WO1994012192A1 - Agents antiviraux - Google Patents

Agents antiviraux Download PDF

Info

Publication number
WO1994012192A1
WO1994012192A1 PCT/AU1993/000606 AU9300606W WO9412192A1 WO 1994012192 A1 WO1994012192 A1 WO 1994012192A1 AU 9300606 W AU9300606 W AU 9300606W WO 9412192 A1 WO9412192 A1 WO 9412192A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
vii
general formula
pharmaceutically acceptable
siw
Prior art date
Application number
PCT/AU1993/000606
Other languages
English (en)
Inventor
Helmut Weigold
Angeline Ingrid Bartholomeusz
Sebastian Mario Marcuccio
George Holan
Original Assignee
Commonwealth Scientific And Industrial Research Organisation
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 Commonwealth Scientific And Industrial Research Organisation filed Critical Commonwealth Scientific And Industrial Research Organisation
Priority to AU55545/94A priority Critical patent/AU5554594A/en
Publication of WO1994012192A1 publication Critical patent/WO1994012192A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01G—COMPOUNDS CONTAINING METALS NOT COVERED BY SUBCLASSES C01D OR C01F
    • C01G41/00—Compounds of tungsten
    • C01G41/006—Compounds containing, besides tungsten, two or more other elements, with the exception of oxygen or hydrogen
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
    • C01P2002/00—Crystal-structural characteristics
    • C01P2002/80—Crystal-structural characteristics defined by measured data other than those specified in group C01P2002/70
    • C01P2002/82—Crystal-structural characteristics defined by measured data other than those specified in group C01P2002/70 by IR- or Raman-data
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
    • C01P2006/00—Physical properties of inorganic compounds
    • C01P2006/80—Compositional purity
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
    • C01P2006/00—Physical properties of inorganic compounds
    • C01P2006/80—Compositional purity
    • C01P2006/82—Compositional purity water content
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to heteropolytungstates and pharmaceutically acceptable derivatives thereof, and to the use of these compounds and
  • Flaviviridae is a newly-recognised large group (in excess of 70 species) of small, enveloped viruses that contain a single strand of positive-sense RNA of 10 kilobases. Flaviviruses are well known to be the causative agents of a number of human diseases including the most important arthropod-borne viral afflictions of civilization - dengue, yellow fever, and Japanese encephalitis. In addition, eight flaviviruses are known to cause disease in domestic or wild animals of economic importance. Yellow fever and dengue fever are widespread and well known as mosquito borne diseases of tropical countries. There are between 30 and 60 million flavivirus infections per year including one million Japanese encephalitis infections.
  • Hepatitis C The extent of Hepatitis C is not known with any degree of certainty because an infection can exist for many years without the patient being aware of the symptoms. Hepatitis C produces a much higher rate of chronic liver infection than Hepatitis B which is a recognised hazard in many countries. About 50% of patients develop chronic infections, compared with 5 to 10% of those infected with Hepatitis B. Chronic infection causes cirrhosis of the liver, impairs liver function, and 20-30 years later causes liver failure. It has been estimated that the rate of infection approaches and may exceed 1% of the population in Australia. There is no proven cure or vaccine for Hepatitis C. Effective vaccines are available for some flaviviruses only, eg for yellow fever, Japanese encephalitis and tick-borne encephalitis. Treatment of dengue fever and Australian encephalitis relies on the patient's own immune defences; infections can be fatal.
  • Heteropolytungstate compounds have been known for over 100 years. Most of their applications stem from their redox chemistry and also their high ionic weights and charges. Their redox chemistry has lead to their use as catalysts for the oxidation of organic substrates such as, for example, propylene to acrylic acid, ethylene to acetaldehyde. In the biological field heteropolytungstates have found use as electron dense stains for electron microscopy, as analytical reagents for proteins and several have also been shown to inhibit viral DNA and RNA polymerases. (J. C. Cherman, et al, Biockem. Biophys. Res. Commun, 1975, 65, 1229; M. Hervé, et al, ibid, 1983, 116, 222.)
  • heteropolytungstates within the scope of this invention include the Keggin and Dawson (also known as the Wells-Dawson) type structures and compounds based on these structures in which one or more of the tungsten atoms are removed and, in the majority of cases, exchanged by other metal atoms.
  • Vacancies in the structures are most often created by the extraction of WO 4+ or W 3 O 6 6+ from the Keggin (XW 12 O 40 n- ) or Dawson (P 2 W 18 O 62 6- ) species. Isomers of these unsaturated (lacunary) polyanions are possible, a consequence of the location of the vacancy.
  • R. Massart R. Contant J. M. Fruchart, J. M. Ciabrini, M. Fournier, Inorg. Chem. 1977, 16, 2916; T. L. Jorris, M. Kozik, N. Casan-Pastor, P. J. Domaille, R. G. Finke, W. K. Miller and L. C. W. Baker, J. Am. Chem. Soc.
  • An oxygen atom on the Keggin structure can also be alkylated with reagents such as trimethyloxonium salts (W. H. Knoth and R. L. Harlow,J. .Am. Chem. Soc.1981, 103, 4265). Some of the oxygen atoms on heteropolytungstates can also be exchanged for fluorine atoms (F. Chauveau, P. Doppelt and J. Lefebvre, Inorg. Chem. 1980, 19, 2803; T. L. Jorris, M.
  • heteropolyanion species are formed by reaction of two W 5 O 18 H 5- ions with metal ions such as the lanthanoids (R. D. Peacock and T. J. R.
  • phosphotungstate groups generally bridged by phosphate group(s) are known (J. Fuchs and R. Palm, Z. Natwforsch. 1988, 43b, 1529 and R. Acerete, J.
  • the central atom in the compounds can vary widely, especially in the case of the simpler Keggin type structures.
  • the central atom in the Dawson type structures is most often phosphorus.
  • Heteropolytungstate species are often more stable in solution than the corresponding heteropolymolybdates.
  • Heteropoly compounds of other metals, such as niobium and vanadium, have also been made but often are stable only over a more limited pH range.
  • Flaviviridae family In particular they inhibit the replication of such viruses stopping the development of an infection.
  • the present invention provides a method
  • M is Mo VI .
  • n 0, 1, 2, 4, or 5;
  • M is V V or Mo VI .
  • n 0 or 1
  • M is Zr
  • n is the number of cations necessary for electrical neutrality of the molecule
  • (c) a hydrate or pharmaceutically acceptable derivative thereof.
  • the compounds of the general formulae I to VII are polyanions with associated cations (A) for electrical neutrality.
  • the cation (A) is a proton, an alkali metal ion, an alkaline earth metal ion, an ammonium ion or an alkylammomum ion of the formula R 4-n H n N + , wherein R is an alkyl group of from 1 to 6 carbon atoms and n is 1, 2, or 3.
  • administration to the recipient is capable of providing (directly or indirectly) a compound of the invention or an active metabolite or residue thereof.
  • the method of the present invention is particularly directed to the treatment or prophylaxis of a flavivirus-associated infection in a patient in need of such treatment or prophylaxis, and the method comprises the administration to said patient of said effective amoimt of the at least one heteropolytungstate compound as broadly described above.
  • the patient may be a human, or an animal such as a domestic or wild animal, particularly an animal of economic importance.
  • an “effective amoimt" of the heteropolytungstate compound as used in accordance with this invention is an amount effective to inhibit flavivirus replication.
  • the present invention also extends to the use of at least one
  • heteropolytungstate selected from
  • the present invention also provides a pharmaceutical composition for the prophylaxis or treatment of a flavivirus-associated infection, which comprises at least one heteropolytungstate selected from
  • compositions of the present invention may comprise an effective amoimt of one or more compounds selected from general formulae I to IV in association with one or more pharmaceutically acceptable carriers or diluents, and optionally other antiviral or other therapeutic agents.
  • Each carrier must be pharmaceutically "acceptable” in the sense of being compatible with the other ingredients of the composition and not injurious to the patient.
  • the compositions of this invention may include other agents conventional in the art having regard to the type of composition in question, for example, those suitable for oral administration may include such further agents as sweeteners, thickeners and flavouring agents.
  • compositions include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration.
  • the compositions may conveniently be presented in unit dosage form and may be prepared by any 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.
  • the compositions 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.
  • a heteropolytungstate compound selected from
  • Presently preferred compounds in accordance with this invention include the compounds listed in Example 1 below.
  • the compounds of general formulae I to VII may be prepared by the literature methods or adaptions thereof, varying reactants and conditions as required to obtain the target compound.
  • General review articles, describing the preparation, structure and properties of many of the compounds, include P.
  • X P V , Si IV Ge IV , Co II , Co lII , Zn II , Cu II , B lII , H l 2, Al lII , Fe lII , V V , Ga lII ,
  • the compounds X Si were prepared following the method of A. Teze and G. Hervé, Inorg. Synth, 1990,.27, 129.(Ed. A. P. Ginsberg) Whiley-Interscience.
  • the compounds X P were prepared following the methods of R. Massart, R.
  • K 7 Zr 2 W 9 PO 39 H 4 19H 2 O were:%P 1.10 (1.00); %W 51.4 (53.17); %Zr 5.98 (5.86); %K 8.49 (8.79); H 2 O 10.9 (11.0); titration of the H + exchanged (on an Amberlite IR-120 [H + ] column) gave end points at 3.9 and 7.0 equivalents of base (KOH). Titration of the product (not proton exchanged) with KOH gave an end point below 0.5 equivalents, suggesting that one of the potassium ions on the product may be partially replaced by a proton. The extent of such an exchange would, presumably, be influenced by the pH of the recrystallization solution.
  • the oxygen on the transition metal atom(s) may be either doubly protonated (H 2 O), singly protonated (OH), or completely deprotonated (O).
  • H 2 O doubly protonated
  • OH singly protonated
  • O completely deprotonated
  • heteropolytungstate chemistry depends on the nature of the transition metal atom, its oxidation state, the basicity of the polyanion formed and the basicity of the solution from which the compounds were isolated.
  • oxygen atoms are necessarily oxo groups and the charge (and hence the number of counter cations (A)) on the polyanion will depend on the number of protons attached to the oxygen atom(s).
  • groups such as, for example, MOH, may dimerize by an intermolecular condensation reaction. Dimers, where formed, of the compounds listed, are also included in the invention.
  • Many of the compounds of the invention can occur in a number of isomeric forms. In fact, it is at times difficult to obtain isomerically pure compounds. All isomers or isomer mixtures are included in this invention. Many of the compounds can undergo one or more electron reductions.
  • the reduced compounds are also included in this invention.
  • the charge on the polyanions can vary, depending upon the extent of protonation of the polyanions, as noted earlier, and upon the oxidation states of the metal atoms.
  • the number of associated counter cations (A) will vary correspondingly.
  • A may be a proton, an alkali metal ion, an alkaline earth metal ion, or ammonium or alkyl ammonium ion of type R 4-n H n N + , where R is an alkyl group of from 1 to 6 carbon atoms, and n is 1, 2 or 3.
  • the required cation is generally introduced into the compound either by use of an ion exchange resin or by precipitation with excess of a salt of that cation.
  • compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, sachets 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 or non-aqueous liquid; 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, electuary or paste.
  • 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 (e.g inert diluent, preservative disintegrant (e.g. sodium starch glycollate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose) surface-active or dispersing agent.
  • a binder e.g inert diluent, preservative disintegrant (e.g. 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 compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.
  • compositions suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavoured basis, usually sucrose and acacia or tragacanth gum; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia gum; and mouthwashes comprising the active ingredient in a suitable hquid carrier.
  • Compositions for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.
  • compositions 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.
  • compositions suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the composition isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the compositions may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile hquid 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 compositions are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.
  • the compounds according to the invention may also be presented for use in the form of veterinary compositions, which may be prepared, for example, by methods that are conventional in the art. Examples of such veterinary compositions, which may be prepared, for example, by methods that are conventional in the art. Examples of such veterinary compositions, which may be prepared, for example, by methods that are conventional in the art. Examples of such veterinary compositions, which may be prepared, for example, by methods that are conventional in the art. Examples of such veterinary compositions, which may be prepared, for example, by methods that are conventional in the art. Examples of such veterinary compositions, which may be prepared, for example, by methods that are conventional in the art. Examples of such veterinary compositions, which may be prepared, for example, by methods that are conventional in the art. Examples of such veterinary compositions, which may be prepared, for example, by methods that are conventional in the art. Examples of such veterinary compositions, which may be prepared, for example, by methods that are conventional in the art. Examples of such veterinary compositions, which may be prepared, for example,
  • compositions include those adapted for:
  • oral administration external application, for example drenches (e.g.
  • aqueous or non-aqueous solutions or suspensions aqueous or non-aqueous solutions or suspensions
  • tablets or boluses powders, granules or pellets for admixture with feed stuffs; pastes for application to the tongue;
  • intramuscular or intravenous injection e.g. as a sterile solution or suspension; or (when appropriate) by intramammary injection where a suspension or solution is introduced into the udder via the teat;
  • topical application e.g. as a cream, ointment or spray applied to the skin;
  • compositions of this invention may include other agents conventional in the art having regard to the type of composition in question, for example, those suitable for oral administration may include such further agents as sweeteners, thickeners and flavouring agents.
  • suitable for oral administration may include such further agents as sweeteners, thickeners and flavouring agents.
  • the compositions according to the invention may be administered for therapy by any suitable route, including oral, rectal, nasal, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous and intradermal).
  • administration will be by the oral route, however it will be appreciated that the preferred route will vary with the condition and age of the recipient, the nature of the composition and the chosen active ingredient.
  • a suitable dose of the active ingredient will be in the range of 3.0 to 120 mg per kilogram body weight of the recipient per day, preferably in the range of 6 to 90 mg per kilogram body weight per day and most preferably in the range 15 to 60 mg per kilogram body weight per day.
  • the desired dose is preferably presented as two, three, four, five, six or more sub-doses administered at appropriate intervals throughout the day. These sub-doses may be administered in unit dosage forms, for example, containing 10 to 1500 mg, preferably 20 to 1000 mg, and most preferably 50 to 700 mg of active ingredient per unit dosage form
  • the active ingredient should be administered to achieve peak plasma concentrations of the active compound of from about 1 to about 100 ⁇ M, preferably about 2 to 50 ⁇ M. This may be achieved, for example, by the
  • a 0.1 to 5% solution of the active ingredient optionally in saline, or orally administered as a bolus containing about 0.1 to about 100 mg/kg of the active ingredient.
  • Desirable blood levels may be maintained by a
  • Example 1 The compounds listed in Example 1 were tested for their ability to inhibit RNA synthesis in an in vitro polymerase assay (Chu and Westaway, 1985, 1987; Brun and Brinton, 1986).
  • flavivirus RNA comprising the genomic 44S RNA, a double-stranded replicative form (RF) and a partially-double-stranded replicative intermediate (Rl) are detected by the incorporation of [ ⁇ - 32 P]GTP.
  • Vero cells were infected at a multiplicity of infection of 7 for Type 2 dengue (DEN-2) virus (New Guinea C strain; Sabin and Schlesinger, 1945) or Kunjin (KUN) virus (strain MRM 61 C; Boulton and Westaway, 1972). Extracts containing RNA-dependent RNA polymerase (RDRP) activity derived from DEN-2 virus-infected cells were prepared at 30 to 36 h p.i., when polymerase activity was at a maximum. Similarly, extracts of KUN virus-infected cells were prepared at the time of maximum polymerase activity at 24 h p.i. (Chu and Westaway, 1985).
  • DEN-2 Type 2 dengue
  • KUN Kunjin
  • the cells were pelleted by centrifugation and resuspended in 10 mM sodium acetate at a concentration of 2x10 7 cells /ml. They were then disrupted by passaging 20 times through a 21 gauge needle followed by 20 times through a 26 gauge needle. The disrupted cells were centrifuged at 800 g for 7 min to obtain a supernatant fraction and a pellet of the nuclear-associated material. All RDRP assays were performed using the supernatant fraction, hereafter referred to as the cell extract, which was stored at -70°C and used after only one cycle of
  • the RDRP activity in the cell extract was assayed as previously described with the following modifications (Chu and Westaway, 1985).
  • the virus-infected cell extract contained 4.5-6 mg/ml of protein.
  • the compound to be tested dissolved in double distilled water and RNasin (0.5 units /ml, Promaga) were added to the cell extract for 10 min prior to the addition of the other components of the RDRP assay.
  • the final reaction mixture (total volume of 50 ⁇ l) contained 50 mM Tris-HCl pH 8.0, 10 mM magnesium acetate, 7.5 mM potassium acetate, 10 mM 2-mercaptoethanol, 6 ⁇ g actinomycin D (AND), 5 mM phosphoenolpyruvate, 3 units/ ⁇ l pyruvate kinase, 0.5 mM ATP, 0.5 mM CTP, 0.5 mM UTP, 25 ⁇ M GTP, 5 ⁇ Ci [a- 32 P] GTP (Amersham, specific activity 410 Ci/mmol), 0.5 units/ml RN asin, 30 ⁇ l of infected cell extract and the test compound (from 0.5 to 100 ⁇ M).
  • the reaction was stopped after 30 min at 37°C by the addition of EDTA to a final concentration of 10 mM.
  • An equal volume of TNE-SDS 50 mM Tris-acetate pH 7.6, 0.1 M sodium acetate, 1 mM EDTA and 2% SDS was added to disrupt membranes.
  • the RNA was then extracted with phenol and precipitated by ethanol.
  • RNA samples were mixed with an equal volume of sample buffer containing 7 M urea in TBE (89 mM Tris-HCl, 89 mM boric acid, 2.5 mM EDTA) and 0.5% bromophenol blue, and were separated by electrophoresis through 3%
  • polyacrylamide gels containing 7 M urea in TBE The gels were fixed in 10% acetic acid, dried and radiolabelled bands detected by autoradiography.
  • the compounds tested inhibited the synthesis of both DEN-2 and KUN RF RNA. There was also a decrease in the amount of Rl detected with increasing
  • formulation A may be prepared by wet granulation of the ingredients with a solution of povidone, followed by addition of magnesium stearate and compression. mg/tablet
  • the following formulation B may be prepared by direct compression of the admixed ingredients.
  • This formulation may be prepared by wet granulation of the ingredients (below) with a solution of povidone followed by the addition of magnesium stearate and compression.
  • a capsule formulation may be prepared by admixing the ingredients of Formulation B in Example 3 above and filling into a two-part hard gelatin capsule.
  • Formulation B (infra) may be prepared in a similar manner.
  • the following controlled release capsule formulation may be prepared by extruding ingredients a, b and c using an extruder, followed by spheronisation of the extrudate and drying. The dried pellets may then be coated with
  • release-controlling membrane (d) and filled into a two-piece, hard gelatin capsule.
  • the active ingredient may be dissolved in most of the water (35°-40°C) and the pH adjusted to between 5.0 and 7.0 with the hydrochloric acid or the sodium hydroxide as appropriate.
  • the batch may then be made up to volume with the water and filtered through a sterile micropore filter into a sterile 10 ml amber glass vial (type 1) and sealed with sterile closures and overseals.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Inorganic Chemistry (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (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

Hétéropolytungstates présentant une activité antiflavivirale répondant aux formules générales (I) à (VII): (I), An[XW12O40] dans laquelle X est choisi entre P?V, SiIV, GeIV, COII, COIII, ZnII, CuII, BIII, HI¿2, Al?III, FeIII, VV, GaIII, MnIV, CIV¿; (II) A¿n?[X2W18O62], dans laquelle X représente P?V¿; (III) A¿n?[XW11O39], dans laquelle X est choisi entre P?V, SiIV, GeIV, BIII, AlIII, GaIII, FeIII, CoIII¿; (IV) A¿n?[XW9O34], dans laquelle X est choisi entre P?V, SiIV, GeIV¿; (V) A¿n?[X2W17-mMmO61], dans laquelle X représente P?V¿, M représente MoVI et m vaut 0, 1, 2, 4 ou 5; (VI) A¿n?[X2W15-mMmO56], dans laquelle X représente P?V¿, M représente V?V ou MoVI¿ et m vaut 0 ou 1; (VII) A¿n?[XM2W9O39], dans laquelle X représente P et M représente Zr; et, dans chacune des formules générales (I) à (VII), A représente un cation, et n représente le nombre de cations nécessaires à la neutralité électrique de la molécule; ou des dimères, des hydrates ou des dérivés pharmaceutiquement acceptables de ces composés. Des compositions pharmaceutiques et des procédés destinés au traitement ou à la prophylaxie d'une infection associée au flavivirus, qui comprennent l'utilisation de ces composés, sont égalements décrits.
PCT/AU1993/000606 1992-12-01 1993-11-29 Agents antiviraux WO1994012192A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU55545/94A AU5554594A (en) 1992-12-01 1993-11-29 Antiviral agents

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
AUPL611592 1992-12-01
AUPL6115 1992-12-01

Publications (1)

Publication Number Publication Date
WO1994012192A1 true WO1994012192A1 (fr) 1994-06-09

Family

ID=3776567

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/AU1993/000606 WO1994012192A1 (fr) 1992-12-01 1993-11-29 Agents antiviraux

Country Status (2)

Country Link
CN (1) CN1093906A (fr)
WO (1) WO1994012192A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998009622A1 (fr) * 1996-09-03 1998-03-12 University Of Iowa Research Foundation Composes contenant du gallium en tant qu'inhibiteurs de pathogenes intracellulaires
WO1999004803A1 (fr) * 1997-07-24 1999-02-04 Biomolecular Research Institute Limited Composes d'heteropolytungstate utilises comme inhibiteurs de l'angiogenese
WO1999021569A1 (fr) * 1997-10-24 1999-05-06 Starpharma Limited Composition antifilovirale a base de polyoxometallates
US6020369A (en) * 1994-09-26 2000-02-01 Schinazi; Raymond F. Method compositions and apparatus for treating and preventing respiratory viral infections
EP2494991A1 (fr) 2007-05-04 2012-09-05 Vertex Pharmaceuticals Incorporated Polythérapie pour le traitement de l'infection par VHC

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE861233A (fr) * 1976-12-03 1978-05-25 Anvar Composes d'heteropolyanions contenant du tungstene combine a de l'antimoine, leur obtention et leurs applications
US4196136A (en) * 1978-11-06 1980-04-01 E. I. Du Pont De Nemours And Company Ligated transition metal derivatives of heteropolyanions
US4557924A (en) * 1985-03-21 1985-12-10 Gte Products Corporation Method of producing crystalline ammonium metatungstate
EP0192842A2 (fr) * 1985-01-31 1986-09-03 Dr. Johannes Heidenhain GmbH Feuille perforée autoportante obtenue par électroformage
JPH01172325A (ja) * 1987-12-28 1989-07-07 Terumo Corp 抗リウマチ剤
JPH02204415A (ja) * 1989-02-03 1990-08-14 Terumo Corp 抗腫瘍剤
JPH02204416A (ja) * 1989-02-03 1990-08-14 Terumo Corp 抗腫瘍剤
JPH03115126A (ja) * 1989-09-29 1991-05-16 Terumo Corp タングステン化合物およびその製造方法

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE861233A (fr) * 1976-12-03 1978-05-25 Anvar Composes d'heteropolyanions contenant du tungstene combine a de l'antimoine, leur obtention et leurs applications
US4196136A (en) * 1978-11-06 1980-04-01 E. I. Du Pont De Nemours And Company Ligated transition metal derivatives of heteropolyanions
EP0192842A2 (fr) * 1985-01-31 1986-09-03 Dr. Johannes Heidenhain GmbH Feuille perforée autoportante obtenue par électroformage
US4557924A (en) * 1985-03-21 1985-12-10 Gte Products Corporation Method of producing crystalline ammonium metatungstate
JPH01172325A (ja) * 1987-12-28 1989-07-07 Terumo Corp 抗リウマチ剤
JPH02204415A (ja) * 1989-02-03 1990-08-14 Terumo Corp 抗腫瘍剤
JPH02204416A (ja) * 1989-02-03 1990-08-14 Terumo Corp 抗腫瘍剤
JPH03115126A (ja) * 1989-09-29 1991-05-16 Terumo Corp タングステン化合物およびその製造方法

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Volume 101, No. 10, issued 03 September 1984, Columbus, Ohio, USA, CONSTANT, ROLAND, "Stabilities of Metal (II) and Alkaline Ion Complexes of Lacunary Heteropolytungstates", page 417, column 2, the Abstract No. 79372h; & J. CHEM. RES.SYNOP., 1984, (4), 120-1, (Eng). *
CHEMICAL ABSTRACTS, Volume 68, No. 24, (1968), CLAUDE TOURNE, "Constitution of Heteropolyanions", page 10705, column 2, the Abstract No. 111059z; & C.R. ACAD. SCI., Paris, Ser. C 266 (10), 702-4, (1968), (Fr). *
CHEMICAL ABSTRACTS, Volume 91, No. 4, issued 23 July 1979, Columbus, Ohio, USA, KNOTH, W.H., "Derivatives of Heteropolyanions", page 781, column 1, the Abstract No. 32039q; & J. AM. CHEM. SOC., 1979, 101(8), 2211-13, (Eng). *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6020369A (en) * 1994-09-26 2000-02-01 Schinazi; Raymond F. Method compositions and apparatus for treating and preventing respiratory viral infections
WO1998009622A1 (fr) * 1996-09-03 1998-03-12 University Of Iowa Research Foundation Composes contenant du gallium en tant qu'inhibiteurs de pathogenes intracellulaires
US5997912A (en) * 1996-09-03 1999-12-07 University Of Iowa Research Foundation Method for inhibiting growth of P. aeruginosa using gallium-containing compounds
US6203822B1 (en) 1996-09-03 2001-03-20 University Of Iowa Research Foundation Gallium-containing compounds for the treatment of infections caused by intracellular pathogens and pathogens causing chronic pulmonary infection
WO1999004803A1 (fr) * 1997-07-24 1999-02-04 Biomolecular Research Institute Limited Composes d'heteropolytungstate utilises comme inhibiteurs de l'angiogenese
WO1999021569A1 (fr) * 1997-10-24 1999-05-06 Starpharma Limited Composition antifilovirale a base de polyoxometallates
EP2494991A1 (fr) 2007-05-04 2012-09-05 Vertex Pharmaceuticals Incorporated Polythérapie pour le traitement de l'infection par VHC

Also Published As

Publication number Publication date
CN1093906A (zh) 1994-10-26

Similar Documents

Publication Publication Date Title
DK175544B1 (da) Anvendelse af azithromycin og derivater deraf til fremstilling af antiprotozoale lægemidler
WO1995011033A1 (fr) Polyoxometallates utilises dans le traitement des infections associees au flavivirus
TWI237024B (en) A novel crystalline form of n-[4-[2-(2-amino-4,7-dihydro-4-oxo-3h-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-l-glutamic acid and process therefor
CZ293494B6 (cs) Farmaceutický prostředek obsahující zvolené hydráty uhličitanu lanthanu
DK169437B1 (da) Chloreret uracilnucleosid, denne forbindelse til anvendelse mod en adenovirusinfektion, anvendelse af forbindelsen til fremstilling af et lægemiddel mod en adenovirusinfektion, farmaceutiske præparater indeholdende forbindelsen samt fremgangsmåde ti l fremstilling af forbindelsen
CN111821310A (zh) 一种瑞德西韦制剂及其适应症
WO1994012192A1 (fr) Agents antiviraux
CA1318850C (fr) Produits pharmaceutiques
WO1993021934A1 (fr) Heteropolytungstates utilises dans le traitement des infections a flavivirus
JP2648329B2 (ja) エイズの予防または治療用医薬組成物
JPH02129125A (ja) 杭ウイルス性ヌクレオシド組合わせ剤
AU4255593A (en) Heteropolytungstates in the treatment of flavivirus infections
GB1577196A (en) Compositions containing erythromycin and metoclopramide
DK150604B (da) Analogifremgangsmaade til fremstilling af calciumoxaprozin
JP3348849B2 (ja) ３−ヒドロキシ−４−ピロンのガリウム錯体の医薬組成物
AU647800B2 (en) Antiviral agents containing heteropolytungstate
JPH09323935A (ja) 抗ウイルス剤、その製造方法及びその応用
JPH0481968B2 (fr)
CN113546067B (zh) 具有抗病毒作用的蒽醌衍生物
RU2172631C2 (ru) Индуктор интерферона пролонгированного действия
CN116850192A (zh) 一种核苷类衍生化合物的药物组合物及其制备方法和用途
CN116474055A (zh) 含有莪术油和冰片的药物组合物的用途
AU8280087A (en) Azithromycin and derivatives as antiprotozoal agents
JPH01163121A (ja) 抗レトロウイルス剤
JPH05213756A (ja) 抗インフルエンザ剤

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AT AU BB BG BR BY CA CH CZ DE DK ES FI GB HU JP KP KR KZ LK LU LV MG MN MW NL NO NZ PL PT RO RU SD SE SK UA US UZ VN

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 BF BJ CF CG CI CM GA GN ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

NENP Non-entry into the national phase

Ref country code: CA

122 Ep: pct application non-entry in european phase