JP3032576B2 - Novel phospholipid derivatives of nucleosides, their preparation and their use as antiviral medicaments - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION Novel phospholipid derivatives of nucleosides, their preparation, and their use as antiviral medicaments The subject of the present invention is a compound of general formula I: Wherein R ₁ represents a linear or branched, saturated or unsaturated alkyl chain having 8 to 15 carbon atoms, which is phenyl, halogen, C ₁ -C ₆ -alkoxy, C _1-
C ₆ - alkylmercapto, C ₁ -C ₆ - alkoxycarbonyl, C ₁ -C ₆ - alkylsulfinyl or C ₁ -C ₆ - alkylsulfonyl group, one or more times, it may optionally be substituted by, R ₂ Represents a straight or branched, saturated or unsaturated alkyl chain having 8 to 15 carbon atoms,
This, phenyl, halogen, C ₁ -C ₆ - alkoxy, C ₁
-C ₆ - alkylmercapto, C ₁ -C ₆ - alkoxycarbonyl or C ₁ -C ₆ - alkylsulfonyl group, one or more times, may be optionally substituted, R ₃ represents hydrogen or a hydroxyl group , R ₄ and R ₅ in each case represent hydrogen or one of the R ₄ and R ₅ groups represents a halogen, hydroxyl, cyano or azide group, and further R ₃ and R ₄ are It can represent the bond between C-2 'and C-3', where n is 0, 1 or 2, and B represents one of the following compounds: (Where R ₆ can be hydrogen, an alkyl chain having 1 to 4 carbon atoms or halogen) (Where R ₇ can be hydrogen, an alkyl chain having 1 to 4 carbon atoms or halogen) (Where R ₈ can be hydrogen, an alkyl chain having 1 to 4 carbon atoms, a halogen or a hydroxyl or amino group) (Where R ₉ is hydrogen or an amino group, and R ₁₀ is
Represents hydrogen, halogen, C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -alkylmercapto, an amino group or an allyl, which may be optionally substituted by a mono- or dialkyl or alkoxy group; The group may be a 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 group ( This is a new class of nucleosides of the formula (I) wherein the aryl or hetaryl group may be mono- or di-substituted with one or more hydroxyl, methoxy or alkyl groups or halogens). Phospholipid derivatives, their tautomers, their physiologically acceptable salts with inorganic and organic acids and bases And a pharmaceutical comprising the methods for their preparation and their compounds.

Since the compounds of the general formula I contain asymmetric carbon atoms, all optically active and racemic mixtures of these compounds are also an object of the invention.

J. Biol. Chem. 265, 6116 (1990) describes that liponucleotides are produced and used as antiviral drugs. However, here, only known nucleosides, such as AZT and ddc, have been studied and synthesized only, which are linked to dimyristoyl phosphatidyl and dipalmitoyl phosphatidyl groups having a fatty acid ester structure.

J. Med. Chem. 33, 1380 (1990) describes a nucleoside complex of a thioether lipid and cytidine diphosphate, which exhibits antitumor activity and can find use in oncology.

Chem. Pharm. Bull. 36, 209 (1988) states that 5 '-(3-SN-phosphatidyl) -nucleoside having anti-leukemic activity, and phospholipase D having transferase activity from the corresponding nucleoside and phosphocholine.
To synthesize them enzymatically in the presence of

The enzymatic synthesis of liponucleotides is, inter alia, Tetrah
edron Lett. 28, 199 (1987) and Chem. Pharm. Bull. 36,
5020 (1988).

The compounds of the present invention also exhibit valuable pharmacological properties. In particular, they are DNA viruses, such as herpes simplex virus, cytomegalovirus, papovavirus, varicella-zoster virus or Epstein-Barr virus,
Or an RNS virus, such as a togavirus, or especially a retrovirus, such as an oncovirus HTLV-I and
II, and suitable for the treatment and prevention of infections caused by lentivirus visna and human immunodeficiency virus HIV-1 and 2.

Compounds of formula I are useful in the treatment of clinical manifestations of retroviral HIV infection in humans, for example, persistent generalized lymphadenopathy (PG
L)), appears to be particularly suitable for the advanced stages of the AIDS-related complex (ARC) and the complete clinical picture of AIDS.

Surprisingly, it has now been found that compounds of general formula I inhibit the growth of DNA and RNA viruses at the stage of DNA and RNA transcription specific for the virus. This substance can affect retrovirus growth by inhibiting reverse transcriptase (Proc. Natl. Acad. Sci. USA 83,1911,198
6 and Nature 325,773,1987). Of particular therapeutic interest is the inhibitory effect on the HIV virus, which causes immunodeficiency AIDS. Currently, for the treatment of AIDS, 3'-azido-3'-deoxythymidine (DE-A-
3608606) is only allowed in AIDS patients. However, due to certain toxic effects of 3'-azido-3'-deoxythymidine on the bone marrow, about 50
Blood transfusions are required in% of patients. The compounds of the general formula I do not have these disadvantages. These compounds are
It acts antivirally at physiologically relevant doses without showing cytotoxic effects.

The compounds of the present invention and their pharmaceutical preparations can also be used for treating and preventing the above-mentioned infections in combination with other medicaments. These drugs, including other drugs available for the treatment and prevention of HIV infection or symptoms associated with this disease, include, for example, 3'-azido-3'-deoxythymidine, 2 ', 3'-dideoxynucleoside, For example, 2'3'-dideoxycytidine, 2'3'-dideoxyadenosine and 2'3'-dideoxyinosine, acyclic nucleosides (eg acyclovir), interferons such as A-interferon, renal efflux inhibitors such as probenicid, Nucleoside transport inhibitors, such as cipyridanol, and immune activity modulators, such as interleukin II, or facilitators, such as granulocyte-macrophage colony factor. The compounds of the invention and the other medicaments may in each case be administered separately, simultaneously, optionally as one or two separate formulations or at different times, so that a synergistic effect is achieved. it can.

Possible salts of the compounds of the general formula I include, inter alia, the salts with the phosphate groups of alkali metals, alkaline earth metals and ammonium. As alkali metal salts, lithium, sodium and potassium salts are preferred. Alkaline earth metal salts include, in particular, magnesium and calcium salts. Ammonium salts according to the invention are alkyl and / or aralkyl groups having 1 to 4 carbon atoms, preferably benzyl groups, up to 4
A salt containing an ammonium ion which can be displaced is understood. Here, the substituents may be the same or different.

The compounds of the general formula I can contain basic groups, in particular amino groups, which can be converted into acid addition salts with a suitable acid.
As acids, for this purpose, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, tartaric acid, citric acid, lactic acid, maleic acid or methanesulfonic acid are considered.

In the general formula I, R ₁ preferably represents a straight-chain C ₁₀ -C ₁₄ -alkyl group which may be substituted by a C ₁ -C ₆ -alkoxy or a C ₁ -C ₆ -alkylmercapto group. In particular, R
₁ represents a decyl, undecyl, dodecyl, tridecyl or tetradecyl group. C ₁ -C ₆ of R ₁ - as alkoxy substituent, preferably methoxy, ethoxy, butoxy and hexyloxy. When R ₁ is substituted with a C ₁ -C ₆ -alkyl mercapto group, the substituent is
In particular, methylmercapto, ethylmercapto, propylmercapto, butylmercapto or hexylmercapto groups, n is understood to be one of the numbers 0, 1 or 2.

R ₂ is preferably a C ₁ -C ₆ -alkoxy group or a C ₁ -C ₆
- C ₁₀ good linear be substituted with an alkyl mercapto group
Means an alkyl radical - -C _14. In particular, R ₂ is decyl,
Represents an undecyl, dodecyl, tridecyl or tetradecyl group. C ₁ -C ₆ of R ₂ - as alkoxy substituent, preferably methoxy, ethoxy and propoxy butoxy and hexyloxy groups.

R ₂ is, C ₁ -C ₆ - when it is substituted with an alkyl mercapto group, the substituent is understood especially methylmercapto, ethylmercapto, a butyl mercapto and hexyl mercapto group.

R ₄ and R ₅ preferably each represent hydrogen, or one of the two groups is preferably a cyano or azide group or a halogen atom, such as fluorine, chlorine,
It is bromine or iodine.

It is particularly preferred that R ₃ and R ₄ represent a hydrogen atom, and
R ₅ is equal to cyano, azide or fluorine, or
R ₅ is equal to hydrogen, and R ₃ / R ₄ is C-2 'and C-
It is a compound representing a bond between 3 '.

In the base B of the general formula I, the radicals R ₆ and R ₇ preferably represent a hydrogen atom, a methyl, ethyl, propyl or butyl group or a halogen atom, for example fluorine, chlorine, bromine or iodine. Particularly suitable for R ₆ or R ₇ are a hydrogen atom, a methyl or ethyl group or a chlorine or bromine atom.

The R ₈ group is suitably a hydrogen atom, a methyl, ethyl, propyl or butyl group, an amino group, or a halogen atom, for example fluorine, chlorine, bromine or iodine, preferably chlorine or bromine.

R ₁₀ is preferably a hydrogen, fluorine, chlorine or bromine atom, a C ₁ -C ₆ -alkoxy group, in particular a methoxy, ethoxy, propoxy, butoxy or hexyloxy group, C ₁
-C ₆ - alkylmercapto group, especially, a methyl mercapto, ethylmercapto, butylmercapto or hexyl mercapto group or an amino group, the amino group, C ₁ -C ₆ - alkyl group, e.g., methyl, ethyl, butyl or by a hexyl group, a hydroxyl -C ₂ -C ₆ -
Alkyl group, e.g., hydroxyl, hydroxypropyl, by hydroxy butyl or hydroxy hexyl group, C ₃ -C ₆ - cycloalkyl group, for example, cyclopropyl, by cyclopentyl or cyclohexyl, an aryl, preferably a phenyl, aralkyl group For example, the aryl group may be mono- or di-substituted, in particular by benzyl, and the aryl group may be substituted by one or more hydroxyl or methoxy groups, for example a C ₁ -C ₆ -alkyl group such as methyl, ethyl, propyl, butyl or hexyl. It may be optionally substituted by a group or by a halogen atom such as fluorine, chlorine or bromine. The amino group may also be substituted by a heteroarylalkyl or hetaryl group, for example, especially a thienyl, furyl or pyridyl group. A heteroarylalkyl group is preferably understood to be a thienylmethyl, furylmethyl or pyridylmethyl group.

In the claimed liponucleotides of general formula I, suitable linked nucleosides are: -2 ', 3'-dideoxy-3'-azidouridine -2', 3'-dideoxy Inosine-2 ', 3'-dideoxyguanosine-2', 3'-dideoxycytidine-2 ', 3'-dideoxyadenosine-3'-deoxythymidine-2', 3'-dideoxy-2 ', 3'-didehydro −N ⁶ −
(O-methylbenzyl) - adenosine 2 ', 3'-dideoxy-2', 3'-didehydro -N ⁶ -
(2-methylpropyl) -adenosine-2 ', 3'-dideoxy-3'-azidoguanosine-3'-deoxy-3'-azidothymidine-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-3'-deoxy-3'-azidothymidine General formula I Can be prepared as follows: 1. A compound of general formula II (Where R ₁ , R ₂ and n have the meanings given above)
With a compound of general formula III (Where R ₃ ′ is hydrogen or a hydroxyl group protected with an oxygen protecting group customary in the art, and R ₄ ′ and R ₅ ′
Is, respectively, hydrogen, halogen, azide, cyano, or one of the R ₄ ′ and R ₅ ′ groups represents a hydroxyl group protected with an oxygen protecting group customary to those skilled in the art, or R ₃ 'and R ₄ ' represent a bond, B has the meaning given above) and inert in the presence of phosphorus oxytrichloride and phosphate and a tertiary nitrogen base such as pyridine or triethylamine. After reacting in a solvent, for example toluene, and hydrolysis has occurred, optionally,
Removal of oxygen protecting groups according to the usual methods in nucleoside chemistry, or 2. compounds of general formula IV (Where R ₁ , R ₂ and n have the above meaning)
With a compound of general formula III, wherein R ₃ ′, R ₄ ′, R ₅ ′ and B have the meaning given above, with phospholipase D
And in an inert solvent such as chloroform in the presence of a suitable buffer, and after the reaction has taken place, optionally the oxygen protecting group is removed, according to the usual methods in nucleoside chemistry.

The preparation of compounds of general formulas II and IV is described in Lipids 22,947 (198
7) and DE-A-3039629.

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

Compounds analogous to the general formula I are described in EP-A-0350287. But there are 1,2 of glycerol
-Only diesters are mentioned.

A medicament comprising a compound of formula I for the treatment of a viral infection can be administered enterally or parenterally in liquid or solid form. Usual dosage forms here include, for example, tablets, capsules, dragees, syrups, solutions or suspensions. As an injection solvent, water containing a usual additive in the case of an injection solution, for example, a stabilizer, a solubilizing agent, a buffer and the like is suitably used. Such additives are, for example, tartaric acid and citrate buffers, ethanol, complexing agents (such as ethylenediamine-tetraacetic acid and its non-toxic salts), high-molecular polymers (such as liquid polyethylene oxide for viscosity adjustment). . Liquid carrier materials for injections must be sterile and are conveniently packaged in ampoules. Solid carrier materials include, for example, starch, lactose, mannitol, methylcellulose, talc,
Highly dispersed silicic acid, polymeric fatty acids such as stearic acid, gelatin, agar, calcium phosphate, magnesium stearate, animal and vegetable fats, solid polymeric polymers such as polyethylene glycol and the like. Compositions suitable for oral administration may contain flavoring or sweetening agents as needed.

The dosage may vary depending on a variety of factors, such as mode of administration, race, age or individual condition. The compounds according to the invention are usually expressed per kg of body weight per day,
It is administered in an amount of 0.1-100 mg, preferably 0.2-80 mg. 1
It is desirable to divide the daily dose into 2 to 5 doses,
Thereby, in each case one or two tablets having an active substance content of 0.5 to 500 mg are administered. The release of the tablet can be delayed and the number of doses per day can be reduced to 1-3. The active substance content of the sustained release tablets can be increased up to 2-1000 mg. The active substance can also be administered by continuous infusion, in which case an amount of 5 to 1000 mg per day is usually sufficient.

In the sense of the present invention, in addition to the compounds described in the examples or by all combinations of meanings defined for the substituents in the claims, the following compounds of the formula I are also compounds of interest: 1 . (2 ', 3'-dideoxy-3'-fluoro-5-chlorouridine) -5'-phosphate (3'-dodecylmercapto-2-decyloxy) -propyl ester 2. (3'-deoxy-3' -Azidothymidine) -5'-
Phosphoric acid (3-dodecylsulfinyl-2-decyloxy) -propyl ester 3. (3'-deoxy-3'-azidothymidine) -5'-
Phosphoric acid (3-dodecylsulfonyl-2-decyloxy) -propyl ester 4. (2'3'-dideoxycytidine) -5'-phosphoric acid (3-dodecylmercapto-2-decyloxy) -propyl ester 5. (2 ' , 3'-Dideoxyinosine) -5'-phosphate (3-dodecylmercapto-2-decyloxy) -propyl ester 6. (2'3'-dideoxyguanosine) -5'-phosphate (3-dodecylmercapto-2) -(Decyloxy) -propyl ester 7. (2'3'-dideoxyadenosine) -5'-phosphate (3-dodecylmercapto-2-decyloxy) -propyl ester 8. (3'-deoxythymidine) -5'-phosphorus Acid (3-dodecylmercapto-2-decyloxy) -propyl ester 9. (3'-deoxy-2 ', 3'-didehydrothymidine)
-5'-phosphate (3-dodecylmercapto-2-decyloxy) -propyl ester 10. (3'-deoxy-3'-fluorothymidine)-
5'-phosphate (3-dodecylmercapto-2-decyloxy) -propyl ester 11. (2'3'-dideoxy-3'-azidoguanosine) -5'-phosphate (3-dodecylmercapto-2-decyloxy) -Propyl ester 12. (2'3'-dideoxy-3'-fluoro-2,6-diaminopurine riboside) -5'-phosphate (3-dodecylmercapto-2-decyloxy) -propyl ester 13. [2 '3'-dideoxy-2'3'-didehydro-N
^6- (2-Methylpropyl) -adenosine] -5'-phosphate (3-dodecylmercapto-2-decyloxy)-
Propyl ester 14. [2'3'-dideoxy-2'3'-didehydro-N
^6- (o-methylbenzyl) -adenosine] -5'-phosphate (3-dodecylmercapto-2-decyloxy)-
Propyl ester 15. (2'3'-dideoxy-2'3'-didehydrocytidine) -5'-phosphate (3-dodecylmercapto-2
-Dodecyloxy) -propyl ester 16. (2'3'-dideoxy-3'-fluoroadenosine) -5'-phosphate (3-undecylmercapto-2-
Dodecyloxy) -propyl ester 17. (2'3'-dideoxy-3'-azidouridine)
-5'-phosphate (3-decylsulfonyl-2-dodecyloxy) -propyl ester 18. (2'3'-dideoxycytidine) -5'-phosphate (3-decylmercapto-2-decyloxy) -propyl ester 19. (2'3'-dideoxyinosine) -5'-phosphate (3-tetradecylmercapto-2-decyloxy)-
Propyl ester 20. (3'-deoxy-3'-azidothymidine) -5 '
-Phosphate (3-tetradecylmercapto-2-decyloxy) -propyl ester 21. (3'-deoxy-3'-azidothymidine) -5 '
-Phosphate (3-pentadecylmercapto-2-decyloxy) -propyl ester 22. (2'3'-dideoxyinosine) -5'-phosphate (3-tridecylmercapto-2-decyloxy) -propyl ester 23. (2'3'-dideoxyinosine) -5'-phosphate (3-dodecylmercapto-2-octyloxy) -propyl ester Example 1a (3'-deoxy-3'-azidothymidine) -5'-phosphate ( 3-dodecylmercapto-2-decyloxy)-
Propyl ester 1.25 g (3 mmol) of 3-dodecylmercapto-2-decyloxy-1-propanol in 40 ml of anhydrous ether
In a solution of 1.2 ml (8.6 mmol) triethylamine, under nitrogen,
At 0 ° C., 0.42 ml (4.5 mmol) of POCl ₃ was added dropwise, followed by stirring for 45 minutes. Next, warm to room temperature, and add 800 mg (3 mm) in a mixture of 15 ml of anhydrous ether and 20 ml of anhydrous toluene.
ol) of 3'-deoxy-3'-azidothymidine (AZT)
Was added dropwise and stirred under reflux for 6 hours (TLC control).

After cooling, 50 ml of water were added and the mixture was stirred vigorously for 2 hours, after which the organic phase was separated, dried over Na ₂ SO ₄ and evaporated in a rotary evaporator. The residue was purified by preparative column chromatography on silica gel 60 using dichloromethane / methanol (9: 1) as eluent.

Yield 540 mg (24% of theory).

Melting point 187 ° C, sintering, turning brown, 220-223
Decomposed at ° C., ³¹ P-NMR: = 0.59 ppm.

Example 1b (3'-Deoxy-3'-azidothymidine) -5'-phosphate (3-dodecylmercapto-2-decyloxy)-
Propyl ester As in the method of Chem. Pharm. Bull. 36, 5020 (1988), 2
mmol of AZT and 5000 U of phospholipase D are suspended in 4 ml of sodium acetate buffer / (CaCl ₂₎ and this is added to 6 mmol of 3-dodecylmercapto-2- in 160 ml of chloroform.
Mix with a solution of decyloxypropyl-1-phosphate monocholine ester and heat to 45 ° C. for 8 hours. Next, Na ₂ SO ₄
And dried under reduced pressure. The residue was purified by column chromatography as in Example 1. Yield 51%. The product was found to be identical to the product of Example 1a (melting point, TLC, ¹ H- and ³¹ P-NMR).

Example (3'-Deoxy-3'-azidothymidine) -5'-phosphate (3-undecylmercapto-2-undecyloxy) -propyl ester was prepared in a similar manner to Example 1a. Yield 27%. 218-220 ° C (decomposition).

Example 3 [2 ', 3'-dideoxy-2', 3'-didehydro -N ⁶ -
(O-Methylbenzyl) -adenosine-5'-phosphate (3-dodecylmercapto-2-decyloxy) -propyl ester 680 mg (1.37 mmol) of phosphoric acid (3-dodecylmercapto-2-decyloxy) in 20 ml of anhydrous pyridine - 2 a solution of propyl ester 337mg of (1 mmol) ', 3'-dideoxy-2', 3'-didehydro -N ⁶ - (o-methylbenzyl) - is mixed with adenosine, DDC of 1.37 g (6.7 mmol)
Was added and mixed at room temperature for 24 hours (TLC control). Pyridine was removed under reduced pressure and the residue was suspended in ether and filtered from undissolved urea. After evaporation of the solvent, the filtrate was purified by column chromatography on silica gel 60 using dichloromethane / methanol (95/5) as eluent. Yield 220 mg (26% of theory).

_{Rf = 0.68 (CH 2 Cl 2} / CH 3 OH / H 2 O = 13/5 / 0.8) Example 4 (3'-deoxy-3'-azidothymidine) -5'-phosphoric acid (3-dodecylmercapto -2 -Decyloxy)-
Propyl ester 13.5 g of phosphoric acid (3-dodecylmercapto-2-decyloxy) in 350 ml of anhydrous pyridine as in Example 3.
Propyl ester, 5.4 g AZT and 27 g DCC, 30
Stir for hours at room temperature and purify as described above to produce the corresponding liponucleotide in 62% yield (analytical data identical to that of Example 1).

Example 5 (3'-Deoxythymidine) -5'-phosphoric acid (3-dodecylmercapto-2-decyloxy) -propyl ester As in Example 3, 1.3 g of phosphoric acid (3- Dodecylmercapto-2-decyloxy)-
The propyl ester, 500 mg of 3'-deoxythymidine and 2.6 g of DCC were stirred for 24 hours at room temperature and purified by chromatography to give the corresponding liponucleotide in 51%.
Prepared in a yield of Rf = 0.45 (CH ₂ Cl ₂ / CH ₃ OH / H ₂ O = 12
/5/0.8) Example 6 (2 ', 3'-dideoxyinosine) -5'-phosphate (3
-Dodecylmercapto-2-decyloxy) -propyl ester 1.3 g of phosphoric acid (3-dodecylmercapto-2-decyloxy)-in 40 ml of anhydrous pyridine, as in Example 3.
The propyl ester, 500 mg of 2'3'-dideoxyinosine and 2.6 g of DCC were stirred at room temperature for 40 hours and purified by chromatography to give a liponucleotide of 61%.
Prepared in a yield of Rf = 0.38 (CH ₂ Cl ₂ / CH ₃ OH / H ₂ O = 13
/5/0.8).

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁷ Identification code FI A61K 31/708 A61K 31/708 A61P 31/12 A61P 31/12 (72) Inventor Martens, Alfred D-6905 Schlie Scheim Beethovenstrasse 20 (72) Inventor Hermann, Dieter D-6900 Heidelberg an der Neckarspitz 13 (58) Fields studied (Int. Cl. ⁷ , DB name) C07H 19/10, 19/20 A61K 31/7068-31/708 A61P 31/12 CA (STN) REGISTRY (STN)

Claims (5)

(57) [Claims] 1. A compound of the general formula I: Wherein R ₁ represents a linear or branched, saturated or unsaturated alkyl chain having 8 to 15 carbon atoms,
₂ represents a straight or branched, saturated or unsaturated alkyl chain having 8 to 15 carbon atoms, and Is a group represented by -2 ', 3'-dideoxy-3'-azidouridine, -2', 3'-dideoxyinosine, -2 ', 3'-dideoxyguanosine, -2', 3'-dideoxyadenosine,- 3'-deoxythymidine, 2 ', 3'-dideoxy-2', 3'-didehydro -N ⁶ -
(O-methylbenzyl) - adenosine, 2 ', 3'-dideoxy-2', 3'-didehydro -N ⁶ -
(2-methylpropyl) -adenosine, -2 ', 3'-dideoxy-3'-azidoguanosine, -2', 3'-dideoxy-3'-fluoro-5-chlorouridine, -3'-deoxy-3 '-Fluorothymidine, -2', 3'-dideoxy-3'-fluoroadenosine, -2 ', 3'-dideoxy-2', 3'-didehydrocytidine, -3'-deoxy-3'-azidothymidine, -2 ', 3'-dideoxy-3'-fluoro-2,6-diaminopurine riboside, and n represents 0, 1, or 2]. Mutants and physiologically acceptable salts thereof with inorganic and organic acids and bases. 2. The compound according to claim 1, wherein R ₁ represents C ₁₀ -C ₁₄ -alkyl. 3. The compound according to claim 1, wherein R ₂ represents C ₈ -C ₁₂ -alkyl. 4. A method according to claim 1, wherein R ₁ represents dodecyl, R ₂ represents decyl,
and In the group represented is 2'3'-dideoxy -2'3'- didehydro -N ⁶ -
2. A compound according to claim 1, which represents a (o-methylbenzyl) -adenosine, 3'-deoxy-3'-azidothymidine, 3'-deoxythymidine or 2'3'-dideoxyinosine group. 5. A compound of the formula I wherein (3'-deoxy-3'-azidothymidine) -5'-phosphate (3-dodecylmercapto-2-decyloxy)-
Propyl ester, (3'-deoxy-3'-azidothymidine) -5'-phosphate (3-undecylmercapto-2-undecyloxy) -propyl ester, 2 ', 3'-dideoxy-2', 3 ' -Didehydro-N ^6-
(O-methylbenzyl) -adenosine-5'-phosphate (3-dodecylmercapto-2-decyloxy) -propyl ester, (3'-deoxythymidine) -5'-phosphate (3-dodecylmercapto-2-decyloxy) ) -Propyl ester, (2 ', 3'-dideoxyinosine) -5'-phosphate (3
-Dodecylmercapto-2-decyloxy) -propyl ester, (3'-deoxy-2 ', 3'-didehydrothymidine)-
5'-phosphoric acid (3-dodecylmercapto-2-decyloxy) -propyl ester, (3'-deoxy-3'-fluorothymidine) -5'-
Phosphoric acid (3-dodecylmercapto-2-decyloxy)
The compound according to claim 1, which is selected from the group consisting of -propyl ester.