Nucleoside analog phosphoramidates as inhibitors of human immunodeficiency virus reproduction

FIELD: organic chemistry, biochemistry, medicine.

SUBSTANCE: invention relates to phosphoramidates of nucleoside analogs comprising 2',3'-dideoxy-2',3'-didehydrothymidine 5'-phosphodimorpholidate of the formula (I) and phosphoramidates of 3'-azido-3'-deoxythymidine of the formula (II) and the formula (III) that inhibit activity in reproduction of human immunodeficiency virus (HIV). Compounds are resistant to effect of dephosphorylating enzymes and able to penetrate into cells and elicit the selective activity in inhibition of DNA biosynthesis catalyzed by HIV-reverse transcriptase.

EFFECT: valuable medicinal and biochemical properties of nucleoside analogs.

4 dwg, 1 tbl, 5 ex

 

The invention relates to new biologically active derivative 5’-phosphate 3’-azido-3’-deoxythymidine and 2’,3’-dideoxy-2’,3’-didehydrothymidine and can be used as antiviral agents, primarily against human immunodeficiency virus (HIV).

It is known that inhibition of reproduction of human immunodeficiency virus can be at different stages of its life cycle, but it is obvious that it is advisable to use inhibitors of the earliest processes. That is why the reverse transcriptase of HIV, the first time the functioning of the enzyme in the replication cycle of the virus, is the most attractive target for suppression of viral replication.

Currently, there are various compounds that inhibit the reproduction of the human immunodeficiency virus. The most effective of the known compounds are 3’-azido-3’-deoxythymidine (azidothymidine or AZT, zidovudine, Retrovir, Timated”), which are used in medical practice (Mitsuya, H.; Broder, S. Inhivition of the in vitro infectivity and cytiopathic effect of human T-lymphotropic virus type III/lymphoadenopathy-associated virus/HTLV-III(LAV) by 2’,3’-dideoxynucleosides. Proc. Nat. Acad. Sci. USA, 1986, 83, 1911-1915), and 2’,3’-dideoxycytidine (ddC, zalcitabine, “GUID”), 2’,3’-dideoxyinosine (ddI, didanosine, videx”), 3’-deoxy-2’,3’-didehydrothymidine (d4T, stavudine, stavudine, zerit) and 3’-thiacytidine (3TC, lamivudine, Epivir”).

Molecular mechanism of action of the compounds includes diffusion inside cells, infected with HIV. He further subjected to triphosphorylation and specific blocks DNA synthesis catalyzed by reverse transcriptase of HIV. Similarly, there are other antiviral nucleosides used in medical practice for the treatment of AIDS: 2’,3’-dideoxycytidine and 2’,3’-dideoxyinosine (Mitsuya, H.; Broder, S. Inhibition of the in vitro infectivity and cytopatic effect of human T-lymphotropic virustype III/lymphoadenopathy-assosiated virus (HTLV-III/LAV) by 2’,3’-dideoxynucleosides. Proc. Nat. Acad. Sci. USA, 1986, 82, 1911-1915), 2’,31-dideoxy-2′,3’-didehydrothymidine (Herdewijn, P.; Balzarini, J.; DeClercq, E.; et al., 3’-Substituted 2’,3’-dideoxynucleoside analogues as potential anti-HIV (HTLV/LAV) agents. J. Med. Chem., 1987, 30, 1270-1278) and 2’,3’-dideoxy-3’-thiothymidine (Soudeyns, H.; Yao, Q.; et al., Anti-human immunodeficiency virus type 1 activity and in vitro toxicity of 2’-deoxy-3’-thiacytidine (BCH-189), a novel heterocyclic nucleoside agents. Antimicrob. Agents Chemother., 1991, 35, 1386-1390).

However, phosphorylation of modified nucleosides cellular enzymes is significantly less effective than the natural nucleosides. The process of transformation of the nucleoside in the body into the corresponding 5’-triphosphate takes about 1.5-2 hours. During this time penetrated into the cells, the virus manages in the form of proviral DNA to integrate into the human genome. Use as drugs nucleoside 5’-triphosphates with nomodifier the bathroom trifosfatnogo part is impossible due to their low stability to the action of enzymes hydrolysis and consequently a low ability to penetrate cells. Thus, the applied drugs, even if they are taken at the time of infection may not protect against HIV infection.

The closest technical solution (prototype) is used as an antiviral drug derivatives of 3’-azido-3’-deoxythymidine containing a modified phosphate group on the 5’-position, namely H-phosphonate AZT (U.S. Patent No. 5043437, IPC 07 N 19/00, publ. 27.08.1991): Nbehave, Ali, Ari, and others, Inhibition of human immunodeficiency virus in cell culture 5’-phosphonates 3’-azido-2’,3’-dideoxynucleosides, Mol. Biol, 1989, 23, N6, 1716-1724). Currently it is used as a medicine under the name “Nikavir” for treatment of AIDS (HIV infection).

However, it was shown that in the body of this connection is mainly exposed to dephosphorylating, becoming AZT (Kuznetsova E.V., Kochanova M.K., and other Reaction 5’-H-phosphonates, 5’-perphosphate and 5’-phosphate modified thymidine in plasma. - They say. Biol, 1995, 29, N2, 415-420).

The technical result of the present invention is the creation and use of new compounds that are resistant to the action of enzymes dephosphorylation, are able to penetrate cells and have the electoral activity in inhibition of DNA biosynthesis, catalyzed by reverse transc what iptat HIV.

This technical result is achieved by the fact that according to the invention are claimed new connections: phosphoramidate nucleoside analogues, including 5’-FotoDepartament 2’,3’-dideoxy-2’,3’-didehydrothymidine (formula I) and phosphoramidite 3’-azido-3’-deoxythymidine (formula II) and (III)inhibiting the activity of reproduction of human immunodeficiency virus and having the following formula:

To obtain the compounds of formulas I-III was used a unified synthetic approach, which consists in the reaction of the nucleoside with phosphorus oxychloride in triethyl phosphate, followed by treatment of the resulting phosphatidate various amines. The resulting phosphoramidite I-III can be isolated and purified by standard methods, for example, extraction, precipitation, chromatography, etc.

The invention is illustrated by the following graphic materials. Figure 1 shows comparative graphs of anti-HIV activity of a compound of formula I in HIV-1 STB 4046 upon simultaneous application with the virus. Figure 2 shows comparative graphs of anti-HIV activity of a compound of formula I when you make it after adsorption of the virus. Figure 3 - the same, anti-HIV activity of the compounds of formula II when used simultaneously with virus entry. Figure 4 - same anti-HIV activity of the compounds is ormula III simultaneous with the virus making

The present invention is illustrated by the following examples of the preparation of these compounds and the results of biochemical tests.

Example 1. Obtaining 5’-FotoDepartament 2’,3’-Dideoxy-2’,3’-didehydrothymidine 5’-FotoDepartament (formula I)

To a solution of 2’,3’-dideoxy-2’,3’-didehydrothymidine (235 mg, 1.05 mmol) in triethyl phosphate (3 ml), at rt, with shaking, was added tert-butanol (8.5 mg, 0.12 mmol) and phosphorus oxychloride (0.35 g, 2.24 mmol). The reaction mixture stood for 16 h at rt, cooled to 4°With, then added a solution of morpholine (1.3 g, 15 mmol) in methanol (5 ml). Then the reaction mixture (suspension) was diluted with ethyl acetate (10 ml) and kept for 18 h at 4°C. the precipitation (chloride morpholine) was filtered, the mother liquor was evaporated and the residue was divided by column chromatography on silica gel (10 g Silasorb in chloroform), elwira gradient (0-5%) of methanol in chloroform. The yield of the title compound 0.87 mmol (82%, UV), the product contained about 2 mol of triethyl phosphate per mole of dimorphoteca. For repeated cleaning was taken half this amount. Purification was performed on silica gel (5 g Silasorb in chloroform), elwira 3% methanol in chloroform. Received 117 mg of target compound (0.264 mmol, 50%).

1H-NMR (D2O): 7.49 (1H, H-6); 6.93 USS (1H, H-1’); d. (J=6.2 Hz, 1H, H-3’); d (J=6.2 Hz, 1H, H-2’); 5.18 USS (1H, H-4’); 4.07 4.22 and 2m (2N H-5’); 3.67 m (4H, CH2O-the research); 3.13 m (4H, CH2N-the research); s (3H, Me of thymine).

31P-NMR (D2O): s.

Example 2. Obtain 3’-Azido-2’,3’-dideoxythymidine 5’-fosforic (methoxime) (formula II)

To a solution of 3’-azido-3’-deoxythymidine (82 mg, 0.31 mmol) in triethyl phosphate (1.7 g) under stirring, at rt, was added tert-butanol (5 mg, 0.06 mmol) and phosphorus oxychloride (86 mg, 0.56 mmol). The reaction mixture stood for 1 h at rt, and then 20 h at 4°C, after which the cooled solution was added methoxime chlorohydrate (309 mg, 3.7 mmol) and triethylamine (0.51 g, 5.05 mmol) in methanol (5 ml). The precipitation was filtered, the mother liquor was evaporated and diluted with ethyl acetate (10 ml). Again, the precipitate was filtered, evaporated liquor, and provided the product is similar to previously described. The yield of the target compound - 58 mg (0.143 mmol, 46%)

1H-NMR (D2O): s (1H, H-6); t (J=6.4 Hz, 1H, H-1’); K (J=6.7 Hz, 1H, H-3’); 4.28-4.15m (3H, 2H-5’+H-4’); 3.62 d, J=17 Hz, 6N, 2 CH3ON); t (J=6.7 Hz, 2H, 2H-2’); s (3H, Me of thymine).

31P-NMR (D2O): s.

Example 3. Obtain 3’-Azido-2’,3’-dideoxythymidine 5’-fostervold (formula III)

To a solution of 3’-azido-3’-deoxythymidine (178 mg, 0.67 mmol) in triethyl phosphate (2.6 g) under stirring, at rt, was added tert-butanol (7 mg, 0.09 mmol) and phosphorus oxychloride (170 mg, 1.09 mmol). The reaction mixture stood for 1 h at rt, and ZAT is m 20 h at 4° With, and then to the cooled solution was added water (55 mg, 3.06 mmol), withstood 40 min at 4°With added morpholine (0.33 g, 3.8 mmol) in methanol (3 ml). The reaction mixture was evaporated and diluted with ethyl acetate (10 ml). The precipitate was filtered, evaporated liquor, and provided the product is similar to the previously described using the elution system chloroform-methanol-25% aqueous ammonia (60:35:5). The yield of the target compound - 182 mg (0.420 mmol, 63%)

1H-NMR (D2O): s (1H, H-6); t (J=6.4 Hz, 1H, H-1’); K (J=6.7 Hz, 1H, H-3’); 4.25-m (3H, 2H-5’+H-4’); m (2H, CH2About the research); m (2H, CH2N-the research); t (J=6.7 Hz, 2H, 2H-2’); s (3H, Me of thymine).

31P-NMR (D2O): s.

The following studies of inhibition of reproduction of HIV.

The study of inhibition of reproduction of HIV includes the cultivation initially infected lymphoid cell line MT-4 in the presence of investigated compounds, the final concentration of which in the culture medium amount of 0.0001-100 mg/ml, for one passage within 4 days.

About the inhibition of reproduction of HIV in culture sensitive cells are judged by the decrease in the accumulation of virousspecificakih protein P24 (according to enzyme-linked immunosorbent assay), as well as to increase the viability of the cells in the presence of the drug compared with control defined on the 4th day cultivated what I staining of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT).

Example 4. Evaluation of the cytotoxicity of compounds

The cytotoxicity of the drug is assessed by adding its cultivation in serum-free medium RPMI-1640 cell suspension MT-4, placed in the wells of 96-hole tablet ("Orange"), to a final concentration of 0.001-100 µg/ml (three wells for each dose), followed by cultivation at 37°C for 4 days. The seeding concentration is 0.5×106cellular particles in a milliliter. The controls are cells without addition of the drug, instead of which make the same amount of serum-free medium. Cell viability count on 4 days of culture, using formosanum method (in vivo staining of cells 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) [Leslie R.Bisset, Hans Lutz, Jurg Boni, Regina Hoffinann-Lehmann, Ruedi Luthy, Jorg Schupbach. Combined effect of zidovudine (ZDV), lamivudine (3TC) and abacavir (ABC) antiretroviral therapy in suppressing in vitro FIV replication. Antiviral Research 53 (2002) 35-45].

The toxicity of different doses of the drug to determine cell viability relative to control, according to the obtained results build dose-dependent curve and determine the concentration by 50% reduce cell viability (CD50). It should be noted that the compounds do not exert toxic effects on cells MT-4 in the effective concentration: 50% toxic dose of 5-6 orders of magnitude exceed effective against HIV-1 dose (the table).

Table

Quantitative characterization of anti-HIV action of connections
ConnectionCD50that μMThe simultaneous introductionAdd after adsorption of the virus
  ID50

PD50
ID90ISID50

PD50
ID90IS
d4T314,00,01

2,4
0,3314000,24

23,8
23,81308,3
I

(IMB-43)
>226<0,0022

0,0022
<0,0022>102727<0,0022

0,22
16,9>102727
AZT37,40,037

18,7
1,8710100,0037

18,7
0,0910100
II

(IMB-94)
740,20,012

0,37
0,2616830,0250,2229608
III

(IMB-101)
>230,760,023

-
1,0100330,070,2 3296,6

Example 5. Study of the effect of the inventive compounds on the reproduction of HIV-1 in culture cells MT-4.

Study of antiviral activity of compounds against HIV-1 is performed on transplantable lines sensitive cells MT-4. For infection use of the supernatant of infected cells stored in liquid nitrogen, multiplicity of infection of 0.2 to 0.5 infectious units per cell. The suspension of cells MT-4 with a concentration of 2.0×106cellular particles in the ml and the viability of at least 90% are placed in the wells of 96-hole tablet directly after making vaccinated material and immediately add the compounds diluted in medium RPMI-1640 without serum to a final concentration of 0.0001-100 mg/ml (three wells for each dose). The controls are infected with HIV-1 cells MT-4 without adding the drug instead of the drug make the same amount of RPMI-1640 medium without additives) and uninfected cells.

Tablet incubated for one hour at 37°for adsorption of the virus, the cells are then diluted to the seeding concentration (0,5x10 in milliliter) nutrient medium RPMI-1640 with the addition of 10% fetal cattle serum, previously inactivated by heating at 56°C for 30 minutes, 300 mg/ml L-glutamine and 100 μg/ml of gentamicin. Then the tablet is placed in a thermostat na° C in an atmosphere of 5% CO2. On the 4th day of cultivation calculate the concentration and cell viability formosanum method. The data and construct graphs of the increase in cell viability relative to control under the influence of increasing doses of drugs, i.e. determine the ability of drugs to protect infected cells from cytopathogenic of the virus. Evaluation of anti-HIV activity of the compounds is performed using the quantitative determination virousspecificakih protein P24 by direct enzyme immunoassay as described in [Leslie R.Bisset, Hans Lutz, Jurg Boni, Regina Hoffmann-Lehmann, Ruedi Luthy, Jorg Schupbach. Combined effect of zidovudine (ZDV), lamivudine (3TC) and abacavir (ABC) antiretroviral therapy in suppressing in vitro FIV replication. Antiviral Research 53 (2002) 35-451], and construct a dose-dependent curves (Fig.1-4), which calculate the concentration, 50 and 90% of suppressing the growth of viral antigen (ID50and ID90). Therapeutic index, or index of selectivity (IS) is considered as the ratio of the 50%toxic concentration of the compound to its 50%effective dose. Compound I (2’,3’-Dideoxy-2’,3’-didehydrothymidine 5’-FotoDepartament) by introducing into the culture of sensitive cells simultaneously with HIV in their effectiveness much more superior to the original drug d4T ID50and two order by ID90when making after adsorption of the virus - the and two orders of magnitude superior to the original drug ID 50at almost the same level 90%inhibition. Connections II (3’-Azido-2’,3’-dideoxythymidine 5’-fosforic (methoxime)) and III (3’-Azido-2’,3’-dideoxythymidine 5’-fostervold) showed activity comparable to the activity of the source of azidothymidine, approximately the same when added simultaneously with HIV and adding in postadsorption conditions. On the basis of these quantitative indicators of inhibition can be judged on the effectiveness of antiviral action of new compounds, which consists in a high degree of suppression of HIV-1 replication in cell cultures MT-4 and exceeding efficiency source d4T and AZT.

Phosphoramidate nucleoside analogues, which represents a 5'-FotoDepartament 2',3'-dideoxy-2',3'-didehydrothymidine (formula I) or phosphoramidite 3'-azido-3'-deoxythymidine (formula II) and (III)inhibiting the activity of reproduction of human immunodeficiency virus and having the following formula:



 

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The invention relates to the synthesis of nucleosides and nucleotides and relates to an improved method of vospominaniia 2', 3'-dideoxynucleosides

d-arabinofuranosyl)-n-purine, method for their preparation and use and pharmaceutical composition" target="_blank">

The invention relates to mono-, di - or tri-esters of 2-amino-6-(C1-C5-alkoxy)-9-(-D-arabinofuranosyl)-N-purine General formula (I)

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where arabinofuranosyl residue substituted for 2'-, 3'- or 5'-positions, and esters formed by carboxylic acids, in which decarbonising part selected from n-propyl, tert-butyl, n-butyl, methoxymethyl, benzyl, phenoxymethyl, phenyl, methanesulfonyl and succinyl

The invention relates to the field of Bioorganic chemistry, in particular, to a method for deoxynucleoside-51-triphosphates General formula:where B is thymine-1-yl, cytosine-1-yl, adenin-1-yl or guanine-1-yl, which are widely used in molecular biology, biotechnology and medicine

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The invention relates to new aminobenzophenone General formula (I)

where R1and R3designate one or more identical or different substituents selected from the group consisting of halogen, (C1-C3)-alkyl, (C1-C3)-alkoxy; provided that, if R1denotes one Deputy, he is in the ortho-position, and if R1refers to several substituents, at least one substituent R1located in the ortho-position; and R2denotes one substituent in the ortho-position, and this Deputy is selected from the group consisting of halogen, (C1-C3)-alkoxy; and R3can additionally denote hydrogen; R4represents hydrogen; X represents oxygen; Q represents -(CO)- or a bond; Y represents (C5-C15)alkyl, (C2-C15)olefinic group; and any of these groups may be optionally substituted by one or more identical or different substituents selected from the group consisting of substituents of formula R5defined below, except that when Q represents a bond, then Y appears lcil, substituted by one or more substituents selected from the group R5; or a group of formula - (Z-O)n- Z, where Z is a (C1-C3)alkyl, n is an integer >1, and the number of atoms in a continuous linear sequence of atoms in the group Y does not exceed 15; R5denotes halogen, hydroxy, amino, (C1-C6)-alkylamino, (C1-C3)alkoxycarbonyl, -COOH, -CONHR' or-COONR'R' R' means (C1-C3)alkyl; or its pharmaceutically acceptable salt

The invention relates to a derivative of hemin or their pharmaceutically acceptable salts and inhibitors of proteolytic enzymes, which are the compounds of General formula (I)

where R1and R2- substituents, which may represent amino acids, derivatives of amino acids, peptides, consisting of 1-15 amino acid residues, derived peptides consisting of 1-15 amino acid residues, and-carboxyl group of amino acids or peptides and side groups of amino acids or peptides can be modified, and it is possible that R1=R2or R1R2=OH; carboxyl group of the porphyrin can be modified methyl or other C2-C8-ester or a physiologically acceptable salt; Y-represents Cl-CH3SOO-; Me represents Fe, with the exception of compounds where

Me=Fe3+, Y-=Cl-,

R1=-LeuLeuValPheOMe, R2=-OH; R1=-ValPheOMe, R2=-OH; R1=-LeuHisOMe,

R2=-OH; R1=-LeuHisAlaOMe, R2=-OH; R1=-LeuHisNHC10H20COOMe, R22=-LeuHisNHC10H20COOMe; R1=-Lys(Tfa)AlaAlaOMe, R2=-OH;

R1=-ValPheOMe, R2=-LeuHisOMe; R1=-LeuLeuValPheOMe, R2=-LeuHisOMe;

R1=-LeuLys(Tfa)LeuOMe, R2=-OH; R1=-LeuLys(Tfa)LeuOMe, R2=-LeuHisOMe;

R1=-Lys(Tfa)AlaAlaOMe, R2=-AlaHisLys(Cbz)LeuOMe; R1=-GlyOBzl,

R2=-GlyOBzl; R1=-HisOMe, R2=-HisOMe; R1=-LeuHisOMe, R2=-LeuHisOMe;

R1=-LeuHisLeuGlyCys(Bzl)OBzl, R2=-LeuHisLeuGlyCys(Bzl)OBzl;

R1=-LeuHisOMe, R2=-OEt; R1=-LeuHisLeuGlyCys(Bzl)OBzl, R2=-OEt; R1=-OBzl,

R2=-OBzl; R1=-OBzl, R2=-OH; R1=-AlaOMe, R2=-OBzl; R1=-HisOMe, R2=-OBzl;

R1=-LeuHisOMe, R2=-OBzl; R1=-LeuHisLeuGlyCys(Bzl)OBzl, R2=-OBzl;

R1=-LeuHisAlaLys(Cbz)GlyCys(Bzl)OBzl, R2=-OBzl; R1=-LeuHisLys(Cbz)OMe,

R2=-OH; R1=-LeuHis(Bzl)Lys(Cbz)OMe, R2=-OH; R1=-LeuHisOMe, R2=-OMe;

R1=-LeuHis(Bzl)Lys(Cbz)OMe, R2=-OMe; R1=-AlaLeuAlaPheAlaCys(Bzl)OMe,

R2=-LeuHis(Bzl)Lys(Cbz)OMe; R1=-AlaLeuAlaPheAlaCys(Bzl)OBzl,

R2=-LeuHis(Bzl)Lys(Cbz)OMe; R1=-LeuHisAlaLys(Cbz)Cys(Bzl)OBzl,

R2=-LeuHis(Bzl)Lys(Cbz)OMe; R1=-LeuHisOMe, R2=-OMe;

R1=-GlyProArgGlyGlyOMe, R2=-OH;

R1=-ArgProProGlyPheSer(Bzl)PheArgGlyGlyOMe, R2=-OH,

two ways to get hemin derivatives of General formula I, hemin derivatives of the formula I, formerly known above, as inhibitors of proteolytic enzymes: the HIV protease, pepsin, trypsin, chymotrypsin

The invention relates to pharmaceutical industry and relates to the creation of a means for inhibiting reproduction enveloped viruses

The invention relates to the field of medicine and pharmaceutics and relates to a composition for the prevention and treatment of HIV-1 infection, including nucleoside reverse transcriptase FROM HIV-1, representing heterocyclics(ACS/thio)anilide, a second inhibitor of HIV-1, which does not choose the same HIV-1 mutant strain, or strains, select the first compound is an inhibitor of HIV-1

The invention relates to bicyclerelated analogues of General formula (1) and the oligonucleotides on the basis thereof, containing one or more structural units of the General formula (1A), where R1represents a hydrogen atom, a protective group, the group of phosphoric acid, etc., R2is sidegroup or amino group which may be substituted, represents a purine-9-ilen, or 2-oxo-1,2-dihydropyrimidin-1-ilen group which may be substituted by one or more substituents

The invention relates to pharmaceutical compositions for inhibiting integrase, which contains as active substance a compound of the formula (I)

where X denotes a hydroxy-group; Y represents a group-COORAin which RArepresents hydrogen or ester residue, or denotes a group-CONRINRCin which RINand RCeach independently of one another denotes hydrogen or amide residue, optionally substituted aryl or optionally substituted heteroaryl, and1means optionally substituted heteroaryl, with the exception of compounds in which Y and/or AND1denote optionally substituted indol-3-yl, or contains its tautomer, prodrug, pharmaceutically acceptable salt or hydrate, compounds of formulas I, II

where X, Y described above, AND1- optional replaced heteroaryl; Z1and Z2indicate the relationship; Z2means a connection, (ness.)alkylene, -CH(OH)-, -S-, -SO2-, -O - or-CO; Z4means a connection, (ness.)alkylene, (ness.)albaniles or-CO-; R1means neobyzantine substituted heterocycle, R2denotes optionally substituted (ness.)alkyl, optionally substituted (ness.)alkyloxy, optionally substituted (ness.)allyloxycarbonyl, optionally substituted aryl, optionally substituted by alloctype, carboxy or halogen; R=0 or 1, with the exception of compounds in which (1) Y and/or AND1denotes optionally substituted indol-3-yl and (2) X denotes a hydroxy-group, Y represents 2-thienyl, AND1denotes a 1H-1,2,4-triazole-3-yl, Z1and Z3each denotes a bond, Z2denotes-NH-, R1denotes phenyl or para-tolyl and p=0; (3) X denotes a hydroxy-group, Y represents 4-methoxyphenyl, or 4-chlorophenyl, AND1means thiazol-5-yl, Z1, Z2, Z3and Z4each represents a bond, R1denotes phenyl, 4-methoxyphenyl or 4-chlorophenyl, R2denotes methyl and p=1; (4) X denotes hydroxyl, Y represents phenyl, 4-were, 4-bromophenyl or 4-chlorophenyl, AND1signifies imidazol-2-yl, Z1and Z3each denotes a bond, Z2denotes methylene, R1denotes phenyl, Z4denotes a bond, R2denotes 4-dimethylaminophenyl or 4-methoxyphenyl, and p=1; (5) X denotes hydroxyl, Y represents phenyl, 4-were-or 4-met is 1 denotes phenyl and p=0; (6) X denotes hydroxyl, Y represents-COORAwhere RAdenotes hydrogen or ethyl, AND1signifies 3-indolyl, imidazo[1,2-a]pyridine-3-yl or imidazo[2,1-b] thiazole-5-yl, Z1, Z2and Z3each represents a bond, R1denotes optionally substituted phenyl, and tautomer, prodrug, pharmaceutically acceptable salt or hydrate; various farmkompanijam, comprising as active ingredient the compound II, the drug compound having anti-HIV activity; the method of obtaining compounds of formula III

as well as the intermediate products of the formula

where Z2denotes a bond, -CO-, -O-, -CH2- or -(CH2)2and R1denotes phenyl, substituted with fluorine, and

where And denotes C-W, where W denotes hydrogen, (ness.)alkyl, (ness.)haloalkyl or halogen, or N, Q denotes trail and L denotes ethoxypropan

The invention relates to new derivatives of thieno[2,3-d]pyrimidine-2,4(1H, 3H)-dione of General formula (I) or their pharmaceutically-acceptable salts, having immunosuppressive activity

FIELD: organic chemistry, biochemistry, medicine.

SUBSTANCE: invention relates to phosphoramidates of nucleoside analogs comprising 2',3'-dideoxy-2',3'-didehydrothymidine 5'-phosphodimorpholidate of the formula (I) and phosphoramidates of 3'-azido-3'-deoxythymidine of the formula (II) and the formula (III) that inhibit activity in reproduction of human immunodeficiency virus (HIV). Compounds are resistant to effect of dephosphorylating enzymes and able to penetrate into cells and elicit the selective activity in inhibition of DNA biosynthesis catalyzed by HIV-reverse transcriptase.

EFFECT: valuable medicinal and biochemical properties of nucleoside analogs.

4 dwg, 1 tbl, 5 ex

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