DE3906357A1 - NEW ACYCLIC NUCLEOSIDE ANALOG, METHOD FOR THE PRODUCTION AND USE OF THESE COMPOUNDS AS ANTIVIRAL MEDICINAL PRODUCTS - 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 R<1> is an aryl group, a heterocyclic ring, a cycloalkyl group, an alkenyl residue, and alkinyl residue, (a), -CN, -N3, an alkoxycarbonyl group, an alkylcarbonyl or aminocarbonyl group, or the residue -CR<2>R<3>R<4>, in which R<2> and R<3> 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

The present invention relates to new acyclic Nucleoside analogues of the general formula I

in which
R represents a hydrogen atom, an aliphatic acyl radical, a monophosphate, diphosphate or triphosphate group,
R¹ is an aryl radical, a saturated, unsaturated or aromatic heterocyclic five- or six-membered ring with one or more heteroatoms, a cycloalkyl or cycloalkenyl radical, a straight-chain or branched alkynyl or alkenyl radical with 2-7 carbon atoms, an alkanedienyl radical, a formyl or cyano -, Azido, C₁-C₆-alkoxycarbonyl, C₁-C₆- alkylcarbonyl or aminocarbonyl group,
or the rest

means, where R², R³ and R⁴ can be the same or different and hydrogen, amino, azido, cyano, C₁-C₆-alkoxycarbonyl, C₁-C₆-alkylcarbonyl-, aminocarbonyl, C₁-C₆-alkylmercapto, C₁-C₆-alkyl, halogen Can be -C₁-C₆-alkyl or azido-C₁-C₆-alkyl,
B represents the pyrimidine and purine bases thymine, uracil, cytosine, adenine, hypoxanthine and guanine, which are substituted in the 1-, 7- or 9-position,
their tautomers, optically active forms or physiologically acceptable salts of inorganic and organic acids. The invention also relates to processes for the preparation of these compounds and medicaments containing these compounds.

In the event that R¹ in the general formula I the rest

represents, and R² and R³ are simultaneously hydrogen and R⁴ represents a hydrogen atom or an azido or isopropyl mercapto group B cannot be the guanine or Be adenine residue. Connections are also excluded, in which R² and R³ are both hydrogen and R⁴ is a methyl group.  

The compounds according to the invention can be optically active or in the form of their racemates. The stereoisomers Compounds can be prepared from the racemic mixtures known methods about diastereomeric salts will. For resolution, z. B. tartaric acid, Malic acid or camphor-10-sulfonic acid can be used.

The antiviral properties of acyclic nucleoside analogues have already been described for a large number of compounds.

In Tetrahedron 1985, 41, 5965 is the synthetic approach to 2 ', 3'-secopyrimidine ribonucleosides described. Seco-nucleosides of adenine are also known as inhibitors adenosine deaminase (Biochem. 1972, 11, 2772) and especially the acyclovir and its N-substituted Derivatives as potent inhibitors of herpes simplex virus replication for types HSV-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. Acta 1987, 70, 219), for acyclic 2'-deoxyguanosine analogues such as 9 - [(3-fluoro-1-hydroxy-2-propoxy) methyl] guanine and its 3-azido, 3-chloro and the 3-unsubstituted Derivative (J. Med. Chem. 1986, 29, 1384), for 1- [(1,3-Dihydroxy-2-propoxy) methyl] pyrimidine (J. Med. Chem. 1988, 31, 144) and the corresponding guanine (J. Med. Chem. 1985, 28, 358) and for 9- [4-hydroxy-3- (hydroxymethyl) but-1-yl] purines and their esters (J. Med. Chem. 1987, 30, 1636).  

DE 36 27 024 A1 (1985) are also acyclic, 2- and 9-substituted 2-aminopurines, such as that 9 - [(3-Fluoro-1-hydroxy-2-propoxy) methyl] guanine - (cf. Chem. Scr. 1986, 26, 179) - and its 3-chloro, 3-bromo, 3-iodo and 3-isopropylthio derivative, with action against HSV-1 described. The 9 - [(3-azido-1-hydroxy-2-propoxy) methyl] adenine is from Can. J. Chem. 1984, 62, 241. The inhibitor and substrate specificity of deoxythymidine kinase (isolated from HSV-1) was made with acyclic nucleoside analogs of pyrimidine and purine bases (Biochem. Pharmacol. 1981, 30, 3071 and Mol. Pharmacol. 1983, 24, 316).

Surprisingly, it has now been found that the compounds of the general formula I the multiplication of DNA or RNA viruses at the level of virus-specific DNA or inhibit RNA transcription. The substances can over the inhibition of the reverse transcriptase enzyme 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 invention Compounds of general formula I suitable for therapy and prophylaxis of infections caused by DNA viruses - such as B. the herpes simplex virus, cytomegalo virus, Papova 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 as well as the Lentiviruses Visna, (HIV-1 and -2) HTLV-III and IV - caused.  

The compounds of the formula appear to be particularly suitable I treat 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 this day, this is the only treatment for AIDS patients AZT (3'-azido-3'-deoxythymidine, DE 36 08 606 A1) approved. Toxic side effects of this drug the bone marrow, however, make up about 50% of those treated Patients need blood transfusions.

The compounds of the general formula I have them No disadvantages. They have an antiviral effect without being pharmacological relevant concentrations to be cytotoxic.

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

If R¹ is an aryl radical, preference is given to it to understand the phenyl radical. The importance of heterocyclic Five or six rings for R1 include rings with 1-4 or 1-5 heteroatoms, the heteroatoms being equal to or can be different and oxygen, nitrogen or Mean sulfur, and the heterocyclic five or Six rings if desired on one or more nitrogen atoms can carry an 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 partially hydrogenated derivatives.

If R¹ is a heterocyclic six-membered ring, then in In this sense, pyridinyl, pyrimidinyl, Pyrazinyl, pyridazinyl and the oxazinyl ring.

R¹ is a cycloalkyl or cycloalkenyl radical, so are to be understood as three- to seven-membered rings. Cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, cyclopentenyl and the cyclohexenyl radical.

The designated alkynyl radicals for R¹ 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 with 2-7, preferably 2-4 carbon atoms, preferably the vinyl, Propenyl or 2-methylpropenyl.

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

R¹ or one of the radicals R², R³ or R⁴ is a C₁- C₆-Alkoxycarbonyl- or C₁-C₆-alkylcarbonyl, so can the alkyl part may be straight-chain or branched and preferably Have 1-4 carbon atoms. The methyl, ethyl, isopropyl and isobutyl radicals are particularly preferred.  

The in the definition of the substituents R², R³ and R⁴ occurring alkyl radicals and the alkyl parts of the above Alkyl mercapto, haloalkyl and azidoalkyl groups can also straight-chain or branched, saturated or unsaturated be and 1-6, preferably 1-4 carbon atoms exhibit.

In this case, the methyl, ethyl, Propyl, isopropyl, methylthio, azidomethyl, azidoethyl and halomethyl radical, meaning fluorine, Chlorine, bromine and iodine for halogen, the said Substituents R², R³ and R⁴ may be the same or different can.

If R¹ does the rest

means, are particularly preferred

• a) Compounds in which R² and R³ are hydrogen are and R⁴ for formyl, cyano or amino, or the Methoxycarbonyl, ethoxycarbonyl, methylcarbonyl, Ethylcarbonyl, aminocarbonyl, methylthio, ethylthio, Fluoromethyl, trifluoromethyl, azidomethyl or azidoethyl radical,  
• b) compounds with R² equal to hydrogen, R³ equal to Methyl and R⁴ are azido, cyano, amino or the Methoxycarbonyl, ethoxycarbonyl, methylcarbonyl, Ethylcarbonyl, aminocarbonyl, methylthio, ethylthio, Ethyl, propyl, fluoromethyl, trifluoromethyl or azidomethyl radical,
• c) Compounds with R² and R³ are methyl and R⁴ with the meaning given under b).

As possible salts of the compounds of the general formula I mainly come with alkali, alkaline earth and ammonium salts of the phosphate groups in question. As alkali salts are Lithium, sodium and potassium salts preferred. As alkaline earth salts come especially magnesium and calcium salts in question. Ammonium salts are used according to the invention Understand salts that contain the ammonium ion that up to four times through alkyl radicals with 1-4 carbon atoms and / or aralkyl radicals, preferably benzyl radicals can be. The substituents can be the same or to be different.

The compounds of general formula I can be basic Contain groups, especially amino groups, with suitable acids are converted into acid addition salts can be. As acids for this come in, for example Consideration: hydrochloric acid, hydrobromic acid, sulfuric acid, Phosphoric acid, fumaric acid, succinic acid, tartaric acid, Citric acid, lactic acid, maleic acid or methanesulfonic acid.  

The substances are used to manufacture drugs of the general formula I in a manner known per se suitable pharmaceutical carrier substances, aroma, Flavors and colors mixed and for example shaped as tablets or drageees or with addition appropriate auxiliaries in water or oil, such as. B. Olive oil, suspended or dissolved. The invention new substances of general formula I and their salts can be enteral or parenteral in liquid or solid form be applied. The preferred injection medium Water for use, which is the same for injection solutions usual additives, such as stabilizers, Contains solubilizers or buffers. Such additives are z. B. tartrate and citrate buffers, ethanol, complexing agents (such as ethylenediaminetetraacetic acid and its non-toxic Salts) and high molecular weight polymers (such as liquid Polyethylene oxide) for viscosity regulation. Solid carriers are z. B. starch, lactose, mannitol, methyl cellulose, Talc, highly disperse silicas, high molecular weight 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 application can flavor and sweeteners if desired contain.  

The compounds according to the invention are usually described in Amounts of 0.1-100 mg, preferably 0.2-80 mg per day and applied per kg body weight. It is preferred that Distribute daily dose over 2-5 applications, with each application 1-2 tablets with an active ingredient content of 0.5-1000 mg can be administered. The tablets can also be delayed, which increases the number of Applications per day reduced to 1-3. The drug content the prolonged-release tablets can be 2-2000 mg be. The active ingredient can also be injected up to given eight times a day or by continuous infusion, amounts of 5-4000 mg per day are usually sufficient.

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

The purine and pyrimidine bases used as starting materials are known and can be bought.

Has proven to be particularly useful for the preparation of the compounds of the general formula I, in which a compound of the general formula II

in which R¹ has the meaning given above, R⁵ a suitable one Protecting group such as B. the trityl, acetyl, Benzoyl, benzyl, trialkylsilyl, aryldialkylsilyl or Alkyldiarylsilyl group and Z is a reactive group, such as Halogen, acetoxy, methylsulfonyloxy or toluenesulfonyloxy, preferably represents a chlorine atom, with a Pyrimidine or purine base brings about and after Splitting off of the protective group R⁵ under literature Conditions of the compounds of the invention Formula I with R equal to hydrogen.

It is expedient to use hexamethyldisilazane bis- or trissilylated pyrimidine or purine bases with a compound of general formula II, in the Z is chlorine, um, is obtained after cleavage the trimethylsilyl protecting groups in a known manner in 9-position substituted purine derivatives or those in the 1-position substituted pyrimidine derivatives of the formula I. Because of the moisture sensitivity of the silylated Purines and pyrimidines are recommended to use a Shielding gas in the reaction vessel, such as. B. nitrogen or Argon. The silyl protective group can be split off, for. B. by boiling the intermediate with a lower one Alcohol, such as methanol or ethanol, happens but usually already during the aqueous work-up. Also advantageous is a method in which you can connect of the formula II in which R¹, R⁵ and Z are the above have given meaning under phase transfer conditions reacted with a pyrimidine or purine base.  

Under conditions of phase transfer catalysis the bases are converted into a corresponding anion, for example by 50% aqueous sodium hydroxide solution. That so Anion is formed by a phase transfer catalyst, for example tris [2- (2-methoxyethoxy) ethyl] amine (TDA-1), hydrophobized and in the organic Phase in which it reacts with the reactive compound of the formula II reacted.

Another advantageous method of making the connections of the formula I represents the solid-liquid phase transfer process using solid, powdery Potassium hydroxide, the above cryptand, and a compound of the 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 ether of the general formula II with Z chlorine can also be used directly using Using tetrabutylammonium iodide as a phase transfer catalyst the pyrimidine or purine base in an inert solvent are implemented (cf. Helv. Chim. Acta 1987, 70, 220) or after adding sodium acetate with di- or triacetylated pyrimidine or purine bases for the reaction brought (see J. Med. Chem. 1986, 29, 1384) or in a mercury cyanide catalyzed reaction with the silylated base are condensed (cf. J. Med. Chem. 1985, 28, 358).  

The implementations according to the procedures described above are advantageously in an inert, aprotic solvent, e.g. B. sulfolane, toluene or xylene. In Question also come dichloromethane, 1,2-dichloroethane, Chlorobenzene, 1,2-dimethoxyethane, dioxane, dimethylformamide and acetonitrile. To trap the hydrogen halide formed a base such as triethylamine, Pyridine or N-ethylmorpholine can be added. The Response times vary depending on the reactant and -Temperature between 4 and 24 hours. The reactions are generally at temperatures between 0 and 150 ° C, preferably carried out at room temperature and 100 ° C.

The chloromethyl ether of the general formula II with Z become chlorine according to methods known from the literature prepared by connecting the general Formula III

in which R¹ and R⁵ have the meaning given above, with Paraformaldehyde or 1,3,5-trioxane in the presence of gaseous or hydrogen chloride adsorbed on silica gel implements and the reaction products without further purification in the next reaction (cf. Helv. Chim. Acta 1987, 70, 219; J. Med. Chem. 1988, 31, 144 and 1986, 29, 1384).

Compounds of the general formula III are e.g. T. known from the literature or are based on this literature (see 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 found in compounds of the general Formula I, in which R is hydrogen, is known Way introduced. The monophosphates are obtained, for example, by making compounds of formula I equal to R. Hydrogen with phosphorus oxychloride in trialkyl phosphate preferably trimethyl phosphate, phosphorylated. The on Triethylammonium salts obtained in this way can be obtained in a known manner Converted into other salts by salting will. The di- or triphosphates of the general formula I are made by using a trialkylammonium salt of the monophosphate Formula I activated and then with a trialkylammonium phosphate or diphosphate condensed becomes. Preferred trialkylammonium ions are Tributylammonium ions used. The activation takes place advantageously under anhydrous conditions 1,1′-carbonyldiimidazole at room temperature in a polar, aprotic solvents, such as. B. Dimethylformamide.  The condensation is also in at room temperature a polar, aprotic solvent. Dimethylformamide is preferred. The response times for Activation and condensation reaction are 3 each Hours to 3 days.

The success of phosphorylation can be determined by thin layer chromatography, -electrophoresis and 31 P NMR spectroscopy to be controlled.

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 the reaction mixture with ice, followed by neutralization and isolation of the product by means of ion exchange chromatography.

The different salts of di- and triphosphates can can also be produced by known methods.

The phosphorylation to the triphosphate of the general Formula I can also be carried out as a one-pot variant will. The presentation is analogous to the regulations by Ludwig (Acta Biochim. Biophys. Acad. Sci. Hung. 1981, 16, 131), Ruth / Cheng (Mol. Pharmcol. 1981, 20, 415) and Kovacs / Ötvös (Tetrahedron Lett. 1988, 29, 4525).  

Preferred for the purposes of the present invention are the compounds mentioned in the examples and by Combination of all meanings mentioned in the claims derivable compound the following acyclic Nucleoside analogues:

1 - [[1- (3-furyl) -2-hydroxyethoxy] methyl] thymine
1 - [[1- (2-furyl) -2-hydroxyethoxy] methyl] thymine
1 - [[1- (3-thienyl) -2-hydroxyethoxy] methyl] thymine
1 - [[1- (2-thienyl) -2-hydroxyethoxy] methyl] thymine
1 - [[1- (1-Cyclopentenyl) -2-hydroxyethoxy] methyl] thymine
1 - [[1- (Oxazolin-2-yl) -2-hydroxyethoxy] methyl] thymine
1 - [[1- (Thiazolin-2-yl) -2-hydroxyethoxy] methyl] thymine
1 - [[1- (Imidazol-2-yl) -2-hydroxyethoxy] methyl] cytosine
1 - [[1- (Oxazol-4-yl) -2-hydroxyethoxy] methyl] cytosine
1 - [[1- (Thiazol-4-yl) -2-hydroxyethoxy] methyl] cytosine
9 - [[1- (1,2,3-Oxadizol-4-yl) -2-hydroxyethoxy] methyl] guanine
9 - [[1- (1,2,3-Thiadiazol-4-yl) -2-hydroxy-ethoxy] methyl] adenine
1 - [[1- (1,2,3-Triazol-4-yl) -2-hydroxyethoxy] methyl] thymine
1 - [[1- (tetrazol-5-yl) -2-hydroxyethoxy] methyl] thymine
1 - [[1- (2-pyridyl) -2-hydroxyethoxy] methyl] thymine
1 - [[1- (3-pyridyl) -2-hydroxyethoxy] methyl] thymine
1 - [[1- (4-pyridyl) -2-hydroxyethoxy] methyl] thymine
1 - [[1- (3-furyl) -2-hydroxyethoxy] methyl] uracil
1 - [(1-Cyclohexen-1-yl-2-hydroxyethoxy) methyl] thymine
1 - [(1-Ethynyl-2-hydroxyethoxy] methyl] thymine
1 - [(1-Propin-1-yl-2-hydroxyethoxy] methyl] thymine
1 - [(1-vinyl-2-hydroxyethoxy] methyl] thymine
1 - [[1- (1-bromovinyl) -2-hydroxyethoxy] methyl] cytosine
1 - [[1- (1-Cyanovinyl) -2-hydroxyethoxy] methyl] cytosine
1 - [(1-propen-2-yl-2-hydroxyethoxy] methyl] thymine
1 - [(1-Cyano-2-hydroxyethoxy] methyl] cytosine
1 - [(1-Azido-2-hydroxyethoxy) methyl] cytosine
1 - [(1-methoxycarbonyl-2-hydroxyethoxy) methyl] cytosine
1 - [(1-aminocarbonyl-2-hydroxyethoxy) methyl] cytosine
1 - [(1-cyanomethyl-2-hydroxyethoxy) methyl] cytosine
1 - [(1-Azidomethyl-2-hydroxyethoxy) methyl] cytosine
1 - [(1-methoxycarbonylmethyl-2-hydroxyethoxy) methyl] thymine
1 - [(1-aminocarbonylmethyl-2-hydroxyethoxy) methyl] thymine
1 - [(1-Methylmercaptomethyl-2-hydroxyethoxy) methyl] thymine
1 - [[1- (2-fluoroethyl) -2-hydroxyethoxy] methyl] thymine
1 - [[1- (2-Azidoethyl) -2-hydroxyethoxy] methyl] thymine
1 - [[1- (1-cyanoethyl) -2-hydroxyethoxy] methyl] thymine
9 - [[1- (2-propyl) -2-hydroxyethoxy] methyl] guanine
1 - [[1- (Methoxycarbonylethan-1-yl) -2-hydroxyethoxy] methyl] thymine
1 - [[1- (aminocarbonylethan-1-yl] -2-hydroxyethoxy] methyl] thymine
9 - [[1- (Methylmercaptoethan-1-yl) -2-hydroxyethoxy] methyl] adenine
1 - [[1- (2-Fluoro-1-azidoethan-1-yl) -2-hydroxyethoxy] methyl] thymine
1 - [[1- (2-Fluoro-1-cyanoethan-1-yl) -2-hydroxyethoxy] methyl] thymine
1 - [[1- (2-Fluoro-1-methoxycarbonylethan-1-yl) -2-hydroxyethoxy] methyl] t-hymine
9 - [[1- (2-Fluoro-1-aminocarbonylethan-1-yl) -2-hydroxyethoxy] methyl] guanine
1 - [[1- (2-Fluoro-1-methylmercaptoethan-1-yl) -2-hydroxyethoxy] methyl] th-ymin
1 - [[1- (1-Azido-2,2,2-trifluoroethan-1-yl) -2-hydroxyethoxy] methyl] thymine
1 - [[1- (1-Cyano-2,2,2-trifluoroethan-1-yl) -2-hydroxyethoxy] methyl] thymine
1 - [[1- (1-Methoxycarbonyl-2,2,2-trifluoroethan-1-yl) -2-hydroxyethoxy] m-ethyl] thymine
1 - [[1- (1-Aminocarbonyl-2,2,2-trifluoroethan-1-yl) -2-hydroxyethoxy] methyl] thymine
9 - [[1- (1-Methylmercapto-2,2,2-trifluoroethan-1-yl) -2-hydroxyethoxy] methyl] adenine
1 - [[1- (2-Azidopropan-2-yl) -2-hydroxyethoxy] methyl] thymine
1 - [[1- (2-Cyanopropan-2-yl) -2-hydroxyethoxy] methyl] thymine
9 - [[1- (2-Methoxycarbonylpropan-2-yl) -2-hydroxyethoxy] methyl] guanine
1 - [[1- (2-aminocarbonylpropan-2-yl) -2-hydroxyethoxy] methyl] thymine
1 - [[1- (2-Methylmercaptopropan-2-yl) -2-hydroxyethoxy] methyl] cytosine
1 - [[1- (2-aminocarbonylpropan-2-yl) -2-hydroxyethoxy] methyl] uracil
9 - [[1- (2-Methoxycarbonylpropan-2-yl) -2-hydroxyethoxy] methyl] guanine

example 1 a) 1-Benzyloxy-2-propanol

15 g (0.1 mol) benzyloxyacetaldehyde (cf. 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 to ether at 30 ° C. and after the addition was complete 4 Heated under reflux for hours. After cooling, 150 ml of saturated NH₄Cl solution were added, the organic phase was separated off, dried over Na₂SO₄ and the solvent was 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) of 1-benzyloxy-2-propanol and 3.0 g (0.1 mol) of paraformaldehyde in 100 ml of 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. Then it was dried over MgSO₄, the filtrate was freed from solvent in a rotary evaporator and the remaining oil 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 separated, dried over Na₂SO₄ and concentrated in a rotary evaporator. The residue was purified by column chromatography on silica gel with dichloromethane / methanol 20/1 as the 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 in 300 ml abs. Dissolved methanol and after addition from 1.5 g palladium on carbon until the absorption of the theoretical amount of hydrogen at room temperature and Normal pressure hydrogenated. After removing the catalyst the filtrate was evaporated and the residue passed through Column chromatography on silica gel 60 with dichloromethane / methanol 20/1 cleaned as eluent. Yield 1.85 g (69% of theory), mp. 104-109 ° C.  

Example 2

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

Example 3

2-Benzyloxy-1-cyclohexylethanol was made analogously to Example 1 Benzyloxyacetaldehyde and Cyclohexylmagnesiumchlorid prepared and by column chromatography on silica gel Ethyl acetate / heptane 1/5 purified as eluent (68% yield, colorless oil). Chloromethylation and reaction with bis (trimethylsilyl) thymine led to column chromatography on silica gel with ethyl acetate / heptane 2/1 as eluent in 83% Yield to 1 - [(2-benzyloxy-1-cyclohexylethoxy) methyl] thymine. From the crude hydrogenation product on palladium Charcoal was obtained after column chromatography on silica gel with ethyl acetate / heptane 2/1 as eluent the 1 - [(1-cyclohexyl 2-hydroxyethoxy) methyl] thymine obtained in 41% yield (Mp 124-127 ° C).

Claims (4)

1. Compounds of the general formula I in the
R represents a hydrogen atom, an aliphatic acyl radical, a monophosphate, diphosphate or triphosphate group,
R¹ is an aryl radical, a saturated, unsaturated or aromatic heterocyclic five- or six-membered ring with one or more heteroatoms, a cycloalkyl or cycloalkenyl radical, a straight-chain or branched alkynyl or alkenyl radical with 2-7 carbon atoms, an alkanedienyl radical, a formyl or cyano -, Azido, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkylcarbonyl or aminocarbonyl
or the rest means, where R², R³ and R⁴ may be the same or different and hydrogen, amino, azido, cyano, C₁-C₆-alkoxycarbonyl, C₁-C₆- alkylcarbonyl-, aminocarbonyl, C₁-C₆-alkylmercapto, C₁-C₆-alkyl, halogen Can be -C₁-C₆-alkyl or azido-C₁-C₆- alkyl,
B represents the pyrimidine and purine bases thymine, uracil, cytosine, adenine, hypoxanthine and guanine, which are substituted in the 1-, 7- or 9-position,
their tautomers, optically active forms or physiologically acceptable salts of inorganic and organic acids, with the proviso that in the event that R₂ and R₃ are simultaneously hydrogen, R₄ cannot be a methyl group, and in the event that R₂ and R₃ are hydrogen, and R₄ represents hydrogen, an azido or isopropyl mercapto group, B cannot denote the guanine or adenine residue. 2. Process for the preparation of compounds of formula I. in the
R represents a hydrogen atom, an aliphatic acyl radical, a monophosphate, diphosphate or triphosphate group,
R¹ is an aryl radical, a saturated, unsaturated or aromatic heterocyclic five- or six-membered ring with one or more heteroatoms, a cycloalkyl or cycloalkenyl radical, a straight-chain or branched alkynyl or alkenyl radical with 2-7 carbon atoms, an alkanedienyl radical, a formyl or cyano -, Azido, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkylcarbonyl or aminocarbonyl,
or the rest means, where R², R³ and R⁴ can be the same or different and hydrogen, amino, azido, cyano, C₁-C₆-alkoxycarbonyl, C₁-C₆-alkylcarbonyl-, aminocarbonyl, C₁-C₆-alkylmercapto, C₁-C₆-alkyl, halogen Can be -C₁-C₆-alkyl or azido-C₁-C₆-alkyl,
B represents the pyrimidine and purine bases thymine, uracil, cytosine, adenine, hypoxanthine and guanine, which are substituted in the 1-, 7- or 9-position,
their tautomers, optically active forms or physiologically acceptable salts of inorganic and organic acids, with the proviso that in the event that R₂ and R₃ are simultaneously hydrogen, R₄ cannot be a methyl group, and in the event that R₂ and R₃ are hydrogen, and R₄ represents hydrogen, an azido or isopropyl mercapto group, B cannot denote the guanine or adenine residue, characterized in that a compound of the formula II in which R¹ has the meaning given above, R⁵ represents a protective group suitable for the hydroxyl function and Z represents a reactive group, causes a reaction with a pyrimidine or purine base and then splits off the protective group R⁵ by methods known per se,
and optionally subsequently converting the compounds of the general formula I thus obtained in which R represents a hydrogen atom into the corresponding mono-, di- or triphosphates. 3. Medicaments containing at least one compound according to claim 1 and pharmaceutical auxiliary or Carriers. 4. Use of compounds according to claim 1 for treatment of viral infections.