Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
  • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
  • C07F9/65586—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system at least one of the hetero rings does not contain nitrogen as ring hetero atom
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
  • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
  • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
  • C07H19/06—Pyrimidine radicals
  • C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses
  • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the present invention relates to new substituted alkyl 2- ⁇ [(2R, 3S, 5R) -5- (4-amino-2-oxo-2H-pyrimidin-1-yl) -3-hydroxy-tetrahydro-furan-2-ylmethoxy ] - phenoxyphosphorylamino ⁇ propionates, nucleoside inhibitors of HCV NS5B RNA polymerase, their use as an agent for HCV NS5B RNA polymerase inhibitor and treatment of viral diseases.
• HCV hepatitis C virus replication inhibitors
• Examples of drug candidates include nucleoside inhibitors of HCV NS5B polymerase: PSI-7977 from Farmaset, USA (Patents US 07964580 B2 and US 8334270 B2) and NM283 (Valopicitabine) from Aidenix (USA) and others [M. J. Sofia, D. Bao, W. Chang, J. Du, D. Nagarathnam, S. Rachakonda, P. G. Reddy, B. S. Ross, P. Wang, H.-R. Zhang, S. Bansal, C. Espiritu, M. Keilman, A. M. Lam, H. M. M. Steuer, Congrong Niu, M. J. Otto, P. A. Furman.
• the most advanced drug candidate is the HCV NS5B nucleoside polymerase inhibitor (isopropyl (S) -2 - ⁇ (S) - [(2R, 3R, 4R, 5R) -5- (2,4-dioxo-3,4-dihydro-2H -pyrimidin-1-yl) -4-fluoro-3-hydroxy-4-methyl-tetrahydrofuran-2-ylmethoxy] -phenoxy-phosphorylamino ⁇ -propanoate (PSI-7977).
• PSI-7977 the nucleotide analog of the polymerase inhibitor.
• interferon which causes many side effects that sometimes cause patients to interrupt or delay treatment
• ribavirin which is part of most classic treatment regimens.
• Nucleoside inhibitors of NS5B polymerase can act either as a substrate of non-natural origin, resulting in chain termination, or as a competitive inhibitor that competes with the binding of nucleotide to polymerase.
• the nucleoside analogue In order to function as a chain terminator, the nucleoside analogue must be absorbed by the cell and converted in vivo to triphosphate in order to compete for the nucleotide binding site of the polymerase. This conversion to triphosphate usually occurs with the participation of cell kinases, which leads to additional structural requirements for a potential nucleoside polymerase inhibitor. Unfortunately, this limits the direct assessment of nucleosides as inhibitors of HCV replication in studies conducted on cells that are susceptible to in situ phosphorylation.
• B adenine, thymidine, uracil, cytidine, guanine and hypoxanthine.
• J.-P. Sommadossi et al. described a series of 3 'prodrugs of 1', 3 'or 4' branched nucleosides for treating flavivirus infections, including HCV infections.
• nucleosides for the treatment of viral HCV.
• KAWatanabe described derivatives of 3 '- hydroxymethyl nucleosides for the treatment of viral diseases.
• WO 02/32920 published April 25, 2002 and WO 02/48165 published June 20, 2002, L. Stuyver et al. described nucleoside derivatives for the treatment of viral diseases.
• WO 03/105770 published December 24, 2003, B. Bhar et al. described a series of carbocyclic nucleoside derivatives that inhibit RNA-dependent RNA polymerase of the virus.
• the nucleosides disclosed in this publication are mainly b-methyl-2 '-hydroxy-substituted nucleosides.
• S.S. Carroll et al. described nucleoside derivatives that inhibit RNA-dependent viral polymerase and methods for treating HCV diseases.
• Fluorine nucleosides describes the use of certain ⁇ -fluorine nucleosides for the treatment of HCV.
• US patent N ° 6348587, issued by Emory University, entitled "2 '-fluorine nucleosides” describes the use of certain ⁇ -fluorine nucleosides for the treatment of HCV.
• Fluoronucleosides discloses a number of families of fluoronucleosides useful in treatment of hepatitis B, HCV, HIV and abnormal cell proliferation. Both fluorine substitution configurations are disclosed.
• Olsen et al. (Oral Session V, Hepatitis C Virus, Flaviviridae; 16 th International Conference on Antiviral Research (Apr. 27, 2003, Savannah, Ga.) P A76) also showed the effect of 2'-modified nucleosides on HCV RNA replication.
• Non-nucleoside allosteric HIV reverse transcriptase inhibitors have a proven effective therapeutic effect both on their own and in combination with nucleoside inhibitors and protease inhibitors.
• Several classes of non-nucleoside HCV NS5B inhibitors have already been described and are currently undergoing testing, including benzimidazoles (H. Hashimoto et al. WO 01/47833, H. Hashimoto et al. WO 03/000254, PLBeaulien et al. WO 03/020240 : A2; PLBeaulien et al. US 6448281 Bl PLBeaulien et al. WO 03/007945 Al); indoles (PLBeaulien et al.
• WO 03/0010141 A2 ; benzothiadiazines, e.g. 7 (D. Dhanak et al. WO 01/85172 Al; D. Dhanak et al. WO 03/037262 A2; KJDuffy et al. WO 03/099801 Al; D.Chai et al. WO 2004052312, D. Chai et al. WO2004052313, D.Chai et al. WO 02/098424, JKPratt et al. WO 2004/041818 Al; JKPratt et al. WO 2004/087577 Al), thiophenes, e.g. 8 (CKChan et al. WO 02 / 100851)
• nucleoside inhibitors described herein can be combined with other nucleoside inhibitors of HCV polymerase, non-nucleoside inhibitors of HCV polymerase, and HCV protease inhibitors. Since other classes of anti-HCV drugs have emerged and are being developed, for example, virus incorporation inhibitors, helicase inhibitors, IRES inhibitors, ribozymes and antisense oligonucleotides, they can also be excellent candidates for use in combination therapy. Derivatives of interferon have already been successfully combined with ribavirin, and interferons and chemically modified interferons will be useful in combination with the nucleosides described here.
• nucleosides are often effective antiviral (e.g. HIV, HCV, Herpes simplex, CMV) and anti-cancer chemotherapeutic agents.
• antiviral e.g. HIV, HCV, Herpes simplex, CMV
• CMV Herpes simplex
• nucleoside derivatives Unfortunately, their practical use is often limited by two factors. First, poor pharmacokinetic properties often limit the absorption of nucleoside from the digestive tract and the intracellular concentration of nucleoside derivatives, and secondly, suboptimal physical properties limit the choice of drug composition that could be used to increase the degree of release of the active ingredient.
• Hepatitis C is still a serious public health problem. It leads to chronic liver disease, which leads to cirrhosis of the liver and hepatocellular carcinoma.
• Azaheterocycle means an aromatic or non-aromatic monocyclic or polycyclic system containing at least one nitrogen atom in a ring.
• Alkyl means an aliphatic hydrocarbon linear or branched group with ⁇ -12 carbon atoms in the chain. Branched means that the alkyl chain has one or more "lower alkyl” (C 1 -C 6 ) alkyl substituents.
• Preferred alkyl groups are lower (Ci-C 6 ) alkyl or methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, n-pentyl , 2-pentyl, 3-pentyl, neo-pentyl, n-hexyl, cyclohexyl.
• Alkyl may have substituents.
• Alkyloxy or “Alkoxy” means an Alkyl O— group in which alkyl is defined in this section. Preferred alkoxy groups are methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy and tert-butoxy.
• Amino group means R'R "N-group, substituted or unsubstituted optionally with the same substituents R 'and R".
• An amino group may have substituents.
• NR k a R k + i a is a group substituted or unsubstituted with optionally identical carbamoyl substituents R k a n R k + i a , including hydrogen, methyl, cycloalkyl, which forms a pyrrolidine ring with a nitrogen atom.
• Aryl means an aromatic monocyclic or polycyclic system comprising from 6 to 14 carbon atoms, preferably from 6 to 10 carbon atoms.
• Aryl may contain one or more “cyclic system substituents”, which may be the same or different.
• Aromatic cycle (aromatic system) means a planar cyclic system in which all atoms of the cycle participate in the formation of a single conjugation system, which, according to the Hückel rule, includes (4n + 2) ⁇ -electrons (n is a non-negative integer).
• aromatic cycles are benzene, naphthalene, anthracene, and the like.
• heteroatom cycles ⁇ -electrons and p-electrons of heteroatoms participate in the conjugation system; their total number is also equal to (4n + 2). Examples of such cycles are pyridine, thiophene, pyrrole, furan, thiazole and the like.
• An aromatic ring may have one or more “ring system substituents” and may be anelated with a non-aromatic ring, heteroaromatic or heterocyclic ring.
• ⁇ -aminoacyl group ( ⁇ -aminoacyl) means
• R 2 k , R 2 k + i and R 2 k + 2 can be hydrogen, C
• Active component drug substance, drug substance, drug-substance
• drug substance drug substance, drug-substance
• drug-substance means a physiologically active substance of synthetic or other (biotechnological, plant, animal, microbial and other) origin, having pharmacological activity and is the active principle of the pharmaceutical composition used for the manufacture and manufacture medicinal product (means).
• Heteroaryl (hetaryl) means an aromatic monocyclic or polycyclic system comprising from 5 to 14 carbon atoms, preferably from 5 to 10, in which one or more carbon atoms are replaced by heteroatoms or heteroatoms such as nitrogen, sulfur or oxygen.
• the prefix “aza”, “oxa” or “thia” before “heteroaryl” means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively.
• the nitrogen atom in the heteroaryl can be oxidized to the ⁇ -oxide.
• Heteroaryl may have one or more “ring system substituents”, which may be the same or different.
• pyrrolyl furanyl, thienyl, pyridinyl, pyrrolidine, imidazolyl, oxazolyl, benzothiadiazole, benzothiazolyl, quinolinyl, imidazolyl, thienopyridinyl-pyridinyl-pyridinyl-pyridinyl-pyridinyl-pyridinyl-pyridinyl-pyridinopyridinyl , thienopyrrolyl, furopyrrolyl, etc.
• Heterocycle means an aromatic or non-aromatic saturated or partially saturated monocyclic or polycyclic system comprising from 3 to 10 carbon atoms, preferably from 4 to 6 carbon atoms, in which one or more carbon atoms are replaced by a heteroatom such as nitrogen, oxygen, sulfur phosphorus.
• aza, "oxa” or “thia” before heterocyclyl means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively.
• Heterocyclyl may have one or more substituents, which may be the same or different.
• the nitrogen and sulfur atoms in the heterocyclyl can be oxidized to ⁇ -oxide, S-oxide or S-dioxide.
• heterocyclyls are piperidinyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxan-2-yl, tetrahydrofuryl, tetrahydrothienyl, etc.
• “Substituted alkenyl” substituted alkenyl may also have one or more of the same or different substituents, including halogen, alkenyloxy, aroyl, heteroaroyl, cyano, hydroxy, alkoxy, carboxy, alkynyloxy, aralkoxy, aryloxy, aryloxycarbonyl, alkylthio, heteroarylthio, arylalkylphony, alkylsulfonyl, heteroaralkyloxy, etc.
• Preferred alkenyl groups are ethenyl, propenyl, n-butenyl, iso-butenyl, 3-methylbut-2-enyl, n-pentenyl and n-hexenyl.
• Substituted alkyl substituted alkyl may have one or more, same or different substituents, including halogen, alkenyloxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, aroyl, heteroaryl, cyano, hydroxy, alkoxy, carboxy, alkynyloxy, aralkoxy, aryloxy, aryloxycarbonyl, , heteroarylthio, aralkylthio, arylsulfonyl, alkylsulfonyl, heteroaralkyloxy R ⁇ Rk + i 8 !
• Rk a and Rk + i a are independently “amino substituents”, the meanings of which are defined in this section, for example, a hydrogen atom , alky , Aryl, aralkyl, heteroaralkyl, heterocyclyl or heteroaryl, or Rk a and Rk + i a, together with the atom N, which they are linked to, form through Rk a and Rk + i a 4 - 7 membered heterocyclyl or heterocyclenyl.
• amino substituents amino substituents R 'and R “are hydrogen, optionally substituted with Ci-Csajiioui, optionally substituted C
• Preferred amino substituents are hydrogen, C 1 -C 5 alkyl, C 1 -C 5 cycloalkyl substituted C 1 to C 5 alkyl ( "substituted alkyl"), optionally simultaneously substituted by 1-3 radicals substituted phenyl (Cp C 5 alkyl, halogen, C1-C5 alkoxy group, SrSzalkiloksikarbonilom), pyridinyl, optionally substituted thiophenyl, optionally substituted furanyl m (cm. "cyclic system substituents").
• Substituents of the cyclic system may be representatives of aryl groups, preferably phenyl or naphthyl, substituted phenyl or substituted naphthyl.
• Aryl can be annelated with a non-aromatic ring system or heterocycle.
• zemeslastyami ring system are hydrogen, halogen (chlorine, fluorine, bromine), optionally substituted C1-C5 alkyl optionally substituted tsikloS1-C5 alkyl, C1-C 5 alkene gidroskigruppa, Ci- C5 alkyloxy (methoxy, ethoxy, propoxy, ethylene glycol diester, methanediol diester), cyano group, C 1 -C 5 alkyloxycarbonyl (methyl, ethyl), alkylthio group (methylthio), carboxy group, aminocarbonyl (see “aminocarbonyl”), phenyl annelated with 5-7 membered saturated a cycle containing 1-3 heteroatoms (nitrogen, oxygen and sulfur atoms of the pre respectfully).
• halogen chlorine, fluorine, bromine
• C1-C5 alkyl optionally substituted tsikloS1-C5 al
• Substituent means a chemical radical that is attached to a molecular skeleton (scaffold, fragment), for example, “substituent alkyl”, “substituent of amino group”, “substituent of carbamoyl”, “substituent of cyclic system”, the meanings of which are defined in this section.
• Preferred aminocarbonyl groups are optionally substituted C 1 -C 5 alkyl, C 1 -C 5 alkenyl, C 1 -C 5 cycloalkyl, optionally substituted aryl (see the substituent of the cyclic system), optionally substituted hetaryl (see the substituent of the cyclic system), optionally substituted heterocyclyl (see the substituent of heterocyclyl) or the amino group R'R "N.
• Preferred hydroxycarbonyl groups are methoxycarbonyl, ethoxycarbonyl, tert-butyloxycarbonyl and benzyloxycarbonyl.
• Carbamoyl substituent means a substituent attached to an aminocarbonyl group, the meaning of which is defined in this section.
• the carbamoyl substituent is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, heteroaralkyloxycarbonylalkyl or R
• ⁇ a R k + i a N-, R ⁇ R k + i ⁇ C ⁇ C ⁇ -anK ii, annelated heteroarylcycloalkenyl, annelated heteroarylheterocyclenyl, annelated heteroarylheterocyclylnalkyl, annelated arylcycloalkenylalkenyl, annelated Preferred carbamoyl substituents are alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkoxy
• Heterocycle substituents may be representatives of aryl groups, preferably phenyl or naphthyl, substituted phenyl or substituted naphthyl.
• Aryl can be anelated with a non-aromatic ring system or heterocycle.
• zemeslastyami ring system are hydrogen, halogen (chlorine, fluorine, bromine), optionally substituted C1-C5 alkyl optionally substituted tsikloS 1 -C 5 alkyl, C 1 C 5 alkene gidroskigruppa, C1-C5 alkyloxy group (methoxy, ethoxy , propoxy, ethylene glycol diester, methanediol diester), cyano group, Ci- C 5 alkyloxycarbonyl (methyl, ethyl), alkylthio group (methylthio), carboxy group, aminocarbonyl (see “aminocarbonyl”), phenyl anelated with 5-7-membered saturated containing 1-3 heteroatoms (nitrogen, oxygen and sulfur atoms are preferred total).
• halogen chlorine, fluorine, bromine
• C1-C5 alkyl optionally substituted tsikloS 1 -C 5 alkyl
• Medical product - a substance (or a mixture of substances in the form of a pharmaceutical composition) in the form of tablets, capsules, injections, ointments and other formulations intended to restore, correct or alter physiological functions in humans and animals, as well as for treatment and disease prevention, diagnosis, anesthesia, contraception, cosmetology and more.
• “Lower alkyl” means a linear or branched alkyl with 1-6 carbon atoms.
• a “therapeutic cocktail” is a simultaneously administered combination of two or more drugs with a different mechanism of pharmacological action and aimed at different biological targets involved in the pathogenesis of the disease.
• “Pharmaceutical composition” means a composition comprising a compound of formula I and at least one of the components selected from the group consisting of pharmaceutically acceptable and pharmacologically compatible excipients, solvents, diluents, carriers, excipients, distributing and perceiving agents, agents delivery, such as preservatives, stabilizers, fillers, grinders, moisturizers, emulsifiers, suspending agents, thickeners, sweeteners, perfumes, flavors, antibacterial agents, fungicides, lubricants, prolonged delivery regulators, the choice and ratio of which depends on the nature and method of administration and dosage.
• suspending agents examples include ethoxylated isostearyl alcohol, polyoxyethylene, sorbitol and sorbitol ether, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, as well as mixtures of these substances. Protection against the action of microorganisms can be provided with a variety of antibacterial and antifungal agents, for example, parabens, chlorobutanol, sorbic acid and the like.
• the composition may also include isotonic agents, for example, sugars, sodium chloride and the like.
• the prolonged action of the composition can be achieved using agents that slow down the absorption of the active principle, for example, aluminum monostearate and gelatin.
• suitable carriers, solvents, diluents and delivery vehicles are water, ethanol, polyalcohols, and also mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as ethyl oleate).
• excipients are lactose, milk sugar, sodium citrate, calcium carbonate, calcium phosphate and the like.
• grinders and distributors are starch, alginic acid and its salts, silicates.
• lubricants are magnesium stearate, sodium lauryl sulfate, talc, and high molecular weight polyethylene glycol.
• the pharmaceutical composition for oral, sublingual, transdermal, intramuscular, intravenous, subcutaneous, local or rectal administration of the active principle, alone or in combination with another active principle, can be administered to animals and humans in a standard administration form, in the form of a mixture with traditional pharmaceutical carriers.
• Suitable unit dosage forms include oral forms such as tablets, gelatine capsules, pills, powders, granules, chewing gums and oral solutions or suspensions, sublingual and buccal administration forms, aerosols, implants, local, transdermal, subcutaneous, intramuscular, intravenous, intranasal or intraocular administration forms and rectal administration forms.
• “Pharmaceutically acceptable salt” means the relatively non-toxic organic and inorganic salts of the acids and bases of the present invention. These salts can be obtained in situ during the synthesis, isolation or purification of the compounds or prepared specially. In particular, base salts can be prepared on the basis of the purified free base of the claimed compound and a suitable organic or inorganic acid.
• salts thus obtained are hydrochlorides, hydrobromides, sulfates, bisulfates, phosphates, nitrates, acetates, oxalates, valeriates, oleates, palmitates, stearates, laurates, borates, benzoates, lactates, tosylates, citrates, maleates, fumarates, succinates, tartrates mesylates, malonates, salicylates, propionates, ethanesulfonates, benzenesulfonates, sulfamates and the like (Detailed description of the properties of such salts is given in Berge SM, et al., Pharmaceutical Salts J. Pharm.
• Salts of the claimed acids can also be specially prepared by reacting the purified acid with a suitable base, and metal and amine salts can be synthesized.
• Metal salts include sodium, potassium, calcium, barium, zinc, magnesium, lithium and aluminum salts, the most desirable of which are sodium and potassium salts.
• Suitable inorganic bases from which metal salts can be obtained are hydroxide, carbonate, sodium bicarbonate and hydride, potassium hydroxide and bicarbonate, potash, lithium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide.
• amines and amino acids are selected that are sufficiently basic to form a stable salt and are suitable for medical use (in particular, they should have low toxicity).
• amines include ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, benzylamine, dibenzylamine, dicyclohexylamine, piperazine, ethylpiperidine, tris (hydroxymethyl) aminomethane and the like.
• tetraalkylammonium hydroxides for example, such as choline, tetramethylammonium, tetraethylammonium and the like, can be used for salt formation.
• amino acids the main amino acids can be used - lysine, ornithine and arginine.
• An object of the present invention is to provide novel RNA polymerase inhibitors.
• RNA polymerase of the general formula 1, their steroisomers, salts, hydrates, solvates or crystalline forms.
• the subject of this invention is the new substituted alkyl 2- ⁇ [(2K, 38.5K) -5- (4-amino-2-oxo-2H-pyrimidin-1-yl) -3-hydroxy-tetrahydro-furan-2-ylmethoxy ] -phenoxy-phosphorylamino ⁇ -propionates of the general formula 1, their steroisomers, salts, hydrates, solvates or crystalline forms:
• R 1 represents C 1 -C 4 alkyl
• R 2 and R 3 are fluorine, or
• R represents fluorine, and R represents methyl; RHR 5 are hydrogen, or
• R 4 represents CgC 6 acyl
• R 5 represents hydrogen
• R 4 represents hydrogen, and R 5 represents a C1-C 6 acyl, or
• R 4 is optionally substituted ⁇ -aminoacyl, and R 5 is hydrogen, or
• R 4 represents hydrogen, and R 5 represent optionally substituted
• R 6 represents hydrogen, methyl, methoxy or a halogen atom.
• R 1 , R 4 , R 5 and R 6 have the above meaning
• the subject of this invention is a method for producing compounds of general formula 1 and general formula 2 of their stereoisomers, pharmaceutically acceptable salts, hydrates, solvates or crystalline forms, by reacting a compound of general formula 4 with a compound of general formula 5
• the subject of this invention is a method for producing a compound of general formula 2 of their steroisomer, salt, hydrate, solvate or crystalline form, by reacting a compound of general formula 4 (1) with a compound of general formula 5 (1).
• R 2 , R 3 have the above meanings.
• the subject of this invention is a method for preparing compounds of general formula 1, their stereoisomers, pharmaceutically acceptable salts, hydrates, solvates or crystalline forms, by reacting a compound of general formula 6 with anhydride of general formula 7 in the presence of 4-dimethylaminopyridine (DMAP) and triethylamine.
• DMAP 4-dimethylaminopyridine
• R 4 are optionally substituted ⁇ -aminoacyl, and R 5 are
• the subject of this invention is a method for producing a compound of general formula 3 of its steroisomer, salt, hydrate, solvate or crystalline form, reacting a compound of general formula 2 with acetic anhydride in the presence of 4-dimethylaminopyridine (DMAP) and triethylamine.
• DMAP 4-dimethylaminopyridine
• the subject of this invention is a method for producing compounds of general formula 1, their stereoisomers, pharmaceutically acceptable salts, hydrates, solvates or crystalline forms, by reacting a compound of general formula 6 with an ⁇ -amino acid of general formula 8 in the presence of 1, ⁇ -carbodiimidazole.
• R 4 is hydrogen
• a R 5 is optionally substituted ⁇ -aminoacyl
• R 1 , R 2 , R 3 and R 6 are as defined above.
• the subject of this invention is a method for producing a compound of general formula 1, its steroisomers, salts, hydrates, solvates of crystalline or polycrystalline forms, by reacting a compound of general formula 9 with an acid of general formula 10 in the presence of 1, ⁇ -carbodiimidazole and subsequent deblocking of the resulting product 11.
• R represents an optionally substituted ⁇ -aminoacyl, and R represents hydrogen
• the subject of this invention is an active component having the properties of a nucleoside inhibitor of RNA polymerase HCV NS5B, which is a substituted alkyl 2 - ⁇ [(2R, ⁇ S, 5R) -5- (4-amino-2-o ⁇ co-2H- ⁇ irimidin-l-yl) -3-hydroxy-tetrahydro-furan-2-ylmethoxy] -phenoxy-phosphorylamino ⁇ -propionate of the general formula 1, its steroisomer, salt, hydrate, solvate or crystalline form (S) - isopropyl 2 - ⁇ [(2R, 3S, 5R ) -5- (4-aMHHO-2-oKco-2H-nHpHMHflHH-l-Mr) -3-raflpoKCH- tetrahydro-furan-2-ylmethoxy] -phenoxy-phosphorylamino ⁇ -propionate of general formula 2 and
• a more preferred nucleoside inhibitor of HCV NS5B RNA polymerase is substituted alkyl (S) -2 - ⁇ [(2R, 3S, 5R) -5- (4-aMHHO-2-OKCo-2H-nnpHMHflHH-1-yl) -4, 4-difluoro-3-hydroxy-tetrahydro-furan-2-ylmethoxy] phenoxyphosphorylamino ⁇ propionate of the general formula 1.1 and substituted alkyl (S) -2- ⁇ [(2R, ⁇ S, 4R, 5R) -5- ( 4-amino-2-o ⁇ co-2H- ⁇ -pyrimidin-l-yl) -4,4-difluopop-3-hydroxy-4- methyl 4-fluoro-tetrahydro-furan-2-ylmethoxy] -phenoxy-phosphorylamino ⁇ -propionate of the general formula 1.2.
• a more preferred nucleoside inhibitor of HCV NS5B RNA polymerase is also substituted alkyl (S) -2 - ⁇ [(2R, 3S, 5R) -5- (4-aMHHo-2-OKCo-2H-pyrimidin-1-yl) -4 , 4-difluoro-3-hydroxy-tetrahydro-furan-2-ylmethoxy] -phenoxy-phosphorylamino ⁇ -propionate of the general formula 1.1.1, 1.1.2 and substituted alkyl (S) -2- ⁇ [(2K, 38.4K 5K) -5- (4-amino-2-oxo-2H-pyrimidin-1-yl) -4,4-difluoro-3-hydroxy-4-methyl-4-fluoro-tetrahydro-furan-2-ylmethoxy] -phenoxy-phosphorylamino ⁇ -propionate of the general formula 1.2.1, 1.2.2.
• nucleoside inhibitor of HCV NS5B RNA polymerase is:
• the subject of this invention is a method for inhibiting the HCV NS5B pH polymerase, which comprises contacting the HCV NS5B RNA polymerase with substituted alkyl 2 - ⁇ [(2R, 3S, 5R) -5- (4-aMHHO-2-OKCo-2H-nnpHMHflHH -l-yl) -3-hydroxy-tetrahydro-furan-2-ylmethoxy] -phenoxy-phosphorylamino ⁇ -propionates of the general formula 1, or (3) -isopropyl 2- ⁇ [(2R, 3S, 5R) -5- ( 4-aMHHo-2-oKco-2H-pyrimidin-1-yl) -3-hydroxy-tetrahydro-furan-2-ylmethoxy] phenoxyphosphorylamino ⁇ propionate of the general formula 2 or (3) -isopropyl 2 - ⁇ [(( 2R, 3S, 5R) -3-acetoxy-5-
• a more preferred method of inhibiting HCV NS5B RNA polymerase is a method which comprises contacting HCV NS5B RNA polymerase with substituted alkyl (8) -2 - ⁇ [(2K, 38.5K) -5- (4-amino-2-oxo -2H-pyrimidin-1-yl) -4,4-difluoro-3-hydroxy-tetrahydro-furan-2-ylmethoxy] -phenoxy-phosphorylamino ⁇ -propionates of the general formula 1.1 or substituted alkyl (S) -2 - ⁇ [(( 2R, 3S, 4R, 5R) -5- (4-amino-2-oxo-2H-pyrimidin-1-yl) -4,4-difluoro-3-hydroxy-4-methyl-4-fluoro-tetrahydrofuran -2-ylmethoxy] -phenoxy-phosphorylamino ⁇ -propionates of the general formula 1.2.
• a more preferred method of inhibiting HCV NS5B RNA polymerase is also a method which comprises contacting HCV NS5B RNA polymerase with substituted alkyl (8) -2 - ⁇ [(2K, 38.5K) -5- (4-amino-2- oxo-2H-pyrimidin-1-yl) - 4,4-difluoro-3-hydroxy-tetrahydro-furan-2-ylmethoxy] -phenoxy-phosphorylamino ⁇ -propionates of the general formula 1.1.1, 1.1.2 or substituted alkyl (S ) -2- ⁇ [(2K, 38.4K, 5K) -5- (4-amino-2-oxo-2H-pyrimidin-1-yl) -4,4-difluoro-3-hydroxy-4-methyl- 4-fluoro-tetrahydro-furan-2-ylmethoxy] -phenoxy-phosphorylamino ⁇ -propionates of the general formula 1.
• the most preferred method of inhibiting HCV NS5B RNA polymerase is a method which comprises contacting HCV NS5B RNA polymerase with a compound selected from:
• the subject of this invention is a pharmaceutical composition for the treatment and prophylaxis of viral infections, including hepatitis C, in the form of tablets, capsules or injections in a pharmaceutically acceptable package, optionally containing an inosine-5-monophosphate dehydrogenase inhibitor and / or hepatitis C protease inhibitor NS3, and / or hepatitis C protease inhibitor NS3 / 4A, and / or an NS5A RNA polymerase inhibitor, comprising a therapeutically effective amount of a compound of general formula 1, 2 or 3, or their steroisomers, salts, hydrates, solvates or crystalline forms.
• a pharmaceutical composition comprising, in a therapeutically effective amount, substituted alkyl (S) -2 - ⁇ [(2R, 3S, 5R) -5- (4-amino-2-oxo-2H-pyrimidin-1-yl) -4 , 4-difluoro-3-hydroxy-tetrahydro-furan-2-ylmethoxy] -phenoxy-phosphorylamino ⁇ -propionate of the general formula 1.1 or substituted alkyl (S) -2 - ⁇ [(2R, ⁇ S, 4R, 5R) -5- (4-amino-2-o ⁇ co-2H- ⁇ irimidin-l-yl) -4,4-difluopop-3-hydroxy-4-methyl-4-fluoro-tetrahydro-furan-2-ylmethoxy] -phenoxy-phosphorylamino ⁇ - propionate of the general formula 1.2.
• composition containing in a therapeutically effective amount a compound selected from: (5) -isopropyl 2- ⁇ [(2R, 3S, 5H) -5- (4-amino-2-oxo-2H-pyrimidine-1 - il) -3 - (2-dimethylamino-acetoxy) -4,4-difluoro-3-hydroxy-tetrahydro-furan-2-ylmethoxy] -phenoxy-phosphorylamino ⁇ -propionate (1.1.1 (1));
• RNA polymerase inhibitor is Daclatasvir (BMS-790052) or Declatasvir (GS-5885).
• the subject of this invention is a medicament containing, as an active principle, an effective amount of a compound of the general formula 1, 2 or 3, their stereoisomers, salts, hydrates, solvates or crystalline forms, for the treatment of any condition caused by the hepatitis C virus.
• a drug containing, as an active principle, an effective amount of substituted alkyl (S) -2- ⁇ [(2R, 3S, 5R) -5- (4-amino-2-oxo-2H-pyrimidin-1-yl) -4,4-difluoro-3-hydroxy-tetrahydro-furan-2-ylmethoxy] -phenoxy-phosphorylamino ⁇ -propionate of the general formula 1.1 or substituted alkyl (S) -2 - ⁇ [(2R, ⁇ S, 4R, 5R) - 5- (4-amino-2-o ⁇ co-2H- ⁇ irimidin-l-yl) -4,4-difluoro-3-hydroxy-4-methyl-4-fluoro-tetrahydro-furan-2-ylmethoxy] phenoxyphosphorylamino ⁇ -propionate of the general formula 1.2.
• a medicament containing, as an active principle, an effective amount of substituted alkyl (S) -2- ⁇ [(2R, ZS, 5R) -5- (4-amino-2-o ⁇ co-2H- ⁇ -pyrimidin-l-yl ) -4,4-difluctop-3-hydroxycitrahydro-furan-2-ylmethoxy] phenoxyphosphorylamino ⁇ propionate of the general formula 1.1.1, 1.1.2 or substituted alkyl (S) -2 - ⁇ [(2R, 3S, 4R, 5R) -5- (4-aMHHO-2-oKco-2H-pyrimidin-1-yl) -4,4-difluoro-3-hydroxy-4-methyl-4-fluoro-tetrahydro-furan-2 - Ilmethoxy] -phenoxy-phosphorylamino ⁇ -propionate of the general formula 1.2.1, 1.2.2.
• a medicament containing, as an active principle, an effective amount of a compound selected from:
• Medicines may be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, topically or rectally).
• the clinical dosage of the active component (s), pharmaceutical composition or combination drug comprising a pharmaceutically effective amount of the active component in patients can be adjusted depending on the therapeutic efficacy and bioavailability of the active ingredients in the body, their metabolic rate and excretion from the body, as well as on the age, gender and stage of the patient’s disease, while the daily dose in adults is usually 10 O 500 mg, preferably 50 O 30 0 mg Therefore, during the preparation of the pharmaceutical compositions of the present invention in dosage units, the above effective dosage must be taken into account, with each dosage unit of the preparation containing 10 O 500 mg, preferably 50 D 300 mg. In accordance with the instructions of a doctor or pharmacist, these drugs can be taken several times during certain periods of time (preferably from one to six times).
• the subject of this invention is a method of treating a disease caused by hepatitis C virus, which comprises administering a therapeutically effective amount of a compound of general formula 1, 2 or 3, or a steroisomer, salt, hydrate, solvate, crystalline form or pharmaceutical composition containing compounds of general formula 1, 2 or 3, or a steroisomer, salt, hydrate, solvate, crystalline form thereof.
• a more preferred method for treating hepatitis C virus-associated disease in subjects in need thereof is a method that comprises administering a therapeutically effective amount of substituted alkyl (S) -2- ⁇ [(2K, 38.5K) -5- (4-amino-2 -oxo-2H-pyrimidin-1-yl) -4,4-difluoro-3-hydroxy-tetrahydro-furan-2-ylmethoxy] -phenoxy-phosphorylamino ⁇ -propionate of the general formula 1.1 or substituted alkyl (8) -2- ⁇ [(2K, 38.4 ⁇ 5) -5- (4-amino-2-oxo-2H-pyrimidin-1 - il) -4,4-difluoro-3-hydroxy-4-methyl-4-fluoro-tetrahydro-furan-2-ylmethoxy] phenoxyphosphorylamino ⁇ propionate of the general formula 1.2.
• a more preferred method for treating hepatitis C virus-associated disease in subjects in need thereof is also a method that comprises administering a therapeutically effective amount of substituted alkyl (S) -2- ⁇ [(2K, 38.5K) -5- (4-amino 2-oxo-2H-pyrimidin-1-yl) -4,4-difluoro-3-hydroxy-tetrahydro-furan-2-ylmethoxy] -phenoxy-phosphorylamino ⁇ -propionate of the general formula 1.1.1, 1.1.2 or substituted alkyl (S) -2 - ⁇ [(2R, 3S, 4R, 5R) -5- (4-aMHHO-2-oKCo-2H-pyrimidin-1-yl) -4,4-difluoro-3-hydroxy-4- methyl 4-fluoro-tetrahydro-furan-2-ylmethoxy] -phenoxy-phosphorylamino ⁇ -propionate total f Formulas 1.2.1, 1.2.2
• a clinical dosage of a pharmaceutical composition for the treatment and prevention of viral infections including hepatitis C, in the form of tablets, capsules or injections in a pharmaceutically acceptable package, optionally containing an inosine-5-monophosphate dehydrogenase inhibitor and / or hepatitis C NS3 protease inhibitor, and / or an NS3 / 4A hepatitis C protease inhibitor and / or an NS5A RNA polymerase inhibitor comprising a compound of general formula 1, 2 or 3, or their steroisomers, salts, hydrates, solvates or crystalline forms, in patients four
• these drugs can be taken several times during certain periods of time (preferably from one to six times).
• any classes of agents that may be useful when combined with the compounds of the present invention in a pharmaceutical composition may include, for example, nucleoside and non-nucleoside HCV polymerase inhibitors, protease inhibitors, helicase inhibitors and medical agents that functionally inhibit internal ribosomal entry site (IRES) and other drugs that inhibit the attachment or entry of the virus into cells, transcription of HCV RNA, replication, maturation or attenuated viruses.
• IRS internal ribosomal entry site
• telaprevir VX-950
• boceprevir SCH-503034
• narlaprevir SCH-9005178
• ITMN-191 R-7227
• TMC-435350 aka TMC-435
• MK-7009 MK-7009
• BI-201335 MK-7009
• BI-2061 ciluprevir
• ACH-1625 ACH-1095
• HCV NS4A inhibitor of concomitant protease factor VX-500
• VX-813 PHX-1766
• PHX2054 IDX-136
• IDX-316 ABT-450 EP-013420 (and related) and VBY-376
• nucleoside HCV polymerase inhibitors (replicases) useful in the present invention include, but are not limited to: R7128, IDX-184, IDX-102, R1479, UNX-08189, PSI-6130, PS
• Non-nucleoside HCV polymerase (replicase) inhibitors useful in the present invention include, but are not Limited: HCV-796, HCV-371, VCH-759, VCH-916, VCH-222, ANA-598, MK-3281, ABT-333, ABT-072, PF-00868554, BI-207127, GS-9190, A-837093, J T-109, GL-59728 and GL-60667.
• novel nucleoside inhibitors of HCV NS5B RNA polymerase of general formula 1, 2 or 3 can be used in the pharmaceutical composition in combination with cyclophillin and immunofillin antagonists (for example, without limitation DEBIO compounds, NM-81 1, as well as cyclosporin and its derivatives ), kinase inhibitors, heat shock protein inhibitors (e.g.
• HSP90, HSP70 other immunomodulatory agents, which may include, but are not limited to, interferons (alpha, beta, omega, gamma, lambda or synthetic) such as Intron A TM , Roferon-A TM, Canferon-AZOO TM, Advaferon TM, Infergen TM, H umoferon TM, Sumiferon MP TM, Alfaferon TM, IFN- ⁇ TM, Feron TM, and the like, interferon compounds derivatized with polyethylene glycol (pegylated), such as: PEG interferon-a-2a
• PEG interferon-a-2b PEG interferon-a-2b (PEGIntron 1 M ), pegylated IFN- ⁇ -con 1 and the like; prolonged formulas and derivatives of interferon compounds, such as albumin-condensed interferon, Albuferon TM, Locteron TM, and the like; interferons with various types of controlled delivery (eg ITCA-638, omega-interferon delivered by DUROS subcutaneous delivery system); compounds that stimulate the synthesis of interferon in cells, such as resiquimod and the like; interleukins; compounds that enhance the development of type 1 helper T cell response, such as SCV-07 and the like; TOLL-like receptor agonists, such as: CpG-10101 (action), isotorabine, ANA773 and the like; thymosin ⁇ -1, ⁇ -245 and ⁇ -246, histamine dihydrochloride, propagermanium; tetrachlorodecaoxide; ampligen;
• any of the above methods including the administration of an NS5B inhibitor, an interferon receptor agonist type 1 (e.g. IFN- ⁇ ) and an interferon receptor agonist type P (e.g. IFN- ⁇ ) can be enhanced by the administration of an effective amount of a TNF-a antagonist.
• Typical non-limiting TNF-a antagonists that are suitable for use in such combination therapy are ENBPJEL TM and HUMIRA TM.
• novel HCV NS5B RNA polymerase inhibitor of general formula 1, 2 or 3 can be used in the pharmaceutical composition in combination with antiprotozoans, and other antiviruses are considered effective in treating HCV infections such as: a prodrug of nitazoxanide.
• Nitazoxanide can be used as an agent in combination with the compounds disclosed in this invention, as well as in combination with other agents useful in the treatment of HCV infection, such as: peginterferon alfa-2a and ribavarin (e.g. Rossignol, JF and Keeffe, EB, Future Microbiol. 3: 539-545, 2008).
• novel nucleoside HCV NS5B RNA polymerase inhibitor of general formula 1, 2 or 3 can also be used in pharmaceutical compositions with alternative forms of interferons and pegylated interferons, ribavirin or its analogues (e.g. Tarabavarin, levovirion), microRNA, slightly harmful RNA compounds (e.g. SIRPLEX-140-N and the like), nucleotide or nucleoside analogs, immunoglobulins, hepatoprotectors, anti-inflammatory agents and other NS5B inhibitors.
• interferons and pegylated interferons e.g. Tarabavarin, levovirion
• microRNA e.g. SIRPLEX-140-N and the like
• slightly harmful RNA compounds e.g. SIRPLEX-140-N and the like
• nucleotide or nucleoside analogs e.g. SIRPLEX-140-N and the like
• immunoglobulins e
• Inhibitors of other targets in the HCV life cycle include NS3 helicase inhibitors; co-factor NS4A inhibitors, antisense oligonucleotide inhibitors such as: ISIS-14803, AVI-4065 and the like; vector-encrypted short hairpin RNA (shRNA); HCV specific ribozymes such as: heptazyme, RPI, 139199 and the like; entry inhibitors such as: HepX-C, HuMax-Heps and the like; alpha glucosidase inhibitors such as: celgosivir, UT-231B and the like; KRE-02003002 and BIVN 401 and IMPDH inhibitors.
• Other representative compounds, HCV inhibitors include the inhibitors disclosed in well-known scientific and patent publications.
• combinations of, for example, ribavirin and interferon can be introduced as a combination therapy with at least one new nucleoside HCV NS5B RNA polymerase inhibitor of general formula 1, 2 or 3, or its stereoisomer, pharmaceutically acceptable salt, hydrate, solvate, crystalline or polycrystalline form.
• the present invention is not limited to the above classes or compounds, and contemplates known and novel compounds and combinations of biologically active agents.
• combination therapies of the present invention include any chemical compatible combinations of the novel nucleoside HCV NS5B RNA polymerase inhibitor of general formula 1, 2 or 3 with other compounds of this patented group or other compounds outside this patent group, and the combination does not exclude anti- the viral activity of the compounds of this patent group or the antiviral activity of the pharmaceutical composition itself.
• Combination therapy may be sequential, i.e. treatment first with one agent and then with another (for example, when each treatment step involves a different compound of the present invention or when one treatment step includes a compound of the present invention and the other involves one or more biologically active agents) or there may be a treatment with both agents simultaneously.
• Sequential therapy may include a significant amount of time after the completion of the first therapy and before the second therapy.
• Treatment with both agents at the same time can be carried out in a single daily dose or in different doses.
• Combination therapy does not need to be limited to two agents and may include three or more agents. Doses for simultaneous and sequential combination therapy will depend on absorption, distribution, metabolic rates and excretion of the components of combination therapy, as well as other factors well known to the specialist. The size of the dose will also vary depending on the severity of the condition that needs to be alleviated. It should be understood that for each particular subject, the specific dosage regimen and schedule can be adjusted in time in accordance with the needs of the individual and the professional judgment of the person who treats or monitors the treatment using the combination therapy method.
• Example 1 General method for producing (5) -isopropyl 2 - ⁇ [(2R, JS, 5J?) - 5- (4-aiwHHO-2-oxo-2H-pyrimidin-1-yl) -3- (2-dimethylamino -acetoxy) -4,4-difluoro-3-hydroxy-tetrahydro-furan-2-ylmethoxy] -phenoxy-phosphorylamino ⁇ -propionate (1.1.1 (1)) and (2K, 38.5K) -5- (4 -amino-2-oxo-2H-pyrimidin-1-yl) -4,4-difluoro-2 - [((8) -1-isopropoxycarbonyl-ethylamino) -phenoxy-phosphoryloxymethyl] -tetrahydrofuran-3-yl ( 8) -1-methyl-pyrrolidine-2-carboxylate (1.1.1 (2)).
• Example 2 General method for producing isopropyl (S) -2 - ( ⁇ (2R, 3R, 5R) -5- [4 - ((R) -2- tert-butoxycarbonylamino-3-methyl-butyrylamino) -2-oxo- 2H-pyrimidin-1-yl] - 4,4-difluoro-3-hydroxy-tetrahydro-furan-2-ylmethoxy ⁇ -phenoxy-phosphorylamino) -propionate (1.1.2 (2)) and isopropyl (S) -2- [((2R, ⁇ R, 5R) -, -d ⁇ op-3-hydroxy-5- ⁇ 4- [((8) -1-methylpyrrolidin-2-carbonyl) amino] -2-oxo-2H-pyrimidine-1 -yl ⁇ - tetrahydro-furan-2-ylmethoxy) -phenoxy-phosphorylamino) -propionate (1.1.2 (3)
• Example 3 General method for the production of alkyl 2 - ((((2R, 3R) -5- (4-aminooxopyrimidin-1 (2H) -yl) -3-hydroxy-2-4,4-difluoro-tetrahydrofuran-2 - yl) methoxy) (phenoxy) phosphorylamino) propanoates of the general formula 1-3.
• Example 4 General method for producing (5) -isopropyl 2 - ( ⁇ (2R, 3R, 5R) -5- [4- (2-dimethylamino-acetylamino) -2-oxo-2H-pyrimidin-1-yl] - 4 , 4-difluoro-3-hydroxy-tetrahydro-furan-2-ylmethoxy ⁇ -phenoxy-phosphorylamino) -propionate (1.1.2 (1)) and (5) -isopropyl 2 - [((2L, 5?, 5L) -4,4-difluoro-3-hydroxy-5- ⁇ 4 - [((5) -1-methylpyrrolidin-2-carbonyl) amino] -2-oxo-2H-pyrimidin-1-yl ⁇ -tetrahydro-furan -2-ylmethoxy) -phenoxy-phosphorylamino) -propionate (1.1.2 (4)).
• R represents hydrogen, and R represents optional
• R 1 , R 2 , R 3 and R 6 have the above meaning.
• Example 6 A pharmaceutical composition in the form of tablets. 1600 mg of starch, 1600 mg of crushed lactose, 400 mg of talc and 1000 mg of (5) -isopropyl 2- ((((2?, ⁇ ) -5- (4-aminooxopyrimidin-1 (2H) -yl) -3- hydroxy-2-4,4-difluoro-tetrahydrofuran-2-yl) methoxy) (phenoxy) phosphorylamino) propanoate. The resulting bar is crushed into granules and sieved through sieves, collecting granules of size 14- 16 mesh The granules obtained are tabletted into a suitable tablet form weighing 560 mg each.
• Example 7 A pharmaceutical composition in the form of capsules.
• the resulting powder mixture is packaged in 300 mg in a suitable size gelatin capsule.
• Example 8 A pharmaceutical composition in the form of injectable compositions for intramuscular, intraperitoneal or subcutaneous injection. 500 mg of (5) -isopropyl 2 - (((((2i?, 3 /?) - 5 - (4-amino-oxopyrimidin-1 (2H) -yl) -3-hydroxy-2-4,4-difluoro-tetrahydrofuran -2-yl) methoxy) (phenoxy) phosphorylamino) propanoate with 300 mg of chlorobutanol, 2 ml of propylene glycol and 100 ml of injection water. The resulting solution is filtered and placed in 1 ml ampoules, which are sealed.
• Example 9 A pharmaceutical composition in the form of tablets. 1600 mg of starch, 1600 mg of ground lactose, 400 mg of talc and 1000 mg of ( ⁇ ) - isopropyl 2- (((((2?, 37?) - 5- (4-aminooxopyrimidin-1 (2H) -yl) -3) are mixed -hydroxy-2-4,4-difluoro-tetrahydrofuran-2-yl) methoxy) (phenoxy) phosphorylamino) propanoate. The resulting bar is crushed into granules and sieved through sieves, collecting granules with a size of 14-16 mesh. The granules obtained are tabletted into a suitable tablet form weighing 560 mg each, which is used in conjunction with a Ribamidine tablet.
• Example 10 A pharmaceutical composition in the form of tablets. 1600 mg of starch, 1600 mg of crushed lactose, 400 mg of talc and 1000 mg of (5) -isopropyl 2- (((((2 ⁇ , ⁇ ?) - 5- (4-aminooxopyrimidin-1 (2H) -yl) -3- hydroxy-2-4,4-difluoro-tetrahydrofuran-2-yl) methoxy) (phenoxy) phosphorylamino) propanoate. The resulting bar is crushed into granules and sieved through sieves, collecting granules with a size of 14-16 mesh. The granules obtained are tabletted into a suitable tablet form weighing 560 mg each, which is used in conjunction with an Asunaprevir tablet (BMS-650032).
• Example 11 A pharmaceutical composition in the form of tablets. 1600 mg of starch, 1600 mg of powdered lactose, 400 mg of talc and 1000 mg of (5) -isopropyl 2- ((((2 ⁇ , 3?) - 5- (4-aminooxopyrimidin-1 (2H) -yl) -3 -hydroxy-2-4,4-difluoro-tetrahydrofuran-2-yl) methoxy) (phenoxy) phosphorylamino) propanoate. The resulting bar is crushed into granules and sieved through sieves, collecting granules with a size of 14-16 mesh.
• the granules obtained are tabletted into a suitable tablet form weighing 560 mg each, which is used in conjunction with a Sofosbuvir tablet (TMS435).
• TMS435 Sofosbuvir tablet
• Example 12 A pharmaceutical composition in the form of tablets. 1600 mg of starch, 1600 mg of crushed lactose, 400 mg of talc and 1000 mg of (5) -isopropyl 2- (((((2 / ?, 3 /?) - 5- (4-aminooxopyrimidin-1 (2H) -yl)) -3-hydroxy-2 ⁇ 4,4-difluoro-tetrahydrofuran-2-yl) methoxy) (phenoxy) phosphorylamino) propanoate.
• the resulting bar is crushed into granules and sieved through sieves, collecting granules with a size of 14-16 mesh.
• the granules obtained are tabletted into a suitable tablet form weighing 560 mg each, which is used in conjunction with a tablet of Daclatasvir (BMS-790052) or Declatasvir (GS-5885).
• Example 13 Determination of antiviral activity (EC 50 ) of nucleoside inhibitors of HCV NS5B RNA polymerase of the general formula 1, 2 and 3.
• test substances The antiviral activity (EC 0 ) of nucleoside inhibitors of HCV NS5B RNA polymerase of the general formula 1, 2 and 3 (hereinafter referred to as test substances) was determined in the Huh7 human hepatoma cell line containing the HCV subgenomic RNA replicon (genotype lb, la and 2a).
• test substances For quantitative determination of viral replication, a variant of the ELISA immunological test for viral core antigen in a 96-well format was used. Cytotoxicity (CC50) of test substances was evaluated in parallel.
• PSI-7977 was used as a comparison drug.
• Huh7 cells were seeded in 96-well plates (7.5x103 cells per well in 100 ⁇ l of culture medium).
• Cells were fixed by adding 250 ⁇ l / well of acetone / methanol (1: 1). After 1 minute, the cells were washed three times with PBS (Phosphate Buffered Saline). After that, the cells were blocked by adding 150 ⁇ l / well of 10% fetal calf serum in PBS for 1 hour at room temperature. Further, the cells were incubated with murine monoclonal antibodies to HCV core antigen, clone C7-50 (Source: Affinity BioReagents; Catalog: MA 1-080) (100 ⁇ l / well, working dilution 1: 500 in 10% fetal calf serum in PBS solution) for two hours at 37 ° C.
• murine monoclonal antibodies to HCV core antigen clone C7-50 (Source: Affinity BioReagents; Catalog: MA 1-080) (100 ⁇ l / well, working dilution 1: 500 in 10% fetal calf serum in PBS solution) for two hours at 37
• Example 14 Determination of the cytotoxicity of nucleoside inhibitors of RNA polymerase HCV NS5B of the General formula 1, 2 and 3.
• Cytotoxicity (CK 50 ) of the tested substances was studied in experiments on the culture of the human hepatoma cell line Huh7. Cell metabolic activity was determined using the ATPLite kit (Perkin Elmer, Boston, USA) in accordance with the manufacturer's instructions. The cytotoxic effect was evaluated by plating cells in a black microplate with a transparent bottom (96 cells, 104 cells per well). Three independent repeats were used for each test substance. Test substances were added after 18 hours, after which the cells were incubated with substances for 96 hours.
• CK 5 4.000 As a quantitative parameter for assessing cytotoxicity, a value of CK 5 4.000 was used, which corresponds to the concentration of the test substance at which 50% of the cells die.
• Calculation of the CK 50 parameter: to calculate the inhibition efficiency (% Ing), we used the formula:% Ing [(L p03 - L E ks) / L PO s - Lothr)] * 100%, where Lpoz is a positive control, luminescence in cells with cells without substance; L neg - negative control, luminescence in cells with medium without cells; LEX - luminescence in cells with a substance in a certain concentration.
• the CC50 values were then calculated using the XLfit 4 program. The results are shown in Table 1.
• Table 1 shows the inhibitory activity of some of the newer nucleoside inhibitors.
• test results of new inhibitors of the general formula 1, 2, 3 indicate their high activity and low cytotoxicity.
• unexpectedly claimed compounds turned out to be more active nucleoside polymerase HCV NS5B inhibitors than the most advanced inhibitor PSI-7977.
• the invention can be used in medicine, veterinary medicine, biochemistry.

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