PL197668B1 - New 2 ', 3'-dideoxy-3'-fluorothimidine analogs as prodrugs with high activity (54) against human immunodeficiency virus (HIV), method of their preparation and pharmaceuticals containing them - Google Patents

Abstract

1. New analogues of 2',3'-dideoxy-3'-fluorothymidine constituting pro-drugs with high activity against the human immunodeficiency virus (HIV), of the general formula 1, wherein R is a 12-bromododecanoyl, 12-methoxydodecanoyl, 11-ethylthiododecanoyl, 12-ethylthiododecanoyl, tetradecanoyl or 12-azidododecanoyl group (with the symbols XF306, XF307, XF308, XF309, XF310, XF311, respectively).

Description

(22) Date of filing: 13/05/2002

REPUBLIC

POLAND

Patent Office of the Republic of Poland

New 2',3'-dideoxy-3'-fluorothymidine analogues constituting highly active prodrugs (54) against viruses and human immunodeficiency virus (HIV), their production and pharmaceuticals containing them (73) Patent holder: Polish Academy of Sciences, Institute of Biochemistry and Biophysics, Warsaw, PL (43) The application was announced: 17/11/2003 BUP 23/03 (72) Inventor(s): Agnieszka Miazga, Nisko, PL Tadeusz Kulikowski, Warsaw, PL Andrzej Piasek, Warsaw, PL (45) The patent was granted on: 30/04/2008 WUP 04/08 (74) Attorney: Iwona Brodowska, Patent Attorney, LEXPAT Legal and Patent Office S.C.

(57) 1. New analogues of 2',3'-dideoxy-3'-fluorothymidine constituting pro-drugs with high activity against the human immunodeficiency virus (HIV), of the general formula 1, wherein R is a 12-bromododecanoyl, 12-methoxydodecanoyl, 11-ethylthiododecanoyl, 12-ethylthiododecanoyl, tetradecanoyl or 12-azidododecanoyl group (with the symbols XF306, XF307, XF308, XF309, XF310, XF311, respectively).

PL 197 668 B1

Description of the invention

The subject of the invention are new prodrugs with high activity against the human immunodeficiency virus (HIV), being analogues of 2-thio and 5'-substituted 2',3'-dideoxy-3'-fluorothymidine of the general formula 1, wherein R is a 12-bromododecanoyl, 12-methoxydodecanoyl, 11-ethylthiododecanoyl, 12-ethylthiododecanoyl, tetradecanoyl or 12-azidododecanoyl group, a method for their preparation and pharmaceutical compositions containing them.

The novel compounds of the invention are prodrugs of the selective, competitive HIV retrovirus inhibitor 2',3'-dideoxy-3'-fluoro-2-thiothymidine (S2FLT, XF302), requiring intracellular hydrolytic cleavage to S2FLT and subsequent intracellular activation-phosphorylation of S2FLT by host kinases to its nucleoside-5'-triphosphate.

Currently, six 5'-O-myristoyl derivatives of 2',3'-dideoxy-3'-fluorothymidine are known, which are among the most active HIV inhibitors in various T cells, significantly more potent HIV inhibitors than the standard drug AZT. Unfortunately, FLT released in the cell is more toxic than AZT towards uninfected lymphocytes (Balzarini J., Baba M., Pauwels R., Herdewijn P., De Clercq E. Biochem. Pharmacol. 1988, 37, 2847-2856). Clinical studies have shown that thrombocytopenia and anemia are dose-limiting toxic effects (Balzarini J., Baba M., Pauwels R., Herdewijn P., De Clercq E. Biochem. Pharmacol. 1988, 37, 2847-2856; Kong X.-B., Zhu Q.-Y., Vidal PM, Watanabe KA, Polsky B., Armstrong D., Ostrander M., Lang S.A. Jr., Chou T.-C. Antimicrob. 1988, 153, 825-818; further clinical trials were discontinued. These observed side effects prompted the Applicant to search for close FLT analogues with reduced cytotoxicity from the 2-thioderivative class (Poopeiko NE, Poznański J., Drabikowska AK, Balzarini J., De Clercq E., Mikhailopulo IA, Shugar D., Kulikowski T. Nucleosides & Nucleotides 1995, 14, 435-437). Compounds of this type show lower toxicity, increased lipophilicity and better penetration through animal cell membranes and the blood-brain barrier compared to FLT. 2',3'-Dideoxy-3'-fluoro-2-thiothymidine (S2FLT, XF302) was previously synthesized by Lewis acid-catalyzed nucleoside condensation of diTMS-2-thiothymine with 1,5-di-O-benzoyl-2,3-dideoxy-3-fluoro-p-ery/Z)ro-pentafuranose (Poopeiko NE, Poznański J., Drabikowska AK, Balzarini J., De Clercq E., Mikhailopulo lA, Shugar D., Kulikowski T. Nucleosides & Nucleotides 1995, 14, 435-437). This laborious procedure yielded a difficult-to-separate mixture of β- and α-anomers in a 1:3 ratio, i.e. a mixture containing mostly inactive α-anomer. As a result, the final yield of _S2FLT decreased to ~ 5%. A newer, more convenient method of S2FLT synthesis based on the transformation of 3'-O-acetyl-2',3'-dideoxy-3'-fluoro-2-ethoxythymidine was described in patent application No. P.-352532 dated February 28, 2002.

Due to their very low toxicity, the above compounds can be used in all stages of AIDS development, including the final phase, i.e. when the number of T4 lymphocytes in patients drops below 200/jL of peripheral blood.

Unexpectedly, it turned out that by the method according to the invention it is possible to obtain a new unknown group of 2,5'-substituted FLT analogues of the general formula 1, wherein R is a 12-bromododecanoyl, 12-methoxydodecanoyl, 11-ethylthiododecanoyl, 12-ethylthiododecanoyl, tetradecanoyl or 12-azidododecanoyl group, by transformation of the known compound 1-(5-O-trityl-2-deoxy-3-D-phreo-pentafuranosyl)-2-ethoxythymine (4) (Joshi B.V., Reese C.B., Varaprasad C.N.N.S. Nucleosides Nucleotides 1995, 14, 209-218) into prodrug compounds exhibiting strong antiretroviral (anti-HIV) activity.

Unexpectedly, it also turned out that the new FLT analogues according to the invention, having a thionic group at position 2 of the FLT pyrimidine ring and a myristoyl group (12-bromododecanoyl, 12-methoxydodecanoyl, 11-ethylthiododecanoyl, 12-ethylthiododecanoyl, tetradecanoyl or 12-azidododecanoyl) at the 5'-position of the 2,3,-dideoxyribose residue, are characterized by very high antiviral activity and a very high selectivity index.

New analogues of 2',3'-dideoxy-3'-fluorothymidine constituting prodrugs with high activity against the human immunodeficiency virus (HIV), of the general formula 1, where R is a 12-bromododecanoyl, 12-methoxydodecanoyl, 11-ethylthiododecanoyl, 12-ethylthiododecanoyl, tetradecanoyl or 12-azidododecanoyl group with the symbols XF306, XF307, XF308, XF309, XF310, XF311, respectively.

PL 197 668 B1

Particularly preferred FLT analogues are compounds of formula 1, where R is a 12-methoxydodecanoyl group and a 12-azidododecanoyl group, i.e. compounds with the symbol XF307 and XF311.

The method for preparing 2',3'-dideoxy-3'-fluorothymidine analogues of the general formula 1, wherein R is a 12-bromododecanoyl, 12-methoxydodecanoyl, 11-ethylthiododecanoyl, 12-ethylthiododecanoyl, tetradecanoyl or 12-azidododecanoyl group (with the symbols XF306, XF307, XF308, XF309, XF310, XF311, respectively) according to the invention consists in the following:

(a) obtaining a compound of formula 2 from a compound of formula 4 (Scheme 11) by thionation of the 2-OEt group with hydrogen sulfide in the presence of tetramethylguanidine at 0°C;

(b) obtaining an intermediate compound of formula 3 by treating compound 2 with diethylaminosulfur trifluoride (DAST) in a dry, non-polar, organic solvent, preferably dichloromethane, at 0°C;

(c) obtaining the intermediate of formula 1a (XF302) from the compound of formula 3 by treating the trityl group with 80% acetic acid for 1.5 h at 80°C;

(d) obtaining compounds of formula 1b - 1f, wherein R is a 12-bromododecanoyl, 12-methoxydodecanoyl, 11-ethylthiododecanoyl, 12-ethylthiododecanoyl or tetradecanoyl acid residue by reacting the corresponding halide of the above-mentioned fatty acid of formula RX, wherein R is as defined above and X is a halogen, with the compound of formula 1a in the presence of dimethylaminopyridine in dichloromethane at room temperature for one hour;

(e) the compound of formula 1g, wherein R is 12-azidedodecanoic acid, is obtained by treating the compound of formula 1b with sodium azide in dimethylformamide at room temperature.

A pharmaceutical agent in the nature of a prodrug of the nucleoside _S2FLT , with high activity against the human immunodeficiency virus (HIV), containing known, pharmaceutically acceptable carriers and excipients, according to the invention is characterized in that its active ingredient is a compound of the general formula 1, wherein R is a 12-bromododecanoyl, 12-methoxydodecanoyl, 11-ethylthiododecanoyl, 12-ethylthiododecanoyl, tetradecanoyl or 12-azidododecanoyl group, hydrolyzing in a cell under the action of esterases to a compound of the formula 1a (XF302) or containing a mixture of any of the compounds of the formula 1b to 1g with a compound of the formula 1a (XF302).

Preferably, the pharmaceutical composition according to the invention comprises compounds of the symbol XF307 and/or XF311, optionally in a mixture with the compound of formula 1a (XF302).

The pharmaceutical agent of the invention shows potent inhibition of HIV-1 and HIV-2 virus growth with an ED ₅₀ of 0.01-0.05 μM in CEM-T ₄ , MT-2 and PBMC cells with a complete lack of cytotoxicity at therapeutic concentrations (CC ₅₀ >200 μM).

The following examples illustrate the invention without limiting its scope.

E x a m p l e I.

1-(2-Deoxy-5-O-trityl-3-D-threo-ribofuranosyl)-2-thiothymine (2)

Hydrogen sulfide was bubbled through a solution of 3.71 g (7.23 mmol) of 1-(5-O-trityl-2-deoxy-3-D-threo-ribofuranosyl)-2-ethoxythymine (4) and 8 ml (63.5 mmol) of tetramethylguanidine in 36 ml of dry pyridine at 0°C for 45 min. After complete saturation, the mixture was left for 20 h at room temperature. The reaction mixture was diluted with 150 ml of chloroform and argon was bubbled through the solution for 30 min and then washed with saturated _NaHCO3 solution (2 x 100 ml) and water (2 x 100 ml). The organic layer was separated, dried over anhydrous _Na2SO4 and evaporated to dryness. The residue was purified by silica gel column chromatography. Elution was carried out with cyclohexane-ethyl acetate (2:1). The fractions containing the product were combined and evaporated to dryness. The product was crystallized from ethanol, yielding 3.1 g (82%) of compound 2 as a white solid: mp 116-118°C; UV Xmax (MeOH) 278 nm; TLC (silica gel) R _f (CHCl ₃ :MeOH 95:) 0.53; ¹ H NMR δ [ppm] (CDCI ₃ ) 1.77 (s, 3H, 5-CH ₃ ), 2.25 (d, 1H, H2), 2.65 (m, 1H, H2'), 2.71 (s, 1H, 3'-OH), 3.53 (dd, 1H, H5), 3.70 (dd, 1H, H5'), 4.14 (m, 1H, H4'), 4.48 (m, 1H, H3'), 6.70 (d, 1H, H1'), 7.28-7.46 (m, 15H, Ph), 7.74 (s, 1H, H6), 9.52 (s, 1H, NH).

Example II

1-(5-O-trityl-2,3-dideoxy-3-fluoro-3-D-ribofuranosyl)-2-thiothymine (3)

3.1 g (6.2 mmol) of 1-(5-O-trityl-2-deoxy-β-D-[beta]-ribofuranosyl)-2-thiothymine (2) was suspended in 150 ml of dry dichloromethane and 2.96 ml (22.38 mmol) of diethylaminosulfur trifluoride (DAST) was added dropwise at 0°C. The mixture was stirred for 2 h at 0°C, then 12 ml of

PL 197 668 B1 pyridine and stirred for another 1 h. The reaction mixture was diluted with chloroform (100 ml) and washed with saturated NaHCO3 solution (2 x 100 ml) and water (100 ml). The organic layer was separated and dried over anhydrous _Na2SO4 and concentrated under reduced pressure to an oil. The oil was purified by chromatography on a silica gel column. Elution was carried out with a gradient of ethyl acetate in cyclohexane (10-60%). Fractions containing compound 3 were combined and evaporated to dryness. Yield 1.23 g (38.1%), UV X _max (MeOH) 278 nm; TLC (silica gel) Rf (CHCl2:MeOH 95:5) 0.77; ¹ H NMR δ [ppm] (CDCI3) 1.47 (s, 3H, 5-CH3), 2.26 (m, 1H, H2'), 2.96 (m, 1H, H2), 3.43 (d, 1H, H5), 3.61 (d, 1H, H5'), 4.41 (d, 1H, H4'), 5.32 (dd, 1H, H3'), 7.11 (dd, 1H, H1'), 7.20-7.45 (m, 15H, Ph), 7.70 (s, 1H, H6).

Example III

1-(2,3-dideoxy-3-fluoro-eD-ribofuranosyl)-2-thiothymine (1a) (S ₂ FLT. XF302)

1.18 g (2.14 mmol) of compound 3 in 20 ml of 80% acetic acid was heated at 80°C for 1.5 h. The mixture was evaporated with toluene and ethanol to dryness and the residue was purified by chromatography on a silica gel column using a gradient of methanol in chloroform (0-2%) as eluent. The fractions containing compound 1a were evaporated to dryness and crystallized from hexane-ethanol. Yield 0.3 g (49.1%); mp 183-184°C; UV λ _max (MeOH) 277.5 nm; TLC (silica gel) Rf (CHCl3;MeOH 95:5) 0.18; ¹ H NMR δ [ppm] (CD3OD) 1.92 (s, 3H, 5-CH3), 2.12 (m, 1H, H2'), 2.76 (m, 1H, H2), 3.83 (2H, d, H5', H5), 4.32 (m, 1H, H4'), 5.28 (dd, 1H, H3'), 7/04 (dd, 1H, H1'), 8/06 (s, 1H, H6).

Example IV

General method for the synthesis of 5'-myristoyl derivatives of S ₂ FLT (1b-e)

To a solution of the appropriate fatty acid (5 mmol) in dry dichloromethane (100 ml) was added dropwise oxalic chloride (1 ml, 10.5 mmol). The mixture was stirred at room temperature for 2 h and then concentrated under reduced pressure to dryness. The dry residue was dissolved in 50 ml of dry dichloromethane and added dropwise to an ice-cooled solution of _S2FLT (1.3 g, 5 mmol) and 4-dimethylaminopyridine (DMAP) (880 mg, 7 mmol) in dry dichloromethane (100 ml). The solution was stirred at 0°C for 20 min and then at room temperature for 2 h. The mixture was washed with saturated aqueous sodium bicarbonate solution (2 x 50 ml) and water (2 x 50 ml). The organic layer was dried over anhydrous _Na2SO4 and concentrated in vacuo to dryness. The dry residue was purified by chromatography on silica gel using chloroform as eluent to give homogeneous products 1 be as oils.

-(5-O-(12-bromododecanoyl)-2,3-dideoxy-3-fluoro-e-D-ribofuranosyl)-2-thiothymine (1b) (XF306)

Yield: 2.08 g, 80%; TLC (silica gel) Rf (toluene - i-PrOH - ethyl acetate 7:1:2) 0.78 ¹ H NMR (CDCl3) 1.20-1.50 (br m; 14H, ( _CH2 ) ₇ ); 1.58-1.70 (m, 2H; CH ₂ CH ₂ CO), 1.84 (quintet, 2H, CH ₂ CH ₂ Br), 1.85-1.95 (m, 1H, H-2'), 1.97 (d, 3H, 5-CH3), 2.33 (t, 2H, CH ₂ CO), 3.04 (ddd, 1H, H2), 3.41 (t, 3H, CH ₂ Br), 4.32 and 4.45 (two dd, 1H each, H5', H5), 4.56 (dt, 1H, H4'), 5.17 (dd, 1H, H3'), 6.91 (dd, 1H, H1% 7.49 (d, 1H, H6), 9.46 (s, 1H,NH ^); MS ⁽ M+H ⁾⁺ 521.1701

-(2,3-dideoxy-3-fluoro-5-O-(12-methoxydodecanoyl)-3-D-ribofuranosyl)-2-thiothymine (1c) (XF307)

Yield 1.56 g, 66%; TLC (silica gel) Rf (toluene - i-PrOH - ethyl acetate 7:1:2) 0.68 ^1H NMR (CDCl3) 1.23-1.34 (br m, 14H, ( _CH2 ) ₇ ), 1.53-1.65 (m, _4H , _CH2CH2CO , _{OCH2CH2 )} , 1.98 (d, 3H, 5-CH3), 1.82-1.96 (m, 1H, H2'), 2.33 (td, 2H, _CH2CO ), 3.04 (m, 1H, H2), 3.34 (s, 3H, OCH3), 3.37 (t, 2H, _OCH2CH2 ), 4.32 and 4.45 (two _dd , 1H each, H5', H5), 4.56 (dt, 1H, H4'), 5.17 (dd; 1H, H3'), 6.92 (dd, 1H, H1% 7.49 (d, 1H, H6^ 9.49 (s, 1H, NH ^); MS ⁽ M+H)+ 473.2431.

-(5-O-(2,3-dideoxy-11-ethylthiododecanoyl))3-fluoro-p-D-ribofuranosyl)-2-thiothymine(1d) (XF308)

Yield 1.32 g, 54%); TLC (silica gel) Rf (toluene - i-PrOH - ethyl acetate 7:1:2) 0.78 ^1H NMR (CDCl3) 1.24-1.38 (br m, 12H, ( _CH2 )6), 1.25 (t, 3H, CH3), 1.54-1.62 (m, 4H, _CH2CH2CO , Cl± _CH2S ), 1.82-1.95 (m, 1H, H-2'), 1.97 ( _d , 3H, 5-CH3), 2.33 (td, _2H , CH2CO), 2.50-2.55 (m, 4H, _CH2CH2S , _CH3CH2S ), 3.04 (m, 1H, H-2), 4.32 and 4.45 (two dd, 1H each, H5', H5), 4.56 (dt, 1H, H4'), 5.17 (dd, 1H, H3) 6.91 (dd, 1H, H1'), 7.48 (d, 1H, H6), 9.37 (s, 1H, NH ^); MS ⁽ M+H)+ 489.3606.

1-(2.3-dideoxy-5-O-(12-ethylthiododecanoyl)-3-fluoro-3-D-ribofuranosyl)-2-thiothymine (1e) (XF309)

Yield 1.25 g, 50%; TLC (silica gel) Rf (toluene - i-PrOH - ethyl acetate 7:1:2) 0.80 ^1H NMR (CDCl3) 1.21-1.41 (br m, 14H, ( _CH2 ) ₇ ), 1.25 (t, 3H, CH3), 1.50-1.66 ( _m , 4H, _CH2CH2S , Cl± _CH2CO ), 1.72-1.91 (m, 1H, H-2'), 1.97 (d, 3H, 5-CH3), _2.33 (t, 2H, CH2CO), 2.48-2.59 ( _m , 4H, _CH2C ] _H2S , CH3CH2S), 3.04 (m, 1H, H-2), 4.31 4.45 (two dd, 1H each, H5', H5), 4.56 (dt, 1H, H4'), 5.17 (dd, 1H, H3'^ 6.91 (dd, 1H, H1·), 7.49 (d, 1H, H6), 9.35 (s, 1H, NH ^); MS ⁽ M+H)+ 503.5422.

PL 197 668 B1

Example V

1-(2,3-dideoxy-3-fluoro-5-O-(tetradodecanoyl)-e-D-ribofuranosyl)-2-thiothymine (1 f) (XF310)

Myristoyl chloride (2.1 mL, 7.7 mmol) was added dropwise to an ice-cooled mixture of S2FLT (2 g, 7.7 mmol) and 4-dimethylaminopyridine (1.5 g, 12.3 mmol) in dry dichloromethane (100 mL). The mixture was stirred at 0°C for 1 h and then 2 h at room temperature. The solution was washed with saturated aqueous sodium hydrogen carbonate solution (2 x 50 mL) and water (2 x 50 mL). The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to dryness. The residue was purified by column chromatography on silica gel using chloroform as eluent. Oily compound 1f (3.77 g, 80%) was obtained; TLC (silica gel) Rf (toluene - i-PrOH - ethyl acetate 7:1:2) 0.79 ¹ H NMR (CDCl3) 0.88 (t, 3H, CH3), 1.16-1.34 (br m, 20H, (CH2)10); 1.68-1.80 (m, 2H, CH2CH2CO), 1.84-1.96 (m, 1H, H2'), 1.97 (d, 3H, 5-CH3), 2.33 (t, 2H, CH2CO), 3.04 (ddd, 1H, H-2), 4.32 and 4.45 (two dd, 1H each, H5', H5), 4.56 (dt, 1H, H4'), 5.17 (dd, 1H, H3') 6.91 (dd, 1H, H1·), 7.49 (d, 1H, H6), 9.41 (s, 1H, NH ^); MS ⁽ M+H ⁾⁺ 471.3048.

Example VI

1-(5-O-(12-azidododecanoyl)-2.3-dideoxy-3-fluoro-e-D-ribofuranosyl)-2-thiothymine (1g) (XF311)

To a solution of 5'-O-(12-bromododecanoyl)-3'-fluoro-2-thiothymidine (1.29 g, 2.4 mmol) in dimethylformamide (28 ml) was added sodium azide (230 mg, 3.5 mmol) and the mixture was stirred at room temperature for 3 h. The solvent was evaporated under reduced pressure to dryness, and the residue was dissolved in chloroform (100 ml) and washed with water (2 x 100 ml). The organic layer was dried over anhydrous Na2SO4 and evaporated in vacuo to dryness. The oily residue was purified by chromatography on silica gel. The column was eluted with chloroform to give oily compound 1 g (1.1 g, 92%); TLC (silica gel) Rf (toluene - i-PrOH - ethyl acetate 7:1:2) 0.79 ^1H NMR (CDCl3) 1.26-1.37 (br m, 14H, (CHab); 1.56-1.65 (m, 4H; CH2CH2CO, CH2CH2N3), 1.82-1.96 (m, 1H, H2'), 1.97 (d, 3H, 5-CH3), 3.04-3.08 (dddd, 1H, H2), 2.33 (t, 2H, CH2CO), 3.26 (t, 2H, CH2N3), 4.32 and 4.45 (two dd, 1H each, H5', H5), 4.56 (dt, 1H, H4'), 5.15 (dd, 1H, H3'), 6.91 (dd, 1H, H1'), 7.49 (d, 1H, H6) 9.37 (s, 1H, NH ^); MS ⁽ M+H)+ 484.2583.

Example VII.

Determination of HIV infection inhibitory activity.

Antiviral activity (ED ₅₀ ) was assayed using a syncytia-inducing laboratory strain of HIV-1 (cat#3) and CEM-T4 and MT-2 cell cultures. Cells were preincubated for 16 h in 10% FCS-RPM1 medium supplemented with various concentrations of the test compound. Virus adsorption was continued for 4 h at 37°C. After incubation with the virus, the cells were centrifuged (6 x 1000 rpm/min), and the unadsorbed virus was washed away. The cells were resuspended in medium containing the test compounds. Three types of controls were used: a virus growth control (infected cells without the test compound), a negative control (uninfected cells), and cells cultured with the known inhibitors AZT and ddC at identical concentrations as the test compounds. The assays were performed in 96-well culture plates. Each well contained 2 x ¹⁰⁵ cells suspended in 200 µl of medium. Samples for each concentration were performed three times. Virus growth was monitored every 3 days by determining the viral p24 protein content according to the Coulter HIV p24 Antigen Assay. Syncytia formation was observed under an inverted microscope. To determine the selectivity index of the tested compounds, the minimum cytotoxic concentrations (CC ₅₀ ) were measured. Cells were cultured for 5 days under standard conditions in 10% FCS-RPM1 medium supplemented with various concentrations of the tested compounds and control compounds. After 5 days, cell viability was determined using the trypan blue displacement method. Among the tested compounds included in formula 1, compounds XF307 and XF311 demonstrated the highest anti-HIV activity (ED ₅₀ = 0.01-0.05 µM) with very low cytotoxicity (CC 50 > 200 µM). The above results showed that these compounds are selective HIV inhibitors with a very good therapeutic index and prospective drugs against HIV/AIDS.

Claims (4)

Patent claims 1. New analogs of Z 1 S 2 dideoose-S 4 fluorothymidine which are prodrugs with high activity against human immunodeficiency virus (HIV) of the general formula 1, where R is 12-bromododecanoyl, 12-methoxydodecanoyl, 11-ethylthiododecanoyl, 12 -ethylthiododecanoyl, tetradecanoyl or 12-azido dodecanoyl (XF306, XF307, XF308, XF309, XF310, XF311, respectively). PL 197 668 B1 2. A method for the preparation of 5'-substituted 2 ', 3'-dideoxy-3'-fluorothimidine analogs of general formula 1, wherein R is 12-bromodecanoyl, 12-methoxydodecanoyl, 11-ethylthiododecanoyl, 12-ethylthiododecanoyl, tetradecanoyl or 12 azidodecanoyl (XF306, XF307, XF308, XF309, XF310, XF311, respectively), characterized in that: (a) obtaining pr ^ ^ ^ ^ ^ ^ rn compound of formula 2 from compound 4 (Scheme 11 by toning the 2-OEt group with hydrogen sulfide in the presence of tetramethylguanidine at 0 ° C; (b) an intermediate of formula 3 is obtained by treating compound 2 with diethylaminosulfur trifluoride (DAST) in a dry non-polar organic solvent, preferably in dichloromethane, at 0 ° C; (c) an intermediate of formula wherein R is hydrogen, tXF302) is obtained from the compound of formula 3 by cleavage of the trityl group with 80% acetic acid for 1.5 h at 80 ° C; (d) compounds of formula 1b-1f are obtained wherein R is 12-bromododecanoyl, 12-methoxydodecanoyl, 11-ethylthiododecanoyl, 12-ethylthiododecanoyl or tetradecanoyl residue by treatment with the appropriate halide of the above-mentioned fatty acid of formula RX, where R is as defined above and X is halogen, for the compound of formula la in the presence of dimethylaminopyridine in dichloromethane at room temperature for one hour; (e) a compound of Formula 1g is obtained, wherein R is R, 12-azido-dodecanoic acid, by treating the compound of Formula Ib in dimethylformamide with sodium azide at room temperature. A pharmaceutical agent of the nature of a prodrug of the nucleoside S ₂ FLT, with high activity against human immunodeficiency virus (HIV), containing known, pharmaceutically acceptable carriers and excipients, characterized in that its active ingredient is a compound of general formula 1, in which R is 12-bromododecanoyl, 12-methoxydodecanoyl, 11-ethylthiododecanoyl, 12-ethylthiododecanoyl, tetradecanoyl or 12-azododecanoyl which is hydrolyzed in the cell by esterases to the compound of formula 1a (XF302) or contains a mixture of which a compound of formula la (XF302). 4. The pharmaceutical composition according to claim 1 A compound according to claim 3, characterized in that it contains compounds with the symbotes XF307 and / or XF311, optionally in a mixture with a compound of formula 1a (XF302).