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WO1995032983A1 - Prevention de l'infection a vih chez des patients ayant ete exposes a ce virus - Google Patents

Prevention de l'infection a vih chez des patients ayant ete exposes a ce virus Download PDF

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Publication number
WO1995032983A1
WO1995032983A1 PCT/SE1995/000524 SE9500524W WO9532983A1 WO 1995032983 A1 WO1995032983 A1 WO 1995032983A1 SE 9500524 W SE9500524 W SE 9500524W WO 9532983 A1 WO9532983 A1 WO 9532983A1
Authority
WO
WIPO (PCT)
Prior art keywords
administration
daim
htv
exposure
hiv
Prior art date
Application number
PCT/SE1995/000524
Other languages
English (en)
Inventor
Bo Öberg
Original Assignee
Medivir Ab
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
Priority claimed from US08/251,316 external-priority patent/US5612319A/en
Priority claimed from SE9500348A external-priority patent/SE9500348D0/xx
Application filed by Medivir Ab filed Critical Medivir Ab
Priority to JP8500731A priority Critical patent/JPH10501217A/ja
Priority to CA002190862A priority patent/CA2190862A1/fr
Priority to AU26331/95A priority patent/AU697612B2/en
Priority to EP95921188A priority patent/EP0763048A1/fr
Publication of WO1995032983A1 publication Critical patent/WO1995032983A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • 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

  • This invention relates to preventing the establishment of HTV infection and /or HTV seroconversion in a human or simian after exposure to HTV.
  • HTV human immunodeficiency virus
  • AZT zidovudine
  • ddl dideoxy inosine
  • Prophylaxis as used in this technical field generally refers to the administration of an active agent to an at-risk individual in sufficient time to achieve and maintain effective concentrations in the target tissues before the individual enters the risk environment. This is the classic meaning of prophylaxis.
  • the position with regard to postexposure administration of anti-HIV agents is even less satisfactory than the above mentioned prophylactic attempts.
  • There are currently 13 published accounts (Niu et al; J Inf Dis 1993:168:1490-501) of seroconversion after accidental exposure to HTV notwithstanding rapid and sustained postexposure administration of large doses of AZT.
  • postexposure treatment has not prevented any HTV-1, HTV-2 or SIV infections (Niu et al, ibid).
  • European patent application 0 391 411 A2 describes a family of nucleoside analogues, including the active agent defined below, which family is implicated in the treatment of herpes infections and to some extent exhibits in vitro activity against HTV in a already infected cell line. No teaching or suggestion as to any prophylactic activity is apparent, which is in line with classical expectations as to the efficacy of nucleoside analogues, as discussed above.
  • International patent application nos. WO 88/08001 and WO 92/06102 extend to various nucleoside analogues of this type and demonstrate their activity against established rerroviral and HTV infections. However, there is no teaching or suggestion that any of their compounds can be administered after exposure to HIV and yet prevent the establishment of HTV infection or seroconversion.
  • the present invention provides a method for preventing the establishment of HTV infection and /or HIV seroconversion in a human or simian comprising the administration of an effective amount of the compound l-[2',3'-dideoxy- 3 (hydroxymethyl)- ⁇ -D-e ⁇ ythro-pentofuranosyl]-cytosine having the formula after exposure of said human or simian to HIV.
  • the invention further provides pharmaceutical compositions for use in this method, comprising an effective amount of the above defined active agent and a pharmaceutically acceptable diluent or carrier therefor.
  • the invention relates to the use of the above defined active agent in the manufacture of a medicament for postexposure administration to a human or simian to prevent the establishment of HIV infection or seroconversion.
  • the method and composition of the invention should be contrasted with such agents as AZT and ddl which at most appear to delay seroconversion until shortly after "treatment” is concluded and do not prevent the establishment of an HTV infection and ultimately the resulting disease.
  • the method and compositions of the present invention will be particularly useful for individuals at risk of accidental occupational exposure to HIV- positive material such as the staff or inmates of establishments such as hospitals, prisons and diagnostic or research laboratories. Such establishments can keep supplies of the compositions of the invention for rapid postexposure deployment in the event of accidental exposure to HTV.
  • the accidental exposure may comprise a needle stick or other surgical injury incurred by health care workers but in a wider context may result from any inadvertant exposure such as through sexual transmission, assault, body fluid splashes, erroneous blood transfusion or reuse of medical implements.
  • An advantage of postexposure administration, as distinct from prophylactic prevention of infection is that it avoids long term administration with potentially expensive agents and improves safety.
  • the currently used HTV agents such as AZT and ddl require life long administration if seroconversion is to be avoided. Additionally, postexposure administration can be extended to individuals not belonging to a high-risk occupation or subpopulation.
  • the above defined active agent is adminstered as soon as practicable following the exposure of the human or simian to HTV.
  • Advantageously administration is commenced within about one day following exposure, especially within eight hours.
  • administration of the active agent is commenced within about 3 hours following exposure and most preferably within about 1 hour.
  • This timescale allows the above defined active agent to be administered as an oral preparation, such as tablets or syrups or percutaneously as a lotion, suppository or enema.
  • at least the initial administration following discovery of the accidental exposure is parenteral, eg by subcutaneous, intramuscular or intravenous routes.
  • Such a formulation will comprise the above defined active agent together with one or more acceptable carriers and optionally other therapeutic ingredients.
  • the carrier(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient.
  • the formulations include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration.
  • the formulations may conveniently be presented in unit dosage form, e.g. tablets and sustained release capsules, and may be prepared by any mehtods well known in the art of pharmacy.
  • Such methods include the step of bringing into association the above defined a ⁇ tve agent with the carrier.
  • the formulations are prepared by uniformly and intimately bringing into association the active agent with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.
  • Formulations for oral administration in the present invention may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active agent; as a powder or granules; as a solution or a suspension of the active agent in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water in oil liquid emulsion and as a bolus etc.
  • suitable carrier includes vehicles such as common excipients e.g. binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone (Povidone), methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sucrose and starch; fillers and carriers, for example corn starch, gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride and alginic acid; and lubricants such as magnesium stearate and other metallic stearates, stearic acid, silicone fluid, talc waxes, oils and colloidal silica.
  • Flavouring agents such as peppermint, oil of wintergreen, cherry flavouring or the like can also be used. It may be desirable to add a colouring agent to make the dosage form readily identifiable.
  • Tablets e.g. binding agents, for example syrup, aca
  • a tablet may be made by compression or moulding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active agent in a free flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface-active or dispersing agent.
  • Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may be optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active agent.
  • Formulations suitable for topical administration include lozenges comprising the active agent in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active agent in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active agent in a suitable liquid carrier.
  • Formulations suitable for topical administration to the skin may be presented as ointments, creams, gels, and pastes comprising the active agent and a pharmaceutically active carrier.
  • An exemplary topical delivery system is a transdermal patch containing the active agent.
  • Formulations for rectal or vaginal administration may be presented as a suppository or pessary with a suitable base comprising, for example, cocoa buter or a salicylate.
  • a suitable base comprising, for example, cocoa buter or a salicylate.
  • Other vaginal preparations can be presented as tampons, creams, gels, pastes, foams or spray formulations containing, in addition to the active agent, such carriers as are known in the art to be appropriate.
  • Formulations suitable for nasal administration wherein the carrier is a solid include a coarse powder having a particle size, for example, in the range 20 to 500 microns which is adminstered in the manner in which snuff is taken, i.e. by rapid inhalation from a container of the powder held up close to the nose.
  • Suitable formulations wherein the carrier is a liquid for adminstration, for example, as a nasal spray or as nasal drops, include aqueous or oily solutions of the active agent.
  • Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injection, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets of the kind previously described.
  • the above defined active agent is advantageously presented in an easily adminstered, rapidly acting form.
  • An example of such a dosage form or package is a self-administered spring-loaded syringe currently used for nerve gas antidotes.
  • administration routes may be administered simultaneously, for instance a vaginal preparation, an intramuscular injection and a tablet may be contemporaneously taken, e.g. in the event of a suspected sexual transmission, to provide effective doses immediately at the site of exposure and in the circulator)' system and for a more sustained rate via the oral route.
  • the above defined active agent is adminstered following exposure to HTV in an amount effective to prevent HTV infection or HIV seroconversion.
  • Suitable amounts include about 0.1 mg/kg bodyweight/day, preferably at least about 0.5 mg/kg/day and more preferably about 10 mg/kg/day. This corresponds to a preferred dosage amount of about 10 mg to about 10 g per day. Larger dosage regimes will tend to be indicated where a particularly large inoculum is suspected to have been transmitted, such as through a contaminated blood line or transfusion, where sustained administration is impractical, such as in a military environment, where the active agent is administered as a single dose "morning after pill" by dinics lacking follow up facilities or where there has been extended delay before the active agent is first administered.
  • the maximum dosage of the active agent is of course dependent on toxicity and the bioavailablity of the dosage route employed but it is noted that unlike therapeutic treatment for established HIV infections with the currently available agents which must be administered indefinitely in order to suppress viraemia, the present invention contemplates administration during a finite period following exposure to HTV. Accordingly transient toxicity which would be intolerable to a long term therapeutic regime may be tolerated in the method of the present invention.
  • Cell culture results indicate that the above defined compound is generally well tolerated by human cells, for instance the ID50 in MT4 cells appears to be around 45 ⁇ g/ml. In vivo simian experiments indicate no detectable toxidt ⁇ ' short term at 30 mg/k ⁇ Vday and bearing in mind the finite administration period, dosages of 100 mg/kg/day or more are feasible.
  • preferred dosage amounts indude a range of from 0.1 to 100 mg/kg bodyweight/day, particularly 0.5 mg/kg/day to 50 mg/kg/day and more particularly 1.0 to 25 mg/kg/day.
  • the finite period of time mentioned in the penultimate paragraph above will be the period of time which is suffident to prevent the establishment of HTV infection or FHV seroconversion when administered after exposure to HIV, but is not so long as to incur unnecessary expense or risk cumulative toxidty in atypically sensitive individuals.
  • the finite period of admninstration will preferably be at least about one day, preferably about 3 days and may be 1 or two weeks, especially where there has been significant delay between exposure to HIV and initial administration of the active agent.
  • Sustained release dosage forms can of course be formulated to release the active agent for the period intended, either as a single dose, or as a twice daily, daily or weekly dosage unit.
  • compositions of the invention may comprise one or more auxilliary antivirals or antimicrobials as congeners etc, either against other common infective agents in HTV positive body fluids or samples, such as hepatitis B or C, or those in use in conventional double or multiple therapy against HTV.
  • auxilliaries include interferon, gamma-globulin, RT and protease inhibitors, AZT and ddl.
  • the compositions of the invention may alternatively or additionally comprise an abortificient such as the oestrogen derivatives employed in "morning after pills" or RU 486.
  • (benzoyloxy)methyl ⁇ -2,3-dideoxy-D-erythro-pentafuranoside is prepared according to the method of Svensson et al; 1991, 56, 2993-2997.
  • the base residue is prepared by suspending 120 mg, 1.08 mmol cytosine in 0.2 ml trimethylchlorosilane and 2 ml hexamethyldisilazane along with crystalline ammonium sulphate, refluxing until clear, vacuum concentration and coevaporation with dry xylene.
  • This preparation is dissolved in 2 ml dichloroethane in a nitrogen atmosphere before 170 mg, 0.46 mmol of the sugar residue is added followed by 0.22 ml, 0.96 mmol t-butyl-dimethyl- triflate. Reaction proceeds for 24 hours at room temperature and is quenched with saturated sodium hydrogen carbonate during agitation for half an hour. This solution is diluted with dichloroethane, washed in the saturated carbonate and concentrated following drying and filtration. The resultant concentrate is subjected for 24 hours at room temperature to 20 ml of saturated methanolic ammonia, before being concentrated, dissolved in water and extracted with dichloroethane.
  • the chromatographically pure compound is prepared into a subcutaneous preparation by dissolving 3.00 g in 300 ml 0.9 % NaCl in pyrogen free water followed by sterile filtration to give a 10 mg/ml solution which is administered subcutaneously at the rate of 1 mg/kg bodyweight.
  • Inoculation The control and test animals, 2 year old macquaque monkeys were inoculated subcutaneously with a moderate (10 monkey infectious doses MID50, as determined by Bottiger et al Antiviral Chemistry and Chemotherapy 1992;3:269-271) dose preparation of HIV-2 (SBL 6669strain) in phosphate buffer
  • test animals were injected subcutaneously with a 10 mg/kg preparation of Example 3 or the corresponding AZT preparation. Treatment was repeated three times per day for 4.5 days. After 8, 10, 14, 17, 24 and 30 days blood samples were assayed for the presence of viral antigen (absorbance at 492 nm) and the presence or absence of virus in the 30 day sample was assayed. All four uninoculated control animals exhibited HTV 7 antigen in the blood between days 14 and 17 and virus could be isolated after 30 days (2 months in one animal). Both of the AZT treated animals showed minor rises in absorbance at day 17 which later dedined. However virus was isolated from both animals at day 30 and in keeping with the usual pattern following cessation of AZT maintenance therapy, it would be expected that the antigen (and free virus titre) would rise in following weeks and months.
  • Example 2a demonstrates that the active ingredient of the invention prevents the establishment of HTV infection in the cynomegalous monkey model.
  • SIV whose native host is the monkey and which results in a more aggressive infection than HTV was then used to investigate appropriate dosages and regimes. Efficacy in the more aggressive SIV model will more than reflect efficacv in the milder HIV infection in humans.
  • Control and test animals were 2 year old macquaque monkeys as above which were inoculated intravenously with 10, 100 or 1 000 MID of SIV sm as listed in Table 1 below.
  • an inoculum of 10 infectious doses is a significantly greater amount of virus than a victim is exposed to in a normal needle stick acddent.
  • This dosage regime also protected one of the two animals subjected to the extremely high inoculum of 1000 MID50.
  • the combination of adminstration within 3 hours plus treatment for only 1 day prevented infection from 100 MID50 virus in one of four monkeys which is a pronounced protective effert bearing in mind the inoculum, time to first adminstration and duration (results not shown in Table 1).
  • each vial represents a dosage form containing 75 mg of active ingredient suitable for providing a dosage of 1 mg/kg for a normal adult male.
  • 12 g of active agent, as prepared in Example 1, is seived through US 60 mesh along with 12 g of dessicated lactose and 0.1 g of magnesium stearate.
  • the resultant fine powder is dosed in 500 mg amounts into hard gelatin capsules to form dosage units of 245 mg representing a dosage of about 32 mg/kg for a normal adult male .
  • the granules are compressed with a trace of magnesium stearate into 700 mg tablets suitable for twice daily administration.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Immunology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Molecular Biology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Virology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Biochemistry (AREA)
  • Genetics & Genomics (AREA)
  • Epidemiology (AREA)
  • Biotechnology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Méthode prévenant le déclenchement de l'infection due au VIH et/ou la séroconversion chez l'homme et le singe, et consistant à administrer à un patient ou à un singe ayant été exposé au VIH une dose efficace du composé 1-[2',3'-didéoxy-3'C-(hydroxyméthyl)-β-D-érythro-pentofuranosyl]-cytosine de formule (I).
PCT/SE1995/000524 1994-05-31 1995-05-11 Prevention de l'infection a vih chez des patients ayant ete exposes a ce virus WO1995032983A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
JP8500731A JPH10501217A (ja) 1994-05-31 1995-05-11 Ｈｉｖの被爆後阻止
CA002190862A CA2190862A1 (fr) 1994-05-31 1995-05-11 Prevention de l'infection a vih chez des patients ayant ete exposes a ce virus
AU26331/95A AU697612B2 (en) 1994-05-31 1995-05-11 Post exposure prevention of HIV
EP95921188A EP0763048A1 (fr) 1994-05-31 1995-05-11 Prevention de l'infection a vih chez des patients ayant ete exposes a ce virus

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US08/251,316 US5612319A (en) 1994-05-31 1994-05-31 Postexposure prevention of HIV infection or seroconversion
US08/251,316 1994-05-31
SE9500348-9 1995-02-01
SE9500348A SE9500348D0 (sv) 1995-02-01 1995-02-01 Post exposure prevention of HIV

Publications (1)

Publication Number Publication Date
WO1995032983A1 true WO1995032983A1 (fr) 1995-12-07

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/SE1995/000524 WO1995032983A1 (fr) 1994-05-31 1995-05-11 Prevention de l'infection a vih chez des patients ayant ete exposes a ce virus

Country Status (6)

Country Link
EP (1) EP0763048A1 (fr)
JP (1) JPH10501217A (fr)
AU (1) AU697612B2 (fr)
CA (1) CA2190862A1 (fr)
IL (1) IL113846A (fr)
WO (1) WO1995032983A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6057305A (en) * 1992-08-05 2000-05-02 Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic Antiretroviral enantiomeric nucleotide analogs
WO2006070004A1 (fr) 2004-12-30 2006-07-06 Medivir Ab Composes utiles dans le traitement du vih
EP1679076A1 (fr) * 2005-01-06 2006-07-12 Medivir Ab Composés pour le traitement de HIV

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0513835D0 (en) * 2005-07-07 2005-08-10 Medivir Ab HIV inhibitors

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1988008001A1 (fr) * 1987-04-16 1988-10-20 Aktiebolaget Astra Nucleosides et analogues de nucleosides, compositions et procedes pharmaceutiques permettant la preparation des composes
EP0391411A2 (fr) * 1989-04-06 1990-10-10 Bristol-Myers Squibb Company 3-Méthyl nucléosides substitués comme agents antiviraux en position 3'
WO1992006102A1 (fr) * 1990-10-02 1992-04-16 Medivir Ab Derives de nucleoside

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1988008001A1 (fr) * 1987-04-16 1988-10-20 Aktiebolaget Astra Nucleosides et analogues de nucleosides, compositions et procedes pharmaceutiques permettant la preparation des composes
EP0391411A2 (fr) * 1989-04-06 1990-10-10 Bristol-Myers Squibb Company 3-Méthyl nucléosides substitués comme agents antiviraux en position 3'
WO1992006102A1 (fr) * 1990-10-02 1992-04-16 Medivir Ab Derives de nucleoside

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6057305A (en) * 1992-08-05 2000-05-02 Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic Antiretroviral enantiomeric nucleotide analogs
US6479673B1 (en) 1992-08-05 2002-11-12 Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic Antiretroviral enantiomeric nucleotide analogs
US6653296B1 (en) 1992-08-05 2003-11-25 Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic Antiretroviral enantiomeric nucleotide analogs
WO2006070004A1 (fr) 2004-12-30 2006-07-06 Medivir Ab Composes utiles dans le traitement du vih
EA011039B1 (ru) * 2004-12-30 2008-12-30 Медивир Аб Приемлемые для лечения вич соединения
US7829548B2 (en) 2004-12-30 2010-11-09 Medivir Ab Compounds useful in the treatment of HIV
EP1679076A1 (fr) * 2005-01-06 2006-07-12 Medivir Ab Composés pour le traitement de HIV

Also Published As

Publication number Publication date
IL113846A0 (en) 1995-08-31
EP0763048A1 (fr) 1997-03-19
AU697612B2 (en) 1998-10-15
AU2633195A (en) 1995-12-21
JPH10501217A (ja) 1998-02-03
CA2190862A1 (fr) 1995-12-07
IL113846A (en) 1999-07-14

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