CA1292987C - Pyrimidine derivatives - Google Patents

Abstract

Abstract Compounds of the formula I

wherein R1 is halogen, C1-4-alkyl or halo-(C1-4--alkyl), R2 is hydrogen, hydroxy or acyloxy, R3 and R4 each are hydrogen or C1-4-alkyl, R5 is aryl or aryloxy, X is 0 or NH and Y is -CO-CH2-, -CH(OH)-CH2, -CH2-CH2-, -S-, -SO- or -SO2-and tautomers thereof, possess antiviral activity and can be used in the form of medicaments for the control and preven-tion of viral infections. They can be manufactured according to methods known per se.

Description

- 12~Z987 The present invention is concerned with pyrimidine aerivatives, a process for their manufacture and medicaments containing said derivatives.

These pyrimidine derivatives have the general formula X
.J~, ¦

-wherein R is halogen, Cl 4-alkyl or halo-(Cl ~--alkyl), R i8 hydrogen, hydroxy or acyloxy, R and R4 each are hydrogen or Cl 4-alkyl, R5 is aryl or aryloxy, X is 0 or NH and Y is -CO-CH2-, -CH(OH)-CH2~, -CH2-CH2-, -S-, -SO- or -S02-, and tautomers thereof.

As used therein, "Cl 4-alkylll means a straight- or branched-chain alkyl group, such as methyl, ethyl, propyl, isopropyl, butyl or t-butyl etc. "Halo-(Cl 4-alkyl)" means an alkyl group as defined earlier carrying one or more halogen atoms; e.g. trifluoromethyl or 2-chloroethyl. The acyloxy group can be derived from an aliphatic, cycloali-phatic, araliphatic or aromatic carboxylic acid, examples of such acids being formic acid, acetic acid, propionic acid, butyric acid, cyclopentylpropionic acid, phenylacetic acid Mé/18.6.87 lZ9Z~?87 and benzoic acid. Preferred acyloxy groups are Cl 4--alkanoyloxy group. ~Aryl" means unsubstituted phenyl group or a phenyl carrying one or more substituents selected from halogen, hydroxy, Cl 4-alkyl, Cl 4-alkoxy, trifluoro-methyl, nitro and phenyl. Examples of such substituted--phenyl groups are 2-chlorophenyl, 2,4- or 2,6-dichloro-phenyl, 2-methylphenyl and 2,6-dimethylphenyl. "Aryloxy"
means an aryl group as defined above which is bonded via an oxygen atom. Examples of aryloxy groups are phenoxy, 2-chlorophenoxy and 2,4-dichlorophenoxy. "Halogen" means fluorine, chlorine, bromine or iodine.

The compounds of formula I and their tautomers in which Y represents -CH(OH)-CHz- or in which R and R have different meanings,-i.e. when R3 represents a hydrogen atom and R represents a Cl 4-alkyl group or when R
and R represent different Cl 4-alkyl groups, contain an agymmetric carbon atom and can accordingly exist as diastereoisomers. The pre8ent invention embraces within its 8cope not only the individual diastereoisomers, but also mixtures thereof.

In formula I above R preferably is Cl 4-alkyl especially ethyl. R preferably is hydroxy or Cl 4--alkanoyloxy, especially hydroxy or acetoxy. R3 and R4 each preferably are hydrogen. R5 preferably is dihalo-phenyl, especially 2,6-dichlorophenyl. X preferably is 0. Y
preferably is -CO-CH2-. -CH(OH)-CH2-, -CH2-CH2- or -S02-, especially -CO-CH2- or -CH(OH)-CH2-.
Especially preferred compounds of the invention are those in which R is ethyl, R is hydroxy or acetoxy, R3 and R4 each are hydrogen, R5 is 2,6-dichlorophenyl, X is 0 and Y is -CO-CH2- or -CH(OH)-CH2-.
Particularly preferred compounds are:

lZ9Z987 3'-O-Acetyl-5'-[3-(2,6-dichlorophenyl)-2-oxopropyl]--2~,5~-dideoxy-5-ethyluridine, 5'-[3-(2,6-dichlorophenyl)-2-oxopropyl]-2~,5~-dideoxy-5-ethyluridine and 55'-~3-(2,6-dichlorophenyl)-2(RS)-hydroxypropyl]-21,5l--dideoxy-5-ethyluridine.

Other preferred compounds provided by the present invention are:
3'-O-Acetyl-2',5'-dideoxy-5-ethyl-5'-[3-(2,6-dimethyl-phenyl)-2-oxopropyl]uridine, 3'-O-acetyl-2',5'-dideoxy-5-ethyl-5'-[3-(2-methyl-phenyl)-2-oxopropyl]uridine, 153'-O-acetyl-5'-[3-(2-chlorophenyl)-2-oxopropyl]-2',5'--dideoxy-5-ethyluridine, 3'-O-acetyl-Z',5'-dideoxy-5-ethyl-5'-(2-oxo-3-phenyl-propyl)uridine, 3'-O-acetyl-2',5'-dideoxy-5-ethyl-5'-t2-oxo-3(R5)--phenylbutyl]uridine~
2',5'-dideoxy-5-ethyl-5'-(2-oxo-3-phenylpropyl)uridine, 2',5'-dideoxy-5-ethyl-5'-[3-(2-methylphenyl)-2-oxo-propyl]uridine, 2l,5l-dideoxy-5-ethyl-5l-[3-(2,6-dimethylphenyl)-2-oxo-propyl]uridine~
5'-[3-(2-chlorophenyl)-2-oxopropyl]-2',5'-dideoxy-5--ethyluridine, 2',5'-dideoxy-5-ethyl-5'-t2-oxo-3(RS)-phenylbutyl]-uridine, 302',5'-dideoxy-5 ethyl-5'-t2(RS)-hydroxy-3-phenylpropyl]-uridine,.
2',5'-dideoxy-5-ethyl-5'-t2(RS)-hydroxy-3-(2-methyl-phenyl)propyl]uridine, 5'-[3-(2~chlorophenyl)-2(RS)-hydroxypropyl]-2',5'--dideoxy-5-ethyluridine, 2',5'-dideoxy-5-ethyl-5'-t2(RS)-hydroxy-3-(Z,6-dimethyl-phenyl)propyl]uridine, ~Z9Z987 2',5'-dideoxy-5-ethyl-5'-(3-phenylpropyl)uridine and 5'-benzylsulphonyl-2',5l-dideoxy-5-ethyluridine.

Other interestinq compound~ are:

2',5l-Dideoxy-5'-t3-(2,6-dimethylphenyl)-2-oxopropyl]-uridine, 3'-0-acetyl-5'-t3(RS)-(2,4-dichlorophenoxy)-2-oxobutyl]-2',5'-dideoxy-5-ethyluridine, 5~-t3(RS)-(2,4-dichlorophenoxy)-2-oxobutyl]-2',5'--dideoxy-5-ethyluridine, 5~-[3(RS)-(2,4-dichlorophenoxy)-2(RS)-hydroxybutyl]--2',5'-dideoxy-5-ethyluridine, 5l-benzylthio-2l,5'-dedeoxy-5-ethyluridine, 5'-(2-chlorobenzylthio)-2',5'-dideoxy-5-ethyluridine, 5'-(2,4-dichlorobenzylthio)-2',~'-dideoxy-5-ethyluri-dine, 5'-(2,6-dichlorobenzylthio)-2',5'-dideoxy-5-ethyluri-dine, 5'-(2-chlorobenzyl~ulphonyl)-2l,5~-dideoxy-5-ethyluri-dine, 5'-(2,4-dichlorobenzylsulphonyl)-2',5'-dideoxy-5-ethyl-uridine and 5'-(2,6-dichlorobenzylsulphonyl)-2',5'-dideoxy-5-ethyl-uridine According to the process provided by the present invention, the compounds of formula I above and their tauto-mers are manufactured by (a) for the manufacture of a compound of formula I or a tautomer thereof in which R i~ hydrogen or acyloxy and Y
is -CO-CH2-, catalytically hydrogenating a compound of the formula 12~Z98~

X

-J~, HN

R4 0 o N
5 1 ll (E) R - C- C- CH= CH ~ II
~Y

wherein Rl R3 R4 R5 d X h h significance and R2 is hydrogen or acyloxy, or a tautomer thereof, or (b) for the manufacture of a compound of formula I or a tautomer thereof in which R is hydrogen or acyloxy and Y
i8 -CH(OH)-CH2-, reducing a compound of formula I or a tautomer thereof in which R2 is hydrogen or acyloxy and Y
is -CO~CH2-, with a complex metal hydride, or (c) for the manufacture of a compound of formula I or a tautomer thereof in which R2 is hydrogen or acyloxy and Y
is -CH2-CH2-, replacing the hydroxy group in a compound of formula I or a tautomer thereof in which R2 i8 hydrogen or acyloxy and Y is -CH(OH)-CH2- by hydrogen, or td) for the manufacture of a compound of formula I or a tautomer thereof in which Y is -S-, reacting a compound of the formula ~Z9Z987 X

J~
HN

O~N ~
R 52 ~ Ill l 2 wherein R , R and X have the above 8 ignificance and R is Cl 4-alkyl or aryl, or a tautomer thereof with an alkali metal derivative of a compound of the general formula HSC(R3~R ,R ) IV

wherein R , R and R have the above significance, at an elevated temperature, or (e) for the manufacture of a compound of formula I or a tautomer thereof in which Y is -SO- or -SO2-, oxidizing a compound of formula I or a tautomer thereof in which Y is -S-, or (f) for the manufacture of a com~ound of formula I or a tautomer thereof in which R i6 hydroxy, deacylating a compound of formula I or a tautomer thereof in which R2 is acyloxy.

The catalytic hydrogenation in accordance with embodi-ment (a) of the proceæs can be carried out in a manner known per se, e.g. in an inert organic golvent, such as an alkanol, e.g. methanol or ethanol, using a noble-metal cata-lyst, such as a palladium or platinum catalyst, which may be supported on an inert carrier material. Palladium-on-carbon (Pd/C) is the preferred catalyst. Conveniently, the cataly-~Z~Z987 tic hydrogenation is carried out at about room temperatureand under atmospheric pressure.

The reduction in accordance with embodiment (b) of the proces~ can be carried out in a manner known per se, e.g. by treatment with sodium borohydride or potassium borohydride or, when R is hydrogen, also with lithium borohydride or an alkali metal aluminium hydride, such as lithium aluminium hydride. This treatment is conveniently carried out in an inert organic solvent and at room temperature to the reflux temperature of the mixture, preferably at about room tempe-rature. When the reduction is carried out using an alkali metal borohydride, suitable solvents are alkanols, e.g.
methanol or ethanol, aliphalic ethers, e.g. diethyl ether or dimethoxyethane, and cyclic ethers, e.g. tetrahydrofuran and dioxan. Suitable solvent6 which can be used when the reduc-tion i8 carried out using an alkali metal aluminium hydride are aliphatic and cyclic ethers such as those mentioned earlier.
The replacement of hydroxy by hydrogen in accordance with embodiment (c) of the process can also be carried out in a manner known per se. For example, the compound of formula I or a tautomer thereof can firstly be converted into the corresponding sulphonic acid ester, such as the mesylate, by treatment with a sulphonic acid halide, such as methanesulphonyl chloride, conveniently in the presence of an acid binding agent, especially a tertiary amine, such as pyridine, and at a low temperature, e.g. about 0C. The obtained sulphonic acid ester can then be converted into the corresponding iodide, e.g. by treatment with an alkali metal iodide, such as sodium iodide, in acetone at an elevated temperature, preferably at the reflux temperature of the mixture. The resulting iodide can then be converted into the desired compound of formula I or a tautomer thereof in which Y represents -CH2-CH2- by catalytic hydrogenation in a lZ~Z~87 known manner, e.g. using a palladium on barium sulphate catalyst.

In the reaction of a compound of formula III or a tauto-mer thereof with an alkali metal derivative, preferably the~odium derivative, of a compound of formula IV in accordance with embodiment (d) of the process the R -S03- group is displaced by the -SC(R3,R4,R5) group. The reaction is conveniently carried out in the presence of an inert organic solvent such, as dimethylformamide, and at about 100C. The alkali metal derivative is expediently formed in situ from the compound of formula IV and an alkali metal hydride, such as sodium hydride.

15 The oxidation in accordance with embodiment (e) of the process can also be carried out in a manner known per se.
For example, a compound of formula III or a tautomer thereof is treated with an organic peracid, such a~ peracetic, perbenzoic, m-chloroperbenzoic or perphthalic acid, expe-diently in a suitable solvent, such as a halogenated hydro-carbon, e.g. chloroform, or an alkanoic acid, e.g. acetic acid and at a temperature between about 0C and room tempe-rature. When peracetic acid is used for the oxidation, this can conveniently be prepared in situ from glacial acetic acid and hydrogen peroxide. When 1 equivalent of an organic peracid is used there is obtained a compound of formula I or a tautomer thereof in which Y represents -S0-, whereas the use of 2 equivalents of organic peracid leads to a compound of formula I or a tautomer thereof in which Y represents 30 ~ SO2 ~ .

The deacylation in accordance with embodiment (f) of the process can be carried out in a manner known per se, e.g. by treatment with an alkali metal Cl 4-alkoxide, such as sodium methoxide, in a Cl 4-alkanol, such as methanol.
Conveniently, this treatment is carried out at about room tempe~ature, although it may be carried out at an elevated lZ92987 temperature if desired.

The compounds of formula II and tautomers thereof which are used as starting materials in embodiment (a) of the present process are novel and also form an object of the present invention. They can be prepared, for example, by firstly reacting a compound of the general formula ClCHzCOC(R3,R ,R ) V

wherein R , R and R have the above significance, with a triarylphosphine, preferably triphenylphosphine, conveniently in an inert organic solvent, such as a halo-genated hydrocarbon, e.g. chloroform, and at an elevated temperature, suitably at the reflux temperature of the reaction mixture, to give a phosphonium chloride of the general formula Cl ~(R )3PCH2COC(R ,R ,R )~ VI

wherein R , R and R have the above significance, and R6 is aryl.

The phosphonium chloride of formula VI is then treated with a strong inorganic base, such as an alkali metal hydride, e.g. sodium hydride, or an alkali metal hydroxide, e.g. sodium hydroxide, and the resulting phosphorane of the general formula (R )3P-CHCOC(R ,R ,R ) VII

wherein R3, R4, R5 and R6 have the above 8igni-ficance, is finally reacted with a compound of the general formula 12~Z~87 x ,1~, ~ 11 O N ~

R2 ' wherein R , R and X have the above significance, or a tautomer thereof under the conditions of a Wittig reaction to give a compound of formula II.

The compounds of formula V, which are required for the preparation of the compounds of formula II and their tauto-mers, are known compounds or analogues of known compounds which can be prepared in a similar manner to the known compounds. The compound~ of formula III and their tautomers, which are used as starting materials in embodiment (d) of the present process are known compounds or analogues of known compounds which can be prepared in a similar manner to the known compounds.

The compounds of formula I and their tautomers possess antiviral activity and can be u~ed in the control or preven-tion of viral infections, for example of herpes simplex viral infections. The in vitro activity of these compounds in inhibiting herpes simplex virus type 2 (HSV-2) thymidine kinase can be demonstrated by means of the following test procedure:

The assay mixture contains 50 mM Tris-HCl, pH 8, 5 mM
magnesium chloride, 5 mM ATP, 0.3 ~M 3H-thymidine (50 Ci/mmol), suitably diluted thymidine kinase extract and various concentrations of the test compounds in a total volume of lOO ~l. Assays are incubated at 37C for 30 l~Z987 minutes and the reaction i6 terminated by immersion in a boiling water bath for 2 minutes. ~5 ~1 aliquots from each assay are then dried on cellulose paper discs and the unphosphorylated H-thymidine i6 removed by washing in 4 mM ammonium formate. The radioactivity remaining bound to the di6cs i8 then measured by scintillation 6pectrophoto-metry. The degree of inhibition at each concentration of the test compound is expressed as a percentage of a control reaction. The IC50 value, namely the concentration of the test compound which inhibit6 enzyme activity by S0%, is then calculated. The results obtained with representative com-pound~ of formula I are compiled in the following Table:

Table Compound of Example No. IC50 (~M) ... . .
3 0.0024 0.016 7 0.17 g 0.6 14c 0.072 The compounds of formula I and their tautomers can be used as medicaments in the form of pharmaceutical prepara-tions which contain them in a6sociation with a compatiblepharmaceutical carrier material. This can be an organic or inorganic carrier 6uitable fo~ entera~, e.g. oral, or parenteral administration. Examples of such carriers are water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols and petroleum jelly. The pharmaceutical preparations can be made up in a solid form, e.g. as tablets, dragees, suppositories -- lZ~2987 or capsules, or in a liquid form, e.g. as solutions, sus-pensions or emulsions; they may be subjected to standard pharmaceutical operations, e.g. sterilization and/or may contain adjuvants, e.g. preserving, stabilizing, wetting or emulsifying agents, salts for varying the osmotic pressure or buffers. They may also contain other therapeutically valuable substance~.

The compound~ of formula I and their tautomers can be administered to adults in a daily dosage of from about 1 to 1000 mg, preferably about 5 to 500 mg. The daily dosage may be administered as a single dose or in divided doses. The above do6age range is given by way of example only and can be varied upwards or downwards depending on factors such as the particular compound being administered, the route of administration, the severity of the indication being treated and the condition of the patient.

~xamDle A solution of 3.30 g of (E)-3'-0-acetyl-5' -t3-(2,6--dichlorophenyl)-2-oxopropylidene]-2l,5l -dideoxy-5-ethyl-uridine in 1.50 1 of methanol was hydrogenated over 1.10 g of 10~ Pd/C catalyst at room temperature and under atmos-pheric pressure for 3 hours. The mixture was filtered andthe filtrate was evaporated. The residue was triturated with diethyl ether to give 2.45 g of 3'-0-acetyl-5~-[3-(Z,6--dichlorophenyl)-2 -oxopropyl]-2',5'-dideoxy-5-ethyluridine, mp 186.
The starting material was prepared as follows:

(A) 50 ml of oxalyl chloride and 0.5 ml of dimethylformamide were added to a stirred suspension of 5.12 g of (2,6-di-chlorophenyl)acetic acid ln 120 ml of toluene. The mixturewas stirred at room temperature for 2.5 hourc and then evaporated to dryness. The residue was suspended in 40 ml of l~Z987 diethyl ether and the suspension was added gradually to 250 ml of a 0.25M solution of diazomethane in diethyl ether.
The mixture was stirred at room temperature for 2 hours and then cooled to oC. Hydrogen chloride was then bubbled through the mixture for 10 minutes. 300 ml of water were added to the mixture and the phases were separated. The organic phase was washed with 200 ml of saturated sodium hydrogen carbonate solution and 300 ml of water, dried over anhydrous sodium sulphate and evaporated to give 6.04 g of 1-chloro-3-(2,6-dichlorophenyl)-2-propanone in form of a white solid. This solid was taken up in 21 ml of chloroform, 7.19 g of triphenylphosphine were added and the solution was stirred and heated under reflux for 6 hours. The mixture was cooled and poured into 200 ml of diethyl ether. The resul-ting precipitate was collected, washed with diethyl ether and dried to give 8.605 g of t3-(2.6-dichlorophenyl)-2-oxo-propyl]triphenylphosphonium chloride in the form of a white solid. Thi~ solid was taken up in 1,5 1 of warm water and the mixture wa~ filtered. The filtrate was stirred while 12.5 ml of 5% sodium hydroxide solution were added. The mixture was extracted twice with 600 ml of diethyl ether each time and the combined extracts were washed with 1 1 of water, dried over anhydrous sodium sulphate and evaporated.
The residue was recrystallized from 150 ml of diethyl ether and yielded 4.286 g of t3-(2,6-dichlorophenyl)-2 -oxopropy-lidene]triphenylphorphorane of melting point 98-100C.

(B) A solution of 2.759 g of 3'-O-acetyl-2'-deoxy-5-ethyl-uridine, 5.75 g of dicyclohexylcarbodiimide and 0.375 ml of dichloroacetic acid in 24 ml of dimethyl sulphoxide was s~irred at room temperature for 27 hours. 0.375 ml of pyridine and 4.286 g of [3-~2,6 -dichlorophenyl)-Z-oxo-propylidene]triphenylphosphorane were added and the mixture was stirred for a further 23 hours. The mixture was filtered and the filtrate was evaporated. The residue was dissolved in 100 ml of ethyl acetate and the solution was washed twice with 100 ml of water each time, dried over anhydrous sodium ~Z~Z987 sulphate and evaporated. The resulting gum was subjected to flash chromatography on a column of silica gel using ethyl acetate/hexane (2:13 for the elution. There were obtained 3.84 g of (E)-3'-O-acetyl-5'-[3-(2,6-dichlorophenyl)-2 -oxopropylidene~-2',5'-dideoxy-5-ethyluridine in form of a white solid of melting point 165C.
ExamDle 2 Analogously to Example 1, there were obtained:

a) from (E)-3'-O-acetyl-2',5'-dideoxy-5-ethyl-5~-[3-(2,6 -dimethylphenyl)-2-oxopropylidene]uridine, mp 126-130C, which was prepared in a manner analogous to that described in Example lA) and B) starting from (2,6-dimethylphenyl)-acetic acid:
3l-O-acetyl-2',5'-dideoxy-5 -ethyl-5'-t3-(2,6-dimethyl-phenyl)-2-oxopropyl~uridine, mp 150-150.5C

b) from (E)-3'-0-acetyl-2',5'-dideoxy-S-ethyl-5~-[3-(2--methylphenyl)-2-oxopropylidene]uridine, mp 124-126C, which was prepared from (2-methylphenyl)acetic acid:
3l-O-acetyl-2',5'-dideoxy-5-ethyl-5' -t3-(2-methyl-phenyl)-2-oxopropyl]uridine, mp 156.5C
c) from (E)-3'-O-acetyl-5' -[3-(2-chlorophenyl)-2-oxo-propylidene]-2~,5~-dideoxy-5-ethyluridine, mp 144-145C, which was prepared from (2-chlorophenyl)acetic acid:
3'-O-acetyl-5'-[3-(2-chlorophenyl)-2-oxopropyl]-2',5' -dideoxy-5-ethyluridine, mp 168.5C

d) from (E)-3'-O-acetyl-Z',5'-dideoxy-5-ethyl-5' -(2-oxo-3--phenylpropylidene)uridine, which was prepared from phenyl-acetic acid:
3l-O-acetyl-2',5'-dideoxy-5 -ethyl-5'-(2-oxo-3-phenyl-propyl)uridine, nmr (CDC13); ~1.10 (t,3), 1.85-2,03 (m,2), 2.10 (s,3), 2.10-2.18 (m,l), 2.30-2.40 (m,3), ~Z9Z987 2.57-2.75 (m,2), 3.72 (s,2), 3.93 (m,l), 4.97 (m,l), 6.27 (dd,l), 7.03 (s,l), 7.17-7.35 (m,5), 8.83 (s,l) e) from (2)-3'-0-acetyl-2',5l-dideoxy-5-ethyl-5l -(2-oxo-3--phenylbutylidene)uridine, which was prepared from 2-phenyl-propanoic acid:
3'-0-acetyl-2',5'-dideoxy-5-ethyl-5'-[2-oxo-3(RS) -phenylbutyl]uridine, nmr (CDC13): ~1.07-1.17 (dt,3), 1.35-1.42 (dd,3), 1.72-2.02 (m,2), 2.05-2.13 (m,l), 2.07(s,3), 2.30-2.43 (m,3), 2.50-2.60 (m,2), 3.72-3.82 (m,l), 3.89 (m,l), 4.94 (m,l), 6.20 (m,l), 7.01 (d,l), 7.19-7.35 (m,5), 8.52 (d,l).

ExamDle 3 A solution of 2 g of 3'-0-acetyl-51-[3-(2,6-dichloro-phenyl)-2-oxopropyl] -2',5'-dideoxy-5l-ethyluridine in 45 ml of O.lM methanolic sodium methoxide solution was stirred at room temperature for 1.5 hours, The solution was diluted with 500 ml of methanol, a polystyrene divinyl benzene cation exchange resin containing sulphonic acid groups (Hl form) was added, the mixture was stirred for 10 minutes and then filtered. The filtrate was evaporated and the residue was triturated with diethyl ether to give 1.72 g of 5'-[3-(2,6-dichlorophenyl)-2-oxopropyl]-2l,5~_dideoxy 5 -ethyluridine, mp 229-230C.
ExamPle 4 Analogously to Example 3, there were obtained:

a) from 3'-0-acetyl-2',5'-dideoxy-5 -ethyl-5l-(2-oxo-3--phenylpropyl)uridine:
2',5'-dideoxy-5-ethyl-5'-(2-oxo-3-phenylpropyl)uridine, mp 148-151C

125~Z987 b) from 3'-0-acetyl-2',5'-dideoxy-5 -ethyl-5'-[3-(2-methyl-phenyl)-2-oxopropyl]uridine:
2',5'-dideoxy-5-ethyl-5' -[3-(2-methylphenyl)-2-oxo-propyl]uridine, mp 165C

c) from 3'-0-acetyl-2',5'-dideoxy-5 -ethyl-5l-[3-(2,6-di-methylphenyl)-2-oxopropyl]uridine:
2~,5~-dideoxy-5-ethyl-5~ -[3-(2,6-dimethylphenyl)-2-oxo-propyl]uridine, mp 223-224C
d) from 3'-0-acetyl-5l-[3-(2-chlorophenyl)-2 -oxopropyl]--2',5'-dideoxy-5-ethyluridine:
5~-[3-(2-chlorophenyl)-2 -oxopropyl]-21,5~-dideoxy-5--ethyluridine, mp 180-181C
e) from 3l-0-acetyl-2l,5'-dideoxy-5 -ethyl-5'-[2-oxo-3(RS)--phenylbutyl]uridine:
2 ', 5 ' -dideoxy-5-ethyl-5' -~2-oxo-3 (RS)-phenylbutyl]-uridine, mp 145C.
ExamDle 5 A golution of 149 mg of 3'-0-acetyl-5'-[3-(2,6-dichloro-phenyl)-2 -oxopropyl]-2',5'-dideoxy-5-ethyluridine and 26 mg of sodium borohydride in 7 ml of dimethoxyethane was stirred at room temperature for 2.5 hours. The solvent was removed by evaporation and the residue was taken up in 22 ml of 5%
ammonium chloride solution and extracted twice with 20 ml of ethyl acetate each time. The extracts were washed with 20 ml of water, dried over anhydrous sodium sulphate and evapora-ted to give 3'-0-acetyl-5'-~3-(2,6 -dichlorophenyl)-2(RS)--hydroxypropyl]-2',5' -dideoxy-5-ethyluridine in the form of a colourless gum. This was dissolved in 3 ml of O.lM sodium methoxide solution and gtirred at room temperature for 1 hour. The solution was then diluted with 150 ml of methanol, stirred with a cros~-linked polystrene/divinyl benzene cation exchange resin containing sulphonic acid groups (H~

lZ~Z987 - 17 _ form) and then filtered. The filtrate was evaporated and the residue was crystallized from ethanol to give 45 mg of 5'-[3-(2,6-dichlorophenyl)-2(RS)-hydroxypropyl]-2',5' -dideoxy-5-ethyluridine, mp 185-186C.
ExamDle 6 Analogously to Example 5, there were obtained:

a) from 3'-O-acetyl-2',5'-dideoxy-5 -ethyl-5'-(3-phenyl-2--oxopropyl)uridine:
2l,5l-dideoxy-5-ethyl-5' -[2(RS)-hydroxy-3-phenyl-propyl]uridine, mp 142C

b~ from 3'-O-acetyl-2',5'-dideoxy-5 -ethyl-5l-[3-(2-methyl-phenyl)-2-oxopropyl]uridine:
2',5'-dideoxy-5~ethyl-5' -~2~RS)-hydroxy-3-(2-methyl-phenyl)- propyl~uridine, mp 161.5-163C

c) from 3'-O-acetyl-5'-t3-(2-chlorophenyl)-2 -oxopropyl]--2',5'-dideoxy-5-ethyluridine:
5'-t3-(2-chlorophenyl)-2(RS) -hydroxypropyl]-2',5'--dideoxy-5-ethyluridine, mp 215-217C

d) from 3'-O-acetyl-2',5'-dideoxy-5 -ethyl-5'-[3-(2,6--dimethylphenyl) 2-oxopropyl]uridine:
2',5'-dideoxy-5-ethyl-5' -[2(RS)-hydroxy-3-(2,6--dimethylphenyl)propyl]uridine, mp 174-178C.

Exam~le 7 A ~olution of 300 mg of 3'-0-acetyl-5' -[2(RS)-hydroxy--3-phenylpropyl]-2~,5' -dideoxy-5-ethyluridine and O.Z ml of methanesulphonyl chloride in 5 ml of pyridine wa~ left to stand at 0C overnight. The mixture was poured on to 40 ml of ice/water, stirred and extracted with 40 ml of ethyl acetate. The extract wa~ dried over anhydrou~ sodium sulphate and evaporated to yield 330 mg of 3~-~-acetyl--2',5'-dideoxy-5-ethyl-5' -t2(RS)-methanesulphonyloxy-3--phenylpropyl]uridine.

A mixture of 240 mg of the latter and 190 mg of sodium iodide in 5 ml of acetone was stirred and heated under reflux for 5.5 hours. The mixture was allowed to cool and was then filtered. The filtrate was evaporated. The residue was taken up in 50 ml of dichloromethane and washed with 10 50 ml of water, twice with 50 ml of 5% sodium thiosulphate solution each time and 50 ml of water, dried over anhydrous sodium sulphate and evaporated to yield 250 mg of 3'-0-acetyl-2',5'-dideoxy-5 -ethyl-5'-[2(RS)-iodo-3-phenyl-propyl~uridine.
A solution of 80 mg of the latter in 5 ml of ethanol was saturated with ammonia. 50 mg of palladium on barium sulphate catalyst were added and the mixture was hydrogena-ted at room temperature and under atmo~tpheric pres~ure for 3 days. The mixture was filtered and the filtrate was evaporated. The re~idue was extracted with several portions of ethyl acetate and the combined extracts were evaporated to give 70 mg of 3'-0-acetyl-2',5'-dideoxy-5 -ethyl-5~-(3--phenylpropyl)uridine.
A solution of 70 mg of the latter in 2 ml of O.lM sodium methoxide solution was stirred at room temperature for 1 hour. A polystrene divinyl benzene cation exchange resin containing sulphonic acid groups (H+ form) was added and ~ 30 the mixture was stirred and filtered. The filtrate was ; evaporated and the residue was triturated with diethyl ether to give 22 mg of 2',5'-dideoxy-5-ethyl-5'-(3-phenylpropyl)-uridine, mp 160-162C.

Example 8 A solution of 0.5 g of benzyl mercaptan in 10 ml of dry -- 19 -- . .

dimethylformamide was treated with 60 mg of a 80% dispersion of sodium hydride in mineral oil. After the effervescence had ceased a solution of 1.64 g of 2'-deoxy-5-ethyl-5'-0--(p-toluenesulphonyl)uridine in 20 ml of dry dimethyl-formamide was added. The mixture was stirred and heated at100C under a nitrogen gas atmosphere. The course of the reaction was followed by thin layer chromatography. After 4 hours the mixture was evaporated to give an oily residue.
This was purified by flash column chromatography on silica gel using methanol/dichloromethane (1:9) for the elution.
The fractions containing the product were combined and evaporated to yield an oil which solidified and was recrystallized from diethyl ether to give 1.46 g of 5'-benzylthio-2',5'-dideoxy-5-ethyluridine, mp 149-151C.
Exam~le 9 1 g of 5'-benzylthio-2',5'-dideoxy-5-ethyluridine was dissolved in 10 ml of glacial acetic acid and the solution was cooled to 0C, whereupon 0,9 ml of 30% hydrogen peroxide was added. The mixture was ~tirred at 0C for 1 hour and then at room temperature for 17 hours. The acetic acid was removed by evaporation and the resulting solid was crystal-lized from approximately 100 ml of methanol to give 0.43 g of 5'-benzylsulphonyl-2~,5l-dideoxy-5-ethyluridine of melting point 232-233C.

ExamD l e 10 In a manner analogous to that described in Example 1, from (E)-3'-0-acetyl-5'-[3(RS)-(2,4 -dichlorophenoxy)-2-oxo-butylidene]-2',5'-dideoxy-5 -ethyluridine, prepared in a manner analogous to that described in Example l(A) and (B) starting f~om 2(RS)-(2,4-dichlorophenoxy)propionic acid, there was obtained:
3l-0-acetyl-5'-[3(RS)-(2,4 -dichlorophenoxy)-2-oxo-lZ9Z987 butyl]-2~,5l-dideoxy-5-ethyluridine of melting point 122-142C.

ExamPle 11 In a manner analogous to that described in Example 3, from 3'-0-acetyl-5'-[3(RS)-(2,4 -dichlorophenoxy)-2-oxo-butyl]-2',5'-dideoxy-5-ethyluridine there was obtained 5'-[3(RS)-(2,4-dichlorophenoxy)-2 -oxobutyl]-2',5'-dideoxy--5-ethyluridine, mp 157-159C.

ExamDle 12 In a manner analogous to that described in Example 5, from 3'-0-acetyl-5'-[3(RS)-(2,4 -dichlorophenoxy)-2-oxo-butyl]-2',5'-dideoxy-5-ethyluridine there was obtained 5l-t3(RS)-~2,4-dichloroPhenoxy)-2(Rs) -hydroxybutyl]-21,5'--dideoxy-5-ethyluridine of mslting point 108-111C.

Example 13 In a manner analogou6 to that described in Example 7, from 3',0-acetyl-2',5'-dideoxy-5-ethyl-5'-f2~RS)-hydroxy-3--(2,6-dimethylphenyl)propyl]uridine there was obtained 2',5'-dideoxy-5-ethyl-5'-t3-(2,6 -dimethylphenyl)propyl]-uridine of melting point 213.5-214C.

ExamDle 14 Analogously to Example 8, there were obtained:

a) from 2'-deoxy-5-ethyl-5'-0-(p-toluenesulphonyl)uridine and 2-chlorobenzyl mercaptan:
5'-(2-chlorobenzylthio)-2',5'-dideoxy-5-ethyluridine, mp lZ~987 b) from 2'-deoxy-5-ethyl-5'-0-(p-toluenesulphonyl)uridine and 2,4-dichlorobenzyl mercaptan:
5'-(2,4-dichlorobenzylthio)-2',5'-dideoxy-5-ethyluridine, mp 169-170C

c) from 2'-deoxy-5-ethyl-5'-0-(p-toluenesulphonyl)uridine and 2,6-dichlorobenzyl mercaptan:
5'-(2,6-dichlorobenzylthio)-2',5'-dideoxy-5-ethyluridine, mp 206-207C.
Exam~le 15 Analogously to Example 9, there were obtained:

a) from 5l-(2-chlorobenzylthio)-2l,5l-dideoxy-5-ethyl-uridine:
5'-(2-chlorobenzyl~ulphonyl)-2',5'-dideoxy-5-ethyluridine, mp 189-lgOC

b) from 5l-(2~4-dichlorobenzylthio)-2l~5l-dideoxy-5-eth uridine:
5'-(2,4-dichlorobenzylsulphonyl)-2',5'-dideoxy-5 -ethyluridine, mp 217-218C

c) from 5'-(Z,6-dichlorobenzylthio)-2',5'-dideoxy-5-ethyl-uridine:
5'-(2,6-dichlorobenzyl~ulphonyl)-2',5'-dideoxy-5 ethyluridine, mp 236-237C.

The following Example illustrates a pharmaceutical preparation containing the compounds of formula I:

lZ9Z987 Tablets may contain the following ingredients:

Inaredient Per tablet 5 Compound of formula I lO0 mg Lactose 70 mg Maize starch 70 mg Polyvinylpyrrolidone 5-mg Magnesium stearate 5 mn Tablet weight250 mg

Claims (15)

1. Compounds of the general formula I

wherein R1 is halogen, C1-4-alkyl or halo-(C1-4--alkyl), R2 is hydrogen, hydroxy or acyloxy, R3 and R4 each are hydrogen or C1-4-alkyl, R5 is aryl or aryloxy, X is O or NH and Y is -CO-CH2-, -CH(OH)-CH2-, -CH2-CH2-, -SO- or -SO2-, and tautomers thereof.

2. Compounds according to claim 1 wherein R5 is aryl,

3. Compounds according to claim 1 wherein R1 is C1-4-alkyl.

4. Compounds according to claim 1 wherein R2 is hydroxy or C1-4-alkanoyloxy.

5. Compounds according to claim 1 wherein R3 and R4 each are hydrogen.

6. Compounds according to claim 1 wherein R5 is dihalophenyl.

7. Compounds according to claim 1 wherein X is O.

8. Compounds according to claim 1 wherein Y is -CO-CH2-, -CH(OH)-CH2-, -CH2-CH2- or -SO2-.

9. Compounds according claim 1 wherein R1 is ethyl, R2 is hydroxy or acetoxy, R3 and R4 each are hydrogen, R5 is 2,6-dichlorophenyl, X is O
and Y is -CO-CH2- or -CH(OH)-CH2.

10. A compound according to claim 1 selected from:
3'-O-Acetyl-5'[3-(2,6-dichlorophenyl)-2-oxopropyl]--2',5'-dideoxy-5-ethyluridine, 5'-[3-(2,6-Dichlorophenyl)-2(RS)-hydroxypropyl]-2',5'--dideoxy-5-ethyluridine and particularly 5'-[3-(2,6-Dichlorophenyl)-2-oxopropyl]-2',5'-dideoxy--5-ethyluridine.

11. A compound according to claim 2 selected from:

3'-O-Acetyl-2',5'-dideoxy-5-ethyl-5'-[3-(2,6-dimethyl-phenyl)-2-oxopropyl]uridine, 3'-O-acetyl-2',5'-dideoxy-5-ethyl-5'-[3-(2-methyl-phenyl)-2-oxopropyl]uridine, 3'-O-acetyl-5'-[3-(2-chlorophenyl)-2-oxopropyl]-2',5'--dideoxy-5-ethyl]uridine,' 3'-O-acetyl-2',5'-dideoxy-5-ethyl-5'-(2-oxo-3-phenyl-propyl)uridine, 3'-O-acetyl-2',5'-dideoxy-5-ethyl-5'-[2-oxo-3(RS)--phenylbutyl]uridine, 2',5'-dideoxy-5-ethyl-5'-(2-oxo-3-phenylpropyl)uridine, 2',5'-dideoxy-5-ethyl-5'-[3-(2-methylphenyl)-2-oxo-propyl]uridine, 2',5'-dideoxy-5-ethyl-5'-[3-(2,6-dimethylphenyl)-2-oxo-propyl]uridine, 5'-[3-(2-chlorophenyl)-2-oxopropyl]-2',5'-dideoxy-5--ethyluridine, 2',5'-dideoxy-5-ethyl-5'-[2-oxo-3(RS)-phenylbutyl]uri-dine, 2',5'-dideoxy-5-ethyl-5'-[2(RS)-hydroxy-3-phenylpropyl]-uridine, 2',5'-dideoxy-5-ethyl-5'-[2(RS)-hydroxy-3-(2-methyl-phenyl)propyl]uridine, 5'-[3-(2-chlorophenyl)-2(RS)-hydroxypropyl]-2',5'-dideoxy-5-ethyluridine, 2',5'-dideoxy-5-ethyl-5'-[2(RS)-hydroxy-3-(2,6-dimethyl-phenyl)propyl]uridine, 2',5'-dideoxy-5-ethyl-5'-(3-phenylpropyl)uridine and 5'-benzylsulphonyl-2',5'-dideoxy-5-ethyluridine.

12. A compound according to claim 1 selected from 2',5'-Dideoxy-5'-[3-(2,6-dimethylphenyl)-2-oxopropyl]-uridine, 3'-O-acetyl-5'-[3(RS)-(2,4-dichlorophenoxy)-2-oxobutyl]-2',5'-dideoxy-5-ethyluridine, 5'-[3(RS)-(2,4-dichlorophenoxy)-2-oxobutyl]-2',5'--dideoxy-5-ethyluridine, 5'-[3(RS)-(2,4-dichlorophenoxy)-2(RS)-hydroxybutyl]--2',5'-dideoxy-5-ethyluridine, 5'-(2-chlorobenzylsulphonyl)-2',5'-dideoxy-5-ethyluri-dine, 5'-(2,4-dichlorobenzylsulphonyl)-2',5'-dideoxy-5-ethyl-uridine and 5'-(2,6-dichlorobenzylsulphonyl)-2',5'-dideoxy-5-ethyl-uridine.

13. Compounds of the general formula II

wherein R1 is halogen. C1-4-alkyl or halo-(C1-4--alkyl), R2' is hydrogen or acyloxy, R3 and R4 each are hydrogen or C1-4-alkyl, R5 is aryl or aryloxy and X is 0 or NH, and tautomers thereof.

14. A medicament, containing a compound of formula I
according to any one of claims 1 to 13 together with a therapeutically acceptable carrier or excipient.

15. The use of a compound of formula I according to any one of claims 1 to 13 for the control or prevention of viral infections.