WO1992008727A1 - L-2'-desoxyuridines et compositions pharmaceutiques les contenant - Google Patents
L-2'-desoxyuridines et compositions pharmaceutiques les contenant Download PDFInfo
- 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
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.
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 |
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)
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)
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 |
-
1990
- 1990-11-13 IT IT02203290A patent/IT1246983B/it active IP Right Grant
-
1991
- 1991-11-09 WO PCT/EP1991/002134 patent/WO1992008727A1/fr active Application Filing
- 1991-11-09 AU AU89232/91A patent/AU8923291A/en not_active Abandoned
Patent Citations (5)
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)
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)
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 |
AU8923291A (en) | 1992-06-11 |
IT9022032A1 (it) | 1992-05-13 |
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 | |
DE3882985T2 (de) | Adenosin-deaminase-stabile anti-retroviral-nukleoside. | |
Slama et al. | Specific inhibition of poly (ADP-ribose) glycohydrolase by adenosine diphosphate (hydroxymethyl) pyrrolidinediol | |
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 | |
US4232154A (en) | Carbocyclic analogs of cytosine nucleosides exhibiting antiviral and antineoplasticactivity | |
EP0716856B1 (fr) | Utilisations thérapeutiques de dérivés du 2',5'-oligoadenylate | |
EP0090405B1 (fr) | Azole-dinucléotides et leurs méthodes de préparation | |
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 | |
KR880000094B1 (ko) | 뉴클레오시드 유도체의 제조방법 |
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 |