+

WO1989002733A1 - Analogues de nucleosides liposomiques pour le traitement du sida - Google Patents

Analogues de nucleosides liposomiques pour le traitement du sida Download PDF

Info

Publication number
WO1989002733A1
WO1989002733A1 PCT/US1988/003210 US8803210W WO8902733A1 WO 1989002733 A1 WO1989002733 A1 WO 1989002733A1 US 8803210 W US8803210 W US 8803210W WO 8902733 A1 WO8902733 A1 WO 8902733A1
Authority
WO
WIPO (PCT)
Prior art keywords
nucleoside analogue
liposome
phosphorylated
composition according
phosphorylated nucleoside
Prior art date
Application number
PCT/US1988/003210
Other languages
English (en)
Inventor
Karl Y. Hostetler
Douglas D. Richman
Original Assignee
The Regents Of The University Of California
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 The Regents Of The University Of California filed Critical The Regents Of The University Of California
Publication of WO1989002733A1 publication Critical patent/WO1989002733A1/fr

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/70Carbohydrates; Sugars; Derivatives thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/10Dispersions; Emulsions
    • A61K9/127Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12Antivirals
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12Antivirals
    • A61P31/14Antivirals for RNA viruses
    • A61P31/18Antivirals for RNA viruses for HIV

Definitions

  • the present invention relates generally to the treatment of viral infections with nucleoside analogues. More particularly, the present invention relates to the encapsulation of modified antiviral nucleoside analogues in liposomes to enhance the effectiveness of the analogues when administered to mammals.
  • nucleoside analogues are designed to inhibit viral functions by preventing the synthesis of new DNA by viral reverse transcriptase during viral replication.
  • Nucleosides are the precursors of DNA or RNA.
  • a nucleoside consists of a pyrimidine or purine base which is linked to a five-carbon sugar.
  • nucleoside triphosphates react with the end of a growing DNA chain.
  • the reaction involves the linking of the phosphate group at the 5' position on the incoming nucleoside triphosphate with the hydroxyl group at the 3' position of the sugar ring on the end of the forming DNA chain.
  • the other two phosphate groups are freed during the reaction thereby resulting in the addition of a nucleotide to the DNA chain.
  • Nucleoside analogues are compounds which mimic the naturally occurring nucleosides sufficiently so that they are able to participate in viral DNA synthesis.
  • antiviral nucleoside analogues have strategically located differences in chemical structure which inhibit the viral enzyme reverse transcriptase or which prevent further DNA synthesis once the analogue has been attached to the growing DNA chain.
  • Azidothymine (AZT) dideoxycytidine
  • dideoxyadenosine dideoxyadenosine
  • acyclovir dideoxyadenosine
  • ribavirin vidarabine
  • AIDS Acquired immune deficiency syndrome
  • HAV human immune deficiency virus
  • AZT Dideoxynucleoside analogues such as AZT are the most potent agents currently known, but in a recent human trial, serious toxicity was noted consisting of anemia (24%) and granulocytopenia (16%) (37, 38).
  • CD4 CD4
  • helper lymphocytes CD4 helper lymphocytes
  • CD4 monocytes and macrophages CD4 monocytes and macrophages.
  • the infection of C34 lymphocytes (3-5) results in a cytoiytic infection and contributes to the progressive immunodeficiency of HIV infection (6, 7).
  • CD4 monocyte/macrophages have been shown to be infected in vitro (8, 9), and in vivo (10-15). Infection of monocyte/macrophages may also contribute to immunodeficiency and to the pathogenesis of HIV induced encephalopathy.
  • these cells may serve as a reservoir for the virus because HIV replication in monocyte/macrophages appears to be more prolonged and less cytolytic than in lymphocytes. (8, 9, 13).
  • liposomes which are nearing the clinical arena (22).
  • liposomal antimonial drugs are several hundred fold more effective than the free drug in treating leishmaniasis as shown independently by Black and Watson (23) and Alving et al (24).
  • Liposome-entrapped amphotericin B appears to be more effective than the free drug in treating immunosuppressed patients with systemic fungal disease (25, 26).
  • Other uses for liposome encapsulation include restriction of doxorubicin toxicity (27) and diminution of aminoglycoside toxicity (22).
  • nucleoside analogues such as iododeoxyuridine (IUDR), acylovir (ACV) and ribavirin into liposomes for treating diseases other than AIDS (16, 17).
  • IUDR iododeoxyuridine
  • ACV acylovir
  • ribavirin ribavirin
  • a new treatment for AIDS in which antiviral nucleoside analogues are trapped within liposomes in a manner which prevents or substantially reduces leakage.
  • This reduction in leakage provides reduced toxicity and the use of liposomes ensures that a greater amount of the antiviral nucleoside analogue reaches the macrophages to thereby increase the effectiveness of these drugs against the HIV infection present in such cells.
  • the analogue of the neucleoside encapsulated in liposomes further enhances the antiviral effect of the formulation by providing a prephosphorylated antivral nucleoside, bypassing an enzymatically deficient step in macrophages which would otherwise greatly limit the antiviral activity of the drug itself (43).
  • the present invention is based on the discovery that leakage of nucleoside analogues from liposomes is greatly reduced if the analogues are converted to phosphate derivatives prior to encapsulation in liposomes. Conversion of the nucleoside analogues to their respective phosphate derivatives is believed not only to prevent leaking of the analogues from the liposomes, but also to increase the effectiveness of the analogues against HIV-infected macrophage cells. As previously mentioned, nucleosides are phosphorylated to the triphosphate form prior to attachment to the growing DNA or RNA chain. Macrophages have been found to have diminished deoxynucleoside kinase activities and a reduced ability to phosphorylate nucleosides.
  • free nucleoside analogues i.e., non-phosphorylated analogues
  • AZT, ddC or ddA are not particularly effective against HIV present in macrophage cells (43).
  • the phosphorylated analogues of the present invention are more effective when presented by the lipsomal delivery system because they by-pass the metabolic block caused by the lack of deoxynucleoside kinase activity in macrophages.
  • the present invention basically involves the encapsulation of phosphorylated antiviral nucleoside analogues within liposomes for use in treating viral infections.
  • this invention has applications to a wide variety of nucleoside analogues which may be used to treat various viral infections, the following description will be in the context of the treatment of patients suffering from Acquired Immune Deficiency
  • AIDS AIDS-related complex
  • ARC AIDS-related complex
  • HTLV-1 or HTLV-2 HTLV-1 or HTLV-2.
  • HIV Human immunodeficiency virus
  • HTLV-III/LAV Human immunodeficiency virus
  • HIV infects the CD4 (T4) helper lymphocyte resulting in the death of these cells.
  • T4 helper lymphocytes depletion of CD4 helper lymphocytes makes the host vulnerable to certain well described opportunistic infections and malignancies. HIV binds to the CD4 receptor of lymphocytes by forming a complex between the 110K viral surface glycoprotein (gp110) and the CD4 antigen (32, 32). Subsequently, the virus is thought to enter the cell by endocytosis as suggested by the finding that productive infection is blocked by NH 4 Cl and amantadine pretreatment of the cells.
  • gp110 110K viral surface glycoprotein
  • 32, 32 the CD4 antigen
  • HIV cells other than the CD4 helper lymphocyte become infected with HIV (28, 29, 30).
  • the virus has been shown to replicate in B cells, promyelocytes and monocytes. It also has been shown that mononuclear phagocytes isolated from brain and lung harbored HIV and normal peripheral blood macrophages produced large quantities of virus. Furthermore, human alveolar macrophages and brain macrophages harbor HIV and the viral cytopathic effects on these cells are much less than that observed in HIV- infected helper T4 lymphocytes. It has been proposed that HIV-infected macrophages and monocytes may serve as a reservoir for virus and that this may be a mechanism for viral persistence and dissemination in the infected host (29, 30).
  • the present invention utilizes the affinity of macrophages for liposomes as a vehicle for directing liposome encapsulated antiviral nucleoside analogues at macrophages, monocytes and any other infected cells which may take up liposomes. Further, phosphorylation of the nucleoside analogue prior to encapsulation provides advantages in that: 1) the nucleoside analogue is prevented from leaking out of the liposome; and 2) the metabolic block associated with the inability of macrophages to phosphorylate free nucleosides is overcome.
  • liposomal encapsulation of the phosphorylated nucleoside is essential to prevent hydrolysis of the phosphate ester by plasma enzymes such as alkaline phosphatase, phosphodiesterases or 5'-nucleotidases.
  • the nucleoside analogues can be any of the known analogues used for treating AIDS including 3'-azido-3'-deoxythymidine (azidothymidine or AZT), 2 ', 3 '-dideoxycytidine (dideoxycytidine or ddC), 2'3'-dideoxyadenosine (dideoxyadenosine or ddA), ribavirin or any other suitable dideoxynucleoside analogue.
  • AZT is a preferred analogue.
  • the analogue is phosphorylated according to conventional procedures such as the phosphorous oxychloride method of Toorchen and Topal (34).
  • the preferred modified analogue is the 5'-monophosphate. Since AZT and other dideoxynucleosides have only the 5'-hydroxyl, only the 5'-monophosphate is formed during phosphorylation. Alternatively, the nucleoside 5'-monophosphate thioester is also effective. Diphosphate and triphosphate analogues of antiviral nucleosides are also effective, however, these diphosphate or triphosphate analogues tend to be less stable than the monophosphate and may be hydrolyzed gradually back to the monophosphate derivative in aqueous solution.
  • the nucleoside analogue is encapsulated in liposomes.
  • the encapsulation can be carried out according to well known liposome encapsulation procedures such as sonication and extrusion. Suitable conventional methods of encapsulation include but are not limited to those disclosed by Bangham et al (18), Olson et al (39), Szoka and Papahadjapoulos (40), Mayhew et al (41), Kim et al (42), Mayer et al (36) and Fukunaga et al (35).
  • the liposomes can be made from any of the conventional synthetic or natural phospholipid liposome materials including phospholipius from natural sources such as egg, plant or animal sources such as phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, sphingomyelin, phosphatidylserine or phosphatidylinositol.
  • natural sources such as egg, plant or animal sources such as phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, sphingomyelin, phosphatidylserine or phosphatidylinositol.
  • Synthetic phospholipids may also be used, such as, but not limited to, dimyristoylphosphatidylcholine, dioleoylphosphatidylcholine, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, dilauroylphosphatidylethanolamine, dimyristoylphosphatidylcholine, dipalmitoylphosphatidylcholine, dioleoylphosphatidylethanolamine and distearoylphosphatidylethanolamine.
  • additives such as cholesterol or other sterols, glycolipids, cerebrosides, gangliosides, sphingolipids, glucopsychosine, or psychosine can also be added as is conventionally known.
  • the relative amounts of phospholipid and additives used in the liposomes may be varied if desired. The preferred ranges are from about 80-99 mole percent phospholipid and 1 to 20 mole percent psychosine or other additive.
  • Cholesterol may be used in amounts ranging from 0 to 50 mole percent.
  • the relative amounts of antiviral nucleoside analogue entrapped in liposomes can be varied with the concentration of entrapped analogue in the liposome aqueous compartment ranging from about 0.001 mM to about 300 mM.
  • the liposome entrapped phosphorylated nucleoside analogue is administered to patients by any of the known procedures utilized for administering liposomes.
  • the liposomes can be administered intravenously, intraperitoneally or intramuscularly as a buffered aqueous solution.
  • Any pharmaceutically acceptable aqueous buffer may be utilized so long as it does not destroy the liposome structure or the activity of the encapsulated phosphorylated nucleoside analogue.
  • One suitable aqueous buffer is 150 mM NaCl containing 5mM Na-Phosphate with a pH of about 7.4; other physiological buffered salt solutions may also be used.
  • the dosage may vary depending upon the extent and severity of the infection. Dosage levels of encapsulated phosphorylated nucleoside analogue should be such that about 0.001 mg/kilogram to 1000 mg/kilogram be administered to the patient on a daily basis.
  • Labeled AZT-5'-monophosphate [ 3 H]AZT-MP) was prepared according to the phosphorous oxychloride method of Toorchen and Topal (34). Twenty nanomoles cf AZT (260 microcuries) was dried under nitrogen. Twenty microliters of trimethylphosphate and 4 microliters of triethylamine were added and the mixture cooled to -10°C. Four microliters of phosphorus oxychloride was added and the mixture was allowed to react at -10 °C for 30 minutes. The reaction was stopped by addition of an equal volume of 0.5 M aqueous triethylamine. AZT was converted to AZT-MP in a yield of greater than 90 percent as judged by HPLC on Altex C18 Ultrosphere-ODS column.
  • liposomal AZT monophosphate The effect of liposomal AZT monophosphate on HIV replication in MT-2 and U937 cells and human macrophages in culture was tested as follows:
  • a thin film of 27 mg cholesterol and 110 mg egg phosphatidylcholine was prepared by rotary evaporation in vacuo and 1 ml of RPMI medium containing 60 nmol of AZT-MP and 6 uCi [ 3 H]AZT-MP was added and the mixture was shaken at 20°C. for 20 min followed by 10 cycles of vortexing to produce MLV containing [ 3 H]AZT-MP.
  • a Lipex Extruder Lipex Biomembranes, Inc.
  • small unilamellar vesicles of 100 nanometer diameter were prepared by the method of Mayer et al (36). This procedure is based on extrusion of large multilamellar vesicles through two stacked polycarbonate filters (Nucleopore, Pleasanton, CA).
  • the resulting liposome preparation was applied to a 1 ⁇ 15 cm column of Sepharose 4B and eluted with RPMI buffer.
  • EV 100 liposomes containing [ 3 H]AZT-MP were added in various concentration to MT-2 and U937 cells growing in ELISA plates; to other wells were added AZT-MP and AZT. After 3 days the MT-2 cells (6 ⁇ 10 5 cells/well) were examined for cytopathic effects (CPE) and the results of CPE grading are shown in Table 3. TABLE 3
  • Liposomes containing [ 3 H]AZT-monophosphate were prepared in RPMI medium by the method of Mayer et al (36) and the liposomal AZT-MP encapsulated was determined by the 3 H content of the pooled liposomal peak. Liposomes containing [ 3 H] -AZT-MP were added to MT-2 cells infected with HIV in a final volume of 0.200 ml of RPMI medium containing 10% fetal calf serum.
  • Liposome A consisted of 67 mole % egg phosphatidylcholine and 33 mole % cholesterol and Liposome B was made up of 6.6 mole % psychosine and 60 mole % egg phosphatidylcholine and 33.3 mole % cholesterol. Grading of CPD was done as described by Haertle et al (44). In this system 1+ corresponds to 1 to 3 syncytia (giant cells) per well.
  • 2+ corresponds to 3-10 syncytia per well and up to 20% cell death; 3+ corresponds to 10-30 syncytia per well and 20-70% drop in cell viability; 4+ corresponds to more than 30 syncytia per well and at least a 70% fall in viable cell count (44).
  • Liposomes containing [ 3 H]AZT-MP were prepared as in Table 1 and added to U937 cells infected with HIV in 0.200 ml of RPMI containing 10% fetal calf serum.
  • Liposome A consisted of 67 mole % egg phosphatidylcholine and 33 mole % cholesterol and liposome B contained 6.6 mole % psychosine and 60 mole % egg phosphatidylcholine and 33 mole % cholesterol. Results are mean of 2 replicates.
  • Liposome of egg phosphatidylcholine containing [ 3 H]AZT-MP in the indicated concentration were prepared as in Tab ⁇ e 1 and added to human macrophages. After 3 days in culture the supernatants were assayed for gp24.
  • Liposome A consisted of 67 mole % egg phosphatidylcholine and 33 mole % cholesterol and liposome B contained 6.6 mole % psychosine and 60 mole % egg phosphatidylcholine and 33 mole % cholesterol. Additional examples of practice are as follows:
  • Liposomes of egg phosphatidylcholine/cholesterol (2/1) (100 nanometer diameter) containing [ 3 H]AZT-MP were prepared in RPMI medium by the extrusion method of Mayer et al (36), and the amount of [ 3 H]AZT-MP encapsulated was determined by 3 H counts in the voiding peak obtained by gel permeating chromatography using Sepharose 4B. Varying amounts of AZT-MP were added and the effect determined on cells infected with HIV by measuring production of HIV antigen gp24 using the DuPont Elisa assay kit. Two liposome types were prepared -- liposome A and liposome B.
  • Liposome A consisted of 67 mole % egg phosphatidylcholine and 33 mole % cholesterol and liposome B contained 6.6 mole % psychosine and 60 mole % egg phosphatidylcholine and 33 mole % cholesterol. The results of the tests are shown in Table 6.
  • the CD4 (T4) antigen is an essential component of the receptor for the AIDS retrovirus.
  • T-lymphocyte T4 molecule behaves as the receptor for human retrovirus LAV.
  • the T4 gene enclodes the AIDS virus receptor and is expressed in the immune system and the brain. Cell 47:333.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Virology (AREA)
  • Communicable Diseases (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oncology (AREA)
  • Molecular Biology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • AIDS & HIV (AREA)
  • Dispersion Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Saccharide Compounds (AREA)

Abstract

La composition décrite s'utilise pour traiter le syndrome d'immunodéficience acquise (SIDA) et des infections rétrovirales apparentées. Cette composition consiste en un analogue de nucléoside phosphorylé qui est encapsulé dans un liposome. Des dérivés de 5'-mono-phosphate d'analogues de didésoxydinucléoside tels que AZT, ddC et ddA sont encapsulés dans des liposomes d'une manière qui empêche ou réduit sensiblement les fuites, ce qui se traduit par des effets secondaires toxiques réduits de ces médicaments et une inhibition accrue de la réplication des virus VIH ou apparentés présents dans des monocytes/macrophages et autres cellules infectées.
PCT/US1988/003210 1987-09-22 1988-09-19 Analogues de nucleosides liposomiques pour le traitement du sida WO1989002733A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US099,755 1979-12-03
US9975587A 1987-09-22 1987-09-22

Publications (1)

Publication Number Publication Date
WO1989002733A1 true WO1989002733A1 (fr) 1989-04-06

Family

ID=22276457

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1988/003210 WO1989002733A1 (fr) 1987-09-22 1988-09-19 Analogues de nucleosides liposomiques pour le traitement du sida

Country Status (4)

Country Link
EP (1) EP0380558A4 (fr)
JP (1) JPH03501253A (fr)
AU (1) AU2526188A (fr)
WO (1) WO1989002733A1 (fr)

Cited By (59)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0350287A3 (fr) * 1988-07-07 1990-08-01 NeXstar Pharmaceuticals, Inc. Dérivés lipidiques de nucléosides antiviraux, incorporation liposomale et méthode d'utilisation
WO1990014074A1 (fr) * 1989-05-22 1990-11-29 Vical, Inc. Formulations liposomiques ameliorees de nucleotides et d'analogues de nucleotides
EP0399438A3 (fr) * 1989-05-22 1991-09-04 Roche Diagnostics GmbH Procédé pour la détermination de la synthèse des acides nucléiques dans les cellules eucaryotes par marquage non-radioactif
EP0461225A4 (en) * 1989-12-08 1993-02-10 City Of Hope Circumvention of human tumor drug resistance
WO1993009805A1 (fr) * 1991-11-15 1993-05-27 Laboratoires Inocosm Composition lipidique polaire d'origine vegetale
EP0674646A4 (fr) * 1989-11-22 1996-01-17 Vestar Inc Derives lipidiques de phosphonoacides destines a etre incorpores dans les liposomes et procede d'utilisation.
US5744461A (en) * 1989-11-22 1998-04-28 Nexstar Pharmaceuticals, Inc. Lipid derivatives of phosphonoacids for liposomal incorporation and method of use
US5817638A (en) * 1988-07-07 1998-10-06 Nexstar Pharmaceuticals, Inc. Antiviral liponucleosides: treatment of hepatitis B
US5817646A (en) * 1991-11-15 1998-10-06 Laboratoires Inocosm Polar lipid composition of plant origin
US6245749B1 (en) 1994-10-07 2001-06-12 Emory University Nucleosides with anti-hepatitis B virus activity
US6252060B1 (en) 1988-07-07 2001-06-26 Nexstar Pharmaceuticals, Inc. Antiviral liponucleosides: treatment of hepatitis B
WO2001012228A3 (fr) * 1999-08-13 2001-08-30 Univ Maryland Biotech Inst Compositions pour le traitement des infections virales, et procedes correspondants
US6395716B1 (en) 1998-08-10 2002-05-28 Novirio Pharmaceuticals Limited β-L-2′-deoxy-nucleosides for the treatment of hepatitis B
US6444652B1 (en) 1998-08-10 2002-09-03 Novirio Pharmaceuticals Limited β-L-2'-deoxy-nucleosides for the treatment of hepatitis B
US6448392B1 (en) 1985-03-06 2002-09-10 Chimerix, Inc. Lipid derivatives of antiviral nucleosides: liposomal incorporation and method of use
US6455073B1 (en) 2000-07-10 2002-09-24 Enzrel, Inc. Covalent microparticle-drug conjugates for biological targeting
US6528515B1 (en) 1998-11-02 2003-03-04 Triangle Pharmaceuticals, Inc. Combination therapy to treat hepatitis B virus
US6599887B2 (en) 1988-07-07 2003-07-29 Chimerix, Inc. Methods of treating viral infections using antiviral liponucleotides
US6602902B2 (en) 1996-05-22 2003-08-05 Protarga, Inc. Dha-pharmaceutical agent conjugates to improve tissue selectivity
US6670342B2 (en) 2000-03-29 2003-12-30 Georgetown University Method of treating hepatitis delta virus infection
WO2004002999A2 (fr) 2002-06-28 2004-01-08 Idenix (Cayman) Limited Promedicaments a nucleosides 2' et 3' destines a traiter les infections aux flavivirus
US6689760B1 (en) 2000-07-10 2004-02-10 Enzrel Inc. Anti-mycobacterial compositions
US6723728B2 (en) 2001-03-01 2004-04-20 Gilead Sciences, Inc. Polymorphic and other crystalline forms cis-FTC
US6761901B1 (en) 2000-05-02 2004-07-13 Enzrel Inc. Liposome drug delivery
US6787526B1 (en) 2000-05-26 2004-09-07 Idenix Pharmaceuticals, Inc. Methods of treating hepatitis delta virus infection with β-L-2′-deoxy-nucleosides
US6824790B2 (en) 2002-01-09 2004-11-30 Enzrel Inc. Liposome drug delivery of polycyclic, aromatic, antioxidant or anti-inflammatory compounds
WO2005003147A2 (fr) 2003-05-30 2005-01-13 Pharmasset, Inc. Analogues de nucleosides fluores modifies
US6875751B2 (en) 2000-06-15 2005-04-05 Idenix Pharmaceuticals, Inc. 3′-prodrugs of 2′-deoxy-β-L-nucleosides
US7138376B2 (en) 2001-09-28 2006-11-21 Idenix Pharmaceuticals, Inc. Methods and compositions for treating hepatitis C virus using 4'-modified nucleosides
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
US7192936B2 (en) 2002-06-28 2007-03-20 Idenix Pharmaceuticals, Inc. Modified 2′ and 3′-nucleoside prodrugs for treating Flaviviridae infections
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
US7456155B2 (en) 2002-06-28 2008-11-25 Idenix Pharmaceuticals, Inc. 2′-C-methyl-3′-O-L-valine ester ribofuranosyl cytidine for treatment of flaviviridae infections
US7582618B2 (en) 2002-06-28 2009-09-01 Idenix Pharmaceuticals, Inc. 2′-C-methyl-3′-O-L-valine ester ribofuranosyl cytidine for treatment of flaviviridae infections
US7598373B2 (en) 2002-12-12 2009-10-06 Idenix Pharmaceuticals, Inc. Process for the production of 2-C-methyl-D-ribonolactone
US7601820B2 (en) 2004-07-21 2009-10-13 Pharmasset, Inc. Preparation of alkyl-substituted 2-deoxy-2-fluoro-D-ribofuranosyl pyrimidines and purines and their derivatives
US7608597B2 (en) 2000-05-23 2009-10-27 Idenix Pharmaceuticals, Inc. Methods and compositions for treating hepatitis C virus
US7824851B2 (en) 2002-11-15 2010-11-02 Idenix Pharmaceuticals, Inc. 2′-branched nucleosides and Flaviviridae mutation
EP2251015A1 (fr) 2000-10-18 2010-11-17 Pharmasset, Inc. Nucléosides modifiés pour traiter des infections virales et une prolifération cellulaire anormale
EP2390257A1 (fr) 1998-02-25 2011-11-30 Emory University 2'-Fluoronucléosides
EP2574341A1 (fr) 2004-03-29 2013-04-03 University Of South Florida Traitement efficace des tumeurs et du cancer avec de la triciribine et composés apparentés
WO2013082476A1 (fr) 2011-11-30 2013-06-06 Emory University Inhibiteurs de jak antiviraux utiles dans le traitement ou la prévention d'infections rétrovirales et autres infections virales
US8492539B2 (en) 2004-09-14 2013-07-23 Gilead Pharmasset Llc Preparation of 2′-fluoro-2′-alkyl-substituted or other optionally substituted ribofuranosyl pyrimidines and purines and their derivatives
US8551973B2 (en) 2008-12-23 2013-10-08 Gilead Pharmasset Llc Nucleoside analogs
US8569478B2 (en) 2005-09-26 2013-10-29 Gilead Pharmasset Llc Modified 4′-nucleosides as antiviral agents
US8580765B2 (en) 2007-03-30 2013-11-12 Gilead Pharmasset Llc Nucleoside phosphoramidate prodrugs
US8618076B2 (en) 2009-05-20 2013-12-31 Gilead Pharmasset Llc Nucleoside phosphoramidates
US8629263B2 (en) 2009-05-20 2014-01-14 Gilead Pharmasset Llc Nucleoside phosphoramidates
US8716263B2 (en) 2008-12-23 2014-05-06 Gilead Pharmasset Llc Synthesis of purine nucleosides
US8716262B2 (en) 2008-12-23 2014-05-06 Gilead Pharmasset Llc Nucleoside phosphoramidates
US8742101B2 (en) 2003-07-25 2014-06-03 Idenix Pharmaceuticals, Inc. Purine nucleoside analogues for treating flaviviridae including hepatitis C
US8841275B2 (en) 2010-11-30 2014-09-23 Gilead Pharmasset Llc 2′-spiro-nucleosides and derivatives thereof useful for treating hepatitis C virus and dengue virus infections
US8859756B2 (en) 2010-03-31 2014-10-14 Gilead Pharmasset Llc Stereoselective synthesis of phosphorus containing actives
US8889159B2 (en) 2011-11-29 2014-11-18 Gilead Pharmasset Llc Compositions and methods for treating hepatitis C virus
US8895531B2 (en) 2006-03-23 2014-11-25 Rfs Pharma Llc 2′-fluoronucleoside phosphonates as antiviral agents
EP3042660A2 (fr) 2008-04-15 2016-07-13 RFS Pharma, LLC. Dérivés de nucléosides pour le traitement d'infections de caliciviridae, y compris des infections de norovirus
US9968628B2 (en) 2000-05-26 2018-05-15 Idenix Pharmaceuticals Llc Methods and compositions for treating flaviviruses and pestiviruses
US11116783B2 (en) 2013-08-27 2021-09-14 Gilead Pharmasset Llc Combination formulation of two antiviral compounds

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4235871A (en) * 1978-02-24 1980-11-25 Papahadjopoulos Demetrios P Method of encapsulating biologically active materials in lipid vesicles
US4291024A (en) * 1978-04-10 1981-09-22 Turcotte Joseph G Cytotoxic liponucleotide analogs
US4544552A (en) * 1982-05-28 1985-10-01 Solco Basel Ag Process for the preparation of cell and tissue regenerating substances
US4704357A (en) * 1985-09-30 1987-11-03 United States Of America As Represented By The Department Of Health And Human Services Immortalized T-lymphocyte cell line for testing HTLV-III inactivation

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0114577A1 (fr) * 1983-01-21 1984-08-01 MAGIS FARMACEUTICI S.p.A. Composition pharmaceutique
EP0152379A3 (fr) * 1984-02-15 1986-10-29 Ciba-Geigy Ag Procédé pour la préparation de compositions pharmaceutiques contenant des liposomes unilamellaires
JPS62501777A (ja) * 1985-08-26 1987-07-16 アメリカ合衆国 2′,3′―ジデオキシシチジンを含有する抗htlv―3/lav剤
US4916122A (en) * 1987-01-28 1990-04-10 University Of Georgia Research Foundation, Inc. 3'-Azido-2',3'-dideoxyuridine anti-retroviral composition
IE63869B1 (en) * 1986-11-06 1995-06-14 Res Dev Foundation Aerosols containing liposomes and method for their preparation
NL8700089A (nl) * 1987-01-15 1988-08-01 Stichting Rega V Z W Therapeutische toepassing van dideoxythymidine en dideoxythymidineen.
IL86009A (en) * 1987-04-10 1991-09-16 Us Health Liposome-encapsulated phosphorylated nucleosides for treatment of retroviral diseases

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4235871A (en) * 1978-02-24 1980-11-25 Papahadjopoulos Demetrios P Method of encapsulating biologically active materials in lipid vesicles
US4291024A (en) * 1978-04-10 1981-09-22 Turcotte Joseph G Cytotoxic liponucleotide analogs
US4544552A (en) * 1982-05-28 1985-10-01 Solco Basel Ag Process for the preparation of cell and tissue regenerating substances
US4704357A (en) * 1985-09-30 1987-11-03 United States Of America As Represented By The Department Of Health And Human Services Immortalized T-lymphocyte cell line for testing HTLV-III inactivation

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
Antimicrobial Agents and Chemotherapy, Vol. 27, No. 6 published June 1985. KENDE et al. "Enhanced Efficacy of Liposome-Encapsulated Ribavirin against Riet Valley Fever Infection in Mice", pages 903-907. *
Biochemical Pharmacology Vol. 35, No. 13 published 1986, COONEY et al. "Initial Studies on the Cellular Pharmacology of 2', 3'-Dideoxycitidine, an Inhibitor of HTLV-III Activity", page 2065-2068. *
New Anti-Retroviral Agents and Delivery System for the Same, (U.S.) Department of Health and Human Services, Washington, D.C., PB87-224382 published 10 April 1987, pages 1-21. *
Proc. Natl. Acad. Sci. USA, Vol. 83 published November 1986, FURMAN et al. "Phosphorylation of 3' - Azido- -3- Deoxythymidine and Selective Interaction of the 5'- Triphosphate with Human Immunodeficienct Virus Reverse Transcriptase", pages 8333-8337. *
See also references of EP0380558A4 *

Cited By (132)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6448392B1 (en) 1985-03-06 2002-09-10 Chimerix, Inc. Lipid derivatives of antiviral nucleosides: liposomal incorporation and method of use
US6252060B1 (en) 1988-07-07 2001-06-26 Nexstar Pharmaceuticals, Inc. Antiviral liponucleosides: treatment of hepatitis B
EP0350287A3 (fr) * 1988-07-07 1990-08-01 NeXstar Pharmaceuticals, Inc. Dérivés lipidiques de nucléosides antiviraux, incorporation liposomale et méthode d'utilisation
US5223263A (en) * 1988-07-07 1993-06-29 Vical, Inc. Liponucleotide-containing liposomes
US5817638A (en) * 1988-07-07 1998-10-06 Nexstar Pharmaceuticals, Inc. Antiviral liponucleosides: treatment of hepatitis B
US6599887B2 (en) 1988-07-07 2003-07-29 Chimerix, Inc. Methods of treating viral infections using antiviral liponucleotides
WO1990014074A1 (fr) * 1989-05-22 1990-11-29 Vical, Inc. Formulations liposomiques ameliorees de nucleotides et d'analogues de nucleotides
EP0399438A3 (fr) * 1989-05-22 1991-09-04 Roche Diagnostics GmbH Procédé pour la détermination de la synthèse des acides nucléiques dans les cellules eucaryotes par marquage non-radioactif
US5455157A (en) * 1989-05-22 1995-10-03 Boehringer Mannheim Gmbh Method for the non-radioactive measurement of the nucleic acid synthesis in eukaryotic cells
EP0674646A4 (fr) * 1989-11-22 1996-01-17 Vestar Inc Derives lipidiques de phosphonoacides destines a etre incorpores dans les liposomes et procede d'utilisation.
US5744461A (en) * 1989-11-22 1998-04-28 Nexstar Pharmaceuticals, Inc. Lipid derivatives of phosphonoacids for liposomal incorporation and method of use
EP0461225A4 (en) * 1989-12-08 1993-02-10 City Of Hope Circumvention of human tumor drug resistance
US5817646A (en) * 1991-11-15 1998-10-06 Laboratoires Inocosm Polar lipid composition of plant origin
WO1993009805A1 (fr) * 1991-11-15 1993-05-27 Laboratoires Inocosm Composition lipidique polaire d'origine vegetale
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
US7468357B2 (en) 1994-10-07 2008-12-23 Emory University Nucleosides with anti-hepatitis B virus activity
US6245749B1 (en) 1994-10-07 2001-06-12 Emory University Nucleosides with anti-hepatitis B virus activity
US7199151B2 (en) 1996-05-22 2007-04-03 Luitpold Pharmaceuticals, Inc. DHA-pharmaceutical agent conjugates of taxanes
US6602902B2 (en) 1996-05-22 2003-08-05 Protarga, Inc. Dha-pharmaceutical agent conjugates to improve tissue selectivity
EP2390257A1 (fr) 1998-02-25 2011-11-30 Emory University 2'-Fluoronucléosides
EP2392580A1 (fr) 1998-02-25 2011-12-07 Emory University 2'-Fluoronucléosides
EP2415776A1 (fr) 1998-08-10 2012-02-08 IDENIX Pharmaceuticals, Inc. Bêta-L-2'-désoxy-nucléosides pour le traitement de l'hépatite B
US6569837B1 (en) 1998-08-10 2003-05-27 Idenix Pharmaceuticals Inc. β-L-2′-deoxy pyrimidine 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
US6395716B1 (en) 1998-08-10 2002-05-28 Novirio Pharmaceuticals Limited β-L-2′-deoxy-nucleosides for the treatment of hepatitis B
US7304043B2 (en) 1998-08-10 2007-12-04 Idenix Pharmaceuticals, Inc. β-L-2′-deoxy-nucleosides for the treatment of hepatitis B
US6444652B1 (en) 1998-08-10 2002-09-03 Novirio Pharmaceuticals Limited β-L-2'-deoxy-nucleosides for the treatment of hepatitis B
US9290533B2 (en) 1998-08-10 2016-03-22 Novartis Ag β-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
US7795238B2 (en) 1998-08-10 2010-09-14 Idenix Pharmaceuticals, Inc. β-L-2′-deoxy-nucleosides for the treatment of hepatitis B
US7572800B2 (en) 1998-11-02 2009-08-11 Gilead Sciences, Inc. Combination therapy to treat hepatitis B virus
EP1382343A1 (fr) 1998-11-02 2004-01-21 Triangle Pharmaceuticals Inc. Thérapie combinée pour le traitement du virus de l'hepatite B
US6528515B1 (en) 1998-11-02 2003-03-04 Triangle Pharmaceuticals, Inc. Combination therapy to treat hepatitis B virus
US6479466B1 (en) 1999-08-13 2002-11-12 University Of Maryland Compositions for treating viral infections, and methods therefor
AU765724B2 (en) * 1999-08-13 2003-09-25 University Of Maryland Biotechnology Institute Compositions for treating viral infections, and methods therefor
WO2001012228A3 (fr) * 1999-08-13 2001-08-30 Univ Maryland Biotech Inst Compositions pour le traitement des infections virales, et procedes correspondants
US7511027B2 (en) 2000-03-29 2009-03-31 Georgetown University Method of treating hepatitis delta virus infection
US6670342B2 (en) 2000-03-29 2003-12-30 Georgetown University Method of treating hepatitis delta virus infection
US6761901B1 (en) 2000-05-02 2004-07-13 Enzrel Inc. Liposome drug delivery
US7387791B2 (en) 2000-05-02 2008-06-17 Oradel Medical Ltd. Liposome drug delivery
US10363265B2 (en) 2000-05-23 2019-07-30 Idenix Pharmaceuticals Llc Methods and compositions for treating hepatitis C virus
US7608597B2 (en) 2000-05-23 2009-10-27 Idenix Pharmaceuticals, Inc. Methods and compositions for treating hepatitis C virus
US10758557B2 (en) 2000-05-23 2020-09-01 Idenix Pharmaceuticals Llc Methods and compositions for treating hepatitis C virus
EP2319856A1 (fr) 2000-05-23 2011-05-11 Idenix (Cayman) Limited Procédés et compositions pour traiter le virus de l'hépatite C
US9968628B2 (en) 2000-05-26 2018-05-15 Idenix Pharmaceuticals Llc Methods and compositions for treating flaviviruses and pestiviruses
US6787526B1 (en) 2000-05-26 2004-09-07 Idenix Pharmaceuticals, Inc. Methods of treating hepatitis delta virus infection with β-L-2′-deoxy-nucleosides
US7585851B2 (en) 2000-06-15 2009-09-08 Idenix Pharmaceuticals, Inc. 3′-prodrugs of 2′-deoxy-β-L-nucleosides
US6875751B2 (en) 2000-06-15 2005-04-05 Idenix Pharmaceuticals, Inc. 3′-prodrugs of 2′-deoxy-β-L-nucleosides
US6455073B1 (en) 2000-07-10 2002-09-24 Enzrel, Inc. Covalent microparticle-drug conjugates for biological targeting
US6689760B1 (en) 2000-07-10 2004-02-10 Enzrel Inc. Anti-mycobacterial compositions
US6676972B2 (en) 2000-07-10 2004-01-13 Oregon Health And Science University Covalent microparticle-drug conjugates for biological targeting
EP2251015A1 (fr) 2000-10-18 2010-11-17 Pharmasset, Inc. Nucléosides modifiés pour traiter des infections virales et une prolifération cellulaire anormale
US8637535B2 (en) 2001-03-01 2014-01-28 Gilead Sciences, Inc. Polymorphic and other crystalline forms of cis-FTC
US7544692B2 (en) 2001-03-01 2009-06-09 Gilead Sciences, Inc. Polymorphic and other crystalline forms of cis-FTC
US6723728B2 (en) 2001-03-01 2004-04-20 Gilead Sciences, Inc. Polymorphic and other crystalline forms cis-FTC
US7138376B2 (en) 2001-09-28 2006-11-21 Idenix Pharmaceuticals, Inc. Methods and compositions for treating hepatitis C virus using 4'-modified nucleosides
US6824790B2 (en) 2002-01-09 2004-11-30 Enzrel Inc. Liposome drug delivery of polycyclic, aromatic, antioxidant or anti-inflammatory compounds
US7316818B2 (en) 2002-01-09 2008-01-08 Oradel Medical Ltd. Liposome drug delivery of polycyclic, aromatic, antioxidant or anti-inflammatory compounds
US7456155B2 (en) 2002-06-28 2008-11-25 Idenix Pharmaceuticals, Inc. 2′-C-methyl-3′-O-L-valine ester ribofuranosyl cytidine for treatment of flaviviridae infections
US7547704B2 (en) 2002-06-28 2009-06-16 Idenix Pharmaceuticals, Inc. Modified 2′ and 3′-nucleoside prodrugs for treating Flaviviridae infections
US7608600B2 (en) 2002-06-28 2009-10-27 Idenix Pharmaceuticals, Inc. Modified 2′ and 3′-nucleoside prodrugs for treating Flaviviridae infections
US7582618B2 (en) 2002-06-28 2009-09-01 Idenix Pharmaceuticals, Inc. 2′-C-methyl-3′-O-L-valine ester ribofuranosyl cytidine for treatment of flaviviridae infections
US7625875B2 (en) 2002-06-28 2009-12-01 Idenix Pharmaceuticals, Inc. 2′ and 3′-nucleoside prodrugs for treating Flaviviridae infections
US7635689B2 (en) 2002-06-28 2009-12-22 Idenix Pharmaceuticals, Inc. Modified 2′ and 3′-nucleoside prodrugs for treating Flaviviridae infections
US7662798B2 (en) 2002-06-28 2010-02-16 Idenix Pharmaceuticals, Inc. 2′ and 3′-nucleoside prodrugs for treating Flaviviridae infections
US7384924B2 (en) 2002-06-28 2008-06-10 Idenix Pharmaceuticals, Inc. Modified 2′ and 3′-nucleoside prodrugs for treating Flaviviridae infections
US7192936B2 (en) 2002-06-28 2007-03-20 Idenix Pharmaceuticals, Inc. Modified 2′ and 3′-nucleoside prodrugs for treating Flaviviridae infections
EP2799442A1 (fr) 2002-06-28 2014-11-05 IDENIX Pharmaceuticals, Inc. Promédicaments à base de nucléosides modifiés en 2' et 3' pour le traitement d'infections par flavivirus
US7365057B2 (en) 2002-06-28 2008-04-29 Idenix Pharmaceuticals, Inc. Modified 2′ and 3′-nucleoside prodrugs for treating Flavivridae infections
EP2332952A1 (fr) 2002-06-28 2011-06-15 IDENIX Pharmaceuticals, Inc. Promédicaments à base de nucléosides modifiés en 2' et 3' pour le traitement d'infections par flavivirus
WO2004002999A2 (fr) 2002-06-28 2004-01-08 Idenix (Cayman) Limited Promedicaments a nucleosides 2' et 3' destines a traiter les infections aux flavivirus
US7858594B2 (en) 2002-08-06 2010-12-28 Novartis Pharma Ag 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
US7323451B2 (en) 2002-08-06 2008-01-29 Idenix Pharmaceuticals, Inc. Crystalline and amorphous forms of beta-L-2′-deoxythymidine
US7928086B2 (en) 2002-09-13 2011-04-19 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
US8158606B2 (en) 2002-09-13 2012-04-17 Novartis, Ag β-L-2′-deoxynucleosides for the treatment of resistant HBV strains and combination therapies
US10525072B2 (en) 2002-11-15 2020-01-07 Idenix Pharmaceuticals Llc 2′-branched nucleosides and flaviviridae mutation
US7824851B2 (en) 2002-11-15 2010-11-02 Idenix Pharmaceuticals, Inc. 2′-branched nucleosides and Flaviviridae mutation
US7598373B2 (en) 2002-12-12 2009-10-06 Idenix Pharmaceuticals, Inc. Process for the production of 2-C-methyl-D-ribonolactone
WO2005003147A2 (fr) 2003-05-30 2005-01-13 Pharmasset, Inc. Analogues de nucleosides fluores modifies
EP2345659A1 (fr) 2003-05-30 2011-07-20 Pharmasset, Inc. Analogues de nucléosides fluores modifiés
EP2604620A1 (fr) 2003-05-30 2013-06-19 Gilead Pharmasset LLC Analogues de nucléosides fluorés modifiés
US7429572B2 (en) 2003-05-30 2008-09-30 Pharmasset, Inc. Modified fluorinated nucleoside analogues
EP2345657A1 (fr) 2003-05-30 2011-07-20 Pharmasset, Inc. Analogues de nucléosides fluores modifiés
US10287311B2 (en) 2003-05-30 2019-05-14 Gilead Pharmasset Llc Modified fluorinated nucleoside analogues
EP3521297A1 (fr) 2003-05-30 2019-08-07 Gilead Pharmasset LLC Analogues de nucléoside fluorés modifiés
EP4032897A1 (fr) 2003-05-30 2022-07-27 Gilead Pharmasset LLC Analogues de nucléoside fluorés modifiés
EP2345658A1 (fr) 2003-05-30 2011-07-20 Pharmasset, Inc. Analogues de nucléosides fluores modifiés
EP2345661A1 (fr) 2003-05-30 2011-07-20 Pharmasset, Inc. Analogues de nucléosides fluores modifiés
US9186369B2 (en) 2003-07-25 2015-11-17 Idenix Pharmaceuticals, Llc Purine nucleoside analogues for treating flaviviridae including hepatitis C
US8742101B2 (en) 2003-07-25 2014-06-03 Idenix Pharmaceuticals, Inc. Purine nucleoside analogues for treating flaviviridae including hepatitis C
EP2574341A1 (fr) 2004-03-29 2013-04-03 University Of South Florida Traitement efficace des tumeurs et du cancer avec de la triciribine et composés apparentés
US7601820B2 (en) 2004-07-21 2009-10-13 Pharmasset, Inc. Preparation of alkyl-substituted 2-deoxy-2-fluoro-D-ribofuranosyl pyrimidines and purines and their derivatives
US8492539B2 (en) 2004-09-14 2013-07-23 Gilead Pharmasset Llc Preparation of 2′-fluoro-2′-alkyl-substituted or other optionally substituted ribofuranosyl pyrimidines and purines and their derivatives
US10577359B2 (en) 2004-09-14 2020-03-03 Gilead Pharmasset Llc Preparation of 2′-fluoro-2′-alkyl-substituted or other optionally substituted ribofuranosyl pyrimidines and purines and their derivatives
US8569478B2 (en) 2005-09-26 2013-10-29 Gilead Pharmasset Llc Modified 4′-nucleosides as antiviral agents
EP3159351A2 (fr) 2005-09-26 2017-04-26 Gilead Pharmasset LLC 3'-azido-4'-ethynyl-nucleosides modifiés en tant qu'agents antiviraux
US8895531B2 (en) 2006-03-23 2014-11-25 Rfs Pharma Llc 2′-fluoronucleoside phosphonates as antiviral agents
US11642361B2 (en) 2007-03-30 2023-05-09 Gilead Sciences, Inc. Nucleoside phosphoramidate prodrugs
US10183037B2 (en) 2007-03-30 2019-01-22 Gilead Pharmasset Llc Nucleoside phosphoramidate prodrugs
US8735372B2 (en) 2007-03-30 2014-05-27 Gilead Pharmasset Llc Nucleoside phosphoramidate prodrugs
US8906880B2 (en) 2007-03-30 2014-12-09 Gilead Pharmasset Llc Nucleoside phosphoramidate prodrugs
US8957046B2 (en) 2007-03-30 2015-02-17 Gilead Pharmasset Llc Nucleoside phosphoramidate prodrugs
US9585906B2 (en) 2007-03-30 2017-03-07 Gilead Pharmasset Llc Nucleoside phosphoramidate prodrugs
US12121529B2 (en) 2007-03-30 2024-10-22 Gilead Sciences, Inc. Nucleoside phosphoramidate prodrugs
US9085573B2 (en) 2007-03-30 2015-07-21 Gilead Pharmasset Llc Nucleoside phosphoramidate prodrugs
US8580765B2 (en) 2007-03-30 2013-11-12 Gilead Pharmasset Llc Nucleoside phosphoramidate prodrugs
EP3042660A2 (fr) 2008-04-15 2016-07-13 RFS Pharma, LLC. Dérivés de nucléosides pour le traitement d'infections de caliciviridae, y compris des infections de norovirus
US8957045B2 (en) 2008-12-23 2015-02-17 Gilead Pharmasset Llc Nucleoside phosphoramidates
US8551973B2 (en) 2008-12-23 2013-10-08 Gilead Pharmasset Llc Nucleoside analogs
US9045520B2 (en) 2008-12-23 2015-06-02 Gilead Pharmasset Llc Synthesis of purine nucleosides
US8716263B2 (en) 2008-12-23 2014-05-06 Gilead Pharmasset Llc Synthesis of purine nucleosides
US8716262B2 (en) 2008-12-23 2014-05-06 Gilead Pharmasset Llc Nucleoside phosphoramidates
US8735569B2 (en) 2009-05-20 2014-05-27 Gilead Pharmasset Llc Nucleoside phosphoramidates
US8633309B2 (en) 2009-05-20 2014-01-21 Gilead Pharmasset Llc Nucleoside phosphoramidates
US9637512B2 (en) 2009-05-20 2017-05-02 Gilead Pharmasset Llc Nucleoside phosphoramidates
US9206217B2 (en) 2009-05-20 2015-12-08 Gilead Pharmasset Llc Nucleoside phosphoramidates
US8618076B2 (en) 2009-05-20 2013-12-31 Gilead Pharmasset Llc Nucleoside phosphoramidates
US9284342B2 (en) 2009-05-20 2016-03-15 Gilead Pharmasset Llc Nucleoside phosphoramidates
US8629263B2 (en) 2009-05-20 2014-01-14 Gilead Pharmasset Llc Nucleoside phosphoramidates
US8642756B2 (en) 2009-05-20 2014-02-04 Gilead Pharmasset Llc Nucleoside phosphoramidates
US8859756B2 (en) 2010-03-31 2014-10-14 Gilead Pharmasset Llc Stereoselective synthesis of phosphorus containing actives
US9394331B2 (en) 2010-11-30 2016-07-19 Gilead Pharmasset Llc 2′-spiro-nucleosides and derivatives thereof useful for treating hepatitis C virus and dengue virus infections
US8841275B2 (en) 2010-11-30 2014-09-23 Gilead Pharmasset Llc 2′-spiro-nucleosides and derivatives thereof useful for treating hepatitis C virus and dengue virus infections
US8889159B2 (en) 2011-11-29 2014-11-18 Gilead Pharmasset Llc Compositions and methods for treating hepatitis C virus
US9549941B2 (en) 2011-11-29 2017-01-24 Gilead Pharmasset Llc Compositions and methods for treating hepatitis C virus
EP3750544A2 (fr) 2011-11-30 2020-12-16 Emory University Inhibiteurs jak destinées à la prévention ou au traitement des infections virales
WO2013082476A1 (fr) 2011-11-30 2013-06-06 Emory University Inhibiteurs de jak antiviraux utiles dans le traitement ou la prévention d'infections rétrovirales et autres infections virales
EP4556010A2 (fr) 2011-11-30 2025-05-21 Emory University Inhibiteurs jak destinées à la prévention ou au traitement d'une maladie causé par une coronaviridée
US11116783B2 (en) 2013-08-27 2021-09-14 Gilead Pharmasset Llc Combination formulation of two antiviral compounds
US11707479B2 (en) 2013-08-27 2023-07-25 Gilead Sciences, Inc. Combination formulation of two antiviral compounds

Also Published As

Publication number Publication date
EP0380558A1 (fr) 1990-08-08
JPH03501253A (ja) 1991-03-22
AU2526188A (en) 1989-04-18
EP0380558A4 (en) 1991-07-31

Similar Documents

Publication Publication Date Title
WO1989002733A1 (fr) Analogues de nucleosides liposomiques pour le traitement du sida
AU680812B2 (en) Lipid derivatives of phosphonoacids for liposomal incorporation and method of use
EP0350287B1 (fr) Dérivés lipidiques de nucléosides antiviraux, incorporation liposomale et méthode d'utilisation
US5463092A (en) Lipid derivatives of phosphonacids for liposomal incorporation and method of use
US6448392B1 (en) Lipid derivatives of antiviral nucleosides: liposomal incorporation and method of use
Hostetler et al. Greatly enhanced inhibition of human immunodeficiency virus type 1 replication in CEM and HT4-6C cells by 3'-deoxythymidine diphosphate dimyristoylglycerol, a lipid prodrug of 3'-deoxythymidine
Mayhew et al. Inhibition of tumor cell growth in vitro and in vivo by 1-β-D-arabinofuranosylcytosine entrapped within phospholipid vesicles
US6599887B2 (en) Methods of treating viral infections using antiviral liponucleotides
AU601848B2 (en) New anti-retroviral agents and delivery system
Steim et al. Lipid conjugates of antiretroviral agents. I. Azidothymidine-monophosphate-diglyceride: anti-HIV activity, physical properties, and interaction with plasma proteins
Zelphati et al. Inhibition of HIV-1 replication in cultured cells with phosphorylated dideoxyuridine derivatives encapsulated in immunoliposomes
Hostetler et al. Phosphatidylazidothymidine and phosphatidyl-ddC: assessment of uptake in mouse lymphoid tissues and antiviral activities in human immunodeficiency virus-infected cells and in Rauscher leukemia virus-infected mice
Konopka et al. Anti-HIV activity of amphotericin B-cholesteryl sulfate colloidal dispersion in vitro
EP0461225B1 (fr) Circonvention de la resistance humaine aux medicaments de la tumeur
Crews et al. Lipids are major components of human immunodeficiency virus (HIV): Modification of HIV lipid composition, membrane organization, and protein conformation by AL‐721®
Schwendener et al. Lipophilic arabinofuranosyl cytosine derivatives in liposomes
JPS63290824A (ja) ウイルス感染症治療剤
Betageri et al. Drug delivery using antibody-liposome conjugates
AU3731989A (en) Chemotherapeutic composition for aids
Mitsuya et al. Toward the rational design of antiretroviral therapy for human immunodeficiency virus (HIV) infection
AU5351490A (en) Inhibition of hiv using synergistic combinations of nucleoside derivatives
US20020055470A1 (en) Circumvention of human tumor drug resistance
Benatti et al. Erythrocyte-Based Targeted Release to Macrophages of an Azidothymidine Homodinucleotide Prevents Retroviral Infection
PT91101B (pt) Processo de preparacao de derivados lipidos de nucleosidos antivirais, de suspensoes de lipossomas e de composicoes farmaceuticas

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU JP

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE FR GB IT LU NL SE

WWE Wipo information: entry into national phase

Ref document number: 1988908811

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1988908811

Country of ref document: EP

WWR Wipo information: refused in national office

Ref document number: 1988908811

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1988908811

Country of ref document: EP

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