NO854041L - PROCEDURE FOR THE PREPARATION OF NEW NUCLEOSIDE DERIVATIVES. - Google Patents

Abstract

Novel nucleoside derivatives of formula (I). and pharmaceutically acceptable acid addition salts thereof, wherein R. and 'are the same or different and represent hydrogen or optionally substituted acyl, optionally substituted cycloalkanoyl. optionally substituted aroyl or optionally substituted heteroaryl exhibit therapeutic activity. Preparation of the compounds is described.

Description

The present invention relates to antiviral pharmaceutical preparations, methods for inhibiting viral multiplication, high nucleoside derivatives which are usable in such preparations and methods for producing them.

More specifically, the invention relates to new nucleoside derivatives of formula (I)

and pharmaceutically acceptable acid addition salts thereof, wherein R and R' are the same or different and denote hydrogen or optionally substituted acyl, preferably optionally substituted straight-chain or branched alkanoyl, optionally substituted cycloalkanoyl, optionally substituted aroyl or optionally substituted heteroaroyl.

Furthermore, the invention relates to pharmaceutical preparations

rates comprising the same compounds, their use as antiviral agents and methods for the preparation of the compounds of formula (I) and their pharmaceutically acceptable acid addition salts.

It is known in the art that the 2'-deoxynucleosides of

the 5-substituted uracil base exhibits a very good in vitro and in vivo antiviral effect [Meth and Find Exptl Clin Pharmacol, 2, 253 (1980)]. Of the known nucleosides, especially (E)-5-(2-bromovinylj-uracil-2<1->deoxynucleosides were effective against herpes simplex virus variants [Proe Nati Acad Sei, USA, 76, 2497 (1979)]. It is also known within

the subject that these compounds suffer from a very rapid cleavage under in vivo conditions and that they are converted into ineffective compounds as a result of processes that take place in living organisms, in which the (3-glycosidic bond is split [Biomed Biochem Acta, 42, 35-38, (1983); Biochemical Pharmacology, 32, (23) 3583-3590 (1983)].

Systematic chemical transformations were made on these compounds effective against herpes simplex variants to increase their stability under in vivo conditions and thus increase their therapeutic activity.

It is known in the art that the 2,2'-anhydro derivatives of indicated compounds are much less effective or biologically ineffective as described for 5-ethyl-, 5-n-propyl- or 5-isopropyl-2,2'- anhydro-1-Ø-D-arabinof uran-oyl-uracil [J Carbohydrates, Nucleosides, Nucleotides, 6, 295-308 (1979)].

The nucleoside derivatives according to the invention exhibit the same or better in vitro antiviral effect than the known uracil derivatives, e.g. 5-ethyl-2'-deoxyuridine or (E)-5-(2-bromovinyl)-2'-deoxyuridine, but they are not cleaved under in vivo conditions, and the in vivo tests which have been carried out with the compounds according to the invention have confirmed that their toxicity is much lower than that of the known nucleoside derivatives.

The preferred antiviral compounds of formula (I) are those in which R and R' independently denote hydrogen or optionally substituted straight-chain or branched alkanoyl, and the acid addition salts thereof.

The most preferred antiviral compounds of formula (I) are the following: (E)-5-(2-bromovinyl)-2,2'-anhydro-1-p-D-arabinofuranosyl-uracil, (E)-5-(2-bromovinyl)- 2,2'-anhydro-3'-acetyl-l-p-D-arabino-furanosyl-uracil, (E)-5-(2-bromovinyl)-2,2*-anhydro-3',5"-diacetyl-l-Ø -D-arabinofuranosyl-uracil and its acid addition salts.

In the above-mentioned formula (I), the "straight-chain or branched-chain alkanoyl group" is preferably a straight-chain or branched-chain alkanoyl group of 1-8 carbon atoms, which is exemplified by formyl-, acetyl-, propionyl-, i-propionyl-, butyryl-, i -butyryl, valeryl, i-valeryl, caproyl, pivaloyl, heptanoyl and octanoyl groups.

The "cycloalkanoyl" group is preferably a cycloalkanoyl group of 4-9 carbon atoms, which is exemplified by the cyclohexanoyl group.

The "aroyl" group is preferably an aroyl group of 7-11 carbon atoms, exemplified by benzoyl or naphthoyl.

The "heteroaroyl" group is preferably an aroyl group with 4-11 carbon atoms and 1 or 2 oxygen, sulfur and/or nitrogen atoms as heteroatoms, which are exemplified by furoyl, nicotinoyl or isonicotinoyl groups.

Indicated groups may be substituted with 1-3 substituents, preferably selected from alkyl and aryl.

The "alkyl" group is preferably an alkyl group with from 1-6 carbon atoms, which is exemplified by methyl-, ethyl-', propyl-, i-propyl-, butyl-, i-butyl-, pentyl-, i-pentyl- , hexyl or i-hexyl groups.

The "aryl" group is preferably an aryl group of 6-10 carbon atoms, e.g. the phenyl or naphthyl group.

The most preferred substituents of the above-mentioned substituents are methyl and phenyl.

Salts of the compounds of formula (I) which can suitably be used in therapy include physiologically acceptable salts of organic acids such as lactic acid, acetic acid, malic acid or p-toluenesulfonic acid, as well as physiologically acceptable salts of inorganic acids such as hydrochloric acid or sulfuric acid .

The new compounds of formula (I), in which R and R' independently of each other are hydrogen or a blocking group, provided that at least one of these denotes a blocking group, are useful intermediates for the preparation of the antiviral compounds of formula (I).

In the above formula, the blocking group can be any blocking group used in organic chemistry, which can be cleaved without damaging (E)-5-(2-bromovinyl)-2,2'-anhydro-1 -Ø-D-arabinof urano-syl-uracil structure.

A preferred blocking group is the (4-methoxy-triphenyl)-methyl group.

The compounds of formula (I) can be prepared by reacting a compound of formula (II)

with a compound of formula (III) in which R is as defined above, after which, if desired, the compounds thus obtained are acylated, deacylated and acylated again with an acylating agent of formula (IV) or (V)

wherein Y has the same meaning as defined for R or R'.

For the preparation of the compounds of formula (I), wherein R = R' = H,

a) a compound of formula (I) is deacylated, in which R and R' are the same or different and denote an acyl group with

sodium methylate, or

b) a compound of formula (I) is deacylated, in which one of R and R' is acyl while the other is a protecting group,

with sodium methylate, after which the protecting group is cleaved.

For the preparation of compounds of formula (I), in which both R and R' denote acyl,

a) a compound of formula (I), in which R' is hydrogen and R is acyl, is acylated with a compound of formula (IV)

or (V), in which Y is as defined above, or

b) a compound of formula (II) is reacted with a compound of formula (III), in which R is as defined above, after which the thus obtained compound of formula (I) is reacted with a compound of formula (IV) or (V), in which Y is as defined above, or c) a compound of formula (I), in which one of R and R' denotes hydrogen and the other denotes acyl, is acylated with a compound of formula (IV) or (V), in which Y is as defined above. For the preparation of compounds of formula (I), in which R denotes hydrogen and R' denotes acyl, a) a compound of formula (I), in which both R and R' denote acyl, is treated with methanolic ammonia, or b) the protective group from a compound of formula (I), wherein R denotes a protecting group and R<*>

denotes acyl.

For the preparation of compounds of formula (I), in which R denotes acyl and R' denotes hydrogen, a) a compound of formula (II) is reacted with a compound of formula (III), in which R is as defined above,

or

b) the protecting group is removed from a compound of formula (I), in which R denotes acyl and R' denotes a

shooting group.

The above-mentioned reactions are illustrated by the subsequent reaction scheme as follows:

After the reaction is complete, the compounds of formula (I) obtained in free base form are converted, if desired, into pharmaceutically acceptable acid addition salts, or the free base is released from the salt.

The product can be separated from the reaction mixture in a known manner, e.g. by solvent, extraction, evaporation of the solvent, etc. The impure product can be further purified according to known methods, e.g. by recrystallization, chromatography or similar methods.

Results of various biological tests described in the following show that the compounds produced according to the invention can regulate different virus variants.

Two herpes simplex virus variants were used in the tests. HVS-1 is designated as "HIL", while HVS-2 is designated as "NAH" in the international literature. Their time for one multiplication was 24-26 hours and their TCID5Q value was 10<6>.

The viruses were grown on a fibroblast culture of diploid chromosomes. The freshly isolated cells were stored in liquid nitrogen, and the thawed cells were used in the tests. Both HVS-1 and HVS-2 can be easily multiplied on these cells. Mycoplasmas were not observed in the cell cultures.

Eagle's minimal essential medium (MEM, GIBCO) with Earle's salts supplemented with 10% aqueous porcine gastric mucin, 10 IU/ml penicillin and 100 g/ml streptomycin was used as culture medium in the tests (pH = 7.4).

The young, practically confluent, cultures of the cells were infected with a virus capable of multiplying very slowly (TCID50= 0.01). After the virus had absorbed (two hours at 37°C), the unabsorbed virus was washed out of the cell culture, and a new culture medium was added to the cell culture. When a 75 percentile cytopathogenic effect could be observed, the cells were then frozen and thawed three times. The broken fragments of the cells were removed by centrifugation (15 min., 30,000 rpm). The virus suspension was stored at -r70°C before use.

A standard microdilution method (Conrath, Theodore, B., Handbook of Microtiter Procedures, 1972, Dynatech Corporation, Cambridge, Massachusetts) with the power indicated above was used to determine the 50 percentile tissue culture infective dose (TCID5q)- The value indicates the dose of the virus that can infect 50% of the inoculated cell cultures.

The effectiveness of the compounds according to the invention

were determined on the basis of their influence on the TCID5Q value of the viruses. The diluted virus suspensions were absorbed onto the cell cultures at a temperature of 37°C for two hours. The unabsorbed virus was removed by washing with phosphate-buffered saline (PBS, pH =2.4). To the cell cultures thus infected, a new culture stock comprising the compounds according to the invention in different concentrations was added. Each test was repeated in four replications. The cell cultures were incubated until the maximum TCID5Q value was reached in untreated, infected cell cultures.

The lowest concentration of active ingredient was determined which could decrease the TCID5Q value of the virus by one log unit. These data characterize well the effectiveness of the compounds, and the compounds can be compared with each other. The data thus obtained are listed in table I.

The in vivo antiviral effect of the compounds according to the invention was determined on mice inoculated with herpes encephalitis. Balb/C mice weighing 18 g were used in the experiments.

The mice were intracerebrally (i.c.) infected without anesthesia with a 10 1D 5 g dose of a virus designated as virus 667 (diluted with 0.05 ml MEM culture stock).

The ID5Q value for virus 667 in mice is 10<6>/0.1 ml. The control animals were treated only with the culture stock. The mice were administered on the day of infection and again every day after infection intraperitoneally with 140 mg/kg of the tested compounds (0.2 ml, once per day). The active ingredients were dissolved in physiological saline, the control group was treated only with physiological saline. The known (E)-5-(2-bromovinyl)-2<1->deoxyuridine was used as a comparison compound. It is stated according to the state of the art that the effective dose of (E)-5-(2-bromovinyl)-2'-deoxyuridine is 140 mg/kg, which is why the test compounds were used in the same dose (Antiviral Research, 2, 255 /1983/ ).

The data obtained are shown in table II.

The toxicity of the compounds on uninfected cell cultures was also determined each day. The results were compared with the data for untreated cell cultures. It could be determined that the compounds produced according to the invention were not toxic in the dose administered.

The antiviral agents according to the invention can be administered in any way that provides contact between the active agent and the agent's site of action in the body. They may be administered by any suitable means available for use in conjunction with pharmaceutical agents, either as individual therapeutic agents or in a combination of therapeutic agents. They can be administered alone, but are generally administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

The dose administered will of course vary, depending on known factors such as the pharmacodynamic characteristics of the particular agent and its mode of action and method of administration, age, health and weight of the recipient, the nature and degree of symptoms, type of accompanying treatment, frequency of the treatment and the desired effect. Usually, a daily dose of active ingredient can be 100-500 mg per kg body weight, administered in divided doses 2-4 times per day or in an extended-release form. These drugs can also be administered parenterally.

In the pharmaceutical preparations, the active ingredient will usually be present in an amount of 0.5-95% by weight based on the total weight of the preparation.

The active ingredient can be administered orally in solid dosage forms such as capsules, tablets, powders, etc., or in liquid dosage forms such as elixirs, syrups, suspensions, etc. It can be administered parenterally in sterile liquid dosage forms.

Gelatin capsules contain the active ingredient and powdered carriers such as lactose, sucrose, mannitol, starch, cellulose derivatives, magnesium stearate, stearic acid etc. Similar diluents can be used to produce compressed tablets. Both tablets and capsules can be manufactured as delayed release products to provide continuous release of drug over a period of hours. Compressed tablets may be sugar-coated or film-coated to mask any off-flavor and protect the tablet from the atmosphere, or may be enteric-coated for selective disintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration may contain coloring agents and flavoring agents to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose) and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water-soluble salt of the active ingredient, suitable stabilizers and, if necessary, buffer substances. Antioxidants such as sodium bisulphite, sodium sulphite or ascorbic acid, either alone or in combination, are suitable stabilizers. Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions may contain preservatives such as benzalkonium chloride, methyl or propyl pareaben and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, A, Oslo, a standard book in this field.

The invention is further illustrated in the following examples.

Example 1

Preparation of (E)-5-(2-bromovinyl)-2,2'-anhydro-3'-0-acetyl-1-ft-D-arabinofuranosyl-uracil-hydrochloride

25 g (0.071 mol) of (E)-5-(2-bromovinyl)-uridine was suspended in 250 ml of dry acetonitrile, after which 35.5 g (0.179 mol) of acetylsalicylic acid chloride was added, and the reaction mixture was stirred for 10 min. at an external temperature of 50-

60°C. After 10 min. a clear solution was obtained. The external heat was removed and the reaction mixture was stirred for an additional hour at room temperature. After 15-20 min.

( crystals precipitated. The crystals were filtered off, after which the mother liquor was concentrated by heating to 50°C. The remaining syrup was triturated with 100 ml of ether, the crystals obtained were filtered off and washed with 20 ml of ether.

The weight of the impure product was 25 g. Sm.p. 120-130°C. The crude product was dissolved in 50 ml of methanol containing 2-3% hydrochloric acid and, if necessary, filtered off and saturated with fivefold the amount of ether. The product thus obtained was allowed to stand overnight in a refrigerator, the precipitated crystals were filtered off and dried. The hydrochloride of the desired compound was thus obtained. Yield: 20-22 g (74-81%). Melting point: 152-155°C.

Elemental analysis:

Example 2

Preparation of (E)-5-(2-bromovinyl)-2,2'-anhydro-3',5'-di-O-acetyl-1-p-D-arabinofuranosyl-uracil

To 7 g of the impure product obtained according to example 1, 40 ml of acetic anhydride, 2 ml of triethylamine and 20 mg of 4-dimethylaminopyridine catalyst were added. The majority of the substances were dissolved immediately. The reaction mixture was allowed to stand overnight and was then concentrated in vacuo at a temperature of 50-60°C. The remaining syrup was taken up with 50 ml of chloroform and was extracted with 2 x 20 ml of saturated aqueous potassium hydrogen carbonate solution. The organic phase was separated, dried over anhydrous magnesium sulfate and evaporated in vacuo after removal of the drying agent. The remaining crystalline product was recrystallized from

ethanol. Yield: 5-5.5 g (64-70%). Melting point: 177°C. Elemental analysis:

Example 3

Preparation of (E)-5-(2-bromovinyl)-2,2'-anhydro-1-p-D-arabinofuranosyl-uracil

To 10 g of the impure product obtained in example 1, 100 ml of 0.5 M sodium methylate was added. A clear solution was obtained which was allowed to stand at room temperature for three hours. The solution was neutralized by the addition of Dowex 50 H+ resin, after which the resin was filtered off and washed, and the mixture was evaporated in vacuo at a temperature of 50°C. The crystalline product was recrystallized from water. Yield: 5-6 g (63-79%). Melting point: 193°C.

Elemental Analysis:

Example 4

Preparation of (E)-5-(2-bromovinyl)-2,2'-anhydro-3'-O-propionyl-1-p-D-arabinofuranosyl-uracil

3.49 g (10 mmol) of (E)-5-(2-bromovinyl)-uridine was suspended in 30 ml of dry acetonitrile, whereupon 6.38 g (30 mmol) of propionyl salicylic acid chloride was added, and the reaction mixture was stirred for 10 my. at a temperature of 50-60°C. After 10 min. a clear solution was obtained. The external heat was then removed and the solution was stirred for an additional hour at room temperature. The product obtained was concentrated in vacuo at a temperature of 50°C. 20 ml of dry methanol was added to the residue, and the evaporation was

repeated to decompose excess acid chloride. To the remaining syrup was added 100 ml of ether, and the solution was stirred for two hours at room temperature. The hydrochloride salt of the desired compound was obtained, which was filtered off and dried. The weight of the impure product was 3 g. Melting point: 150-160°C.

The impure product obtained as described was dissolved in 10-20 ml of methanol, and sodium methylate was added until the pH of the solution was adjusted to 5 (pH was checked with indicator paper). The solution thus obtained was evaporated in vacuo, and the residue was taken up with 20 ml of ethyl acetate. The precipitate was filtered off, washed with 2 x 5 ml of ethyl acetate, after which the combined solutions were concentrated in vacuo at a temperature of 50°C. The residue thus obtained was dissolved in 5 ml of ethanol and allowed to stand at room temperature. The final product crystallized slowly and was filtered off and dried the next day. Yield: 2.5 g (64.43%). Sm.p. 191-192°C. Rf = 0.56 in a mixture of ethyl acetate and methanol.

Elemental analysis (C^H^Br^Og; Mw = 387.19):

Examples 5-10

By following the method described in Examples 1-4 using suitable starting materials, the compounds listed in Table III were prepared.

Example 11

Preparation of ( E )- 5-( 2-bromovinyl)- 2, 2'- anhydro- 5'-( 4-methoxytriphenylmethyl)- 1- 3- D- arabinofuranosyl- uracil

3.31 g (10 mmol) of (E)-5-(2-bromovinyl)-2,2*-anhydro-1-(3-D-arabinofuranosyl-uracil) was dissolved in 20 ml of dry pyridine, after which 3.12 g (11.4 mmol) of 4-methoxytriphenylmethyl chloride was added with stirring. The solution was stirred for 20 hours at room temperature and then evaporated to dryness. The residue was dissolved in chloroform and extracted with water. After drying, the organic phase was evaporated and then dissolved in methanol and dried on 20 g of silica gel by vacuum distillation.The substance thus obtained was placed on a silica gel column and was eluted with an 8:2 mixture of ethyl acetate and petroleum ether and then an 8:2 mixture of ethyl acetate and methanol. The fractions containing the desired product were evaporated, and the product was crystallized from a mixture of cyclohexane and methanol.Yield: 2.5-2.8 g (80-90%). M.p. 121°C.

Elemental analysis:

Example 12

Preparation of (E)-5-(2-bromovinyl)-2,2'-anhydro-3'-O-acyl-1-p-D-arabinofuranosyl-uracil

3.0 g (5 mmol) of 5'-(4-methoxytriphenylmethyl)-2,2'-anhydro-(E)-5-(2-bromovinyl)-uridine was dissolved in 10 ml of dry pyridine, after which 11 mmol of the suitable carboxylic acid chloride was added dropwise with stirring and while cooling with ice. The reaction mixture was stirred overnight, after which 50 ml of methanol was added. The solution was evaporated in vacuo, after which the residue was dissolved in chloroform and extracted with 3 x 5 ml of water. The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness in vacuo. The residue was dissolved in 150 ml of 80% acetic acid and allowed to stand at room temperature for four hours. The homogeneous solution

ning was evaporated to dryness. The residue crystallized after the addition of chloroform. The crystals were filtered off and washed with chloroform. Yield: 2.5-4 mmol of the desired product (50-80%)

Example 13

Preparation of ( E )- 5-( 2- bromovinyl)- 2, 2'- anhydro- 3'- benzoyl-1- 3- D- arabinofuranosyl- uracil

3.02 g (5 mmol) of 5'-(4-methoxytriphenylmethyl)-2,2'-anhydro-(E)-5-(2-bromovinyl)-uridine was dissolved in 10 ml of dry pyridine, and 1.28 ml (11 mmol) of benzoyl chloride was added dropwise to the solution while stirring and while cooling with ice. The reaction mixture was stirred at room temperature overnight, after which 50 ml of methanol was introduced. The solution was evaporated in vacuo, the residue was dissolved in chloroform and extracted with water three times. The organic phase was evaporated to dryness, and the solid residue was dissolved in 150 ml of 80% acetic acid with stirring. After four hours, the reaction mixture was evaporated in vacuo, and the entire water content was removed by repeated azeotropic distillations with ethanol. The residue was crystallized from chloroform. The product was filtered off and dried. Yield: 1.6 g (75%). Melting point: 240-241°C. Rf = 0.50 (in a 95:5 mixture of ethyl acetate and methanol).

Elemental analysis:

Following the method described above, the compounds of Examples 6-10 were prepared. The physical constants of the compounds were the same as described in Table (I), although the yields were as follows:

Examples 14-16

Preparation of ( E )- 5-( 2- bromovinyl)- 2, 2'- anhydro- 5'- O- acyl-1- p- D- arabinofuranosyl- uracils

10 mmol of (E)-5-(2-bromovinyl)-2,2,-anhydro-3",5'-di-0-acyl-1-p-D-arabinofuranosyl-uracil was dissolved in 100 ml of methanolic ammonium hydroxide solution (methanol saturated with ammonia at a temperature of 0°C and diluted to one

tenth of the ammonia concentration before use). The flask containing the reaction mixture and closed with a stopper was allowed to stand at room temperature for 10-20 min. and was then evaporated to dryness. The solid product thus obtained was recrystallized from methanol. The chemical structure of the products was confirmed by NMR spectroscopy, while their purity was checked by measuring the melting point and by thin-layer chromatography. The TLC analysis was carried out on silica gel using a 9:1 mixture of benzene and methanol as eluent, and the spots were detected in UV light.

The physical constants and yields of (E)-5-(2-bromovinyl)-2,2'-anhydro-5'-O-acyl-1-p-D-arabinofuranosyl-uracils are listed in Table IV.

Examples 17-29

Preparation of (E)-5-(2-bromovinyl)-2,2'-anhydro-3',5'-di-O-acyl-1-p-D-arabinofuranosyl-uracil derivatives

1. Preparation of (E)-5-(2-bromovinyl)-2,2'-anhydro-1-p-D-arabinofuranosyl-uracils by acylation of (E)-5-(2-bromovinyl)-2,2'- anhydro-1-(3-D-arabinof uranosyl-uracil).

a) Acylation with an acid anhydride

To 1 mmol of (E)-5-(2-bromovinyl)-2, 2'-anhydro-1-(3-D-arabinofuranosyl-uracil) was added 5 mmol of the appropriate acid anhydride (acetic anhydride, propionic anhydride, etc.), 0.2 ml of triethylamine and 4-5 mg of 4-dimethylaminopyridine catalyst, after which the mixture was heated to 60-80°C while excluding moisture. A clear solution was obtained which was allowed to stand at room temperature. After half an hour the crystals began to precipitate. After 5-6 hours, the crystals thus obtained were filtered off and washed with a small amount of ether.The impure product was recrystallized from an alcohol.

b) Acylation with an acid chloride

To 1 mmol of (E)-5-(2-bromovinyl)-2,2'-anhydro-1-p-D-arabinofuranosyl-uracil was added 3 ml of dry pyridine and 2.5 mmol of the appropriate acid chloride. The reaction mixture was heated to a temperature of 60-80°C while excluding moisture. A clear solution was obtained. After approx. an hour, the first crystals were formed. The precipitated crystals were filtered off after 3-4 hours and were then washed with a small amount of cold ethanol and recrystallized from ethanol or dimethylformamide. 2. Preparation of the desired compound by acylation of (E)-5-(2-bromovinyl)-2,2'-anhydro-3'-O-acyl-1-p-D-arabinofuranosyl-uracil.

a) Acylation with an acid anhydride

The acylation can be carried out as indicated above

method la) using a lower carboxylic acid anhydride.

b) Acylation with an acid chloride

The method described under lb) can be followed, but 1.25 mmol

of the acid chloride is added instead of 2.5 mmol of acid chloride, calculated for 1 mmol of the starting compound.

The compounds prepared as above, their physical constants, yields, elemental analysis data and the starting materials used are listed in Table V.

Capsules

Drops

The hydrochloride salt of the compound of formula (I), wherein

Infusion solution

The hydrochloride salt of the compound of formula (I), wherein

R = acetyl, R' = H 6 g dissolved in physiological saline solution,

filled in 2.0-5.0 ml ampoules after sterile filtration q.s. 1000 ml

Claims (9)

1. Compound of Formula (I) wherein R and R' are the same or different and denote hydrogen or optionally substituted acyl, preferably optionally substituted straight-chain or branched alkanoyl, optionally substituted cycloalkanoyl, optionally substituted aroyl or optionally substituted heteroaroyl, and pharmaceutically acceptable acid addition salts thereof. 2. Compound according to claim 1 of formula (I), in which R and R' are the same or different and denote hydrogen or optionally substituted straight-chain or branched alkanoyl with from 1-8 carbon atoms, optionally substituted cycloalkanoyl with from 4-9 carbon atoms, optionally substituted aroyl with from 7-11 carbon atoms or heteroaroyl with from 4-11 carbon atoms and 1 or 2 oxygen, sulfur and/or nitrogen atoms as heteroatoms, or pharmaceutically acceptable acid addition salts thereof. 3. Compound according to claim 1 of formula (I), in which R and R' are the same or different and denote hydrogen or optionally substituted straight-chain or branched alkanoyl with from 1-4 carbon atoms, and pharmaceutically acceptable acid addition salts thereof. 4. Compound according to claim 1 of formula (I), characterized in that the optionally present substituents are alkyl and/or aroyl groups. 5. Compound according to claim 1 of formula (I), characterized in that the optionally present substituents are alkyl groups with from 1-6 carbon atoms and/or carboxylic aryl with from 6-10 carbon atoms. 6. Compound according to claim 1, characterized in that it is (E)-5-(2-bromovinyl)-2,2'-anhydro-1-p-D-arabinofuranosyl-uracil, (E)-5-(2-bromovinyl)-2 ,2'-anhydro-3'-acetyl-l-p-D-arabinofuranosyl-uracil, (E)-5-(2-bromovinyl)-2,2'-anhydro-3', 5'-diacetyl-arabinofuranosyl-uracil, and pharmaceutical acceptable acid addition ion salts thereof. 7. Compound according to claim 1 of formula (I), characterized in that R and R' are equal or different and denote hydrogen or a suitable blocking group, provided that at least one of R and R' is a blocking group. 8. Compound according to claim 1 of formula (I), characterized in that R and R' are the same or different and denote hydrogen or (4-methoxytriphenyl)-methyl, provided that at least one of R and R' is (4-methoxy- triphenyl)-methyl. 9. Process for the preparation of a compound of formula (I) and pharmaceutically acceptable acid addition salts thereof, wherein R and R' are the same or different and denote hydrogen or optionally substituted acyl, preferably optionally substituted straight-chain or branched alkanoyl, optionally substituted cycloalkanoyl, optionally substituted aroyl or optionally substituted heteroaroyl, characterized in that a compound of formula (II) is reacted with a compound of formula (III) in which R is as defined above, after which one or more of the following reactions are carried out: a) acylation of a compound of formula (I), in which at least one of R and R' is hydrogen, with a compound of formula (IV) or (V) in which Y has the same meaning as defined for R or R', b) deacylation of a compound of formula (I), in which at least one of R and R' denotes acyl, with methanolic ammonia or sodium methylate, c) introduction of a blocking group into the compound of formula (I), in which one of R and R' represents hydrogen, acylation of the thus obtained compound with an acylating agent of formula (IV) or (V), and deacylation of the thus obtained compound, and converting the compound of formula (I) obtained in free base into a pharmaceutically acceptable acid addition salt, or releasing the free base form from the salt.