CZ18093A3 - Novel derivatives of phospholipid nucleosides, process of their preparation as well as their use as antiviral medicaments - Google Patents

Description

New derivatives of nucleoside phospholipids, processes for their preparation, as well as their use as antiviral drugs

Technical field

The present invention provides novel nucleoside phospholipid derivatives of formula X

R 6 is a linear or branched, saturated or unsaturated C 8 -C 15 alkyl chain which may optionally be substituted one or more times by phenyl, halogen, C 1 -C 6 alkoxy, C 1 -C 6 -alkylmercapto, C 1 -C 6 -alkyl groups C1-C6-alkoxycarbonyl, C1-C6-alkylsulfinyl or C1-C6-alkylsulfonyl groups,

E ₂ linear or branched, saturated or unsaturated C 8 -C 15 alkyl chain which may optionally be substituted one or more times by phenyl, halogen, C 1 -C 6 -alkoxy, C 1 -C 6 -alkyrmercap to C1-C6-alkoxycarbonyl or C1-C6-alkylsulfonyl groups,

E ^ is hydrogen or hydroxy,

E 2, E 2 hydrogen or one of the radicals E 2 and E 2, halogen, hydroxy, cyano or azido and in addition E 2 and E 2 may represent an additional bond between C-2 * and C-3 *>

n 0,1 or 2 a

B represents one of the following compounds I / O

II .0

wherein Eg may be a C 1 -C 4 alkyl chain or a halogen,

where εγ can be hydrogen, a C 1 -C 4 alkyl chain or a halogen,

wherein εθ can be an alkyl chain of 1 to 4 carbon atoms, a halogen or a hydroxy group;

wherein _Rg may be hydrogen or amino and 10-halo, C ^ -Cg-alkoxy,

C 1 -C 6 alkylmethoxy or amino, which may be mono substituted or disubstituted with C 1 -C 6 -alkyl groups,

C 4 -C 8 -alkoxy groups, hydroxy-C 1 -C 8 alkyl groups and / or C 1 -C 8 -cycloalkyl groups, aryl groups, hetaryl groups, aralkyl groups or hetarylalkyl groups, which may optionally be in the aryl group or a hetaryl radical substituted with one or more hydroxy, methoxy or alkyl or halogen, or allyl, which may optionally be substituted with monoalkyl or dialkyl or alkoxy groups, their tautomers or their physiologically tolerable salts of inorganic or organic acids or bases, and the process their manufacture and medicaments containing these compounds.

Since the compounds of formula I contain asymmetric carbon atoms, all optically active forms and racemic mixtures thereof are also within the scope of the present invention.

BACKGROUND OF THE INVENTION

J. Biol. Chem. 265, 6112 (1990) describes the manufacture and use of liponucleotides as antiviral drugs. However, only known nucleosides such as AZT and ddC, coupled with dimyristoylphosphatidyl residues and dipalmitoylphosphatidyl residues with their fatty acid ester structure have been investigated and synthesized.

In J. Med. Chem. 22 »1380 (1990) disclose nucleoside conjugates of thioether lipids with a cytidine diphosphate having an antitumoral (antitumor) effect and can be used in oncology.

Chem. Pharm. Bull. 36, 209 (1988) disclose 5 ^of - (3-SN-phosphatidyl) nucleosides with antileukemic activity, as well as their enzymatic synthesis from the corresponding nucleosides and phosphocholines in the presence of phospholipase D with transferase activity.

The enzymatic synthesis of liponucleotides is inter alia. also described in Tetrahedron Lett. 28, 199 (1937) and Chem, Pharm. Bull. JO 5020 (1988).

The compounds of the present invention also exhibit valuable pharmacological properties. It is particularly suitable for the treatment and prophylaxis of infections caused by LNA viruses such as herpes simplex virus (plain herpes), zytomegaly virus, Papova virus, varicella zoster virus (varicella zoster virus) or Epstein-Barr virus or RNA viruses such as toga viruses or especially retroviruses such as the HEDV-I and II viruses, as well as the lentiviruses visna and the human immunodeficiency virus HIV-1 and 2.

In particular, the compounds of formula I appear to be useful in the treatment of clinical manifestations of HIV retroviral infection in humans, such as prolonged generalized lymphadenopathy (PGI) (unspecified lymph node disease), advanced stage of AIDS related complex (ARC) and clinical fully developed AILS.

Surprisingly, it has now been found that the compounds of formula I inhibit the proliferation of LNA or RNA viruses at the level of virus-specific LNA or RNA transcription. by inhibiting the enzyme reverse transcriptase, they can influence the reproduction of retroviruses / cf. Why. Nati. Acad. Sci. USA 83, 1911, 1986- and Nature 325, 773 1987). Of particular interest is the inhibitory effect on HIV, the causative agent of immune-compromised AILS. Only 3 * - azido-3 * - desoxythymidine (LE-A-3608606) is now accepted for the treatment of AIDS in AIDS patients. Minor

The 6-toxic effects of 3 ^of -azido-3desoxythymidine on the bone marrow require that blood transfusions be performed in about 50% of treated patients. The compounds of formula I do not have these drawbacks. They act antivirally without being cytotoxic at pharmacologically relevant doses. SUMMARY OF THE INVENTION

The present invention provides novel nucleoside phospholipid derivatives of the above formula I.

The compounds of the present invention and their pharmaceutical compositions can be used in combination with other drugs for the treatment and prophylaxis of the above infections. Examples of such other drugs include agents that can be used for the treatment and prophylaxis of HIV infections or diseases associated with such diseases as, for example, 3 ^z -azido-3 ^z- desoxythymidine, 2? 3didesoxynucleosides such as 2? 3? -Didesoxycytidine, 2? 3'-didesoxyadenosine and 2 *, 3 * -deoxyoxyinine, acyclic nucleosides (e.g., aocyclovir), interferons such as A-interferon, renal secretion inhibitors such as probenicide, nucleoside-based transport inhibitors such as dipyridamole. but also immune modulators such as interleukin II or stimulating factors such as granulocyte macrophage colony factor. The compounds of the present invention can be administered alone, optionally, optionally in one or two separate formulations or at different times, so as to achieve a synergistic effect.

As possible salts of the compounds according to the invention of the general formula I which may be used, in particular, alkali metal salts, alkaline earth salts and ammonium salts can be used. As alkali metal salts, lithium, sodium or potassium salts are preferred

Especially magnesium and calcium salts are suitable. The term ammonium salts according to the invention means salts which contain an ammonium ion which can be substituted up to four times with 1-4 carbon atoms and / or aralkyl radicals, preferably benzyl radicals. The substituents may be the same or different.

The compounds of the formula I can contain basic groups, in particular amino groups, which can be converted into suitable acid addition salts by suitable acids. Suitable salts for this purpose are sulfuric acid, phosphoric acid, fumaric acid, succinic acid, tartaric acid, citric acid, lactic acid, maleic acid or methanesulfonic acid.

In formula I, A is preferably a linear ^C 1O ° ^C 14 -alkyl which may be further substituted by lower-alkoxy or Cj-Cg-alkylmerkaptoskupinou.E · ^ particular represents a decyl, undecyl, dodeoylovou, nebotetradecylovou tridecyl group. Suitable C 1 -C 8 -alkoxy substituents are methoxy, ethoxy, butoxy and hexyloxy. When R 1 is substituted with a C 1 -C 8 -alkylmer by a captive moiety, this term refers in particular to methylmercapto from the residue, the ethylmercapto residue, the propylmercapto residue, the butylmercapto residue and the hexylmercapto residue to the numbers 0,1 or 2.

Preferably, ^C 2 ^-C 10 represents a linear ^C 10 ^-C 14 -alkyl group which may still be substituted by a C 1 -C 8 -alkoxy or C 1 -C 8 -alkylmercapto group. R ₂ represents in particular a decyl, undecyl, dodeoyl, tridecyl or tetradecyl group. Suitable C8-alkoxy substituents Kg are preferably methoxy, ethoxy, propoxy, butoxy-8 and hexyloxy.

When R _{2 is} substituted with a C 1 -C 8 -alkyl mercapto radical, this is particularly understood to mean a methyl mercapto, ethyl mercapto, butyl mercapto and hexyl mercapto.

R ₄ and R 8 are preferably hydrogen or preferably a cyano group or an azido group or a halogen atom such as fluorine, chlorine, bromine or iodine over one of the two radicals.

Particularly preferred are compounds in which R 1. and R 6 represents a hydrogen atom and R 8 is a cyano group, and i is a group or fluoro, optionally R 8 is hydrogen and R 6 / R 6 represents another bond between C-2 * and C-3 '.

In bases B of formula (I), the radicals R 8 are R? preferably a hydrogen atom, a methyl, ethyl, propyl or butyl residue, or a halogen atom such as fluorine, chlorine, bromine or iodine. Particularly preferred for R 8 or R 8 is R? a hydrogen atom, a methyl or ethyl residue and a chlorine or bromine atom.

The radical R 8 is preferably a hydrogen atom, a methyl, ethyl, propyl or butyl radical, an amino group or a halogen atom such as fluorine, chlorine, bromine or iodine, preferably chlorine or bromine.

R ₁₀ is preferably hydrogen, fluorine, chlorine or bromine, C 1 -C 8 -alkoxy, in particular methoxy, ethoxy, propoxy, butoxy or hexyloxy, C 1 -C 8 -alkyl mercapto, in particular methylmercapto, ethyl imercapto butyl, imercapto or hexylmercapto or amino, which may be monosubstituted or disubstituted with C 1 -C 8 -alkyl such as methyl, ethyl, butyl or hexyl, hydroxy-C 8 -C 8 -alkyl, such as hydroxy ethyl, hydroxypropyl, hydroxybutyl or hydroxyhexyl, a C 1 -C 8 -cycloalkyl radical, such as a cyclopropyl, γ-clopehtyl or cyclohexyl radical, aryl, preferably phenyl, aralkyl radical, such as, in particular, benzyl, which may optionally be further substituted by one or more hydroxy or methoxy, C1-C6-alkyl groups such as for example methyl, ethyl, propyl, butyl or hexyl or halogen atoms such as fluorine, chlorine or bromine. The amino group may also be substituted by a heterarylalkyl or a hetaryl radical, such as, for example, a thienyl radical, a furyl radical or a pyridyl radical. Heteroarylalkyl is preferably a thienylmethyl, furylmethyl or pyridylmethyl radical.

Preferred coupled nucleosides in the claimed better nucleotides of formula I are:

- 2 ', 3'-didesoxy-3-azidouridine

2? 3 ^Z- oxidesoxyinosine

- 2? 3 ^z - didesoxyguanosine

- 2? 3 ^z - didesoxycytidine

- 2? 3 ^of -didesoxyadenosine

- 3 ^from -oxyoxythymidine

- 2? 3 ^z -didesoxy-2? 3 ^z - didehydro-N 4 - (o-methylbenzyl) adenosine

- 2 - 3 ^z -didesoxy-2 - 3 ^z -ideide-N - (2-methylpropyl) adenosine

- 2 ^ 3 ^z - didesoxy-3-azidoguanosine-3 - iesoxy-3 ^{Z -} azidothymidine

- 2 * 3'-didesoxy-3 ^of -fluoro-5-chlorouridine

- 3 ^from -oxy-3 ^from -fluorothymidine

- 2'-3-didesoxy-3 ^from -fluoradenosine-2'-3'-didesoxy-3 ^from fluoro-2,6-diaminopurinriboside

-10- 2, 3-ethoxy-2,3'-2,3'-dihydrocytidine

- 2-desoxy-3, 3 ^x -didehydrothymidin

- 3'-desoxy-3-azidothymidine

Compounds of formula (I) may be prepared by forming a compound of formula (II)

1.

/ 0 /

II

CH - S - R ₁

CH - 0 - Rg / 11 /,

CHg-OH in which R5, R8 and u are as defined above, is reacted with a compound of formula III

(111) wherein n '* is hydrogen or a hydroxy protecting group skilled in the art with an oxygen protecting group and

R @ 4 or hydrogen, halogen, azido, cyano or one of the radicals R @ 1 and R @ 4 represents a hydroxyl group protected by one skilled in the art with a conventional oxygen protecting group. , or R 6 and R 6 represent a further bond and

B has the above meanings, in the presence of phosphorus oxitrichloride and a phosphoric acid ester, and a target. a nitrogenous base, for example pyridine or triethylamine, in an inert solvent such as toluene and, after hydrolysis, optionally deprotecting the oxygen protecting group by methods customary in nucleoside chemistry, or

2. a compound of formula XV

CH ₂ - S - RJ ·

CH - 0 - R ₂

AND/,

CH.

_CH2 - o - ce p _2/0 / ®

CHp - N - CH, \

CH, in which R 1, R ₂ and π are as defined above, is reacted with a compound of formula III in which r 1, R 2, R 3 and B are as defined above, in the presence of phospholipase D in an inert solvent such as for example, chloroform, in the presence of a suitable buffer, and after the reaction has been carried out, the oxygen protecting group is optionally cleaved by methods customary in nucleoside chemistry.

Preparation of compounds of general formula

II <is described

-12v lipids 22, 947 (1987) and in DE-A-3O39629.

The preparation of compounds of formula III is described, for example, in BP-A 0 286 028 and WO 90/08147.

Compounds similar to the general formula I are described in EP-A-0 350 287. However, only 1,2-diesters of glycerin are described there.

Drugs containing compounds of formula I for the treatment of viral infections may be administered in liquid or solid form enterally or parenterally. Conventional forms of medicaments, such as tablets, capsules, dragees, syrups, solutions or suspensions, are suitable. The preferred injection medium is water, which contains additives customary for injection solutions, such as stabilizing agents, solubilizers and buffers. Such additives are, for example, tartrate buffer and oitrate buffer, ethanol, complexing agents such as ethylenediaminetetraacetic acid and non-toxic salts thereof, high molecular weight polymers such as liquid polyethylene oxide to control viscosity. Liquid carriers for injectable solutions must be sterile and preferably filled into ampoules. Solid carriers are, for example, starches, lactose, mannitol, methyl-cellulose, talc, high disperse silicas, higher molecular fatty acids such as stearic acid, gelatin, agar-agar, calcium phosphate. , magnesium stearate, animal and vegetable oils, solid high molecular weight polymers such as polyethylene glycols, etc. For oral administration, suitable formulations may optionally contain flavorings and sweeteners.

The dosage may depend on various factors such as the mode of administration, the species, the age or the individual condition. The compounds of the invention are usually administered in an amount of 0.1 to 100 mg, preferably 0.2 to 80 mg.

15 per day and per kg body weight. Preferably, the daily dose is divided into 2 to 5 administrations, with 1 to 2 tablets containing 0.5 to 500 mg of active ingredient being administered per administration. The tablets may also be delayed, thereby reducing the number of applications per day to 1-3. The active ingredient content of the delayed tablets may be 2 to 1000 mg. The active ingredient may also be administered by sustained infusion, usually 5 to 1000 mg per day.

For the purposes of the present invention, the following compounds of the general formula I are suitable in addition to the compounds mentioned in the examples and combinations of all the substituents mentioned in the claims:

1. (3-Dodecylmercapto-2-decyloxy) propyl ester (2,3,4-didesoxy-3'-fluoro-5-chloruridine) -5'-phosphoric acid

2. / 3-dodecýlsulfinyl-2-decyloxy / Propylester / ^of 3-desoxy-3 * -azidothymidin / -5'-phosphoric acid

3. (3'-Dodecylsulfonyl-2-decyloxy) propyl ester (3'-desoxy-3'-azidothymidine) -5'-phosphoric acid

4. (3-Dodecylmercapto-2-decyloxy) propyl ester (2,3-d'-dide). 5'-phosphoric acid

5. (3-Dodecylmercapto-2-decyloxy) propyl ester (2 ', 3'-didesoxyinosine) -5'-phosphoric acid

6. (3-Dodecylmercapto-2-decyloxy) propyl ester (2,3,4-didesoxyguaxicsin) -5'-phosphoric acid

7. (3-Dodecylmercapto-2-decyloxy) propyl ester (2 ', 3'-didesoxyadenosine) -5'-phosphoric acid

8. (3-Dodecylmercapto-2-decyloxy) propyl ester (3'-desoxythymidine) -5-phosphoric acid

9th / 3-dodecylmercapto-2-decyloxy / propyl / 3'DESO 7 ^χ "2>3'-didehydrothymidine / -5'-phosphoric acid. / 3 - do de cy lmerkap to-2-decyloxy / propyle ster / 3'-de with xy-3 * - fluorothymidine / -5-phosphoric acid

-1411. (3-dodecylmercapto-2-decyloxy) propyl ester (2,3,4 -idesidesoxy-3'-azidoguanosine) -5-phosphoric acids

12. (3-Dodecylmercapto-2-deoyloxy) propyl ester (2,3-d'ididesoxy-3'-fluoro-2,6-diarainopurinriboside) -5'-phosphoric acid

13th / 3-dodecylmercapto-2-decyloxy / propyl / 2 ^ 3'didesoxy 2Í3 ^{Z-didehydro-N} @ - / 2-Eethylpropyl / adenosine / -5'-phosphoric acid

14. (3-Dodecylgercapto-2-decyloxy) propyl ester (2,3-d'ididesoxy-2,3'-didehydro-N '- (o-methylbenzyl) -adenosine) -5 ^z -phosphoric acid

15. (3-Decylmercapto-2-dodecyloxy) propyl ester (2,3-didesoxy-2,3-dhydroxytytidine) -5'-phosphoric acid

16. 3'-Undecylmercapto-2-dodecyloxy (propyl ester) 2 '

3-Didesoxy-3'-fluoradenosine / -5-phosphoric acid -....... —- .............. .... - ....... ...........,

17. (3-Decylsulfonyl-2-dodeoyloxy) propyl ester (2 ', 3'-didesoxy-3'-azidouridine) -5'-phosphoric acid

18. (3-Decylmercapto-2-decyloxy) propyl ester (2,3,4-didesoxycitidine) -5'-phosphoric acid

19 · (3-dodecylmercapto-2-dodecyloxy) propyl ester (23'-didesoxyinosine) -5'-phosphoric acid

20. (3-Tetradecylmercapto-2-deoyloxy) propyl ester (3-ethoxy-3-azidothymidine) -5'-phosphoric acid

21. (3-Pentadecylmercapto-2-decyloxy) propyl ester (3'-desoxy-3-azidothymidine) -5'-phosphoric acid

22. (3-Trideoylmercapto-2-decyloxy) propyl ster (2'-3didesoxyinosine) -5'-phosphoric acid

23. (3-Dodecyl mercapto-2-octyloxy) propyl ether (2,3-didesoxyinosine) -5'-phosphoric acid

Examples of embodiments of the invention

Example la / 3-dodecylmercapto-2-decyloxy / propyl / 3'-desoxy-3'-azidothymidine / ^Z -5 - phosphoric acid

To a solution consisting of 1.25 g (3 mmol) of 3-dodecylmercapto-2-decyloxy-1-propanol and 1.2 ml (8.6 mmol) of triethylamine in 40 ml of absolute ether was added dropwise under nitrogen at 0 ° C 0.42 ml (4.5 mmol) of POCl 2 and stirred for a further 45 minutes. After allowing the solution to warm to room temperature, a solution consisting of 800 mg (3 mmol) of (3'-desoxy-3'-azidothymidine) was added dropwise. AZT] in a mixture consisting of 15 ml of absolute ether and 20 ml of absolute toluene and stirred for 6 hours under reflux (DC control) by thin layer chromatography //.

After cooling, 50 ml of water was added, the mixture was stirred vigorously for 2 w, then the organic phase was separated, dried over Na ₂ SO ₄ and concentrated on a rotary evaporator. The residue was purified by preparative column chromatography on silica gel 60 with dichloromethane / methanol 9: 1 as eluent. Yield 540 mg (24 $ theor./).

M.p. 187 ° C sintering, 220-223 ° C decomp. 0.59 ppm.

Example 1b (3-dodecylmercapto-2-decyloxy) propyl ester (3'-desoxy-3'-azidothymidine) -5-phosphoric acid

Analogously to the prescription in Chem. Pharm. Bull. 36,

5020 (1988), 2 mmol AZT and 5000 U phospholipase D were suspended in 4 ml of sodium acetate buffer (CaCl ₂₎ , supplemented with a solution consisting of 6 mmol of 3-dodecylmercapto-2-decyloxypropyl-1-phosphoric acid monoeholine ester in 160 ml of chloroform and heated at 45 ° C for 8 h. It was then dried over Ma ₂ SO 4 and the solvent was removed in vacuo. The residue was purified as in Example 1a by column chromatography. Yield 51 ·

The product showed to be identical to the product of Example 1 a / m.p. , ΡΟ, ^ Ξ- and 31ρ _ ^^ /.

Example 2 (3-undecylmercapto-2-undecyloxy) propyl ester (3 desoxy-3 ^from -azidothymidine) -5 * -phosphoric acid

Produced according to Example 1 a. Yield 27 m.p.

218 DEG-222 DEG C. (decomposition)

EXAMPLE 3/3-dodecylmercapto-2-decyloxy / propyl / 2 ^ 3'didesoxy ^from 2, 3 ^from didehydro-N @ - / o-methylbenzyl / adenósin5 phosphoric 'acid

680 mg / 1.37 mmol. / / 3-dodecylmercapto-2-decyloxy / -propyl ester in 20 ml absolute pyridine doplnily337 mg / 1 mmol / 3 ^ 2 ^of -ůiú®so hydroxy-2 ^ 3 ^from didehydro-N - / o-methylbenzyl / adenosinň and after addition of 1.37 g (6.7 mmol) of DCC was stirred for 24 hours at room temperature (DC control). Then the pyridine was removed in vacuo, the residue was suspended in ether and filtered from undissolved urea. Purified by column chromatography over silica gel 60 with dichloromethane / methanol 95/5 as eluent. Yield 220 mg (26% of theory)

0.68 / CH ₂ Cl ₂ / CH ₃ OH / H ₂ O 13/5 / 0.8.

Example 4 (3-Dodecylmercapto-2-decyloxy) propyl ester (3 * desoxy-3 ^from -azidothymidine) -5-phosphoric acid

Analogous to Example 3, 13.5 g of (3-to17-decylmercapto-2-decyloxy) propyl phosphate, 5.4 g of AZT and 27 g of PCC in 350 ml of absolute pyridine were prepared by stirring at room temperature for 30 hours and purifying as the corresponding liponucleotide described above in 62% yield (analytical data are identical to those of Example 1).

Example 5

3-Dodeoylmercapto-2-decyloxy (propyl ester) 3'-desoxythymidine / -5-phosphoric acid

Analogously to Example 3, t-phosphate from (3-dodecylmercapto-2-decyloxy) propyl ester, 500 mg of 3'-desoxythymidine and 2.6 g of LCC in 40 ml of absolute pyridine was made by stirring for 24 hours at room temperature and chromatographic purification corresponding to the liponucleotide in 51 yield. £ _f = 0.45 / of CH₂Cl₂ / CH? OH / HgO 12/5 / 0,8 /.

Example 6 (3-dodecylmercapto-2-decyloxy) propyl ester (2 ', 3'-didesoxyinosine) -5-phosphoric acid

Analogously to Example 3, from 1.3 g of (3-dodecylmercapto-2-decyloxy) propyl phosphate, 500 mg of 2? 3? -Didesoxyinosine and 2.6 g of LCC in 40 ml of absolute pyridine were stirred for 40 hours at room temperature. and, by tographic purification, said liponucleotide in 61% yield. Sf = 0.38 (CH ₂ Cl ₂ / CH ₃ OH / H ₂ O 13/5 / 0.8).

Claims (8)

& A Τ Β Ν ϊ Ο V & NATIONAL 1. Compounds of formula I (0) CH ₂ - 3 i IJ i , -M-L in µB OH 3Λ0 / / .WQbd and ž 6 J | i i oi ^ oa 6 5 L g o (. • f · kterém in which means R a linear or branched, saturated or unsaturated alkyl chain having 8-15 carbon atoms which may optionally be substituted jed- Nou or polysubstituted phenyl groups, halo genes, C _r C θ - alcoholic xyskup INAM C ^ -C g - alkyl mercapto groups. C 1 -C 8 -alkoxycarbonyl, C 1 -C 8 -alkylsulfinyl or C 1 -C 8 -alkylsulfonyl groups, Rg linear or branched, saturated or unsaturated alkyl chain having 8-15 carbon atoms which may optionally be mono- or polysubstituted by phenyl groups, halogens, CQ-Cg-alkoxy, C ^ -C _η alkylmercapto, C ^ -Cg-alkylcarbonyl groups or C1-C6-alkylsulfonyl groups, R ^ is hydrogen or hydroxy, R 4, R 4 hydrogen or one of the radicals R 4 and R 4 represent halogen, hydroxy, cyano or azido and, in addition, R 4 and R 4 may represent an additional bond between C-2 ^# and C-3 *, n 0, 1 or 2a B one of the following compounds: wherein R _g may be hydrogen, an alkyl chain of 1 to 4 hydrogen atoms or halogen, wherein R 6 may be hydrogen, an alkyl chain of 1 to 4 carbon atoms or halogen, wherein R g may be hydrogen, an alkyl chain of 1 to 4 carbon atoms , halogen or hydroxy or amino, wherein R 8 may be hydrogen or amino, and R 6 is hydrogen, halogen, C 1 -C 8 -alkoxy, C 1 -C 8 -alkyl mercapto or amino, which may be mono- or disubstituted C 1-6 alkyl, C 1 -C 8 -alkoxy, hydroxy-C 8 -C 8 -alkyl and / or -C 8 -cycloalkyl, aryl, hetazyl, •, aralkyl or hetarylalkyl groups, which may optionally be substituted in the aryl or hetaryl radical one or more hydro, methoxy or alkyl; or Halogens, or allyl, which may optionally be substituted by monoalkyl or dialkyl or alpha alkoxy, their tautomers and their physiologically tolerable salts of inorganic or organic acids or bases. 2. Compounds according to claim 1 wherein E is C ^ -o _{lo 14} -aiiyi. Compounds according to claim 1 or 2, wherein Eg is C 8 ^-C 12 -alkyl. Compounds according to one of Claims 1 to 3, in which the group represents a residue selected from: -22- 2- (3-didesoxy-3'-azidouridine) - 2? 3 ^of -didesoxyinosine - 2 ', 3 ^of -didesoxyguanosine 2 ^Z 3 -Didesoxycytidine - 2 ', 3'- dedesoayadenosine - 3'-desoxythymidine - 2'3'-didesoxy-2,3'-didehydro-N ⁶ - (o-methylbenzyl) adenosine - 2,3 ^Z - didesoxy-2 ^z , 3 ^z -didehydro-N - (2-methylpropyl) adenosine - 2 _'F 3'-dideoxy-3--azidoguanosin ^of 3-desoxy-3 ^{from Z} azidothymidine - 2 ', 3'-didesoxy-3'-fluoro- 5-chloruridine - 3-desoxy-3-fluorothymidine - 2 ', 3'-didesoxy-3-fluoroadenosine-23 ^from - lidesesoxy-3 ^from fluoro-2,6-diaminopurinriboside - 2,3 ^of -didesoxy-2,3'-didehydrocytidine-3-desoxy-2,3'-didehydrothymidine -------------- 3-Desoxy-3 ^from -azidothynidine g. compounds according to claim 1, wherein E 1 represents dodecyl, R 2 decyl and a group -23 _z , r 2,3-didesoxy-2,3-didehydro-N - (O-methylbenzyl) adenosine residue, 3'-desoxy-3-azidothymidine residue, A 3'-desoxythymidine residue or a 2'-3'-didesoxyinosine residue. Process for the preparation of compounds of the formula I according to one of Claims 1 to 5, characterized in that a compound of the formula II ^{/ 0 /} n is reacted in a manner known per se. CH ₂ -1-R, / 11 /, CH-0-R _CH2 - OH wherein ^ »^ 2 ⁿ defined above, with a compound of formula III / 111 /, L____ -24 in which he represents R @ 1 is hydrogen or hydroxy protected by a person skilled in the art a metal oxygen protecting group; and R ^ and R ^ is hydrogen, halo, azidozbytek, kyanozbytek not ^ς 'bo one of the radicals R and a hydroxy group protected with ordinary skill oxygen protecting group, or R ^ and R ^ represent an additional bond and B as defined above, in the presence of phosphorus oxitrichloride and a phosphoric acid ester; a nitrogenous base, for example pyridine or triethylamine, in an inert solvent such as toluene and, after hydrolysis, optionally cleaved by methods conventional in the nucleoside chemistry of an oxygen protecting group, or 2. a compound of formula 17 II ⁿ CH _O - S - R _n ^{1 2} CH - O - B ₂ 0 II CH ₂ - 0 - P - CH ₂ / o / ³ © / CH. - N - CH. CH. (IV), as defined above, leave the formula (III) in which R 1, R ₂ and _n are to be reacted with the compound R 1, R 1, R 2 and B as defined above, in the presence of phospholipase D in an inert solvent , such as chloroform, in the presence of a suitable buffer and after the reaction is optionally cleaved by methods A compound known in nucleoside chemistry is used to protect an oxygen moiety, and then the optionally obtained compounds are converted into physiologically tolerable salts. A medicament comprising at least one compound according to any one of claims 1 to 5 and conventional carriers and excipients. Use of compounds according to one of claims 1 to 5 for the manufacture of medicaments for the treatment of viral infections. « Annotation formula / 1 /