WO1993016092A1

WO1993016092A1 - New lipophosphonic acid-nucleoside conjugates and their use as antiviral medicaments

Info

Publication number: WO1993016092A1
Application number: PCT/EP1993/000295
Authority: WO
Inventors: Dieter Herrmann; Alfred Mertens; Harald Zilch
Original assignee: Boehringer Mannheim Gmbh
Priority date: 1992-02-12
Filing date: 1993-02-08
Publication date: 1993-08-19
Also published as: AU3454093A; DE4204031A1

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

New lipid phosphonic acid nucleoside concretes and their use as antiviral drugs

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

RX-X-CH ₂

R ₂ -Y-CH

Z.

II (i).

CH ₂ -CH ₂ -P-0-Nuc OH

in the

_{l 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 -alkoxy carbonyl, Ci-Cg-alkylsulfinyl or Ci-Cg-alkylsulfonyl groups can be substituted,

R _{2 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] _- C ₆ -alkoxy-, Ci-Cg-alkylmercapto-, Ci-Cs -Alkoxycarbon- yl- or Ci-Cg-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 contain asymmetric carbon atoms, all optically active forms and racemic mixtures of these compounds are also the subject of the present invention.

In J. Biol. Che. 265, 6112 (1990) and EP 0350 287 describe the production and use of liponucleotides as antiviral drugs. However, only those known to nucleosides, such as e.g. AZT (azidothymidine) and ddC (2 •, 3'-dideoxycytidine), coupled dimyristoylphosphatidyl and dipalmitoylphosphatidyl residues with their fatty acid ester structure.

J. Med. Chem. 3_3, 1380 (1990) describes nucleoside conjugates of thioether lipids with cytidine diphosphate which have an antitu oral effect and could be used in oncology. In Chem. Phar. Bull. _36/209 (1988) 5 '- (3-sn-phosphatidylcholine dyl) nucleoside described with antileukemic activity, as well as their enzymatic synthesis from the corresponding nucleosides and phosphocholines in the presence of phospholipase D with transferase activity.

J. Med. Chem. 3_4, 1408 (1991) likewise describes nucleoside conjugates with an anti-HIV-1 activity which are substituted in the sn-2 position of the lipid part by methoxy or ethoxy.

The compounds of the present invention 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 cyto egalie virus, papova viruses, the varicella zoster virus or epstein-barr virus or RNA viruses such as toga viruses or in particular retroviruses such as the oncoviruses HTLV-I and II , as well as the lentiviruses Visna and the human immunodeficiency virus HIV-1 and 2.

The compounds of the formula I appear to be particularly suitable for the treatment of the clinical manifestations of retroviral HIV infection in humans, such as persistent generalized lymphadenopathy (PGL), the advanced stage of the AIDS-related complex (ARC) and the clinical picture of AIDS.

Surprisingly, it has now been found that compounds of the general formula I are the multiplication of DNA or RNA viruses in vivo. inhibit better in the FVL model on the mouse than the previously known liponucleotides. The inhibitory effect on the HI virus, the cause of the immune deficiency disease AIDS, is of particular therapeutic interest. Only 3 'azido-3' deoxythy idin (DE-A- _ _

3608606) approved for AIDS patients. However, toxic side effects of 3 'azido-3' deoxythymidine on the bone marrow require blood transfusions in about 50% of the patients treated. The compounds of the general formula I do not have these disadvantages. They have an antiviral effect without being cytotoxic in pharmacologically relevant doses.

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 other drugs include agents that are useful for the treatment and prophylaxis of HIV infections or diseases accompanying this disease, such as 3'-azido-3'-deoxythymidine, 2 ', 3'-dideoxynucleosides such as e.g. 2 ', 3'-dideoxycytidine, 2', 3'-dideoxyadenosine and 2 ', 3 • -dideoxy-inosine, acyclic nucleosides (e.g. acyclovir) or non-nucleoside RT inhibitors, such as. B. HEPT, nevirapine or L-697,661 and corresponding derivatives. The compounds of the present invention and the other medicament can each be administered individually, simultaneously, if appropriate in a single or two separate formulations or at different times.

Possible salts of the compounds of the general formula I 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 having 1-4 carbon atoms and / or aralkyl radicals, preferably benzyl radicals. The substituents can be the same or different. -D-

The compounds of the general formula I can contain basic groups, in particular amino groups, which can be converted into acid addition salts using suitable inorganic or organic acids. Examples of suitable acids for this purpose are: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fu aric acid, succinic acid, tartaric acid, citric acid, lactic acid, maleic acid or methanesulfonic acid.

In the general formula I, Rj preferably denotes a straight-chain C 1 -C 4 -alkyl group which can also be substituted by a C 1 -C 6 -alkoxy or a C 1 -C 6 -alkyl mercapto group. Ri represents in particular a decyl, undecyl, dodecyl, tridecyl or tetradecyl group. Preferred Ci-Cg-alkoxy substituents of Ri are the methoxy, ethoxy, butoxy and the hexyloxy groups. 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 the hexyl mercapto residue.

R ₂ preferably represents a straight chain Cιo ~ ^c i ₄ ~ Yl ^Alk "group which may be substituted by a Ci-Cβ-alkoxy group or a Cι ~ Cg alkylmercapto group. R ₂ in particular represents 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. Is R ₂ is substituted by a C 1 -C 6 alkyl mercapto group including in particular the methyl mercapto, ethyl mercapto, butyl mercapto and hexyl mercapto residues.

X is preferably sulfur, sulfinyl or sulfonyl and Y is oxygen. Z is preferably an oxygen atom. The Nuc radical stands for a nucleosidic radical which is bonded via the 5 'position to the phosphonic acid of the lipophilic part of the formula I. The following residues derived from nucleosides or nucleoside analogs are suitable as nucleoside residues, for example:

in which

R3 is hydrogen or a hydroxy group,

^R 4, ^R 5 are each hydrogen or one of the radicals R4 and R _{5 is} halogen, a hydroxyl, a cyano or an azido group and, moreover, R3 and R can represent a further bond between C-2 'and C-3' ,

B represents a basic group of the formula III from the series of the purine or pyrimidine bases

(purple;

(IHb)

(III)

(IIIc)

(IHd) in which

R _{6 can be} hydrogen, an alkyl chain with 1-4 carbon atoms or halogen, g '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 can be hydrogen, an alkyl chain with 1-4 carbon atoms, halogen, or a hydroxy or an amino group,

Rg can be hydrogen or an amino group, and

Rio hydrogen, halogen, C -Cg-alkoxy, C -Cg-alkylmercapto, or an amino group which can be mono- or disubstituted by C-Cg-alkyl-, Ci-Cg-alkoxy-, hydroxy-C ₂ - Cg- alkyl and / or C ₃ -Cg cycloalkyl, aryl, hetaryl, aralkyl or hetarylalkyl groups, which may optionally be substituted in the aryl or hetaryl radical by one or more hydroxyl, methoxy or alkyl groups or halogen , 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 of the type -CH ₂ -CH ₂ -0-CH - B or -CH ₂ -0-CH ₂ -CH ₂ -B, derived from seconucleoside derivatives, as for example in W090 / 09998 or WO90 / 09999, wherein R ₃ , ₄ , R ₅ and B have the meaning given above.

In particular, such nucleoside analogs come into consideration for Nuc, which differ from the known antiviral compounds, such as. B. carbovir (carbocyclic cyclopentane derivative of 2 ', 3' -dideoxy-2 ', 3' -didehydro-guanosine), HEPT (1- [(2-hydroxyethoxy) methyl] -6-phenylthio-thymine) and the like Derive derivatives, ganciclovir, azidothymidine (AZT) or acyclovir. In this sense, Nuc means in particular the radical -CH ₂ -CH (CH ₂ 0H) -0-CH ₂ -B or -CH ₂ -CH -0-CH ₂ -B, where B is a group of the formula III c with R ~ - A ino represents.

R ₄ and R5 are preferably each 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 R ₃ and R _{4 represent} a hydrogen atom and R5 is cyano, azido or fluorine, or R ₅ is hydrogen and R ₃ / R4 is a further bond between C-2 • and C-3 ' represent.

In the bases B of the general formula III, the radicals Rg or R7 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 Rg or R7.

The radical Rg 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 o preferably denotes a hydrogen, fluorine, chlorine or bromine atom, a Ci-Cg-alkoxy group, in particular a methoxy, ethoxy, propoxy, butoxy or hexyloxy group, a Ci-Cg-alkyl mercapto group, in particular a methyl mercapto group, Ethylmercapto, butylmercapto or hexyl mercapto group, or an amino group which can be mono- or disubstituted by a C ~ Cg alkyl group, such as. B. the methyl, ethyl, butyl or hexyl group, by a hydroxy-C ₂ -Cg-alkyl group, such as. B. the hydroxyethyl, hydroxypropyl, hydroxybutyl or hydroxyhexyl group, by a C3-Cg-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 Ci-Cg-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, e.g. B. the thienyl, furyl or pyridyl. The heterarylalkyl radical is preferably understood to mean the thienylmethyl, furylmethyl or pyridylmethyl radical.

The following nucleosides are particularly suitable as coupling components for the preparation of the lipid-nucleotide conjugates of the formula I:

, 3 • Dideoxy-3'-azidouridine

, 3 '-dideoxyinosine

, 3 '-dideoxyguanosine

, 3 '-dideoxycytidine

, 3 '-dideoxyadenosine

-Desoxythymidine

, 3'-dideoxy-2 ', 3'-didehydro-N ⁶ - (o-methylbenzyl) adenosine

, 3'-Dideoxy-2 •, 3'-didehydro-N ⁶ - (2-methylpropyl) adenosine _ _

, 3 '-Dideoxy-3' -azidoguanosine

-Desoxy-3'-azidothymidine

, 3 '-dideoxy-3'-fluoro-5-chlorouridine

-Desoxy-3 • -fluorothymidine

, 3'-dideoxy-3'-fluoroadenosine

, 3 '-Dideoxy-3' -fluoro-2,6-diaminopurine riboside

, 3'-dideoxy-2 ', 3'-didehydrocytidine

-Desoxy-2 ', 3' -dehydehydrothy idin

The compounds of general formula I can be prepared by

1. a compound of the general formula V,

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

Nu-OH (VI)

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

(Via)

in which R3 represents hydrogen or a hydroxyl group protected by an oxygen protective group familiar to the person skilled in the art and R ₄ 'u. R5 'in each case represents hydrogen, halogen, an azido, a cyano or one of the radicals R4' and R5 'is a hydroxyl group protected by an oxygen protective group familiar to the person skilled in the art, or R ₃ ' and R4 'represent a further bond and B is the has the meanings given above,

in the presence of a condensing agent, such as. B. an optionally substituted benzenesulfonic acid chloride, preferably 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 has taken place, optionally cleaves the oxygen protecting groups in accordance with the methods customary in nucleoside chemistry, or

2. a compound of the general formula VII

CH ₂ -X-Rι

CH-YR ₂ CH ₃

I z | ₊ II

CH ₂ -CH ₂ -P-0-CH ₂ -CH ₂ -N-CH ₃ (VII),

(0) CH ₃

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 ', R4', R5 ¹ and B have the meanings given, in the presence of phospholipase D in an inert solvent, such as z. B. chloroform, in the presence of a suitable buffer and after the reaction, if appropriate, splits off the oxygen protecting group in accordance with the processes customary in nucleoside chemistry.

The compounds of the general formulas V and VII are prepared analogously to Lipids 2_2, 947 (1987) and J. Med. Chem. 34, 1377 (1991).

The preparation of the compounds of general formula VI or Via are described for. B. in EP-A 0 286 028 and WO 90/08147.

Compounds similar to general 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 are possible, such as 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 ethylene-diaminetetraacetic acid and their non-toxic salts, high molecular weight polymers, such as liquid polyethylene oxide, for regulating the viscosity. 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 application, 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 ingredient content of 0.5-500 mg being administered with each application. The tablets can also be delayed, which reduces the number of applications per day to 1-3. The active substance content of the retarded tablets can be 2 - 1000 mg. The active ingredient can also be given by continuous infusion, the amounts of 5-1000 mg per day normally being 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. 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-Dodecylsulfonyl-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 '-fluorthymidine) 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-N ⁶ - (2-ethylpropyl) adenosine] ester

14. 4-Dodecylmercapto-3-decyloxybutanephosphonic acid 5'- [2 ', 3'-dideoxy-2', 3'-didehydro-N ⁶ - (o-methylbenzyl) adenosine] ester 15. 4-Decylmercapto-3-dodecyloxybutanephosphonic acid 5 • - (2 ', 3' -dideoxy-2 ', 3' -idehydrocytidine) ester

16. 4-Undecylmercapto-3-dodecyloxybutanthiophosphonic acid 5'- (2 ', 3' -dideoxy-3 '-fluoradenosine) 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. 5'- (3'-Deoxy-3'-azidothymidine) ester of 4-tetradecylmercapto-3-decyloxybutanephosphonic acid

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-Dodecylmercäpto-3-decyloxybutanephosphonic acid 5 '- (3' -deoxy-3 '-azidothymidine) ester.

3 g (6.1 mmol) of 4-dodecylmercapto-3-decyloxybutanephosphonic acid and 1.63 g (6.1 mmol) of AZT were twice with 30 ml of abs. Pyridine added and evaporated. The residue was abs in 30 ml. Dissolved pyridine, mixed with 5.45 g (18 mmol) 2,4,6-triisopropylbenzenesulfonyl chloride under nitrogen and stirred for 24 h at room temperature.

15 ml of water were then added, the mixture was stirred at room temperature 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 dichloroethane 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 8/2), Rf = 0.60 (CH ₂ Cl ₂ / MeOH / H ₂ 0 6.5 / 2.5 / 0.4) on TLC plates Merck 5715, silica gel 60 F.

The 4-dodecylmercapto-3-decyloxybutanephosphonic acid was obtained from diethyl 3-epoxybutanephosphonic acid (Synth. Commun. 487, 1979) by reaction with dodecyl mercaptan, subsequent reaction of the alcoholate of 4-dodecyl-mercapto-3-hydroxybutane phosphonodisylphosphonic acid with desylphosphonate made with trimethylsilyl bromide and water. Example 2

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, Plt) 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 ip day 0 (+ 1 h) - day + 13; Day 14;

²⁾ X ^* ± SEM, n = number of animals / group

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

Example 3

Efficacy in HIV-infected cell culture

As a matter of routine, triplicate determinations were carried out largely automatically in the MT2 system in microtiter plates with at least 4 concentrations (Biomek from Beck onwards) (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 according to the cytopathic effect (syncytia), MTT test (vitality of the cells) and transfer of the supernatant for new infection.

Claims

Patent claims

1. Compounds of the general formula I,

R _l -X-CH ₂

I

in the

a straight-chain or branched, saturated or unsaturated alkyl chain with 1-20 carbon atoms, which may optionally be replaced one or more times by phenyl, halogen, Ci-Cg-alkoxy, C -Cg-alkylmercapto, C -C -alkoxycarbonyl, C -Cg -Alkylsulfinyl or Cι~Cg alkylsulfonyl groups can be substituted,

R ₂ is a straight-chain or branched, saturated or unsaturated alkyl chain with 1-20 carbon atoms, which may optionally be replaced one or more times by phenyl, halogen, Ci-Cg-alkoxy, Ci-Cg-alkylmercapto, C -Cg-alkoxycarbonyl or Ci -Cg-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 nucleoside derivative,

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

2. Compounds of the formula I according to claim 1, characterized in that Nuc is a nucleoside radical of the formula II or IV

is, where

R ₃ hydrogen or a hydroxy group,

R ₄ /R5 each represent hydrogen or one of the radicals R ₄ and R5 represents halogen, a hydroxy, a cyano or an azido group and also

R ₃ and R4 can represent another bond between C-2* and C-3 ',

B represents a basic group of the formula III

(purple)

(Ulb)

(III),

(never)

where

Rg can be hydrogen, an alkyl chain with 1-4 carbon atoms or halogen,

R 'can be a hydrogen atom or a benzyl or phenylthio radical, 7 can be hydrogen, an alkyl chain with 1-4 carbon atoms or halogen,

R- can be hydrogen, an alkyl chain with 1-4 carbon atoms, halogen, or a hydroxy or an amino group,

Rg can be hydrogen or an amino group, and

Rio hydrogen, halogen, Ci-Cg-alkoxy, Ci-Cg-alkyl-ercapto, or an amino group which may be mono- or disubstituted by Ci-Cg-alkyl, Ci-Cg- Alkoxy, hydroxy-C ₂ -Cg-alkyl and/or c ₃ -Cg-cycloalkyl, aryl, hetaryl, aralkyl or hetaryl alkyl groups, which may optionally be replaced by one or more in the aryl or hetaryl radical Hydroxy, methoxy or alkyl groups or halogen can be substituted, or allyl, which can optionally be substituted with mono- or dialkyl or alkoxy groups,

or Nuc a cyclobutane, oxetanozine or a residue derived from seco-nucleoside derivatives of the type -CH -CH - 0-CH ₂ -B, -CH ₂ -0-CH ₂ -CH ₂ -B or -CH ₂ - CH(CH ₂ OH)-0-CH ₂ -B, where B has the meaning given above.

3. Compounds of the formula I according to claim 1 or 2, characterized in that R is a C o-Ci ₄ -Al yl group which can be substituted by a Ci-Cg-alkoxy or C -Cg-alkyl mercapto group.

4. Compounds of the formula I according to claim 1, 2 or 3, characterized in that R represents a C _Q -Ci4-alkyl group which can be substituted by a Ci-Cg-alkoxy or C -Cg-alkyl mercapto group.

5. Compounds of the formula I according to one of claims 2 -

4, characterized in that R ₃ and R4 each represent a hydrogen atom or R ₃ and R4 together represent a bond.

6. Compounds of the formula I according to one of claims 2 -

5, characterized in that R5 represents a hydrogen atom or fluorine atom, or a cyano or azido group.

7. Compounds of the formula I according to any one of claims 2 - 6, characterized in that Rg represents a hydrogen atom or a Cι-C4 alkyl group and Rg ' represents a hydrogen atom.

8. Compounds of formula I according to any one of claims 2-6, characterized in that R ₃ represents a hydrogen or halogen atom or an amino group.

9. Compounds of the formula I according to any one of claims 2-6, characterized in that Rio represents a hydrogen or halogen atom or a Ci-Cg-alkoxy or amino group.

10. A process for the preparation of compounds of the formula I according to claims 1-9, characterized in that

1. a compound of the general formula V,

CH ₂ -X-Rι

I

CH-YR ₂

1 f (v) ,

CH ₂ -CH ₂ -P-OH OH

in which Ri, 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 means a compound of the formula (Via),

in which R ₃ 'represents hydrogen or a hydroxy group protected by an oxygen protecting group familiar to those skilled in the art and R • and R ₅ ' each represent hydrogen, halogen, an azido, a cyano or one of the radicals R ₄ ' and R5' an oxygen protecting group familiar to those skilled in the art means a protected hydroxy group, or R ₃ * and R ₄ ' represent a further bond and B has the meanings given above,

in the presence of a condensing agent and a tert. Nitrogen base, e.g. B. pyridine or lutidine, in an inert solvent such as. B. toluene, or directly in abs. Pyridine reacts and, after hydrolysis, the oxygen protecting groups are optionally removed in accordance with the methods customary in nucleoside chemistry, or

2. a compound of the general formula VII

CH _- _YR2CH3

I+

CH ₂ -CH ₂ -P-0-CH ₂ -CH ₂ -N-CH ₃ (VII),

(0) _CH3 in which Ri, 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 ', R4', R5' and B have the meanings given, in the presence of phospholipase D in an inert solvent, such as. B. chloroform, reacts in the presence of a suitable buffer and, after the reaction, the oxygen protecting group is optionally split off in accordance with the usual methods in nucleoside chemistry.

11. Medicaments containing at least one compound according to one of claims 1 - 9 in addition to pharmaceutical auxiliaries or carriers.

12. Use of compounds of the formula I according to any one of claims 1-9 for the production of medicaments for the treatment of viral or retroviral infections or diseases caused by these infections.

13. A process for the production of pharmaceuticals according to claim 11, characterized in that a compound of the formula I is processed with conventional pharmaceutical auxiliaries or carriers to give pharmaceutical dosage forms.