WO1992008727A1 - L-2'-desoxyuridines and pharmaceutical compositions containing them - Google Patents

L-2'-desoxyuridines and pharmaceutical compositions containing them Download PDF

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WO1992008727A1
WO1992008727A1 PCT/EP1991/002134 EP9102134W WO9208727A1 WO 1992008727 A1 WO1992008727 A1 WO 1992008727A1 EP 9102134 W EP9102134 W EP 9102134W WO 9208727 A1 WO9208727 A1 WO 9208727A1
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pharmaceutically acceptable
compound
acceptable salts
formula
pharmaceutical compositions
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PCT/EP1991/002134
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French (fr)
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Stefano Iotti
Francesco Paolo Colonna
Anna Maria Garbesi
Silvio Spadari
Federico Focher
Giovanni Ciarrocchi
Federico Arcamone
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Consiglio Nazionale Delle Ricerche
Menarini Ricerche Sud S.P.A.
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07HSUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06Pyrimidine radicals

Definitions

  • the present invention relates to L-2'-desoxyuridine of general formula (I)
  • the analogous monophosphates thus formed undergo a successive transformation into di-phosphates by the action of the viral thymidino-kinase (TK) and then to triphosphate nucleotides by action of unspecific cellular enzymes.
  • TK viral thymidino-kinase
  • Such analogous triphosphates behave as selective inhibitors of viral DNA polymerases, or, more frequently, as improved substrates, being preferentially incorporated in the viral DNA destroying its functionality.
  • the preferred compounds of general formula (I) suitable for the above said purposes are: - 1-(2-desoxy- ⁇ -L-erythro-pentafuranosyl)-2,4-(1H,3H)
  • the reaction mixture is then diluted with an equal volume of water, the pH is brought to 3 by addition of Dowex 50 (H + ) ion exchange resin, then filtered washing the resin with 200 ml water; filtrate and washing water are put together and evaporated under reduced pressure.
  • the residue is then co-evaporated for three times with absolute ethanol, dissolved in 50 ml of same solvent, made alkaline by addition of triethylamine, evaporated under reduced pressure and dried by co-evaporation with 50 ml toluene (twice).
  • the residue is kept for one night under reduced pressure over phosphoric anhydride, then 200 ml absolute ethanol are added and the solution obtained is brought to pH 2.5 by addition of concentrated hydrochloric acid and heated on reflux for 2 hrs.
  • reaction mixture is made alkaline by addition of triethylamine and evaporated; the residue is chromatographed on silica gel eluting with a methylene chloride/methanol 85ml/15ml mixture.
  • the obtained compound is then dissolved in 200 ml absolute ethanol, 0.5 ml concentrated hydrochloric acid and 1 g palladium 10% on carbon are added, followed by hydrogenation at normal pressure for 3 hrs.
  • the reaction mixture is filtered on Celite, which is washed with 100 ml ethanol.
  • the filtrate are put together, made alkaline with triethylamine and evaporated under reduced pressure.
  • the residue is crystallized from 8 ml absolute ethanol.
  • the biolgical activity of the compounds according to the present invention in the treatment of viral infections was evaluated employing HSV 1 TK and cell TK.
  • Fig. 1 shows the L-thymidine effect on the enzymathic activities of Herpes simplex 1 virus TK and of the human one.
  • Fig. 1 shows that L-thymidine inhibits the phosphorylation of (D)-thymidine by Herpes simplex 1 TK ( ⁇ ) , but not by human TK
  • the test consists in measuring the amount of (D)-thymidine substrate phosphorylated to (D)-TMP (ordinates) in the presence of growing L-thymidine concentrations (abscissae).
  • the viral or cellular purified enzyme (0.07 units) was incubated for 15 minutes at 37°C in 25 ⁇ l of a mixture containing 30 mM Hepes-K, pH 7-5, 6 mM MgCl 2 , 6 mM ATP, 0.5 mM dithiothreitol (DTT), 10 ⁇ M [ 3 H]Thy (25 Ci/mmole) and various L-thymidine concentrations.
  • the reaction is stopped depositing 20 ⁇ l of the mixture on DE-81 filters which are immediately soaked in an excess of 1 mM ammonium formiate, pH 5.6, in order to eliminate the (D)-[ 3 H] thymidine not transformed into monophosphate and which cannot therefore bind itselft with the positive charges of the DE-81 filter.
  • the filters are then washed in distilled water for 5 minutes and dehydrated in ethyl alcohol for 5 minutes.
  • the radioactive D-TMP bound to the filter was evaluated in a ⁇ radiation counter.
  • L-thymidine competes with D-thymidine for the active site of the viral enzyme, as proved by the competitive type inhibition curves reported in Fig. 2, which is a representation according to Lineweaver-Burk of the effect of L-thymidine on the TK activity of Herpes simplex virus in the presence of different concentrations of D-[ 3 H] thymidine substrate (expressed in the abscissae as the inverse of concentration).
  • the viral enzyme (0.07 units) was incubated for 15 minutes at 37°C in 25 ⁇ l of a mixture containing 30 mM Hepes-K, pH 7.5. 6 mM MgCl 2 , 6 mM ATP, 0.5 mM dithiothreitol (DTT), various concentrations of D-[ 3 H]thymidine(25 Ci/mmol) and various concentrations of L-thimidine (0 ⁇ M [ ⁇ ], 2 ⁇ M [ ⁇ ], 5 ⁇ M [ ⁇ ] , 10 UM [ ⁇ ], 15 mM [ ⁇ ]). The reaction is stopped by depositing 20 ⁇ l of the mixture on DE-81 filters which are processed as indicated in Fig. 1. The D-TMP values are reported as the inverse of the concentration on the ordinates. From the experiment one concludes that Km for D-thymidine viral enzyme is 2.8 ⁇ M and that Ki for L-thymidine is 2 ⁇ M.
  • the investigated nucleosides and nucleotides were separated by the reverse-phase method employing the Bio-Rad 100 MAPS preparative system.
  • a reverse-phase C 18 Bio Sil ODS-5S (0.4 ⁇ 15 cm) column was employed under the following conditions: injected volume 20 ⁇ l: UV : 260 nm; temperature : room; eluent : buffer A (20 mM KH 2 PO 4 , pH 5.6), buffer B (20 mM KH 2 PO 4 , pH 5.6, 6 ⁇ % methanol).
  • the specific conditions for separating L-thiomidine ATP are as follows: from 0 to 20 min. a 0% to 70% buffer B gradient; from 20 to 30 min. a 70% to 77% buffer B gradient and from 30 to 32 min. a 11% to 1002 buffer B gradient. Flux was 0.5 ml/min.
  • the enzymatic reaction (0.3 units viral enzyme) was performed as previously described, except that, instead of 6 mM ATP, 100 ⁇ M [ ⁇ -32 P] ATP 1500 cpm/pmol was employed and that the 37°C incubation was protracted to 30 min.
  • the results obtained are reported in Fig. 3, in which on the abscissae of each panel A, B and C the number of fractions eluted by the column is reported. In each fraction, the radioactivity was determined, which is reported as counts per minute (cpm) on the respective ordinates.
  • Panel A shows the control data without Thy
  • panel B the data for 10 ⁇ M L-thymidine
  • panel C the data for 10 ⁇ M D-thymidine in the assay.
  • viral TK phosphorylizes L-thymidine: in fact, in the presence of L-thymidine a radioactivity peak in the same position as D-TMP (Panel C) is obtained.
  • viral TK phosphorylizes 10% of the L-thymidine present in the assay, which is comparable to what is obtained with natural D-thymidine.
  • compositions according to the present invention comprise, as an active component, a therapeutically effective amount of a L-desoxyuridine of general formula (I) in which R and R' have the previously indicated meanings, or one of its pharmaceutically acceptable salts, in association with one or more pharmaceutically acceptable excipients or vehicles.
  • the pharmaceutical compositions according to the invention may be administered per os, parenterally and topically in suitable pharmaceutical formulations, for instance as sterile solutions for injectable use, tablets, capsules, powders, granulates, syrups, colloyria, ointments, creams, suppositories, ovules, bougies, etc.
  • the active principle is contained in the pharmaceutical compositions according to the invention in amounts variable between 50 mg and 2 g per dose, depending on the way of administration.
  • Useful excipients in the formulations according to the invention are e.g. jellying agents, auxiliaries for gelatine capsules, antioxidants, dispersing agents, emulsifiers, anti-foam agents, taste correcting agents, preservers, solubilyzing agents, etc.

Abstract

L-2'-desoxyuridines of formula (I) are described, wherein R=H, CH2OC2H5, CH2OH, CH3, -CH=CBrH and R'=OH, F, N3, and their use for the preparation of pharmaceutical compositions useful for the treatment of viral infections in men and in animals.

Description

L-2'-DESOXYURIDINES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM.
Invention field
The present invention relates to L-2'-desoxyuridine of general formula (I)
Figure imgf000003_0001
wherein R = H, CH2OC2H5, CH2OH, CH3, -CH=CBrH and R' = OH, F, N3 and their use for the preparation of pharmaceutical compositions having antiviral properties.
Prior Art
L-2'-desoxynucleosides of formula (I) in which R = H, CH3,
CH2OH and R' = OH are known and their synthesis was effected as described in the literature [Coll. Czech. Chem. Comm. 37 , p.4072 (1972)] starting from L-arabinose and cyanamid as shown hereinbelow, R and R' being as defined supra, H excluded:
Figure imgf000004_0001
It is known furthermore that derivatives of 2'-desoxyuridine belonging to the natural series D are phosphorylated by viral thymidino-kinase [Y.C. Cheng, "Antimetabolites in Biochemistry, Biology and Meidine", Pergamon Press (1979)]. In "Nucleic Acid Research" 1976, 3 (8), 2143-54 (Eng) is reported that L-uridine, L-cytidine and L-thymidine when administered to mice are largely eliminated in the urine in unmodified form leaving in some tissues only traces of phosphorylated metabolites.
In the light of the cited literature, therefore, it was neither known nor could be foreseen that also non-natural 2'-desoxyuridines of the L-series would behave similarly to the natural compounds of the D-series, and even less that they could be employed in the pharmaceutical field.
Detailed description of the invention
We have now surprisingly found, and this is an object of the present invention, that compounds of general formula (I) in which R = H, CH2OC2H5, CH2OH, CH3, -CH=CBrH and R' = OH, F, N3, are substrates of HSV 1 and HSV 2 thymidino-kinase (that is they are phosphorylated by the viral enzyme) while they are wholly inert to the action of mammalian thymidino-kinase.
The phosphorylation of these compounds by the viral enzyme is of considerable importance, allowing to obtain drugs capable of inhibiting the development of pathogenous viruses. In fact, in the infected cell, the analogous monophosphates thus formed undergo a successive transformation into di-phosphates by the action of the viral thymidino-kinase (TK) and then to triphosphate nucleotides by action of unspecific cellular enzymes. Such analogous triphosphates behave as selective inhibitors of viral DNA polymerases, or, more frequently, as improved substrates, being preferentially incorporated in the viral DNA destroying its functionality.
In the healthy cell, where, the activation of the non-natural analogous compounds to mono- and di-phosphates does not take place, neither does their transformation to triphosphates, with a consequent sharp reduction of the toxic effects in the areas not affected by the viral infection.
Particularly the present invention relates to pharmaceutical compositions having antiviral properties containing as active principle an L-2'-desoxyuridine of general formula (I), wherein R = H, CH2OC2H5, CH2OH, CH3, -CH=CBrH and R' = OH, F, N3 and a pharmaceutically acceptable excipient or vehicle. The compounds of formula (I) wherein R = -CH=CBrH, CH3, and R' = OH, F, N3, with the proviso that when R = CH3, R' is not OH, are new.
According to the present invention, the preferred compounds of general formula (I) suitable for the above said purposes are: - 1-(2-desoxy-β-L-erythro-pentafuranosyl)-2,4-(1H,3H)
pyrimidindione (R = H, R' = OH)
- 1-(2-desoxy-β-L-erythro-pentafuranosyl)-5-hydroxymethylen- 2,4-(1H,3H)-pyrimidindione (R = CH2OH, R' = OH) - 1-(2-desoxy-β-L-erythro-pentafuranosyl)-5-ethoxymethylen- 2,4-(1H,3H)-pyrimidindione (R = CH2OC2H5, R' = OH)
- 1-(2-desoxy-β-L-erithro-pentafuranosyl)-5-methyl-2,4- (1H,3H)-pyrimidindione (R = CH3, R' = OH)
- 1-(2-desoxy-β-L-erythro-pentafuranosyl)-5-(E-2-bromovinyl)- 2,4-(1H,3H)-pyrimidindione (R = -CH=CBrH, R' = OH)
- 1-(2,3-didesoxy-3-azido-β-L-erythro-pentafuranosyl)-5- methyl-2,4-(1H,3H)-pyrimidindione (R = CH3, R' = N3)
- 1-(2,3-didesoxy-3-fluoro-β-L-erythro-pentafuranosyl)-5- methyl-2,4-(1H,3H)-pyrimidindione (R = CH3, R' = F)
The first four compounds were described in the literature without, however, any reference to their antiviral properties and their ensuing pharmaceutical use, while the others are new. For illustrative, non limiting, purposes, we are now reporting the preparation of one compound according to the present invention.
EXAMPLE 1
Synthesis of 1-(2-desoxy-β-L-erythro-pentafuranosyl)-5-methyl-2,4(1H,3H)-pyrimidindione (R = CH3, R' = OH).
A mixture of 4.6 g L-2'-desoxyuridine (compound of formula (I) in which R = H, R' = OH), 20 ml 1 M KOH and 20 ml aqueous 37% formaldehyde is kept at 60°C for five days, adding every 24 hours 5 ml 1 M KOH and 5 ml aqueous 31% formaldehyde. The reaction mixture is then diluted with an equal volume of water, the pH is brought to 3 by addition of Dowex 50 (H+) ion exchange resin, then filtered washing the resin with 200 ml water; filtrate and washing water are put together and evaporated under reduced pressure. The residue is then co-evaporated for three times with absolute ethanol, dissolved in 50 ml of same solvent, made alkaline by addition of triethylamine, evaporated under reduced pressure and dried by co-evaporation with 50 ml toluene (twice). The residue is kept for one night under reduced pressure over phosphoric anhydride, then 200 ml absolute ethanol are added and the solution obtained is brought to pH 2.5 by addition of concentrated hydrochloric acid and heated on reflux for 2 hrs.
After cooling, the reaction mixture is made alkaline by addition of triethylamine and evaporated; the residue is chromatographed on silica gel eluting with a methylene chloride/methanol 85ml/15ml mixture.
The obtained compound is then dissolved in 200 ml absolute ethanol, 0.5 ml concentrated hydrochloric acid and 1 g palladium 10% on carbon are added, followed by hydrogenation at normal pressure for 3 hrs. The reaction mixture is filtered on Celite, which is washed with 100 ml ethanol. The filtrate are put together, made alkaline with triethylamine and evaporated under reduced pressure. The residue is crystallized from 8 ml absolute ethanol.
Thus 2 g L-thymidine [α]D 20º= - 18.5° (c = 1% in water).
With a method similar to the one described in the literature for the compounds derived from D-2'-desoxyuridine, and employing the suitable reagents , one can obtain also the other previously indicated compounds of formula (I) .
Biological activity
The biolgical activity of the compounds according to the present invention in the treatment of viral infections was evaluated employing HSV 1 TK and cell TK.
Fig. 1 shows the L-thymidine effect on the enzymathic activities of Herpes simplex 1 virus TK and of the human one. Fig. 1 shows that L-thymidine inhibits the phosphorylation of (D)-thymidine by Herpes simplex 1 TK (□) , but not by human TK
(♦) .
The test consists in measuring the amount of (D)-thymidine substrate phosphorylated to (D)-TMP (ordinates) in the presence of growing L-thymidine concentrations (abscissae). The viral or cellular purified enzyme (0.07 units) was incubated for 15 minutes at 37°C in 25 μl of a mixture containing 30 mM Hepes-K, pH 7-5, 6 mM MgCl2, 6 mM ATP, 0.5 mM dithiothreitol (DTT), 10 μM [3H]Thy (25 Ci/mmole) and various L-thymidine concentrations.
The reaction is stopped depositing 20 μl of the mixture on DE-81 filters which are immediately soaked in an excess of 1 mM ammonium formiate, pH 5.6, in order to eliminate the (D)-[3H] thymidine not transformed into monophosphate and which cannot therefore bind itselft with the positive charges of the DE-81 filter. The filters are then washed in distilled water for 5 minutes and dehydrated in ethyl alcohol for 5 minutes. The radioactive D-TMP bound to the filter was evaluated in a β radiation counter.
One can clearly observe a specific inhibition of viral TK; in fact at 5 μg/ml viral TK is 90% inhibited, whereas the human one is completely resistent. Human TK proved to be fully resistent to L-thymidine even at the highest investigated dose (200 μg/ml).
L-thymidine competes with D-thymidine for the active site of the viral enzyme, as proved by the competitive type inhibition curves reported in Fig. 2, which is a representation according to Lineweaver-Burk of the effect of L-thymidine on the TK activity of Herpes simplex virus in the presence of different concentrations of D-[3H] thymidine substrate (expressed in the abscissae as the inverse of concentration).
The viral enzyme (0.07 units) was incubated for 15 minutes at 37°C in 25 μl of a mixture containing 30 mM Hepes-K, pH 7.5. 6 mM MgCl2, 6 mM ATP, 0.5 mM dithiothreitol (DTT), various concentrations of D-[3H]thymidine(25 Ci/mmol) and various concentrations of L-thimidine (0 μM [□], 2 μM [♦], 5 μM [■] , 10 UM [♢], 15 mM [■]). The reaction is stopped by depositing 20 μl of the mixture on DE-81 filters which are processed as indicated in Fig. 1. The D-TMP values are reported as the inverse of the concentration on the ordinates. From the experiment one concludes that Km for D-thymidine viral enzyme is 2.8 μM and that Ki for L-thymidine is 2 μM.
To check whether L-thymidine is phosphorylated by the viral enzyme, as happens for D-thymidine, IDU, TFT, ACU etc., or whether it simply inhibits the synthesis of the natural substrate competing for the active site, as it happens for the other compounds which we have studied, such as phenyl- desoxyguanosine (Ph-dG) we have analysed by HPLC the products of the reaction catalyzed by viral TK, between [γ-32P] ATP and L-thymidine.
The investigated nucleosides and nucleotides were separated by the reverse-phase method employing the Bio-Rad 100 MAPS preparative system.
A reverse-phase C18 Bio Sil ODS-5S (0.4 × 15 cm) column was employed under the following conditions: injected volume 20 μl: UV : 260 nm; temperature : room; eluent : buffer A (20 mM KH2PO4, pH 5.6), buffer B (20 mM KH2PO4, pH 5.6, 6θ% methanol). The specific conditions for separating L-thiomidine ATP are as follows: from 0 to 20 min. a 0% to 70% buffer B gradient; from 20 to 30 min. a 70% to 77% buffer B gradient and from 30 to 32 min. a 11% to 1002 buffer B gradient. Flux was 0.5 ml/min. The enzymatic reaction (0.3 units viral enzyme) was performed as previously described, except that, instead of 6 mM ATP, 100 μM [γ -32P] ATP 1500 cpm/pmol was employed and that the 37°C incubation was protracted to 30 min. The results obtained are reported in Fig. 3, in which on the abscissae of each panel A, B and C the number of fractions eluted by the column is reported. In each fraction, the radioactivity was determined, which is reported as counts per minute (cpm) on the respective ordinates.
Panel A shows the control data without Thy, panel B the data for 10 μM L-thymidine and panel C the data for 10 μM D-thymidine in the assay.
As can be seen from Fig. 3, viral TK phosphorylizes L-thymidine: in fact, in the presence of L-thymidine a radioactivity peak in the same position as D-TMP (Panel C) is obtained.
In the 30 min. reaction, viral TK phosphorylizes 10% of the L-thymidine present in the assay, which is comparable to what is obtained with natural D-thymidine.
Pharmaceutical Compositions
The pharmaceutical compositions according to the present invention comprise, as an active component, a therapeutically effective amount of a L-desoxyuridine of general formula (I) in which R and R' have the previously indicated meanings, or one of its pharmaceutically acceptable salts, in association with one or more pharmaceutically acceptable excipients or vehicles. The pharmaceutical compositions according to the invention may be administered per os, parenterally and topically in suitable pharmaceutical formulations, for instance as sterile solutions for injectable use, tablets, capsules, powders, granulates, syrups, colloyria, ointments, creams, suppositories, ovules, bougies, etc.
The active principle is contained in the pharmaceutical compositions according to the invention in amounts variable between 50 mg and 2 g per dose, depending on the way of administration.
Useful excipients in the formulations according to the invention are e.g. jellying agents, auxiliaries for gelatine capsules, antioxidants, dispersing agents, emulsifiers, anti-foam agents, taste correcting agents, preservers, solubilyzing agents, etc.

Claims

1. L-2'-desoxyuridines of general formula (I)
Figure imgf000014_0001
wherein R = -CH=CBrH, CH3 and R' = OH, F, N3, with the proviso that when R = CH3, R' is not OH, and their pharmaceutically acceptable salts.
2. Compound of general formula (I) according to claim 1, wherein R = -CH=CBrH and R' = OH and its pharmaceutically acceptable salts.
3. Compound of general formula (I) according to claim 1, wherein R = CH3 and R' = No and its pharmaceutically acceptable salts.
4 . Compound of general formula ( I ) according to claim 1 , wherein R = CH3 and R' = F and its pharmaceutically acceptable salts .
5. Pharmaceutical compositions containing as active principle an effective amount of a compound according to claim 1 and pharmaceutically acceptable excipients or vehicles.
6.Pharmaceutical composition according to claim 5 wherein the active principle is a compound of formula (I) wherein R = -CH=CBrH and R' = OH and its pharmaceutically acceptable salts.
7.Pharmaceutical composition according to claim 5 wherein the active principle is a compound of formula (I) wherein R = CH3 and R' = N3 and its pharmaceutically acceptable salts.
8.Pharmaceutical composition according to claim 5 wherein the active principle is a compound of formula (I) wherein R = CH3 and R' = F and its pharmaceutically acceptable salts.
9 . Pharmaceutical compositions according to claim 5 having antiviral acivity.
10. Pharmaceutical compositions according to claim 5 for the therapeutic treatment of Herpes simplex.
11. Pharmaceuticals compositions containing as active principle an effective amount of a compound of formula (I)
Figure imgf000015_0001
wherein R = H, CH2OC2H5, CH2OH and R' = OH, F, N3 or R = CH3 and R' = OH and their pharmaceutically acceptable salts and pharmaceutically acceptable excipients or vehicles.
12. Pharmaceutical composition according to claim 11 wherein the active principle is a compound of formula (I) wherein R = H and R' = OH and its pharmaceutically acceptable salts.
13. Pharmaceutical composition according to claim 11 wherein the active principle is a compound of formula (I) wherein R = CH2OH and R' = OH and its pharmaceutically acceptable salts .
14. Pharmaceutical composition according to claim 11 wherein the active principle is a compound of formula ( I ) wherein R = CH2OC2H5 and R' = OH and its pharmaceutically acceptable salts .
15. Pharmaceutical composition according to claim 11 wherein the active principle is a compound of formula (I) wherein R = CH3 and R' = OH and its pharmaceutically acceptable salts.
16. Pharmaceutical compositions according to claim 11 having antiviral activity.
17. Pharmaceutical compositions according to claim 11 for the therapeutic treatment of Herpes simplex
18. Pharmaceutical compositions according to claims 5 or 11 wherein the active principle is contained in an amount of between 50 mg and 2 g.
19. Pharmaceutical compositions according to claims 5 or 11, for parenteral, oral or topical administration.
20. Pharmaceutical compositions according to claims 5 or 11 in the form of injectable sterile solutions, tablets, capsules, granulates, powders, syrups, collyria, ointments, creams, suppositories, ovules, bougies.
PCT/EP1991/002134 1990-11-13 1991-11-09 L-2'-desoxyuridines and pharmaceutical compositions containing them WO1992008727A1 (en)

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