WO1990009998A1 - Novel acyclic nucleoside analogues, process for their production and use of these compounds as anti-viral drugs - Google Patents

Abstract

The invention concerns novel acyclic nucleoside and nucleotide analogues of general formula (I), in which R is an atom of hydrogen, an aliphatic acyl group with 1 to 20 C-atoms, or a monophosphate, diphosphate or triphosphate group, A is one of the pyrimidine bases thymine, uracil or cytosine, substituted in the 1-position, or one of the purine bases adenine, hypoxanthine or guanine, substituted in the 7 or 9-position, and R1 is an aryl group, a heterocyclic ring, a cycloalkyl group, an alkenyl residue, and alkinyl residue, (a), -CN, -N¿3?, an alkoxycarbonyl group, an alkylcarbonyl or aminocarbonyl group, or the residue -CR?2R3R4¿, in which R?2 and R3¿ are hydrogen or alkyl, plus tautomers, optically active isomers and physiologically compatible salts of these compounds. The invention also includes a process for the production of these compounds and drugs containing them.

Description

Novel acyclic nucleoside analogues, processes for their preparation and use of these compounds as antiviral drugs.

The present invention relates to new acyclic nucleoside and nucleotide analogs of the general formula I

in welcher

in which

R is a hydrogen atom, an aliphatic C ₁ -C ₂₀ acyl radical, a monophosphate, diphosphate or

 Represents triphosphate group,

A represents the pyrimidine bases thymine, uracil or cytosine or purine bases adenine, hypoxanthine or guanine, which are substituted in the 1- or 7- or 9-position, and

R ¹ a) in the event that A is a thymine, uracil or

Cytosine group means an aryl radical, a saturated, unsaturated or aromatic heterocyclic five- or six-membered ring with one or more heteroatoms, a C ₃ -C ₇ cycloalkyl or C ₅ -C ₇ cycloalkenyl radical, a straight-chain or branched C ₂ -C ₇ Alkynyl or C ₂ -C ₇ alkenyl radical, a C ₄ -C ₈ alkanedienyl radical, a formyl, cyano, azido, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ alkylcarbonyl or Aminocarbonyl group, or the radical -CR ² R ³ R ^4, wherein R ² and R ³ are independently hydrogen or a C ₁ - C ₆ alkyl group and R ⁴ is hydrogen, amino, azido, cyano, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ alkylcarbonyl, aminocarbonyl, C ₁ -C ₆ alkylmercapto, C ₁ -C ₆ alkyl, haloC ₁ -C ₆ alkyl or azidoC ₁ -C ₆ alkyl, or b) in the event that A is an adenine, hypoxanthine or guanine group, R _{1 is} a saturated, unsaturated or aromatic heterocyclic five or six ring with one or more

Heteroatoms, a C ₃ -C ₇ cycloalkyl or C ₅ -C ₇ cycloalkenyl radical, a straight-chain or branched C ₂ -C ₇ alkynyl or C ₂ -C ₇ alkenyl radical, a C ₄ -C ₈ alkanedienyl radical , a formyl, cyano, azido, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ alkylcarbonyl or aminocarbonyl group, or the radical -CR ² R ³ R ⁴ , where R ₂ and R _{3 are} Hydrogen atom and R ^{4 is} a cyano, C ₁ -C ₆ alkoxylcarbonyl, C ₁ -C ₆ alkylcarbonyl,

Aminocarbonyl-, haloalkyl or azido-C ₁ -C ₆ -alkyl mean their tautomers, optically active forms or physiologically tolerable salts of inorganic and organic acids.

The invention also relates to processes for the preparation of these compounds and medicaments containing these compounds.

The compounds according to the invention can be optically active or in the form of their racemates. The stereoisomeric compounds can be prepared from the racemic mixtures by methods known per se using diastereomeric salts. For example, tartaric acid, malic acid or camphor-10-sulfonic acid can be used for the resolution. Compounds with a similar structure are already known. EP-A-0,217,207 describes compounds which have the guanine group as base A and in which R represents a hydrogen atom or an acyl group and R ^{1 represents} the group -CH ₂ -R ⁴ , where R ^{4 is} an azido, amino or alkylthio group. These compounds are useful for the treatment of diseases caused by viruses. Similar compounds in which R ^{1 can be} a methyl group (R ² = R ³ = R ⁴ = H) are also known from J.Med.Chem 1986, 29, 1384-89.

Guanine and hypoxanthine derivatives for the treatment of autoimmune diseases are also known from EP-A-0,249,247, in which R ¹ includes a C ₁ -C ₈ alkyl group or a

Phenyl group and R can represent a hydrogen atom.

The compound in which A represents a guanine group, R ^{1 represents} the methyl group and R represents a hydrogen atom is from Biochem. Pharmacol. 1981, 30, 3071 and Mol. Pharmacol. 1983, 24, 316 known.

Furthermore, the compound 9 - [(3-azido-1-hydroxy-2-propoxy) methyl] adenine and the corresponding 3-amino derivative from Can.J. Chem. 1984, 62, 241-252 with antiviral activity. Tetrahedron 1985, 41, 5965 describes the synthetic access to 2 ', 3'-secopyrimidine ribonucleosides. Seco-nucleosides of adenine are also known as inhibitors of adenosine deaminase (Biochem. 1972, 11, 2772) and in particular acyclovir and its N-substituted derivatives are potent inhibitors of herpes simplex virus replication in the HSV types -1 and HSV-2 (J.Med.Chem. 1988, 31, 1351 and literature cited there).

An anti-therapeutic effect is also described for ring-opened analogues of adenine nucleosides (Helv.Chim. and its 3-azido, 3-chloro and the 3-unsubstituted derivative (J.Med.Chem. 1986, 29, 1384).

The invention was based on the object of making available new compounds of the formula I which have increased activity compared to the compounds known from the prior art, and to make them available in the form of medicaments. In addition, the compounds should have a lower level of side effects and the lowest possible toxicity.

Surprisingly, it has now been found that the compounds of general formula I increase the DNA or. RNA viruses at the level of virus-specific DNA or. Inhibit RNA transcription. By inhibiting the enzyme reverse transcriptase, the substances can specifically inhibit the multiplication of retroviruses (cf. Proc.

Natl. Acad. Sci. USA 1986, 83, 1911 and Nature 1987, 325, 773).

Because of these properties, the compounds of general formula I according to the invention are suitable for the therapy and prophylaxis of infections caused by DNA viruses such as e.g. the herpes simplex virus, cytomegalo virus,

Papilloma virus, varicella zoster virus or Epstein-Barr virus - or RNA viruses - such as toga viruses or in particular retroviruses such as the onco viruses HTLV-I and II and the lentiviruses Visna, HIV-1 and -2 (HTLV-III and IV) - are caused.

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. To date, only AZT (3'-azido-3'-deoxythymidine, DE 3,608,606 AI) has been approved for the treatment of AIDS patients. However, toxic side effects of this drug on the bone marrow require blood transfusions in about 50% of 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 concentrations.

If R in the general formula I is an aliphatic acyl radical, this can be straight-chain or branched, saturated or unsaturated and contain 1-20, preferably 1-10 carbon atoms. The acetyl, propionyl, isopropionyl and tert-butyryl radicals are particularly preferred.

If R ^{1 is} an aryl radical, it should preferably be understood to mean the phenyl radical. The meaning of heterocyclic five or six rings for R ¹ includes rings with 1- 4 or 1-5 heteroatoms, where the heteroatoms can be the same or different and mean oxygen, nitrogen or sulfur, and the heterocyclic five or six rings if desired on one or several nitrogen atoms can carry one oxygen atom.

Preferred heterocyclic five-membered rings are the furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl,

 Thiadiazolyl, triazolyl and the tetrazolyl ring and their di- and tetrahydro derivatives.

If R ^{1 is} a heterocyclic six-membered ring, the pyridinyl, pyrimidinyl,

 Pyrazinyl, pyridazinyl and the oxazinyl ring.

If R ^{1 is} a cycloalkyl or cycloalkenyl radical, then three to seven-membered rings are to be understood. The cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl and cyclohexenyl radical are preferred.

The designated alkynyl radicals for R ¹ with 2-7, preferably 2-4 carbon atoms, are straight-chain or branched and preferably represent the ethynyl and propynyl radical.

Straight-chain or branched alkenyl radicals having 2-7, preferably 2-4, carbon atoms, are preferably the vinyl, propenyl or 2-methylpropenyl radical.

Alkanedienyl radicals can contain 4-8 carbon atoms, with the butadienyl radical being particularly preferred.

If R ¹ or one of the radicals R ² , R ³ or R ^{4 stands} for a C ₁ -C ₆ alkoxycarbonyl or C ₁ -C ₆ alkylcarbonyl radical, the alkyl part can be straight-chain or branched and preferably 1-4 C- Have atoms. The methyl, ethyl, isopropyl and isobutyl radicals are particularly preferred.

The alkyl radicals occurring in the definition of the substituents R ² , R ³ and R ⁴ as well as the "alkyl" parts of the alkyl mercapto, haloalkyl and

Azidoalkyl groups can also be straight-chain or branched, saturated or unsaturated and have 1-6, preferably 1-4 carbon atoms.

In this case, the methyl, ethyl,

Propyl, isopropyl, methylthio, azidomethyl, azidoethyl and halomethyl radical, with the meaning fluorine, chlorine, bromine and iodine for halogen, where the substituents R ² , R ³ and R ^{4 may be the} same or different. If R ^{1 does} the rest

bedeutet, so sind besonders bevorzugt a) Verbindungen, in denen R² und R³ gleich Wasserstoff sind und R⁴ für Formyl, Cyano oder Amino, bzw. den Methoxycarbonyl-, Ethoxycarbonyl-, Methylcarbonyl-, Ethylcarbonyl-, Aminocarbonyl-, Methylthio-, Ethylthio-, Fluormethyl-, Trifluormethyl-, Azidomethyl oder Azidoethylrest steht, b) Verbindungen mit R² gleich Wasserstoff, R³ gleich

means, particularly preferred are a) compounds in which R ² and R ³ are hydrogen and R ^{4 is} formyl, cyano or amino, or methoxycarbonyl, ethoxycarbonyl, methylcarbonyl, ethylcarbonyl, aminocarbonyl, methylthio , Ethylthio, fluoromethyl, trifluoromethyl, azidomethyl or azidoethyl radical, b) compounds with R ² being hydrogen, R ^{3 being the} same

Methyl and R ⁴ are azido, cyano, amino or the methoxycarbonyl, ethoxycarbonyl, methylcarbonyl, ethylcarbonyl, aminocarbonyl, methylthio, ethylthio, ethyl, propyl, fluoromethyl, trifluorraethyl or azidomethyl radical, c) Compounds with R ² and R ³ are methyl and R ⁴ with the meaning given under b).

The bases A are preferably the pyrimidine bases, for example thymine.

R ¹ means in particular a phenyl, C ₅ -C ₆ cycloalkyl, for example cyclohexyl, C ₃ -C ₅ alkenyl, for example 1-propen-2-yl; or the -CR ₂ R ₃ R ₄ group, where R ² and R ^{3 represent} a hydrogen atom and R ^{4 represents} a C ₁ -C ₄ alkyl group, for example the methyl group. R is preferably a hydrogen atom and the triphosphate group.

Possible salts of the compounds of the general formula I are, in particular, alkali metal, alkaline earth metal and ammonium salts of the phosphate groups. As alkali salts are

Lithium, sodium and potassium salts are preferred. 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.

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 acids. Examples of suitable acids for this purpose are: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, tartaric acid, citric acid, lactic acid, maleic acid or methanesulfonic acid.

For the manufacture of medicaments, the substances of the general formula I are mixed in a manner known per se with suitable pharmaceutical carriers, flavorings, flavors and colors and shaped, for example, as tablets or dragées or with the addition of appropriate auxiliaries in water or oil, such as, for. B. olive oil, suspended or dissolved. The new substances of general formula I according to the invention and their salts can be administered enterally or parenterally in liquid or solid form. Water is preferably used as the injection medium, which contains the additives customary for injection solutions, such as stabilizers, solubilizers or buffers. Such additives are z. B. tartrate and citrate buffer, ethanol, complexing agents (such as ethylenediaminetetraacetic acid and their

non-toxic salts) and high molecular weight polymers (such as liquid polyethylene oxide) for viscosity regulation.

Solid carriers are e.g. B. starch, lactose, mannitol, methyl cellulose, talc, highly disperse silicas, high molecular fatty acids (such as stearic acid), gelatin, agar, calcium phosphate, magnesium stearate, animal and vegetable fats and solid high molecular weight polymers (such as polyethylene glycols). Preparations suitable for oral administration can, if desired, contain flavorings and sweeteners.

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, with 1 to 2 tablets with an active substance content of 0.5-1000 mg being administered for 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 - 2000 mg. The active ingredient can also be given by injection one to eight times a day or by continuous infusion, with amounts of 5 to 4000 mg per day usually being sufficient.

The compounds of the general formula I according to the invention can be prepared by various methods known per se, suitable protective groups being introduced beforehand and being split off again later.

The purine and pyrimidine bases used as starting materials are known and commercially available.

in der R¹ die oben angegebene Bedeutung hat, R⁵ eine geeignete Schutzgruppe wie z.B. die Trityl-, Acetyl-, For the preparation of the compounds of the general formula I, a process has proven to be particularly expedient in which a compound of the general formula II

in which R ^{1 has} the meaning given above, R ^{5 is} a suitable protective group such as, for example, the trityl, acetyl,

Benzoyl, benzyl, trialkylsilyl, aryldialkylsilyl or alkyldiarylsilyl group and Z represents a reactive group such as halogen, acetoxy, methylsulfonyloxy or toluenesulfonyloxy, preferably a chlorine atom, with one

Brings pyrimidine or purine base to the reaction and after splitting off the protective group R ⁵ under known conditions the compounds of the invention

Formula I with R equal to hydrogen.

If the pyrimidine or purine bases bis or trissilylated with hexamethyldisilazane are expediently reacted with a compound of the general formula II in which Z is chlorine, the trimethylsilyl protective groups are split off in a known manner to give the 9-position Substituted purine derivatives or the pyrimidine derivatives of formula I substituted in the 1-position. Because of the sensitivity to moisture of the silylated purines and pyrimidines, the use of a protective gas in the reaction vessel, such as, for example, is recommended Nitrogen or argon. The silyl protective group can be split off e.g.

done by boiling the intermediate with a lower alcohol, such as methanol or ethanol, but usually happens during the aqueous work-up. A method is also advantageous in which a compound of the formula II in which R ¹ , R ⁵ and Z have the meaning given above is reacted with a pyrimidine or purine base under phase transfer conditions.

Under the conditions of phase transfer catalysis, the bases are converted into a corresponding anion,

for example by 50 percent. aqueous sodium hydroxide solution. That so The anion formed is hydrophobized by a phase transfer catalyst, for example tris [2- (2-methoxyethoxy) ethyl] amine (TDA-1), and transported into the organic phase in which it reacts with the reactive compound of the formula II.

Another advantageous method for preparing the compounds of formula I is the solid-liquid phase transfer process using solid, powdered potassium hydroxide, the above-mentioned cryptand, and a compound of formula II and a pyrimidine or. Purine base in an aprotic solvent (see Seela et al., Helv. Chim. Acta 1988, 71.1;

J.Chem.Soc. PTI 1988, 697).

The chloromethyl ethers of the general formula II with Z equal to chlorine can also be reacted directly using tetrabutylammonium iodide as phase transfer catalyst with the pyrimidine or purine base in an inert solvent (cf. Helv.Chim. Acta 1987. 70, 220) or after being mixed with Sodium acetate are reacted with di- or triacetylated pyrimidine or purine bases (see J.Med.Chem. 1986, 29, 1384) or are condensed in a mercury-cyanide-catalyzed reaction with the silylated base (see J.Med .Chem.

 1985, 28, 358).

The reactions according to the methods described above are advantageously carried out in an inert, aprotic solvent, e.g. Sulfolan, toluene or xylene performed. Also suitable are dichloromethane, 1,2-dichloroethane, chlorobenzene, 1,2-dimethoxyethane, dioxane, dimethylformamide and acetonitrile. A base such as triethylamine, pyridine or N-ethylmorpholine can optionally be added to trap the hydrogen halide formed. The reaction times are depending on the reactant and

-temperature between 4 and 24 hours. The reactions are generally carried out at temperatures between 0 and 150 ° C, preferably room temperature and 100 ° C.

The chloromethyl ethers of the general formula II with Z equal to chlorine are prepared by processes known from the literature, in which a compound of the general formula III

in der R¹ und R⁵ die oben angegebene Bedeutung haben, mit Paraformaldehyd oder 1,3,5-Trioxan in Gegenwart von gasförmigem oder an Kieselgel adsorbiertem Chlorwasserstoff umsetzt und die Reaktionsprodukte ohne weitere Reinigung in die nächste Reaktion einsetzt (vgl. Helv.Chim. Acta 1987, 70, 219; J.Med.Chem. 1988, 31, 144 und 1986, 29, 1384).

in which R ¹ and R ^{5 have} the meaning given above, are reacted with paraformaldehyde or 1,3,5-trioxane in the presence of gaseous hydrogen chloride or adsorbed on silica gel and the reaction products are used in the next reaction without further purification (cf. Helv.Chim Acta 1987, 70, 219; J.Med.Chem. 1988, 31, 144 and 1986, 29, 1384).

Compounds of the general formula III are partly. Known from the literature or are presented based on this literature (cf. literature cited above and Tetrahedron Lett. 1988, 29, 2737 and 1988, 29, 2459; J.Org.

Chem. 1988, 53, 4131; J.Am.Chem.Soc. 1978, 100, 1481;

Tetrahedron Lett. 1984, 25, 3225).

The phosphate groups are introduced in a known manner in compounds of the general formula I in which R is hydrogen. The monophosphates are obtained, for example, by phosphorylating compounds of the formula I where R is hydrogen with phosphorus oxychloride in trialkyl phosphate, preferably trimethyl phosphate. The triethylammonium salts obtained in this way can be converted into other salts by salting in a known manner. The di- or triphosphates of the general formula I are prepared by activating a trialkylammonium salt of the monophosphate of the formula I and then using a trialkylammonium phosphate or diphosphate is condensed. Tributylammonium ions are preferably used as trialkylammonium ions. The activation is advantageously carried out under anhydrous conditions using 1,1'-carbonyldiimidazole at room temperature in a polar, aprotic solvent, such as, for example, dimethylformamide.

The condensation is also carried out at room temperature in a polar, aprotic solvent.

Dimethylformamide is preferred. The reaction times for activation and condensation reaction are 3 hours to 3 days each.

The success of the phosphorylation can be checked by thin layer chromatography, electrophoresis and ³¹ P NMR spectroscopy.

Preferably the phosphorylation is lower

Temperature, particularly advantageously carried out at 0-10 ° C. The reaction time is 5 hours to 1 day, preferably 7-15 hours.

Working up is carried out, for example, by hydrolysis of the reaction mixture with ice, subsequent neutralization and isolation of the product by means of ion exchange chromatography.

The various salts of the di- and triphosphates can also be prepared by known methods.

The phosphorylation to the triphosphate of the general

Formula I can also be carried out as a one-pot variant. The presentation follows the rules of Ludwig (Acta Biochim. Biophys. Acad. Sei. Hung. 1981, 16, 131), Ruth / Cheng (Mol. Pharmcol. 1981, 20, 415) and Kovacs / ötvös (Tetrahedron Lett. 1988, 29, 4525). For the purposes of the present invention, preference is given to the following acyclic compounds in addition to the compounds mentioned in the examples and the compound which can be derived by combining all the meanings mentioned in the claims

Nucleoside analogues:

1. 1 - [[1- (3-furyl) -2-hydroxyethoxy] methyl] thymine 2. 1 - [[1- (2-furyl) -2-hydroxyethoxy] methyl] thymine 3. 1 - [[1- (3-thienyl) -2-hydroxyethoxy] methyl] thymine 4. 1 - [[1- (2-thienyl) -2-hydroxyethoxy] methyl] thymine

5. 1 - [[1- (1-Cyclopentenyl) -2-hydroxyethoxylmethyl] thymine

6. 1 - [[1- (oxazolin-2-yl) -2-hydroxyethoxy] methyl] thymine

7. 1 - [[1- (Thiazolin-2-yl) -2-hydroxyethoxy] methyl] thymine

8. 1 - [[1- (imidazol-2-yl) -2-hydroxyethoxy] methyl] cytosine

9. 1 - [[1- (Oxazol-4-yl) -2-hydroxyethoxy] methyl] cytosine

10. 1 - [[1-thiazol-4-yl) -2-hydroxyethoxy] methyl] cytosine

11. 9 - [[1- (1,2,3-θxadiazol-4-yl) -2-hydroxyethoxy] methyl guanine

12. 9 - [[1- (1,2,3-Thiadiazol-4-yl) -2-hydroxy-ethoxy] methyl adenine

13. 1 - [[1- (1,2,3-triazol-4-yl) -2-hydroxyethoxy] methyl] thymine

14. 1 - [[1- (tetrazol-5-yl) -2-hydroxyethoxy] methyl] thymine 15. 1 - [[1- (2-pyridyl) -2-hydroxyethoxy] methyl] thymine

16. 1 - [[1- (3-pyridyl) -2-hydroxyethoxy] methyl] thymine

17. 1 - [[1- (4-pyridyl) -2-hydroxyethoxy] methyl] thymine

18. 1 - [[1- (3-furyl) -2-hydroxyethoxy] methyl] uracil

19. 1 - [(1-Cyclohexen-1-yl-2-hydroxyethoxy) methyl] thymine

20. 1 - [(1-ethynyl-2-hydroxyethoxy) methyl] thymine

21. 1 - [(1-propin-1-yl-2-hydroxyethoxy) methyl] thymine

22. 1 - [(1-vinyl-2-hydroxyethoxy) methyl] thymine

23. 1 - [[1- (1-bromovinyl) -2-hydroxyethoxy] methyl] cytosine

24. 1 - [[1- (1-cyanovinyl) -2-hydroxyethoxy] methyl] cytosine

25. 1 - [(1-propen-2-yl-2-hydroxyethoxy) methyl] thymine

26. 1 - [(1-cyano-2-hydroxyethoxy) methyl] cytosine

27. 1 - [(1-Azido-2-hydroxyethoxy) methyl] cytosine

28. 1 - [(1-methoxycarbonyl-2-hydroxyethoxy) methyl] cytosine

29. 1 - [(1-aminocarbonyl-2-hydroxyethoxy) methyl] cytosine

30. 1 - [(1-cyanomethyl-2-hydroxyethoxy) methyl] cytosine

31. 1 - [(1-Azidomethyl-2-hydroxyethoxy) methyl] cytosine

32. 1 - [(1-methoxycarbonylmethyl-2-hydroxyethoxy) methyl] thymine 33. 1 - [(1-aminocarbonylmethyl-2-hydroxyethoxy) methyl] thymine

34. 1 - [(1-Methylmercaptomethyl-2-hydroxyethoxy) methyl] thymine

35. 1 - [[1- (2-fluoroethyl) -2-hydroxyethoxy] methyl] thymine

36. 1 - [[1- (2-Azidoethyl) -2-hydroxyethoxy] methyl] thymine

37. 1 - [[1- (1-cyanoethyl) -2-hydroxyethoxy] methyl] thymine

38.9 - [[1- (2-propyl) -2-hydroxyethoxy] methyl] guanine

39. 1 - [[1- (Methoxycarbonylethan-1-yl) -2-hydroxyethoxy] methyl] thymine

40. 1 - [[1- (aminocarbonylethan-1-yl] -2-hydroxyethoxy] methyl] thymine

41.9 - [[1- (Methylmercaptoethan-1-yl) -2-hydroxyethoxy] methyl] adenine

42. 1 - [[1- (2-Fluoro-1-azidoethan-1-yl) -2-hydroxyethoxy] methyl] thymine

43. 1 - [[1- (2-Fluoro-l-cyanoethan-l-yl) -2-hydroxyethoxy] methyl] thymine

44. 1 - [[1- (2-Fluoro-1-methoxycarbonylethan-1-yl) -2-hydroxyethoxy] methyl] thymine

45.9 - [[1- (2-Fluoro-1-aminocarbonylethan-1-yl) -2-hydroxyethoxy] methyl] guanine

46. 1 - [[1- (2-Fluoro-1-methylmercaptoethan-1-yl) -2-hydroxyethoxy] methyl] thymine 47. 1 - [[1- (1-Azido-2,2,2-trifluoroethan-1-yl) -2-hydroxyethoxy] methyl] thymine

48. 1 - [[1- (1-Cyano-2,2,2-trifluoroethan-1-yl) -2-hydroxyethoxy] methyl] thymine

49. 1 - [[1- (1-methoxycarbonyl-2,2,2-trifluoroethan-1-yl) -2-hydroxyethoxy] methyl] thymine

50. 1 - [[1- (1-aminocarbonyl-2,2,2-trifluoroethan-1-yl) -2-hydroxyethoxy] methyl] thymine

51.9 - [[1- (1-Methylmercapto-2,2,2-trifluoroethan-1-yl) -2-hydroxyethoxy] methyl] adenine

52. 1 - [[1- (2-Azidopropan-2-yl) -2-hydroxyethoxy] methyl] thymine

53. 1 - [[1- (2-Cyanopropan-2-yl) -2-hydroxyethoxy] methyl] thymine

54.9 - [[1- (2-Methoxycarbonylpropan-2-yl) -2-hydroxyethoxy] methyl] guanine

55. 1 - [[1- (2-aminocarbonylpropan-2-yl) -2-hydroxyethoxy] methyl] thymine

56. 1 - [[1- (2-Methylmercaptopropan-2-yl) -2-hydroxyethoxy] methyl] cytosine

57. 1 - [[1- (2-aminocarbonylpropan-2-yl) -2-hydroxyethoxy] methyl] uracil

58.9 - [[1- (2-Methoxycarbonylpropan-2-yl) -2-hydroxyethoxy] methyl] guanine example 1

1 - [(1-Methyl-2-hydroxyethoxy) methyl] thymine a) 1-benzyloxy-2-propanol

15 g (0.1 mol) benzyloxyacetaldehyde (see Synth.

Commun. 1988, 18, 359) in 70 ml abs. At 0-10 ° C., the methylmagnesium iodide prepared from 2.4 g (0.1 mol) of magnesium and 6.23 ml (0.1 mol) of methyl iodide in 50 ml of ether was added at 30 ° C. over 30 minutes and, after the addition was complete, the mixture was refluxed for 4 hours. After cooling, 150 ml of saturated NH ₄ Cl solution were added

separated organic phase, dried over Na ₂ SO ₄ and the solvent removed in vacuo. Yield 15.2 g (91% of theory), R _f 0.5 (heptane / methyl ethyl ketone 2/1) b) 1-benzyloxy-2-chloromethyloxypropane

In a suspension of 8.3 g (0.05 mol) 1-benzyloxy-2-propanol and 3.0 g (0.1 mol) paraformaldehyde in 100 ml abs. Dichloromethane was passed in at 0 ° C. until the precipitate had completely dissolved dry hydrogen chloride gas (1-3 hours) and the clear solution was stirred at 0 ° C. for 8 hours. The mixture was then dried over MgSC ₄ , the filtrate was freed from solvent in a rotary evaporator and the oil which remained was used in the next reaction without further purification.

R _f 0.59 (ethyl acetate / heptane 1/1) c) 1 - [(1-Methyl-2-benzyloxy-ethoxy) methyl] thymine

The crude product of the chloromethyl ether of the last reaction was abs in 70 ml. Dissolved dichloromethane and at room temperature under nitrogen within 15 minutes to a solution of 13.5 g (0.05 mol) of bis (trimethylsilyl) thymine in 70 ml abs. Dripped dichloromethane. After the addition was complete, the mixture was heated to 50 ° C. for 20 hours. Then 100 ml of water were added, the organic phase was separated off, dried over Na ₂ SO ₄ and concentrated in a rotary evaporator. The residue was purified by column chromatography

Silica gel cleaned with dichloromethane / methanol 20/1 as eluent. Yield over both steps 8.2 g (54% of theory), light yellow oil, R _f 0.56. d) 1 - [(1-methyl-2-hydroxyethoxy) methyl] thymine

3.8 g of 1 - [(1-methyl-2-benzyloxyethoxy) methyl] thymine were dissolved in 300 ml of abs. Dissolved methanol and hydrogenated after addition of 1.5 g of palladium on carbon until the theoretical amount of hydrogen is taken up at room temperature and normal pressure. After the catalyst had been separated off, the filtrate was evaporated and the residue was purified by column chromatography on silica gel 60 using dichloromethane / methanol 20/1 as the eluent.

Yield 1.85 g (69% of theory), mp. 104-109 ° C.

Example 2

1 - [(2-Hydroxy-1-phenylethoxy) methyl] thymine

Analogously to Example 1, 2-benzyloxy-1-phenylethanol was prepared by reacting benzyloxyacetaldehyde with phenyllithium at -80 ° C. in 59% yield. Chloromethylation and reaction with bis- (trimethylsilyl) thymine yielded 1 - [(2-benzyloxy-1-phenylethoxy) methyl] thymine as a white solid from the mp. After column chromatography on silica gel with ethyl acetate / heptane 1/1 as eluent in 53% yield. 104-106 ° C. The hydrogenation on palladium on carbon led to the 1 - [(2-hydroxy-1-phenylethoxy) methyl] thymine (mp. 114-116 ° C.) in 74% yield.

Example 3

1 [(1-cyclohexyl-2-hydroxyethoxy) methyl] thymine

2-Benzyloxy-1-cyclohexylethanol was prepared analogously to Example 1 from benzyloxyacetaldehyde and cyclohexylmagnesium chloride and purified by column chromatography on silica gel with ethyl acetate / heptane 1/5 as the eluent (68% yield, colorless oil). Chloromethylation and reaction with bis- (trimethylsilyl) thymine led to 1 - [(2-benzyloxy-1-cyclohexylethoxy) methyl] -thymine after column chromatography on silica gel with ethyl acetate / heptane 2/1 as eluent in 83% yield. After the column chromatography on silica gel with ethyl acetate / heptane 2/1 as eluent, the 1 - [(1-cyclohexyl-2-hydroxyethoxy) methyl] thymine was obtained in 41% yield from the crude product of the hydrogenation on palladium on carbon (mp. 124- 127 ° C). Example 4

1 - [(1-propen-2-yl-2-hydroxyethyloxy) methyl] thymine

Analogously to Example 1, the 4- (t-butyldiphenylsilyloxy) -3-hydroxy-2-methylbutene-1 was prepared by reacting t-butyldiphenylsilyloxyacetaldehyde with 2-propenylmagnesium bromide at RT and then heating to 60 ° C. in 42% yield . Chloromethylation with paraformaldehyde / HCl and subsequent reaction of the crude product with bis (trimethylsilyl) thymine yielded the 1 - [[2- (t-butyldiphenylsilyloxy) ethoxy-1 in 19% yield after column chromatography on silica gel with ethyl acetate / heptane 1/1 as eluent -propen-2-yl] methyl] thymine. The cleavage of the silyl protective group by means of TBAF led after column chromatography with dichloromethane / 5% MeOH as eluent to the desired 1 - [(1-propen-2-yl-2-hydroxyethoxy) methyl] thymine in 43% yield (mp> 102 ° C ( Dec.).

Example 5

1 - [(1-ethyl-2-hydroxyethoxy) methyl] thymine

Analogously to Ex. 1, the 1 - [(1-ethyl-2-hydroxyethoxy) methyl] thymine in 62% yield by hydrogenation was the 1 - [(1-ethyl-2-benzyloxy) methyl] thymine, which by reaction of benzyloxyacetaldehyde with ethyl magnesium iodide, subsequent chloromethylation and reaction with bis (trimethylsilyl) thymine

(Mp 57-60 ° C). Example 6

1 - [(1-Methyl-2-hydroxyethoxy) methyl] thymine triphosphate

0.2 mmol 1 - [(1-methyl-2-hydroxyethoxy) methyl] thymine (Ex. 1) were in absolute. Suspended toluene and brought to dryness in a high vacuum at room temperature (2x 1 ml). The residue was dissolved in 2 ml of trimethyl phosphoric acid at 25 ° C., cooled in an ice bath, 85 mg (0.4 mmol) of Proton Sponge (1,8-bis-dimethylamino-naphthalene) were added, 0.027 ml (0.15 mmol) of phosphorus oxychloride were added dropwise and after 15 minutes 0.04 ml absolute. DMF added. The mixture was stirred in an ice bath for a further 15 minutes and then added dropwise to a solution of 0.5 mmol bis (tributylammonium) pyrophosphate, 2 ml DMF, 2 ml pyridine and 0.2 ml tributylamine while cooling with ice. After 5 minutes, 2 ml of a 0.2 molar aqueous triethylammonium hydrogen carbonate solution were added to stop the reactions, the mixture was diluted with water after 30 minutes, applied to a Sephadex DEAE column and with a 0.1-0.5 molar, linear gradient eluted from triethylammonium hydrogen carbonate. The desired fractions were combined and the was obtained after two lyophilization

Title compound as a tris-triethylammonium in 31% yield.

³¹ P NMR (D ₂ O / EDTA addition): δ = -7.68 (d, P-α), -8.18 (d, P-ɣ), -20.24 (t, P-ß).

Example 7

1 - [(2-Hvdroxy-1-phenylethoxy) methyl] thymine triphosphate

Analogously to Example 6, the 1 - [(2-hydroxy-1-phenylethoxy) methyl] thymine triphosphate as tris-triethylammonium salt was obtained from Example 2 by phosphorilization in 37% yield. ³¹ P NMR (D ₂ O / EDTA addition): δ = -7.82 (d, P-α), -8.32

 (d, P-ɣ), -20.15 (t, P-ß).

Example 8

1 - [(1-Cyclohexyl-2-hydroxyethoxy) methyl] thymine triphosphate

Analogously to Example 6, Example 3 obtained from

Phosphorilation of the 1 - [(1-cyclohexyl-2-hydroxyethoxy) methyl] -thymine triphosphate as the tris-triethylammonium salt in 23% yield. ³¹ P NMR (D ₂ O / EDTA addition): 5 = -7.61 (d, P-α), -7.92 (d, P-ɣ), -20.15

 (t, P-ß).

Example 9

1 - [(1-ethyl-2-hydroxyethoxy) methyl] thymine triphosphate

Analogously to Example 6, 1 - [(1-ethyl-2-hydroxyethoxy) methyl] thymine (Example 5) was obtained by phosphorylation to give 1- [(1-ethyl-2-hydroxyethoxy) methyl] thymine triphosphate as tris triethylammonium salt in 34% yield, ³¹ P-NMR (D ₂ O / EDTA addition): δ = -7.76 (d, P-α), -8.27 (d, P-ɣ), -20.17 (t, P-ß ).

Claims

Claims 1. Compounds of the general formula I

in the R is a hydrogen atom, an aliphatic C ₁ -C ₂₀ acyl radical, a monophosphate, diphosphate or  Represents triphosphate group, A represents the pyrimidine bases thymine, uracil or cytosine or purine bases adenine, hypoxanthine or guanine, which are substituted in the 1- or 7- or 9-position, and R ¹ a) in the event that A is a thymine, uracil or Cytosine group means an aryl radical, a saturated, unsaturated or aromatic heterocyclic five- or six-membered ring with one or more heteroatoms, a C ₃ -C ₇ cycloalkyl or C ₅ -C ₇ cycloalkenyl radical, a straight-chain or branched C ₂ -C ₇ Alkynyl or C ₂ -C ₇ alkenyl radical, a C ₄ -C ₃ alkanedienyl radical, a formyl, cyano, azido, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ alkylcarbonyl or Aminocarbonyl group, or the radical -CR ² R ³ R ⁴ , where R ² and R ³ independently of one another are hydrogen or a C ₁ -C ₆ alkyl group and R ^{4 is} hydrogen, amino, azido, cyano, C ₁ -C ₆ alkoxycarbonyl -, C ₁ -C ₆ - Are alkylcarbonyl, aminocarbonyl, C ₁ -C ₆ -alkyl mercapto, C ₁ -C ₆ -alkyl, halogen-C ₁ -C ₆ -alkyl or azido-C ₁ -C ₆ -alkyl, or b) if that A is an adenine, hypoxanthine or guanine group, Ri denotes a saturated, unsaturated or aromatic heterocyclic five- or six-membered ring with one or more heteroatoms, a C ₃ -C ₇ cycloalkyl or C ₅ -C ₇ cycloalkenyl radical, a straight-chain or branched C ₂ -C ₇ - Alkynyl or C ₂ -C ₇ alkenyl radical, a C ₄ -C ₈ alkanedienyl radical, a formyl, cyano, azido, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ alkylcarbonyl or aminocarbonyl group , or the radical -CR ² R ³ R ⁴ , where R ₂ and R _{3 is} a hydrogen atom and R ^{4 is} a cyano, C ₁ -C ₆ alkoxylcarbonyl, C ₁ -C ₆ alkylcarbonyl, aminocarbonyl, haloalkyl or azido-C ₁ -C ₆ -alkyl, their tautomers, optically active forms or physiologically tolerable salts of inorganic and organic acids. 2. Compounds according to claim 1, characterized in that R ^{1 represents} a saturated, unsaturated or aromatic heterocyclic five- or six-membered ring with one or more heteroatoms and these five- or six-membered rings are a furanyl, thienyl, pyrrolyl, Pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl or oxazinyl group and their corresponding di- and tetrahydric derivatives. 3. Compounds according to claim 1 or 2, characterized in that A is a thymine, uracil or cytosine group and R ^{1 is} a phenyl, C ₅ -C ₆ cycloalkyl or C ₂ -C ₇ alkenyl group or the radical -CR ² R ³ R ⁴ , where R ² and R ^{3 are} hydrogen or a C ₁ -C ₆ alkyl group and R ^{4 is} hydrogen, amino, azido, cyano, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ alkylcarbonyl, aminocarbonyl, C ₁ -C ₆ alkylmercapto, C ₁ -C ₆ alkyl, halo-C ₁ -C _6- alkyl or azido-C ₁ -C ₆ alkyl. 4. Compounds according to claim 1 or 2, characterized in that A an adenine, hypoxanthine or guanine group and R ^{1 is} a C ₅ -C ₆ cycloalkyl, C ₃ -C ₅ alkenyl or the Radical -CR ² R ³ R ⁴ mean, wherein R ² and R ^{3 are} hydrogen and R ^{4 represents} a cyano, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ alkylcarbonyl, aminocarbonyl, halo C ₁ -C ₆ alkyl or azido C ₁ -C ₆ alkyl group. 5. Compounds according to any one of claims 1-4, characterized in that R represents a hydrogen atom, a C ₁ -C ₆ alkylcarbonyl or the triphosphate group. 6. A process for the preparation of compounds according to claims 1-5, characterized in that a compound of formula II

in which R ^{1 has} the meaning given above, R ^{5 represents} a protective group suitable for the hydroxyl function and Z represents a reactive group, reacting with a pyrimidine or purine base and then splitting off the protective group R ⁵ according to methods known per se, and if appropriate subsequently subsequently doing so Compounds of the general formula I obtained, in which R represents a hydrogen atom, are converted into the corresponding mono-, di- or triphosphates or into their pharmacologically acceptable salts. 7. Medicament containing at least one compound  according to one of claims 1-6 and pharmaceutical auxiliaries or carriers. 8. Use of compounds according to any one of claims 1-5 for the manufacture of medicaments for the treatment of viral infections.