WO1992008727A1 - L-2'-desoxyuridines et compositions pharmaceutiques les contenant - Google Patents

L-2'-desoxyuridines et compositions pharmaceutiques les contenant Download PDF

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Publication number
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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WIPO (PCT)
Prior art keywords
pharmaceutically acceptable
compound
acceptable salts
formula
pharmaceutical compositions
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PCT/EP1991/002134
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English (en)
Inventor
Stefano Iotti
Francesco Paolo Colonna
Anna Maria Garbesi
Silvio Spadari
Federico Focher
Giovanni Ciarrocchi
Federico Arcamone
Original Assignee
Consiglio Nazionale Delle Ricerche
Menarini Ricerche Sud S.P.A.
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Application filed by Consiglio Nazionale Delle Ricerche, Menarini Ricerche Sud S.P.A. filed Critical Consiglio Nazionale Delle Ricerche
Publication of WO1992008727A1 publication Critical patent/WO1992008727A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine 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'-désoxyuridines de la formule (I), où R=H, CH2OC2H5, CH2OH, CH3, -CH=CBrH et R'=OH, F, N3, et leur utilisation dans la préparation de compositions utiles au traitement d'infections virales chez l'homme et les animaux.
PCT/EP1991/002134 1990-11-13 1991-11-09 L-2'-desoxyuridines et compositions pharmaceutiques les contenant WO1992008727A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT02203290A IT1246983B (it) 1990-11-13 1990-11-13 L-2'-desossiuridine e composizioni farmaceutiche che le contengono.
IT22032A/90 1990-11-13

Publications (1)

Publication Number Publication Date
WO1992008727A1 true WO1992008727A1 (fr) 1992-05-29

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AU (1) AU8923291A (fr)
IT (1) IT1246983B (fr)
WO (1) WO1992008727A1 (fr)

Cited By (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994005687A1 (fr) * 1992-09-04 1994-03-17 University Of Birmingham Nucleosides pyrimidiniques antiviraux
WO1995007287A1 (fr) * 1993-09-10 1995-03-16 Centre National De La Recherche Scientifique (Cnrs) COMPOSES 2' OU 3'-DEOXY- ET 2', 3'-DIDEOXY-β-L-PENTOFURANONUCLEOSIDES, PROCEDE DE PREPARATION ET APPLICATION THERAPEUTIQUE, NOTAMMENT ANTI-VIRALE
WO1996013512A2 (fr) * 1994-10-24 1996-05-09 Genencor International, Inc. Nucleosides de l-ribofuranosyle
US5565438A (en) * 1994-01-28 1996-10-15 University Of Ga Research Foundation L-nucleosides for the treatment of epstein-bar virus
US5703058A (en) * 1995-01-27 1997-12-30 Emory University Compositions containing 5-fluoro-2',3'-didehydro-2',3'-dideoxycytidine or a mono-, di-, or triphosphate thereof and a second antiviral agent
US5728575A (en) * 1990-02-01 1998-03-17 Emory University Method of resolution of 1,3-oxathiolane nucleoside enantiomers
US5753789A (en) * 1996-07-26 1998-05-19 Yale University Oligonucleotides containing L-nucleosides
US5808040A (en) * 1995-01-30 1998-09-15 Yale University L-nucleosides incorporated into polymeric structure for stabilization of oligonucleotides
US5852027A (en) * 1991-02-22 1998-12-22 Emory University Antiviral 1,3-dioxolane nucleoside analogues
US5885972A (en) * 1994-10-24 1999-03-23 Genencor International, Inc. L-pyranosyl nucleosides
US5914331A (en) * 1990-02-01 1999-06-22 Emory University Antiviral activity and resolution of 2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane
WO2000009531A2 (fr) * 1998-08-10 2000-02-24 Novirio Pharmaceuticals Limited β-L-2'-DESOXY-NUCLEOSIDES POUR LE TRAITEMENT DE L'HEPATITE B
EP1027359A2 (fr) * 1996-10-16 2000-08-16 ICN Pharmaceuticals, Inc. L nucleosides monocycliques, analogues et leurs utilisations
US6114343A (en) * 1990-02-01 2000-09-05 Emory University Antiviral activity and resolution of 2-hydroxymethyl-5-(5-flurocytosin-1-yl)-1,3-oxathiolane
WO2001096353A2 (fr) * 2000-06-15 2001-12-20 Idenix (Cayman) Limited 3'-PROMEDICAMENTS DE 2'-DESOXY-ss-L-NUCLEOSIDES
US6391859B1 (en) 1995-01-27 2002-05-21 Emory University [5-Carboxamido or 5-fluoro]-[2′,3′-unsaturated or 3′-modified]-pyrimidine nucleosides
US6444652B1 (en) 1998-08-10 2002-09-03 Novirio Pharmaceuticals Limited β-L-2'-deoxy-nucleosides for the treatment of hepatitis B
EP1254911A1 (fr) * 1996-10-16 2002-11-06 ICN Pharmaceuticals, Inc. L- nucleosides monocycliques, analogues et leurs utilisations
JP2003513984A (ja) * 1999-11-12 2003-04-15 フアーマセツト・リミテツド ２’−デオキシ−ｌ−ヌクレオシドの合成
US6787526B1 (en) 2000-05-26 2004-09-07 Idenix Pharmaceuticals, Inc. Methods of treating hepatitis delta virus infection with β-L-2′-deoxy-nucleosides
US6875751B2 (en) 2000-06-15 2005-04-05 Idenix Pharmaceuticals, Inc. 3′-prodrugs of 2′-deoxy-β-L-nucleosides
EP1431304A3 (fr) * 1998-08-10 2005-05-25 Idenix (Cayman) Limited Beta-L-2'-deoxy-nucléosides pour le traitement de l'hépatite B
US6911424B2 (en) 1998-02-25 2005-06-28 Emory University 2′-fluoronucleosides
US6949522B2 (en) 2001-06-22 2005-09-27 Pharmasset, Inc. β-2′- or 3′-halonucleosides
EP1600451A2 (fr) * 1999-11-12 2005-11-30 Pharmasset Limited Synthèse de 2'-déoxy-L-nucléosides
US7186700B2 (en) 2002-09-13 2007-03-06 Idenix Pharmaceuticals, Inc. β-L-2′-deoxynucleosides for the treatment of resistant HBV strains and combination therapies
US7323451B2 (en) 2002-08-06 2008-01-29 Idenix Pharmaceuticals, Inc. Crystalline and amorphous forms of beta-L-2′-deoxythymidine
US7439351B2 (en) 1993-09-10 2008-10-21 The Uab Research Foundation 2′ or 3′ -deoxy and 2′, 3′-dideoxy-β-L-pentofuranonucleo-side compounds, method of preparation and application in therapy, especially as anti-viral agents
CN1911237B (zh) * 1998-08-10 2010-09-15 艾丹尼克斯(开曼)有限公司 用于治疗乙型肝炎的β-L-2＇-脱氧-核苷
AU2007216721B2 (en) * 1998-08-10 2011-05-19 Centre National De La Recherche Scientifique Beta-L-2'-Deoxy Nucleosides for the Treatment of Hepatitis B
AU2011211428B2 (en) * 1998-08-10 2013-02-07 Centre National De La Recherche Scientifique Beta-L-2'-Deoxy Nucleosides for the treatment of Hepatitis B
US8895531B2 (en) 2006-03-23 2014-11-25 Rfs Pharma Llc 2′-fluoronucleoside phosphonates as antiviral agents
US10100076B2 (en) 2000-10-18 2018-10-16 Gilead Pharmasset Llc Modified nucleosides for the treatment of viral infections and abnormal cellular proliferation

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US6069252A (en) * 1990-02-01 2000-05-30 Emory University Method of resolution and antiviral activity of 1,3-oxathiolane nucleoside enantiomers
US5728575A (en) * 1990-02-01 1998-03-17 Emory University Method of resolution of 1,3-oxathiolane nucleoside enantiomers
US5827727A (en) * 1990-02-01 1998-10-27 Emory University Method of resolution of 1,3-oxathiolane nucleoside enantiomers
US5914331A (en) * 1990-02-01 1999-06-22 Emory University Antiviral activity and resolution of 2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane
US7160999B2 (en) 1990-02-01 2007-01-09 Emory University Method of resolution and antiviral activity of 1,3-oxathiolane nucleoside enantiomers
US6346627B1 (en) 1990-02-01 2002-02-12 Emory University Intermediates in the synthesis of 1,3-oxathiolane nucleoside enantiomers
US7468436B2 (en) 1990-02-01 2008-12-23 Emory University Method of resolution and antiviral activity of 1,3-oxathiolane nucleoside enantiomers
US6642245B1 (en) 1990-02-01 2003-11-04 Emory University Antiviral activity and resolution of 2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane
US6114343A (en) * 1990-02-01 2000-09-05 Emory University Antiviral activity and resolution of 2-hydroxymethyl-5-(5-flurocytosin-1-yl)-1,3-oxathiolane
US5892025A (en) * 1990-02-01 1999-04-06 Emory University Method of resolution and antiviral activity of 1,3-oxathiolane nucleoside enantiomers
US5852027A (en) * 1991-02-22 1998-12-22 Emory University Antiviral 1,3-dioxolane nucleoside analogues
WO1994005687A1 (fr) * 1992-09-04 1994-03-17 University Of Birmingham Nucleosides pyrimidiniques antiviraux
US7439351B2 (en) 1993-09-10 2008-10-21 The Uab Research Foundation 2′ or 3′ -deoxy and 2′, 3′-dideoxy-β-L-pentofuranonucleo-side compounds, method of preparation and application in therapy, especially as anti-viral agents
WO1995007287A1 (fr) * 1993-09-10 1995-03-16 Centre National De La Recherche Scientifique (Cnrs) COMPOSES 2' OU 3'-DEOXY- ET 2', 3'-DIDEOXY-β-L-PENTOFURANONUCLEOSIDES, PROCEDE DE PREPARATION ET APPLICATION THERAPEUTIQUE, NOTAMMENT ANTI-VIRALE
FR2709754A1 (fr) * 1993-09-10 1995-03-17 Centre Nat Rech Scient Composés 2' ou 3'-déoxy- et 2', 3'-didéoxy-beta-L-pentofuranonucléosides, procédé de préparation et application thérapeutique, notamment anti-virale.
US5587362A (en) * 1994-01-28 1996-12-24 Univ. Of Ga Research Foundation L-nucleosides
US5565438A (en) * 1994-01-28 1996-10-15 University Of Ga Research Foundation L-nucleosides for the treatment of epstein-bar virus
US5567688A (en) * 1994-01-28 1996-10-22 Univ. Of Ga Research Foundation L-nucleosides for the treatment of hepatitis B-virus
US5885972A (en) * 1994-10-24 1999-03-23 Genencor International, Inc. L-pyranosyl nucleosides
WO1996013512A2 (fr) * 1994-10-24 1996-05-09 Genencor International, Inc. Nucleosides de l-ribofuranosyle
WO1996013512A3 (fr) * 1994-10-24 1997-02-06 Genencor Int Nucleosides de l-ribofuranosyle
US5559101A (en) * 1994-10-24 1996-09-24 Genencor International, Inc. L-ribofuranosyl nucleosides
US6391859B1 (en) 1995-01-27 2002-05-21 Emory University [5-Carboxamido or 5-fluoro]-[2′,3′-unsaturated or 3′-modified]-pyrimidine nucleosides
US7419966B2 (en) 1995-01-27 2008-09-02 Emory University [5-carboxamido or 5-fluoro]-[2′,3′-unsaturated or 3′-modified]-pyrimidine nucleosides
US5703058A (en) * 1995-01-27 1997-12-30 Emory University Compositions containing 5-fluoro-2',3'-didehydro-2',3'-dideoxycytidine or a mono-, di-, or triphosphate thereof and a second antiviral agent
US6680303B2 (en) 1995-01-27 2004-01-20 Emory University 3′,5-difluoro-2′,3′-didehydropyrimidine nucleosides and methods of treatment therewith
US5808040A (en) * 1995-01-30 1998-09-15 Yale University L-nucleosides incorporated into polymeric structure for stabilization of oligonucleotides
US5753789A (en) * 1996-07-26 1998-05-19 Yale University Oligonucleotides containing L-nucleosides
EP1027359A4 (fr) * 1996-10-16 2001-07-25 Icn Pharmaceuticals L nucleosides monocycliques, analogues et leurs utilisations
EP1027359A2 (fr) * 1996-10-16 2000-08-16 ICN Pharmaceuticals, Inc. L nucleosides monocycliques, analogues et leurs utilisations
EP1254911A1 (fr) * 1996-10-16 2002-11-06 ICN Pharmaceuticals, Inc. L- nucleosides monocycliques, analogues et leurs utilisations
US8168583B2 (en) 1998-02-25 2012-05-01 University Of Georgia Research Foundation, Inc. 2-fluoronucleosides
US6911424B2 (en) 1998-02-25 2005-06-28 Emory University 2′-fluoronucleosides
US7662938B2 (en) 1998-02-25 2010-02-16 Emory University 2′-fluoronucleosides
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US7307065B2 (en) 1998-02-25 2007-12-11 Emory University 2′-Fluoronucleosides
EP2392580A1 (fr) 1998-02-25 2011-12-07 Emory University 2'-Fluoronucléosides
US9180138B2 (en) 1998-02-25 2015-11-10 University Of Georgia Research Foundation, Inc. 2′-fluoronucleosides
EP2415776A1 (fr) 1998-08-10 2012-02-08 IDENIX Pharmaceuticals, Inc. Bêta-L-2'-désoxy-nucléosides pour le traitement de l'hépatite B
US7304043B2 (en) 1998-08-10 2007-12-04 Idenix Pharmaceuticals, Inc. β-L-2′-deoxy-nucleosides for the treatment of hepatitis B
AU2013203196B2 (en) * 1998-08-10 2015-09-17 Centre National De La Recherche Scientifique Beta-L-2'-Deoxy Nucleosides for the Treatment of Hepatitis B
US6946450B2 (en) 1998-08-10 2005-09-20 Idenix Pharmaceuticals, Inc. β-L-2′-deoxy-nucleosides for the treatment of hepatitis B
AU2011211428B2 (en) * 1998-08-10 2013-02-07 Centre National De La Recherche Scientifique Beta-L-2'-Deoxy Nucleosides for the treatment of Hepatitis B
US7795238B2 (en) 1998-08-10 2010-09-14 Idenix Pharmaceuticals, Inc. β-L-2′-deoxy-nucleosides for the treatment of hepatitis B
CN1911237B (zh) * 1998-08-10 2010-09-15 艾丹尼克斯(开曼)有限公司 用于治疗乙型肝炎的β-L-2＇-脱氧-核苷
US6395716B1 (en) 1998-08-10 2002-05-28 Novirio Pharmaceuticals Limited β-L-2′-deoxy-nucleosides for the treatment of hepatitis B
US6566344B1 (en) 1998-08-10 2003-05-20 Idenix Pharmaceuticals, Inc. β-L-2′-deoxy-nucleosides for the treatment of hepatitis B
US6569837B1 (en) 1998-08-10 2003-05-27 Idenix Pharmaceuticals Inc. β-L-2′-deoxy pyrimidine nucleosides for the treatment of hepatitis B
JP2007269798A (ja) * 1998-08-10 2007-10-18 Indenix Pharmaceuticals Ltd Ｂ型肝炎の治療のためのβ−Ｌ−２’−デオキシ−ヌクレオシド
EP1431304A3 (fr) * 1998-08-10 2005-05-25 Idenix (Cayman) Limited Beta-L-2'-deoxy-nucléosides pour le traitement de l'hépatite B
US6444652B1 (en) 1998-08-10 2002-09-03 Novirio Pharmaceuticals Limited β-L-2'-deoxy-nucleosides for the treatment of hepatitis B
CN101120947B (zh) * 1998-08-10 2010-11-24 艾丹尼克斯(开曼)有限公司 用于治疗乙型肝炎的β-L-2′-脱氧-核苷
US9290533B2 (en) 1998-08-10 2016-03-22 Novartis Ag β-L-2′-deoxy-nucleosides for the treatment of hepatitis B
AU2007216721B2 (en) * 1998-08-10 2011-05-19 Centre National De La Recherche Scientifique Beta-L-2'-Deoxy Nucleosides for the Treatment of Hepatitis B
WO2000009531A3 (fr) * 1998-08-10 2000-06-15 Norivio Pharmaceuticals Ltd β-L-2'-DESOXY-NUCLEOSIDES POUR LE TRAITEMENT DE L'HEPATITE B
WO2000009531A2 (fr) * 1998-08-10 2000-02-24 Novirio Pharmaceuticals Limited β-L-2'-DESOXY-NUCLEOSIDES POUR LE TRAITEMENT DE L'HEPATITE B
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IT1246983B (it) 1994-12-12
IT9022032A0 (it) 1990-11-13
IT9022032A1 (it) 1992-05-13

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