NL8100177A - 5-Halovinyl-2',3'-di:deoxy-uridine derivs. - useful as antiviral agents against herpes simplex - Google Patents

Abstract

2',3'-Dideoxyuridine derivs. of formula (I) are new: (where Y is halogen, X is NH2 or N3, and the wavy line indicates the erythro or threo configuration). (I) are antiviral agents with low toxicity and high and specific activity against herpes simplex, e.g. with ID5O values as low as 0.07-0.2 mcg/ml against HSV-1 and 20 mcg/ml against HSV-2. E-5-(2-bromovinyl)-3'-amino- 2',3'-dideoxyuridine (Ia) is specifically claimed.

Description

* 4 i

Br / lh / 11 Rega.

3'-Amino or azido derivatives of E-5- (2-halovinyl) -2'-deoxyuriine

The invention relates to a group of new deoxyuridine compounds, as well as to their chemical synthesis and to the use of these substances in pharmaceutical preparations.

The deoxyuridine compounds of the invention can be represented by formula 1 of the formula sheet wherein Hal represents a halogen atom, X an amino or azido group and the jagged line an erythro or threo configuration.

Research has shown that said deoxyuridins have an antiviral effect. In particular, the compound of formula 1 with Hal = Br and X = in erythro configuration is distinguished by a powerful antiviral action, which is very specific to herpes simplex virus.

In addition, these compounds have a remarkably low toxicity and therefore a high antiviral index against said type of virus. The compounds are therefore useful for preparing pharmaceutical preparations and for treating diseases caused by herpes simplex in humans and animals.

The prior art already includes many deoxyuridine compounds with antiviral activity. A general overview of this has been given by E. De Clercq et al in J. Carbohydrates, Nucleosides, Nucleotides, 5 (3}, 187r224 (1978). Referenced for further details. It should be noted, however, that the antiviral activity of most of these compounds are not particularly specific because they exhibit similar activity against various DNA viruses such as vaccinia and herpes simplex In addition, the toxicity of most of these compounds and in particular of the commonly used standard compound 5-iodine- is 2'-deoxyuridine should not be neglected, it is therefore a favorable circumstance that the compounds according to the invention do in part have such a specific 810 0 17 7. * 0 -2-

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L · -: · * "possess antiviral activity against one type of virus (herpes simplex) and that the toxicity of these compounds is extremely low, as mentioned above. Especially the compound of formula 1 with Hal = Br and X = NH2 in erythro- position, or 5 E-5- (2-bromovinyl) -31-amino-21,3'-dideoxyuridine, due to its high antiviral index, far exceeds the standard compound 5-iodo-2'-deoxyuridine.

It is noted that a specific antiviral activity against herpes simplex virus as well as a low toxicity in a cell culture have also recently been reported for E-5- (2-bromovinyl) -21-deoxyuridine and E-5- (2 iodo-vinyl) -2'-deoxy-uridine. Compare E. De Clercq et al. In Proceedings National Academy of Science USA, 76, No. 6, 2947-2951 (1979). Compared to this, the compound E-5- (2-bromovinyl) -31-15 amino-2 ', 3'-dideoxyuridine appears to be at least as specific and equally toxic, while it also appears to have some depot action. The compounds of the invention therefore represent a welcome extension of the physician's arsenal to combat diseases caused by herpes simplex.

The invention therefore provides deoxyuridine compounds, as represented by formula 1, wherein Hal represents a halogen atom, X an amino or azido group, and the cartelin an erythro or threo configuration. In particular, it provides the compound E-5- (2-bromovinyl) -3'-amino-2 ', 3'-dideoxyuridine. Furthermore, according to the invention there is provided a pharmaceutical composition with antiviral activity, characterized in that it contains a compound of formula 1 as active ingredient. In addition, the invention also provides a method of preparing the "deoxyuridine compounds of formula 1 and a method" of preparing said pharmaceutical preparation.

The compounds according to the invention can in principle be prepared in various ways.

A preferred chemical synthesis is shown on the formula sheet by the scheme of formulas 2-10. This synthesis includes two variants A and B, both of which contemplate introducing an amino or azido group at the 31-8100177-1-3 position of an E-5- (2-halo-vinyl) -2-deoxyuridine.

In variant A ', after the 5'-hydroxyl group is protected, a mesyl group (itethylsulfonyl group) or a tosyl group is first introduced in place 3', which is then replaced by an azido group 5, followed by deprotection of the 5 * hydroxyl group and optionally converting the azido group to an amino group. When replacing the mesyl or tosyl group with the azido group, two isomers can be isolated, namely the ejythro isaner and the threo isomer, depending on the position of the azido group in position 3 ', which isomers then separately to the next operations can be subject.

In variant B, the starting material is first converted into an internal 2,3'-anhydrous compound after the 5'-hydroxyl group has been protected and a 3'-iresyl or tosyl-15 group has been introduced, after which this 2,3r-anhydro compound is converted treated with an azide to introduce a 3'-azido group, followed by deprotection of the 5'-hydroxyl group and optionally conversion of the azido group to an amino group. This variant 20 has one more step, but delivers the end product only in erythro form.

Both variants of the synthesis according to the formula sheet will now be described in more detail.

In the first stage of both variants, the starting material becomes of formula. 2 first treated with an agent to protect the 5'-hydroxyl group. This can be done, for example, with trityl chloride in pyridine at a temperature from room temperature to the boiling point of the solvent. Immediately afterwards, the 3 * -hydroxyl-30 group is converted into a mssyloxy or tosyloxy group by treatment with mesyl or tosyl chloride in the same or other solvent. Since this reaction is exothermic, it is best to run it at room temperature or below.

In the second stage of variant A, the product of formula 3 obtained is treated directly with an azide to replace the S'-mesyloiny or tosyloxy group with an azido group. This can be done, for example, with sodium azide in dimethylformamide, at a temperature between room temperature and 8100177 ψ 9 * Λ ---- -4- the boiling point of the solvent. The time should be relatively short (1-30 minutes) to avoid unwanted diversions. Nevertheless, this always results in a mixture of two isomers # the threo isomer of formula 5 and the erythroisomer of formula 6 # which can be separated from one another by conventional means such as column chromatography.

In the third step of variant A, the hydroxyl protecting group in the 51-position of the compound of formula 5 or 6 is removed, which can be done, for example, with acetic acid or another acid in water.

• An azido compound of formula 8 or • 9, which falls under the definition of formula 1, is obtained.

If it is desired to prepare a compound with a 3-amino group 15, the product of formula 8 or 9 is treated in a fourth step with an agent to convert the azido group to an amino group. This can be done, for example, with tr ± Enyphosphine in dry pyridine # followed by treatment with ammonia. The reaction already proceeds well at room temperature and the product of formula 7 or 10 obtained only needs little purification.

In variant B, the product of formula 3 obtained in the first stage is converted in a second stage to an internal: 2 # 3'-anhydro compound of formula 4. This; 25 can be done, for example, with. a base # such as sodium hydroxide # in aqueous ethanol. An excess of base should be avoided because of the danger of rearrangement to a 2'-deoxyxylofuranosyl derivative. The reaction can take place at any temperature between room temperature and the boiling point of the solvent.

In the third step of variant B, the resulting 2,3'-anhydro compound of formula 4 is directly converted into a compound with a 3'-azido group, which can be done with an azide, for example lithium or sodium azide, in dimethylformamide. The temperature can be between room temperature and the boiling point of the solvent. The product of formula 6 obtained is obtained exclusively in erythro form.

8100177 -5-

After this, in a fifth step, the hydroxy-protecting group in position 5 'can be removed and, in a sixth step, the 3'-azido group can optionally be converted into an amino group, in the same manner as discussed in variant 51-A.

According to variant B, the compounds of formulas 9 and 10 can be obtained in a reasonably good yield. If these compounds are to be prepared with variant A, the yield is of course less, because a mixture of the erythro and the threo isomer is always obtained there in the second stage.

Using the described synthesis, the position of the uracil core with respect to the sugar residue (configuration) and the position of the groups around the vinyl -15 group (E-configuration) is fixed from the beginning, so that in this respect no separation need to take place between isomers.

The starting material of formula 2 has been previously described (compare E. De Clercq et al., Proc. Nat. Acad.

20 Sc. USA, 76, 2947-2951, (1979)) and can be synthesized in various ways, for example, by coupling the deoxyribose derivative to E-5- (2-halo-vinyl) -uracil, or by introducing an E-5- ( 2-halo-vinyl group in 2-de-oxyuridine The preferred chemical synthesis as well as the physical constants of the final products are further explained. the following examples, which, however, cannot be construed as limiting the invention.

Example I

a) E-5- (2-bromovinyl) -21-deoxy-31-O-mesyl-5'-O-trityluridine. (formula 3).

7 grams (21 mmol) of E-5- (2-bromovinyl) -2'-deoxyuridine of formula 2 were heated to 100 ° C with 6,960 g (25 mmol) of chlorotriphenyl-35 methane in 50 ml of anhydrous pyridine for 90 minutes. The solution was then cooled to 0 ° C and 9.6 ml (14.4 g, 124 mmol) of netane sulfonyl chloride was added dropwise over a half hour. After the 8100177 -6-.

; I

solution was stirred overnight at 0-5 ° C, 4 ml of water was added and the reaction mixture was slowly poured into 1.5 liters of vigorously stirred ice water. The mixture was extracted with 4 x 250 ml ethyl acetate, then the organic layer twice, carbon black 150 ml of 2N HCl to remove residual pyridine, washed twice with 5% sodium bicarbonate solution and finally with water. After drying on Na 2 SO 4, the ethyl acetate layer was evaporated to dryness under reduced pressure.

The. brown oil obtained was purified by column chromatography on silica gel using benzene-acetone (9: 1) as eluent. The combined eluates were evaporated to dryness and used as such for subsequent conversions. The yield was 11 g (80%).

The compound) could also be crystallized from propanol-2, whereby a. white product was formed which was homogeneous according to thin layer chromatography (TLC). on silica gel (Rf: 0.47 with benzene acetone (8: 2) and 0.85 with chloroform-methanol (8: 2)) and melted at 105-107 ° C (dec). On standing, the product was slowly detritylated as shown by TLC analysis.

B) E-5- (2-bromovinyl) -3'-azido-21,3'-dideoxyuridine. (Formula 9) and E-5- (2-bromovinyl) -1- (3-azido-2,3 dideoxy (D-threo-pento-furanosyl) uracil (Formula 8).

A solution of 3.265 g (5 mmol) of the compound of formula 3 in 13 ml of dry dimethylformamide was added dropwise over a 10 minute period to a reflux mixture of 1 g (15 mmol) of sodium azide in 40 ml of dry dimethylformamide. After completion of the addition, heating was continued for another 25 minutes.

The reaction mixture was then quickly cooled in an ice bath and the solvent was removed under reduced pressure at room temperature. The residue was triturated with chloroform and filtered. The filtrate was evaporated and treated with 80% aqueous acetic acid for 1 hour at the temperature of a steam bath to remove the trityl group.

After evaporation of the solvent in vacuo, the residue was chromatographed on a column of silica gel using benzene-acetone (9: 1) as eluent. The erythro isomer of formula 9 was first eluted in the form of an oil.

8100177 -7-

Yield 0/540 g. On TLC on silica gel, the product was found to be pure (Rf 0.27 with benzene acetone (8: 2) and 0.77 with chloroform-methanol (8: 2)) - IR spectrum, * /, 2100 cm * " 1 (N3) The product has not yet been obtained in crystalline form.

The product of formula 8 was eluted second from the column and crystallized from water-methanol (2: 1). The yield was 0.610 g and the melting point 153-155 ° C.

TLC on silica gel gave Rf 0.06 with benzene acetone (8: 2) and 0.65 with chloroform-methanol (8: 2). IR spectrum, * ^, 2120 cm -1 (N3); m / e 357 (M +).

c) E-5- (2-bromovinyl) -1- (3-amino-2,3-dideoxy- / -D-threo-pento-furanosyl) uracil (Formula 7).

A mixture of 0.250 g (0.7 mmol) of threo-azido derivative of formula 8 and 0.325 g of triphenylphosphine in dry pyridine was stirred at room temperature for 1 hour. Then 0.3 ml of concentrated ammonium hydroxide was added and the mixture was allowed to stand overnight. The solvent was removed in vacuo after which the residue was dissolved in 1M ammonium hydroxide and extracted with benzene (3x) and with ether (3x). The organic extract was washed with water after which the combined water layer was evaporated to dryness and purified by column chromatography on silica gel. The column was eluted. with chloroform-25

methanol (1: 1) after which the fractions were combined with the desired product and evaporated to dryness. Finally, the residue was crystallized from water-ethanol (10: 1) to yield 0.090 g of white crystals, m.p. 143-145 ° C. On TLC on silica gel, Rf 0.19 with chloroform-methanol (8: 2) was obtained, m / e 331 (M +). = + 42.5 ° (c 0.2 in IN

NaOH).

Example II

a) E-5- (2-bromovinyl) -21-deoxy-31 -O-me.s.yl-51 -O-trityluridine (formula 3)

The said compound was obtained in the same manner as in Example I (a).

8100 17 7 4 *: -8- b) E-5- (2-bromovinyl) -2,31-anhydro-2'-deoxy-5'-O-trityl-uridine (Formula 4).

mtmmm "11 g (16.8 mmol}" of the non-crystallized derivative of formula 3 was dissolved in 200 ml of 80% aqueous ethanol. Then an equivalent amount of sodium hydroxide (16.5 ml / .Ί, Ο N) was added and the solution was stirred at boiling temperature for 1 hour, after which the reaction according to TLC was completed. The resulting solution was cooled and evaporated to dryness. The residue was taken up in water and the solid formed was filtered off and washed with water and ether. washed until colorless The yield was 7.520 g or 13.5 mmol (80%) and the melting point was 186-188 ° C. On TLC on silica gel, the product showed only one spot (Rf: 0.13 with benzene-acetone (8: 2) and 0.79 with chloroform-methanol (8: 2)) This product was used for the next step without further recrystallization.

C) E-5- (2-bromovinyl) -3'-azido-21,3-dideoxyuridine (formula 9).

7.5 g (13.5 ramcbl) of the anhydro compound of formula 4 were dissolved in 200 ml dimethylformamide. Then 10.5 g of lithium azide and 1.7 g of benzoic acid were added and the resulting solution was added at 100 ° C. stirred overnight. The course of the reaction was monitored by TLC using chloroform-methanol (8: 2) as the solvent system, and found that the reaction was nearly complete since only a trace of the starting material was left. The dimethylformamide was removed in vacuo at room temperature. The residue was crystallized from water ethanol (2: 1) to yield 7.0 g of slightly crude product of formula 6 which was immediately de-tritylated,

To this end, the crude compound of formula 6 was dissolved in 150 ml of 80% aqueous acetic acid, after which the mixture was heated on a steam bath with stirring for 0.5 hour. TLC was found to be no starting material remaining. The mixture was evaporated to dryness under reduced pressure, after which the residue was purified by column chromatography over silica gel with chloroform-methanol (95: 5) as eluent. On evaporation of the combined fractions, 2.0 g (5.6 mmol, 41% / 8100177 1 -9-S - total yield) of the relatively pure compound of formula 9 were obtained in the form of a oil obtained. This product was identical in every respect to the corresponding compound of Example I (b). At TLC, Rf: 0.77 was obtained with chloro-5 form-methanol (8: 2).

d) E-5- (2-bromovinyl) -3 * -amino-2 *, 31-dideoxyuridine (formula O).

A mixture of 1.8 g (5.0 mmol) azido derivative of formula 9 and 2.36 g triphenylphosphine in 20 ml dry pyridine was stirred at room temperature for 1 hour. Then 2 ml of concentrated ammonium hydroxide was added and the solution was stored at room temperature overnight. The pyridine was removed under reduced pressure, water was added and evaporated as well. The residue was dissolved in 1M ammonium hydroxide and extracted with benzene and twice with ether. The water layer was evaporated to dryness and the residue was purified by column chromatography over silica gel. Elution of the column with. chloroform-methanol (1: 1) gave a product with positive ninhydrin reaction, which was finally crystallized from methanol to yield 0.900 g (54%) of 20 white crystals, mp 192-193 ° C (dec).

2 4 q

This product had the following properties: Z * 7D = +13.5 (c 0.5 in 1N NaOH); m / e 331 (M +); TLC (Ef: -0.20 with chloroform-methanol (8: 2)); NMR (il ^ SO-dg) 8.1 (s, 1H, H-6), 7.18 (d, 1H, vinyl-H, J = .13Hz), 6.72 (d, 1H, vinyl-H , J = 25 13Hz), 5.98 (t, 1H, Η — 1 '), 4.55 (exchangeable protons), 3.60 (m, 4H, H-5 *, H-4 *, H-31 2.08 (m, 2H, H-2 ').

8100177 '-' I::. .-10-

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Organic tests.

A series of biological tests are described below, which demonstrate the antiviral activity, low toxicity and high antiviral index of the compounds according to the invention.

In these tests, the effect of the compounds of formula 1 and related compounds on the growth and yield of viruses in cell cultures was measured.

The compounds tested were: '10 derivatives of formula 7-10 and. formula 4 of the formula sheet (prepared according to the previous examples), E-5- (2-bromovinyl) -2'-deoxyuridine (see Proc. Nat. Acad. Sc. USA 76_, 2947-2951 (1979)) and 5- iodo-21-deoxyuridine (supplied by Ludeco, Brussels). All these compounds were β anomers.

The compounds were tested for vaccinia virus, three strains of herpes simplex-1 virus (strain KOS, strain Malntyre. And strain F) and three strains of herpes simplex-2 virus (strain G, strain Lyons and strain 196). These viruses were grown partly in cell cultures of primary rabbit kidney cells (PRK) and partly also in a large number of other cell cultures.

The technique for measuring virus growth in cell cultures has been described by E. De Clercq et al. Biochem. Pharmacol. 24, 523-527, (1975).

25 Trial 1

In this test, the inhibitory activity of the compounds of the invention and related compounds on vaccinia viruses, Herpes simplex-1 and herpes simplex-2 in PRK cell cultures was measured. Cells 30 were grown to confluence on plastic material microplates (PRK). At confluence, the cells were seeded with 100 CGID ^ g of the virus in question. One CCID ^ g or "cell culture infecting dose-5Q" is the dose of virus required to infect 50% of the cell cultures. . One hour after inoculation of the virus, the compounds were added at various concentrations (ranging from 0.001 µg / ml to 400 / 9-5 / ml). The ID ^ q was determined for each virus cell system. The ID ^ -g or "inhibitory dose-50" is 8100177

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* -11- the concentration of the compound required to decrease the cytopathic effect on the virus by 50% - This cytopathic effect (CPE) was recorded as soon as it was completed in the untreated virus-infected cell cultures (generally 3 days after inoculation of the cells with the virus). The results are shown in Table A below, where the data are mean values from three separate runs each.

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Table A shows that the compound of formula 10 shows a powerful and very specific antiviral activity against herpes sinplex viruses especially of type 1, but hardly any effect against vaccinia virus. In these respects, 5 the compound substantially corresponds to the known E-5- (2-bromovinyl) -2'-deoxyuridine, while it is clearly distinguished from the 5-iodo-2 by its specific action against type 1 of herpes sinplex virus. deoxyuridine. The compounds of formulas 9.7 and 8 also exhibit a partially specific antiviral activity, which, however, gradually decreases relative to the compound of formula 10. The anhydro compound of formula 4 is ineffective.

Trial 2

In this test, the inhibitory activity of the compound of formula 10 and some related compounds on the KOS strain of herpes simplex-1 was measured in a large number of cell cultures. The method of measurement was the same as that of Test 1. And the results are shown in Table B.

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^ B lo o · ο o J§ ώ |> $ ΙΛ | j 8100177 -15- From table B it appears that the compound of formula 10 versus herpes simplex virus type 1 has an almost as good effect as E-5- (2-bromovinyl) -2'-deoxyuridine and 5-iodo-2'-deoxyuridine.

5 Trial 3

Furthermore, the inhibitory effect of the compound of formula 10 and E-5- (2-bromovinyl) -2'-deoxyuridine on the multiplication of herpes simplex-1 (strain KOS) virus in PEK cell cultures was measured.

Confluent single layers of PKK cells in plastic material Petri dishes (55 mm diameter) were inoculated with herpes simplex-1 (4.5 log-PFE / 0.5 mm / Petri dish) and at 37 ° C for 1 hour. incubated. Immediately afterwards, the test compounds were added, each at doses of 0.01, 0.1, 1, 10 and 100 µg / ml. The cells were harvested either on day 0 (immediately after incubation with virus), or on day 1, 2 or 3 (after further incubation at 37 ° C). The virus yield in the cells was determined by slice formation in Vero cell cultures (VERO = continuous renal cell culture of green monkeys). The results are collected in Figures 1 and 2, with Figure 1 being for the compound E-5- (2-bromovinyl) -2'-deoxyuridine and Figure 2 for the compound of Formula 10. PFE refers to slab forming units.

It can be seen from Figures 1 and 2 that the inhibitory effect of both compounds in low concentration (0.01 µg / ml) is virtually the same, but that differences will occur at higher concentrations? while, the inhibitory effect of the known compound increases only gradually, as the concentration increases, the compound of formula 10 has a lower concentration at a smaller concentration (eg 0.1 µg / ml) and at higher concentrations ( e.g. 10 and 100 jog / ml) a stronger inhibitory effect than the known compound. The latter indicates a stronger antiviral activity of the compound of formula 10 at higher concentrations.

35 Trial 4

The anti-metabolic activity of the compound of formula 10 and related compounds in PRK cell cultures was measured.

8100177 y + - - **; 7 -i6- '”

To this end, the incorporation of certain radiolabeled DNA precursors into the DNA of the cells and the effect of the said compounds was investigated. The technique has been described by De Clercg et al. In Biochem. Pharmacol., 26, 5, 794-797 (1977) and by De Clercq et al. In Molecular Pharmaco-. logy, 14, 422-430 (1978).

3

The DNA precursors used were (methyl-H) (21-deoxythymidine) (TdR) ön (Ι '^ ’- ^ Η) (21-deoxyuridine) (UdR).

The cells were exposed to 0.12. ^ 1101 per 0.01 nmol (methyl-3H) TdR (per 10 ^ cells) or 0.25 ^ UCi per 0.006 nmol (i1 ^ 1H) UdR (per 10 cells) in the presence of the compounds in various concentrations (ranging from 1 to 200 µg / ml). The uptake of the radiolabeled preproduction was then measured as described and the 1Dj-q determined. The ID, -q corresponds to the inhibitory dose-50, which is the concentration of the compound required to increase the uptake of either (methyl- ^ H) TdR or (1 ', 2 * - ^ H) UdR by 50% to brake. The results are shown in Table C below.

TABLE "C

20

Antimetabolic action in PRK cell cultures.

7 ”Γ ID50 (pg / ml)

Compound (Methyl-'3H) TdR (11,2'-3H) UdR

recording recording 25 —----—-

Formula 10> 100, 90, 80> 100, 90 E-5- (2-bromoviny1) -2'-deoxyuridine 90, 75, 60 20, 5-5-iodo-2'-deoxyuridine 2,1,5,1 0 , 3, 0.2 30

Table C shows that the substance of formula 10 does not cause inhibition of the uptake of (methyl-H) TdR or (1 *, 2 * - H) UdR in the DNA of the cells, unless the concentration is increased to 80, 90 or 100 µg / ml or higher. In this regard, the new compound is even slightly better (i.e. less toxic) than the known E-5- (2-bromovinyl) -21-deoxyuridine, and considerably better than the known substance 5-iodo-2'-deoxyuridine.

8100177 -17-

Trial 5

Finally, the antiviral index of the compound of Formula 10 and related compounds in PRK cell cultures was determined as a result of the measurements made in the previous 5 experiments.

The antiviral index A was determined as the ratio of ID ^ for the incorporation of (methyl-H) TdR in DNA of the cells to the ID ^ -q for the inhibition of herpes simplex-1 (strain KOS) virus ( compare tables A and C). The antiviral index B was determined as the ratio of ID5Q for the uptake of (1 *, 2'-3H) UdR in DNA of the cells to the ID5Q for the inhibition of herpes simplex-1 (strain KOS) virus ( compare tables A and C). The results are shown in Table D below.

15 TABLE D

Antiviral index in PRK cell cultures.

Antiviral index

Connection ~ ^ B

Formula 10 ^ 900> 950 E-5- (2-bromovinyl) -21-deoxyuridine 3750 875 5-iodo-2, -deoxyuridine 15 2/5 y--

Table D shows that the antiviral index for the compound of the invention is certainly greater than 900 or 950. Since this compound showed little or no toxicity at the highest concentration tested (100 µg / ml), the exact antiviral index could not be accurately determined. However, it was of the same order of magnitude as that of E-5- (2-bromovinyl) -2'-deoxyuridine.

From the foregoing it will be clear that the compounds according to the invention have a clear antiviral effect, and the substance E-5- (2-bromotinyl) -31-amino-21,3'-dide-oxyuridine even an excellent and very specific have antiviral activity against herpes simplex virus, while 8100177 V- "" -18- its toxicity in cell culture is almost nil. The compound of formula 10 is very similar in this respect to the known compound E-5- (2- bromovinyl) -2'-deoxyuridine, but appears to be distinguished therefrom by a more potent action at higher concentrations, therefore, the compounds of the invention can be used advantageously for the preparation of pharmaceutical preparations and for the treatment of diseases affecting humans And animals are caused by herpes.simplex virus.

Pharmaceutical preparations containing the substances according to the. invention as active ingredients may be in the form of. powders, suspensions, solutions, emulsions and also of ointments and. pastes and can be used for parenteral (intradermal, intramuscular, intrathecal, ...} injections, oral, rectal, intravaginal and intranasal or topical administration (for example, to skin lesions, mucous membranes, or the eye). prepared by combining the active ingredient or active ingredients with pharmaceutically acceptable excipients commonly used for this purpose. These excipients can be aqueous or non-aqueous solvents, stabilizers, suspending agents, dispersants, wetting agents and the like, and will Be aware of the person skilled in the art of the pharmaceutical art Furthermore, the composition may contain any suitable additive such as polyethylene glycols and optionally dyes, perfumes and the like.

The pharmaceutical preparations will usually contain the active ingredient in a concentration of at least 0.1% (weight part / volume part). The actual concentration will depend on the disease to be treated and the chosen mode of administration. In general, this concentration will be between 0.1 and 100%.

8100177

Claims (10)

1. Deoxyuridine compounds, as shown, of formula 1, wherein Hal represents a halogen atom, X an amino or azido group and the jagged line represents an erythro or threo configuration. 5 2. E-5- (2-bromovinyl) -31-amino-2 ', 31-dideoxyuridine. 3. Process for preparing deoxyuridine compounds, characterized in that compounds of formula 1, wherein Hal, X and the jagged line have the indicated meaning 10, are prepared in a manner known for analogous compounds. 4. Process according to claim 3, characterized in that they are prepared by introducing an azido or amino group at the 3 'position of an E-5- (2-halo-vinyl) -21-deoxyuridine. 5. Process according to claim 4, characterized in that the compounds of formula 1 are prepared by (a) in a starting compound of formula 2, after the 5-1-hydroxyl group is protected, an iresyl or tosyl group on the 20 into position 3 ', replacing this itesyl or tosyl group with an azido group, followed by deprotection of the 5'-hydroxyl group and optionally converting the azido group to an amino group, (b) by a starting compound of formula .2, after the 5 * -25 hydroxyl group has been protected, to be converted into an internal 2,3'-anhydro compound, treat this 2,31-anhydro compound with an azide to introduce a 3'-azido group, followed by deprotection and, if desired, conversion from the azido group.to an amino group. Pharmaceutical composition with antiviral activity, characterized in that it contains a compound of formula 1, in which Hal, X and the jagged line have the indicated meaning, as active ingredient. 7. A composition according to claim 6, with special application for the treatment of herpes simplex infections, characterized in that it contains E-5- (2-bromovinyl) -3 * -amino-21,3 dideoxyuridine as active ingredient. 8100177 -20- 8. A method of preparing a pharmaceutical composition having an antiviral activity, characterized in that one or more compounds of formula 1, wherein Hal. X and the serrated line have the indicated meaning, in a dosage form suitable for therapeutic use. Process according to claim 8, characterized in that said compound is mixed with a pharmaceutically acceptable carrier. 10. Method for treating. viral infections in humans and animals, characterized in that these infections are treated with a therapeutically effective amount of a compound of formula 1, wherein Hal, X and the jagged line have the indicated meaning. 8100177