+

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

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

Info

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
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutically acceptable
compound
acceptable salts
formula
pharmaceutical compositions
Prior art date
Application number
PCT/EP1991/002134
Other languages
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.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
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

Links

Classifications

    • 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.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Saccharide Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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
IT22032A/90 1990-11-13
IT02203290A IT1246983B (it) 1990-11-13 1990-11-13 L-2'-desossiuridine e composizioni farmaceutiche che le contengono.

Publications (1)

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

Family

ID=11190463

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1991/002134 WO1992008727A1 (fr) 1990-11-13 1991-11-09 L-2'-desoxyuridines et compositions pharmaceutiques les contenant

Country Status (3)

Country Link
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

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0217580A2 (fr) * 1985-09-17 1987-04-08 The Wellcome Foundation Limited Nucléosides thérapeutiques
EP0254268A2 (fr) * 1986-07-24 1988-01-27 The Wellcome Foundation Limited Nucléosides fluorées, leur préparation et leur utilisation pharmaceutique contre le SIDA
WO1989006655A1 (fr) * 1988-01-19 1989-07-27 Universite Pierre Et Marie Curie (Paris Vi) Procede de synthese de l'azido-3'-desoxy-3'-thymidine et analogues
FR2627492A1 (fr) * 1988-02-24 1989-08-25 Irceba Nouveaux derives de l'amino-5(prime)-dideoxy-2(prime)-5(prime)-uridine, procede pour les preparer et compositions pharmaceutiques contenant ces composes
EP0352248A1 (fr) * 1988-07-20 1990-01-24 Medivir Aktiebolag Dérivés de nucléosides

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0217580A2 (fr) * 1985-09-17 1987-04-08 The Wellcome Foundation Limited Nucléosides thérapeutiques
EP0254268A2 (fr) * 1986-07-24 1988-01-27 The Wellcome Foundation Limited Nucléosides fluorées, leur préparation et leur utilisation pharmaceutique contre le SIDA
WO1989006655A1 (fr) * 1988-01-19 1989-07-27 Universite Pierre Et Marie Curie (Paris Vi) Procede de synthese de l'azido-3'-desoxy-3'-thymidine et analogues
FR2627492A1 (fr) * 1988-02-24 1989-08-25 Irceba Nouveaux derives de l'amino-5(prime)-dideoxy-2(prime)-5(prime)-uridine, procede pour les preparer et compositions pharmaceutiques contenant ces composes
EP0352248A1 (fr) * 1988-07-20 1990-01-24 Medivir Aktiebolag Dérivés de nucléosides

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
COLLECTION OF CZECHOSLOVAK CHEMICAL COMMUNICATIONS. vol. 37, no. 12, December 1972, PRAGUE CS pages 4072 - 4087; A.HOLY: 'Nucleic Acid Components and their Analogues. CLIII. Preparation of 2'-deoxy - L Ribonucleosides of the Pyrimidine Series.' cited in the application see abstract SA 52789 030see page 4073, compound VII see page 4075, compounds XX, XXI, XXII *
JOURNAL OF ORGANIC CHEMISTRY. vol. 56, no. 11, 24 May 1991, EASTON US pages 3591 - 3594; J.WENGEL ET AL.: 'Synthesis of L-3'-Azido-3'-deoxythymidine and its Stereoisomers' see the whole document *

Cited By (78)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
EP2390257A1 (fr) 1998-02-25 2011-11-30 Emory University 2'-Fluoronucléosides
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
EP1600451A3 (fr) * 1999-11-12 2008-09-10 Pharmasset, Inc. Synthèse de 2'-déoxy-L-nucléosides
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
EP1600451A2 (fr) * 1999-11-12 2005-11-30 Pharmasset Limited Synthèse de 2'-déoxy-L-nucléosides
US6787526B1 (en) 2000-05-26 2004-09-07 Idenix Pharmaceuticals, Inc. Methods of treating hepatitis delta virus infection with β-L-2′-deoxy-nucleosides
JP2004533403A (ja) * 2000-06-15 2004-11-04 イデニクス（ケイマン）リミテツド ２’−デオキシ−β−Ｌ−ヌクレオシドの３’−プロドラッグ
AU2001266927B2 (en) * 2000-06-15 2006-12-14 Centre National De La Recherche Scientifique (Cnrs) 3'-prodrugs of 2'-deoxy-beta-L-nucleosides
WO2001096353A3 (fr) * 2000-06-15 2002-04-18 Novirio Pharmaceuticals Ltd 3'-PROMEDICAMENTS DE 2'-DESOXY-ss-L-NUCLEOSIDES
JP4639032B2 (ja) * 2000-06-15 2011-02-23 イデニクス（ケイマン）リミテツド ２’−デオキシ−β−Ｌ−ヌクレオシドの３’−プロドラッグ
US6875751B2 (en) 2000-06-15 2005-04-05 Idenix Pharmaceuticals, Inc. 3′-prodrugs of 2′-deoxy-β-L-nucleosides
US7585851B2 (en) 2000-06-15 2009-09-08 Idenix Pharmaceuticals, Inc. 3′-prodrugs of 2′-deoxy-β-L-nucleosides
WO2001096353A2 (fr) * 2000-06-15 2001-12-20 Idenix (Cayman) Limited 3'-PROMEDICAMENTS DE 2'-DESOXY-ss-L-NUCLEOSIDES
AP1771A (en) * 2000-06-15 2007-08-23 Idenix Cayman Ltd 3'-Prodrugs of 2'-deoxy-?-L-nucleosides.
US10100076B2 (en) 2000-10-18 2018-10-16 Gilead Pharmasset Llc Modified nucleosides for the treatment of viral infections and abnormal cellular proliferation
US6949522B2 (en) 2001-06-22 2005-09-27 Pharmasset, Inc. β-2′- or 3′-halonucleosides
US7323451B2 (en) 2002-08-06 2008-01-29 Idenix Pharmaceuticals, Inc. Crystalline and amorphous forms of beta-L-2′-deoxythymidine
US7589079B2 (en) 2002-08-06 2009-09-15 Novartis Ag Crystalline and amorphous forms of beta-L-2′-deoxythymidine
EP2607370A2 (fr) 2002-08-06 2013-06-26 Novartis AG Forme amorphe de beta- L-2 '-déoxythymidine
US7858594B2 (en) 2002-08-06 2010-12-28 Novartis Pharma Ag Crystalline and amorphous forms of beta-L-2′-deoxythymidine
US8158606B2 (en) 2002-09-13 2012-04-17 Novartis, Ag β-L-2′-deoxynucleosides for the treatment of resistant HBV strains and combination therapies
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
US7928086B2 (en) 2002-09-13 2011-04-19 Novartis Ag β-L-2′-deoxynucleosides for the treatment of resistant HBV strains and combination therapies
US8895531B2 (en) 2006-03-23 2014-11-25 Rfs Pharma Llc 2′-fluoronucleoside phosphonates as antiviral agents

Also Published As

Publication number Publication date
IT1246983B (it) 1994-12-12
IT9022032A0 (it) 1990-11-13
IT9022032A1 (it) 1992-05-13
AU8923291A (en) 1992-06-11

Similar Documents

Publication Publication Date Title
WO1992008727A1 (fr) L-2'-desoxyuridines et compositions pharmaceutiques les contenant
Acs et al. Biological and biochemical properties of the analogue antibiotic tubercidin
Slama et al. Specific inhibition of poly (ADP-ribose) glycohydrolase by adenosine diphosphate (hydroxymethyl) pyrrolidinediol
DE3882985T2 (de) Adenosin-deaminase-stabile anti-retroviral-nukleoside.
Imazawa et al. Synthesis of 3'-azido-2', 3'-dideoxyribofuranosylpurines
EP0352248A1 (fr) Dérivés de nucléosides
US5661136A (en) 2-halo-2'-fluoro ARA adenosines as antinoplastic agents
FI61315C (fi) Foerfarande foer framstaellning av antivirala 9-(beta-d-arabinofuranosyl)purin-5'-fosfater
EP0291917B1 (fr) Oxétanocines
JPH0822866B2 (ja) プリンおよびピリミジン塩基のｎ−ホスホニルメトキシアルキル誘導体
Fox et al. Characterization of labeled ribonucleic acid from tissue grown on 14C-containing cytokinins
US4177348A (en) Carbocyclic analogs of cytosine nucleosides
US4990498A (en) 2- and 8-azido(2'-5')oligoadenylates and antiviral uses thereof
KR890000762B1 (ko) 1-β-D-아라비노프라노실-(E)-5-(2-할로게노비닐)우라실-5'-인산의 제조방법
US4386076A (en) (E)-5-(2-Halogenovinyl)-arabinofuranosyluracil, process for preparation thereof, and uses thereof
US4396623A (en) Carbocyclic analogs of uracil nucleosides as antiviral agents
US3919193A (en) 3-Deazaguanosine and derivatives thereof
US4594415A (en) Azole dinucleotide compositions and methods of use
US6281201B1 (en) Base-modified derivatives of 2′,5′-oligoadenylate and antiviral uses thereof
Fedorov et al. 3'-C-branched 2'-deoxy-5-methyluridines: Synthesis, enzyme inhibition, and antiviral properties
EP0716856B1 (fr) Utilisations thérapeutiques de dérivés du 2',5'-oligoadenylate
US4232154A (en) Carbocyclic analogs of cytosine nucleosides exhibiting antiviral and antineoplasticactivity
EP0090405B1 (fr) Azole-dinucléotides et leurs méthodes de préparation
KR880000094B1 (ko) 뉴클레오시드 유도체의 제조방법
Chu et al. Nucleosides. 104. Synthesis of 4-amino-5-(D-ribofuranosyl) pyrimidine C-nucleosides from 2-(2, 3-O-isopropylidene-5-O-trityl-D-ribofuranosyl) acetonitrile

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU BB BG BR CA CS FI HU JP KP KR LK MC MG MN MW NO PL RO SD SU US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE BF BJ CF CG CH CI CM DE DK ES FR GA GB GN GR IT LU ML MR NL SE SN TD TG

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载