Substituted (2r,3r,5r)-3-hydroxy-(5-pyrimidin-1-yl)tetrahydrofuran-2-ylmethyl aryl phosphoramidates

FIELD: chemistry.

SUBSTANCE: present invention relates to a novel (2R,3R,5R)-3-hydroxy-(5-pyrimidin-1-yl)tetrahydrofuran-2-ylmethyl aryl phosphoramidate of general formula I or a stereoisomer or a pharmaceutically acceptable salt thereof, having properties of nucleoside inihibitors of RNA polymerase NS5B of the hepatitis C virus. The invention also relates to a method of producing compounds, pharmaceutical compositions and a medicinal agent based on said compounds. In general formula 1 , R1 is hydrogen, (CH3)2[(CH3)3C]Si, C2-C6acyl, optionally substituted with a benzyloxy group, NR5R6 group, wherein R5 and R6 are independently hydrogen or C1-C4alkyl; 1-pyrrol-2-ylcarbonyl, piperidin-3-ylcarbonyl or piperidin-4-ylcarbonyl; R2 and R3 are F or R2 is F or OH and R3 is CH3; R4 is hydrogen or methyl; Ar is phenyl, pyridyl or naphthyl, where the phenyl, pyridyl or naphthyl is optionally substituted with at least one of C1-3alkyl, C2-4alkenyl, C2-4alkynyl, C1-3alkoxy, F, Cl, Br, I, nitro, cyano, -N(C1-3alkyl)2; Pm is 2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl or 4-(4-amino-2-oxo-2H-pyrimidin-1-yl), wherein the amino group is optionally substituted with 1-pyrrol-2-ylcarbonyl, piperidin-3-ylcarbonyl, piperidin-4-ylcarbonyl or a C(O)R8 radical, where R8 is C1-C4alkyl, optionally substituted with a NR6R7 group, where R6 and R7 are independently hydrogen or C1-C4alkyl; C1-3alkoxy, optionally substituted with a phenyl; X is O or N-R9, where R9 is C1-C4alkyl, optionally substituted with OH or OCH3; n=1, 2 or 3.

EFFECT: compounds can be used to prevent and treat viral infections, including hepatitis C.

12 cl, 1 tbl, 11 ex

 

The present invention relates to new substituted esters phosphoramides acid and their use as agents for treatment of viral diseases. These compounds are inhibitors of the replication of RNA-dependent RNA virus and are useful as inhibitors of the NS5B polymerase of the hepatitis C virus and for hepatitis C. the hepatitis C Virus, along with other important human pathogens such as yellow fever virus, West Nile virus, a virus Dengue (Dengue) and hepatitis GBV-C, belongs to the Flavivirus (Flaviviridae genus).

It is known that NS5B is a protein of hepatitis b virus [Vincent Soriano et al., Hepatitis C therapy with HCV NS5B polymerase inhibitors, Expert Opinion on Pharmacotherapy, June 2013, Vol.14, No.9, Pages 1161-1170]. Development of antiviral drugs for hepatitis C virus (HCV) is an increasingly rapid pace. Among inhibitors of HCV polymerase, sofosbuvir marketed as a unique companion for ribavirin as therapy for most HCV genotypes 2 or 3.

Modern treatment of chronic hepatitis C, based on the combination of pegylated interferon and ribavirin, is effectively only 50% of patients. Special targeted antiviral therapy represents a promising approach to eradicate the infection. Review [Legrand-Abravanel F, Nicot F, Izopet J. New NS5B polymerase inhibitors for hepatitis C. Expert Opin Investig Drugs. 2010 Aug; 19(8):963-75] has the basics�attention is the progress on the development of polymerase inhibitors of the hepatitis C virus, which have undergone clinical studies in recent years. Nucleos(t)IDE analogues is aimed at the active site of the HCV polymerase and acts as agents breaking a chain. They have high activity against all genotypes. Non-nucleoside achieve inhibition of the polymerase by binding to one of at least four allosteric enzyme sites. Most of them have genotype-specific activity and they can quickly select resistant strains if HCV replication is not completely suppressed. Nevertheless, they provide additional opportunities for the treatment of infected patients. Inhibitors of NS5B polymerase will be an integral part of a more effective anti-HCV therapy in combination with interferon or other antiviral agents direct action.

In the last decade, intensive efforts were focused on the opening of both: nucleos(t)IDE and non-nucleoside NS5B polymerase of HCV. These efforts have led to some promising agents undergoing phase clinical studies. Review [WJ Watkins, Ray AS, Chong LS. HCV NS5B polymerase inhibitors. Curr Opin Drug Discov Devel. 2010 Jul; 13(4):441-65] traces the history of optimization of chemical series, which led to the development of clinical candidates, and summarizes previous research in this area with emphasis on wedge�tration efficiency and the impact on future combined studies.

Examples of drug candidates can serve nucleoside inhibitors of the NS5B polymerase of HCV, PSI-7977 company Pharmasset (USA) and NM283 (Valopicitabine) company Idenix (USA), etc. [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. Steuer, Congrong Niu, M. J. Otto, P. A. Furman. Discovery of a β-D-20-Deoxy-20-r-fluoro-20-beta-C-methyluridine Nucleotide Prodrug (PSI-7977) for the Treatment of Hepatitis With Virus. J. Med. Chem. 2010, 53, 7202-7218; Pat. US 7964580 B2; US Pat 8334270 B2.].

To date, the hepatitis C is a serious public health problem. It leads to chronic liver disease, turning to cirrhosis and hepatocellular carcinoma.

In this regard, the search for new highly effective protivovirusnyh medicines now continues to be one of the main directions of development of new pharmacological agents for the treatment of a wide and diverse range of viral infections, including HCV. So up to the present time is the actual synthesis of new compounds and their use as antiviral active component for pharmaceutical compositions and medicines, including HCV.

The following are the definitions of terms used in the description of this invention:

"Alkyl" means aliphatic linear or branched hydrocarbon group with 1-12 carbon atoms in the chain. Time�atlanna means, which the alkyl chain has one or more "lower alkyl" substituents. The alkyl may have one or more identical or different substituents ("alkyl substituents") including halogen, alkenylacyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, aroyl, cyano, hydroxy, alkoxy, carboxy, alkyloxy, Alcoxy, aryloxy, aryloxyalkyl, alkylthio, heteroaromatic, Uralkali, arylsulfonyl, alkylsulfonates, annelirovannymi heteroarylboronic, annelirovannymi heteroalicyclic, annelirovannymi heterooligomerization, annelirovannymi heteroaryl heterocyclyl, annelirovannymi arylchloroalkanes, annelirovannymi aristically, annelirovannymi arylheteroacetic, annelirovannymi arithmetiles, alkoxycarbonyl, arelaxation, heteroarylboronic or RkaRk+1aN-, RkaRk+1aNC(=O)-, RkaRk+1aNC(=S)-, RkaRk+1aNSO2-, where Rkaand Rk+1aindependently from each other represent "amino substituents of the group", the value of which is determined in this section, for example, a hydrogen atom, alkyl, aryl, aralkyl, heteroalkyl, heterocyclyl or heteroaryl, or Rkaand Rk+1atogether with the N atom to which they are linked,�will pull your boots off R kaand Rk+1a4-7 membered heterocyclyl or heterocyclyl. Preferred alkyl groups are methyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, n-propyl, ISO-propyl, n-butyl, tert-butyl, n-pentyl, 3-pentyl, methoxyethyl, carboxymethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, benzyloxycarbonylamino and pyridinedicarboxylate. The preferred "alkyl substituents" are cycloalkyl, aryl, heteroaryl, heterocyclyl, hydroxy, alkoxy, alkoxycarbonyl, Alcoxy, aryloxy, alkylthio, heteroaromatic, Uralkali, alkylsulfonyl, arylsulfonyl, alkoxycarbonyl, arelaxation, heteroarylboronic or RkaRk+1aN-, RkaRk+1aNC(=O)-, annelirovannymi arylheteroacetic, annelirovannymi arithmetiles.

"Alkyloxy (alkoxy)" means CnH2n+1O - group in which alkyl is defined in this section. Preferred alkyloxy groups are methoxy, ethoxy, n-propoxy, ISO-propoxy and n-butoxy.

"Aryl" means an aromatic monocyclic or polycyclic system containing from 6 to 14 carbon atoms, mainly from 6 to 10 carbon atoms. Aryl can contain one or more "substituents of the cyclic system, which can be the same or different. �the representatives of aryl groups are phenyl, substituted phenyl, naphthyl, and substituted naphthyl. Aryl may be anaeroven with non-aromatic cyclic system or heterocycle.

"Aryloxy" means aryl-O - group, where aryl is defined in this section.

Representatives of aryloxy groups are phenoxy and 2-naphthyloxy.

"Hydrate" means stoichiometric or non-stoichiometric compositions of the compounds or their salts with water.

"Deputy" means a chemical radical that is attached to scaffold (fragment), for example, "the Deputy alkyl", "Deputy amino group", "Deputy carbamoyl", "Deputy cyclic system".

"Active ingredient" (drug substance, drug substance, drug-substance) means a physiologically active substance of synthetic or other (biotechnological, vegetable, animal, microbial or other origin that possess pharmacological activity and which is the active ingredient of the pharmaceutical composition used for the production and manufacture of a medicinal product (funds).

"The drug (small molecule), a substance (or mixture of substances in the form of a pharmaceutical composition) in the form of tablets, capsules, injections, ointments and other ready-made forms for restoring, correcting or modifying physiological f�of NCCI in humans and animals, and also for the treatment and prevention of diseases, diagnostics, anesthesia, contraception, cosmetology and others.

"Lower alkyl" means linear or branched alkyl with 1-4 carbon atoms.

"Therapeutic cocktail" is simultaneously administrarea combination of two or more drugs with different mechanism of pharmacological action and aimed at different biomechani involved in the pathogenesis of the disease.

"Pharmaceutical composition" means a composition that includes a compound of formula 1 or 2 and at least one component selected from the group consisting of pharmaceutically acceptable and pharmacologically compatible fillers, solvents, diluents, carriers, auxiliary, distributing and perceiving means, means of delivery, such as preservatives, stabilizers, fillers, shredders, moisturizers, emulsifiers, suspendresume agents, thickeners, sweeteners, flavors, fragrances, antibacterial agents, fungicides, lubricants, regulators prolonged delivery, the selection and ratio of which depends on the nature and mode of appointment and dosage. Examples suspendida agents are ethoxylated isostearoyl alcohol, polyoxyethylene, sorbitol and sorbitol ether, microcrystal�the algebraic cellulose, Metagalaxy aluminum, bentonite, agar-agar and tragakant and mixtures of these substances. Protection from the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, sorbic acid and similar compounds. The composition may also include isotonic agents, for example sugars, sodium chloride and the like. Prolonged action of the composition can be achieved with agents that slow down the absorption of the active principle, for example, aluminum monostearate and gelatin. Examples of suitable carriers, solvents, diluents and delivery vehicles include water, ethanol, property, as well as mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as ethyloleate). Examples of fillers include lactose, milk sugar, sodium citrate, calcium carbonate, calcium phosphate and the like. Examples of shredders and distributing funds include starch, alginic acid and its salts, silicates. Examples of lubricants are magnesium stearate, sodium lauryl sulfate, talc, and polyethylene glycol with high molecular weight. Pharmaceutical composition for oral, sublingual, transdermal, intramuscular, intravenous, subcutaneous, local�or rectal administration of the active principle, one or in combination with another active early, can be introduced animals and people in the standard form of introduction, or as a mixture with traditional pharmaceutical carriers. Suitable standard forms of administration include oral forms such as tablets, gelatin capsules, pills, powders, granules, chewing gums and oral solutions or suspensions, sublingual and buccal forms of administration, aerosols, implants, local, transdermal, subcutaneous, intramuscular, intravenous, intranasal or intraocular forms of administration and rectal forms of administration.

"Pharmaceutically acceptable salt" means relatively non-toxic organic and inorganic salts of acids and bases, as claimed in the present invention. These salts can be obtained in situ during the synthesis, separation or purification of compounds or prepared. In particular, salts of the bases can be obtained specifically, based on the purified free base of the claimed compounds and a suitable organic or inorganic acid. Examples of the thus obtained salts are hydrochloride, hydrobromide, sulfates, bisulfate, phosphates, nitrates, acetates, oxalates, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, tosylate, citrate, maleate, fumarate, bitches�inaty, tartrate, mesylate, malonate, salicylates, propionates, econsultancy, benzolsulfonat, sulfamate and similar (for a Detailed description of the properties of such salts is given in Berge S. M., et al., "Pharmaceutical Salts" J. Pharm. Sci. 1977, 66: 1-19). Salts of the stated acids can also be specially obtained by the reaction of purified acid with a suitable base, can be synthesized metal salts and amines. The metal salts are sodium, potassium, calcium, barium, zinc, magnesium, lithium and aluminum, the most desirable of which are salts of sodium and potassium. Suitable inorganic bases, of which can be obtained metal salts are the hydroxide, carbonate, bicarbonate and sodium hydride, hydroxide, carbonate and bicarbonate, potassium hydroxide, lithium hydroxide, calcium hydroxide, magnesium hydroxide, zinc. As the organic bases, which can be obtained salts of the stated acids, selected amines and amino acids that have sufficient basicity to form a stable salt, and suitable for use in medical purposes (in particular, they must have low toxicity). Such amines include ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, benzylamine, dibenzylamine, dicyclohexylamine, piperazine, ethylpiperidine, Tris(gidroximetil)aminomethan and similar. Cu�IU, for the salt formation can be used hydroxides of tetraalkylammonium, such as, choline, Tetramethylammonium, tetraethylammonium and the like. As amino acids can be used basic amino acids such as lysine, ornithine and arginine.

The object of the present invention are compounds that represent new substituted esters aminophosphonic acid - (2R,3R,5R)-3-hydroxy-(5-pyrimidine-1-1-yl)tetrahydrofuran-2-ylmethyl the aryl phosphoramidate of the General formula 1, or its stereoisomers, or a pharmaceutically acceptable salt,

where:

R1represents hydrogen, (CH3)2[(CH3)3S]Si, C2-C6acyl, optionally substituted benzyloxycarbonyl, NR5R6the group in which R5and R6are independently hydrogen or C1-C4alkyl; 1-pyrrol-2-ylcarbonyl, piperidine-3-ylcarbonyl or piperidine-4-ylcarbonyl;

R2and R3represent F or R2represents F or HE R3represents CH3;

R4represents hydrogen or methyl;

Ar represents phenyl, pyridyl or naphthyl, where phenyl, pyridyl or naphthyl are optionally substituted with at least one of: C1-3alkyl, C2-4of alkenyl, C2-4alkynyl, S1-3ALCO�si F, CL, Br, I, nitro, cyano, -N(C1-3alkyl)2;

Pm represents a 2,4-diokso-3,4-dihydro-2H-pyrimidine-1-yl or 4-(4-amino-2-oxo-2H-pyrimidine-1-yl), in which the amino group is optionally substituted 1-pyrrol-2-ylcarbonyl, piperidine-3-ylcarbonyl, piperidine-4-ylcarbonyl or a radical C(O)R8where R8represents C1-C4alkyl, optionally substituted NR6R7group, where R6and R7are independently hydrogen or C1-C4alkyl; C1-3alkoxy, optionally substituted by phenyl;

X represents O or N-R9where R9represents C1-C4alkyl, optionally substituted HE or och3;

n=1,2 or 3.

Preferred new substituted ethers aminophosphonic acids are compounds of the General formula 1.1, or the General formula 2.1, or a stereoisomer, or pharmaceutically acceptable salt,

where R1, R2, R3and X have the above value.

Preferred new substituted ethers aminophosphonic acids are compounds of the General formula 1.2 or the General formula 2.2, or a stereoisomer, or pharmaceutically acceptable salt,

where R1, R2, R3and X have the above value.

More pre�respectful new substituted ethers aminophosphonic acids are compounds of the General formula 1, selected from the group consisting of: ((2R,3R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl p-tolyl (S)-2-oxo-tetrahydrofuran-3-yl-phosphoramidic 1(1),

((2R,3R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl 4-chlorophenyl (S)-2-oxo-tetrahydrofuran-3-yl-phosphoramidic 1(2),

((2R,3R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl 2,4-dichlorophenyl (S)-2-oxo-tetrahydrofuran-3-yl-phosphoramidic 1(3),

(2R,3R,5R)-5-(4-atsetamido-2-oxopyrimidine-1(2H)-yl)-4,4-debtor-2-(((S)-(S)-2-oxitetraciclina-3-ylamino)(phenoxy)phosphoryloxy)methyl)tetrahydrofuran-3-yl acetate 1(4),

benzyl 1-(2R,4R,5R)-4-(benzyloxycarbonyloxy)-3,3-debtor-5-(((S)-((S)-(2-oxitetraciclina-3-ylamino)(phenoxy)phosphoryloxy)methyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidine-4-ylcarbamate 1(5),

benzyl 1-((2R,4R,5R)-4-(benzyloxycarbonyloxy)-3,3-debtor-5-(((1-methyl-2-oxopyrrolidin-3-ylamino)(phenoxy)phosphoryloxy)methyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidine-4-ylcarbamate 1(6),

benzyl 1-((2R,4R,5R)-4-(benzyloxycarbonyloxy)-3,3-debtor-5-(((1-methyl-2-oxopiperidin-3-ylamino)(phenoxy)phosphoryloxy)methyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidine-4-ylcarbamate 1(7),

((2R,3R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl phenyl 1-methyl-2-oxopiperidin-3-ifosfamide 1(8),

((2R,3R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl phenyl 2-ecoocean-3-yl-phosphoramidic 1(9),

benzyl 1-((2R,4R,5R)-4-(benzyloxycarbonyloxy)-5-(((5,5-dimethyl-2-oxitetraciclina-3-ylamino)(phenoxy)phosphoryloxy)methyl)-3,3-deverticalization-2-yl)-2-oxo-1,2-dihydropyrimidine-4-ylcarbamate 1(10),

((2R,3R,5R)-5-(2,4-diokso-3,4-dihydropyrimidine-1(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl phenyl 5,5-dimethyl-2-oxitetraciclina-3-ifosfamide 1(11),

(R)-((2R,3R,5R)-5-(2,4-diokso-3,4-dihydropyrimidine-1(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl phenyl ((S)-2-oxitetraciclina-3-yl)phosphoramidic 1(12),

((2R,3R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl phenyl 1-methyl-2-oxopyrrolidin-3-ifosfamide 1(13),

((2R,3R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl phenyl 5,5-dimethyl-2-oxitetraciclina-3-ifosfamide 1(14),

(R)-((2R,3R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl phenyl 1-methyl-2-oxopyrrolidin-3-ifosfamide 1(15),

((2R,3R,5R)-5-(2,4-diokso-3,4-dihydropyrimidine-1(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl phenyl 2-oxitetraciclina-3-ifosfamide 1(16),

((2R,3R,4R,5R)-5-(2,4-diokso-3,4-dihydropyrimidine-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methyl phenyl (S)-2-oxitetraciclina-3-ifosfamide 1(17)

((2R,3R,5R)-5-(2,4-diokso-3,4-dihydropyrimidine-1(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)IU�yl phenyl 1-methyl-2-oxopyrrolidin-3-ifosfamide 1(18),

((2R,3R,5R)-3-(tert-butyldimethylsilyloxy)-5-(2,4-diokso-3,4-dihydropyrimidine-1(2H)-yl)-4,4-deverticalization-2-yl)methyl phenyl 1-methyl-2-oxopyrrolidin-3-ifosfamide 1(19),

((2R,3R,5R)-3-(tert-butyldimethylsilyloxy)-5-(2,4-diokso-3,4-dihydropyrimidine-1(2H)-yl)-4,4-deverticalization-2-yl)methyl phenyl 1-methyl-2-oxopiperidin-3-ifosfamide 1(20),

((2R,3R,5R)-5-(2,4-diokso-3,4-dihydropyrimidine-1(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl phenyl (R)-2-oxitetraciclina-3-ifosfamide 1(21)

((2R,3R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl phenyl (S)-2-oxitetraciclina-3-ifosfamide 1(22),

(2R,3R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4,4-debtor-2 -(((( S)-2-oxitetraciclina-3-ylamino)(phenoxy)phosphoryloxy)methyl)tetrahydrofuran-3-yl acetate 1(23),

((2R,3R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-3-(tert-butyldimethylsilyloxy)-4,4-deverticalization-2-yl)methyl phenyl (S)-2-oxitetraciclina-3-ifosfamide 1(24),

((2R,3R,4R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methyl phenyl (S)-2-oxitetraciclina-3-ifosfamide 1(25),

((2R,3R,4R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methyl phenyl 5,5-dimethyl-2-oxitetraciclina-3-ifosfamide 1(26),

((2R,3R,4R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)m�Teal phenyl 1-methyl-2-oxopyrrolidin-3-ifosfamide 1(27),

(S)-((2R,3R,5R)-5-(2,4-diokso-3,4-dihydropyrimidine-1(2H)-yl)- 4,4-debtor-3-hydroxymitragynine-2-yl)methyl phenyl ((R)-2-oxitetraciclina-3-yl)phosphoramidic 1(28),

((2R,3R,5R)-5-(2,4-diokso-3,4-dihydropyrimidine-1(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl phenyl 1-methyl-2-oxopyrrolidin-3-ifosfamide 1(29), and

(S)-((2R,3R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl phenyl 1-methyl-2-oxopyrrolidin-3-ifosfamide

,,

,,

,,

,

,,

,,

,,

,,

,,

,,

,,

,,

,,

,,

The object of the present invention is a method for producing a compound of formula 1 or its stereoisomer of the compound of formula 6 with a compound of formula 4 and the subsequent mixing with the amine of formula 8,

where Ar, n, R1, R2, R3, R4, R9and Pm have the above value.

The object of the present invention is a method for producing a compound of formula 1 or its stereoisomer, where R1represents acyl, the acylation of a compound of formula 1, where R1represents hydrogen.

The object of the present invention is a method of producing compounds of the General formula 1 or its stereoisomer, where R1is a dimethyl-tert-butyldimethylsilyl, mixing dimethyl-tert-butyldimethylsilyl chloride with a compound of formula 1, where R1represents hydrogen.

The object of the present invention is a method of producing compounds of the General formula 1 or its stereoisomer, the interaction of the amine of formula 3 with a compound of the General formula 4 and subsequent mixing with the compound of formula 6,

where Ar, n, R1, R2, R3, R4and Pm have the above value.

The separation of racemic mixtures of compounds of the General formula 1 in stereos�measures is carried out either by crystallization and/or LC, or performed by crystallization and/or HPLC.

The starting compounds used in the above process of obtaining a new substituted ether aminophosphonic acid represented by the General formula 1, its stereoisomers, pharmaceutically acceptable salts, are commercially available compounds or they can be obtained easily known from the literature methods. The quality of the connections is controlled using LCMS and NMR spectra.

To determine the antiviral activity of substituted esters aminophosphonic acid of the General formula 1 (test compounds) is used HCV replicons analysis. As a test cell line used in HCV replicons analysis, take a cell line of human hepatoma Huh7 containing the HCV replicon (genotype 1b, Con1 strain). The cells are sown in 96-well plates in a density of 7.5×103cells per well in 50 μl of growth medium. The basic solutions of the test compounds were prepared just before use in a nutrient medium, DMEM (IX DMEM, Cellgro; cat. # 10-013-CV) in the form 2X double sinks. Just cook 11 series 3-fold dilutions of test compounds from 2 double sinks in a nutrient medium with a final concentration range of 20 nm to 0.2 PM. At least 4 hours after cells were seeded, initiate the processing of compounds by EXT�effect to each plate, 50 μl of a certain breeding compounds. The final concentration of the tested compounds is from 10 nm to 0.1 PM after dilution 1:1 of available nutrient. The final concentration of DMSO is 0.5%. Cells and inhibitors were incubated for three days at 37°C/5% CO2. Environment removed from the plates by careful tapping. The cells are fixed by adding 100 µl of a mixture of acetone/methanol (1:1) for 1 minute, then three times washed with a buffer solution of PBS, and then blocked by adding 150 μl/well of 10% fetal calf serum (FBS) in PBS solution for 1 hour at room temperature. The cells three times washed with buffer solution, PBS, and incubated with antibodies to measles-antigen hepatitis C mAb 100 µl/well (Affinity BioReagents; cat. # MA-080, 1 mg/ml stock was diluted 1:4000 in 10% FBS-PBS) for 2 hours at 37°C. Cells were washed 3 times with PBS solution and incubated with goat antibodies to mouse immunoglobulins (HRP-Goat Anti-Mouse antibody) in an amount of 100 μl/well (diluted 1:3,500 in 10% FBS-PBS) for 1 hour at 37°C. Cells were washed 3 times with PBS solution and incubated with OPD solution of 100 μl/well (1 OPD tablet + 12 ml citrate/phosphate buffer + 5 µl of 30% H2O2on the tablet) for 30 minutes in the dark at room temperature. The reaction is stopped by addition of 2 n of H2SO4in the amount of 100 μl/well, and measuring the optical density at A490X on multichannel spectrophotome�tre Victor 3V 1420 (Perkin Elmer). The values of EC50for each tested compound was calculated from the equations of best fit using XLFit.

The cytotoxicity of the tested compounds examined in experiments on the culture of the cell line human hepatoma Huh7. The number of living cells is determined using the ATPLite kit (Perkin-Elmer, Boston, USA), according to manufacturer's instructions. The cells are sown in 96-well black microplate glass bottom a density of 7.5×103cells per well in 50 μl medium. After 18 hours was initiated by treatment of compounds by adding to each plate, 50 μl of a certain breeding compounds. Each dilution of the compounds tested in three parallel experiments. Cells and inhibitors were incubated for 96 hours at 37°C/5% CO2. Tablets washed twice with phosphate-saline buffer PBS (0.2 ml/well), and then lisarow cells by adding 0.05 ml/well of cell buffer (all these reagents included in the kit ATPLite). After incubation for 5 minutes on a rotating platform add 0.05 ml/well of the buffer substrate. After incubation for a further 5 minutes to stand the tablet in the dark for 10 minutes and measure luminescence of the device TopCount NXT (Packard, Perkin Elmer). The value of EC50for all tested compounds are defined by the program�we XLfit 4.1.

The results of these studies show that the new substituted esters aminophosphonic acid of the General formula 1 are potent inhibitors of the HCV in vitro with low cytotoxicity.

Inhibiting activity (EC50in terms of HCV replicons analysis of some new substituted esters aminophosphonic acid of the General formula 1 presented in table 1. As seen from table 1 new NS5B inhibitors of the General formula 1 possess micromolar cytotoxicity (CC50and mu activity (EC50), which, as a rule, considerably higher activity of the known inhibitor PSI-7851 live [EC50=75 nm. E. Murakami, T. Tolstykh, H. HLW, S. Niu, H. M. Micolochick Steuer, D. Bao, W. Chang, C. Espiritu, S. Bansal, A. M. Lam, M. J. Otto, M. J. Sofia, P. A. Furman. Mechanism of Activation of PSI-7851 live and Its Diastereoisomer PSI-7977. J. Biol. Chem., 285(45), 34337-34347 (2010)].

Table 1
The activity of NS5B inhibitors of the General formula 1 to HCV genotype 1b (10% FBS)
No. inhibitorFormulaEC50nm
1(4)42.1
1(7)552.3

1(8)873.3
1(8)*HCl905.7
1(10)28.3
1(12)162.2

1(16)458.9
1(17)273.6
1(19)Is at 40.54
1(22)19.8

1(23)27.0
1(24)285.4
1(30)219.3
PSI-7851 live59.4*
* experimental data of the inventors.

The object of the present invention is the use of a substituted ether aminophosphonic acid of the General formula 1, or its stereoisomers, or its pharmaceutically acceptable salt as an active component, which possesses the properties of nucleoside RNA polymerase NS5B of hepatitis C virus,

where:

R1represents hydrogen, (CH3)2[(CH3)3S]Si2-C6acyl, optionally substituted benzyloxycarbonyl, NR5R6the group in which R5and R6are independently hydrogen or C1-C4alkyl; 1-pyrrol-2-ylcarbonyl, piperidine-3-ylcarbonyl or piperidine-4-ylcarbonyl;

R2and R3represent F or R2represents F or HE R3represents CH3;

R4represents hydrogen or methyl;

Ar represents phenyl, pyridyl or naphthyl, where phenyl, pyridyl or naphthyl are neoba�Acelino substituted with at least one of: C 1-3alkyl, C2-4of alkenyl, C2-4alkenyl, C1-3Alaksi, F, Cl, Br, I, nitro, cyano, -N(C1-3alkyl)2;

Pm represents a 2,4-diokso-3,4-dihydro-2H-pyrimidine-1-yl or 4-(4-amino-2-oxo-2H-pyrimidine-1-yl), in which the amino group is optionally substituted 1-pyrrol-2-ylcarbonyl, piperidine-3-ylcarbonyl, piperidine-4-ylcarbonyl or a radical C(O)R8where R8represents C1-C4alkyl, optionally substituted NR6R7group, where R6and R7are independently hydrogen or C1-C4alkyl; C1-3alkoxy, optionally substituted by phenyl;

X represents O or N-R9where R9represents C1-C4alkyl, optionally substituted HE or och3;

n=1, 2, or 3.

According to the present invention, more preferable are compounds represented by the General formula 1, or its stereoisomers, or its pharmaceutically acceptable salt, selected from:

((2R,3R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl p-tolyl (S)-2-oxo-tetrahydrofuran-3-yl-phosphoramidic 1(1),

((2R,3R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl 4-chlorophenyl (S)-2-oxo-tetrahydrofuran-3-yl-phosphoramidic 1(2),

((2R,3R,5R)-5-(4-amino-2-oxopyrimidine-12H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl 2,4-dichlorophenyl (S)-2-oxo-tetrahydrofuran-3-yl-phosphoramidic 1(3),

(2R,3R,5R)-5-(4-atsetamido-2-oxopyrimidine-1(2H)-yl)-4,4-debtor-2-(((S)-(S)-2-oxitetraciclina-3-ylamino)(phenoxy)phosphoryloxy)methyl)tetrahydrofuran-3-yl acetate 1(4),

benzyl 1-(2R,4R,5R)-4-(benzyloxycarbonyloxy)-3,3-debtor-5-(((S)-((S)-(2-oxitetraciclina-3-ylamino)(phenoxy)phosphoryloxy)methyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidine-4-ylcarbamate 1(5),

benzyl 1-((2R,4R,5R)-4-(benzyloxycarbonyloxy)-3,3-debtor-5-(((1-methyl-2-oxopyrrolidin-3-ylamino)(phenoxy)phosphoryloxy)methyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidine-4-ylcarbamate 1(6),

benzyl 1-((2R,4R,5R)-4-(benzyloxycarbonyloxy)-3,3-debtor-5-(((1-methyl-2-oxopiperidin-3-ylamino)(phenoxy)phosphoryloxy)methyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidine-4-ylcarbamate 1(7),

((2R,3R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl phenyl 1-methyl-2-oxopiperidin-3-ifosfamide 1(8),

((2R,3R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl phenyl 2-ecoocean-3-yl-phosphoramidic 1(9),

benzyl 1-((2R,4R,5R)-4-(benzyloxycarbonyloxy)-5-(((5,5-dimethyl-2-oxitetraciclina-3-ylamino)(phenoxy)phosphoryloxy)methyl)-3,3-deverticalization-2-yl)-2-oxo-1,2-dihydropyrimidine-4-ylcarbamate 1(10),

((2R,3R,5R)-5-(2,4-diokso-3,4-dihydropyrimidine-1(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl phenyl 5,5-dimethyl-2-oxitetraciclina-3-ifosfamide� 1(11),

(R)-((2R,3R,5R)-5-(2,4-diokso-3,4-dihydropyrimidine-1(2H)-yl)- 4,4-debtor-3-hydroxymitragynine-2-yl)methyl phenyl ((S)-2-oxitetraciclina-3-yl)phosphoramidic 1(12),

((2R,3R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl phenyl 1-methyl-2-oxopyrrolidin-3-ifosfamide 1(13),

((2R,3R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl phenyl 5,5-dimethyl-2-oxitetraciclina-3-ifosfamide 1(14),

(R)-((2R,3R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl phenyl 1-methyl-2-oxopyrrolidin-3-ifosfamide 1(15),

((2R,3R,5R)-5-(2,4-diokso-3,4-dihydropyrimidine-1(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl phenyl 2-oxitetraciclina-3-ifosfamide 1(16),

((2R,3R,4R,5R)-5-(2,4-diokso-3,4-dihydropyrimidine-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methyl phenyl (S)-2-oxitetraciclina-3-ifosfamide 1(17)

((2R,3R,5R)-5-(2,4-diokso-3,4-dihydropyrimidine-1(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl phenyl 1-methyl-2-oxopyrrolidin-3-ifosfamide 1(18),

((2R,3R,5R)-3-(tert-butyldimethylsilyloxy)-5-(2,4-diokso-3,4-dihydropyrimidine-1(2H)-yl)-4,4-deverticalization-2-yl)methyl phenyl 1-methyl-2-oxopyrrolidin-3-ifosfamide 1(19),

((2R,3R,5R)-3-(tert-butyldimethylsilyloxy)-5-(2,4-diokso-3,4-dihydropyrimidine-1(2H)-yl)-4,4-deverticalization-2-yl)methyl 1 phenyl-meth�l-2-oxopiperidin-3-ifosfamide 1(20),

((2R,3R,5R)-5-(2,4-diokso-3,4-dihydropyrimidine-1(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl phenyl (R)-2-oxitetraciclina-3-ifosfamide 1(21)

((2R,3R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl phenyl (S)-2-oxitetraciclina-3-ifosfamide 1(22),

(2R,3R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4,4-debtor-2 -(((( S)-2-oxitetraciclina-3-ylamino)(phenoxy)phosphoryloxy)methyl)tetrahydrofuran-3-yl acetate 1(23),

((2R,3R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-3-(tert-butyldimethylsilyloxy)-4,4-deverticalization-2-yl)methyl phenyl (S)-2-oxitetraciclina-3-ifosfamide 1(24),

((2R,3R,4R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methyl phenyl (S)-2-oxitetraciclina-3-ifosfamide 1(25),

((2R,3R,4R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methyl phenyl 5,5-dimethyl-2-oxitetraciclina-3-ifosfamide 1(26),

((2R,3R,4R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methyl phenyl 1-methyl-2-oxopyrrolidin-3-ifosfamide 1(27),

(S)-((2R,3R,5R)-5-(2,4-diokso-3,4-dihydropyrimidine-1(2H)-yl)- 4,4-debtor-3-hydroxymitragynine-2-yl)methyl phenyl ((R)-2-oxitetraciclina-3-yl)phosphoramidic 1(28),

((2R,3R,5R)-5-(2,4-diokso-3,4-dihydropyrimidine-1(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl phenyl 1-methyl-2-oxopyrrolidin--ifosfamide 1(29), and

(S)-((2R,3R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl phenyl 1-methyl-2-oxopyrrolidin-3-ifosfamide 1(30).

The object of the present invention is a pharmaceutical composition for prevention and/or treatment of viral infections, including hepatitis C, containing the active ingredient in a therapeutically effective quantity represented by the General formula 1, or its stereoisomer, or its pharmaceutically acceptable salt, and pharmaceutically acceptable excipient selected from a filler, carrier, solvent,

where:

R1represents hydrogen, (CH3)2[(CH3)3S]Si C2-C6acyl, optionally substituted benzyloxycarbonyl, NR5R6the group in which R5and R6are independently hydrogen or C1-C4alkyl; 1-pyrrol-2-ylcarbonyl, piperidine-3-ylcarbonyl or piperidine-4-ylcarbonyl;

R2and R3represent F or R2represents F or HE R3represents CH3;

R4represents hydrogen or methyl;

Ar represents phenyl, pyridyl or naphthyl, where phenyl, pyridyl or naphthyl are optionally substituted with at least one of: C1-3alkyl, C2-4of alkenyl, C2-4alkyne�l, C1-3alkoxy, F, Cl, Br, I, nitro, cyano, -N(C1-3alkyl)2;

Pm represents a 2,4-diokso-3,4-dihydro-2H-pyrimidine-1-yl or 4-(4-amino-2-oxo-2H-pyrimidine-1-yl), in which the amino group is optionally substituted 1-pyrrol-2-ylcarbonyl, piperidine-3-ylcarbonyl, piperidine-4-ylcarbonyl or a radical C(O)R8where R8represents C1-C4alkyl, optionally substituted NR6R7group, where R6and R7are independently hydrogen or C1-C4alkyl; C1-3alkoxy, optionally substituted by phenyl;

X represents O or N-R9where R9represents C1-C4alkyl, optionally substituted HE or och3;

n=1, 2, or 3.

According to the present invention, more preferred is a pharmaceutical composition comprising the active ingredient in a therapeutically effective quantity represented by the General formula 1, or its stereoisomer, or its pharmaceutically acceptable salt, and pharmaceutically acceptable excipient selected from a filler, carrier, solvent, where the substituted ether aminophosphonic acid of the General formula 1 is selected from:

((2R,3R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl p-tolyl (S)-2-oxo-tetrahydrofuran-3-yl-phosphoramidic 1(1),

((2R,3,5 R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl 4-chlorophenyl (S)-2-oxo-tetrahydrofuran-3-yl-phosphoramidic 1(2),

((2R,3R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl 2,4-dichlorophenyl (S)-2-oxo-tetrahydrofuran-3-yl-phosphoramidic 1(3),

(2R,3R,5R)-5-(4-atsetamido-2-oxopyrimidine-1(2H)-yl)-4,4-debtor-2-(((S)-(S)-2-oxitetraciclina-3-ylamino)(phenoxy)phosphoryloxy)methyl)tetrahydrofuran-3-yl acetate 1(4),

benzyl 1-(2R,4R,5R)-4-(benzyloxycarbonyloxy)-3,3-debtor-5-(((S)-((S)-(2-oxitetraciclina-3-ylamino)(phenoxy)phosphoryloxy)methyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidine-4-ylcarbamate 1(5),

benzyl 1-((2R,4R,5R)-4-(benzyloxycarbonyloxy)-3,3-debtor-5-(((1-methyl-2-oxopyrrolidin-3-ylamino)(phenoxy)phosphoryloxy)methyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidine-4-ylcarbamate 1(6),

benzyl 1-((2R,4R,5R)-4-(benzyloxycarbonyloxy)-3,3-debtor-5-(((1-methyl-2-oxopiperidin-3-ylamino)(phenoxy)phosphoryloxy)methyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidine-4-ylcarbamate 1(7),

((2R,3R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl phenyl 1-methyl-2-oxopiperidin-3-ifosfamide 1(8),

((2R,3R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl phenyl 2-ecoocean-3-yl-phosphoramidic 1(9),

benzyl 1-((2R,4R,5R)-4-(benzyloxycarbonyloxy)-5-(((5,5-dimethyl-2-oxitetraciclina-3-ylamino)(phenoxy)phosphoryloxy)methyl)-3,3-deverticalization-2-yl)-2-oxo-1,2-dihydropyrimidine-4-ylcarbamate 1(10),

((2R,3R,5R)-5-(2,4-diokso-3,4-dihydropyrimidine-1(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl phenyl 5,5-dimethyl-2-oxitetraciclina-3-ifosfamide 1(11),

(R)-((2R,3R,5R)-5-(2,4-diokso-3,4-dihydropyrimidine-1(2H)-yl)- 4,4-debtor-3-hydroxymitragynine-2-yl)methyl phenyl ((S)-2-oxitetraciclina-3-yl)phosphoramidic 1(12),

((2R,3R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl phenyl 1-methyl-2-oxopyrrolidin-3-ifosfamide 1(13),

((2R,3R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl phenyl 5,5-dimethyl-2-oxitetraciclina-3-ifosfamide 1(14),

(R)-((2R,3R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl phenyl 1-methyl-2-oxopyrrolidin-3-ifosfamide 1(15),

((2R,3R,5R)-5-(2,4-diokso-3,4-dihydropyrimidine-1(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl phenyl 2-oxitetraciclina-3-ifosfamide 1(16),

((2R,3R,4R,5R)-5-(2,4-diokso-3,4-dihydropyrimidine-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methyl phenyl (S)-2-oxitetraciclina-3-ifosfamide 1(17)

((2R,3R,5R)-5-(2,4-diokso-3,4-dihydropyrimidine-1(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl phenyl 1-methyl-2-oxopyrrolidin-3-ifosfamide 1(18),

((2R,3R,5R)-3-(tert-butyldimethylsilyloxy)-5-(2,4-diokso-3,4-dihydropyrimidine-1(2H)-yl)-4,4-deverticalization-2-yl)methyl phenyl 1-methyl-2-ocsober�lidin-3-ifosfamide 1(19),

((2R,3R,5R)-3-(tert-butyldimethylsilyloxy)-5-(2,4-diokso-3,4-dihydropyrimidine-1(2H)-yl)-4,4-deverticalization-2-yl)methyl phenyl 1-methyl-2-oxopiperidin-3-ifosfamide 1(20),

((2R,3R,5R)-5-(2,4-diokso-3,4-dihydropyrimidine-1(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl phenyl (R)-2-oxitetraciclina-3-ifosfamide 1(21)

((2R,3R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl phenyl (S)-2-oxitetraciclina-3-ifosfamide 1(22),

(2R,3R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4,4-debtor-2 -(((( S)-2-oxitetraciclina-3-ylamino)(phenoxy)phosphoryloxy)methyl)tetrahydrofuran-3-yl acetate 1(23),

((2R,3R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-3-(tert-butyldimethylsilyloxy)-4,4-deverticalization-2-yl)methyl phenyl (S)-2-oxitetraciclina-3-ifosfamide 1(24),

((2R,3R,4R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methyl phenyl (S)-2-oxitetraciclina-3-ifosfamide 1(25),

((2R,3R,4R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methyl phenyl 5,5-dimethyl-2-oxitetraciclina-3-ifosfamide 1(26),

((2R,3R,4R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methyl phenyl 1-methyl-2-oxopyrrolidin-3-ifosfamide 1(27),

(S)-((2R,3R,5R)-5-(2,4-diokso-3,4-dihydropyrimidine-1(2H)-yl)- 4,4-debtor-3-hydroxymitragynine-2-yl)methyl phenyl ((R)-2-OK�tetrahydrofuran-3-yl)phosphoramidic 1(28),

((2R,3R,5R)-5-(2,4-diokso-3,4-dihydropyrimidine-1(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl phenyl 1-methyl-2-oxopyrrolidin-3-ifosfamide 1(29), and

(S)-((2R,3R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl phenyl 1-methyl-2-oxopyrrolidin-3-ifosfamide 1(30).

More preferred pharmaceutical composition may additionally contain at least one drug substance selected from the group comprising: an inhibitor of inosine 5-monophosphate dehydrogenase, an inhibitor of the NS3 protease of the hepatitis C protease inhibitor NS3/4A of hepatitis C and the inhibitor of RNA polymerase NS5A.

The object of the present invention is a medicament for the prevention and treatment of viral infections, including hepatitis C, in the form of tablets, capsules, injections, ointments, rectal suspensions and gels, placed in pharmaceutically acceptable packing, containing a therapeutically effective amount of the active ingredient, which are compounds of the General formula 1, or a new pharmaceutical composition.

The object of the present invention is a method for the prevention and treatment of diseases caused by hepatitis C virus, comprising introducing a therapeutically effective amount of the active component, representing compounds of the General formula 1, or a new pharmaceutical industry�tion of the composition to a subject, the needy in this,

where:

R1represents hydrogen, (CH3)2[(CH3)3S]Si, C2-C6acyl, optionally substituted benzyloxycarbonyl, NR5R6the group in which R5and R6are independently hydrogen or C1-C4alkyl; 1-pyrrol-2-ylcarbonyl, piperidine-3-ylcarbonyl or piperidine-4-ylcarbonyl;

R2and R3represent F or R2represents F or HE R3is a CH3;

R4represents hydrogen or methyl;

Ar represents phenyl, pyridyl or naphthyl, where phenyl, pyridyl or naphthyl are optionally substituted with at least one of: C1-3alkyl, C2-4of alkenyl, C2-4alkenyl, C1-3alkoxy, F, Cl, Br, I, nitro, cyano, -N(C1-3alkyl)2;

Pm represents a 2,4-diokso-3,4-dihydro-2H-pyrimidine-1-yl or 4-(4-amino-2-oxo-2H-pyrimidine-1-yl), in which the amino group is optionally substituted 1-pyrrol-2-ylcarbonyl, piperidine-3-ylcarbonyl, piperidine-4-ylcarbonyl or a radical C(O)R8where R8represents C1-C4alkyl, optionally substituted NR6R7group, where R6and R7are independently hydrogen or C1-C4alkyl; C1-3Alcock�and, optionally substituted phenyl;

X represents O or N-R9where R9represents C1-C4alkyl, optionally substituted HE or OCH3;

n=1, 2, or 3.

According to the present invention, more preferred is a method for the prevention and treatment of diseases, comprising introducing a therapeutically effective amount of the active component, representing compounds of the General formula 1, or a new pharmaceutical composition to a subject in need this, where compounds of the General formula 1 is selected from:

((2R,3R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl p-tolyl (S)-2-oxo-tetrahydrofuran-3-yl-phosphoramidic 1(1),

((2R,3R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl 4-chlorophenyl (S)-2-oxo-tetrahydrofuran-3-yl-phosphoramidic 1(2),

((2R,3R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl 2,4-dichlorophenyl (S)-2-oxo-tetrahydrofuran-3-yl-phosphoramidic 1(3),

(2R,3R,5R)-5-(4-atsetamido-2-oxopyrimidine-1(2H)-yl)-4,4-debtor-2-(((S)-(S)-2-oxitetraciclina-3-ylamino)(phenoxy)phosphoryloxy)methyl)tetrahydrofuran-3-yl acetate 1(4),

benzyl 1-(2R,4R,5R)-4-(benzyloxycarbonyloxy)-3,3-debtor-5-(((S)-((S)-(2-oxitetraciclina-3-ylamino)(phenoxy)phosphoryloxy)methyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimido�n-4-ylcarbamate 1(5),

benzyl 1-((2R,4R,5R)-4-(benzyloxycarbonyloxy)-3,3-debtor-5-(((1-methyl-2-oxopyrrolidin-3-ylamino)(phenoxy)phosphoryloxy)methyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidine-4-ylcarbamate 1(6),

benzyl 1-((2R,4R,5R)-4-(benzyloxycarbonyloxy)-3,3-debtor-5-(((1-methyl-2-oxopiperidin-3-ylamino)(phenoxy)phosphoryloxy)methyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidine-4-ylcarbamate 1(7),

((2R,3R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl phenyl 1-methyl-2-oxopiperidin-3-ifosfamide 1(8),

((2R,3R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl phenyl 2-ecoocean-3-yl-phosphoramidic 1(9),

benzyl 1-((2R,4R,5R)-4-(benzyloxycarbonyloxy)-5-(((5,5-dimethyl-2-oxitetraciclina-3-ylamino)(phenoxy)phosphoryloxy)methyl)-3,3-deverticalization-2-yl)-2-oxo-1,2-dihydropyrimidine-4-ylcarbamate 1(10),

((2R,3R,5R)-5-(2,4-diokso-3,4-dihydropyrimidine-1(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl phenyl 5,5-dimethyl-2-oxitetraciclina-3-ifosfamide 1(11),

(R)-((2R,3R,5R)-5-(2,4-diokso-3,4-dihydropyrimidine-1(2H)-yl)- 4,4-debtor-3-hydroxymitragynine-2-yl)methyl phenyl ((S)-2-oxitetraciclina-3-yl)phosphoramidic 1(12),

((2R,3R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl phenyl 1-methyl-2-oxopyrrolidin-3-ifosfamide 1(13),

((2R,3R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4,4-�iftar-3-hydroxymitragynine-2-yl)methyl phenyl 5,5-dimethyl-2-oxitetraciclina-3-ifosfamide 1(14),

(R)-((2R,3R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl phenyl 1-methyl-2-oxopyrrolidin-3-ifosfamide 1(15),

((2R,3R,5R)-5-(2,4-diokso-3,4-dihydropyrimidine-1(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl phenyl 2-oxitetraciclina-3-ifosfamide 1(16),

((2R,3R,4R,5R)-5-(2,4-diokso-3,4-dihydropyrimidine-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methyl phenyl (S)-2-oxitetraciclina-3-ifosfamide 1(17)

((2R,3R,5R)-5-(2,4-diokso-3,4-dihydropyrimidine-1(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl phenyl 1-methyl-2-oxopyrrolidin-3-ifosfamide 1(18),

((2R,3R,5R)-3-(tert-butyldimethylsilyloxy)-5-(2,4-diokso-3,4-dihydropyrimidine-1(2H)-yl)-4,4-deverticalization-2-yl)methyl phenyl 1-methyl-2-oxopyrrolidin-3-ifosfamide 1(19),

((2R,3R,5R)-3-(tert-butyldimethylsilyloxy)-5-(2,4-diokso-3,4-dihydropyrimidine-1(2H)-yl)-4,4-deverticalization-2-yl)methyl phenyl 1-methyl-2-oxopiperidin-3-ifosfamide 1(20),

((2R,3R,5R)-5-(2,4-diokso-3,4-dihydropyrimidine-1(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl phenyl (R)-2-oxitetraciclina-3-ifosfamide 1(21)

((2R,3R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl phenyl (S)-2-oxitetraciclina-3-ifosfamide 1(22),

(2R,3R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4,4-debtor-2 -(((( S)-2-oxitetraciclina-3-ylamino)(phenoxy)phosphoryloxy)IU�yl)tetrahydrofuran-3-yl acetate 1(23),

((2R,3R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-3-(tert-butyldimethylsilyloxy)-4,4-deverticalization-2-yl)methyl phenyl (S)-2-oxitetraciclina-3-ifosfamide 1(24),

((2R,3R,4R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methyl phenyl (S)-2-oxitetraciclina-3-ifosfamide 1(25),

((2R,3R,4R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methyl phenyl 5,5-dimethyl-2-oxitetraciclina-3-ifosfamide 1(26),

((2R,3R,4R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methyl phenyl 1-methyl-2-oxopyrrolidin-3-ifosfamide 1(27),

(S)-((2R,3R,5R)-5-(2,4-diokso-3,4-dihydropyrimidine-1(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl phenyl ((R)-2-oxitetraciclina-3-yl)phosphoramidic 1(28),

((2R,3R,5R)-5-(2,4-diokso-3,4-dihydropyrimidine-1(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl phenyl 1-methyl-2-oxopyrrolidin-3-ifosfamide 1(29), and

(S)-((2R,3R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl phenyl 1-methyl-2-oxopyrrolidin-3-ifosfamide 1(30).

The clinical dosage of the pharmaceutical composition containing as an active ingredient at least one substituted ether aminophosphonic acid of the General formula 1, or a stereoisomer, or pharmaceutically acceptable salt, can be corrected in at�animosty from: therapeutic efficacy and bioavailability of the active ingredients in the body of the patient, the speed of their metabolism and excretion from the body, and depending on the age, sex and severity of the patient's symptoms, the daily dose in adults is usually 10~500 mg. Therefore, during the preparation of the pharmaceutical compositions of the present invention in the form of dosage units it is necessary to consider the above-mentioned effective dosage, wherein each unit dosage of the drug should contain 10~500 mg of the substituted ether aminophosphonic acid of the General formula 1, or its stereoisomers, or a pharmaceutically acceptable salt.

In accordance with the instructions of the doctor or pharmacist these medications can be taken several times within a certain period of time (preferably one to six times).

The object of the present invention is a method of inhibiting RNA polymerase NS5B of hepatitis C, comprising contacting the RNA polymerase NS5B of hepatitis C with the compounds of the General formulas 1, 1.1, 1.2, 2.1, or 2.2, or their stereoisomers, or pharmaceutically acceptable salts.

The object of the present invention is also a therapeutic cocktail for prophylaxis and treatment of humans and animals, inficirovannyh Flaviviridae, including hepatitis C virus, comprising as one component of a pharmacologically effective amount of a substituted ether aminophosphonic acid obatala 1, or its stereoisomer, or a pharmaceutically acceptable salt, or a pharmaceutical composition containing a substituted ether aminophosphonic acid of the General formula 1, or a stereoisomer, or pharmaceutically acceptable salt.

Therapeutic cocktails for the prevention and treatment of the above flavivirus diseases, including hepatitis C, along with drugs of the present invention may include other active components, such as: inhibitors of inosine-5-monophosphate dehydrogenase, for example, Ribavirin (allowed) and Ibumetin; inhibitors of NS3 protease of hepatitis C e.g. Telaprevir and Boceprevir; inhibitors of RNA polymerase NS5A, for example, VX222, R7128, PF-868554, ANA598; inhibitors of alpha-glucosidase, for example, aminoplast Celgosivir; and TLR agonists receptors, hepatoprotectors, cyclosporine, various proteins (for example, interferons), antibodies, vaccines, etc.

For combined therapy of any classes of agents that may be useful combined with the compounds of the present invention include, for example, nucleoside and non-nucleoside polymerase inhibitors of hepatitis C protease inhibitors, inhibitors of helicase, NS4A inhibitors and the medical agents that functionally inhibit the internal ribosomal site of entry (IRES) and other medicaments that inhibit be�of cells or the occurrence of the virus, broadcasting RNA of hepatitis C, replicatio or HCV maturation, or virus isolation.

Specific compounds in these classes and useful in this invention include, but are not limited to, macrocyclic, heterocyclic and linear HCV protease inhibitors such as Telaprevir (VX-950), Boceprevir (SCH-503034), Nalapril. (SCH-900518), ITMN-191 (R-7227), TMC-435350 (a.k.a. TMC-435), MK-7009, BI-201335, BI-2061 (Ciluprevir), BMS-650032, ACH-1625, ACES 1095 (connecting factor inhibitor of HCV protease NS4A), VX-500, VX-813, PHX-1766, PHX2054, IDX-136, IDX-316, ABT-450 EP-013420 (and congeners), and inhibitors of nucleoside polymerase (replication enzyme) HCV useful in this invention include, but are not limited to, R7128, PSI-7851 live, IDX-184, IDX-102, R1479, UNX-08189, PSI-6130, PSI-938 and PSI-879 and various other nucleoside and nucleotide analogs and HCV inhibitors including (but not limited to) derived from 2'-C-methyl modified nucleosides and nucleotides; and 7'-deaza modified nucleosides and nucleotides. Inhibitors nonnucleoside polymerase (replication enzyme) HCV useful in this invention include, but are not limited to, HCV-796, HCV-371, VCH-759, VCH-916, VCH-222, ANA-598, MK-3281, ABT-333, ABT-072, PF-00868554, BI-207127, GS-9190, A-837093, JKT-109, GL-59728 and GL-60667.

In addition, NS5B inhibitors of the present invention can be used in combination with antagonists cyclophilin and immunophilin (e.g., without limitation DEBIO compounds, NM-811, as well as cyclop�Rin and its derivatives), inhibitors of kinases, inhibitors of heat shock proteins (eg. HSP90, HSP70), other immunomodulatory agents that may include, without limitation, the interferons (alpha, beta, omega, gamma, lambda or synthetic), such as Intron A™, Roferon-A™, Canferon-A300™, Advaferon™, Infergen™, Humoferon™, Sumiferon MP™, Alfaferon™, IFN-β™, Feron™, and the like, interferon compounds, derivateservlet polyethylene glycol (pegylated), such as PEG interferon-α-2A (Pegasys™)That PEG interferon-α-2b (PEGIntron™), pegylated IFN-α-con 1 and the like; a time-released formula and derivatives of interferon compounds such as the albumin-condensed interferon, Albuferon™, Locteron™, and the like; interferons with various types of controlled delivery (e.g. ITCA-638, omega-interferon delivered by subcutaneous DUROS delivery system); compounds that stimulate the synthesis of interferon in cells, such as Resiquimod and the like; interleukins; compounds that enhance the development of the response of a type 1 helper T cells, such as SCV-07 and the like; TOLL - like receptor agonists such as CpG-10101 (effect), Isotorabine, ANA773 and the like; Thymosin α-1, ANA-245 and ANA-246, histamine dihydrochloride, Propagermanium; Tetrachlorodecaoxide; Ampligen; IMP-321; K. RN-7000; antibodies, such as Civacir, XTL-6865 and the like and prophylactic and therapeutic vaccines such as: Inno Vac, HCV E1E2/MF59 and the like. In addition, any of the above methods, incl�schy introduction NS5B inhibitor, agonist receptor interferon type 1 (eg. IFN-α) and agonist receptor interferon type P (eg. IFN-γ), can be enhanced by the introduction of an effective amount of TNF-α antagonist. Typical, but not limited to, TNF-α antagonists that are suitable for use in such combination therapies include ENBREL™ and HLJMIRA™.

In addition, NS5B inhibitors of the present invention can be used in combination with Antiprotozoal and other antivirus software that is considered effective in the treatment of HCV infection, such as a prodrug Nitazoxanide. Nitazoxanide can be used as an agent in combination with the compounds disclosed in this invention, and in combination with other agents useful in the treatment of HCV infection, such as Peginterferon alfa-2a and Ribavarin (eg. Rossignol, JF and Keeffe, EB, Future Microbiol. 3:539-545, 2008).

NS5B inhibitors of the present invention can also be used in combination with alternative forms of interferons and pegylated interferons, Ribavirin or its analogs (eg. Tarabavarin, Levovirion), microRNA, malovrednyh RNA compounds (eg. SIRPLEX-140-N and the like), analogs of nucleotides or nucleosides, immunoglobulins, liver, anti-inflammatory agents and other inhibitors of NS5A. Inhibitors of other targets in the HCV life cycle include inhibitors of NS3 helicase inhibitors; NS4A co-factor, ing�bitory antisense oligonucleotides such as ISIS-14803, AVI-4065 and the like; vector-encoded short hairpin RNA (shRNA); specific HCV ribozymes such as Heptazyme, RPI, 139199, and the like; entry inhibitors such as: Nerej-C, HuMax-nurse, and the like; inhibitors of alpha-glucosidase, such as Celgosivir, UT-231B and the like; KPE-02003002 and BIVN 401 and IMPDH inhibitors. Other exemplary compounds as HCV inhibitors include inhibitors disclosed in well-known scientific and patent publications.

Additionally, the combination of, for example, Ribavirin and interferon can be administered as combination therapy with at least one substituted ether aminophosphonic acid of the General formula 1, or a stereoisomer, or pharmaceutically acceptable salt. The present invention is not limited to the above classes or connections and considers known and new compounds and combinations of biologically active agents. Have in mind that the combined therapy of the present invention include any chemically compatible combination of patentable compounds in this group with other compounds patentable group or other compounds outside of patentable group, and the combination does not eliminate the antiviral activity of compounds of this group patentable or antiviral activity of the pharmaceutical composition.

Combination therapy may be�ü consistent, i.e. the first treatment with one agent and then another (for example, when each stage of treatment involves another compound of the present invention or when one stage of treatment comprises the compound of the present invention, and the other involves one or more biologically active agents) or can be treatment with both agents at the same time. Sequential therapy may involve significant time after the completion of the first stage of therapy and prior to the second stage of therapy. Treatment with both agents at the same time can be carried out in a single daily dose or in separate doses. Combination therapy does not require the restriction to two agents and may include three or more agents. Doses for simultaneous and sequential combination therapy will depend on the absorption, distribution, metabolism and excretion of the components of the combination therapy, as well as other factors well known to the specialist. The size of the dose will also vary depending on the severity of the condition, which should be eased. For each special subject of a specific regimen of doses and schedules may be adjusted over time in accordance with individual need and the professional judgment of the person who treats or supervises the treatment method of combination therapy.

Performance�awinnie following examples illustrate, but do not limit the invention.

Example 1. General method of obtaining compounds of General formula 1

((2R,3R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl phenyl (S)-2-oxitetraciclina-3-ifosfamide 1.2(1).

Mixed 2.18 mmol (300 mg) amine with 3 2.18 mmol aryl dichlorophosphate 4 in 15 ml of dichloromethane and cooled in an argon atmosphere to -70°C. To this mixture was added a solution of 0.6 ml of triethylamine (4.36 mmol) in 3 ml of dichloromethane and the reaction mixture was stirred for 30 minutes at -70°C. Remove the cooling and allow the reaction mixture to warm to room temperature. Dichloro methane was evaporated, the residue was added ether, filtered, and a precipitate, which was washed with ether. The filtrate is evaporated and the residue chromatographic on silica gel using the eluent ethyl acetate-hexane 1:1, 2:1. Get the aryl amidophosphate 5. Dissolve the aryl amidophosphate 5 (2.9 mmol), substituted 1-((2R,4S,5R)-4-hydroxy-5-(gidroximetil)tetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione 6(1) (2.9 mmol)or substituted 4-amino-1-((2R,4S,5R)-4-hydroxy-5-(gidroximetil)tetrahydrofuran-2-yl)pyrimidine-2(1H)-he 6(2) (2.9 mmol) and 433 ml (2.9 mmol) of DBU in 20 ml of acetonitrile and the reaction mixture is boiled for 16 hours. The reaction mixture was cooled, diluted with ethyl acetate and washed with water. The organic layer is dried over Na2/sub> SO4and evaporated in vacuo. Purification of the product is carried out using a HPLC method without acid in the mobile phase. Get compound of General formula 1, including:

((2R,3R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl p-tolyl (S)-2-oxo-tetrahydrofuran-3-yl-phosphoramidic 1(1), LC-MS (ESI) [M+H]+517;

((2R,3R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl 4-chlorophenyl (S)-2-oxo-tetrahydrofuran-3-yl-phosphoramidic 1(2), LC-MS (ESI) [M+H]+537;

((2R,3R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl 2,4-dichlorophenyl (S)-2-oxo-tetrahydrofuran-3-yl-phosphoramidic 1(3), LC-MS (ESI) [M+H]+572;

benzyl 1-(2R,4R,5R)-4-(benzyloxycarbonyloxy)-3,3-debtor-5-(((S)-((S)-(2-oxitetraciclina-3-ylamino)(phenoxy)phosphoryloxy)methyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidine-4-ylcarbamate 1(5), LC-MS (ESI) [M+H]+771.1H NMR (DMSO-d6, 400 MHz) δ 11.04 (s, 1H), 8.02 (d, J=7.6 Hz, 1H), 7.39 (m, 13H), 7.23 (m, 2H), 7.18 (m, 1H), 7.13 (d, J=7.2 Hz, 1H), 6.35 (t, J=8.6 Hz, 1 H), 6.15 (DD, J1=12.4 Hz, J2=10.4 Hz, 1H), 5.38 (m, 1H), 5.24 (AB sys, J=12.0 Hz, 2H), 5.21 (s, 2H), 4.58 (m, 1H), 4.51 (m, 1H), 4.43 (m, 1H), 4.27 (m, 2H), 4.15 (m, 1H), 2.36 (m, 1H), 2.01 (m, 1H);

((2R,3R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl phenyl 2-ecoocean-3-yl-phosphoramidic 1(9), LC-MS (ESI) [M+H]+531;

((2R,3R,5R)-5-(2,4-diokso-3,4-dihidro�rimidine-1(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl phenyl 5,5-dimethyl-2-oxitetraciclina-3-ifosfamide 1(11), LC-MS (ESI) [M+H]+532;

((2R,3R,5R)-5-(2,4-diokso-3,4-dihydropyrimidine-1(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl phenyl 2-oxitetraciclina-3-ifosfamide 1(16), LC-MS (ESI) [M+H]+504;

((2R,3R,4R,5R)-5-(2,4-diokso-3,4-dihydropyrimidine-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methyl phenyl (S)-2-oxitetraciclina-3-ifosfamide 1(17), LC-MS (ESI) [M+H]+500,1H NMR (DMSO-d6, 400 MHz) δ 11.47 (s, 1H), 7.55 (d, J=7.6 Hz, 1H), 7.39 (m, 2H), 7.26 (m, 2H), 7.19 (m, 1H), 6.13 (m, 1H), 6.03 (m, 1H), 5.89 (m, 1H), 5.58 (m, 1H), 4.30 (m, 5H), 4.05 (m, 1H), 3.83 (br m, 1H), 2.33 (m, 1H), 2.00 (m, 1H), 1.25 (m, 3H);

((2R,3R,5R)-3-(tert-butyldimethylsilyloxy)-5-(2,4-diokso-3,4-dihydropyrimidine-1(2H)-yl)-4,4-deverticalization-2-yl)methyl phenyl 1-methyl-2-oxopyrrolidin-3-ifosfamide 1(19), LC-MS (ESI) [M+H]+631;

((2R,3R,5R)-5-(2,4-diokso-3,4-dihydropyrimidine-l(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl phenyl (R)-2-oxitetraciclina-3-ifosfamide 1(21), LC-MS (ESI) [M+H]+504,1H NMR (DMSO-d6, 400 MHz) δ 11.61 (s, 1H), 7.55 (m, 1H), 7.38 (m, 2H), 7.23 (m, 3H), 6.50 (br m, 1H), 6.13 (m, 2H), 5.65 (m, 1H), 4.25 (m, 7H), 2.34 (m, 1H), 2.00 (m, 1H);

((2R,3R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4,4-debtor-3-

hydroxymitragynine-2-yl)methyl phenyl (S)-2-oxitetraciclina-3-ifosfamide 1(22), LC-MS (ESI) [M+H]+503,1H NMR (DMSO-d6, 400 MHz): δ of 7.70 (d, J=7,2 Hz, 1H), 7,40 (m, 4H), 7,25 (m, 3H), 6,38 (m, 1H), from 6.22 (m, 1H), 5,80 (D. d, J1=7,6 Hz, J2=2,8 Hz, 1H), 5,20 (b.s, 1H), to 5.05 (m, 1H), 4,28 (m, 2H), 3,58-422 (m, 4H), is 2.40 (m, 1H), 2,04 (m, 1H);

((2R,3R,5R)-5-(2,4-diokso-3,4-dihydropyrimidine-l(2H)-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methyl phenyl (S)-2-oxitetraciclina-3-ifosfamide, LC-MS (ESI) [M+H]+498;

((2R,3R,5R)-5-(4-amino-2-oxopyrimidine-l(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl pyridine-2-yl(S)-2-oxo-tetrahydrofuran-3-yl-phosphoramidate, LC-MS (ESI) [M+H]+504;

((2R,3R,5R)-5-(4-amino-2-oxopyrimidine-l(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl naphthalene-1-yl(S)-2-oxo-tetrahydrofuran-3-yl-phosphoramidate, LC-MS (ESI) [M+H]+553;

((2R,3R,5R)-5-(4-amino-2-oxopyrimidine-l(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl 4-vinylphenol(S)-2-oxo-tetrahydrofuran-3-yl-phosphoramidate, LC-MS (ESI) [M+H]+529;

((2R,3R,5R)-5-(4-amino-2-oxopyrimidine-l(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl 3-ethynylphenyl(S)-2-oxo-tetrahydrofuran-3-yl-phosphoramidate, LC-MS (ESI) [M+H]+527;

((2R,3R,5R)-5-(4-amino-2-oxopyrimidine-l(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl-methoxyphenyl(S)-2-oxo-tetrahydrofuran-3-yl-phosphoramidate, LC-MS (ESI) [M+H]+533;

((2R,3R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl 4-nitrophenyl (S)-2-oxo-tetrahydrofuran-3-yl-phosphoramidate, LC-MS (ESI) [M+H]+548;

((2R,3R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl 4-cyanophenyl (S)-2-oxo-tetrahydrofuran-3-yl-phosphoramidate, LC-MS (ESI) [M+H]+528;

((2R,3R,5R)-5-(4-amino-2-oxopyrimidine-1 (2H)-yl)-4,4-debtor-3-

hydroxymitragynine-2-yl)methyl 4-(dimethylamino)phenyl (8)-2-oxo-tetrahydrofuran-3-yl-phosphoramidate, LC-MS (ESI) [M+H]+546.

Example 2. General method of obtaining compounds of General formula 1

To a solution of 0.8 mmol of the aryl phosphorodichloridate 4 in 5 ml of MeCN was added, dropwise, a solution of 0.67 mmol of alcohol 6 and N-methylimidazole (55 mg, 0.67 mmol) in 4 ml of MeCN at -10°C and the mixture was stirred at -10°C for 5 h. then was added a solution of 0.8 mmol of amine hydrochloride 8 and N-methylimidazole (131 mg, 1.6 mmol) in 10 ml DCM and the mixture was stirred at room temperature for 12 h. the Mixture was evaporated in vacuum. Purification of the product is carried out using HPLC method without acid in the mobile phase. Get compounds of the General formula 1,1.1 and 1.2, including: benzyl 1-((2R,3R,5R)-4-(benzyloxycarbonyloxy)-3,3-debtor-5-(((1-methyl-2-oxopyrrolidin-3-ylamino)(phenoxy)phosphoryloxy)methyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidine-4-ylcarbamate 1(6), LC-MS (ESI) [M+H]+784;

benzyl 1-((2R,3R,5R)-4-(benzyloxycarbonyloxy)-3,3-debtor-5-(((1-methyl-2-oxopiperidin-3-ylamino)(phenoxy)phosphoryloxy)methyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidine-4-ylcarbamate 1(7), LC-MS (ESI) [M+H]+798;

((2R,3R,5R)-3-(tert-butyldimethylsilyloxy)-5-(2,4-diokso-3,4-dihydropyrimidine-1(2H)-yl)-4,4-deverticalization-2-yl)methyl phenyl 1-methyl-2-oxopiperidin-3-ilpost�Amidah 1(20), LC-MS (ESI) [M+H]+645;

((2R,3R,5R)-5-(4-(1-pyrrol-2-ylcarbonyl)-2-oxopyrimidine-1(2H)-yl)-4,4-debtor-3-(1-pyrrol-2-ylcarbonyl)tetrahydrofuran-2-yl)methyl phenyl 2-oxo-tetrahydrofuran-3-yl-phosphoramidate, LC-MS (ESI) [M+H]+689;

benzyl 1-((2R,3R,5R)-4-(benzyloxycarbonyloxy)-3,3-debtor-5-(((1-gidroximetil-2-

oxopyrrolidin-3-ylamino)(phenoxy)phosphoryloxy)methyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidine-4-ylcarbamate, LC-MS (ESI) [M+H]+800;

benzyl-((2R,3R,5R)-4-(benzyloxycarbonyloxy)-3,3-debtor-5-(((1-methoxymethyl-2-

oxopyrrolidin-3-ylamino)(phenoxy)phosphoryloxy)methyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidine-4-ylcarbamate, LC-MS (ESI) [M+H]+814.

Example 3. (2R,3R,5R)-5-(4-atsetamido-2-oxopyrimidine-1(2H)-yl)-4,4-debtor-2-(((S)-(S)-2-oxitetraciclina-3-ylamino)(phenoxy)phosphoryloxy)methyl)tetrahydrofuran-3-yl acetate 1(4) and (2R,3R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4,4-debtor-2 -(((( S)-2-oxitetraciclina-3-ylamino)(phenoxy)phosphoryloxy)methyl)tetrahydrofuran-3-yl acetate 1(23). To a solution of compound 1(22) (100 mg, 0.2 mmol) in 2 ml of pyridine add Ac2O (41 mg, 0.4 mmol) and the mixture was stirred for 12 h. the Solution was evaporated in vacuo, the residue dissolved in DCM, washed with water, dried over Na2SO4, evaporated in vacuum and separated by HPLC method without acid. Get compound 1(23), LC-MS (ESI) [M+H]+545,1H NMR (DMSO-d6, 400 MHz) δ 7.44 (�, 5H), 7.23 (m, 3H), 6.18 (m, 2H), 5.74, 5.79 (2D, J=7 Hz, 1H), 5.38 (brm, 1H), 4.40 (m, 3H), 4.26 (m, 2H), 4.15 (m, 2H), 2.35 (m, 1H), 2.14, 2.15 (2 s, 3H), 2.01 (m, 1H) and the compound 1(4), LC-MS (ESI) [M+H]+587,1H NMR (DMSO-d6, 400 MHz) δ 11.05 (s, 1H), 7.93, 8.04 (2D, J=7.6 Hz, 1H), 7.38 (m, 2H), 7.23 (m, 5H), 6.34 (m, 1H), 6.17 (m, 1H), 5.42 (m, 1H), 4.45 (m, 3H), 4.27 (m, 2H), 4.16 (m, 2H), 2.35 (m, 1H), 2.15, 2.16 (2 s, 3H), 2.12 (s, 3H), 2.01 (m, 1H);

In a similar manner from the corresponding parent compounds receive ((2R,3R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4,4-debtor-3-(methylenedianiline)tetrahydrofuran-2-yl)methyl phenyl (S)-2-oxo-tetrahydrofuran-3-yl-phosphoramidate, LC-MS (ESI) [M+H]+588;

((2R,3R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4,4-debtor-3-(piperidine-3-ylcarbonyl)tetrahydrofuran-2-yl)methyl phenyl (S)-2-oxo-tetrahydrofuran-3^Il-phosphoramidate, LC-MS (ESI) [M+H]+614;

((2R,3R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4,4-debtor-3-(piperidine-4-ylcarbonyl)tetrahydrofuran-2-yl)methyl phenyl (S)-2-oxo-tetrahydrofuran-3-yl-phosphoramidate, LC-MS (ESI) [M+H]+614;

((2R,3R,5R)-5-(4-(methylenedianiline)-2-oxopyrimidine-1(2H)-yl)-4,4-debtor-3-(methylenedianiline)tetrahydrofuran-2-yl)methyl phenyl (S)-2-oxo-tetrahydrofuran-3-yl-phosphoramidate, LC-MS (ESI) [M+H]+673.

Example 4. ((2R,3R,5R)-5-(4-Amino-2-oxopyrimidine-1(2H)-yl)-3-(tert-butyldimethylsilyloxy)-4,4-deverticalization-2-yl)methyl phenyl (S)-2-oxitetraciclina-3-ifosfamide 1(24). To a solution connected�I 1(22) (112 mg, 0.22 mmol) in 1 ml of pyridine is added TBDMSCl (84 mg, 56 mmol) and the mixture was stirred at 50°C for 48 h. the Solution was evaporated in vacuo, the residue dissolved in DCM, washed with water, dried over Na2SO4, evaporated in vacuo and purified by chromatographytandem on SiO2(eluent MeCN: i-PrOH=10:1). Get compound 1(24), LC-MS (ESI) [M+H]+617,1H NMR (DMSO-d6, 400 MHz) δ 7.50 (m, 1H), 7.40 (m, 4H), 7.22 (m, 3H), 6.20 (m, 1H), 6.12 (m, 1H), 5.78 (m, 1H), 4.38 (m, 2H), 4.26 (m, 3H), 4.12 (m, 2H), 2.33 (m, 1H), 0.88 (s, 9H), 0.10 (s, 3H), 0.09 (s, 3H).

Example 5. Benzyl l-((2R,4R,5R)-4-(benzyloxycarbonyloxy)-5-(((5,5-dimethyl-2-oxitetraciclina-3-ylamino)(phenoxy)phosphoryloxy)methyl)-3,3-deverticalization-2-yl)-2-oxo-1,2-dihydropyrimidine-4-ylcarbamate 1(10) and ((2R,3R,5R)-5-(4-amino-2-oxopyrimidine-l(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl phenyl 5,5-dimethyl-2-oxitetraciclina-3-ifosfamide 1(14) is prepared in accordance with the following scheme.

A solution of 673 mg (1.27 mmol) of bis-CBZ-gemcitabine 9, 500 mg (1.65 mmol) of phenyl 5,5-dimethyl-2-oxo-tetrahydrofuran-3-ylphosphorothioate 10 and 135 mg (1.65 mmol) of N-methylimidazole in 20 ml dry MeCN boiled for 48 h. the Mixture was evaporated in vacuo, dissolved in 40 ml of DCM, washed twice with water, dried over Na2SO4and evaporated in vacuo. The residue was dissolved in a mixture of 1:1 CHCl3/Me2WITH and filtered through a layer of 2 cm SiO2, evaporated in�kuume. Get compound 1(10), LC-MS [M+H]+799, which is hydrogenated in 25 ml of i-PrOH over 100 mg of 10% Pd/C. HPLC separation is performed without acid and get compound 1(14), LC-MS (ESI) [M+H]+531,1H NMR (DMSO-d6, 400 MHz) δ 7.48 (m, 1H), 7.39 (m, 4H), 7.23 (m, 3H), 6.43 (m, 1H), 6.14 (m, 2H), 5.75 (m, 1H), 4.35 (m, 3H), 4.19 (m, 1H), 4.05 (m, 1H), 2.33 (m, 1H), 1.85 (m, 1H), 1.35 (s, 3H), 1.31 (s, 3H).

Example 6. ((2R,3R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl phenyl (S)-2-oxitetraciclina-3-ifosfamide 1(22). A solution of 2 g (2.6 mmol) of compound 1(5) is hydrogenated in 150 ml of isopropanol over 200 mg of 10% Pd/C. After completion of the reaction (LC-MS monitoring), the mixture was filtered through celite, evaporated in vacuo and purified by chromatographytandem on a column of SiO2(eluent MeCN: t-BuOH=5:1) obtain compound 1(22), LC-MS (ESI) [M+H]+503,1H NMR (DMSO-d6, 400 MHz) δ 7.44, 7.49 (2D, J=7.6 Hz, 1H), 7.39 (m, 4H), 7.23 (m, 3H), 6.40, 6.44 (2D, J=6.0 Hz, 1H), 6.14 (m, 2H), 5.73, 5.77 (2D, J=7.6 Hz, 1H), 4.42 (m, 1H), 4.35 (m, 1H), 4.27 (m, 2H), 4.17 (m, 2H), 4.05 (m, 1H), 2,35 (m, 1H), 2,01 (m, 1H).

Example 7. ((2R,3R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl phenyl 1-methyl-2-oxopyrrolidin-3-ifosfamide 1(13), (S)- 1(15) and (R)-isomer 1(30). A solution of compound 1(6) (108 mg, 0.14 mmol) is hydrogenated in 20 ml of dioxane over 100 mg of 10% Pd/C and get compound 1(13), LC-MS (ESI) [M+H]+516.1H NMR (DMSO-d6, 400 z) δ 7.47 (m, 2H), 7.37 (m, 3H), 7.27 (m, 2H), 7.19 (m, 1H), 6.42 (m, 1H), 6.18 (m, 1H), 5.89 m, 1H), 5.75 (m, 1H), 4.32 (m, 3H), 4.05 (m, 1H), 3.82 (m, 1H), 3.20 (m, 2H), 2.73 (s, 3H), 2.19 (m, 1H), 1.67 (m, 1H). HPLC separation without acid gives a fast moving isomer, presumably (R)-isomer 1(30), LC-MS (ESI) [M+H]+516, and slow moving isomer, presumably (8)-isomer 1(15), LC-MS (ESI) [M+H]+516.

Example 8. ((2R,3R,5R)-5-(4-amino-2-oxopyrimidine-l(2H)-yl)-4,4-debtor-3-hydroxymitragynine-2-yl)methyl phenyl 1-methyl-2-oxopiperidin-3-ifosfamide 1(8). A solution of compound 1(7) (194 mg, 0.24 mmol) is hydrogenated in 20 ml of ethanol over 100 mg of 10% Pd/C. HPLC separation without acid gives compound 1(8), LC-MS (ESI) [M+H]+530. Connection 1(8) was dissolved in a small amount of methanol and add an equivalent amount of 0.2 M hydrogen chloride in methanol. The solvent was distilled off, the resulting product was washed with ether and dried in vacuum. The yield of hydrochloride 1(8)*HCl 90%.

Example 9. Obtaining pharmaceutical compositions in the form of tablets. Mix 1600 mg of starch, 1600 mg of powdered lactose, 400 mg of talc and 1000 mg (2R,3R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4,4-debtor-2-((((8)-2-oxitetraciclina-3-ylamino)(phenoxy)phosphoryloxy)methyl)tetrahydrofuran-3-yl acetate 1(23). The resulting block is ground into granules and sieved through a sieve, collecting the granules size 14-16 mesh. The resulting granules are tableted in the appropriate form tablets weighing 560 mg each.

Example 10. Obtaining pharmaceutical compositions in the form� capsules. Thoroughly mix (2R,3R,5R)-5-(4-amino-2-oxopyrimidine-l(2H)-yl)-4,4-debtor-2 -(((( S)-2-oxitetraciclina-3-ylamino)(phenoxy)phosphoryloxy)methyl)tetrahydrofuran-3-yl acetate 1(23) with lactose powder in a 2:1 ratio. The obtained powdery mixture was Packed on 300 mg into gelatinous capsules of suitable size.

Example 11. Obtaining pharmaceutical compositions in the form of injectable compositions for intramuscular, intraperitoneal or subcutaneous injection. Mix 500 mg mixed (2R,3R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4,4-debtor-2 -(((( S)-2-oxitetraciclina-3-ylamino)(phenoxy)phosphoryloxy)methyl)tetrahydrofuran-3-yl acetate 1(23) with 300 mg of chlorobutanol, 2 ml of propylene glycol and 100 ml of injectable water. The resulting solution was filtered and placed in 1 ml ampoules, which are sealed.

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

where:
R1represents hydrogen, (CH3)2[(CH3)3S]Si, C2-C6acyl, optionally substituted benzyloxycarbonyl, NR5R6the group in which R5and R6are independently hydrogen or C1-C4alkyl; 1-pyrrol-2-ylcarbonyl, piperidine-3-ylcarbonyl or piperidine-4-ylcarbonyl;
R2and R3represent F or R2represents F or HE R 3represents CH3;
R4represents hydrogen or methyl;
Ar represents phenyl, pyridyl or naphthyl, where phenyl, pyridyl or naphthyl are optionally substituted with at least one of C1-3alkyl, C2-4of alkenyl, C2-4alkenyl, C1-3alkoxy, F, Cl, Br, I, nitro, cyano, -N(C1-3alkyl)2;
Pm represents a 2,4-diokso-3,4-dihydro-2H-pyrimidine-1-yl or 4-(4-amino-2-oxo-2H-pyrimidine-1-yl), in which the amino group is optionally substituted 1-pyrrol-2-ylcarbonyl, piperidine-3-ylcarbonyl, piperidine-4-ylcarbonyl or a radical C(O)R8where R8represents C1-C4alkyl, optionally substituted NR6R7group, where R6and R7are independently hydrogen or C1-C4alkyl; C1-3alkoxy, optionally substituted by phenyl;
X represents O or N-R9where R9represents C1-C4alkyl, optionally substituted HE or och3;
n=1,2 or 3.

2. Compounds according to claim 1 of the General formula 1.1, or the General formula 2.1, or a stereoisomer, or pharmaceutically acceptable salt

where R1, R2, R3and X have the above value.

3. Compounds according to claim 1 of General formula 1.2 or the General formula 2.2, or a stereoisomer, or farm�citiesi acceptable salt

where R1, R2, R3and X have the above value.

4. Compounds according to claim 1, comprising :








5. The method of obtaining compounds of General formula 1 or its stereoisomer of the compound of formula 6 with a compound of formula 4 and the subsequent mixing with the amine of formula 8,

where Ar, n, R1, R2, R3, R4, R9and Pm have the above significance, and the resulting compound of formula 1, where R1means hydrogen, optionally converted into a corresponding acyl or dimethyl-tert-butylsilane connection.

6. The production method according to claim 5 compounds of the General formula 1 or its stereoisomer, where R1represents acyl, the acylation of a compound of formula 1, where R1represents hydrogen.

7. The production method according to claim 5 compounds of the General formula 1 or its stereoisomer, where R1�predstavljaet a dimethyl-tert-Boticelli, by mixing dimethyl-tert-Boticelli chloride with a compound of formula 1, where R1represents hydrogen.

8. The active ingredient, having the properties of nucleoside RNA polymerase NS5B of hepatitis C virus, which are compounds of the General formula 1, 1.1, 1.2, 2.1 or 2.2 according to any one of claims. 1-4, or their stereoisomers, or a pharmaceutically acceptable salt.

9. Pharmaceutical composition for prevention and treatment of viral infections, including hepatitis C, containing an active component according to claim 8 in a therapeutically effective amount and at least one pharmaceutically acceptable excipient.

10. A medicament for the prevention and treatment of viral infections, including hepatitis C, in the form of tablets, capsules, injections, ointments, rectal suspensions and gels, placed in pharmaceutically acceptable packing, containing an effective amount of an active component according to claim 8 or a pharmaceutical composition according to claim 9.

11. Method of prevention and treatment of diseases caused by the hepatitis C virus, the introduction of therapeutically effective quantity of the active component according to claim 8 or a pharmaceutical composition according to claim 9 or medicinal product according to claim 10.

12. Method for inhibiting RNA polymerase NS5B of hepatitis C virus by contacting RNA polymerase NS5B of hepatitis C with the compounds of the General Fort�uly 1, 1.1, 1.2, 2.1 or 2.2 according to any one of claims. 1-4, or their stereoisomers, or pharmaceutically acceptable salts.



 

Same patents:

FIELD: organic chemistry, peptides.

SUBSTANCE: invention proposes a method for labeling phosphorylated peptides, method for adsorption of phosphorylated peptides and compounds possessing high coordination capacity with respect to phosphorylated peptides that are used in such methods, and compounds used as parent substances. Chelating compound is represented by the formula (I): wherein X represents linker group; Y represents fluorescent group or biotin as labeling group. Compound of the formula (I) provides easy detection and identification of phosphorylated peptide in a sample prepared from a living body.

EFFECT: improved methods of preparing and analysis.

13 cl, 9 dwg, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to quinolines substituted by phosphorus-containing group of formula and applicable in medicine, wherein Z represents V1 and V2 are independently specified in hydrogen or halogen; one of R and R` represent phosphorus-containing substitute Q; the other one is specified in hydrogen or methoxyl; wherein the phosphorus-containing substitute Q represents A represents O; L represents C1-6alkyl; J represents NH or C3-6heterocycloalkyl and J is optionally substituted by G3; X is absent or represents -C(=O)-; X is absent or represents C1-6alkyl; each of R1 and R2 are independently specified in C1-6alkyl or C1-6alkoxy; G3 represents C1-6alkyl, R3S(=O)m-, R5C(=O)- or R3R4NC(=O)-; R3, R4 and R5 are independently specified in 3 or C1-6alkyl; m is equal to 0-2.

EFFECT: there are presented new protein kinase inhibitors effective for treating the diseases associated with abnormal protein kinase activity.

20 cl, 42 ex, 8 tbl, 3 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to field of organic chemistry, namely to heterocyclic compound of formula (I) or its racemate, enantiomer, diastereoisomer and their mixture, as well as to their pharmaceutically acceptable salt, where A is selected from the group, consisting of carbon atom or nitrogen atom; when A represents carbon atom, R1 represents C1-C6-alkoxyl; R2 represents cyano; when A represents nitrogen atom, R1 hydrogen atom or C1-C6-alkoxyl; where said C1-C6-alkoxyl is optionally additionally substituted with one C1-C6-alkoxyl group; R2 is absent; R3 represents radical, which has the formula given below: or , where D represents phenyl, where phenyl is optionally additionally substituted with one or two halogen atoms; T represents -O(CH2)r-; L represents pyridyl; R4 and R5 each represents hydrogen atom; R6 and R7 each is independently selected from hydrogen atom or hydroxyl; R8 represents hydrogen atom; R9 represents hydrogen atom or C1-C6-alkyl; r equals 1 and n equals 2 or 3. Invention also relates to intermediate compound of formula (IA), method of obtaining compound of formulae (I) and (IA), pharmaceutical composition based on formula (I) compound and method of its obtaining and to application of formula (I) compound.

EFFECT: novel heterocyclic compounds, inhibiting activity with respect to receptor tyrosine kinases EGFR or receptor tyrosine kinases HER-2 are obtained.

18 cl, 12 ex, 4 tbl

FIELD: medicine, pharmaceutics.

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

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

18 cl, 1 tbl, 14 ex

FIELD: medicine, pharmaceutics.

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

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

6 cl, 16 dwg, 3 tbl, 4 ex

FIELD: medicine, pharmaceutics.

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

EFFECT: new P2Y12 receptor antagonists are produced.

25 cl, 126 ex, 5 tbl

FIELD: chemistry.

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

EFFECT: high-yield end product.

26 cl, 5 tbl, 50 ex

FIELD: medicine; pharmacology.

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

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

46 cl, 1 tbl, 233 ex

FIELD: chemistry.

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

EFFECT: obtaining of new biologically active substances.

184 cl, 52 tbl, 62 ex

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

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

EFFECT: valuable medicinal and biochemical properties of compounds.

69 cl, 7 tbl, 64 ex

FIELD: medicine, pharmaceutics.

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

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

18 cl, 1 tbl, 14 ex

FIELD: medicine, pharmaceutics.

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

EFFECT: obtaining novel compounds.

21 cl, 1 dwg, 2 tbl, 83 ex

FIELD: chemistry.

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

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

12 cl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention refers to the way of production of amide nitrilotrismethylenephosphonic acid ammonium salt used in creation of fire resistant composite materials based on thermoplasts with the formula: The method consists in the following: nitrilotrismethylenephosphonic acid is amidated at a high temperature under the influence of gas ammonia under some pressure until pH of the 1% solution of the obtained product makes up 6-6.5.

EFFECT: simplification of the synthesis process and reduction of the prime cost of amide nitrilotrismethylenephosphonic acid ammonium salt.

2 cl, 1 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of formula VIII suitable in medicine as T3 mimetic drugs: VIII, where G is O, -S(=O)2- or -CH2-; R2 is halogen, alkyl, -CF3, -OCF3, alkoxy or cyano; R3 and R4 are H, halogen, alkyl or -(CRa2)maryl; T is selected from -(CRa2)k-, -CRb=CRb-(CRa2)n-, -(CRa2)n-CRb=CRb, -(CRa2)-CRb=CRb-(CRa2)-, O(CRa2)(CRa2)n-, -S(CRa2)(CRa2)n-, -N(Rc)(CRb2)(CRa2)n-, -N(Rb)C(O)(CRa2)n-, -(CRa2)nCH(NRbRc) -C(O)(CRa2)m-, -(CRa2)mC(O)-, -(CRa2)C(O)(CRa2)n-, -(CRa2)n C(O)(CRa2)- and -C(O)NH(CRb2)(CRa2)p-; Ra, Rb, Rc, R1, R6, R7, R8 and R9 are H, halogen or alkyl; or R6 and T with C atom form a 5-6-members ring with 0-2 groups -NRi-, -O- or -S-; Ri is H, -C(O)alkyl, alkyl or aryl; R5 is OH, alkoxy, -OC(O)Re, -OC(O)ORh, -F, -NHC(O)Re, -NHS(=O)Re, -NHS(=O)2Re, -NHC(S)NH(Rh) or -NHC(O)NH(Rh); Re is alkyl, -(CRa2)n-aryl, -(CRa2)n-cycloalkyl or -(CRa2)n- heterocycloalkyl; Rh is H or alkyl; X is P(O)YRllY'Rll; Y and Y' are O or -NRv-; R11 is H, alkyl, -C(Rz)2-OC(O)Ry, -C(RZ)2-O-C(O)ORy, -alkyl-S-C(O)Ry, -[C(Rz)2]q-COORy, -cycloalkylene-COORy, aryl, -C(Rz)2OC(O)SRy, -C(Rx)2COORy or two R11 and R11 form a cycle; k is within 1 to 4; m is within 0 to 3; n is within 0 to 2; p is within 0 to 1; q is 2 or 3; Rv, Rz, Ry and Rx are H or alkyl, or two Rx and Rx form a cycle.

EFFECT: production of new thymomimetic drugs.

19 cl, 80 ex, 10 tbl, 13 dwg

FIELD: chemistry.

SUBSTANCE: present invention relates to a method of producing thionylamide cyan-anhydride of methylphosphonic acid of formula CH3P(O)(CN)N=S=O, which can be used as a semi-finished product in organophosphorus synthesis. The disclosed method lies in obtaining the end product by reacting thionylamide chloroanhydride of methylphosphonic acid with alkoxydimethylsilylcyanides of general formula (CH3)2Si(OR)CN, where R = CH3, C2H5,C3H7, i-C3H7 at 40°C for 20 minutes.

EFFECT: design of a new method of producing organophosphorus compounds.

1 cl, 5 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a method of producing methyl-phosphonic acid thionylamide esters of formula: CH3P(O)(OR)N=S=O, where R = i-C3H7, C4H9, i-C4H9, which can be used as semi-finished products in organophosphorus synthesis. The disclosed method lies in obtaining end products by reacting thionylamide choroanhydride of methyl-phosphonic acid with alkoxytrimethylsilanes of general formula (CH3)3SiOR, where R = i-C3H7, C4H9, i-C4H9 at 40-50°C for 2 hours.

EFFECT: design of a new method of producing the said compounds.

1 cl, 2 ex, 2 tbl

FIELD: chemistry of organophosphorus compounds, chemical technology.

SUBSTANCE: invention relates to novel compounds used for extraction of rare-earth metal ions and comprising phosphoneamide compound represented by he formula [1]: wherein R1 means aryl group, aralkyl group under condition that each group can comprise a substitute chosen from alkoxy-groups; R2 means alkyl group, alkenyl group, aryl group, aralkyl group under condition that each group can comprise a substitute chosen from alkyl groups, alkoxy-groups; R3 means hydrogen atom, aryl group, aralkyl group under condition that each group can comprise a substitute chosen from alkyl groups, alkoxy-groups, halogen atoms; and two radical R can be combined to form alkylene group. Also, invention relates to a method for extraction of rare-earth metal ions and to a method for reverse extraction of rare-earth metal ions. Invention provides preparing novel phosphoneamide compounds and method for extraction and reverse extraction of rare-earth metal ions.

EFFECT: improved preparing method, valuable properties of compounds.

3 cl, 4 tbl, 44 ex

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

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

EFFECT: valuable medicinal and biochemical properties of compounds.

69 cl, 7 tbl, 64 ex

The invention relates to new derivatives of anhydride methylenephosphonic acid of the formula I, where Y1, Y2, Y3and Y4group OR1, NR2R3, OCOR1, OCNR2R3, O(CO)OR1, O(SO2R1or OP(O)R2(OR3), where R1, R2and R3- H, C1-22alkyl, aryl, possibly substituted, or SiR3where R3- C1-C4alkyl, provided that at least one of the groups Y1, Y2, Y3and Y4other than the group OR1or NR2R3, Q1and Q2Is H, F, Cl, Br, I, methods of obtaining these new compounds as well as pharmaceutical preparations containing these new compounds
Up!