EP0706530A1

EP0706530A1 - Liponucleotides of desoxynucleosides, their preaparation and their use as anti-viral drugs

Info

Publication number: EP0706530A1
Application number: EP94922244A
Authority: EP
Inventors: Harald Zilch; Dieter Herrmann
Original assignee: Roche Diagnostics GmbH; Boehringer Mannheim GmbH
Current assignee: Roche Diagnostics GmbH
Priority date: 1993-07-01
Filing date: 1994-06-29
Publication date: 1996-04-17
Also published as: WO1995001362A1; AU7344994A; DE4321978A1; CA2165979A1; JPH08512040A

Abstract

The invention concerns phospholipid derivatives of desoxynucleosides, the derivatives consisting of a lipid unit with a substituted C3 base structure linked via a phosphate or thiophosphate to the desoxynucleoside.

Description

Liponucleotides of deoxynucleosides, their preparation and their use as antiviral drugs

The present invention relates to new phospholipid derivatives of deoxynucleosides and β-D-arabinofuranosylpyrimidines which link a lipid part which is a substituted Cg backbone via a phosphate or thiophosphate to a corresponding nucleoside, and their use as antiviral drugs.

The invention relates to compounds of the formula I

in the

is a straight-chain or branched, saturated or unsaturated aliphatic radical having 1-20 carbon atoms, which may be substituted one or more times by phenyl, halogen, C 1 -C 6 -alkoxy, C 1 -C 6 -alkylmer-

ORIGIN capto, C ..- Cg-alkoxycarbonyl, C ^ Cg-alkylsulfinyl or Ci-Cß-alkylsulfonyl groups can be substituted,

R represents a straight-chain or branched, saturated or unsaturated aliphatic radical having 1-20 carbon atoms which is optionally substituted one or more times by phenyl, halogen, C _j -CG-alkoxy, Cι-C6-Alkylmer- Capto, C ₁ -Cg alkoxycarbonyl or C4 _| -Cg-alkylsulfonyl groups can be substituted,

3 R is hydrogen or hydroxy,

R is a straight-chain or branched C ₅ -C ₈ alkyl, C ₂ -C ₇ alkenyl or

C ₂ -C ₇ alkynyl radical which is optionally substituted by halogen,

5 R represents oxygen or the imino group,

X represents a valence line, oxygen, sulfur, sulfinyl or sulfonyl,

Y has the same meaning as X, where the two groups X and Y can be the same or different,

Z can be oxygen or sulfur,

their tautomers and their physiologically tolerable salts of inorganic and organic acids or bases.

Since the compounds of the general formula contain asymmetric carbon atoms, all optically active forms and racemic mixtures of these compounds are also the subject of the present invention.

J. Biol. Chem. 265, 6112 (1990) and EP 0 350 287 describe the production and use of liponucleotides as antiviral drugs. However, only those known to nucleosides, such as e.g. AZT and ddC, coupled dimyristoylphosphatidyl and dipalmitoylphosphatidyl residues with their fatty acid ester structure.

ORIGINAL DOCUMENTS J. Med. Chem. 33, 1380 (1990) describes nucleoside conjugates of thioether lipids with cytidine diphosphate which have an antitumor effect and are used in oncology.

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

Patent application PCT / EP91 / 01541 describes liponucleotides with a cyclic sugar part in the nucleoside with antiviral activity.

The acyclovir-phospholipid conjugate of L-a-dimyristoylphosphatidyl acid and acyclovir is described in Acta Chem. Scand., Ser. B, 39, 47 (1985) [Cf. also Organophosphorus Chem. 18, 187 (1987)].

New cytarabine derivatives with cytostatic activity are described in DE-OS 4111730. These compounds are not substituted in the 5 position of the base.

The ether / thioether lipids of the present invention are new and also have valuable pharmacological properties. They are particularly suitable for the therapy and prophylaxis of infections caused by DNA viruses such as e.g. the herpes simplex virus, the cytomegalovirus, Papova viruses, the varicella zoster virus, hepatitis VB / C virus or Epstein-Barr virus or RNA viruses such as toga viruses or retroviruses like the Onko -Viruses HTLV-I and II, as well as the lentiviruses Visna and human immunodeficiency virus HIV-1 and 2, are caused.

The compounds of the formula appear particularly suitable for the treatment of the clinical manifestations of viral herpes infection in humans, i.a. also in AIDS patients. The compounds of the general formula have an antiviral effect without being unspecifically cytotoxic in pharmacologically relevant doses.

The compounds of the formula I are also suitable for the treatment of hyperlipidemia, in particular hypercholesterolemia. In addition, the substances mentioned are inactivators / inhibitors of uracil reductase and are therefore suitable on the basis of their antitumor activity for the treatment of malignancies Diseases. Due to the inactivating properties of uracil reductase, the compounds mentioned can also be used for the therapy of organ-specific and generalized autoimmune diseases, such as psoriasis, systemic lupus erythematosus, rheumatoid arthritis and other autoimmune diseases.

The compounds are furthermore distinguished by very good oral tolerance with good bioavailability.

The compounds of the present invention and their pharmaceutical preparations can also be used in combination with other medicaments for the treatment and prophylaxis of the above-mentioned infections. Examples of these further drugs involve agents that accompanying the treatment and prophylaxis of HIV infections or disease conditions are used such as 3'-azido-3'-deoxythymidine, ^2, 3'-dideoxynucleosides such. B. 2 \ 3 ^' -dides-oxycytidine, 2', 3'-dideoxyadenosine and 2 \ 3'-dideoxyinosine or non-nucleoside RT inhibitors such as HEPT, nevirapine or L-697,661 and corresponding derivatives. The compounds of the present invention and the other drug (s) can each be administered individually, at the same time optionally in a single or separate formulations or at different times.

Possible salts of the compounds of the general formula are, in particular, alkali metal, alkaline earth metal and ammonium salts of the phosphate group. Lithium, sodium and potassium salts are preferred as alkali salts. Magnesium and calcium salts are particularly suitable as alkaline earth metal salts. According to the invention, ammonium salts are understood to be salts which contain the ammonium ion, which can be substituted up to four times by alkyl radicals with 1-4 carbon atoms and / or aralkyl radicals, preferably benzyl radicals. The substituents can be the same or different.

In the general formula, R preferably denotes a straight-chain C ₈ -C ₁₄ alkyl group which can also be substituted by a C 1 -C 6 alkoxy or a C 1 -C 6 alkyl mercapto group. R represents in particular a decyl,

Undecyl, dodecyl, tridecyl or tetradecyl group. As Ci-Cß-alkoxy-

1 of R preferably come the methoxy, ethoxy, butoxy and

ORIGINAL DOCUMENTS 1 the hexyloxy groups in question. If R is substituted by a C 1 -C 6 -alkyl mercapto residue, this means in particular the methyl mercapto, ethyl mercapto, propyl mercapto, butyl mercapto and the hexyl mercapto residue.

R preferably denotes a straight-chain C ₈ -C ₁₄ alkyl group which can also be substituted by a C 1 -C 6 -alkoxy group or a C 1 -C 6 -alkyl mercapto group. R represents in particular a decyl, undecyl, dodecyl, tridecyl or tetra

2 decyl group. As C ^ -Cg alkoxy substituents of R are preferably

Methoxy, ethoxy, propoxy, butoxy and the hexyloxy group in question.

2 If R is substituted by a C 1 -C 6 -alkyl mercapto residue, this means in particular the methyl mercapto, ethyl mercapto, butyl mercapto and hexyl mercapto residue.

5 R is preferably oxygen.

X and Y preferably represent an oxygen or sulfur atom, Z is preferably an oxygen atom.

4 R preferably represents an unsaturated hydrocarbon radical which, in the case of

Alkenyls can be substituted by halogen, in particular bromine, and particularly preferably an alkynyl radical.

Very particularly preferred coupled nucleosides in the claimed liponucleotides of the general formula I are:

1- (ß-D-arabinofuranosyl) -5-ethynyluracil,

2'-deoxy-5-prop-1-vinyl uridine

1 - (ß-D-arabinofuranosyl) -5-prop-1-vinyl uracil

1- (ß-D-arabinofuranosyl) -5-prop-2-inyluracil

2'-deoxy-5-prop-2-ynyluridine

The compounds of the formula can be represented by

1. a compound of formula II,

1 2 in which R, R, X, Y and Z have the meanings given, with a compound of the general formula III,

3 4 5 in which R, R and R have the meaning given above, with DCC in pyridine or in the presence of 2,4,6-triisopropylbenzenesulfonyl chloride and a tert. Nitrogen base, e.g. Pyridine or lutidine, in an inert

Solvents such as e.g. Toluene, or reacted directly in pyridine and, after hydrolysis, optionally cleaves the oxygen protecting groups in accordance with the methods customary in nucleoside chemistry, or

a compound of formula IV,

1 2 in which R, R, X and Y have the meanings given, with a

Compound of the general formula V,

3 4 5 in which R, R, R and Z have the meaning given above, with DCC in pyridine or in the presence of 2,4,6-triisopropylbenzenesulfonyl chloride and a tert. Nitrogen base, e.g. Pyridine or lutidine, in an inert solvent, e.g. Toluene, or reacted directly in pyridine and, after hydrolysis, optionally cleaves the oxygen protecting groups in accordance with the methods customary in nucleoside chemistry, or

3. a compound of formula VI

ORIGINAL DOCUMENTS

1 2 in which R, R, X, Y and Z have the meanings given above, with

3 4 5 .-. a compound of the formula III in which R, R and R have the meanings given, 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, if appropriate, splits off the oxygen protecting group in accordance with the methods customary in nucleoside chemistry.

The preparation of the compounds of the formulas II and IV are described in DE 39 29 217.7 and WO 91/05558.

The preparation of the compounds of general formula I II is in Antiviral Chem. Chemother. 3, 293 (1992) and the literature cited therein, and in the patent documents EP465164 (1992), EP461815 (1991), EP346108 (1989) and EP272065.

Compounds similar to Formula I are described in EP-A-0350287. The corresponding 1,2-diesters of glycerol are described there.

The medicaments containing compounds of the formula I for the treatment of viral infections can be administered enterally or parenterally in liquid or solid form. The usual forms of application come into question, such as

ORI wise tablets, capsules, dragees, syrups, solutions or suspensions. Water is preferably used as the injection medium, which contains the additives customary for injection solutions, such as stabilizers, solubilizers and buffers. Such additives are, for example, tartrate and citrate buffers, ethanol, complexing agents such as ethylenediaminetetraacetic acid and their non-toxic salts, high molecular weight polymers such as liquid polyethylene oxide for viscosity regulation. Liquid carriers for injection solutions must be sterile and are preferably filled into ampoules. Solid carriers are, for example, starch, lactose, mannitol, methyl cellulose, talc, highly disperse silicic acids, higher molecular fatty acids, such as stearic acid, gelatin, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats, solid high molecular polymers, such as polyethylene glycols, etc. Preparations suitable for oral applications can, if desired, contain flavorings or sweeteners.

The dosage can depend on various factors, such as the mode of administration, species, age or individual condition. The compounds according to the invention are usually applied in amounts of 0.1-100 mg, preferably 0.2-80 mg per day and per kg of body weight. It is preferred to distribute the daily dose over 2-5 applications, 1-2 tablets with an active substance content of 0.5-500 mg being administered for each application. The tablets can also be retarded, which reduces the number of applications per day to 1-3. The active substance content of the retarded tablets can be 2- 1000mg. The active ingredient can also be given by continuous infusion, the amounts of 5- 1000 mg per day are usually sufficient.

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

1.5 '- [1- (β-D-arabinofuranosyl) -5-ethynyluracil] phosphoric acid (3-dodecylmercapto-2-decyloxy) -1-propyiester

2. 5 '- [1- (β-D-arabinofuranosyl) -5-ethynyluracil] phosphoric acid (3-dodecylsulfinyl-2-decyloxy) -1-propyl ester

ORIGINAL DOCUMENTS 3. 5 '- [1- (β-D-arabinofuranosyl) -5-ethynyluracil] phosphoric acid (3-dodecylsulfonyl-2-decyloxy) -1-propyl ester

4. 5 '- [1- (β-D-arabinofuranosyl) -5-prop-1-ynyluracii] phosphoric acid (3-dodecylmercapto-2-decyloxy) -1-propyl ester

5. 5 '- [2'-Deoxy-5-prop-2-ynyluridine] phosphoric acid (3-undecylmercapto-2-decyloxy) -1-propyl ester

6. 5 '- [2'-deoxy-5-prop-1-vinyluridinephosphoric acid- (3-dodecyloxy-2-decyloxy) -1-propyl ester

7. 5 '- [1- (β-D-arabinofuranosyl) -5-prop-2-ynyuridine] phosphoric acid (3-dodecylmercapto-2-nonyloxy) -1-propyl ester

8. 5 '- [1- (β-D-arabinofuranosyl) -5-prop-1-ynyluracil] phosphoric acid (3-dodecylmercapto-2-decylmercapto) -1-propyl ester

9. 5 '- [1- (β-D-arabinofuranosyl) -5-prop-2-ynyluridine] phosphoric acid (3-undecylmercapto-2-decyloxy) -1-propyl ester

10. 5 '- [2'-Deoxy-5-prop-1-vinyluridinjphosphoric acid- (3-tridecylmercapto-2-decyloxy) -1-propyl ester

11. 5 '- [2'-Deoxy-5-prop-2-ynyluridine] phosphoric acid (3-tridecylmercapto-2-decyloxy) -1-propyl ester

12. 5 '- [1 - (β-D-arabinofuranosyl) -5-ethynyluracil] phosphoric acid (3-dodecylmercapto-2-dodecyloxy) -1-propyl ester

13. 5 '- [1- (β-D-arabinofuranosyl) -5-prop-2-ynyluridine] phosphoric acid (3-dodecyimercapto-2-undecyloxy) -1-propyl ester

14. 5 '- [2'-Deoxy-5-prop-1-ynyluridine] phosphoric acid (2,3-bis (dodecylmercapto) -1 -propyl ester

O 15. 5 '- [2'-Deoxy-5-prop-2-ynyluridine] phosphoric acid (3-decylmercapto-2-dodecyloxy) -1-propyl ester

16. 5 '- [2'-Deoxy-5-prop-1-vinyluridinephosphoric acid- (3-undecyloxy-2-dodecyloxy) -1-propyl ester

17. 5 '- [1- (β-D-arabinofuranosyl) -5-prop-1-ynyluracil] phosphoric acid (3-decylsulfonyl-2-dodecyloxy) -1-propyl ester

18. 5 '- [1 - (β-D-arabinofuranosyl) -5-ethynyluracil] phosphoric acid (3-decyloxy-2-decyloxy) -1-propyl ester

19. 5 '- [1 - (β-D-arabinofuranosyl) -5-prop-1-ynyluracil] phosphoric acid- (3-dodecylmercapto-2-dodecyioxy) -1-propyiester

20. 5 '- [2'-Deoxy-5-prop-1-ynyluridine] phosphoric acid (3-tetradecyl-mercapto-2-decyloxy) -1-propyl ester

21. 5 '- [1- (β-D-arabinofuranosyl) -5-ethynyluracil] phosphoric acid (3-pentadecyimercapto-2-decyloxy) -1-propyl ester

22. 5 '- [1 - (β-D-arabinofuranosyl) -5-prop-2-ynyluridine] phosphoric acid (3-tridecylmercapto-2-decyloxy) -1-propyl ester

23. 5 '- [2'-Deoxy-5-prop-1-vinyluridinephosphoric acid- (3-dodecylmercapto-2-octyloxy) -1-propyl ester

24. 5 '- [2'-deoxy-5-prop-1-vinyluridine] phosphoric acid (3-dodecylmercapto-2-decyloxy) -1-propyl ester

25. 5 '- [2'-Deoxy-5-prop-2-ynyluridine] phosphoric acid (3-dodecylmercapto-2-decyioxy) -1-propyl ester

26. 5 '- [1- (β-D-arabinofuranosyl) -5-prop-2-ynyluridine] phosphoric acid (3-dodecylmercapto-2-decyloxy) -1-propyl ester

AGEN 27. 5 '- [1- (β-D-arabinofuranosyl) -5-ethynyluracil] phosphoric acid- (3-undecylmercapto-2-undecyloxy) -1-propyiester

28. 5 '- [2'-Deoxy-5-prop-2-ynyuridine] phosphoric acid (3-undecylmercapto-2-undecyioxy) -1-propyl ester

29. 5 '- [2'-Deoxy-5-prop-1-ynyluridine] phosphoric acid (3-undecylmercapto-2-undecyloxy) -1-propyl ester

30. 5 '- [1 - (β-D-arabinofuranosyl) -5-prop-1-vinyluracil] phosphoric acid (3-undecylmercapto-2-undecyloxy) -1-propyl ester

31. 5 '- [1 - (β-D-arabinofuranosyl) -5-prop-2-ynyluridine] phosphoric acid (3-undecylmercapto-2-undecyloxy) -1-propyl ester

32. 5 '- [1- (β-D-arabinofuranosyl) -5-prop-1-vinyluracil] phosphoric acid (3-dodecylsulfinyl-2-decyloxy) -1-propyl ester

33. 5 '- [2'-Deoxy-5-prop-1-ynyluridine] phosphoric acid (3-dodecylsulfinyl-2-decyloxy) -1-propyl ester

34. 5 '- [2'-Deoxy-5-prop-2-ynyluridine] phosphoric acid (3-dodecylsulfinyl-2-decyloxy) -1-propyl ester

35. 5 '- [1 - (β-D-arabinofuranosyl) -5-prop-2-ynyluridine] phosphoric acid (3-dodecylsulfinyl-2-decyloxy) -1-propyl ester

36. 5 '- [1 - (β-D-arabinofuranosyl) -5-ethynyluracil] phosphoric acid (3-undecylsulfinyl-2-undecyloxy) -1-propyl ester

37. 5 '- [1- (β-D-arabinofuranosyl) -5-prop-1-vinyluracil] phosphoric acid (3-undecylsulfinyl-2-undecyloxy) -1-propyl ester

38. 5 '- [2'-deoxy-5-prop-1-ynyluridine] phosphoric acid (3-undecylsulfinyl-2-undecyloxy) -1-propyl ester

ORIGINAL DOCUMENTS example 1

Phosphoric acid (3-dodecylmercapto-2-decyloxy) -1-propyl ester

A suspension of 4.26g P4O .. _Q in 60ml abs. 13 ml of hexamethyldisiloxane were added to pyridine at RT and the mixture was heated at 100 ° C. for 1 hour. The mixture was then cooled slightly, 25 g of 3-dodecylmercapto-2-decyloxy-1-propanol were added and the mixture was heated at 100 ° C. for a further 2.5 hours.

After cooling completely to RT and removing the volatile constituents in vacuo, the phosphate could be extracted with ether from an aqueous suspension of the residue. The evaporation residue of the ether phase was purified by column chromatography on silica gel 60 or RP18. Yield 18.7g (63%), R 0.66 (CH ₂ CI ₂ / MeOH / H ₂ O 6.5 / 2.5 / 0.4) on TLC plates Merck 5715, Kieselge. 60.

Alternatively, the phosphoric acid ester can be prepared as follows:

A solution of 770 g of 3-dodecylmercapto-2-decyioxy-1-propanoi and 219 g of 2,6-lutidine in 7.51 toluene is added dropwise at 0-3 ° C. to 322 g of phosphorus oxychloride in 7.51 toluene and then complete addition stirred at 0 ° C for a further 3 h. The precipitated hydrochloride is then filtered off with suction, washed with toluene and the filtrate is slowly added to a triethylammonium hydrogen carbonate solution (prepared by units of CO ₂ in a mixture of 463 g of triethylamine in 4.51 water until the emulsion remains clear).

After 2 h at RT, the emulsion is mixed with 3.71 1 N hydrochloric acid and 4.51 saturated sodium chloride solution and broken up by filtration. The organic phase is evaporated and the oily residue (900 g) is used directly in the next reaction.

ORIGINAL DOCUMENTS 5'-f1 -ß-D-arabinofuranosv0-5-prop-1-vinyluracill phosphoric acid- (3-dodecyl mercapto-2-decyloxy) -1-propyl ester

14.5 g (30 mmol) of phosphoric acid (3-dodecylmercapto-2-decyloxy) -1-propyiester were washed twice with 20 ml of abs. Pyridine added and evaporated. The residue was abs in 200ml. Pyridine taken up, mixed with 27g (85mmol) 2,4,6-triisopropylbenzenesurfonyl chloride under nitrogen and stirred at 20 ° C for 2 h. After adding 8.47 g (30 mmol) of 1 - (ß-D-arabinofuranosyl) -5-prop-1-vinyl uracil in 30 ml abs. Pyridine was stirred at 40 ° C for a further 24 h. Then 100 ml of water were added, the mixture was stirred at RT for a further 2 h and the solvent was removed in a rotary evaporator.

The oily residue was freed of pyridine residues by evaporation with toluene and purified by column chromatography on RP18 with a linear gradient of methanol / water 7/3 to 9.5 / 0.5 as the eluent. Yield 9.36 g (41% of theory); Oil. Rf = 0.78 (H ₂ O / MeOH 0.5 / 9.5) on RP8, R - 0.25 (CH ₂ CI ₂ / MeOH / H ₂ O 6.5 / 2.5 / 0.4) on TLC plates Merck 5715 silica gel 60 F.

Example 2

5 '- [1- (ß-D-arabinofuranosyl) -5-ethynyluracil] phosphoric acid- (3-dodecylmercapto-2-decyloxy) -1-propyiester was obtained analogously to Example 1 from 1 (ß-D-arabinofuranosyl) - 5-ethynyluracil made in 27% yield, oil; R 0.72 (OMeO 0.5 / 9.5) on RP8, R _f = 0.30 (CH ₂ CI ₂ / MeOH / H ₂ O 6.5 / 2.5 / 0.4) on TLC plates Merck 5715, silica gel 60.

Example 3

5 '- [2'-deoxy-5-prop-1-ynyuridine] phosphoric acid- (3-dodecylmercapto-2-decyioxy) -1-propyiester was prepared analogously to Example from 2'-deoxy-5-prop-1-vinyluridine in 23% yield produced; Oil, 0.28 (CH ₂ CI ₂ / MeOH / H ₂ O 6.5 el 60.

ORIGINAL DOCUMENTS Example 4

Efficacy and tolerability in the friend virus leukemia model

Female Balb / c mice, 6-8 weeks old (Iffa Credo), were given 0.2 ml of a virus-containing spleen supernatant per day i.p. inoculated. The animals were i.p. daily from day 0 (start: 1 h after virus inoculation) to day 13. treated with the substance to be examined in doses of 6.25 mg, 12.5 mg, 25 mg and 50 mg per kg.

Before the start of therapy and on day 13, the parameters body weight and small blood count (WBC, RBC, Hb, Hkt, PIt) and on day 14 after killing the animals, the individual spleen weights were determined as parameters for viremia.

Table: Influence of the test substances on FV leukemia in vivo: Average spleen weight on day + 14 after virus inoculation

'' Therapy daily i.p. Day 0 (+ 1 h) - day + 13; Day 14;

'X + SEM, n = number of animals / group

ORIGINAL DOCUMENTS The substances according to the invention are investigated according to the same scheme as for AZT. The results obtained show that the substances investigated have a dose-dependent effect on virus-related splenomegaly and can therefore be used in the therapy of retroviral infections.

Example 5

Efficacy in HIV-infected cell culture

As a matter of routine, triplicate determinations were carried out largely automatically (Biomek from Beckman) in the MT2 system in microtiter plates with at least 4 concentrations (standard deviation <5%). In parallel approaches, both the toxicity (cells + substance) and the antiviral effect (cells + substance + virus) were determined.

MT2 cells were pre-incubated with the substance to be examined and infected with HIV-1 (HTLV-III-B, MOI 0.03). The supernatant was removed, replaced with medium (including substance) and incubated for 7 days.

This was followed by an evaluation of the cytopathic effect (syncytia), MTT test (vitality of the cells) and transfer of the supernatant for new infection.

Claims

1. liponucleotides of the formula I,

in the

RI is a straight-chain or branched, saturated or unsaturated alkyl chain with 1-20 carbon atoms, which may be substituted one or more times by phenyl, halogen, C 1 -C 6 -alkoxy, 041-Cg-alkylmercapto, C- | -C6-alkoxycarbonyl- C 1 -C 6 -alkylsulfinyl or C 1 -C 6 -alkylsulfonyl groups can be substituted,

2

R is a straight or branched, saturated or unsaturated alkyl chain having 1-20 carbon atoms, optionally containing one or more times by phenyl, halogen, C _j -CG-alkoxy, C ^ -C alkylmercapto, Ci-CSS alkoxy carbonyl or C _j -Cg alkylsulfonyl groups can be substituted,

3 R is hydrogen or hydroxy,

4 R is a straight-chain or branched C _c -Cg alkyl, C ₂ - Cy alkenyi or

C ₂ -Cyalkynyl radical which is optionally substituted by halogen, c R represents oxygen or the imino group,

X represents a valence line, oxygen, sulfur, sulfinyl or suifonyl,

ORIGINAL DOCUMENTS Y has the same meaning as X, where the two groups X and Y can be the same or different,

Z can be oxygen or sulfur,

• i 2. Liponucleotides according to claim 1, characterized in that R denotes a C ₈ -C ₁₄ alkyl group with a chain, which can be substituted by a C _j -Cg alkoxy or a C _j -Cg alkyl mercapto group.

1 liponucleotides according to claim 2, characterized in that R is a

Decyl, undecyl, dodecyl, tridecyl or tetradecyl group, which can be substituted by a methoxy, ethoxy, butoxy, hexyloxy, methylmercapto, ethyl mercapto, propylmercapto, butylmercapto or hexyl mercapto group.

Liponucleotides according to one of claims 1-3, characterized in

2 that R is a straight-chain C ₈ -C ₁₄ alkyl group, which by a

C ^ -Cg alkoxy or C _j -Cg alkyl mercapto group can be substituted.

2

5. Liponucleotides according to claim 4, characterized in that R is a

Decyl, undecyl, dodecyl, tridecyl or tetradecyl group, which can be substituted by a methoxy, ethoxy, propoxy, butoxy, hexyloxy, methylmercapto, ethylmercapto, butylmercapto or hexyl mercapto group.

6. A process for the preparation of liponucleotides of the formula I according to any one of claims 1-5, characterized in that

1. a compound of formula II,

1 2 in which R, R, X, Y and Z have the meanings given, with egg

in which R, R and R have the meaning given above, with DCC in pyridine or in the presence of 2,4,6-triisopropylbenzenesulfonic acid chloride and a tert. Nitrogen base, for example pyridine or lutidine, in an inert solvent, such as toluene, or directly in pyridine and, after hydrolysis, optionally cleaves the oxygen protecting groups in accordance with the methods customary in nucleoside chemistry, or

2. a compound of the formula IV,

ORIGINAL DOCUMENTS

1 2 in which R, R, X and Y have the meanings given, with a compound of the general formula V,

3 4 5 in which R, R, R and Z have the meaning given above, with DCC in

Pyridine or in the presence of 2,4,6-triisopropylbenzenesulfonyl chloride and a tert. Nitrogen base, e.g. Pyridine or lutidine, in an inert solvent, e.g. Toluene, or reacted directly in pyridine and, after hydrolysis, optionally cleaves the oxygen protecting groups in accordance with the methods customary in nucleoside chemistry, or

3. a compound of the formula VI

ORIGINAL

1 2 in which R, R, X, Y and Z have the meanings given above, with

3 4 5 a compound of the formula III in which R, R and R are the specified ones

Have meanings in the presence of phospholipase D in an inert solvent such as e.g. Chloroform, in the presence of a suitable

Buffer brings to the reaction and after the reaction, if necessary, according to the usual in nucleoside chemistry

Splits off oxygen protecting group, and

then, if appropriate, the compounds of the formula I are converted into their physiologically tolerable salts.

Medicaments containing at least one liponucleotide of the formula I according to one of claims 1-5 and further pharmaceutically customary auxiliaries or carriers.

8. Use of liponucleotides of the formula I according to one of claims 1-5 for the manufacture of medicaments for the treatment of viral or retroviral infections.

ORIGINAL DOCUMENTS