhibitors semipretioase HCV NS3 described in WO 02/08198, Schering Corporation, and WO 02/48157, Bristol Myers Squibb. In WO 98/17679, Vertex Pharmaceuticals, and WO 02/48116, Bristol Myers Squibb, also described inhibitors of HCV protease;

2) Derivatives of thiazolidine who find acceptable inhibition in the analysis of HPLC with reversed-phase fusion protein NS3/4A and the substrate NS5A/5B (Sudo K. et al., Antiviral Research, 1996, 32, 9-18), especially compound RD-1-6250 with condensed cinnamonny residue substituted with long alkyl chain, RD4 6205 and RD4 6193;

3) Thiazolidine and benzanilide identified in Kakiuchi N. et al. J. EBS Letters 421, 217 to 220; N. Takeshita et al., Analytical Biochemistry, 1997, 247, 242-246;

4) Phenanthridinone, the irradiation of the surrounding activity against protease in a test SDS-PAGE and autoradiography and isolated from the fermentation broth of a culture of Streptomyces sp., Sch 68631 (Chu M. et al., Tetrahedron Letters, 1996, 37, 7229, 7232), and Sch 351633, isolated from the fungi Penicillium griseofulvum, which demonstrates activity in a scintillation proximal trial (Chu M. et al., Bioorganic and Medicinal Chemistry Letters 9, 1949-1952);

5) Inhibitors of helicase (Diana G.D. et al., Compounds, compositiobs and methods for treatment of hepatitis C, U.S. patent No. 5633358; Diana G.D. et al., Piperidine derivatives, pharmaceutical compositions thereof and their use in the treatment hepatitis C, PCT WO 97/36554);

6) Nucleotide polymerase inhibitors and gliotoxin (Ferrari R. et al., Journal of Virology, 1999, 73, 1649-1654) and natural product cerulenin (Lohmann V. et al., Virology, 1998, 249, 108-118);

7) Antisense phosphorotioate oligodeoxynucleotide (S-one), complementary to the segments in the sequence of the 5'-noncoding region (NCR) of the virus (Alt M. et al., Hepatology, 1995, 22, 707-717), or nucleotides 326-348 comprising 3'-terminal part of the NCR and nucleotides 371-388 located in the coding Corr region HCV RNA (Alt M. et al., Archives of Virology, 1997, 142, 589-599; Galderisi U. et al., Journal of Cellular discrimination, 1999, 181, 251-257);

8) Inhibitors of IRES-dependent translation (N. Ikeda et al., Agent for the prevention and treatment of hepatitis C, the publication of the Japan patent JP-08268890; Kai Y. et al. Prevention and treatment of viral diseases, a publication of the Japan patent JP-10101591);

9) Ribozymes such as nuclearsafety ribozymes (Maccjak, D.J. et al., Hepatology 1999, 30, abstract 995), and ribozymes described in U.S. patent No. 6043077, Barber et al., and U.S. patent No. 5869253 and 5610054, Draper et al.; and

10) For the treatment of Flaviviridae infection has also been developed analogues of the well is of Leonidov;

11) Any of the compounds described Idenix Pharmaceuticals in the publications of international patent number WO 01/90121 and WO 01/92282;

12) Compounds in other patents describing the use of certain nucleoside analogues for the treatment of infection of hepatitis C virus, and these patents include: PCT/SA/01316 (WO 01/32153; registered November 3, 2000), PCT/CA01/00197 (WO 01/60315; registered 19 February 2001), registered BioChem Pharma, Inc. (now Shire Biochem, Inc.); PCT/US02/01531 (WO 02/057425; registered on January 18, 2002) and PCT/US02/03086 (WO 02/057287, registered on January 18, 2002), registered Merck & Co., Inc., PCT/EP01/09633 (WO 02/18404; published August 21, 2001), registered Roche, and PCT publication no WO 01/72246 (registered 13 April 2001), WO 02/32920 (registered 18 October 2001) and WO 02/48165, Pharmasset, Ltd., the PCT publication no WO 99/43691, Emory University, entitled "2'-Formulised", which describes the use of certain 2'-pornological for treatment of HCV.

14) a variety of Other compounds, including 1-aminoalkylsilane (U.S. patent No. 6034134, Gold et al.), alkaliphile (U.S. patent No. 5922757, Chojkier et al.), vitamin E and other antioxidants (U.S. patent No. 5922757, Chojkier et al.), squalene, amantadine, bile acids (U.S. patent No. 5846964, Ozeki et al.), N-(phosphonacetyl)-L-aspartic acid (U.S. patent No. 5830905, Diana et al.), benzodioxane (U.S. patent No. 5633388, Diana et al.), derivatives floor is Danilovo acid (U.S. patent No. 5496546, Wang et al.), 2', 3'-dideoxyinosine (U.S. patent No. 5026687, Yarchoan et al.), the benzimidazole (U.S. patent No. 5891874, Colacino et al.), extracts of plants (U.S. patent No. 5837257, Tsai et al., U.S. patent No. 5725859, Omer et al., and U.S. patent No. 6056961) and piperidine (U.S. patent 5830905, Diana et al.).

15) Other compounds currently in preclinical or clinical development for the treatment of diseases caused by the hepatitis C virus include: interleukin-10, developed by Schering-Plough, IP-501, developed Interneuron, merimepodib (VX-497), developed by Vertex, amantadine® (Symmetrel), developed by Endo Labs Solvay, heptazyme®, developed by RPI, IDN-6556, developed Indun Pharma., XTL-002 developed by XTL., HCV/MF59, developed by Chiron, civacir® (immune globulin hepatitis C), developed by NABI, levovirin®, developed by ICN/Ribapharm, viramidine®, developed by ICN/Ribapharm, zadaxin® (thymosin alpha-1), developed by Sci Clone, thymosin plus targeted interferon developed Sci Clone, zeplin® (histamine dihydrochloride), developed by Maxim, VX 950/LY 570310 developed by Vertex/Eli Lilly, ISIS 14803, developed by Isis Pharmaceutical/Elan, IDN-6556, developed Idun Pharmaceuticals, Inc., JTK 003 developed AKROS Pharma, BILN-2061, developed by Boehringer Ingelheim, CellCept (mycophenolate mofetil), developed by Roche, T67, an inhibitor of β-tubulin developed Tularik, a therapeutic vaccine directed to E2, developed by Innogenetics, K788, developed by Fujisawa Healthcare, Inc., IdB 1016 (siliphos, oral siebenpfeiffer), inhibitors of replication of RNA (VP50406), developed by ViroPharma/Wyeth, a therapeutic vaccine developed by Intercell, a therapeutic vaccine developed by Epimmune/Genencor, IRES inhibitor developed by Anadys, ANA 245 and ANA 246, developed by Anadys, immunotherapy (Tarapur)developed Avant, a protease inhibitor developed by Corvas/SChering, inhibitor of helicase developed by Vertex, fusion inhibitor, developed by Trimeris, treatment of T cells developed CellExSys, a polymerase inhibitor, developed by Biocryst, chemical compounds targeting RNA developed by PTC Therapeutics, dication, developed by Immtech, Int., protease inhibitor developed by Agouron, a protease inhibitor developed by Chiron/Medivir, antisense therapy, developed by AVI BioPharma, antisense therapy, developed by Hybridon, blood purifier, developed by Aethlon Medical, therapeutic vaccine developed by Merix, protease inhibitor being developed by Bristol-Myers Squibb/Axys, ChronVacC, therapeutic vaccine developed by Tripep, UT 231B, developed by United Therapeutics, protease inhibitors, helicase and polymerase developed Genelabs Technologies, IRES inhibitors, developed Immusol, R803, developed by Rigel Pharmaceuticals, infergen® (interferon of alfacon-1), developed by InterMune Anaferon (PR is natural interferon), developed by Viragen, Albuferon®, developed by Human Genome Sciences, Rebif® (interferon beta-1A), developed by Ares-Serono, omega interferon, developed by BioMedicine, oral interferon alpha, developed by Amarillo Biosciences, and interferon gamma, interferon Tau, and interferon gamma-1b, developed by InterMune.

VI. The pharmaceutical composition

The hosts, including humans, infected with pestiviruses, flaviviruses, HCV, or in any other state, described here, or infected by another organism that can replicate through an RNA-dependent viral RNA polymerase, or suffering from any other described the disease can be treated by administration to the patient an effective amount of an active compound, or its pharmaceutically acceptable prodrug or salt in the presence of a pharmaceutically acceptable carrier or diluent. The active materials can be introduced in any suitable way, for example oral, parenteral, intravenous, intradermal, subcutaneous or local way, in liquid or solid form.

The preferred dose of a compound for pestivirus, flavivirus or HCV will be in the range of from about 1 to 50 mg/kg, preferably 1-20 mg/kg of body weight per day, more generally 0.1 to about 100 mg per kilogram body weight of recipient per day. May be preferable Bo is its low dose, for example, a dose of 0.5-100 mg, 0.5 to 50 mg, 0.5-10 mg, or 0.5-5 mg per kilogram of body weight per day. Can be applied even lower doses, and, therefore, the ranges may include 0.1-0.5 mg per kilogram of body weight per day. The range of effective doses pharmaceutically acceptable salts and prodrugs can be calculated based on the mass of the initial nucleoside, which must be delivered. If salt and prodrug itself has an activity effective dose can be estimated, as described above, using the mass of salt or prodrug, or other methods known to the expert in this field.

The connection is suitable manner is introduced into a unified any suitable dosage form, including but not limited to, specified, dosage form, containing 7-3000 mg, preferably 70-1400 mg of the active ingredient of the generic drug form. Usually is suitable oral dose of 50-1000 mg contained in one or more dosage forms with 50, 100, 200, 250, 300, 400, 500, 600, 700, 800, 900 or 1000 mg May be preferable lower doses, for example, from 10-100 up 1-50 mg of the Expected doses are 0.1 to 50 mg, or 0.1-20 mg, or 0.1 to 10.0 mg. in Addition, lower doses can be used in the case of the introduction of neuroretinal way, as, for example, by injection or inhalation.

In the ideal is learn the active ingredient must be introduced to achieve the peak plasma concentrations of the active compound of from about 0.2 to 70 μm, preferably, from about 1.0 to 10 μm. This can be achieved, for example, intravenous injection of a 0.1 to 5% solution of the active ingredient, optionally in saline, or the introduction of active ingredient in the form of a bolus.

The concentration of the active compounds in the composition of the medicinal product will depend on absorption, inactivation and rate of excretion of the drug, as well as other factors known to the person skilled in the art. It should be noted that the magnitude of the doses will also vary with the severity of the condition, which should be eased. In addition, it should be clear that for any particular subject charts and graphs of certain drugs must be adjusted in accordance with the needs of the patient and the professional opinion of the expert, misleading or overseeing the introduction of the compositions, and that the concentration ranges set forth herein are only exemplary and are not intended to limit the scope or practice of the claimed composition. The active ingredient can be entered one at a time or may be divided into a number of smaller doses, which must be entered through varying intervals of time.

The preferred method of introducing the active compound is an oral way. Peroral the major compositions typically contain an inert diluent or edible carrier. They can be incorporated into gelatin capsules or extruded into pellets. For the purpose of oral therapeutic injection of the active compound may be mixed with excipients and used in the form of tablets, lozenges or capsules. Pharmaceutically compatible binding agents, and/or supporting materials may be included as part of the composition.

Tablets, pills, capsules, lozenges and the like can contain any of the following ingredients, or compounds of similar nature: a binder such as microcrystalline cellulose, tragacanth gum or gelatin; excipients, such as starch or lactose; disintegrity agent, such as alginic acid, primogel or corn starch; lubricating substance, such as magnesium stearate or sterate; agent, giving a slide, such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin, or corrigent, such as peppermint, methyl salicylate or orange corrigent. When a uniform dosage form is a capsule, it contains in addition to the material specified above type, a liquid carrier such as fatty oil. In addition, standardized dosage forms can contain various other materials which modify the physical form of uniform dose,for example, coatings of sugar, shellac or other intersolubility agents.

The connection can be introduced as a component of an elixir, suspension, syrup, wafer, chewing gum or the like. A syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and corrigentov.

The compound or its pharmaceutically acceptable prodrug or salt can also be mixed with other active materials that do not weaken the desired action, or with materials that enhance the desired action, such as antibiotics, antifungal agents, anti-inflammatory agents or other anti-virus agents, including other nucleoside compounds. Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application can include the following components: a sterile diluent such as water for injection, saline solution, fatty oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methylparaben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates, and the coefficients for the regulation of toychest, such as sodium chloride or dextrose. The parenteral preparation can be enclosed in ampoules, available syringes or vials on many doses, made of glass or plastic.

When administered intravenously preferred carrier is physiological saline or phosphate buffered saline (PBS).

In a preferred embodiment, the active compounds produce media that can protect the compound against rapid removal from the body, for example in the form of a preparation with controlled release formulation, including implants and microencapsulated delivery systems. Can be used biodegradable, biocompatible polymers such as ethylene vinyl acetate polymer, polyanhydride, polyglycolic acid, collagen, polyarteritis and polylactic acid. Methods of obtaining such drugs should be known to the person skilled in the art. The materials can be obtained commercially from Alza Corporation.

Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) are also preferred as pharmaceutically acceptable carriers. They can be obtained by methods known to the person skilled in the art, for example as described in U.S. patent No. 522811 (which is incorporated herein by reference in its entirety). For example, liposomal preparations can be obtained by dissolving appropriate lipid(s) (such as stearoylethanolamine, stearoylethanolamine, arachidonylglycerol and cholesterol) in an inorganic solvent that is then evaporated to education after evaporation of a thin film of dried lipid on the surface of the container. An aqueous solution of active compound or its monophosphate, diphosphate and/or trifosfatnogo derived then injected into the container. The contents of the container then mix with turbulence manual way to release lipid material from the walls of the container and dispersion of lipid aggregates with education thereby liposomal suspension.

VII. The method of obtaining the active connections

The nucleosides of the present invention can be synthesized by any method known in this field. In particular, the synthesis of these nucleosides can be achieved either by alkylation appropriately modified sugar, followed by glycosylation or glycosylation and subsequent alkylation of the nucleoside. The following non-limiting embodiments of illustrate some General methodology of the nucleosides of the present invention.

A. Total synthesis of 1'-C-branched nucleosides

1'-C-Branched rib the nucleosides of the following structure:

where the radix, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, Y, W1, W2, W3X, X1X2and X3have the values defined here, can be obtained in one of the following General methods.

1) Modification of the lactone

The key starting material for this method is appropriately substituted lactone. The lactone can be purchased or can be obtained by any known method, including methods of epimerization, substitution and cyclization. The lactone can be optionally protected with a suitable protecting group, preferably acyl or silyl group, by methods well known to the person skilled in the art, as indicated Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991. Protected lactone can then be subjected to combination with a suitable agent combinations, such as ORGANOMETALLIC nucleophile to the carbon atom, such as a Grignard reagent, an organolithium compound, nitidulid or R6-SiMe3in TBAF with the use of a suitable non-polar solvent at a suitable temperature to obtain 1'-alkylated sugar.

Optional activated sugar can then be combined with the base by methods well known specialist in this area is, as indicated Townsend Chemistry of Nucleosides and Nucleotides, Plenum Press, 1994. For example, acylated sugar can be combined with similarbank base under the action of a Lewis acid such as tin tetrachloride, titanium tetrachloride or trimethylsilyltriflate, in a suitable solvent at a suitable temperature.

Then nuke can be freed from the protective groups by methods well known to the person skilled in the art, as indicated Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991.

In a specific embodiment, the desired compound is 1'-C-branched ribonucleosides. Synthesis of ribonucleoside shown in scheme 1. In the alternative case, the required connection is deoxyribonucleoside. To obtain these nucleosides formed ribonucleoside can optionally be protected by methods well known to the person skilled in the art, as indicated Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, and then 2'-HE can be restored to a suitable regenerating agent. 2'-Hydroxyl optional can be activated to facilitate recovery, i.e. through restoration by the method of Barton.

Scheme 1

2. An alternative way to obtain 1'-C-branched nucleosides

The key material for this method is a suitable way of replacing the military hexose. Hexose can be purchased or can be obtained by any known method, including how the standard epimerization (for example, by treatment with alkali), substitution and combination. Hexose can be selectively protected to obtain a suitable hexaferrite, as indicated Townsend Chemistry of Nucleosides and Nucleotides, Plenum Press, 1994.

1'-Hydroxyl can be optionally activated by a suitable removable group such as acetyl group or halogen, by acylation or halogenation, respectively. Optional activated sugar can then be subjected to the combination with the base means, well known to the person skilled in the art, as indicated Townsend Chemistry of Nucleosides and Nucleotides, Plenum Press, 1994. For example, acylated sugar can be combined with similarbank base under the action of a Lewis acid such as tin tetrachloride, titanium tetrachloride or trimethylsilyltriflate, in a suitable solvent at a suitable temperature. In the alternative case, halogenide can be combined with similarbank base in the presence of trimethylsilyltriflate.

Group 1'-CH2HE, if it is protected, can be selectively released from the protective group by methods well known in the field. The resulting primary hydroxyl can be functionalized to produce different C-branched n is Leonidov. For example, the primary hydroxyl can be restored with the formation of bromide using a suitable reducing agent. In the alternative case, the hydroxyl can be activated before restoring to facilitate the reaction, i.e. through the restoration by the method of Barton. In an alternative embodiment, the primary hydroxyl can be oxidized to the aldehyde, and then subjected to combination with the nucleophile to the carbon atom, such as a Grignard reagent, an organolithium compound, nitidulid or R6-SiMe3in TBAF with the use of a suitable non-polar solvent at a suitable temperature.

In a specific embodiment, the desired compound is 1'-branched ribonucleosides. Synthesis of ribonucleoside shown in scheme 2. In the alternative case, the required connection is deoxyribonucleoside. To obtain these nucleosides formed ribonucleoside can optionally be protected by methods well known to the person skilled in the art, as indicated Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, and then 2'-HE can be restored to a suitable regenerating agent. 2'-Hydroxyl optional can be activated to facilitate recovery, i.e. through restoration by the method of Barton.

Scheme 2

In addition, the L-enantiomers corresponding to the compounds of the invention may be obtained by the same General methods (1 or 2) on the basis of the corresponding L-sugars and L-nucleoside enantiomer as starting material.

C. Total synthesis of 2'-C-branched nucleosides

2'-C-Branched ribonucleosides the following structure:

where the radix, R1, R2, R3, R4, R5, R6, R7, R9, R10, Y, W1, W2, W3X, X1X2and X3have the values defined here, can be obtained in one of the following General methods.

1. Glycosylation of the base of the nucleoside appropriately modified sugar.

The key starting material for this method is the appropriately substituted the sugar with the 2'-OH, 2'-H and removed with a suitable group (LG), for example, acyl group or halogen. Sugar can be purchased or can be obtained by any known method, including standard methods of epimerization, substitution, oxidation and reduction. Substituted sugar can then be oxidized with a suitable oxidizing agent in a compatible solvent at a suitable temperature to obtain 2'-modified sugar. Possible oxidizing agents are Jones reagent (a mixture of chromic acid is you and sulfuric acid), the Collins reagent (dipyridine(VI)oxide), reagent Measles (chlorproma pyridinium, pyridinium dichromate, acid dichromate, potassium permanganate, MnO2, ruthenium tetroxide, catalysts migration phases, such as chromic acid or permanganate deposited on a polymeric carrier, Cl2-pyridine, N2About2-molybdate of ammonium, NaBrO2-CAN, NaOCl in HOAc, copper chromite, copper oxide, Raney Nickel, palladium acetate, reagent of Meerwein-Pondorf-Verley (tert-piperonyl aluminum with another ketone) and N-bromosuccinimide.

Then the combination of ORGANOMETALLIC nucleophile to the carbon atom, such as a Grignard reagent, an organolithium compound, nitidulid or R6-SiMe3in TBAF with the ketone with a suitable non-polar solvent at a suitable temperature to obtain 2'-alkilirovanny sugar. Alkilirovanny sugar can be optionally protected with a suitable protecting group, preferably acyl or silyl group, by methods well known to the person skilled in the art, as indicated Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991.

Optional activated sugar can then be subjected to the combination with the base means, well known to the person skilled in the art, as indicated Townsend Chemistry of Nucleosides and Nucleotides, Plenum Press, 1994. For example, acylated sugar can combin is e s similarbank base under the action of a Lewis acid such as tin tetrachloride, titanium tetrachloride or trimethylsilyltriflate, in a suitable solvent at a suitable temperature. In the alternative case, halogenide can be combined with similarbank base in the presence of trimethylsilyltriflate.

Then nuke can be freed from the protective groups by methods well known to the person skilled in the art, as indicated Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991.

In a specific embodiment, the desired compound is a 2'-branched ribonucleosides. Synthesis of ribonucleoside shown in scheme 3. In the alternative case, the required connection is deoxyribonucleoside. To obtain these nucleosides formed ribonucleoside can optionally be protected by methods well known to the person skilled in the art, as indicated Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, and then 2'-HE can be restored to a suitable regenerating agent. 2'-Hydroxyl optional can be activated to facilitate recovery, i.e. through restoration by the method of Barton.

Scheme 3

2. Modification of pre-formed nuke.

The key starting material for this method is the appropriately substituted nucleoside 2'-OH, 2'-H. Nucleos the d can be purchased or can be obtained by any known method, includes standard ways of combination. The nucleoside can be optionally protected with suitable protective groups, preferably acyl or silyl group, by methods well known to the person skilled in the art, as indicated Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991.

Suitable protected nucleoside can then be oxidized with a suitable oxidizing agent in a compatible solvent at a suitable temperature to obtain 2'-modified sugar. Possible oxidizing agents are Jones reagent (a mixture of chromic acid and sulfuric acid), Collins reagent (dipyridine(VI)oxide), reagent Measles (chlorproma pyridinium, pyridinium dichromate, acid dichromate, potassium permanganate, MnO2, ruthenium tetroxide, catalysts migration phases, such as chromic acid or permanganate deposited on a polymeric carrier, Cl2-pyridine, N2About2-molybdate of ammonium, NaBrO2-CAN, NaOCl in HOAc, copper chromite, copper oxide, Raney Nickel, palladium acetate, reagent of Meerwein-Pondorf-Verley (tert-piperonyl aluminum with another ketone) and N-bromosuccinimide.

Then nuke can be freed from the protective groups by methods well known to the person skilled in the art, as indicated Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991.

In a specific embodiment, assests is of the desired compound is a 2'-branched ribonucleosides. Synthesis of ribonucleoside shown in scheme 4. In the alternative case, the required connection is deoxynucleoside. To obtain these nucleosides formed ribonucleoside can optionally be protected by methods well known to the person skilled in the art, as indicated Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, and then 2'-HE can be restored to a suitable regenerating agent. 2'-Hydroxyl optional can be activated to facilitate recovery, i.e. through restoration by the method of Barton.

Scheme 4

In another embodiment, the desired compounds are L-enantiomers. Therefore, the L-enantiomers corresponding to the compounds of the invention may be obtained such as the above-mentioned General methods based on the corresponding L-sugars and L-nucleoside enantiomer as starting material.

S. Total synthesis of 3'-C-branched nucleosides

3'-C-Branched ribonucleosides the following structure:

where the radix, R1, R2, R3, R4, R5, R6, R7, R8, R9, Y, W1, W2, W3X, X1X2and X3have the values defined here, can be obtained in one of the following General methods.

1. Glycosylation basis of the project of nucleoside appropriately modified sugar.

The key starting material for this method is the appropriately substituted sugar with 3'-OH, 3'-H and removed with a suitable group (LG), for example, acyl group or halogen. Sugar can be purchased or can be obtained by any known method, including standard methods of epimerization, substitution, oxidation and reduction. Substituted sugar can then be oxidized with a suitable oxidizing agent in a compatible solvent at a suitable temperature with 3'-modified sugar. Possible oxidizing agents are Jones reagent (a mixture of chromic acid and sulfuric acid), Collins reagent (dipyridine(VI)oxide), reagent Measles (chlorproma pyridinium, pyridinium dichromate, acid dichromate, potassium permanganate, MnO2, ruthenium tetroxide, catalysts migration phases, such as chromic acid or permanganate deposited on a polymeric carrier, Cl2-pyridine, N2About2-molybdate of ammonium, NaBrO2-CAN, NaOCl in HOAc, copper chromite, copper oxide, Raney Nickel, palladium acetate, reagent of Meerwein-Pondorf-Verley (tert-piperonyl aluminum with another ketone) and N-bromosuccinimide.

Then the combination of ORGANOMETALLIC nucleophile to the carbon atom, such as a Grignard reagent, an organolithium compound, nitidulid or R6-SiMe3in TBAF with the ketone and with the use of a suitable non-polar solvent at a suitable temperature to obtain 3'-C-branched sugar. 3'-C-Branched sugar can be optionally protected with a suitable protecting group, preferably acyl or silyl group, by methods well known to the person skilled in the art, as indicated Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991.

Optionally protected sugar can then be subjected to the combination with the base means, well known to the person skilled in the art, as indicated Townsend Chemistry of Nucleosides and Nucleotides, Plenum Press, 1994. For example, acylated sugar can be combined with similarbank base under the action of a Lewis acid such as tin tetrachloride, titanium tetrachloride or trimethylsilyltriflate, in a suitable solvent at a suitable temperature. In the alternative case, halogenide can be combined with similarbank base in the presence of trimethylsilyltriflate.

Then nuke can be freed from the protective groups by methods well known to the person skilled in the art, as indicated Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991.

In a specific embodiment, the desired compound is 3'-C-branched ribonucleosides. Synthesis of ribonucleoside shown in scheme 5. In the alternative case, the required connection is deoxyribonucleoside. To obtain these nucleosides formed ribonucleoside can neobyazatel is to protect ways, well-known specialist in this field, as indicated Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, and then 2'-HE can be restored to a suitable regenerating agent. 2'-Hydroxyl optional can be activated to facilitate recovery, i.e. through restoration by the method of Barton.

Scheme 5

2. Modification of pre-formed nuke

The key starting material for this method is the appropriately substituted nucleoside 3'-OH, 3'-H. Nucleoside can be purchased or can be obtained by any known method, including methods of combination. The nucleoside can be optionally protected with suitable protective groups, preferably acyl or silyl group, by methods well known to the person skilled in the art, as indicated Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991.

Appropriately protected nucleoside can then be oxidized with a suitable oxidizing agent in a compatible solvent at a suitable temperature to obtain 2'-modified sugar. Possible oxidizing agents are Jones reagent (a mixture of chromic acid and sulfuric acid), Collins reagent (dipyridine(VI)oxide), reagent Measles (chlorproma pyridinium, pyridinium dichromate, acid is Achromat, the potassium permanganate, MnO2, ruthenium tetroxide, catalysts migration phases, such as chromic acid or permanganate deposited on a polymeric carrier, Cl2-pyridine, N2About2-molybdate of ammonium, NaBrO2-CAN, NaOCl in HOAc, copper chromite, copper oxide, Raney Nickel, palladium acetate, reagent of Meerwein-Pondorf-Verley (tert-piperonyl aluminum with another ketone) and N-bromosuccinimide.

Then nuke can be freed from the protective groups by methods well known to the person skilled in the art, as indicated Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991.

In a specific embodiment, the desired compound is 3'-C-branched ribonucleosides. Synthesis of ribonucleoside shown in scheme 6. In the alternative case, the required connection is deoxyribonucleoside. To obtain these nucleosides formed ribonucleoside can optionally be protected by methods well known to the person skilled in the art, as indicated Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, and then 2'-HE can be restored to a suitable regenerating agent. 2'-Hydroxyl optional can be activated to facilitate recovery, i.e. through restoration by the method of Barton.

Scheme 6

In another embodiment, the desired joint the mi are the L-enantiomers. Therefore, the L-enantiomers corresponding to the compounds of the invention may be obtained such as the above-mentioned General methods based on the corresponding L-sugars and L-nucleoside enantiomer as starting material.

D. Total synthesis of 4'-C-branched nucleosides

4'-C-Branched ribonucleosides the following structure:

where the radix, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, Y, W1, W2, W3X, X1X2and X3have the values defined here, can be obtained in one of the following General methods.

1. Modification pentavalent

The key starting material for this method is the appropriately substituted pentadienylboranes. Pentadienylboranes can be purchased or can be obtained by any known method, including standard methods of epimerization, substitution and cyclization.

In a preferred embodiment, pentadienylboranes obtained from appropriately substituted hexose. Hexose can be purchased or can be obtained by any known method, including standard methods of epimerization (for example, by alkaline treatment), substitution and combination. Hexose can be either in the form of furano is s or cyklinowanie by any method, known in this field, such as the methodology described Townsend Chemistry of Nucleosides and Nucleotides, Plenum Press, 1994, preferably, selective protection hexose with obtaining appropriate hexaferrite.

4'-Hydroxymethylene hexaferrite can then be oxidized with a suitable oxidizing agent in a compatible solvent at a suitable temperature to obtain 4'-allmodifications sugar. Possible oxidizing agents are reagents Swarna, Jones reagent (a mixture of chromic acid and sulfuric acid), Collins reagent (dipyridine(VI)oxide), reagent Measles (chlorproma pyridinium, pyridinium dichromate, acid dichromate, potassium permanganate, MnO2, ruthenium tetroxide, catalysts migration phases, such as chromic acid or permanganate deposited on a polymeric carrier, Cl2-pyridine, N2About2-molybdate of ammonium, NaBrO2-CAN, NaOCl in HOAc, copper chromite, copper oxide, Raney Nickel, palladium acetate, reagent Meerwein-Pondorf-Verley (tert-piperonyl aluminum with another ketone) and N-bromosuccinimide, although preferred is the use of H3PO4, DMSO and DCC in a mixture of benzene/pyridine at room temperature.

Then pentadienylboranes can be optionally protected with a suitable protecting group, preferably acyl or silyl group, by methods well known specialist is in this area, as indicated Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991. In the presence of a base such as sodium hydroxide, protected pentadienylboranes can then be combined with a suitable electrophilic alkyl, halogenation (for example, CF3), alkenyl or quinil (e.g., allyl) to obtain 4'-alkylated sugar. Alternatively, protected pentadienylboranes can be combined with the appropriate compound containing a carbonyl, such as formaldehyde, in the presence of a base such as sodium hydroxide, in a suitable polar solvent, such as dioxane, at a suitable temperature, the product combination can then restore suitable regenerating agent to obtain 4'-alkylated sugar. In one embodiment, the restore is performed using PhOC(S)Cl, DMAP, preferably in acetonitrile, at room temperature, followed by processing ACCN and TMSS when boiling under reflux in toluene.

Optional activated sugar can then be combined with the base means, well known in this area, as indicated Townsend Chemistry of Nucleosides and Nucleotides, Plenum Press, 1994. For example, acylated sugar can be combined with similarbank base under the action of a Lewis acid such as tin tetrachloride, titanium tetrachloride or trimate silicrylic, in a suitable solvent at a suitable temperature.

Then nuke can be freed from the protective groups by methods well known to the person skilled in the art, as indicated Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991.

In a specific embodiment, the desired compound is 4'-C-branched ribonucleosides. In the alternative case, the required connection is deoxyribonucleoside. To obtain these deoxyribonucleosides educated ribonucleoside can be optionally protected by methods well known to the person skilled in the art, as indicated Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, and then 2'-HE can be restored to a suitable regenerating agent. 2'-Hydroxyl optional can be activated to facilitate the reaction, i.e. by restoring the reaction Barton.

In another embodiment of the invention, the desired compounds are L-enantiomers. Therefore, the L-enantiomers corresponding to the compounds of the invention may be obtained such as the above-mentioned General methods based on the corresponding L-pentavalent as source material.

That is, the Total synthesis of 2'- and/or 3'-prodrugs

The key starting material for this method is the appropriately substituted 1', 2', 3' Il is 4'-branched β-D or β-L-nucleosides. Branched nucleoside can be purchased or can be obtained by any known method, including the methods described here. Branched nucleoside can be optionally protected with a suitable protecting group, preferably, a silyl group, by methods well known to the person skilled in the art, as indicated Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991. Protected branched nucleoside can then be combined with a suitable acyl donor, such as acylchlorides or acid anhydride, in a suitable proton or an aprotic solvent at a suitable temperature to obtain 2'- and/or 3'-prodrugs of 1',2',3' or 4'-branched β-D or β-L-nucleoside. Alternatively protected branched nucleoside can then be combined with appropriate introducing the acyl compound such as carboxylic acid, the introduction of such acyl as acyl alanovoy acid and/or amino acids, optionally, in the presence of a suitable agent combination, in a suitable aprotic solvent at a suitable temperature to obtain 2'- and/or 3'-prodrugs of 1',2',3' or 4'-branched β-D or β-L-nucleoside. Possible reagents combinations are any reagents that promotirovat combinations and include, but are not limited to, reagents, Mitsunobu (for example, Diisopropylamine the Silat and diethylazodicarboxylate) with triphenylphosphine or different carbodiimide.

For example, aminoalcohols, you can simply atrificial using acid chlorides of the acids in boiling under reflux a mixture of acetonitrile-benzene (see the following scheme 7: publication Synthetic Communications, 1978, 8(5), 327-333 included so as a reference). Alternatively, the esterification may be conducted using anhydride, as described in the publication J. Am. Chem. Soc., 1999, 121(24), 5661-5664, which included this image as a reference. Cm. figures 2, 3 and 4.

Scheme 7

ACN: acetonitrile

The present invention is described by way of illustration in the following examples. The average person skilled in the art should be understood that these examples are in no way limiting and that can be done variations of details, not beyond being and scope of the present invention.

EXAMPLE 1: Obtain 1'-C-methylephedrine using 6-amino-9-(1-deoxy-β-D-psychogenesis)purine

The melting point was determined on the device Mel-temp II and not corrected. NMR spectra were recorded on a spectrometer Bruker AMX 400 at 400 MHz for1H NMR and 100 MHz for13With NMR using TMS as internal standard. Chemical shifts (δ) are indicated in parts per million (ppm) and the signals are indicated as s (singlet), d (doublet), t (triplet), q (Quartet), m (mu is tiplet) or user. with (broadened singlet). IR spectra were measured on an infrared spectrometer Nicolet 510P with FT (Converter Fourier). Mass spectra were recorded on a mass spectrometer high resolution Micromass Autospec. TLC was carried out on Uniplates (silica gel)purchased from Analtech Co. Column chromatography was performed using either silica gel-60 (220-440 mesh) for flash chromatography or silica gel G for TLC grade, > 440 mesh) for vacuum column flash chromatography. UV spectra were obtained on a spectrophotometer Beckman DU 650. Elemental analysis was performed Atlantic Microlab, Inc., Norcross, GA, or Galbraith Laboratories, Inc., Knoxville TN. HPLC was carried out on the system Waters HPLC (Millipore Corporation, Milford, MA)equipped with a regulator Model 600, photodiode array detector Model 996 and automatic sampler Model 717 plus. For control systems, data acquisition and processing software has been used Millennium 2010. To determine the optical rotation was used charlatanry polarimetric detector polarimeter Perkin-Elmer, model MS (Wilton, CT).

Synthesis of 1'-With-Metallbau-8-methyladenine

Specified in the title compound can also be obtained in accordance with the published method (J. Farkas, and F. Sorm, "Nucleic acid components and their analogues. XCIV. Synthesis of 6-amino-9-(l-deoxy-β-D-psicofuranosyl)purine Collect. Czech. Chem. Commun. 1967, 32, 2663-2667; J. Farkas, Collect. Czech. Chem. Commun. 1966, 31,1535) (Scheme 8).

Scheme 8

The same clicks the zoom, but, using the appropriate sugar and purine bases receive the following nucleosides of formula XXIV.

where R1, R2, R3X1X2and Y have the values defined here.

Alternatively, using the appropriate sugar and pyrimidine bases receive the following nucleosides of formula XXV:

where R1, R2, R3X1X2and Y have the values defined here.

Alternatively, using the appropriate sugar and pyrimidine or purine bases receive the following nucleosides of formula XXVI

where R1, R2, R3, R6X and base have the values defined here.

Alternatively, using the appropriate sugar and pyrimidine or purine bases receive the following nucleosides of formula XXVII

where R1, R2, R6X and base have the values defined here.

Alternatively, using the appropriate sugar and pyrimidine or purine bases receive the following nucleosides of formula XXVIII

where R1, R2, R6X and base have the values defined here.

In an alternative slouches using the appropriate sugar and pyrimidine or purine bases receive the following nucleosides of formula XXIX

where R1, R6, R7, R8, X, R9, R10and the base have the values defined here.

EXAMPLE 2: Obtaining 2'-C-Metallbau-8-methyladenine

Specified in the header connection receive in accordance with the published method (R.E. Harry-O kuru, J.M. Smith, and M.S. Wolfe, “A short, flexible route toward 2'-C-branched ribonucleosides”, J. Org. Chem. 1997, 62, 1754-1759) (Scheme 9).

Scheme 9

(a) Periodical Dess-Martina; (b) MeMgBr/TiCl4; (c) BzCl, DMAP, Et3N; (d) bis(trimethylsilyl)acetamide", she N6-benzyladenine, TMSOTf; (e) NH3/MeOH.

3'-Prodrug of 2'-branched nucleoside receive in accordance with the published method (Synthetic Communications, 1978, 8(5), 327-333; J. Am. Chem. Soc., 1999, 121(24), 5661-5664). In the alternative case of a 2'-branched nucleoside can be esterified without protection (scheme 9b). Carbonyldiimidazole (377 mg, of 2.33 mmol) are added to a solution of N-(tert-butoxycarbonyl)-L-valine (507 mg, of 2.33 mmol) in 15 ml of anhydrous tetrahydrofuran. The mixture is stirred at 20°C for one hour and at 50°C for 10 minutes and then added to a solution of 4-amino-1-(3,4-dihydroxy-5-hydroxymethyl-3-methyltetrahydrofuran-2-yl)-1H-pyrimidine-2-she (500 mg, of 1.95 mmol), 4-(dimethylamino)pyridine (25 mg, of € 0.195 mmol), triethylamine (5 ml) in anhydrous N,N-dimethylformamide (10 ml), which was stirred at 50 the C. The reaction mixture was stirred at 50°C for one hour and then analyzed HPLC. The HPLC analysis shows the formation of 52% of the desired complex ester, 17% of the original material in addition to unwanted side products. 3'-Oh 4-amino-1-(3,4-dihydroxy-5-hydroxymethyl-3-methyltetrahydrofuran-2-yl)-1H-pyrimidine-2-he has a tendency to selectively interact when combined with BOC-Val.

Similarly, but using the appropriate sugar and purine bases receive the following nucleosides of formula XXX

where R1, R2, R3X1X2and Y have the values defined here.

Alternatively, using the appropriate sugar and pyrimidine bases receive the following nucleosides of formula XXXI

where R1, R2, R3X1X2and Y have the values defined here.

Alternatively, using the appropriate sugar and pyrimidine or purine bases receive the following nucleosides of formula XXXII

where R1, R2, R3, R6X and base have the values defined here.

Alternatively, using the appropriate sugar and pyrimidine or purine bases receive the following nucleosides of formula XXXIII

where R1, R2, R6X and base have the values defined here.

Alternatively, using the appropriate sugar and pyrimidine or purine bases receive the following nucleosides of formula XXXIV

where R1, R2, R6X and base have the values defined here.

Alternatively, using the appropriate sugar and pyrimidine or purine bases receive the following nucleosides of formula XXXV

where R1, R6, R7, R9, R10X and base have the values defined here.

EXAMPLE 3: Obtaining 3'-To-Metallbau-8-methyladenine

Specified in the title compound can be obtained in accordance with the published method (R.F. Nutt, M.J. Dickinson, F. W. Holly and E. Walton, “Branched-chain sugar nucleosides. III. 3'-C-methyladenin”, J. Org. Chem. 1968, 33, 1789-1795) (scheme 10).

Scheme 10

(a) RUO Li2/NaIO4; (b) MeMgI/TiCl4; (c) HCl/MeOH/H2O; (d) BzCl/pyridine; (e) AcBr, HBr/AcOH; (f) hartati(II)-6-benzamidophenyl; (g) NH3/MeOH.

Similarly, but using the appropriate sugar and purine bases receive the following nucleosides of formula XXXVI

where R1, R2, R3X1X2and Y have the values defined here.

In the Alt ERN case, using the appropriate sugar and pyrimidine bases receive the following nucleosides of formula XXXVII

where R1, R2, R3X1X2and Y have the values defined here.

Alternatively, using the appropriate sugar and pyrimidine or purine bases receive the following nucleosides of formula XXXVIII

where R1, R2, R3, R6X and base have the values defined here.

Alternatively, using the appropriate sugar and pyrimidine or purine bases receive the following nucleosides of formula XXXIX

where R1, R2, R6X and base have the values defined here.

Alternatively, using the appropriate sugar and pyrimidine or purine bases receive the following nucleosides of formula XXXX

where R1, R2, R6X and base have the values defined here.

Alternatively, using the appropriate sugar and pyrimidine or purine bases receive the following nucleosides of formula XXXXI

where R1, R6, R7, R8, R9X and base have the values defined here.

EXAMPLE 4: Obtain 1-O-methyl-2,3-O-isopropylidene-β-D-ribofuranose - (1)

Specified in the header joint which can be obtained in accordance with the published method (Leonard, N.J. Carraway, K.L. “5-Amino-5-deoxyribose derivatives. Synthesis and use in the preparation of “reversed” nucleosides” J. Heterocycl. Chem. 1966, 3, 485-489).

A solution of 50.0 g (0.34 mol) of dry D-ribose in 1.0 l of acetone, 100 ml of 2,2-dimethoxypropane, 200 ml of methanol containing 20 ml of methanol saturated with hydrogen chloride at 0°C, stirred overnight at room temperature. The resulting solution is neutralized with pyridine and evaporated under reduced pressure. The resulting oil is partitioned between 400 ml of water and 400 ml of methylene chloride. The aqueous layer was extracted twice with methylene chloride (400 ml). The combined organic extracts dried over sodium sulfate and evaporated under reduced pressure. The residue is purified column chromatography on silica gel [eluent: stepwise gradient of methanol (1-2%) in methylene chloride], thus obtaining the pure I (52.1 g, 75%) as a yellow syrup.1H-NMR (CDCl3): δ 5,00 (c, 1H, H-1), a 4.86 (d, 1H, H-2, J2-3=5,9 Hz), br4.61 (d, 1H, H-3, J3-2=5,9 Hz), 4,46 (t, 1H, H-4, J4-5=2.7 Hz), of 3.77-3,61 (m, 2H, H-5 and H-5'), of 3.46 (s, 1H, OCH3), a 3.0-2,4 (Sirs, 1H, OH-5)and 1.51 (s, 3H, CH3), of 1.34 (s, 3H, CH3); MS (matrix GT): FAB > 0 m/z 173 (M-OCH3)+.

EXAMPLE 5: Receiving 1-O-methyl-2,3-O-isopropylidene-β-D-pentadienylboranes - (2)

Specified in the header connection receive in accordance with the published method (Jones, G. H.; Moffatt, J. G. Oxidation of carbohydrates by the sulfoxide-carbodiimide and related methods. Oxidation with dicyclohexylcarbodiimide-DMSO, diisopropycarbodiimide-DMSO, acetic anhydride-DMSO, and phosphorus pentoxide-DMSO: in Methods in Carbohydrate Chemistry; Whisler, R. L. and Moffatt, J. L. Eds; Academic Press: New York, 1972; 315-322).

Compound 1 twice evaporated with anhydrous pyridine. To a solution of 1 (68,2 g, 0.33 mol) in anhydrous benzene (670 ml), DMSO (500 ml) and pyridine (13.4 ml) add dicyclohexylcarbodiimide (DCC, 137,8 g, 0.67 mol). To the resulting solution, cooled to 0°C., add a solution of anhydrous crystalline orthophosphoric acid (16.4 g, 0,167 mmol) in anhydrous DMSO (30 ml). The mixture is stirred for 1.5 hours at 0°C and 18 hours at room temperature in an argon atmosphere, diluted with ethyl acetate (1000 ml). Add a solution of oxalic acid dihydrate (63,1 g, 0.38 mol) in DMSO (30 ml) and the reaction mixture was stirred at room temperature for 1 hour and then filtered to remove precipitated dicyclohexylamine (DCU). The filtrate is concentrated to a volume of approximately 600 ml under reduced pressure and neutralized with a saturated aqueous solution of sodium bicarbonate (400 ml). Add a saturated solution of salt (200 ml) and the organic layer extracted with ethyl acetate (4 x 1000 ml). The combined organic layers are concentrated to a volume of about 2000 ml, washed with saturated aqueous sodium bicarbonate (2 × 700 ml) and saturated salt solution (2 × 700 ml) before drying over sodium sulfate and evaporated under reduced pressure is I. A small portion of the crude residue purified by chromatography on silica gel [eluent: chloroform/ethyl ether, 8:2], to confirm the structure of compound 2, which is obtained as a yellow solid.1H-NMR (CDCl3): δ being 9.61 (s, 1H, H-5), 5,12 (s, 1H, H-1), to 5.08 (d, 1H, H-2, J2-3=5,9 Hz), a 4.53 (d, 1H, H-3, J3-2=6,0 Hz), 4,51 (s, 1H, H-4), of 3.48 (s, 1H, OCH3), and 1.56 (s, 3H, CH3), of 1.36 (s, 3H, CH3); MC (matrix GT): FAB > 0 m/z 203 (M+H)+, 171 (M-10 OCH3)+.

EXAMPLE 6: Obtain 4-C-hydroxymethyl-1-O-methyl-2,3-O-isopropylidene-β-D-ribofuranose - (3)

Specified in the title compound can be obtained in accordance with the published method (Leland, D. L.; Kotick, M. P., "Studies on 4-C-(hydroxymethyl)pentofuranoses. Synthesis of 9-[4-C-(hydroxymethyl)-a-L-threo-pentofuranosyl]adenine"Carbohydr. Res. 1974, 38, C9-C11; Jones, G. H.; Taniguchi, M.; Tegg, D.; Moffatt, J. G. of 4'-substituted nucleosides, 5. Hydroxylation of nucleoside 5'-aldehydes"J. Org. Chem.1979, 44, 1309-1317; Gunic, E.; Girardet, J.-L.; Pietrzkowski, Z.; Esler, C.; Wang, G. "Synthesis and cytotoxicity of 4'-C - and 5'-C-substituted Tovocamvcins"Bioorg, Med. Chem.2001, 9, 163-170).

To a solution of the crude material (2)obtained above, and 37% aqueous formaldehyde (167 ml) in dioxane (830 ml) is added aqueous sodium hydroxide (2 n, 300 ml). The mixture is stirred at room temperature for 4 hours and neutralized by adding demeksa 50 W X 2 (H+-form). The resin is separated by filtration, washed with methanol and the combined filtrates are concentrated to dryness and evaporated several times with absolue is ethanol. Formate sodium, which is precipitated from absolute ethanol is removed by filtration, the filtrate is concentrated to dryness and the residue purified column chromatography on silica gel [eluent: stepwise gradient of methanol (0-4%) in chloroform], thus obtaining the compound 3 (42.2 g, 54% of 1), which is recrystallized from cyclohexane. So pl. = 94-95 (decomp.) (lit. data: 94-96,5; 97-98: references: 3, 4),1H-NMR (DMSO-d6): δ 4,65 (s, 1H, H-1), of 4.44-4,37 (m, 3H, H-2, H-3 and OH-6), 4,27 (t, 1H, OH-5, J=5.6 Hz, J=6.0 Hz), 3,42-to 3.34 (m, 2H, H-5 and H-6), 3,29 (DD, 1H, H-5', J5'-OH=5.4 Hz, J5-5'=to 11.4 Hz), 3,11 (DD, 1H, H-6', J6'-OH=5.7 Hz, J6-6'=10,9 Hz), 3,03 (s, 3H, OCH3), 1,48 (c, 3H CH3), of 1.05 (s, 3H CH3); MC (matrix GT): FAB > 0 m/z 469 (2M+H)+, 235 (M+H)+, 203 (M-OCH3)+ FAB<0 m/z 233 (M-H)-.

EXAMPLE 7: Obtain 6-O-monoethoxylate-4-C-hydroxymethyl-1-O-methyl-2,3-diisopropylidene-β-D-ribofuranose - (4)

Specified in the title compound can be obtained in accordance with the published method (Gunic, E.; Girardet, J.-L.; Pietrzkowski, Z.; Esler, C.; Wang, G. “Synthesis and citotoxicity of 4'-C - and 5'-C-substituded Toyocamycins” Bioorg. Med. Chem. 2001, 9, 163-170).

To a solution of 3 (41,0 g, 175 mmol) in pyridine (700 ml) is added in portions dimethoxytrityl (60,5 g, 178 mmol) at +4°C. the Reaction mixture is stirred for 3 hours at room temperature. After adding methanol, the reaction mixture was concentrated (200 ml) and then dissolved in ethyl acetate (2 liters). The PR is anceschi layer was washed with 5% aqueous sodium hydrogen carbonate solution, with water and dried over sodium sulfate and then evaporated to dryness. Purification of column chromatography on silica gel [eluent: ethyl acetate/hexane, 15/85] gives a pure compound 4 (63,0 g, 68%) as syrup.1H-NMR (CDCl3): δ 7.5 to 6,9 (m, 13H, MMTr), 4,89 (s, 1H, H-1), 4,72-to 4.62 (m, 3H, H-2, H-3 and OH-5), 3,82 (DD, 1H, H-5, J5-OH=5.5 Hz, J5-5'=10.5 Hz), 3,79 (s, 6H, OCH3), of 3.54 (DD, 1H, H-5', J5'-OH=4,9 Hz, J5'-5=10.5 Hz), and 3.31 (s, 3H, OCH3), 3,24 (d, 1H, H-6, J6-6'=9,2 Hz), 3,13 (d, 1H, H-6', J6'-6=9,2 Hz), 1,24 (s, 3H, CH3)and 1.15 (s, 3H CH3); MS (matrix GT): FAB > 0 m/z 303 (DMTr)+.

EXAMPLE 8: Obtain 5-O-benzoyl-4-C-hydroxymethyl-1-O-methyl-2,3-O-isopropylidene-β-D-ribofuranose - (5)

Specified in the title compound can be obtained in accordance with the published method (Gunic, E.; Girardet, J.-L.; Pietrzkowski, Z.; Esler, C.; Wang, G. “Synthesis and citotoxicity of 4'-C - and 5'-C-substituded Toyocamycins” Bioorg. Med. Chem. 2001, 9, 163-170).

To a solution of 4 (of 2.51 g, and 4.68 mmol) in anhydrous pyridine (37 ml) is added in an atmosphere of argon benzoyl chloride (1,09 ml, 9,36 mmol) and the reaction mixture was stirred for 13 hours at room temperature. Then the reaction mixture was cooled to 0°C and the reaction stopped by ice water (100 ml). The aqueous layer was extracted with methylene chloride (3 x 200 ml). The combined organic layers washed with saturated aqueous sodium hydrogen carbonate (2 x 150 ml), water (1 x 150 ml) and then dried over sodium sulfate and arevut under reduced pressure. The residue is dissolved in 80% acetic acid (70,2 ml) and the mixture is stirred at room temperature for 3 hours and concentrated to dryness. Purification of column chromatography on silica gel [eluent: chloroform] to give pure compound 5 (1.40 g, 88%) as syrup.1H-NMR (CDCl3): δ of 8.1 to 7.4 (m, 5H, C6H5CO)5,08 (c, 1H, H-1), of 4.77 (DD, 2H, H-2 and H-3, J=6,1 Hz, J=8,2 Hz), 4,51 (kV, 2H, H-5 and H-5', J=11.5 Hz, J5-5'=23,8 Hz), 3,91 (t, 2H, H-6 and H-6', J=12.3 Hz), to 4.38 (s, 1H, OCH3), 2,2-1,8 (USS, 1H, OH-6), of 1.57 (s, 3H, CH3), to 1.38 (s, 3H, CH3); MS (matrix GT): FAB > 0 m/z 677 (2M+H)+, 339 (M+H)+, 307 (M-OCH3)+, 105 (C6H5CO)+FAB<0 m/z 121 (C6H5CO2)-.

EXAMPLE 9: Obtain 5-O-benzoyl-4-C-methyl-1-O-methyl-2,3-O-isopropylidene-β-D-ribofuranose - (6)

Specified in the title compound can be obtained in accordance with the published method (Gunic, E.; Girardet, J.-L.; Pietrzkowski, Z.; Esler, C.; Wang, G. “Synthesis and citotoxicity of 4'-C - and 5'-C-substituted Toyocamycins” Bioorg. Med. Chem. 2001, 9, 163-170).

A solution of 5 (37.6 g, 0,111 mol), 4-dimethylaminopyridine (DMAP, of 40.7 g of 0.333 mol) and phenoxythiocarbonyl in anhydrous acetonitrile (1000 ml) was stirred at room temperature for 1 hour and concentrated to dryness. The residue is dissolved in methylene chloride (500 ml) and sequentially washed with 0.2 M hydrochloric acid (2 x 500 ml) and water (500 ml) before drying over sodium sulfate, evaporated under reduced pressure is evaporated several times with anhydrous toluene. The crude material was dissolved in anhydrous toluene (880 ml) and added Tris(trimethylsilyl)silane (TMSS, 42.9 ml, 0,139 mol) and 1,1'-azobis(cyclohexanecarbonitrile) (ACCN, 6.8 g, 27.8 mmol). The reaction mixture is stirred at the boil under reflux for 45 minutes, cooled to room temperature and concentrate under reduced pressure. The resulting residue is purified column chromatography on silica gel [eluent: stepwise gradient of diethyl ether (5-20%) in petroleum ether], thus obtaining a pure compound 6 (26,4 g, 74%) as a pale yellow syrup.1H-NMR (DMSO-d6): δ 8,0-7,5 (m, 5H, C6H5CO), is 4.85 (s, 1H, H-1), 4,63 (DD, 2H, H-2 and H-3, J=6,1 Hz, J=11,6 Hz), 4,24 (d, 1H, H-5, J5-5'=11,1 Hz), 4,10 (d, 1H, H-5', J5'-5=11,1 Hz), 3,17 (s, 1H, OCH3), to 1.38 (s, 3H, CH3), of 1.30 (s, 3H, CH3), 1,25 (s, 3H, CH3); MS (matrix GT): FAB > 0 m/z 291 (M-OCH3)+, 105 (C6H5CO)+FAB<0 m/z 121 (C6H5CO2)-.

EXAMPLE 10: Obtain 5-O-benzoyl-4-C-methyl-1,2,3-O-acetyl-α,β-D-ribofuranose - (7)

Compound 6 (22,5 g, 70 mmol) is suspended in 80% aqueous acetic acid solution (250 ml). The solution is heated at 100°C for 3 hours. The volume then reduce by half and evaporated with absolute ethanol and pyridine. The oily residue is dissolved in pyridine (280 ml) and then cooled to 0°C. Add acetic anhydride (80 ml) and 4-dimethyl shall aminopyridin (500 mg). The reaction mixture was stirred at room temperature for 3 hours and then concentrated under reduced pressure. The residue is dissolved in ethyl acetate (1 l) and washed sequentially with saturated aqueous sodium bicarbonate, 1 M hydrochloric acid and water. The organic layer is dried over sodium sulfate and evaporated under reduced pressure. The resulting residue is purified column chromatography on silica gel [eluent: stepwise gradient of diethyl ether (30-40%) in petroleum ether], thus obtaining a pure compound 7 (16.2 g, 60%) as light yellow syrup. A small portion of the material re-purified by chromatography on silica gel [same system as eluent] to separate α - and β-anomers.

α-Anomer:1H-NMR (DMSO-d6): δ 8,1-7.5 (m, 5H, C6H5CO), 6,34 (PT, 1H, H-1, J=2.4 Hz, J=2.1 Hz), 5,49 (m, 2H, H-2 and H-3), to 4.33 (q, 2H, H-5 and H-5', J=11,6 Hz, J=18.7 Hz), of 2.15 (s, 3H, CH3CO2), 2,11 (s, 3H, CH3CO2), 2,07 (s, 3H, CH3CO2), to 1.37 (s, 3H, CH3); MS (matrix GT): FAB > 0 m/z 335 (M-CH3CO2-)+, 275 (M-CH3CO2-+H)+, 105 (C6H5CO)+, 43 (CH3CO)+FAB<0 m/z 121 (C6H5CO2)-, 59 (CH3CO2)-.

β-Anomer:1H-NMR (DMSO-d6): δ 8,1-7.5 (m, 5H, C6H5CO), of 5.99 (s, 1H, H-1), 5,46 (d, 1H, H-2, J2-3=5.3 Hz), and 5.30 (d, 1H, H-2, J2-3=5.3 Hz), 4,3 (d, 1H, H-5, J5-5'=11.7 Hz), 4,19 (d, 1H, H-5', J5'-5=11.7 Hz), 2,10 (s, 3H, CH3CO2), to 2.06 (s, 3H, CH3CO2), 2,02 (s, 3H, CH3CO2), of 1.30 (s, 3H, CH3); MS (matrix GT): FAB > 0 m/z 335 (M-CH3CO2-)+, 275 (M-CH3CO2-+H)+, 105 (C6H5CO)+, 43 (CH3CO)+FAB<0 m/z 121 (C6H5CO2)-, 59 (CH3CO2)-.

EXAMPLE 11: Obtain On-6-diphenylcarbinol-N2-isobutyryl-9-(2,3-di-O-acetyl-5-O-benzoyl-4-C-methyl-β-D-ribofuranosyl)-8-methylguanine - (18)

To a suspension of O-6-diphenylcarbinol-8-methyl-N2-isobutylamine in anhydrous toluene (20 ml) is added N,O-bis(trimethylsilyl)ndimethylacetamide (1,92 ml, 7.9 mmol). The reaction mixture is allowed the opportunity to be heated by boiling under reflux for 1 hour. Compound 7 (1.55 g, 3.93 mmol) dissolved in toluene (10 ml) and add trimethylsilyltrifluoromethane (TMSTf) (915 ml, 4,72 mmol). The mixture is heated at the boil under reflux for 30 minutes. The solution is then cooled to room temperature and neutralized with 5% aqueous sodium hydrogen carbonate solution. The reaction mixture was diluted with ethyl acetate (200 ml). The organic phase is washed with 5% aqueous sodium hydrogen carbonate solution (150 ml) and water (2 x 150 ml). The organic layer is dried over Na2SO4and evaporated to dryness. The residue is purified colonoscopy because it allows the Noah chromatography on silica gel [eluent: stepwise gradient of diethyl ether (70-90%) in petroleum ether], while receiving the connection 18.

EXAMPLE 12: 9-(4-C-methyl-β-D-ribofuranosyl)-8-methylguanine - (19)

Specified in the title compound can be obtained in accordance with the published method from compound 18 (Waga, T.; Nishizaki, T.; Miyakawa, I.; Orhui, H.; Meguro, H. “Synthesis of 4'-C-methylnucleosides” Biosci. Biotechnol. Biochem. 1993, 57, 1433-1438).

A solution of 18 in a solution of ammonia in methanol (preferably, saturated at -10°C) (20 ml) was stirred at room temperature overnight. The solvent is evaporated under reduced pressure and the residue is distributed between methylene chloride (60 ml) and water (60 ml). The aqueous layer was washed with methylene chloride (2 x 60 ml), concentrated under reduced pressure. The residue is purified by chromatography on RP18 column [eluent water/acetonitrile, 95/5], while receiving the connection 19.

EXAMPLE 13: 9-(2,3-Di-O-acetyl-5-O-benzoyl-4-C-methyl-β-D-ribofuranosyl)-8-methyladenine - (20)

A solution of 7 (1.10 g, and 2.79 mmol) in anhydrous acetonitrile (50 ml) is treated with 8-methyladenine and tin chloride (IV) (SnCl4, 660 μl, to 5.58 mmol) and stirred at room temperature overnight. The solution is concentrated under reduced pressure, diluted with chloroform (100 ml) and treated with a cold saturated aqueous NaHCO3(100 ml). The mixture is filtered on celite and the precipitate washed with hot chloroform. The filtrates are combined washed with water (100 ml) and saturated solution of the m salt (100 ml), dried (Na2SO4) and evaporated under reduced pressure. The residue is purified column chromatography on silica gel [eluent: stepwise gradient of methanol (3-5%) in dichloromethane], while receiving the connection 20.

EXAMPLE 14: 9-(4-C-methyl-β-D-ribofuranosyl)-8-methyladenine - (21)

Specified in the title compound can be obtained in accordance with the published method from compound 20 (Waga, T.; Nishizaki, T.; Miyakawa, I.; Orhui, H.; Meguro, H. “Synthesis of 4'-C-methylnucleosides” Biosci. Biotechnol. Biochem. 1993, 57, 1433-1438).

A solution of compound 20 in a solution of ammonia in methanol (preferably, saturated at -10°C) (50 ml) was stirred at room temperature overnight. The solvent is evaporated under reduced pressure and the residue is distributed between methylene chloride (100 ml) and water (100 ml). The aqueous layer was washed with methylene chloride (2 x 100 ml) and concentrate under reduced pressure. The residue is purified by chromatography on silica gel [eluent: stepwise gradient of methanol (10-30%) in ethyl acetate], while receiving the connection 21.

In a similar way, but using the appropriate sugar and purine bases, get the following nucleosides of formula XXXXII.

where R1, R2, R3X1X2and Y have the values defined here.

EXAMPLE 15: Obtain 1-(5-O-benzoyl-4-C-methyl-2,3-O-acetyl-β-D-ribofuranosyl)-6-Metalurh the sludge - (8)

A suspension of 6-methyluracil treated with hexamethyldisilazane (HMDS, 21 ml) and a catalytic amount of ammonium sulfate for 17 hours while boiling under reflux. After cooling to room temperature the mixture is evaporated under reduced pressure and the residue obtained as a colourless oil, diluted with anhydrous 1,2-dichloroethane (7.5 ml). To the resulting solution was added compound 7 (0,99 g, 2.51 mmol) in anhydrous 1,2-dichloroethane (14 ml) followed by the addition trimethylsilyltrifluoromethane (TMSTf, of 0.97 ml, 5,02 mmol). The solution is stirred for 2.5 hours at room temperature in an argon atmosphere, then diluted with chloroform (150 ml), washed with the same volume of a saturated aqueous solution of sodium bicarbonate and finally with water (2 x 100 ml). The organic phase is dried over sodium sulfate, then evaporated under reduced pressure. The resulting crude material is purified column chromatography on silica gel [eluent: stepwise gradient of methanol (0-2%) in chloroform], while receiving net connection 8.

EXAMPLE 16: Obtain 1-(4-C-methyl-β-D-ribofuranosyl)-6-methyluracil - (9)

Specified in the title compound can be obtained in accordance with the published method from compound 8 (Waga, T.; Nishizaki, T.; Miyakawa, I.; Orhui, H.; Meguro, H. “Synthesis of 4'-C-methylnucleosides” Biosci. Biotechnol. Biochem. 1993, 57, 1433-1438).

R is the target 8 in a solution of ammonia in methanol (previously saturated at -10°C) (27 ml) was stirred at room temperature overnight. The solvent is evaporated under reduced pressure and the residue is distributed between methylene chloride (40 ml) and water (40 ml). The aqueous layer was washed with methylene chloride (2 x 40 ml), concentrated under reduced pressure and evaporated several times with absolute ethanol. Recrystallization from a mixture of absolute ethanol/methanol gives compound 9.

EXAMPLE 17: Obtain 1-(5-O-benzoyl-4-C-methyl-2,3-O-acetyl-β-D-ribofuranosyl)-4-thio-6-methyluracil - (10)

The reagent Lawesson (926 mg, to 2.29 mmol) is added in an argon atmosphere to a solution of 8 in anhydrous 1,2-dichloroethane (65 ml) and the reaction mixture was stirred over night while boiling under reflux. The solvent is evaporated under reduced pressure and the residue purified column chromatography on silica gel [eluent: stepwise gradient of methanol (1-2%) in chloroform], thus obtaining a pure compound 10.

EXAMPLE 18: Obtain 1-(4-C-methyl-β-D-ribofuranosyl)-4-thio-6-methyluracil - (11)

A solution of compound 10 in a solution of ammonia in methanol (previously saturated at -10°C) (27 ml) was stirred at room temperature overnight. The solvent is evaporated under reduced pressure and the residue is distributed between methylene chloride (40 ml) and water (40 ml). The aqueous layer was washed with methylene chloride (2 x 40 ml), concentrated under reduced pressure. The crude material is purified column of chromatogr is via on silica gel [eluent: stepwise gradient of methanol (5-7%) in methylene chloride], while receiving the connection 11, which lyophilized.

EXAMPLE 19: Obtaining cleaners containing hydrochloride form 1-(4-C-methyl-β-D-ribofuranosyl)-6-methylcytosine - (12)

Compound 11 is treated with a solution of ammonia in methanol (previously saturated at -10°C) (12 ml) at 100°C. in a bomb stainless steel for 3 hours, then cooled to room temperature. The solvent is evaporated under reduced pressure and the residue is distributed between methylene chloride (40 ml) and water (40 ml). The aqueous layer was washed with methylene chloride (2 x 40 ml), concentrated under reduced pressure. The crude material is purified column chromatography on silica gel [eluent: methylene chloride/methanol/ammonium hydroxide, 65/30/5]. The collected fractions evaporated under reduced pressure and absolute ethanol (6.3 ml). To the solution was added 2 n hydrochloric acid (1.5 ml) and the mixture is stirred before concentrating under reduced pressure. The procedure was repeated twice and the coupling 12 is then precipitated from absolute ethanol.

EXAMPLE 20: Obtaining 1-(5-O-benzoyl-4-C-methyl-2,3-O-acetyl-β-D-ribofuranosyl)-6-methylthymine - (13)

A suspension of 6-methylthymine treated with hexamethyldisilazane (HMDS, 17 ml) and a catalytic amount of ammonium sulfate during the night while boiling under reflux. After cooling to room temperature the mixture is evaporated under reduced is the t and the rest, obtained as a colourless oil, diluted with anhydrous 1,2-dichloroethane (6 ml). To the resulting solution was added compound 7 (1.0 g, 2,53 mmol) in anhydrous 1,2-dichloroethane (14 ml) followed by the addition trimethylsilyltrifluoromethane (TMSTf, and 0.98 ml of 5.06 mmol). The solution is stirred for 5 hours at room temperature in an argon atmosphere, then diluted with chloroform (150 ml), washed with the same volume of a saturated aqueous solution of sodium bicarbonate and finally with water (2 x 100 ml). The organic phase is dried over sodium sulfate, then evaporated under reduced pressure. The resulting crude material is purified column chromatography on silica gel [eluent: 2% methanol in chloroform], thus obtaining a pure compound 13.

EXAMPLE 21: Obtain 1-(4-C-methyl-β-D-ribofuranosyl)-6-methylthymine - (14)

Specified in the title compound can be obtained in accordance with the published method from compound 13 (Waga, T.; Nishizaki, T.; Miyakawa, I.; Orhui, H.; Meguro, H. “Synthesis of 4'-C-methylnucleosides” Biosci. Biotechnol. Biochem. 1993, 57, 1433-1438).

A solution of 13 in a solution of ammonia in methanol (previously saturated at -10°C) (60 ml) was stirred at room temperature overnight. The solvent is evaporated under reduced pressure and the residue is distributed between methylene chloride (60 ml) and water (60 ml). The aqueous layer was washed with methylene chloride (2 x 60 ml), the concentration of irout under reduced pressure and evaporated several times with absolute ethanol. Recrystallization from methanol gives compound 14.

EXAMPLE 22: Obtain 1-(5,2,3-tri-O-acetyl-4-C-methyl-β-D-ribofuranosyl)-6-methylthymine - (15)

A solution of 14 in anhydrous pyridine (7.4 ml) is treated with acetic anhydride (1.2 ml) and stirred at room temperature for 3 hours. The solvent is evaporated under reduced pressure and the residue purified column chromatography on silica gel [eluent: stepwise gradient of methanol (0-5%) in methylene chloride], while receiving the connection 15.

EXAMPLE 23: Obtain 1-(5,2,3-tri-O-acetyl-4-C-methyl-β-D-ribofuranosyl)-4-thio-6-methylthymine - (16)

The reagent Lawesson (119 mg, 0.29 mmol) is added in an argon atmosphere to a solution of 15 in anhydrous 1,2-dichloroethane (11 ml) and the reaction mixture was stirred over night while boiling under reflux. The solvent is evaporated under reduced pressure and the residue purified column chromatography on silica gel [eluent: stepwise gradient of methanol (1-2%) in chloroform], thus obtaining a pure compound 16.

EXAMPLE 24: Obtaining cleaners containing hydrochloride form 1-(4-C-methyl-β-D-ribofuranosyl)-5-methyl-6-methylcytosine - (17)

The connection 16 is treated with a solution of ammonia in methanol (previously saturated at -10°C) (10 ml) at 100°C. in a bomb stainless steel for 3 hours, then cooled to room temperature. The solvent is evaporated under reduced is the first pressure and the residue is distributed between methylene chloride (30 ml) and water (30 ml). The aqueous layer was washed with methylene chloride (2 x 30 ml), concentrated under reduced pressure. The crude material is purified column chromatography on silica gel [eluent: 20% methanol in methylene chloride], while receiving the connection 17. This compound is dissolved in EtOH 100% (1.5 ml), treated with 2 N. a solution of hydrochloric acid (0.3 ml) and the mixture is stirred before concentrating under reduced pressure. The procedure was repeated twice and the connection 17 precipitated from absolute ethanol.

Alternatively, using the appropriate sugar and pyrimidine bases receive the following nucleosides of formula XXXXIII

where R1, R2, R3X1X2and Y have the values defined here.

Alternatively, using the appropriate sugar and pyrimidine or purine bases receive the following nucleosides of formula XXXXIV

where R1, R2, R3, R6X and base have the values defined here.

Alternatively, using the appropriate sugar and pyrimidine or purine bases receive the following nucleosides of formula XXXXV

where R1, R2, R6X and base have the values defined here.

Alternatively, using the right sugar and pyrimidine or purine bases receive the following nucleosides of formula XXXXVI

where R1, R2, R6X and base have the values defined here.

Alternatively, using the appropriate sugar and pyrimidine or purine bases receive the following nucleosides of formula XXXXVII

where R1, R6, R7, R8, R9, R10X and base have the values defined here.

VIII. Biological tests

To determine the activity of the tested compounds against viruses suitable are multiple analyses. Some of these biological tests described below.

EXAMPLE 25: Activity against flaviviruses or pestiviruses

Compounds that may be active against flaviviruses or pestiviruses through inhibition of polymerase flavivirus or pestivirus, by inhibiting other enzymes needed in the replication cycle, or in other ways.

Analysis of the phosphorylation of the nucleoside with the active triphosphate

To determine the cellular metabolism of the compounds of HepG2 cells obtained from the American Type Culture Collection (Rockville, MD), grown in flasks for tissue culture at 225 cm3in minimal essential medium, supplemented with essential amino acids, 1% penicillin-streptomycin. Wednesday update every three on the I-cells subcultured one week. After separation of the adhered monolayer with a 10-minute exposure to 30 ml of a mixture of trypsin-EDTA and three consecutive washes environment confluent HepG2 cells are seeded at a density of 2.5 x 106cells per well in 6-hole tablet and exposed to 10 μm of [3H]-labeled active compound (500 disintegrations / min/pmol) for certain periods of time. Cells are incubated at 37°C in an atmosphere with 5% CO2. At selected time points, the cells are washed three times with ice, phosphate buffered saline (PBS). Intracellular active connection and its relevant metabolites extracted by incubation of the cellular precipitate over night at -20°C With 60% methanol followed by extraction of an additional 20 ál of cold methanol for one hour in an ice bath. The extracts are then combined, dried by passing a weak stream of air passing through the filter, and store at -20°C until HPLC analysis.

Analysis of the bioavailability held on abacadabra monkeys

Within 1 week prior to study abacadabra monkey surgically implanted permanent venous catheter and subcutaneous venous input device (VAP) to facilitate the collection of blood and conduct an objective examination, including evaluation of Hematology and biochemistry with the adjustable tap wrenches blood, and record the weight. Each monkey (six) receives approximately 250 µci3N-activity with each dose of active compound at the dose level of 10 mg/kg dose concentration of 5 mg/ml, or by intravenous bolus (3 monkeys, intravenous)or oral feeding through a stomach tube (3 monkeys, oral administration). Each dosing syringe is weighed before dosing to the gravimetric method to determine the amount of the drug. Urine samples are collected through a clamp device for external urinals (ship) at certain time intervals (approximately 18-0 hours before dosing, 0-4, 4-8, and 8-12 hours after dosing) and process. Blood samples collected (before dosing, 0,25, 0,5, 1, 2, 3, 6, 8, 12 and 24 hours after dosing) also through a permanent venous catheter and VAP or from a peripheral vessel, if the procedure is permanent venous catheter is impossible. The blood and urine samples analyzed to determine the maximum concentration (Cmax), the time when the maximum concentration (Tmax), area under the curve (AUS), half-life gradually entered the compound (T1/2), the clearance CL), volume in the steady state and distribution (Vss) and bioavailability (F).

Analysis Toxics the STI for bone marrow

Cells of human bone marrow collected from volunteers with normal health and mononuclear cell population is separated by gradient centrifugation Ficoll-Hypaque as described previously, Sommadossi J-P, Carlisle R. "Toxicity of 3'-azido-3'-deoxythymidine and 9-(1,3-dihydroxy-2-propoxymethyl)guanine for normal human hematopoietic progenitor cells in vitro", Antimicrobial Agents and Chemotherapy 1987; 31:452-454; and Sommadossi J-P, Schinazi RF, Chu CK, Xie M-Y. "Comparison of cytotoxicity of the (-)- and (+)-enantiomer of 2',3'-dideoxy-3'-thiacytidine in normal human bone marrow progenitor cells" Biochemical Pharmacology 1992; 44:1921-1925. Analyses of culture for CFU-GM and BFU-E carried out using the method of two-layer soft agar or methylcellulose. Medicines are bred in an environment of tissue culture and filtered. After keeping 14-18 days at 37°C in an atmosphere of humidified air with 5% CO2the number of colonies with more than 50 cells are counted using an inverted microscope. The results are presented as percentage inhibition of the formation of colonies in the presence of the drug compared to control cultures with the solvent.

Analysis of toxicity to mitochondria

The HepG2 cells were cultured in 12-hole tablets, as described above, and exposed to various concentrations of drugs as listed Pan-Zhou X-R, Cui L, Zhou X-J, Sommadossi J-P, Darley-Usmer VM “Differential effects of antiretroviral nucleoside analogs on mitochondrial function in HepG2 cell” Antimicrob. Agents Chemother. 2000; 44:496-503. The levels of lactic acid in cultural the Noah environment 4 days after exposure to drugs was measured using a kit for analysis of lactic acid Boehringer. The levels of lactic acid and normalize by the number of cells measured by counting hemocytometer.

Analysis of cytotoxicity

Cells are seeded at a rate of between 5 x 103and 5 x 104/well in 96-well tablets in a nutrient medium and cultured overnight at 37°C in humidified atmosphere with CO2(5%). Then add a new nutrient medium containing medicines after breeding. After incubation for 4 days of culture fix in 50% TCA and stained with sulforhodamine C. the Optical density is determined at 550 nm. The concentration of cytotoxicity was expressed as the concentration required to reduce the number of cells by 50% (SS50).

Analysis of cell protection (CPA)

The analysis is performed essentially as described Baginski, S. G.; Pevear, D.C.; Seipel, M.; Sun, S.C.C.; Benetatos, C.A.; Chunduru, S.K.; Rice, C.M. and M. S. Collett “Mechanism of action of a pestivirus antiviral compound” PNAS USA 2000, 97(14), 7981-7986. The MDBK cells (ATSC) seeded on 96-well culture plates (4000 cells per well) 24 hours before use. After infection with BVDV (strain NADL, ATSS) at multiplicity of infection (MOI) of 0.02 forming plaques units (PFU) per cell as infected and uninfected cells add compound after serial dilutions in culture medium to the final concentration of DMSO of 0.5%. Each breeding experience in four replications. The density of cells and for agenie virus regulate, to ensure continuous growth of the cells during the experiment and to achieve more than 90% of virus-induced destruction of cells in the untreated controls four days after infection. After four days the tablets record 50% TCA and stained with sulforhodamine C. the Optical density of the wells is determined in a microplate reader at 550 nm. The value of the 50% effective concentration (EC50) is defined as the concentration that causes 50% reduction of the cytopathic effect of the virus.

Analysis of reducing plaque formation

For each connection effective concentration determined in duplicate in 24-hole tablets through analyses reduce plaque formation. Monolayers of cells infect 100 PFU/well of virus. Then the monolayers add compound serial dilutions in MEM, supplemented with 2% inactivated serum and 0.75% methylcellulose. The culture is then incubated at 37°C for 3 days, then fixed with 50% ethanol and 0.8% crystal violet, washed and air-dried. Then count the plaques to determine the concentration for 90% suppression of the virus.

Analysis of the reduction of output (yield) virus

For each compound concentration to obtain a 6-log reduction in viral load is determined in a double loop 24-hole tablets analysis and reduction of output. The analysis is performed as described Baginski, S. G.; Pevear, D.C.; Seipel, M.; Sun, S.C.C.; Benetatos, C.A.; Chunduru, S.K.; Rice, C.M. and M. S. Collett “Mechanism of action of a pestivirus antiviral compound” PNAS USA 2000, 97(14), 7981-7986, with minor modifications. Briefly, MDBK cells seeded on 24-hole plates (2 x 105 cells per well) 24 hours before infection with BVDV (strain NADL) at multiplicity of infection (MOI) of 0.1 PFU per cell. Compound serial dilutions added to the cells in a nutrient medium with a final concentration of DMSO of 0.5%. Each breeding experience in three replications. After three to culture cells monolayers of cells and supernatant) are lysed by three cycles of freezing/thawing and release of virus quantify the analysis belascoaran. Briefly, MDBK cells seeded on 6-hole plates (5 x 105 cells per well) 24 hours before use. Cells inoculant 0.2 ml of the tested lysates for 1 hour, washed and covered with 0.5% agarose in culture medium. After 3 days the monolayers of cells fixed in 3.5% formaldehyde and stained with 1% crystal violet (wt./about. in 50% ethanol) to visualize plaques. Plaques are counted to determine the concentration to get a 6-log reduction in viral load.

EXAMPLE 26: Antiviral activity in vitro

Antiviral activity in vitro was tested in the following cell lines: MT-4 for HIV; Vero 76, the kidney cells of African the fir green monkeys for SARS; KSS for virus bovine viral diarrhea; Sb-1 for type 1 poliovirus Sabin; CVBS-2, CVBS-3, CVBS-4 and CVA-9 for viruses, Coxsackie b-2, b-3, b-4 and a-9 and REO-1 (double-stranded) RNA viruses. Notes: BVDV = virus bovine viral diarrhea; YFV = yellow fever virus, DENV = dengue virus; WNV = West Nile virus, CVBS-2 = Coxsackievirus b-2; Sb-1 = poliovirus type 1 Sabin and REO = double-stranded RNA virus.

The results of determining SS50EU50for β-D-2'-C-methyl-7-methyl-6-phenyl-3,3A,5,8A-tetrahydro-1,3,4,5,7a-pentasa-SIMM-indocin-8-she (compound F)

CC50CC50CC50EC50EC50EC50EC50EC50EC50
ConnectionMT-4Vero 76BHKSb-1CVBS-2CVBS-3CVBS-4CVA-9REO-1
F>100 >100>10043374939602

The results of determining SS50and for β-D-2'-C-methyl-7-methyl-6-phenyl-3,3A,5,8A-tetrahydro-1,3,4,5,7a-pentasa-SIMM-indocin-8-she (compound F)

CC50
ConnectionBVDVYFVDENV2WNVCVBS-2Sb-1REO
F>100102,51,3137432

This invention has been described with reference to its preferred options for implementation. And the above detailed description of the invention, the person skilled in the art will be obvious variations and modifications of the invention.

1. The compound of formula (IX):

or its pharmaceutically acceptable salt,
where R1and R2independently represent H; phosphate or C(O)R', where R' represents an unbranched, branched or cyclic alkyl (including lower alkyl), amino acid, aryl including phenyl, alkaryl, aralkyl, including benzyl, alkoxyalkyl, including methoxymethyl, aryloxyalkyl, such as phenoxymethyl, or substituted alkyl (including lower alkyl), aryl including phenyl, optionally substituted by chlorine, bromine, fluorine, iodine,1-C4-alkyl or C1-C4-alkoxy, sulphonate esters such as alkyl - or aralkylamines, including methanesulfonyl, mono -, di - or trifosfatnogo ether, trityl or monomethacrylate, substituted benzyl, alkaryl, aralkyl, including benzyl, alkoxyalkyl, including methoxymethyl, aryloxyalkyl, such as phenoxymethyl;
X represents O;
base* is a purine base;
R12is(Y3)3;
Y3independently represents H and
R13represents fluorine.

2. The compound according to claim 1, where R1and R2represent N.

3. Pharmaceutical composition having inhibitory activity against hepatitis C containing an effective quantity is of the compound or its pharmaceutically acceptable salt according to any one of claims 1 and 2 in a pharmaceutically acceptable carrier.

4. The pharmaceutical composition according to claim 3, where the carrier is suitable for oral delivery.

5. The pharmaceutical composition according to claim 4, where the compound or its pharmaceutically acceptable salt, a standard dosage forms.

6. The composition according to claim 5, where the standard dosage form contains about 0.1-50 mg or 50-1000 mg of the compound or its pharmaceutically acceptable salt.

7. The composition according to claim 5, where the specified standard dosage form is a tablet or capsule.

8. The pharmaceutical composition according to claim 3, further containing a second antiviral agent.

9. The pharmaceutical composition of claim 8, where the second antiviral agent is selected from the group comprising interferon, ribavirin, an interleukin, a NS3 protease inhibitor, an inhibitor of cysteinate, phenanthridine, derived thiazolidin, thiazolidin, benzanilide, inhibitor of helicase, a polymerase inhibitor, a nucleotide analogue, gliotoxin, cerulenin, antisense phosphorothioate oligodeoxynucleotide, an inhibitor of IRES-dependent translation, and a ribozyme.

10. The pharmaceutical composition according to claim 9, where the second antiviral agent is interferon.

11. The pharmaceutical composition of claim 10, where the second antiviral agent is selected from the group including targeted interferon 2A, interferon of alphacon-1, natural interferon, alboher is h, interferon beta-1A, omega interferon, interferon alpha, interferon gamma, interferon Tau, interferon Delta, and interferon gamma-1b.

12. The pharmaceutical composition according to claim 3 where the compound or its pharmaceutically acceptable salt is essentially in pure form.

13. The pharmaceutical composition according to claim 3 where the compound or its pharmaceutically acceptable salt contains at least 90 wt.% β-D-isomer.

14. The pharmaceutical composition according to claim 3 where the compound or its pharmaceutically acceptable salt contains at least 95 wt.% β-D-isomer.

15. The pharmaceutical composition according to claim 3, further containing a pharmaceutically acceptable carrier suitable for oral, parenteral, inhalation or intravenous delivery.

16. The pharmaceutical composition according to claim 3, where the pharmaceutically acceptable salt is selected from the group comprising tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, α-Ketoglutarate, α-glycerol, formate, fumarate, propionate, glycolate, lactate, pyruvate, oxalate, maleate, salicylate, sulfate, nitrate, bicarbonate, carbonate, Hydrobromic, hydrochloride, dihydrochloride salt and phosphoric acid.

17. The pharmaceutical composition according to clause 16, where the pharmaceutically acceptable salt is cleaners containing hydrochloride salt.

18. The use of compounds or headlamp is asepticheski acceptable salt according to any one of claims 1 and 2 when receiving drugs having inhibitory activity against hepatitis C.

19. Use p, where the medicinal product further comprises a second antiviral agent.

20. The application of claim 19, where the second antiviral agent is selected from the group comprising interferon, ribavirin, an interleukin, a NS3 protease inhibitor, an inhibitor of cysteinate, phenanthridine, derived thiazolidin, thiazolidin, benzanilide, inhibitor of helicase, a polymerase inhibitor, a nucleotide analogue, gliotoxin, cerulenin, antisense phosphorothioate oligodeoxynucleotide, an inhibitor of IRES-dependent translation, and a ribozyme.

21. The application of claim 20, where the second antiviral agent is interferon.

22. Use item 21, where the second antiviral agent is selected from the group including targeted interferon 2A, interferon of alphacon-1, natural interferon, Albuferon, interferon beta-1A, omega interferon, interferon alpha, interferon gamma, interferon Tau, interferon Delta, and interferon gamma-1b.

23. Use p, where the compound or its pharmaceutically acceptable salt, a standard dosage forms.

24. The application of item 23, where the standard dosage form contains about 0.1-50 mg or 50-1000 mg of the compound or its pharmaceutically acceptable salt.

25. Use item 23 where the specified standard dosage form is a tablet or capsule.

26. Use p, where Obedinenie or its pharmaceutically acceptable salt is, essentially, in its pure form.

27. Use p, where the compound or its pharmaceutically acceptable salt contains at least 90 wt.% β-D-isomer.

28. Use p, where the compound or its pharmaceutically acceptable salt contains at least 95 wt.% β-D-isomer.

29. Use p, where the pharmaceutically acceptable salt is selected from the group comprising tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, α-Ketoglutarate, α-glycerol, formate, fumarate, propionate, glycolate, lactate, pyruvate, oxalate, maleate, salicylate, sulfate, nitrate, bicarbonate, carbonate, Hydrobromic, hydrochloride, dihydrochloride salt and phosphoric acid.

30. The application of clause 29, where the pharmaceutically acceptable salt is cleaners containing hydrochloride salt.



 

Same patents:

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: present invention pertains to ester lipids of halogenated adenine nucleotides with formula I, which can be used in treating cancerous diseases. (I), where R1 - C1-C20-alkyl, can be substituted with C1-C6-alkoxyl radical, C1-C6-alkylmercaptan radical, C1-C6-alkylsulfenyl or C1-C6-alkylsulfonyl groups, R2 - C1-C20-alkyl, which can be substituted with C1-C6-alkoxyl radical, C1-C6-alkylmercaptan radical or C1-C6-alkylsulfonyl group, R3 - amino group, X - sulphur atom, sulfenyl or sulfonyl group, Y - oxygen atom.

EFFECT: obtaining new biologically active compounds.

3 cl, 9 ex, 1 tbl

FIELD: radiolabeled compounds, biochemistry.

SUBSTANCE: invention relates to a novel labeled analogue of the physiologically active compound, namely, tritium-labeled acyl-coenzyme A of the general formula (I): wherein Acyl means [5,6-3H]-(5,6-dihydro)-arachidonoyl or [6,7-3H]-linoleyl.

EFFECT: valuable medicinal and biochemical properties of compound.

2 dwg, 4 ex

FIELD: medicine, pharmacology, bioorganic chemistry, pharmacy.

SUBSTANCE: invention relates to the effective using amount of β-L-2'-deoxynucleoside of the formula (I) or (II) used in manufacturing a medicinal agent used in treatment of hepatitis B, pharmaceutical compositions containing thereof, and methods for treatment of hepatitis B. Proposed agent shows the enhanced effectiveness in treatment of hepatitis B.

EFFECT: enhanced and valuable medicinal properties of agent.

83 cl, 6 tbl, 11 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to acyclic nucleoside phosphonate derivatives of the formula (1): wherein means a simple or double bond; R1 means hydrogen atom; R2 and R3 mean hydrogen atom or (C1-C7)-alkyl; R7 and R8 mean hydrogen atom or (C1-C4)-alkyl; R4 and R5 mean hydrogen atom or (C1-C4)-alkyl possibly substituted with one or more halogen atoms, or -(CH2)m-OC(=O)-R6 wherein m means a whole number from 1 to 5; R6 means (C1-C7)-alkyl or 3-6-membered heterocycle comprising 1 or 2 heteroatoms taken among the group consisting of nitrogen (N) and oxygen (O) atoms; Y means -O-, -CH(Z)-, =C(Z)-, -N(Z)- wherein Z means hydrogen atom, hydroxy-group or halogen atom, or (C1-C7)-alkyl; Q (see the claim invention); its pharmaceutically acceptable salts or stereoisomers. Also, invention proposes methods for preparing compounds of the formula (1) and their using in treatment of hepatitis B or preparing a medicinal agent designated for this aim.

EFFECT: improved preparing method, valuable medicinal properties of compounds and agent.

16 cl, 10 tbl, 87 ex

FIELD: organic chemistry, medicine, virology.

SUBSTANCE: invention relates to technology of organic compounds, namely, to 5'-aminocarbonylphosphonates d4T that are inhibitors of the human immunodeficiency virus reproduction. Invention describes 5'-aminocarbonylphosphonates d4T of the general formula: wherein R' means hydrogen atom (H), alkyl, aryl; R'' means hydrogen atom (H), alkyl, aryl; R', R'' mean cyclic alkyl; R means alkyl. These compounds are inhibitors of the human immunodeficiency virus reproduction. Invention provides preparing new compounds eliciting valuable biological properties.

EFFECT: valuable medicinal properties of compounds.

2 dwg, 1 tbl, 5 ex

The invention relates to nucleoside analogs of formula (1) in which R1represents H or a group protecting the hydroxyl, R2represents H, a group protecting the hydroxyl group of phosphoric acid, a protected group, phosphoric acid or a group of the formula P(R3R4in which R3and R4are the same or different and represent a hydroxyl group, a protected hydroxyl group, alkoxygroup, allylthiourea, cyanoacetylurea, amino group, substituted alkyl group; And represents alkylenes group containing from 1 to 4 carbon atoms, and a represents a substituted purine-9-ilen group or substituted 2-oxopyrimidine-1-ilen group containing at least one Deputy, selected from hydroxyl groups, protected hydroxyl groups, amino groups, protected amino groups, alkyl groups

The invention relates to methods for treating diseases caused by hepatitis B virus (also known as HBV and Epstein-Barr (also known as EBV, which include the introduction of an effective amount of one or more of the active compounds disclosed here, or farmatsevticheskii acceptable derivatives or prodrugs of one of these compounds

The invention relates to new nukleotidfosfatazu derived from the remnants of lipid esters of General formula I, in which R1, R2represent a linear or branched saturated alkyl chain containing 1-20 carbon atoms; R3, R5represent hydrogen, hydroxyl group; R4represents a hydroxyl group; X represents a sulfur atom, sulfinyl or sulfonyloxy group; Y represents an oxygen atom; b is a purine and/or pyrimidine base, provided that at least one of the residues R3or R5represents hydrogen; their tautomers, their optically active forms and racemic mixtures, or their physiologically acceptable salts with inorganic and organic acids and/or bases, and also to processes for their preparation and medicines containing the above-mentioned connection

FIELD: chemistry.

SUBSTANCE: invention describes novel macrocyclic compounds of formulae pharmaceutically acceptable salts or stereoisomers thereof, where R1 = -OR5, -NH-SO2R6; R2 = hydrogen; R3 = C1-6-alkyl; R4 = isoquinolinyl, possibly substituted; n equals 4 or 5; R5 = hydrogen; R6 = C3-7-cycloalkyl, and a pharmaceutical composition containing said compounds.

EFFECT: novel compounds have hepatitis C virus replication inhibitory action and can be used in medicine.

6 cl, 32 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention describes novel macrocyclic compounds of general formulae (I-c) (I-d), pharmaceutically acceptable salt or stereoisomer thereof, where R1 = -OR11 or -NH-SO2R12; R2 = hydrogen and R3 =C1-6-alkyl; n = 3-6; W is a radical of formula , where R5 = phenyl, possibly substituted with C1-6alkyl or alkoxy; thiazolyl, possibly substituted with C1-6alkyl; or pyridyl; R11 denotes hydrogen; R12 = C3-7-cycloalkyl, and a pharmaceutical composition containing said compounds.

EFFECT: said compounds are hepatitis C virus inhibitors and can be used in medicine.

3 cl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: pharmaceutical composition, which has anti-viral activity against hepatitis C, includes solid suspension, obtained by extrusion of melt of hydrochloride (2R,3S,4R,5R)-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-2-azido-3,4-bis-isobutiryoxytetrahydrofuran-2-ylmethyl ether of isobutyric acid (I) and block-copolymer polyethyleneglycol (PEG)/polypropylenglycol (PPG). Preferably block-copolymer PEG/PPG represents poloxamer 188.

EFFECT: pharmaceutical composition has improved speed of dissolution and bio-availability.

14 cl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, and concerns an immunostimulating combination for prevention and treatment of hepatitis C. Substance of the invention consists in creation of the immunostimulating combination containing poly I - poly C [poly (I:C)] used as an Toll-like receptor TLR3 agonist, CD40 agonist, a polypeptide which includes protein NS3 of hepatitis C virus, or a fragment of said protein exhibiting ability to CD8+ and CD4+ response induction, and the agonist is chosen from anti-CD40- antibodies, CD40L (natural ligand CD40) and their fragments which keep their ability to bind with CD40. The invention also includes application of said combination for preparing a drug, a pharmaceutical composition, a vaccine, a kit for introduction of the combination and a method for inducing an immune response on hepatitis C virus.

EFFECT: higher clinical effectiveness and lower toxicity.

24 cl, 5 ex, 1 tbl, 5 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds with HCV protease inhibiting activity, as well as methods for synthesis of such compounds. In another version, the invention relates to pharmaceutical compositions containing said compounds, as well as methods of using said compounds to treat disorders associated with HCV protease.

EFFECT: high inhibiting activity of compounds.

48 cl, 5 tbl, 833 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to pediatrics and can be used for treatment of congenital hepatitis C in children of first year of life. Method includes introduction of viferon, continuous treatment being carried out for 12-18 months. Additionally introduced is algirem in form of syrup in dose 5 mg/kg per day, diluted for two intakes after meal and ursodeoxycholic acid in day dose 20 mg/kg, divided per two intakes.

EFFECT: application of invention makes it possible to increase efficiency of treatment of congenital hepatitis C.

2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, and concerns a method of preparing a influenza vaccine. Substance of the invention includes influenza virus infection of chicken embryos, incubation, sampling of a virus-containing fluid, purification of influenza virus, concentration and final virus purification by gel filtration HW-65C carrier column chromatography. Purified virions are destroyed by the detergent β-octylglucoside to be removed then. Three half-finished vaccines prepared with the use of received with use of H1N1, H3N2 and B serotypes are combined so that the hemagglutinin concentration in each serotype is about 30 mcg/ml.

EFFECT: reduction in price of the method of preparing the influenza vaccine and its improvement.

5 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of formula (I) where R1 is chosen from ethyl, n-propyl, isopropyl or isobutyl, and to its pharmaceutically acceptable salts. Besides, the invention refers to a pharmaceutical composition on the basis of said compounds used for treating a hepatitis C virus (HCV) mediated disease, and also to a method of treating the hepatitis C virus (HCV) mediated disease, and to the method of selective O-acylation nucleoside II for producing O-acyl nucleoside I in an alkaline reaction medium including the stages: (i) dissolution of II and DMAP in a heterogeneous mixture of water and a solvent and addition of a water base for pH control between approximately 7.5 to approximately 12; (ii) optional addition of a sufficient amount of saturated aqueous NaCl for preparing a diphase reaction mixture; (iii) addition of an acidating agent and an accessory base sufficient for pH preservation between approximately 7.5 to approximately 12; (iv) reaction monitoring and interruption of adding said acidating agent and said base after sufficient conversion provided; (v) optional contact of O-acylnucleoside with the pharmaceutically acceptable acid to produce a pharmaceutically acceptable salt.

EFFECT: production of the pharmaceutical composition for treating the hepatitis C virus (HCV) mediated disease.

9 cl, 2 tbl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I) where values of the substitutes are disclosed in the patent claim.

EFFECT: compounds can be applied for treating the infections caused by Pneumovirinae subfamily viruses (RSV, PCB).

53 cl, 502 ex, 11 tbl

FIELD: medicine.

SUBSTANCE: invention relates to field of medicine and deals with method of obtaining lice culture influenza vaccine. Essence of the invention includes method of obtaining virus-containing substance by cultivation of one of cold-adapted influenza virus reassortants with enoculation dose, with multiplicity of infection not lower than 0.0001 EID50/cell in MDCK cell culture on micro-carriers, which have concentration not less than 1 g/l, with application as micro-carrier material of porous polypropelene, in supporting serum-free nutritional medium, containing proteolytic enzyme in amount 0.25-50.0 mcg/ml, and stabilising additive, which includes sorbitol, or sucrose, or peptone from soya in concentration 0.5-4.0 wt%, collection of virus-containing liquid after cultivation is carried out at least 2 times when specific influenza virus activity before each collection of virus-containing liquid reaches at least 7.0 Ig EID50/ml, concentration and purification of virus substance from ballast admixtures, introduction into purified substance before drying of stabilising additives, with application as such of either proline, glycene, lactose, glutamine-acidic sodium, sucrose, gelatins in final concentration (1.5-5), (1.5-5), (1.5-10), (1.5-5), (5-30) and (1-10) wt % respectively, or sucrose, gelatose and soya peptone in final concentration (1-8), (1-8) and (1-8) wt % respectively, or sorbitol and gelatose in final concentration (3-8) and (3-8) wt % respectively.

EFFECT: obtaining more thermostable vaccine with high output.

2 cl, 6 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medicine and pharmaceutical industry. Medication for prevention of bird flu of mammals includes as active component oxidised dextran with molecular weight 35-60 kDa in concentration 0.4-4.0 wt % in pharmaceutically acceptable solvent. As pharmaceutically acceptable solvent it includes water for injections or physiological solution or physiologically acceptable buffer solution.

EFFECT: invention ensures increase of preventive action efficiency.

2 cl, 3 ex, 1 dwg

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