WO1995018800A1 - Derives de l'acide 2-desoxy-2,3-deshydro-n-acetylneuraminique (dana) - Google Patents

Derives de l'acide 2-desoxy-2,3-deshydro-n-acetylneuraminique (dana) Download PDF

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Publication number
WO1995018800A1
WO1995018800A1 PCT/EP1995/000040 EP9500040W WO9518800A1 WO 1995018800 A1 WO1995018800 A1 WO 1995018800A1 EP 9500040 W EP9500040 W EP 9500040W WO 9518800 A1 WO9518800 A1 WO 9518800A1
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Prior art keywords
compound
pyran
dihydro
formula
administration
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Application number
PCT/EP1995/000040
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English (en)
Inventor
Paul William Smith
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Biota Scientific Management Pty Ltd
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 Biota Scientific Management Pty Ltd filed Critical Biota Scientific Management Pty Ltd
Priority to AU25908/95A priority Critical patent/AU2590895A/en
Publication of WO1995018800A1 publication Critical patent/WO1995018800A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms

Definitions

  • This invention relates to a chemical compound and to its use in medicine.
  • the invention concerns a novel ⁇ -D-neuraminic acid derivative, methods for its preparation, pharmaceutical formulations containing it and its use as an antiviral agent.
  • Enzymes with the ability to cleave N-acetyl neuraminic acid (NANA), also known as sialic acid, from other sugars are present in many micro-organisms. These include bacteria such as Vibrio cholerae, Clostridium perfringens, Streptococcus pneumoniae, and Arthrobacter sialophilus, and viruses such as influenza virus, parainfluenza virus, mumps virus, Newcastle disease virus, fowl plague virus, and Sendai virus. Most of these viruses are of the orthomyxovirus or paramyxovirus groups, and carry a neuraminidase activity on the surface of the virus particles.
  • NANA N-acetyl neuraminic acid
  • neuraminidase-possessing organisms are major pathogens of man and/or animals, and some, such as influenza virus, Newcastle disease virus, and fowl plague virus, cause diseases of enormous economic importance.
  • neuraminidase inhibitors might prevent infection by neuraminidase-bearing viruses.
  • Most of the known neuraminidase inhibitors are analogues of neuraminic acid, such as 2-deoxy-2,3-didehydro-N- acetylneuraminic acid (DANA) and its derivatives.
  • DANA 2-deoxy-2,3-didehydro-N- acetylneuraminic acid
  • FANA 2-deoxy-2,3-dehydro-N- trifluoroacetyl-neuraminic acid
  • the present invention accordingly provides (4S, 5R, 6R)-4-guanidino-5- methanesulphonylamino-6-[(IS,2R)-1,2,3-trihydroxy-propyl- 5,6-dihydro-4H- pyran-3-carboxylic acid of formula (II)
  • a pharmaceutically acceptable derivative is meant any pharmaceutically acceptable salt, ester, or salt of such ester, of the compound of formula (II) or any other compound which, upon administration to the recipient, is capable of providing (directly or indirectly) the compound of formula (II) or an antrvirally active metabolite or residue thereof.
  • the compound of formula (II) may be modified to provide pharmaceutically acceptable derivatives thereof at any of the functional groups in the compound of formula (II).
  • derivatives are compounds modified at the carboxyl function, hydroxyl functions or at amino groups.
  • compound of interest include alkyl (such as methyl, ethyl or propyl e.g. isopropyl) or aryl (e.g. phenyl, benzoyl) esters and acetyl esters of the compound of formula (II).
  • compositions of the compound of formula (II) may be derivatised at more than one position.
  • Pharmaceutically acceptable salts of the compound of formula (II) include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acids include hydrochloric, hydrobromic, sulphuric, nitric, perchloric, fumaric, maleic, phosphoric, glycollic, lactic, salicylic, succinic, toluene- p-sulphonic, tartaric, acetic, citric, methanesulphonic, formic, benzoic, malonic, naphthalene-2-sulphonic and benzenesuiphonic acids. Other acids such as oxalic, while not in themselves pharmaceutically acceptable may be useful in the preparation of salts useful as intermediates in obtaining the compound of the invention and its pharmaceutically acceptable acid addition salts.
  • Salts derived from appropriate bases include alkali metal (e.g. sodium), alkaline earth metal (e.g. magnesium), ammonium and NR4 + (where R is Chalky! salts.
  • references hereinafter to the compound of the invention include the compound of formula (II) and pharmaceutically acceptable derivatives thereof.
  • the compound of formula (II) possesses antiviral activity.
  • this compound is an inhibitor of viral neuraminidase of orthomyxoviruses and paramyxoviruses in particular neuraminidase, for example the viral neuraminidase of influenza A and B, parainfluenza, mumps and Newcastle disease.
  • the compound of formula (II) or a pharmaceutically acceptable derivative thereof for use as an active therapeutic agent in particular as an antiviral agent for example in the treatment of orthomyxovirus and paramyxovirus infections.
  • a method for the treatment of a viral infection for example orthomyxovirus and paramyxovirus infections in a mammal including man comprising administration of an effective amount of the compound of formula (II) or a pharmaceutically acceptable derivative thereof.
  • a method for the treatment of a viral infection for example orthomyxovirus and paramyxovirus infections in a mammal including man comprising administration of an effective amount of the compound of formula (II) or a pharmaceutically acceptable derivative thereof.
  • use of the compound of the invention for the manufacture of a medicament for the treatment of a viral infection.
  • a suitable dose will be in the range of from about 0.1 to 750mg/kg of bodyweight per day, preferably in the range of 0.5 to 60 mg/kg/day, most preferably in the range of 1 to 20mg/kg/day.
  • Treatment is preferably commenced before or at the time of infection and continued until virus is no longer present in the respiratory tract.
  • the compound is also effective when given post-infection, for example after the appearance of established symptoms.
  • treatment is given 1-4 times daily and continued for 3-7, e.g. 5 days post infection.
  • the desired dose may be presented in a single dose or as divided doses administered at appropriate intervals, for example as two, three, four or more sub-doses per day.
  • the compound is conveniently administered in unit dosage form for example containing 10 to 1500mg, conveniently 20 to 1000mg, most conveniently 50 to 700mg of active ingredient per unit dosage form.
  • the compound of the invention may be administered as the raw chemical it is preferable to present the active ingredient as a pharmaceutical formulation.
  • the invention thus further provides a pharmaceutical formulation comprising the compound of formula (II) or a pharmaceutically acceptable derivative thereof together with one or more pharmaceutically acceptable carriers therefor and, optionally, other therapeutic and/or prophylactic 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 thereof.
  • compositions include those suitable for oral, rectal, nasal, topical (including buccal and sub-lingual), vaginal or parenteral (including intramuscular, sub-cutaneous and intravenous) administration or in a form suitable for administration to the respiratory tract (including the nasal passages) for example by inhalation or insufflation.
  • the formulations may, where appropriate, be conveniently presented in discrete dosage units and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association the active compound with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
  • compositions suitable for oral administration may conveniently 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, a suspension or as an emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • Tablets and capsules for oral administration may contain conventional excipients such as binding agents, fillers, lubricants, disintegrants, or wetting agents.
  • the tablets may be coated according to methods well known in the art.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non- aqueous vehicles (which may include edible oils), or preservatives.
  • the compound according to the invention may also be formulated for parenteral administration (e.g. by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative.
  • the compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents.
  • the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilisation from solution, for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.
  • the compound according to the invention may be formulated as ointments, creams or lotions, or as a transdermal patch.
  • Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
  • Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents, thickening agents, or colouring agents.
  • Formulations suitable for topical administration in the mouth include lozenges comprising active ingredient in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • compositions suitable for rectal administration wherein the carrier is a solid are most preferably presented as unit dose suppositories.
  • Suitable carriers include cocoa butter and other materials commonly used in the art, and the suppositories may be conveniently formed by admixture of the active compound with the softened or melted carriers) followed by chilling and shaping in moulds.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • the neuraminidase inhibitors may be administered by any of the methods and formulations employed in the art for administration to the respiratory tract.
  • the compounds may be administered in the form of a solution or a suspension or as a dry powder.
  • Solutions and suspensions will generally be aqueous for example prepared from water alone (for example sterile or pyrogen-free water) or water and a physiologically acceptable co-solvent (for example ethanol, propylene glycol, polyethlene glycols such as PEG 400).
  • a physiologically acceptable co-solvent for example ethanol, propylene glycol, polyethlene glycols such as PEG 400.
  • Such solutions or suspensions may additionally contain other excipients for example preservatives (such as benzalkonium chloride), solubilising agents/surfactants such as polysorbates (e.g. Tween 80, Span 80, benzalkonium chloride), buffering agents, isotonicity-adjusting agents (for example sodium chloride), absorption enhancers and viscosity enhancers.
  • Suspensions may additionally contain suspending agents (for example microcrystalline cellulose, carboxymethyl cellulose sodium).
  • Solutions or suspensions are applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or spray.
  • the formulations may be provided in single or multidose form. In the latter case a means of dose metering is desirably provided.
  • a dropper or pipette this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension.
  • a spray this may be achieved for example by means of a metering atomising spray pump.
  • Administration to the respiratory tract may also be achieved by means of an aerosol formulation in which the compound is provided in a pressurised pack with a suitable propellant such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluroroethane, carbon dioxide or other suitable gas.
  • a suitable propellant such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluroroethane, carbon dioxide or other suitable gas.
  • CFC chlorofluorocarbon
  • the aerosol may conveniently also contain a surfactant such as lecithin.
  • the dose of drug may be controlled by provision of a metered valve.
  • the compounds may be provided in the form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine (PVP).
  • a powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine (PVP).
  • PVP polyvinylpyrrolidine
  • the powder carrier will form a gel in the nasal cavity.
  • the powder composition may be presented in unit dose form for example in capsules or cartridges of e.g. gelatin or blister packs from which the powder may be administered by means of an inhaler.
  • the compound In formulations intended for administration to the respiratory tract, including intranasal formulations, the compound will generally have a small particle size for example of the order of 5 microns or less. Such a particle size may be obtained by means known in the art, for example by micronisation.
  • formulations adapted to give sustained release of the active ingredient may be employed.
  • the compound of the invention may also be used in combination with other therapeutic agents, for example other anti-infective agents.
  • the compound of the invention may be employed with other antiviral agents.
  • the invention thus provides in a further aspect a combination comprising the compound of formula (II) or a pharmaceutically acceptable derivative thereof together with another therapeutically active agent, in particular an antiviral agent.
  • Suitable therapeutic agents for use in such combinations include other anti- infective agents, in particular anti-bacterial and anti-viral agents such as those used to treat respiratory infections.
  • anti-bacterial and anti-viral agents such as those used to treat respiratory infections.
  • other compounds effective against influenza viruses such as amantadine, rimantadine and ribavirin, may be included in such combinations.
  • each compound of the invention When the compound of the invention is used with a second therapeutic agent active against the same virus the dose of each compound may either be the same as or differ from that employed when each compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art.
  • the compound of formula (II) and its pharmaceutically acceptable derivatives may be prepared by any method known in the art for the preparation of compounds of analogous structure.
  • the compounds of formula (II) may be prepared by the methods described below.
  • the compound of formula (II) may be prepared from the compound of formula (III)
  • Reagents suitable to introduce the guanidino function include S-methylisourea and aminoiminomethanesulphonic acid in the presence of a base such as an alkali metal carbonate, for example potassium carbonate.
  • the compound of formula (III) may be prepared from an azide of formula (IV)
  • R represents alkyl, such as, for example, methyl, by reduction.
  • the reduction is conveniently effected using triphenylphosphine in a suitable solvent such as an ether, for example tetrahydrofuran, in the presence of a base.
  • suitable bases include tertiary amines such as, for example, triethylamine.
  • Azides of formula (IV) may be prepared from compounds of formula (V)
  • a methanesulphonyl halide such as methanesulphonyl chloride
  • a base such as a tertiary amine, for example, pyridine.
  • reaction is conveniently effected in a suitable organic solvent, such as a halogenated hydrocarbon, for example, dichloromethane, preferably at low temperature, such as about 0°C.
  • a suitable organic solvent such as a halogenated hydrocarbon, for example, dichloromethane
  • Compounds of formula (V) may be prepared by conventional methods from a suitably protected analogue, such as the compound of formula (VI) (4-azido- Neu5, 7, 8, 9-Ac 4 5Boc2en1Me)
  • the protecting group may be removed at any convenient subsequent stage in the reaction sequence.
  • the protecting groups used in the preparation of compounds of formula (II) may be used in conventional manner. See for example 'Protective Groups in Organic Chemistry' Ed. J. F. W. McOmie (Plenum Press 1973) or 'Protective Groups in Organic Synthesis' by T. W . Greene and P.G. M. Wuts (John Wiley and Sons 1991).
  • Conventional amino protecting groups may include for example aralkyl groups, such as benzyl, diphenylmethyl or triphenylmethyl groups; and acyl groups such as N-benzyloxycarbonyl or t-butoxycarbonyl.
  • Hydroxy groups may be protected, for example, by aralkyl groups, such as benzyl, diphenylmethyl or triphenylmethyl groups, acyl groups, such as acetyl, silicon protecting groups, such as trimethylsilyl groups, or as tetrahydropyran derivatives.
  • aralkyl groups such as benzyl, diphenylmethyl or triphenylmethyl groups
  • acyl groups such as acetyl
  • silicon protecting groups such as trimethylsilyl groups, or as tetrahydropyran derivatives.
  • an aralkyl group such as benzyl
  • an acyl group such as N-benzyloxycarbonyl may be removed by hydrolysis with, for example, hydrogen bromide in acetic acid or by reduction, for example by catalytic hydrogenation
  • silicon protecting groups may be removed, for example, by treatment with fluoride ion
  • tetrahydropyran groups may be cleaved by hydrolysis under acidic conditions
  • the compound of the invention as a salt, for example as an acid addition salt
  • this may be achieved by treating the free base of general formula (I) with an appropriate acid, preferably with an equivalent amount, or with creatinine sulphate in a suitable solvent (e.g. aqueous ethanol).
  • a suitable solvent e.g. aqueous ethanol

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'acide (4S, 5R, 6R)-4-guanidino-5-méthanesulfonylamino-6-[(1S, 2R)-1,2,3-trihydroxypropyl-5,6-dihydro-4H-pyranne-3-carboxylique, ses dérivés ainsi que ses solvates physiologiquement tolérables sont des inhibiteurs de la neuraminidase virale.
PCT/EP1995/000040 1994-01-07 1995-01-05 Derives de l'acide 2-desoxy-2,3-deshydro-n-acetylneuraminique (dana) WO1995018800A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU25908/95A AU2590895A (en) 1994-01-07 1995-01-05 Derivatives of 2-deoxy-2,3-dehydro-N-acetylneuraminic acid (DANA)

Applications Claiming Priority (2)

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GB9400206A GB9400206D0 (en) 1994-01-07 1994-01-07 Chemical compound
GB9400206.0 1994-01-07

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WO1995018800A1 true WO1995018800A1 (fr) 1995-07-13

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Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0823428A2 (fr) * 1996-07-22 1998-02-11 Sankyo Company Limited Dérivés de l'acide neuraminique, leur préparation et utilisation médicale
US5763483A (en) * 1995-12-29 1998-06-09 Gilead Sciences, Inc. Carbocyclic compounds
US5859284A (en) * 1996-08-23 1999-01-12 Gilead Sciences, Inc. Preparation of carbocyclic compounds
US5866601A (en) * 1995-02-27 1999-02-02 Gilead Sciences, Inc. Carbocyclic compounds
US5886213A (en) * 1997-08-22 1999-03-23 Gilead Sciences, Inc. Preparation of carbocyclic compounds
US5919819A (en) * 1995-08-08 1999-07-06 Biota Scientific Management Pty Ltd. Dihydropyran derivatives as viral neuraminidase inhibitors
US5952375A (en) * 1995-02-27 1999-09-14 Gilead Sciences, Inc. Compounds and methods for synthesis and therapy
WO1999054290A1 (fr) * 1998-04-23 1999-10-28 Abbott Laboratories Inhibiteurs de neuraminidases
US5994377A (en) * 1996-10-21 1999-11-30 Gilead Sciences, Inc. Piperidine compounds
US6111132A (en) * 1997-12-12 2000-08-29 Gilead Sciences, Inc. Compounds and methods for synthesis and therapy
US6340702B1 (en) 1996-07-22 2002-01-22 Sankyo Company, Limited Neuraminic acid derivatives, their preparation and their medical use
US6451766B1 (en) 1996-07-22 2002-09-17 Sankyo Company, Limited Neuraminic acid derivatives, their preparation and their medical use
US6455571B1 (en) 1998-04-23 2002-09-24 Abbott Laboratories Inhibitors of neuraminidases
WO2002076971A1 (fr) * 2001-03-08 2002-10-03 Biocryst Pharmaceuticals, Inc. Composes d'inhibition de la neuraminidase de paramyxovirus
US6518305B1 (en) 1998-04-23 2003-02-11 Abbott Laboratories Five-membered carbocyclic and heterocyclic inhibitors of neuraminidases
US6518438B2 (en) 1996-08-23 2003-02-11 Gilead Sciences, Inc. Preparation of cyclohexene carboxylate derivatives
US6593314B1 (en) 1999-10-19 2003-07-15 Abbott Laboratories Neuraminidase inhibitors
US7205333B2 (en) 2000-09-08 2007-04-17 Wen-Yang Wu Multivalent neuraminidase inhibitor conjugates

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991016320A1 (fr) * 1990-04-24 1991-10-31 Biota Scientific Management Pty Ltd Derives et analogues d'acide 2-deoxy-2,3-didehydro-n-acetyle neuraminique et leur utilisation comme agents antiviraux

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991016320A1 (fr) * 1990-04-24 1991-10-31 Biota Scientific Management Pty Ltd Derives et analogues d'acide 2-deoxy-2,3-didehydro-n-acetyle neuraminique et leur utilisation comme agents antiviraux

Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5866601A (en) * 1995-02-27 1999-02-02 Gilead Sciences, Inc. Carbocyclic compounds
US5952375A (en) * 1995-02-27 1999-09-14 Gilead Sciences, Inc. Compounds and methods for synthesis and therapy
US6225341B1 (en) 1995-02-27 2001-05-01 Gilead Sciences, Inc. Compounds and methods for synthesis and therapy
US5919819A (en) * 1995-08-08 1999-07-06 Biota Scientific Management Pty Ltd. Dihydropyran derivatives as viral neuraminidase inhibitors
US5763483A (en) * 1995-12-29 1998-06-09 Gilead Sciences, Inc. Carbocyclic compounds
EP0823428A2 (fr) * 1996-07-22 1998-02-11 Sankyo Company Limited Dérivés de l'acide neuraminique, leur préparation et utilisation médicale
EP0823428A3 (fr) * 1996-07-22 1998-02-25 Sankyo Company Limited Dérivés de l'acide neuraminique, leur préparation et utilisation médicale
CN1127494C (zh) * 1996-07-22 2003-11-12 三共株式会社 神经氨酸衍生物,它们的制备及其医药用途
US6451766B1 (en) 1996-07-22 2002-09-17 Sankyo Company, Limited Neuraminic acid derivatives, their preparation and their medical use
US6340702B1 (en) 1996-07-22 2002-01-22 Sankyo Company, Limited Neuraminic acid derivatives, their preparation and their medical use
US6204398B1 (en) 1996-08-23 2001-03-20 Gilead Sciences, Inc. Preparation of cyclohexene carboxylate derivatives
US6518438B2 (en) 1996-08-23 2003-02-11 Gilead Sciences, Inc. Preparation of cyclohexene carboxylate derivatives
US6057459A (en) * 1996-08-23 2000-05-02 Gilead Sciences, Inc. Preparation of carbocyclic compounds
US5859284A (en) * 1996-08-23 1999-01-12 Gilead Sciences, Inc. Preparation of carbocyclic compounds
US5994377A (en) * 1996-10-21 1999-11-30 Gilead Sciences, Inc. Piperidine compounds
US6376674B1 (en) 1996-10-21 2002-04-23 Gilead Sciences, Inc. Piperidine compounds
US5886213A (en) * 1997-08-22 1999-03-23 Gilead Sciences, Inc. Preparation of carbocyclic compounds
US6111132A (en) * 1997-12-12 2000-08-29 Gilead Sciences, Inc. Compounds and methods for synthesis and therapy
WO1999054290A1 (fr) * 1998-04-23 1999-10-28 Abbott Laboratories Inhibiteurs de neuraminidases
US6518305B1 (en) 1998-04-23 2003-02-11 Abbott Laboratories Five-membered carbocyclic and heterocyclic inhibitors of neuraminidases
US6455571B1 (en) 1998-04-23 2002-09-24 Abbott Laboratories Inhibitors of neuraminidases
US6593314B1 (en) 1999-10-19 2003-07-15 Abbott Laboratories Neuraminidase inhibitors
US7205333B2 (en) 2000-09-08 2007-04-17 Wen-Yang Wu Multivalent neuraminidase inhibitor conjugates
WO2002076971A1 (fr) * 2001-03-08 2002-10-03 Biocryst Pharmaceuticals, Inc. Composes d'inhibition de la neuraminidase de paramyxovirus

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Publication number Publication date
AU2590895A (en) 1995-08-01
GB9400206D0 (en) 1994-03-02

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