+

WO1993010774A1 - Nucleoside pyrimidine anti-hbv - Google Patents

Nucleoside pyrimidine anti-hbv Download PDF

Info

Publication number
WO1993010774A1
WO1993010774A1 PCT/GB1992/002189 GB9202189W WO9310774A1 WO 1993010774 A1 WO1993010774 A1 WO 1993010774A1 GB 9202189 W GB9202189 W GB 9202189W WO 9310774 A1 WO9310774 A1 WO 9310774A1
Authority
WO
WIPO (PCT)
Prior art keywords
active ingredient
compound
prop
hepatitis
formulation
Prior art date
Application number
PCT/GB1992/002189
Other languages
English (en)
Inventor
Dorothy Jane Martin Purifoy
Original Assignee
The Wellcome Foundation Limited
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 Wellcome Foundation Limited filed Critical The Wellcome Foundation Limited
Publication of WO1993010774A1 publication Critical patent/WO1993010774A1/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

Definitions

  • the present invention relates to a 5-prop-l-ynyl-l-(5-0-trimethylace- tyl-3-D-arabinofuranosyl)uracil nucleoside and physiologically and pharmaceutically acceptable salts thereof, for use in the treatment or prophylaxis of hepatitis B viral infections.
  • HBV hepatitis B Virus
  • the virus is aetiologically associated with primary hepatocellular carcinoma and is thought to cause 80% of the world's liver cancer.
  • HBV illness In the United States more than ten thousand people are hospitalised for HBV illness each year, an average of 250 die with fulminant disease.
  • the United States currently contains an estimated pool of 500,000 to 1-million infectious carriers. Chronic active hepatitis will develop in over 25% of carriers, and often progresses to cirrhosis. It is estimated that 5000 people die from HBV related cirrhosis each year in the USA, and that perhaps 1000 die from HBV-related liver cancer.
  • European patent publication no. 22384A1 discloses a general class of nucleosides for the therapeutic or prophylatic treatment of infections caused by a retrovirus, including HIV, or by hepatitis B virus.
  • One feature of the invention provides use of 5-prop-l-ynyl-l-(5-0-tri- methylacetyl-0-D-arabinofurano «yl)ur*cil, i.e. the compound of formula
  • the invention also provides a method for the treatment or prophylaxis of a mammal (particularly a human) having a hepatitis B viral infection comprising administration to said mammal of an effective amount of the compound of 5-prop-l-ynyl-l-(5-0-trimethylacetyl- ⁇ -D- arabinofuranosyl)uracil or a physiologically acceptable salt thereof.
  • Yet another feature of the invention is an anti-hepatitis B pharmaceu ⁇ tical formulation comprising 5-prop-l-ynyl-l-(5-0-trimethylacetyl- ⁇ -D- arabinofuranosyl)uracil or a physiologically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • Yet a further feature of the invention is the use of 5-prop-l-ynyl-l- (5-0-trimethylacetyl-3-D-arabinofuranosyl)uracil, or a physiologically acceptable salt thereof in the treatment or prophylaxis of a hepatitis B viral infection.
  • Hepatitis B viral conditions which may be treated in accordance with the invention have been discussed in the introduction hereinbefore.
  • the compounds of the invention By the use of the compounds of the invention an advantageous therapeutic effect for the treatment or prophylaxis of hepatitis B infections can be achieved.
  • such compounds are readily absorbed from the gastro-intestinal tract and can therefore be administered by the oral route to achieve high plasma levels of the parent nucleoside.
  • physiologically acceptable salts of the invention include base salts, for example derived from an appropriate base, such as alkali metal (e.g. sodium), alkaline earth metal (e.g. magnesium) and ammonium and NX, (wherein X is C. , alkyl) salts.
  • alkali metal e.g. sodium
  • alkaline earth metal e.g. magnesium
  • ammonium and NX ammonium and NX, (wherein X is C. , alkyl) salts.
  • physiologically acceptable salts we mean to include pharmaceutically acceptable salts.
  • the compound of the invention 5-prop-l-ynyl-l-(5-0-trimethylacetyl- ⁇ - D-arabinofuranosyl)uracil or a physiologically salt thereof) may be administered to a mammal including a human ("the recipient") by any route appropriate to the clinical condition to be treated; suitable routes include oral, rectal, nasal, topical (including buccal and sublingual) , vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural) . It will be appreciated that the preferred route may vary, for example, according to the age, weight and sex of the recipient and the nature and severity of the condition to be treated.
  • a suitable, effective dose will be in the range 1 to lOOmg per kilogram body weight per day and most preferably in the range 5 to 30 mg per kilogram body weight per day; an optimum dose is about 15 mg per kilogram body weight per day.
  • the effective dose may be presented as two, three, four or more sub-doses administered at appropriate intervals throughout the day.
  • sub-doses may be administered in unit dosage forms, for example, containing 10 to 2000 mg, preferably 20 to 500 mg and most preferably 100 to 400 mg of a compound of the invention per unit dosage form.
  • the dose may be administered as a continuous infusion.
  • the compounds of the invention may be administered for the treatment or prophylaxis of viral infections alone or in combination with other therapeutic agents, for example, with other antiviral agents such as 9-(2-hydroxy-ethoxymethyl)guan ⁇ ne (acyclovir) used to treat herpes viral infections in particular HSV and most notably those involving the HSV (1) variety, with 3'-deoxy-3'-azidothymidine (zidovudine) or a 2' ,3'-dideoxynucleoside for example 2' ,3'-dideoxy cytidine, 2' ,3'-dideoxyinosine, 2' ,3'-dideoxyadenosine or 2' ,3'-dideoxy guanosine, used to treat retroviral infections in particular Human Immunodefeciency Virus (HIV) infections, interferons particularly ⁇ -interferon and soluble proteins such as CD4, or any other agents such as analagesics or antipyretics which
  • a medicament for use in the invention preferably in the form of a pharmaceutical formulation comprising at least one compound of the invention ("the active ingredient"), together with one or more pharmaceutically 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 formulations and not deleterious to the recipients thereof.
  • Formulations of the invention include those suitable for administra ⁇ tion by any of the aforementioned routes which may conveniently be presented in unit dosage form prepared by any of the methods well known in the art of pharmacy. Such methods include the. step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, If necessary, shaping the product.
  • Formulations of the invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; as an edible foam or whip; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be presented as a bolus, or paste or may be contained within liposomes.
  • 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 Ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder (for example povidone, gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent, dlsintegrant (for example sodium starch glycollate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose) , surface-active or dispersing agent.
  • Moulded tablets may be made by moulding in a suitable machine, a mixture of the powdered active ingredient moistened with an inert liquid diluent.
  • the tablets are optionally coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein, using for example, hydroxypropylmethylcellulose in varying proportions to provide the desired release profile, or to be soluble or effervescent when added to liquid.
  • a capsule may be made by filling a loose or compressed powder on an appropriate filling machine, optionally with one or more additives.
  • suitable additives include binders such as povidone; gelatin, lubricants, inert diluents and disintegrants as for tablets.
  • Capsules may also be formulated to contain pellets or discrete sub-units to provide slow or controlled release of the active ingredient. This can be achieved by extruding and spheronising a wet mixture of the drug plus an extrusion aid (for example microcrys- talline cellulose) plus a diluent such as lactose.
  • the spheroids thus produced can be coated with a semi-permeable membrane (for example ethyl cellulose, Eudragit WE30D) to produce sustained release properties.
  • An edible foam or whip formulation ideally comprises; 50-70% of an edible oil, particularly a vegetable oil, including corn oil, peanut oil, sunflower oil, olive oil and soybean oil; 2-10% of one or more surfactants particularly lecithin, polyols, polyol polymer esters including glyceryl fatty acid esters, polyglyceryl fatty acid esters (e.g. decaglycerol tetraoleate) , or sorbitan fatty acid esters (e.g.
  • sorbitan monostearate 1-4% of a propellant which is suitable for ingestion, notably a compressed gas propellant especially nitrogen, nitrous oxide or carbon dioxide, or a gaseous hydrocarbon especially propane, butane or isobutane; 0.5-30% of one or more viscosity modifiers of particle size in the range 10-50 microns in diameter, particularly powdered sugars or colloidal silicon dioxide; and optionally 0.5-1% of one or more suitable, non-toxic colourings, flavourings or sweetners.
  • the active ingredient is preferably present in such formulations in a concentration of 10-46%, advantageously 30%.
  • An edible foam or whip formulation as described above may be prepared in a conventional manner, for example by mixing the edible oil, surfactant(s) and any other soluble ingredients, adding the viscosity modifier(s) and milling the mixture to form a uniform dispersion and suspension. The active ingredient is blended into the milled mixture until evenly dispersed. Finally, a metered quantity of propellant is incorporated to the mixture after said mixture has been measured into a suitable dispensing container.
  • the formulations are preferably applied as a topical ointment or cream containing the active ingredient in an amount of, for example, 0.075 to 20% w/w, preferably 0.2 to 15% w/w and most preferably 0.5 to 10% w/w.
  • the active ingredients may be employed with either a paraffinic or a water-miscible ointment base.
  • the active ingredients may be formulated in a cream with an oil-in-water cream base or as a water-in-oil base.
  • the aqueous phase of the cream base may include, for example, at least 40-45% w/w of a polyhydric alcohol, i.e. an alcohol having two or more hydroxyl groups such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol and mixtures thereof.
  • the topical formulations may include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulphoxide and related analogues.
  • the oily phase of an emulsion formulation according to the invention may comprise merely an emulsifier (otherwise known as an emulgent) , but desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil.
  • a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stablilizer. It is also preferred to include both an oil and a fat.
  • the emulsifer(s) with or without stabilizer(s) make up the so-called emulsifying wax
  • the wax together with the oil and/or fat make up the so-called emulsifying ointment base which forms the oily phase of the cream formulations.
  • Emulgents and emulsion stabilizers suitable for use in the formulation of the present invention include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl mono-stear te and sodium lauryl sulphate.
  • the choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils likely to be used in pharmaceutical emulsion formulations is very low.
  • the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers.
  • Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.
  • Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.
  • a suitable carrier especially an aqueous solvent.
  • the ingredient is preferably rresent in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10%, particularly about 1.5% w/w.
  • Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavoured material, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert material such as gelatin and glycerin, or sucrose and acacia; and mouth-washes comprising the active ingredient in a suitable liquid carrier.
  • Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or higher fatty alcohol (e.g. hard wax, European Pharmacopoeia) or triglycerides and saturated fatty acids (e.g. Witepsol) .
  • a suitable base comprising for example cocoa butter or higher fatty alcohol (e.g. hard wax, European Pharmacopoeia) or triglycerides and saturated fatty acids (e.g. Witepsol) .
  • 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 administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
  • Suitable formulations wherein the carrier is a liquid, for administration as a nasal spray or as nasal drops, include aqueous or oily solutions of the active ingredient.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known In the art to be appropriate.
  • Formulations suitable for parenteral administration include aqueous and non- aqueous sterile injection solutions which may contain anti-oxidants, 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 a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • Preferred unit dosage formulations are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.
  • formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents.
  • the compounds of the invention may be prepared by any method known in the art for the preparation of similar compounds (examples include methods described in UK Patent Specification No. 1 601 020, EP Publications Nos. 61283 and 27065, or Robins M.J. and Barr, P.J. J. Org. Chem. (1983) 48, 1854-1862), as well as the processes described In the Examples given hereinafter.
  • B is a purine or pyrimidine base (other than 5-prop-l-ynyl-uracil) , with 5-prop-l-ynyluracil; and optionally thereafter or simultaneously therewith, where the resulting compound is a compound of formula (I), converting it into a salt thereof; or where the resulting compound is a salt, converting it into a different salt or a compound of formula (I) .
  • the active compound can be brought into association with a carrier and formulated as an anti-HBV pharmaceutical formulation.
  • a compound of formula (I) may be prepared from a compound of formula (II) , the preparation of which is described in EP Publication No. 272065, for example by acylation using an appropriate acylating agent such as trimethylacetylhalide (e.g. chloride) or trimethylacetic anhydride, advantageously in the presence of a base such as pyridine or triethylamine which may also serve as a solvent medium for the reaction at a temperature in the range of 0 -70 C advantageously 0°-30°C, preferably 0-15 C.
  • the ratio of acylating agent to compound of formula (II) is preferably about 1.2:lw/w.
  • a compound of formula (I) may be prepared from a compound of formula (II) by transesterification using an appropriate ester of trimethylacetic acid (e.g. the methyl ester) In the presence of a base such as pyridine or triethylamine which may also serve as a solvent medium for the reaction.
  • an appropriate ester of trimethylacetic acid e.g. the methyl ester
  • a base such as pyridine or triethylamine which may also serve as a solvent medium for the reaction.
  • esterification reaction may be carried out for - example in a solvent such as pyridine or dimethylformamide in the presence of a coupling agent such as N,N-dicyclohexylcarbodiI- mide, optionally in the presence of a catalytic base such as 4-dime hylamInopyridine using the acylating agents referred to above. Subsequently, the ester obtained as reaction product may be isolated in conventional manner.
  • a solvent such as pyridine or dimethylformamide
  • a coupling agent such as N,N-dicyclohexylcarbodiI- mide
  • a catalytic base such as 4-dime hylamInopyridine
  • group B is preferably a purine or pyrimidine base capable of donating the esterified sugar to a 5-prop-l-ynyluracil base using for example an enzyme such as a phosphorylase enzyme in the presence of a phosphate salt at a pH of 5.0 - 9.0 and a temperature of 15 -90 C, advantageously 40°-60°C.
  • an enzyme such as a phosphorylase enzyme in the presence of a phosphate salt at a pH of 5.0 - 9.0 and a temperature of 15 -90 C, advantageously 40°-60°C.
  • Salts according to the invention may also be prepared in conventional manner for example by reaction of a compound of formula (II) with an appropriate base to form the corresponding base salt followed by acylation. Again, salts may be prepared by reaction of the esterified compound with a base such as sodium hydride to form the corresponding sodium salt. Other derivatives according to the invention can also be prepared in conventional manner.
  • a suspension of sodium hydride (0.05g of 80% w/v suspension in oil, 1.66mmol, (washed several times with dry tetrahydrofuran) in dry tetrahydrofuran (4ml) was added to a stirred solution of 5-prop-l-ynyl-l-(5-trimethylacetyl- -D-arabinofuranosyl)uracil (0.06g, 1.64mmol) in dry tetrahydrofuran, ensuring complete exclusion of moisture. The solvent was evaporated after 1 hour to give O.lg of the required sodium salt.
  • formulations A, B and C are prepared by wet granulation of the ingredients with a solution of povidone, followed by addition of magnesium stearate and compression.
  • formulations, D and E are prepared by direct compression of the admixed ingredients.
  • the lactose used in formulation E is of the direct compression type.
  • the formulation is prepared by wet granulation of the ingredients (belov) with a solution of povidone followed by the addition of magnesium stearate and compression.
  • a capsule formulation is prepared by admixing the uncompressed ingredients of Formulation D in Example B above and filling into a two-part hard gelatin capsule.
  • Formulation B (infra) is prepared in a similar manner.
  • Capsules are prepared by melting the Macrogol 4000 BP, dispersing the active ingredient in the melt and filling the melt into a two-part hard gelatin capsule.
  • Capsules are prepared by dispersing the active Ingredient in the lecithin and arachis oil and filling the dispersion into soft, elastic gelatin capsules.
  • controlled release capsule formulation is prepared by extruding ingredients (a), (b) , and (c) below, using an extruder, followed by spheronisation of the extrudate and drying. The dried pellets are then coated with release- controlling membrane (d) and filled into a two-piece, hard gelatin capsule.
  • Example E Intramuscular Injection
  • the active ingredient is dissolved in the glycofurol.
  • the benzyl alcohol is then added and dissolved, and water added to 3 ml.
  • the mixture is then filtered through a sterile micropore filter and sealed in sterile 3 ml glass vials (type 1) .
  • the sodium benzoate is dissolved in a portion of the purified water and the sorbitol solution added.
  • the active ingredient is added and dispersed.
  • the glycerol is dispersed the thickener (dispersible cellulose) .
  • the two dispersions are mixed and made up to the required volume with the purified water.
  • Example H Suppository mp/suppositorv
  • the active ingredient is used as a powder wherein at least 90% of the particles are of 63 ⁇ m diameter or less.
  • Witepsol H15 is melted in a steam- acketed pan at 45°C maximum.
  • the active ingredient is sifted through a 200 ⁇ m sieve and added to the molten base with mixing, using a silverson fitted with a cutting head, until a smooth dispersion is achieved. Maintaining the mixture at 45 C, the remaining Witepsol H15 is added to the suspension and stirred to ensure a homogenous mix.
  • the entire suspension is passed through a 250 ⁇ m stainless steel screen and, with continuous stirring, is allowed to cool to 40 C. At a temperature of 38°C to 40°C 2.02g of the mixture is filled into suitable plastic moulds. The suppositories are allowed to cool to room temperature.
  • the active compound is dissolved in a mixture of purified water and glycerol and heated to 70 C.
  • the remaining ingredients are heated ttooggeetthheerr aatt 7700 CC..
  • the human HBV producer cell line of HepG2, 2.2.15 described and characterized by Sells et al.. PNAS 84:1005, 1987 and J. Virol. 62:2836, 1988, has been shown to share many characteristics of the HBV chronically infected hepatocyte. It is infectious as demonstrated by the ability to cause disease in chimpanzees. This cell line was utilized in vitro to identify compounds with anti-HBV activity.
  • Monolayer cultures were treated with l-100 ⁇ M of the active compound l-(/9-D-arabinofuranosyl)-5-prop-l-ynyluracil, for ten days.
  • Supernatant media containing extracellular virion DNA were harvested on day ten, treated with proteinase K (1 mg/mL) and sodium dodecyl sulfate (1%), and incubated at 50°C for one hour. DNA was extracted with equal volumes of phenol followed by chloroform and then precipitated by ammonium acetate and propanol.
  • the DNA precipitate was dissolved and collected on nitrocellulose using the procedure of Schleicher and Schuell (S & S, 10 Optical Ave., Keene, NH 03431, Publication #700, 1987), and treated as described by Southern, J. Mol. Biol. 98:503, 1975. Cells were harvested, and the intracellular DNA was obtained after cell lysis with guanidine isothiocyanate. The intracellular DNA was handled in the same manner as the extracellular DNA. After precipitation by ammonium acetate and propanol, the intracellular DNA precipitate was dissolved, cut by restriction endonuclease, Hind III, applied to agarose gel and then treated as described by Southern to determine the quantity of replicative Intermediate forms. The antiviral effect of the drug was determined by measuring a reduction of the amount of Dane particles extruded into the culture medium (extracellular DNA) and a similar decrease in the intracellular replicative intermediates (intracellular replicative form) .
  • parentheses is % reduction in intracellular hepatitis B virus DNA replicative form.
  • Example 1 Long Evans Rats were administered the compound of Example 1 and the parent compound by gavage at a dose of 50mg/kg.
  • the urine was collected for 24 and 48 hours post-dose, ultrafiltered, and analysed by reverse-phase high-pressure liquid chromatography.
  • the oral bioavallablllty of the Example 1 compound and the parent compound was expressed as the percent of the dose exreted in the urine over the 48 hour period of collection, as l-( -D-arabinofuranosyl)-5-prop-l-ynyl- uracil, i.e. the parent compound.
  • CCID 5 _ The concentration required for a 50% inhibition of cell viability at 96 hours is termed CCID 5 _.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Molecular Biology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention se rapporte à 5-prop-1-ynyl-1-(5-0-triméthylacetyl-β-D-ara-bynofuranosyl) uracil et à ses sels pharmaceutiquement acceptables, utilisés dans le traitement des infections virales de l'hépatite B.
PCT/GB1992/002189 1991-11-27 1992-11-26 Nucleoside pyrimidine anti-hbv WO1993010774A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB919125271A GB9125271D0 (en) 1991-11-27 1991-11-27 Anti-hbv pyrimidine nucleoside
GB9125271.8 1991-11-27

Publications (1)

Publication Number Publication Date
WO1993010774A1 true WO1993010774A1 (fr) 1993-06-10

Family

ID=10705355

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1992/002189 WO1993010774A1 (fr) 1991-11-27 1992-11-26 Nucleoside pyrimidine anti-hbv

Country Status (5)

Country Link
AU (1) AU2952092A (fr)
GB (1) GB9125271D0 (fr)
TW (1) TW213922B (fr)
WO (1) WO1993010774A1 (fr)
ZA (1) ZA929197B (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1988004662A1 (fr) * 1986-12-19 1988-06-30 Astra Läkemedel Aktiebolag Utilisation de nucleosides pour la fabrication d'un medicament destine aux traitements de maladies causees par un retrovirus ou par le virus de l'hepatite b
EP0322384A1 (fr) * 1987-11-03 1989-06-28 Medivir Aktiebolag Nucléosides pour utilisation en thérapie
EP0375164A1 (fr) * 1988-11-23 1990-06-27 The Wellcome Foundation Limited Composés antiviraux
EP0461815A1 (fr) * 1990-06-09 1991-12-18 The Wellcome Foundation Limited Anti-HBV nucléosides pyrimidiniques

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1988004662A1 (fr) * 1986-12-19 1988-06-30 Astra Läkemedel Aktiebolag Utilisation de nucleosides pour la fabrication d'un medicament destine aux traitements de maladies causees par un retrovirus ou par le virus de l'hepatite b
EP0322384A1 (fr) * 1987-11-03 1989-06-28 Medivir Aktiebolag Nucléosides pour utilisation en thérapie
EP0375164A1 (fr) * 1988-11-23 1990-06-27 The Wellcome Foundation Limited Composés antiviraux
EP0461815A1 (fr) * 1990-06-09 1991-12-18 The Wellcome Foundation Limited Anti-HBV nucléosides pyrimidiniques

Also Published As

Publication number Publication date
ZA929197B (en) 1994-05-26
AU2952092A (en) 1993-06-28
TW213922B (fr) 1993-10-01
GB9125271D0 (en) 1992-01-29

Similar Documents

Publication Publication Date Title
RU2116789C1 (ru) Способ ингибирования вирусных инфекций гепатита в
EP0272065B1 (fr) Composés antiviraux
RU2139884C1 (ru) Моноэфирные соединения, фармацевтическая композиция
EP0294114B1 (fr) Composés antiviraux
IE84129B1 (en) Therapeutic nucleosides
EP0285432B1 (fr) Nucléosides thérapeutiques
EP0625158B1 (fr) Nucleosides therapeutiques de la serie 2',3'-dideoxy-3'-fluoro-purine
EP0351215B1 (fr) Ester de 9-(2-hydroxyéthoxyméthyl)guanine
EP0461815A1 (fr) Anti-HBV nucléosides pyrimidiniques
US5637574A (en) Therapeutic nucleosides
WO1992016215A1 (fr) Utilisation de 3'-azido-2',3'-dideoxyguanosine pour le traitement de l'hepatite b
EP0375164B1 (fr) Composés antiviraux
WO1993010774A1 (fr) Nucleoside pyrimidine anti-hbv
JPH0232094A (ja) 抗感染性ヌクレオシド
EP0475992A1 (fr) Nucleosides therapeutiques
US5175274A (en) Therapeutic nucleosides
CA2439322A1 (fr) Nucleosides therapeutiques

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU CA JP KR US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载