MXPA98000402A - Pirimid nucleosid derivatives - Google Patents

Abstract

The present invention relates to compounds of the general formula (I), wherein R 1 represents aryl, R 2 represents a lower alkyl, R 3 represents an acyl group derived from an amino acid and R 4 represents hydrogen or fluorine and the asterisk denotes that the configuration in the of carbon indicated by means of this, is (S) or (R), and its pharmaceutically acceptable addition salts are antiviral agents

Description

"DERIVATIVES OF PYRIMIDINE NUCLEOSID" FIELD OF THE INVENTION The present invention relates to pyrimidine nucleoside derivatives, to a process for their manufacture and to pharmaceutical preparations containing these nucleosides.

DESCRIPTION OF THE INVENTION The pyrimidine nucleoside derivatives provided by the present invention are compounds of the following general formula: where R1 represents an aryl, R2 represents a lower alkyl, R3 represents an acyl group Ref.26545 derived from an amino acid, R4 represents hydrogen or fluorine and the asterisk denotes that the configuration at the carbon atom indicated therein is (S ) or (R), and their pharmaceutically acceptable acid addition salts. EP-A-257 378 discloses compounds corresponding to formula I, but containing as R3 inter alia an acyl group derived from aliphatic, cycloaliphatic, araliphatic or aromatic carboxylic acid instead of an acyl group derived from an amino acid, so as its use as antiviral agents. The compounds of the formula I and their pharmaceutically acceptable acid addition salts have valuable pharmacological properties. In particular, they inhibit viral thymidine kinase and are useful according to this in the treatment or prophylaxis of viral infections, especially those caused by the herpes simplex virus (HSV). In addition, they also have excellent solubility in the aqueous medium. As used herein, the term "aryl" means an unsubstituted phenyl or substituted phenyl by means of one or more halogen atoms, for example, fluorine, chlorine, bromine, or iodine atoms, and / or a lower alkyl, a lower alkoxy, aryl, trifluoromethyl or nitro groups, for example, 4-chlorophenyl, p-tolyl, 4-methoxyphenyl, 2,4-dichlorophenyl, 2,4-dichloro-5-methoxyphenyl and the like. The term "lower alkyl" means a straight or branched chain alkyl group containing 1-4 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl and the like. The term "lower alkoxy" means a lower alkyl group as defined above that is attached via an oxygen atom, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and the like. The amino acids from which the acyl group denoted by R3 is derived in formula I are preferably α-amino acids, which may be both natural and non-natural, for example, glycine, alanine, valine, leucine, isoleucine, norleucine, phenylalanine, tyrosine , serine, cysteine, cystine, threonine, methionine, tryptophan, proline, 3- or 4-hydroxy-proline, asparagine, glutamine, ornithine, arginine, lysine, aspartic acid, glutamic acid, sarcosine and the like. However other amino acids from which R3 can be derived include the β-amino acids such as, for example, β-alanine. It will be appreciated that the compounds of the formula I can exist as optically pure diastereomers or as mixtures of these diastereoisomers and that the invention includes within its scope, not only the diastereoisomers, but also their mixtures. Preferred compounds of the formula I are those in which R1 represent the phenyl substituted by one or more substituents which may be the same or different, preferably by a halogen and a lower alkoxy, especially 2,4-dichloro-5-methoxyphenyl. R2 preferably represents methyl. Preferably, R3 represents an acyl group derived from a natural a-amino acid, especially L-valyl. R4 preferably represents fluorine. In addition, the configuration at the carbon atom indicated by the asterisk is preferably (S). L- [5- [2 (S) - (2,4-dichloro-5-methoxyphenoxy) -propion-amido] -2,5-dideoxy-2-fluoro-3-OL-valyl-β-D-arabino -furanosyl] -5-ethyluracil is a preferred compound especially of the formula I mentioned hereinabove. Examples of other compounds that are within formula I are: l- [5- [2 (S) - (2,4-dichloro-5-methoxyphenoxy) -propion-amido] -2,5-dideoxy-2- fluoro-3-OD-valyl-β-D-arabino-furanosyl] -5-ethyluracil l- [5- [2 (S) - (2, 4,6-trichloro-3-methoxyphenoxy) -propion-amido] -2,5-dideoxy-2-fluoro-3-OL-valyl-β-D-arabino-furanosyl] -5-ethyluracil l- [5- [2 (S) - (2,4-dibromo-5-methoxyphenoxy) -propion-amido] -2,5-dideoxy-2-fluoro-3-0-L-valyl-β-D-arabino-furanosyl] - 5-ethyluracil, and l- [5- [2 (R) - (2,4-dichloro-5-methoxyphenoxy) -propion-amido] -2,5-dideoxy-2-fluoro-3-0-L-vali1 -β-D-arabino-furanosyl] -5-ethyluracil In accordance with the process provided by the present invention, the compounds of the formula I and their pharmaceutically acceptable addition salts are prepared by reacting a compound of the general formula wherein RX, R2 and R4 and the asterisk have the meaning given above, with an N-protected amino acid and subsequently separating from the N-protecting group and, if desired, converting the compound of the formula I obtained, into an acid addition salt pharmaceutically acceptable. The reaction of a compound of formula II with an N-protected amino acid is an acylation which can be carried out using reagents, solvents as well as protecting groups and methods for their removal which will be well known to those skilled in the art.

In a preferred embodiment, a compound of formula II is reacted with an amino acid that is N-protected by tert-butoxycarbonyl (Boc) in the presence of ethyl dimethyl-aminopropyl carbodiimide hydrochloride and 4-dimethylamino-pyridine and the subsequent deprotection is carried out by means of treatment with hydrogen chloride. The compounds of the formula I can be converted into pharmaceutically acceptable acid addition salts by treatment with a suitable organic or inorganic acid according to the methods known per se. Examples of these acids are hydrohalic acids, for example, hydrochloric acid and hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, citric acid, fumaric acid, malic acid, maleic acid, succinic acid, acid tartaric, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, and the like. The starting materials of formula II mentioned above are the known compounds or analogs of known compounds which can be prepared in analogy with the known compounds or with the detailed Example given below. As will be apparent from the foregoing, the compounds of the formula I and their pharmaceutically acceptable salts of the compounds of the formula I are useful as antiviral agents. The activity of the compounds of the formula I can be demonstrated on the basis of the following test procedure for the inhibition of HSV-2 thymidine kinase: In this test procedure, the assay mixture contains 50 mmol of Tris HCl, pH 8, 5 mmol of magnesium chloride, 5 mmol of ATP, 0.3 μmol of 3 H-thymidine (50 Ci / mmol), an appropriately diluted enzyme preparation and various concentrations of the test compounds in a total volume of 100 μL. The assays were incubated at 37 ° C for 30 minutes and the reaction was terminated by immersion in a boiling water bath for 2 minutes. Aliquots of 85 μL of each assay were then dried on cellulose-DEAE paper discs and the non-phosphorylated 3H-thymidine was removed by washing with 4 mmol of ammonium formite. The remaining radioactivity bound to the discs is then measured by scintillation spectrophotometry. The degree of inhibition at each concentration of the test compound is expressed as a percentage of the control reaction (100%) after subtracting a measured blank value representing the amount of radioactivity bound to the disc of a reaction containing heat-deactivated enzymes. Then the IC5or value is calculated, namely the concentration of the test compound which inhibits the activity of the enzyme by 50%. In the previous test the l- [5- [2 (S) - (2,4-dichloro-5-methoxyphenoxy) -propion-amido] -2,5-dideoxy-2-fluoro-3-0-L-valil -β-D-arabino-furanosyl] -5-ethyluracil has an IC50 of 1.1 nmol against the thymidine kinase of HSV-2 and 18 nmol against the thymidine kinase of HSV-1. The compounds of the formula I and their pharmaceutically acceptable addition salts can be used as medicaments, for example, in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, for example, in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. The administration can, however, also be performed rectally, for example in the form of suppositories, or parenterally, for example, in the form of solutions for injections. The compounds of the formula I and their pharmaceutically acceptable acid addition salts can be processed with pharmaceutically inert, organic or inorganic carriers for the production of the pharmaceutical preparations. Lactose, corn starch or its derivatives, talc, stearic acid or its salts and the like can be used, for example, as carriers for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like.; depending on the nature of the active ingredient generally, however, carriers are not required in the case of soft gelatin capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like. The pharmaceutical preparations may also contain preservatives. solubilizers, stabilizers, humectants, emulsifiers, sweeteners, colorants, flavorings, salts to vary the osmotic pressure, regulators, masking agents and antioxidants. They may also contain other therapeutically valuable substances. Medicaments containing a compound of the formula I or its pharmaceutically acceptable acid addition salt and a therapeutically inert excipient are also an object of the present invention, as is a process for the production of these medicaments which comprises taking one or more compounds from Formula I or its pharmaceutically acceptable acid addition salts and, if desired, one or more other therapeutically valuable substances in a galenic administration form together with a pharmaceutically compatible carrier. As mentioned above, the compounds of the formula I and their pharmaceutically acceptable acid addition salts can be used according to the invention as therapeutically active substances, especially as antiviral agents. The dose can vary within wide limits and, of course, will be adapted to the requirements of the individual in each particular case. In general, in the case of administration in adults a daily dose of about lmg to 1000 mg, preferably around 5 mg to 500 mg, should be adequate. The daily dose can be administered as a single dose or in divided doses. Finally, the use of the compounds of the formula I and their pharmaceutically acceptable acid addition salts for the production of the medicaments, especially the antiviral drugs, is also an object of the invention. The following Examples are intended to illustrate the present invention in more detail, but are not intended to limit its scope in any way.

EXAMPLE 1 (A) 30.0 g (0.058 mol) of l- [5- [2 (S) - (2,4-dichloro-5-methoxyphenoxy) -propion-amido] -2,5-dideoxy-2-fluoro-β- D-arabino-furanosyl] -5-ethyluracil, 25.0 g (0.115 mol) of N-Boc-L-valine and 1 1 of anhydrous dimethylformamide were placed in a four-necked container of 3 1. The solution is stirred under nitrogen and it was cooled to 10 ° C in an ice bath. 7.04 g (0.058 mol) of 4-dimethyl-aminopyridine and 22.1 g (0.115 mol) of ethyldimethylaminopropyl carbodiimide hydrochloride were added and the mixture was allowed to warm to room temperature. After stirring for an additional 18 hours the solvent was removed by evaporation. The residue was dissolved in 1.3 1 dichloromethane and the solution was washed three times with 400 ml of a saturated sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate and evaporated. The crude product was dried at room temperature under vacuum to give 65.46 g of a light brown foam. This was dissolved with heating in a mixture of 10 ml of ethyl acetate and 10 ml of hexane and the solution was subjected to flash chromatography on silica gel while eluting with ethyl acetate / hexane (1: 1) and collected 250 ml fractions. The fractions containing the product were combined and evaporated to give a white foam which, after crystallization of a mixture of ethyl acetate and 60-80% petroleum ether, gave 40.22 g (96.7%) of l- [3- 0- [N (tert-butoxycarbonyl) -L-valyl] -5- [2 (S) - (2,4-dichloro-5-methoxyphenoxy) -propion-amido] -2,5-dideoxy-2-fluoro- β-D-arabino-furanosyl] -5-ethyluracil as a white crystalline solid, mp 117-122 ° C. (B) 40.22 g (0.056 mol) of l- [3-0- [N- (tert-butoxycarbonyl) -L-valyl] -5- [2 (S) - (2,4-dichloro-5-methoxyphenoxy) -propion-amido] -2,5-dideoxy-2-fluoro-β-D-arabino-furanosyl] -5-ethyluracil were dissolved in 400 ml of dry ethyl acetate. The solution was cooled to 0 ° C and the cold saturated solution of hydrogen chloride in 800 ml of ethyl acetate was added. The solution was allowed to warm to room temperature and was stirred for 4 hours and then evaporated. The residue was dried at room temperature in vacuo to give 37.0 g of a whitish foam. This was dissolved in 120 ml of distilled water and the solution was dried by freezing. The residue was dried at 60 ° C in a vacuum to give 35.471 g (96.8%) of l- [5- [2 (S) - (2,4-dichloro-5-methoxyphenoxy) -propion-amido] hydrochloride] 2, 5-dideoxy-2-fluoro-3-OL-valyl-β-D-arabino-furanosyl] -5-ethyluracil as a white solid. A sample was crystallized from hot isopropanol and gave a white crystalline solid, m.p. 132-157 ° C (decomp.).

The l- [5- [2 (S) - (2,4-dichloro-5-methoxyphenyl) -propion-amido] -2,5-dideoxy-2-fluoro-β-D-arabino-furanosyl] -5- Ethyluracil used as a starting material was prepared as follows: (i) A mixture of 29.6 g (0.125 mol) of methyl (R) -2-trifluoro-methanesulfonyloxypropionate, 24.16 g (0.125 mol) of 2,4-dichloro-5-methoxyphenol and 17.52 g (0.127 mol) of potassium carbonate in 400 ml of acetonitrile is stirred under nitrogen and heated at 70 ° C for 1 hour. The mixture was allowed to cool to room temperature and filtered. The filtrate was evaporated and the residue was partitioned between 400 ml of ethyl acetate and 400 ml of water. The separated organic phase was dried over anhydrous magnesium sulfate and evaporated to give 34.4 g (98.4%) of methyl (S) -2- (2,4-dichloro-5-methoxyphenoxy) -propionate as a light yellow oil. it crystallized, during rest. (ii) 125 ml (0.125 mol) of sodium hydroxide solution ÍM were added to a solution of 34.9 g (0.125 mol) of ethyl (S) -2- (2,4-dichloro-5-methoxyphenoxy) propionate in 200 ml of ethanol. The solution is stirred at room temperature for 40 minutes and then adjusted to pH 1 with 2M hydrochloric acid. The majority of the solvent was evaporated and the residue was partitioned between 400 ml of ethyl acetate and 400 ml of water. The separated organic phase was dried over anhydrous magnesium sulfate and evaporated to give 32.4 g (97.7%) of (S) -2- (2, 4-dichloro-5-methoxyphenoxy) propionic as a white solid, m.p. 114-115 ° C. (iii) 24.2 g (0.091 mol) of (S) -2- (2,4-dichloro-5-methoxy-phenoxy) propionic acid were suspended in a mixture of 150 ml of toluene and 0.5 ml of dimethylformamide and the suspension was suspended. it stirred under nitrogen. 15.0 ml (0.17 mol) of oxalyl chloride were added, producing a vigorous evolution of the gas. The mixture is stirred for 1 hour to give a homogeneous solution. The solvents were removed by evaporation, the residue was taken up in 100 ml of diethyl ether and the solution was added to a solution of 24.6 g (0.090 mol) of 1- (5-amino-2,5-dideoxy-2-fluoro- β-D-arabino-furanosyl) -5-ethyluracil in 290 ml of a 0.31M sodium hydroxide solution. The heterogeneous mixture was stirred vigorously for 10 minutes to give a white precipitate which was filtered and washed first with water and then with diethyl ether. The crude product was crystallized from hot methanol to give 33.1 g (69.7%) of l- [5- [2 (S) - (2,4-dichloro-5-methoxyphenoxy) -propion-amido] -2.5 -dideoxy-2-fluoro-β-D-arabino-furanosyl] -5-ethyluracil as a white crystalline solid, mp 195-196 ° C.

EXAMPLE 2 (A) Linking l- [5- [2 (S) - (2,4-dichloro-5-methoxyphenoxy) -propion-amido] -2,5-dideoxy-2-fluoro-β-D-arabino -furanosyl] -5-ethyluracil with N-Boc-D-valine in a manner analogous to that described in Example 1 (A) gives the l- [3-0- [N (tert-butoxycarbonyl) -D-valil ] -5- [2 (S) - (2,4-dichloro-5-methoxyphenoxy) -propion-amido] -2,5-dideoxy-2-fluoro-β-D-arabino-furanosyl] -5-ethyluracil as a white solid, mp 101 ° C (decomp.). (B) The removal of the protecting group of l- [3-0- [N- (tert-butoxycarbonyl) -D-valyl] -5- [2 (S) - (2,4-dichloro-5-methoxyphenoxy) - propion-amido] -2,5-dideoxy-2-fluoro-β-D-arabino-furanosyl] -5-ethyluracil in a manner analogous to that described in Example 1 (B) gives the hydrochloride of l- [5- [ 2 (S) - (2,4-dichloro-5-methoxyphenoxy) -propion-amido] -2,5-dideoxy-2-fluoro-3-0-D-valyl-β-D-arabino-furanosyl] -5 -ethyluracil as a white solid pf 140 ° C (decomp.).

EXAMPLE 3 (A) Linking l- [5- [2 (S) - (2,4,6-trichloro-3-methoxyphenoxy) -propion-amido] -2,5-dideoxy-2-fluoro-β-D-arabino -furanosyl] -5-ethyluracil with N-Boc-L-valine in a manner analogous to that described in Example 1 (A) gives 1- [3-0- [N (tert-butoxycarbonyl) -L-valyl] - 5- [2 (S) - (2,4,6-trichloro-3-methoxyphenoxy) -propion-amido] -2,5-dideoxy-2-fluoro-β-D-arabino-furanosyl] -5-ethyluracil as a white solid, mp 147-149 ° C. (B) The removal of the protecting group of l- [3-0- [N- (tert-butoxycarbonyl) -L-valyl] -5- [2 (S) - (2,4,6-trichloro-3-methoxyphenoxy) ) -propion-amido] -2,5-dideoxy-2-fluoro-β-D-arabino-furanosyl] -5-ethyluracil in a manner analogous to that described in Example 1 (B) gives the hydrochloride of l- [5] - [2 (S) - (2,4,6-trichloro-3-methoxyphenoxy) -propion-amido] -2,5-dideoxy-2-fluoro-3-0-L-valyl-β-D-arabino- furanosyl] -5-ethyluracil as a white solid, mp 150-160 ° C. L- [5- [2 (S) - (2,4,6-trichloro-5-methoxyphenoxy) -propion-amido] -2,5-dideoxy-2-fluoro-β-D-arabino-furanosyl] - 5-Ethyluracil used as the starting material was prepared in the following manner: Analogously to that described in Example l (i) - (iii), by reacting the methyl (R) -2-trifluoromethanesulfonyloxypropionate with 2. , 4,6-trichloro-3-methoxyphenol, hydrolyzing the resulting methyl (S) -2- (2,4,6-trichloro-3-methoxyphenoxy) -propionate, converting (S) -2- (2, 4, 6-trichloro-3-methoxyphenoxy) propionic obtained in the acid chloride and linking the latter with 1- (5-amino-2,5-dideoxy-2-fluoro-β-D-arabino-furanosyl) -5-ethyluracil l- [5- [2 (S) - (2,4,6-trichloro-3-methoxyphenoxy) -propion-amido] -2,5-dideoxy-2-fluoro-β-D-arabino-furanosyl was obtained ] -5-ethyluracil as a white solid, mp 210-211 ° C.

EXAMPLE 4 (A) Linking l- [5- [2 (S) - (2,4-dibromo-3-methoxyphenoxy) -propion-amido] -2,5-dideoxy-2-fluoro-β-D-arabino-furanosyl ] -5-ethyluracil with N-Boc-L-valine in a manner analogous to that described in Example 1 (A) gives 1- [5- [2 (S) - (2,4-dibromo-5-methoxyphenoxy) -propion-amido] -3-0- [N-tert-butoxycarbonyl) -L-valyl] -2,5-dideoxy-2-fluoro-β-D-arabino-furanosyl] -5-ethyluracil as a white solid, pf 101-111 ° C. (B) The removal of the protecting group of l- [5- [2 (S) - (2,4-dibromo-5-methoxyphenoxy) -propion-amido] -3-0- [N- (tert-butoxycarbonyl) - L-valyl] -2,5-dideoxy-2-fluoro-β-D-arabino-furanosyl] -5-ethyluracil in a manner analogous to that described in Example 1 (B) gives the hydrochloride of l- [5- [ 2 (S) - (2,4-dibromo-5-methoxyphenoxy) -propion-amido] -2,5-dideoxy-2-fluoro-3-0-L-β-D-arabino-furanosyl] -5-ethyluracil as a white solid, mp 148 ° C. L- [5- [2 (S) - (2,4-dibromo-5-methoxyphenoxy) -propion-amido] -2,5-dideoxy-2-fluoro-β-D-arabino-furanosyl] -5- Ethyluracil used as a starting material was prepared in the following manner: Analogously to that described in Example 1 (i) - (iii), reacting methyl (R) -2-trifluoromethanesulfonyloxypropionate with 2,4 -dibromo-5-methoxyphenol, hydrolyzing the resulting methyl (S) -2- (2,4-dibromo-5-methoxyphenoxy) propionate, converting the acid (S) -2- (2,4-dibromo-5-methoxyphenoxy) ) propionic obtained in the acid chloride and linking the latter with 1- (5-amino-2, 5-dideoxy-2-fluoro-β-D-arabino-furanosyl) -5-ethyluracil was obtained l- [5- [ 2 (S) - (2,4-dibromo-5-methoxyphenoxy) -propion-amido] -2,5-dideoxy-2-fluoro-β-D-arabino-furanosyl] -5-ethyluracil as a white solid, mp 223-224 ° C.

EXAMPLE 5 (A) Linking l- [5- [2 (R) - (2,4-dichloro-5-methoxyphenoxy) -propion-amido] -2,5-dideoxy-2-fluoro-β-D-arabino-furanosyl ] -5-ethyluracil with N-Boc-L-valine in a manner analogous to that described in Example 1 (A) gives 1- [3-0- [N (tert-butoxycarbonyl) -L-valyl] -5- [2 (R) - (2,4-dichloro-5-methoxyphenoxy) -propion-amido] -2,5-dideoxy-2-fluoro-β-D-arabino-furanosyl] -5-ethyluracil as a white solid, pf 110 ° C (decomp.). (B) The removal of the protecting group of l- [3-0- [N- (tert-butoxycarbonyl) -L-valyl] -5- [2 (R) - (2,4-dichloro-5-methoxyphenoxy) - propionamido] -2,5-dideoxy-2-fluoro-β-D-arabino-furanosyl] -5-ethyluracil in a manner analogous to that described in Example 1 (B) gives the hydrochloride of l- [5- [2 ( R) - (2,4-dichloro-5-methoxyphenoxy) -propion-amido] -2,5-dideoxy-2-fluoro-3-0-L-valyl-β-D-arabino-furanosyl] -5-ethyluracil as a white solid, mp 153-160 ° C. The l- [5- [2 (R) - (2,4-dichloro-5-methoxyphenoxy) -propion-amido] -2,5-dideoxy-2-fluoro-β-D-arabino-furanosyl] -5- Ethyluracil used as starting material was prepared in the following manner: Analogously to that described in Example l (i) - (iii), reacting methyl (S) -2-trifluoromethanesulfonyloxypropionate with 2,4- dichloro-5-methoxyphenol, hydrolyzing the resulting methyl (R) -2- (2,4-dichloro-5-methoxyphenoxy) -propionate, converting the acid (R) -2- (2,4-dichloro-5-methoxyphenoxy) ) propionic obtained in the acid chloride and the latter bound with 1- (5-amino-2, 5-dideoxy-2-fluoro-β-D-arabino-furanosyl) -5-ethyluracil was obtained l- [5- [ 2 (R) - (2,4-dichloro-5-methoxyphenoxy) -propion-amido] -2,5-dideoxy-2-fluoro-β-D-arabino-furanosyl] -5-ethyluracil as a faded white solid, pf 151-156 ° C. The following example illustrates a pharmaceutical preparation containing a compound of formula I.

EXAMPLE A Tablets containing the following ingredients can be produced in conventional manner.

Ingredient per tablet Compound of 100 mg formula I Lactose 70 mg Corn starch 70 mg Polyvinylpyrroli. Done 5 mg Magnesium stearate 5 mg Tablet weight 250 mg It is noted that in relation to this date the best method known by the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, the content of the following is claimed as property

Claims (17)

1. The compounds of the general formula characterized in that R1 represents aryl, R2 represents a lower alkyl, R3 represents an acyl group derived from an amino acid, R4 represents hydrogen or fluorine and the asterisk denotes that the configuration at the carbon atom indicated by it is (S) or (R ), and their pharmaceutically acceptable acid addition salts.

2. The compounds according to Claim 1, characterized in that the configuration at the carbon atom indicated by the asterisk is (S).

3. The compounds according to Claim 1 or Claim 2, characterized in that R1 represents substituted phenyl.

4. The compounds according to Claim 3, characterized in that the substituted phenyl group is 2,4-dichloro-5-methoxyphenyl.

5. The compounds according to any of Claims 1-4, characterized in that R 2 represents methyl.

6. The compounds according to any of Claims 1-5, characterized in that R3 represents an acyl group derived from a natural a-amino acid.

7. The compounds according to Claim 6, characterized in that R3 represents L-valyl.

8. The compounds according to any of Claims 1-7, characterized in that R 4 represents fluorine.

9. The l- [5- [2 (S) - (2,4-dichloro-5-methoxyphenoxy) -propion-amido] -2,5-dideoxy-2-fluoro-3-OL-valil-β-D-arabino -furanosyl] -5-ethyluracil.

10. The l- [5- [2 (R) - (2,4-dichloro-5-methoxyphenoxy) -propion-amido] -2,5-dideoxy-2-fluoro-3-OL-valil-β-D-arabino -furanosyl] -5-ethyluracil.

11. The compounds according to any of Claims 1-10, characterized in that they are used as therapeutically active substances.

12. The compounds according to any of Claims 1-10, characterized in that they are used as antiviral agents.

13. A process for the manufacture of the claimed compounds in any of Claims 1 to 10, the process is characterized in that it comprises reacting a compound of the general formula where R ^ R ^ R4 and the asterisk have the meaning given in Claim 1, with an N-protected amino acid and subsequently separating the N-protecting group and, if desired, converting the compound of the formula I obtained into a salt of pharmaceutically acceptable acid addition.

14. A medicament, characterized in that it contains a compound according to any of Claims 1-10 and a compatible pharmaceutical carrier.

15. An antiviral drug, characterized in that it contains a compound according to any of Claims 1-10 and a compatible pharmaceutical carrier.

16. The use of a compound according to any of Claims 1-10, for the production of antiviral drugs.

17. The invention, characterized in that it is as defined here above.