DE4204031A1 - NEW LIPID PHOSPHONIC ACID-NUCLEOSIDE CONJUGATES AND THEIR USE AS ANTIVIRAL MEDICINAL PRODUCTS - Google Patents

Abstract

New phospholipidic derivates of nucleosides have general formula (I), in which R1 is a straight or branched, saturated or unsaturated alkyl chain with 1-20 carbon atoms, which may if required be substituted one or several times by phenyl, halogen, C1-C6-alkoxy, C1-C6-alkylmercapto, C1-C6-alkoxycarbonyl, C1-C6-alkylsulfinyl or C1-C6-alkylsulfonyl groups; R2 is a straight or branched, saturated or unsaturated alkyl chain with 1-20 carbon atoms, which may if required be substituted one or several times by phenyl, halogen, C1-C6-alkoxy, C1-C6-alkylmercapto, C1-C6-alkoxycarbonyl or C1-C6-alkylsulfonyl groups; X is a valency bond, oxygen, sulphur, the sulfinyl or the sulfonyl group; Y is a valency bond, an oxygen or sulphur atom; Z can be oxygen or sulphur, and Nuc is a residue derived from a nucleoside derivate. Also disclosed are the tautomers of these compounds and their physiologically tolerable salts of inorganic and organic acids or bases, as well as a process for preparing the same and medicaments containing these compounds.

Description

The present invention relates to new phospholipid Derivatives of nucleosides of the general formula I

in the
R _{1 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, C ₁ -C ₆ alkyl mercapto, C ₁ - C ₆ alkoxy carbonyl, C ₁ -C ₆ alkylsulfinyl or C ₁ -C ₆ alkylsulfonyl groups can be substituted,
R _{2 is} a straight-chain or branched, saturated or unsaturated alkyl chain with 1-20 carbon atoms, optionally one or more times by phenyl, halogen, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyl mercapto, C ₁ -C ₆ -alkoxycarbon yl- or C ₁ -C ₆ -alkylsulfonyl groups can be substituted,
X represents a valence line, oxygen, sulfur, the sulfinyl or the sulfonyl group,
Y is a valence line, an oxygen or sulfur atom,
Z can be oxygen or sulfur, and
Nuc represents a residue derived from a nucleoside derivative,
their tautomers and their physiologically tolerable salts of inorganic and organic acids or bases, and processes for their preparation and medicaments containing these compounds.

Since the compounds of general formula I are asymmetric Containing carbon atoms are also all optical active forms and racemic mixtures of these compounds Subject of the present invention.

In J. Biol. Chem. 265, 6112 (1990) and EP 03 50 2S7 the Production and use of liponucleotides as antiviral Drugs described. Have been studied and synthesized but here only the known nucleosides, such as. B. AZT (Azidothymidine) and ddC (2 ′, 3′-dideoxycytidine), coupled Dimyristoylphosphatidyl- and Dipalmitoylphosphatidylreste with their fatty acid ester structure.

J. Med. Chem. 33, 1380 (1990) describes nucleoside conjugates of Thioetherlipiden with cytidine diphosphate described, the one have antitumor effect and use in the Could find oncology.

In Chem. Pharm. Bull. 36, 209 (1988) 5 '- (3-SN-Phosphati dyl) nucleosides with antileukaemic activity and their enzymatic synthesis from the corresponding Nucleosides and phosphocholines in the presence of phospho lipase D with transferase activity.

J. Med. Chem. 34, 140S (1991) also contains nucleoside Conjugates with an anti-HIV-1 activity described in  sn-2 position of the lipid part by methoxy or ethoxy sub are established.

The compounds of the present invention also have valuable pharmacological properties. In particular they are suitable for the therapy and prophylaxis of infections, which are caused by DNA viruses such. B. the herpes simplex virus that Cytomegaly virus, Papova virus, the varicella zoster virus or Epstein-Barr virus or RNA viruses such as Toga virus or especially retroviruses like the oncoviruses HTLV-I and II, as well as the lentiviruses Visna and human immunodeficiency virus HIV-1 and 2.

The compounds of the formula I appear to be particularly suitable to treat the clinical manifestations of retro viral HIV infection in humans, such as the persistent generalized lymphadenopathy (PGL), the advanced Stage of the AIDS-related complex (ARC) and the clinical Full screen of AIDS.

Surprisingly, it has now been found that compounds of general formula I the multiplication of DNA or RNA viruses in vivo, e.g. B. in the FVL model on the mouse, better inhibit than the previously known liponucleotides. Of special therapeu Tical interest is the inhibitory effect on the HI virus, the Causing the immune deficiency disease AIDS. For treatment of AIDS today is only 3'-azido-3'deoxythymidine (DE-A 36 08 606) approved for AIDS patients. However, do toxic side effects of 3'-azido-3'-deoxythymidine the bone marrow in about 50% of the treated patients Blood transfusions required. The connections of all General Formula I do not have these disadvantages. they seem antiviral, without cyto in pharmacologically relevant doses to be toxic.

The compounds of the present invention and their pharma preparations can also be combined with other medicines used to treat and prevent the above infections mentioned. Examples of this  Other drugs include agents that are used for treatment and prophylaxis of HIV infection or this disease accompanying diseases can be used such as 3'-azido-3'- deoxythymidine, 2 ', 3'-dideoxynucleosides such as. B. 2 ', 3'- Dideoxycytidine, 2 ', 3'-dideoxyadenosine and 2', 3'-dideoxy inosine, acyclic nucleosides (e.g. acyclovir) or not nucleoside RT inhibitors, such as. B. HEPT, nevirapine or L-697,661 and corresponding derivatives. The connections of the present invention and the other drug can each individually, at the same time in one if necessary single or two separate formulations, or too below be administered at different times.

As possible salts of the compounds of general formula I come especially alkali, alkaline earth and ammonium salts Phosphate group in question. As alkali salts are lithium, Sodium and potassium salts preferred. Come as alkaline earth salts especially magnesium and calcium salts in question. Under According to the invention, ammonium salts are understood to be salts which contain the ammonium ion up to fourfold by alkyl residues with 1-4 carbon atoms and / or aralkyl residues before adds benzyl radicals, may be substituted. The substituents can be the same or different.

The compounds of general formula I can be basic Groups, especially amino groups, contain those suitable Neten acids can be converted into acid addition salts. Examples of suitable acids for this purpose are: salt acid, hydrobromic acid, sulfuric acid, phosphoric acid, Fumaric acid, succinic acid, tartaric acid, citric acid, milk acid, maleic acid or methanesulfonic acid.

In the general formula I, R ₁ preferably denotes a straight-chain C ₁₀ -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 ₁ represents in particular a decyl, undecyl, dodecyl, tridecyl or tetradecyl group. As C ₁ -C ₆ alkoxy substituents of R ₁ , the methoxy, ethoxy, butoxy and hexyloxy groups are preferred. If R ₁ 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 hexyl mercapto residues.

R ₂ preferably denotes a straight-chain C ₁₀ -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 ₂ represents in particular a decyl, undecyl, dodecyl, tridecyl or tetradecyl group. The C ₁ -C ₆ alkoxy substituents of R ₂ are preferably the methoxy, ethoxy, propoxy, butoxy and the hexyloxy group .

If R ₂ 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.

X is preferably sulfur, sulfinyl or sulfonyl and Y equal to oxygen. Z is preferably an oxygen atom.

The rest of Nuc stands for a nucleoside derivative, which via the 5'-position on the phosphonic acid of the lipophilic part of the Formula I is bound. As nucleosides or nucleoside analogues For example, the following residues are possible:

in which
R _{3 is} hydrogen or a hydroxyl group,
R _4, R _{5 are} each hydrogen or one of the radicals R ₄ and R _{5 is} halogen, a hydroxyl, a cyano or an azido group and also R ₃ and R _{4 are} a further bond between C-2 'and C-3' can represent
B means one of the following compounds:

in which
R _{6 can be} hydrogen, an alkyl chain with 1-4 carbon atoms or halogen,
R ₆ ′ can be a hydrogen atom or a benzyl or phenylthio radical,
R _{7 can be} hydrogen, an alkyl chain with 1-4 carbon atoms or halogen,
R _{8 can be} hydrogen, an alkyl chain with 1-4 carbon atoms, halogen or a hydroxy or an amino group,
R _{9 can be} hydrogen or an amino group, and
R _{10 is} hydrogen, halogen, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyl mercapto, or an amino group which can be mono- or disubstituted by C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy -, Hydroxy-C ₂ - C ₆ -alkyl and / or C ₃ -C ₆ -cycloalkyl, aryl, hetaryl, aralkyl or hetarylalkyl groups, which are optionally in the aryl or hetaryl radical by one or more hydroxy, Methoxy or alkyl groups or halogen may be substituted, or allyl, which may optionally be substituted with mono- or dialkyl or alkoxy groups.

Nuc can also be of the carbocyclic type

or a cyclobutane, oxetanozine residue or a residue derived from seconucleoside derivatives of the type -CH₂-CH₂-O-CH₂- B or -CH ₂ -O-CH ₂ -CH ₂ -B, such as. B. described in WO90 / 09998 or WO90 / 09999, wherein R ₃ , R ₄ , R ₅ and B have the meaning given above.

In particular, such nucleoside analogs come in for Nuc Question that differs from the well-known antiviral verb applications such as B. carbovir, HEPT, gangciclovir, AZT or Derive acyclovir.

R ₄ and R _{5 are} each preferably hydrogen or one of the two radicals is preferably a cyano or azido group or a halogen atom, such as fluorine, chlorine, bromine or iodine.

Particularly preferred are compounds in which R₃ and R _{4 represent} a hydrogen atom and R ₅ is cyano, azido or fluorine, or R ₅ is hydrogen and R₃ / R _{4 is} a further bond between C-2 'and C-3' represent.

In the bases B of the general formula III, the radicals R ₆ and R ₇ preferably denote a hydrogen atom, a methyl, ethyl, propyl or butyl radical, or a halogen atom, such as fluorine, chlorine, bromine or iodine. A hydrogen atom, the methyl or ethyl radical and a chlorine or bromine atom are particularly preferred for R₆ or R ₇ .

The radical R₈ is preferably a hydrogen atom Methyl, ethyl, propyl or butyl, an amino group or a halogen atom such as fluorine, chlorine, bromine or iodine before adds chlorine or bromine.

R ₁₀ preferably denotes a hydrogen, fluorine, chlorine or bromine atom, a C ₁ -C ₆ alkoxy group, in particular a methoxy, ethoxy, propoxy, butoxy or hexyloxy group, a C ₁ -C ₆ alkyl mercapto group, in particular a methyl mercapto, ethyl mercapto, butyl mercapto or hexyl mercapto group, or an amino group which may be mono- or disubstituted by a C ₁ -C ₆ alkyl group, such as, for. B. the methyl, ethyl, butyl or hexyl group, by a hydroxy-C ₂ -C ₆ alkyl group, such as. B. the hydroxyethyl, hydroxypropyl, hydroxy butyl or hydroxyhexyl group, by a C ₃ -C ₆ cycloalkyl, such as. B. the cyclopropyl, cyclopentyl or cyclohexyl radical, preferably by aryl phenyl, by an aralkyl radical, such as in particular benzyl, which may also have one or more hydroxyl or methoxy groups, by C ₁ -C ₆ alkyl groups, such as. B. the methyl, ethyl, propyl, butyl or hexyl group or by halogen atoms such as fluorine, chlorine or bromine may be substituted. The amino group can also be substituted by a heterarylalkyl or hetaryl radical, such as, in particular, for. B. the thienyl, furyl or pyridyl. The heterarylalkyl radical is preferably understood to mean the thienylmethyl, furylmethyl or pyridylmethyl radical.

Preferred coupled nucleosides in the claimed lipo Nucleotides of the general formula I are:

-2 ′, 3′-dideoxy-3′-azidouridine
-2 ′, 3′-dideoxyinosine
-2 ′, 3′-dideoxyguanosine
-2 ′, 3′-dideoxycytidine
-2 ′, 3′-dideoxyadenosine
-3'-deoxythymidine
-2 ′, 3′-dideoxy-2 ′, 3′-didehydro-N⁶- (o-methylbenzyl) adenosine
-2 ′, 3′-dideoxy-2 ′, 3′-didehydro-N⁶- (2-methylpropyl) adenosine
-2 ′, 3′-dideoxy-3′-azidoguanosine
-3'-deoxy-3'-azido-thymidine
-2 ′, 3′-dideoxy-3′-fluoro-5-chlorouridine
-3'-deoxy-3'-fluorothymidine
-2 ′, 3′-dideoxy-3-fluoroadenosine
-2 ′, 3′-dideoxy-3′-fluoro-2,6-diaminopurine riboside
-2 ′, 3′-dideoxy-2 ′, 3′-didehydrocytidine
-3'-deoxy-2 ', 3'-didehydrothymidine

The compounds of general formula I can be represented in which one

1. a compound of the general formula V

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

Nuc-OH (VI)

in which Nuc has the meaning given above  preferably denotes a group of the formula (VIa),

in which R ₃ 'represents hydrogen or a hydroxy group protected by an oxygen protecting group familiar to the person skilled in the art and R ₄ , u. R ₅ , in each case hydrogen, halogen, an azido, a cyano or one of the radicals R ₄ 'and R ₅ ' means a hydroxy group protected by an oxygen protecting group familiar to the person skilled in the art, or R ₃ 'and R ₄ ' represent a further bond and B has the meanings given above, in the presence of 2,4,6-triisopropylbenzenesulfonic acid chloride and a tert. Nitrogen base, e.g. As pyridine or lutidine, in an inert solvent such as. B. toluene, or directly in abs. Brings pyridine to the reaction and, after hydrolysis, optionally cleaves the oxygen protecting groups in accordance with the methods customary in nucleoside chemistry, or
2. a compound of the general formula VII

in which R ₁ , R ₂ , X, Y and Z have the meanings given above, with a compound of the general formula VI or. VIa, in which R ₃ ', R ₄ ', R ₅ 'and B have the meanings given, in the presence of phospholipase D in an inert solvent, such as. As chloroform, brings in the presence of a suitable buffer to the reaction and, if appropriate, splits off the oxygen protecting group after the reaction, in accordance with the methods customary in nucleoside chemistry.

The preparation of the compounds of general formula V and VII is carried out analogously to Lipids 22, 947 (1987) and J. Med. Chem. 34, 1377 (1991).

The preparation of the compounds of general formula VI and VIa are described for. B. in EP-A 02 86 028 and WO 90 08 147.

Compounds similar to general formula I are described ben in EP-A0 350 287. There are the corresponding 1,2-diesters of glycerin.

The medicament containing compounds of formula I for Treatment of viral infections can be in liquid or solid form can be applied enterally or parenterally. Here at the usual application forms come into question, such as for example tablets, capsules, dragees, syrups, solutions or suspensions. The preferred injection medium Water for use, which is the usual for injection solutions Additives such as stabilizers, solubilizers and Contains buffer. Such additives are e.g. B. tartrate and Citrate buffer, ethanol, complexing agents such as ethylene diamine tetraacetic acid and its non-toxic salts, high moles kular polymers, such as liquid polyethylene oxide for viscose crime regulation. Liquid carriers for injection solutions must be sterile and are preferably dispensed in ampoules fills. Solid carriers are, for example, starch, Lactose, mannitol, methyl cellulose, talc, highly disperse Silicas, higher molecular fatty acids, such as stearic acid, Gelatin, agar-agar, calcium phosphate, magnesium stearate,  animal and vegetable fats, solid high molecular weight Polymers, such as polyethylene glycols, etc. For oral Preparations suitable for applications can, if desired Contain flavorings or sweeteners.

The dosage can depend on various factors, such as appliques manner, species, age or individual condition hang. The compounds of the invention are becoming more common wise in amounts of 0.1-100 mg, preferably 0.2-80 mg applied per day and per kg body weight. Is preferred spread the daily dose over 2-5 applications, whereby with each application 1-2 tablets with an active ingredient content of 0.5-500 mg can be administered. The tablets can also be retarded, which increases the number of applications tions reduced to 1-3 per day. The drug content of the prolonged-release tablets can be 2-1000 mg. The effect substance 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 those in FIGS Examples mentioned and the combination all meanings of the substituent mentioned in the claims Enter the following compounds of formula I in question:

1. 4-Dodecylmercapto-3-decyloxybutanephosphonic acid 5'- (2 ', 3'-dideoxy-3'-fluoro-5-chlorouridine) ester
2. 4-Dodecylmercapto-3-decyloxybutanephosphonic acid 5 '- (3'- deoxy-3'-azido-thymidine) ester
3. 4-Dodecylmercapto-3-decyloxybutanephosphonic acid 5 '- (3'- deoxy-3'-azido-thymidine) ester
4. 4-Dodecylmercapto-3-decyloxybutanephosphonic acid 5'- (2 ', 3'-dideoxycytidine) ester
5. 4-Dodecylmercapto-3-decyloxybutanephosphonic acid 5'- (2 ', 3'-dideoxyinosine) ester
6. 4-Dodecylmercapto-3-decyloxybutanephosphonic acid 5'- (2 ', 3'-dideoxyguanosine) ester
7. 4-Dodecylmercapto-2-decyloxybutanthiophosphonic acid 5'- (2 ', 3'-dideoxyadenosine) ester
8. 4-Dodecyloxy-3-decyloxybutanephosphonic acid 5 '- (3'-deoxy-thymidine) ester
9. 4-Dodecylmercapto-3-decyloxybutanephosphonic acid 5 '- (3'- deoxy-2', 3'-didehydrothymidine) ester
10. 4-Dodecylmercapto-3-decyloxybutanephosphonic acid 5 '- (3'- deoxy-3'-fluorothymidine) ester
11. 4-Dodecylmercapto-2-decyloxybutanthiophosphonic acid 5'- (2 ', 3'-dideoxy-3'-azidoguanosine) ester
12. 4-Dodecylmercapto-3-decylmercaptobutanephosphonic acid 5'- (2 ', 3'-dideoxy-3'-fluoro-2,6-diaminopurine riboside) ester
13. 4-dodecyloxy-3-decyloxybutanephosphonic acid 5 '- [2', 3'- dideoxy-2 ', 3'-didehydro-N⁶- (2-methylpropyl) - adenosine] ester
14. 4-Dodecylmercapto-3-decyloxybutanephosphonic acid 5'- [2 ', 3'-dideoxy-2', 3'-didehydro-N⁶- (o-methylbenzyl) adenosine] ester
15. 4-Decylmercapto-3-dodecyloxybutanephosphonic acid 5'- (2 ', 3'-dideoxy-2', 3'-didehydrocytidine) ester
16. 4-Undecylmercapto-3-dodecyloxybutanthiophosphonic acid 5'- (2 ', 3'-dideoxy-3'-fluoroadenosine) ester
17. 4-Decylsulfonyl-3-dodecyloxybutanephosphonic acid 5'- (2 ', 3'-dideoxy-3'-azidouridine) ester
18. 4-Undecyloxy-3-decyloxybutanephosphonic acid 5 ′ - (2 ′, 3′- dideoxycytidine) ester
19. 4-Dodecyloxy-3-decyloxybutanephosphonic acid 5 '- (3'-deoxy-3'-fluorothymidine) ester
20. 4-Dodecylmercapto-3-dodecyloxybutanephosphonic acid 5'- (2 ', 3'-dideoxyinosine) ester
21. 4-Tetradecylmercapto-3-decyloxybutanephosphonic acid 5'- (3'-deoxy-3'-azidothymidine) ester
22. 4-Pentadecylmercapto-3-decyloxybutanthiophosphonic acid 5 '- (3'-deoxy-3'-azidothymidine) ester
23. 4-Tridecylmercapto-3-decylmercaptobutanephosphonic acid 5'- (2 ', 3'-dideoxyinosine) ester
24. 4-Dodecylmercapto-3-octyloxybutanephosphonic acid 5'- (2 ', 3'-dideoxyinosine) ester

Example 1 4-dodecylmercapto-3-decyloxybutanephosphonic acid-5 ′ - (3′-deoxy- 3'-azidothymidine) esters

3 g (6.1 mmol) of 4-dodecylmercapto-3-decyloxybutanephosphonic acid and 1.63 g (6.1 mmol) AZT were twice with 30 ml abs. Pyridine added and evaporated. The residue became 30 ml abs. Dissolved pyridine, under nitrogen with 5.45 g (18 mmol) 2,4,6-triisopropylbenzenesulfonic acid chloride are added and the mixture is 24 h stirred at RT.  

15 ml of water were then added, the mixture was stirred at RT for a further 2 h and the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel 60 using a linear gradient from dichloromethane to dichloromethane / methanol 7.5 / 2.5 as the eluent. Yield 2.75 g (61% of theory), oil. R _f = 0.24 (CH ₂ Cl ₂ / MeOH S / 2), R _f = 0.60 (CH ₂ Cl ₂ / MeOH / H ₂ O 6.5 / 2.5 / 0.4) on TLC plates Merck 5715, silica gel 60 F.

The 4-dodecylmercapto-3-decyloxybutanephosphonic acid was made from 3-Epoxybutanephosphonic acid diethyl ester known from the literature (Synth. Commun. 487, 1979) by reaction with dodecylmercap tan, subsequent reaction of the alcoholate of 4-dodecyl with mercapto-3-hydroxybutanephosphonic acid diethyl ester Decyl bromide and saponification of the diethyl phosphonic acid made using trimethylsilyl bromide and water.

Claims (5)

1. Phospholipid derivatives of nucleosides of the general formula I in the
R _{1 is} a straight-chain or branched, saturated or unsaturated alkyl chain with 1-20 carbon atoms, optionally one or more times by phenyl, halogen, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyl mercapto, C ₁ -C ₆ - alkoxycarbonyl, C ₁ -C ₆ alkylsulfinyl or C ₁ -C ₆ alkylsulfonyl groups may be substituted,
R _{2 is} a straight-chain or branched, saturated or unsaturated alkyl chain with 1-20 carbon atoms, optionally one or more times by phenyl, halogen, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyl mercapto, C ₁ -C ₆ - alkoxycarbonyl or C ₁ -C ₆ alkylsulfonyl groups can be substituted,
X represents a valence line, oxygen, sulfur, the sulfinyl or the sulfonyl group
Y is a valence line, an oxygen or sulfur atom,
Z can be oxygen or sulfur, and
Nuc is a nucleoside derivative,
their tautomers and their physiologically tolerable salts of inorganic and organic acids or bases. 2. A process for the preparation of compounds of the formula I according to claim 1, characterized in that 1. a compound of the general formula V in which R ₁ , R ₂ , X, Y and Z have the meanings given, with a compound of the general formula VINuc-OH (VI) in which Nuc has the meaning given above, preferably a group of the formula (VIa) in which R ₃ 'represents hydrogen or a hydroxy group protected by an oxygen protecting group familiar to the person skilled in the art and R ₄ ' u. R ₅ 'is in each case hydrogen, halogen, an azido, a cyano or one of the radicals R ₄ ' and R ₅ 'is a hydroxyl group protected by an oxygen protective group familiar to the person skilled in the art, or R ₃ and R _{4 represent} a further bond and B is the has the meanings given above,
in the presence of 2,4,6-triisopropylbenzenesulfonic acid chloride and a tert. Nitrogen base, e.g. As pyridine or lutidine, in an inert solvent such as. B. toluene, or directly in abs. Brings pyridine to the reaction and after hydrolysis, if necessary, splits off the oxygen protecting groups in accordance with the methods customary in nucleoside chemistry, or 2. a compound of the general formula VII in which R ₁ , R _2, X, Y and Z have the meanings given above, with a compound of the general formula VI or Bwz. VIa, in which R ₃ ', R4', R ₅ 'and B have the meanings given, in the presence of phospholipase D in an inert solvent, such as. As chloroform, brings in the presence of a suitable buffer to the reaction and, if appropriate, splits off the oxygen protective group after the reaction, in accordance with the methods customary in nucleoside chemistry. 3. Medicaments containing at least one compound according to claim 1 in addition to pharmaceutical auxiliary or Carriers.   4. Use of compounds of formula I according to claim 1 for the manufacture of medicinal products for the treatment of viral or retroviral infections or through them Infections caused diseases.