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WO1995031202A1 - Composes-cages, procedes pour les preparer et leur utilisation en tant qu'agents antiviraux - Google Patents

Composes-cages, procedes pour les preparer et leur utilisation en tant qu'agents antiviraux Download PDF

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Publication number
WO1995031202A1
WO1995031202A1 PCT/AU1995/000283 AU9500283W WO9531202A1 WO 1995031202 A1 WO1995031202 A1 WO 1995031202A1 AU 9500283 W AU9500283 W AU 9500283W WO 9531202 A1 WO9531202 A1 WO 9531202A1
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WIPO (PCT)
Prior art keywords
compound
formula
optionally substituted
optionauy
viral infection
Prior art date
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PCT/AU1995/000283
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English (en)
Inventor
Sebastian Mario Marcuccio
Kathleen Anne Turner
George Holan
Peter Osvath
Alan Mcleod Sargeson
Helmut Weigold
Rodney Geue
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Commonwealth Scientific And Industrial Research Organisation
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Publication date
Priority claimed from AUPM5656A external-priority patent/AUPM565694A0/en
Priority claimed from AUPM5720A external-priority patent/AUPM572094A0/en
Application filed by Commonwealth Scientific And Industrial Research Organisation filed Critical Commonwealth Scientific And Industrial Research Organisation
Priority to AU24397/95A priority Critical patent/AU2439795A/en
Publication of WO1995031202A1 publication Critical patent/WO1995031202A1/fr

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    • 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
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings

Definitions

  • the present invention relates to cage (Sarcophagine) compounds, processes for their preparation and their use in therapy, particularly for the treatment and/or prophylaxis of viral infections including Acquired Immune Deficiency Syndrome (hereinafter referred to as "AIDS"), Hepatitis B, Hepatitis C, Herpes and Cytomegalovirus (hereinafter referred to as "CMV").
  • AIDS Acquired Immune Deficiency Syndrome
  • Hepatitis B Hepatitis B
  • Hepatitis C Herpes
  • CMV Cytomegalovirus
  • the causative agent for AIDS is a member of the family Retroviridae. This virus will be identified hereinafter as "HIV". Infection with HTV is associated with depletion of T4 lymphocytes, brain disease and several types of cancer including Kaposis sarcoma. Patients infected with the virus also have a high incidence of opportunistic infections and a significantly reduced life span.
  • HLTV-1 Human T- cell Lymphotropic Virus Type 1
  • Retroviridae possess a unique enzyme, reverse transcriptase, which is necessary for their replication. As this enzyme is not normally present in uninfected cells, it is considered a target for antiviral drugs.
  • Another virus utilizing reverse transcriptase during replication is the Hepatitis B Virus (hereinafter referred to as "HBV") which is a member of the family Hepadnaviridae. HBV causes widespread morbidity and mortality and is the main cause of primary hepatocellular carcinoma in individuals who are chronic carriers of the virus. It is also the cause of canine arthritis/encephalitis, feline arthritis and duck hepatitis.
  • Herpesvirus responsible for human disease are Herpes Simplex virus (e.g., cold sores), Cytomegalovirus (e.g., salivary gland disease), Varicella-Zoster (e.g. chickenpox and shingles) and Epstein-Barr virus (e.g., infectious mononucleosis).
  • Herpes Simplex virus (HSV) infections is recommended only in cases involving infection of slowly dividing host tissues, such as in keratoconjunctivitis. This is made necessary by the fact that idoxuridine (IUdR) and arabinoadenosine (ARA-A) can interfere with both viral DNA and host DNA, causing severe side effects.
  • Acyclovir is also approved for use against initial infections of herpes genitalis.
  • the drug is used to control localized herpes simplex infections for both genital and labial herpes in patients whose natural defences are impaired and unable to control the spread of the infection. This drug reduces the length of time that live virions are present in the vesicles. This viral shedding in the lesion allows the virus to be transferred from one person to another through sexual contact, and the disease is highly contagious when sores are present.
  • Cytomegalic inclusion disease occurs most frequently in infants and is a viral disease of the salivary glands and other tissues. It is caused by the intrauterine (congenital) or postnatal transmission of CMV. Although rare, CID may also occur in adults receiving immunosuppressive therapy. Like other herpes viruses, CMV infections result in vesicular eruption of host tissues. The virus is not only found in the salivary glands but also the kidneys, liver, brain, lungs and eyes. Tissue destruction can be fatal or result in severe brain damage, blindness, deafness and heart defects.
  • CMV is believed to be able to enter a latent period, as do other herpes viruses, resulting in a delay in the onset of symptoms of up to two years. At present, there is no treatment for this disease.
  • a vaccine of attenuated CMV has been developed, but its value in preventing infection is questionable.
  • Flaviviruses are known to be the causative agents of a number of human diseases including the most important arthropod-borne viral afflictions of maiJrind - dengue, yellow fever, and Japanese encephalitis. In addition, eight flaviviruses 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.
  • Hepatitis C There are between 30 and 60 million flavivirus infections per year including one million Japanese encephalitis infections.
  • 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 Uver infection than Hepatitis B which is a recognised hazard in many countries.
  • 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 Haviviruses only, for example, 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. An antiviral drug to control infections with flaviviruses is thus highly desirable.
  • Cage compounds have been known for over 20 years (A. M. Sargeson, Pure and Applied Chemistry, Vol 58 page 1511(1986) and Chemistry in Australia, May 1992 page 176). Most of their applications stem from their redox chemistry and electron transfer properties. Their redox chemistry has led to their use as catalysts for the oxidation or reduction of organic substrates such as, for example, propylene to acrylic acid, ethylene to acetaldehyde. Their redox properties also led to their use as electron relays in the direct conversion of water to hydrogen using sunlight as energy source. In the biological field, cage ligands have been used to remove toxic metals, for example Cu and Fe, from the body by complexation followed by normal elimination of the stable complex.
  • toxic metals for example Cu and Fe
  • cage compounds with long alkyl chain tails which are consequently surface-active, have the power to disrupt biological membranes and may be useful as anthelmintics.
  • the cage ligands or complexes have not previously been used as control agents for viral infections.
  • cage compounds of Formula 1 below are inhibitors of the replication of Retroviruses, Herpesviruses, Hepadnaviruses and Flaviviruses.
  • a method for the treatment and/or prophylaxis of a viral infection which comprises administration of an effective amount of a compound of Formula 1 :
  • M is a metal capable of forming hexacoordinate complexes
  • Y is an integer between 1 and 6 inclusive; n is O or 1; m is O or 1;
  • a to A ⁇ inclusive are metal coordinating groups which may be the same or different and are selected from NH, N, O and S;
  • R! and R ⁇ may be the same or different and are selected from hydrogen, halogen, nitro, cyano, optionally substituted alkyl, optionally substituted alkylene, optionally substituted aryl, hydroxy, optionally substituted alkoxy, optionally substituted alkyenyloxy, optionally substituted alkynyloxy, optionally substituted aryloxy, optionally substituted acyloxy, optionally substituted amino, optionally substituted ammonium, optionally substituted cycloalkyl, optionally substituted acyl, optionally substituted saturated or unsaturated heterocyclyl, optionally substituted heteroaryl, carbamato, thiocarboxylato, amidino, alkoxycarbonyl, mercaptothiocarbonyl, alkoxythiocarbonyl, thiocarbamato, zinc halide and a sugar moiety; and
  • R3 to Rl4 and R ⁇ ' to R ⁇ ' inclusive may be the same or different and are selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted alkylene, hydroxy, optionally substituted alkoxy, optionally substituted alkyenyloxy, optionally substituted alkynyloxy, optionally substituted aryloxy, optionally substituted acyloxy, optionally substituted amino, optionally substituted ammonium, optionally substituted cycloalkyl, optionally substituted acyl, optionally substituted aryl, optionally substituted saturated or unsaturated heterocyclyl, optionally substituted heteroaryl, carbamato, thiocarboxylato, amidino, alkoxycarbonyl, mercaptothiocarbonyl, alkoxythiocarbonyl, thiocarbamato and a sugar moiety; or one or more of the groups A to A ⁇ may be linked to an adjoining carbon atom by a double bond with the absence of the corresponding to R
  • viral infection is used herein in its broadest sense and includes any infection caused by a Retrovirus such as HTV or HLTV-1; Herpesvirus such as CMV; Hepadnavirus such as HBV and duck hepatitis virus; or Flavivirus such as yellow fever virus, dengue virus and Japanese encephalitis virus.
  • retrovirus such as HTV or HLTV-1
  • Herpesvirus such as CMV
  • Hepadnavirus such as HBV and duck hepatitis virus
  • Flavivirus such as yellow fever virus, dengue virus and Japanese encephalitis virus.
  • viral infections may include AIDS, Inner T-cell leukemia, cold sores, genital herpes, CID, chicken pox, shingles, infectious mononucleosis, Hepatitis B, Hepatitis C, non-A non-B Hepatitis, canine arthritis/encephaltis, feline arthritis, duck hepatitis, dengue fever, yellow fever and Japanese encephalitis.
  • the subject may be
  • an “effective amount” of the compound of Formula 1 is an amount sufficient to inhibit or reduce viral replication, generally by greater than 50% (as measured by viral DNA levels or reverse transcriptase activity).
  • salts of the compound of Formula 1 are preferably pharmaceutically acceptable, but it will be appreciated that non-pharmaceutically acceptable salts also fall within the scope of the present invention, since these are useful as intermediates in the preparation of pharmaceutically acceptable salts.
  • pharmaceutically acceptable salts include salts of pharmaceutically acceptable cations such as sodium, potassium, lithium, calcium, magnesium, ammonium and alkylammonium; acid addition salts of pharmaceutically acceptable inorganic acids such as hydrochloric, orthophosphoric, sulphuric, phosphoric, nitric, carbonic, boric, sulfamic and hydrobromic acids; or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulphonic, trihalomethanesulphonic, toluenesulphonic, benzen
  • pharmaceutically acceptable derivative any pharmaceutically acceptable salt, hydrate or any other compound which, upon administration to the subject, is capable of providing (directly or indirecdy) a compound of Formula 1 or an antivirally active metabolite or residue thereof.
  • pro-drug is used herein in its broadest sense to include those compounds which are converted in vivo to compounds of Formula 1.
  • tautomer is used herein in its broadest sense to include compounds of Formula 1 which are capable of existing in a state of equilibrium between two isomeric forms. Such compounds may differ in the bond connecting two atoms or groups and the position of these atoms or groups in the compound,
  • isosomer is used herein in its broadest sense and includes structural, geometric and stereo isomers. As the compound of Formula 1 may have one or more chiral centres, it is capable of existing in enantiomeric forms.
  • the compounds of the invention may be electrically neutral or be polycations with associated anions for electrical neutrality.
  • Suitable associated anions include sulphate, tartrate, citrate, chloride, nitrate, nitrite, phosphate, perchlorate, halosulfonate or trihalomethylsulfonate.
  • a 1 to A 6 , R 1 to R 14 and R 3 ' to R 14 ' are as defined above.
  • the compounds of Formula 1 include compounds of Formula 3 as shown below.
  • the compounds of Formula 3 may be formed during the preparation of the compounds of Formula 1.
  • the compounds of Formula 3 form a further aspect of the present invention.
  • R 1 , R2, M and n are as defined above.
  • the metal may be an alkali metal such as sodium or lithium; an alkaline earth metal such as magnesium; or a transition metal such as vanadium, titanium, chromium, manganese, iron, cobalt, nickel, copper, zinc, ruthenium, silver, cadmium, iridium, platinum, indium or mercury.
  • the metal is a Group 9 metal such as cobalt.
  • halogen denotes fluorine, chlorine, bromine or iodine, preferably chlorine, bromine or iodine.
  • alkyl used either alone or in compound words such as “optionally substituted alkyl” or “optionally substituted cycloalkyl” denotes straight chain, branched or cyclic alkyl, preferably CJ_3Q alkyl or cycloalkyl.
  • straight chain and branched alkyl examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, amyl, isoamyl, sec-amyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl, hexyl, 4-methylpentyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl, 1,3- dimethylbutyl, 1,2,2,-trimethylpropyl, l,l,2-trimethylpropyl, heptyl, 5-methylhexyl, 1- methylhexyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 4,4-dimethylpentyl, 1,2-dimethylpentyl
  • cyclic alkyl examples include mono- or polycyclic alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and the like.
  • alkenyl used either alone or in compound words such as “alkenyloxy” denotes groups formed from straight chain, branched or cyclic alkenes including ethylenically mono-, di- or poly-unsaturated alkyl or cycloalkyl groups as defined above, preferably C 2-2 o alkenyl.
  • alkenyl examples include vinyl, allyl, 1-methylvinyl, butenyl, iso-butenyl, 3-methyl-2-butenyl, 1-pentenyl, cyclopentenyl, 1-methyl-cyclopentenyl, 1-hexenyl, 3-hexenyl, cyclohexenyl, 1- heptenyl, 3-heptenyl, 1-octenyl, cyclooctenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 3- decenyl, 1,3-butadienyl, l-4,pentadienyl, 1,3-cyclopentadienyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,3-cyclohexadienyl, 1,4-cyclohexaidenyl, 1,3-cycloheptadienyl, 1,3,5-cycloheptat
  • alkoxy used either alone or in compound words such as “optionally substituted alkoxy” denotes straight chain or branched alkoxy, preferably C1.30 alkoxy. Examples of alkoxy include methoxy, ethoxy, n-propyloxy, isopropyloxy and the different butoxy isomers.
  • acyl used either alone or in compound words such as "optionally substituted acyl” or “optionally substituted acyloxy” denotes carbamoyl, aliphatic acyl group and acyl group containing an aromatic ring, which is referred to as aromatic acyl or a heterocyclic ring which is referred to as heterocyclic acyl, preferably C1.30 acyl.
  • acyl examples include carbamoyl; straight chain or branched alkanoyl such as formyl, acetyl, propanoyl, butanoyl, 2- methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl and icosanoyl; alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl and heptyloxycarbonyl; cycloalky
  • phenylacetyl phenylpropanoyl, phenylbutanoyl, phenylisobutyl, phenylpentanoyl and phenylhexanoyl
  • naphthylalkanoyl e.g. naphthylacetyl, naphthylpropanoyl and naphthylbutanoyl
  • aralkenoyl such as phenylalkenoyl (e.g.
  • phenylpropenoyl, phenylbutenoyl, phenylmethacrylyl, phenylpentenoyl and phenylhexenoyl and naphthylalkenoyl e.g. naphthylpropenoyl, naphthylbutenoyl and naphthylpentenoyl
  • aralkoxycarbonyl such as phenylalkoxycarbonyl
  • benzyloxycarbonyl aryloxycarbonyl such as phenoxycarbonyl and naphthyloxycarbonyl; aryloxyalkanoyl such as phenoxyacetyl and phenoxypropionyl; arylcarbamoyl such as phenylcarbamoyl; arylthiocarbamoyl such as phenylthiocarbamoyl; arylglyoxyloyl such as phenylglyoxyloyl and naphthylglyoxyloyl; arylsulfonyl such as phenylsulfonyl and naphthylsulfonyl; heterocycUccarbonyl; heterocycUcalkanoyl such as thienylacetyl, thienylpropanoyl, thienylbutanoyl, thienylpentanoyl, thienylhexano
  • aryl used either alone or in compound words such as “optionally substituted aryl”, “optionally substituted aryloxy” or “optionally substituted heteroaryl” denotes single, polynuclear, conjugated and fused residues of aromatic hydrocarbons or aromatic heterocyclic ring systems.
  • aryl examples include phenyl, biphenyl, terphenyl, quaterphenyl, phenoxyphenyl, naphthyl, tetrahydronaphthyl, anthracenyl, d-Lhydroanthracenyl, benzanthracenyl, dibenzanthracenyl, phenanthrenyl, fluorenyl, pyrenyl, indenyl, azulenyl, chrysenyl, pyridyl, 4- phenylpyridyl, 3-phenylpyridyl, thienyl, furyl, pyrryl, pyrrolyl, furanyl, imadazolyl, pyrrolydinyl, pyridinyl, piperidinyl, indolyl, pyridazinyl, pyrazolyl, pyrazinyl, thiazolyl, pyrimidinyl, quin
  • heterocyclyl used either alone or in compound words such as “optionaUy substituted saturated or unsaturated heterocyclyl” denotes monocycUc or polycycUc heterocyclyl groups containing at least one heteroatom atom selected from nitrogen, sulphur and oxygen.
  • Suitable heterocyclyl groups include N-containing heterocycUc groups, such as, unsaturated 3 to 6 membered heteromonocycUc groups containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl or tetrazolyl; saturated 3 to 6-membered heteromonocycUc groups containing 1 to 4 nitrogen atoms, such as, pyrroUdinyl, imidazolidinyl, piperidino or piperazinyl; unsaturated condensed heterocycUc groups containing 1 to 5 nitrogen atoms, such as, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazo
  • optionalaUy substituted means that a group may or may not be further substituted with one or more groups selected from alkyl, alkenyl, alkynyl, aryl, halo, haloalkyl, haloalkenyl, haloalkynyl, haloaryl, hydroxy, alkoxy, alkenyloxy, aryloxy, carboxy, benzyloxy haloalkoxy, haloalkenyloxy, haloaryloxy, nitro, nitroalkyl, nitroalkenyl, nitroalkynyl, nitroaryl, nitroheterocyclyl, azido, amino, alkylamino, alkenylamino, alkynylamino, arylamino, ber_zyl___ ⁇ ino, acylamino, acyl, alkenylacyl, alkynylacyl, arylacyl, acylamino, acyl, alken
  • the present invention also provides a compound of Formula 1 as defined above for use in the treatment and/or prophylaxis of a viral infection.
  • Compounds of Formula 1, 2 or 3 which fall within the ambit of the present invention include the compounds of Tables 1 to 6 and Figure 1 which follow.
  • Amine groups in the compounds Usted may be reversibly converted to ammonium under acidic conditions and the present invention includes both basic and protonated forms of such amine groups.
  • the present invention also extends to a pharmaceutical or veterinary composition for the treatment and/or prophylaxis of a viral infection which comprises a compound of Formula 1, 2 or 3 as defined above in association with a pharmaceutically or veterinarily acceptable carrier, diluent, adjuvant and/or excipient.
  • the compound of Formula 1, 2 or 3 hereinafter referred to as the "active ingredient” 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 wiU be by the oral route, however it wUl be appreciated that the preferred route wUl vary with the condition and age of the subject and the chosen active ingredient.
  • the compositions of the present invention comprise at least one compound of Formula 1, 2 or 3, together with one or more pharmaceutically acceptable carriers, diluents adjuvants and/or excipients and optionally other antiviral or therapeutic 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 methods weU 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, diluents, ajduvants and/or excipients or finely divided solid carriers or both, and then if necessary shaping the product.
  • a tablet may be made by compression or moulding, optionaUy 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-Unked 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-Unked 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 dUuent.
  • the tablets may optionaUy be coated or scored and may be formulated so as to provide slow or controUed release of the active ingredient therein using, for example, hydroxypropylmethyl ceUulose in varying proportions to provide the desired release profile. Tablets may optionaUy 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 Uquid 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 subject; 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 (lyophiUzed) condition requiring only the addition of the sterile Uquid 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 hereinabove described, or an appropriate fraction thereof, of an active ingredient.
  • the compounds of Formula 1, 2 or 3 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.
  • veterinary compositions include those adapted for: (a) oral administration, external appUcation, for example drenches (e.g. aqueous or non-aqueous solutions or suspensions); tablets or boluses; powders, granules or peUets for admixture with feed stuffs; pastes for appUcation to the tongue; (b) parenteral administration for example by subcutaneous, 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 binders, sweeteners, thickeners, flavouring agents, disintegrating agents, coating agents, preservatives, lubricants and/or time delay agents.
  • Suitable sweeteners include sucrose, lactose, glucose, aspartame or saccharin.
  • Suitable disintegrating agents include corn starch, methylceUulose, polyvinylpyrroUdone, xanthan gum, bentonite, alginic acid or agar.
  • Suitable flavouring agents include peppermint oil, oil of wintergreen, cherry, orange or raspberry flavouring.
  • Suitable coating agents include polymers or copolymers of acryUc acid and/or methacryUc acid and/or their esters, waxes, fatty alcohols, zein, sheUac or gluten.
  • the compounds of Formula 1, 2 or 3 may be prepared by processes described in the scientific literature.
  • the metal atom in the compounds of Formula 1 or 3 may be incorporated or exchanged by the processes described in P. Comba, L. M. Engelhardt, J. M. Harrowfield, G. A. Lawrance, L. L. Martin, A. M. Sargeson and A. H. White, J. Chem. Soc. Chem. Commun. 1985, 174; P. Bernhard and A. M. Sargeson, J. Chem. Soc. Chem. Commun. 1985, 1516; I. J. Clark.1. 1. Creaser, L. M. Engelhardt, J. M. Harrowfield, E. R. Krausz, G. M.
  • the compounds of Formula 2 may be prepared by processes described in L. L. Martin, Ph. D. Thesis, Australian National University, 1986, pp 229-233. D. J. Bull, Ph. D. Thesis, Australian National University, 1991, pp 41; Bottomley, G. A.; Clark, I. A.; Creaser, 1. 1.; Engelhardt, L. M.; Geue, R. J.; Hagen, K. S.; Harrowfield, J. M.; Lawrance, G. A.; Lay, P. A.; Sargeson, A. M.; See, A. J.; Skelton, B. W.; White, A. H.; and Wilner, F. R., Aust. J. Chem. , 1994, 47, 143.
  • R R ⁇
  • the present invention further provides a process for the preparation of a compound of
  • the end-capping process is based on a series of reactions which take place at terminal amine groups of hgands co-ordinated to the metal atom.
  • a metal complex having ligands with terminal primary amino groups is treated with formaldehyde and base. It is believed that deprotonation of one amine group is followed by condensation with formaldehyde to give a co-ordinated carbinolamine, which eliminates water to give an imine.
  • the imine may then be attacked by a nucleophUe, such as, an amine or a carbanion leading to a coupled species. Under the conditions of the reaction, this mechanism may occur one or more times to give the cage molecule.
  • the nucleophilic species may contain one or more functional groups, such as, an aldehyde, carboxylate or nitrile. These functional groups may also attack the co-ordinated amines and lead to ring closure, in which case fewer than three units of formaldehyde are required to form the cap. Depending on the nature of the metal complex, the capping process can take place on one or both ends of the molecule to give the cage. This sequence of the coupUng reactions and the nucleophUic attack may vary, but the overall result is the formation of the caps, leading to encapsulation of the metal.
  • functional groups such as, an aldehyde, carboxylate or nitrile.
  • the process may be performed in any suitable solvent, for example, water or acetonitrile.
  • the order of addition of the reagents can also be varied. It is not necessary for the reagents to be fuUy dissolved for the reaction to occur.
  • Either aqueous formaldehyde or paraformaldehyde may be the source of formaldehyde.
  • a variety of different bases, such as, inorganic hydroxides and carbonates or tertiary amines may be used in the process.
  • the cage may be modified, for example, by attaching functional groups or by reduction.
  • the (2 M HCl) eluate was taken to dryness, diluted to 500 mL with water, loaded onto a column of SP-Sephadex C-25 (35 x 4 cm) and eluted with K2SO4 (0.1 M).
  • the leading half of the single yellow band that was eluted contained the desired product.
  • This material was desalted by treatment with Dowex-HCl, and rechromatographed on SP-Sephadex C-25, using Na3citrate (0.05 M) as eluant.
  • the single yeUow band was coUected in four fractions and the second and third of these contained only the desired product. (The first and fourth fractions were largely the target molecule as weU, but were not pure).
  • the product was desalted on Dowex, stripped to dryness, and dissolved in the minimum amount of boUing methanol. Upon cooUng to 0°C, the product was obtained as a well- crystallised material.
  • reaction mixture was quenched with excess glacial acetic acid, d uted with 0.5 M HCl (500 mL) and loaded onto a column of Dowex 50W-X2 cation exchange resin.
  • the column was washed with water, then IM HCl and the adsorbed complexes were removed as a single band with 2M HCl.
  • the eluate was taken to dryness, and the crude product was dissolved in water (15 mL).
  • NaHCO3 (0.90 g) was added, followed immediately by a solution containing NaBH4 (0.079 g) and Na2CO3 (l.Og) in water (10 mL), and the solution was stirred for 30 minutes.
  • the reaction mixture was quenched with excess IM HCl (caution, frothing) and air was bubbled through the solution for 15 minutes.
  • the solution was loaded onto a column of Dowex 50W-X2 cation exchange resin, washed with water, then IM HCl and the desired complex was removed with 2M HCl. The column was then washed with 6M HCl to remove some polymeric impurity.
  • the (2M) fraction which contained the metal complexes was stripped to dryness, and the crude product was taken up in the minimum volume of hot water and diluted with an equal volume of 2-propanol, giving the desired product as a well-crystallised material.
  • reaction mixture was quenched with glacial acetic acid (20 mL), dUuted with 0.05 M HCl (750 mL) and loaded onto a column of Dowex 50W-X2 cation exchange resin.
  • the column was washed with successively with water, 0.5 M HCl and IM HCl and the adsorbed complexes were removed as a single band with 2 - 4 M HCl.
  • Some material was removed from the column with concentrated HCl/Absolute Ethanol (1:1), but this was shown by n.m.r. to contain none of the desired product.
  • reaction mixture was quenched with glacial acetic acid (5 mL), diluted with 0.05 M HCl (200 mL) and loaded onto a column of Dowex 50W-X2 cation exchange resin.
  • the column was washed with successively with water, 0.5 M HCl and IM HCl and the adsorbed complexes were removed as a single band with 2 - 4 M HCl.
  • the solution was taken to dryness and dissolved in water (50 mL). NaHCO3 (1.6 g) was added, immediately followed by NaB__4 (0.158 g, 4.2 mmol), dissolved in water (20 mL) containing Na2CO3 (2.0 g).
  • the product was dissolved in water (250 mL), loaded onto a column of SP-Sephadex C-25, and eluted with 0.1 M Na3Citrate. Two well-separated bands, (Bl orange and B2 yellow) were removed and desalted with Dowex HCl. The orange band (B 1) was loaded onto a column of SP-Sephadex C-25, and elution with 0.1 M K2SO4 gave three bands, which were separately desalted and taken to dryness.
  • the leading portion was pure [Co((CH3CH2 ⁇ CH2CH2 ⁇ ,CH3CH2 ⁇ CH2CH2 ⁇ CH2)-absar)]Cl3 (Compound 6.4), whUe the trailing portion was [Co((HO,CH3CH2OCH2CH2OCH2)-absar)]Cl3 (Compound 6.5).
  • the column was washed successively with water and IM HCl and the product was eluted with 2-4 M HCl and taken to dryness.
  • the product was dissolved in water (250 mL), loaded onto a column of SP-Sephadex C-25 and eluted with 0.1 M Na3_itrate.
  • Two weU-separated bands, (B 1 orange and B2 yellow) were removed and desalted with Dowex/HCl.
  • the orange band (B 1) was loaded onto a column of SP-Sephadex C- 25 and elution with 0.1 M K2SO4 gave one principal band, foUowed by a very small diffuse band. These were separately desalted and taken to dryness.
  • the orange eluate is collected and loaded onto a 4cm deep column of Dowex 50W-X4 which is then washed with water and IM hydrochloric acid.
  • the orange product is removed with 3M hydrochloric acid and the eluate concentrated at ca 5 torr and 30°C to give an orange solid.
  • This is recrystalUsed (water/acetone) to give N- [Co(8-ethyls_j-l-yl)]-N'-dimethylaminopropyl-N"-ethylguanidine trichloride (257mg, 78%) as an orange soUd.
  • the compounds of the invention were tested in a HTV screen by the MTT method (J.
  • MT-4 cells (2.5 x 10 4 / weU) were challenged with fflV- 1 (HTLV-mB) or fflV-2 (LAV-2 ROD) at a concentration of 100 CCED50 and incubated in the presence of various concentrations of the test compounds, which were added immediately after challenge with the virus. After 5 days culture at 37°C in a CO2 incubator, the number of viable ceUs was assessed by the MTT(tetrazolium) method. Antiviral activity of the compounds is expressed in Table 7 below as ED50 ( ⁇ mol/L). A control test was performed using the known anti-HTV treatment AZT, and a number of comparison compounds were also run through the screen.
  • ED50 ⁇ mol/L
  • Hepatocytes were purified from the ceU mass using PercoU density gradients (Pharmacia, Sweden) foUowing a modification of the manufacturer's specifications.
  • the gradient medium stock solution (SIP; stock isotonic PercoU) consisted of nine parts PercoU mixed with one part 1.5 M NaCl solution. PercoU of the required density of 1.05 g/ml was then generated by diluting six parts SIP with four parts MEM at a final pH of 7.4. Five ml of hepatocyte cell suspension was layered onto 30 ml of this solution and centriruged at 20,000 rpm for 20 min at 20°C in a JA-20 fixed angle rotor (Beckman, USA).
  • Hepatocytes were dUuted and subsequently seeded with L 15 complete (L 15) which consisted of L 15 media supplemented with 15 mM Tris, insuUn, glucose, hydrocortisone hemisuccinate, penicillin and streptomycin according to Tuttleman et al, supra and 5% FBS was also included. Hepatocytes were seeded at approximately 2.0 x 10 6 cells per well into 6 well multiplates (Greiner, West Germany) or at approximately 0.5 x 10 6 cells per well into 24 well plates (Costar, Cambridge Mass.).
  • Hepatocytes were allowed to attach overnight before the first medium change (on day lpost plating) and were maintained with L 15 complete media, at 37°C in a 5% CO 2 humidified incubator, for a total of 10 days The culture medium in both control and treated cultures (see below) was changed every second day.
  • Total intracellular viral DNA was extracted from cell lysates by a modification of the method of Tuttleman et al, supra. Cells were lysed in a solution containing 0.5% sodium dodecyl sulphate (SDS), 20 mM Tris-HCl (pH 7.4), 10 mM EDTA, 5 mM EGTA, and 150 mM NaCl. DNA was extracted from all samples by digestion with 200 ug per ml of proteinase K (International Biosciences Incorporated, USA) at 37°C for 1 hour, and deproteinised by extraction with an equal volume of phenolxhloroform (1:1), followed by chloroform.
  • SDS sodium dodecyl sulphate
  • aqueous phase was coUected and adjusted to 0.2 M NaCl and the nucleic acids precipitated with 2 volumes of absolute ethanol at -20°C overnight.
  • the peUets were washed in 70% ethanol and then air dried and finally redispersed in TE buffer (10 mM Tris-HCl (pH 8), 1 mM EDTA).
  • a fuU length clone of the Australian strain of DHBV was propagated in E. coU and the plasmid extracted using standard techniques (J. Sambrook, E. F. Fritsch and T. Maniatis "Molecular Cloning: A Laboratory Manual” Second Edition Cold Spring Harbour Laboratory Press 1989).
  • the cloned DHBV DNA sequences were excised from the plasmid by EcoRi digestion and were separated by preparative gel electrophoresis using a Prep-A-Gene DNA purification kit (Bio-Rad, Hercules CaUf.) according to the manufacturer's recommendations.
  • a 648 bp DNA fragment was also prepared by further digesting the EcoRi DHBV and purifying the smaller fragment as described above.
  • DHBV DNA in cell culture was detected by slot-blot hybridization.
  • Extracted DNA dissolved in TE buffer was diluted in 6x saline sodium citrate (SSC) lxSSC is 0.15M NaCl + 0.15M sodium citrate, pH7.0), denatured by rapid boiling and quenching then serially diluted in 6xSSC.
  • SSC 6x saline sodium citrate
  • lxSSC 0.15M NaCl + 0.15M sodium citrate, pH7.0
  • a commercial slot-blot apparatus was used to apply the DNA samples to nitrocellulose hybridisation membranes (Hybond C extra, Amersham International, England).
  • DNA was baked onto membranes at 80°C for 2 hours before pre-hybridisation in a buffer consisting of 50% deionised formamide, 6xSSC, 5mM NaH 2 PO 4 (pH 6.5), 2 x Denhardt solution and 100 mg/ml of herring sperm DNA (Boeringer Manheim, Germany).
  • a hybridization oven Hybaid, England
  • heat- denatured radio-labeUed DHBV DNA probe was added to a concentration of at least 2xl0 6 cpm and hybridisation aUowed to proceed overnight at 42°C.
  • membranes were washed twice in 2 x SSC-0.1% SDS at 24°C and twice in 0.1 x SSC/0.1% SDS for 30 min at 50°C to remove unbound probe.
  • Radiolabelled DHBV probe bound to the air-dried filters was detected with the aid of intensifying screens by autoradiography at -70°C onto X-OMAT RP film, (Eastman Kodak Co., USA).
  • test compounds were prepared in sterile deionised distiUed water.
  • stock solutions were prepared in cell culture grade dimethyl sulphoxide (DMSO ).
  • DMSO dimethyl sulphoxide
  • dilutions of test compound stock solutions were prepared in deionised distiUed water or DMSO at lOOx the final test concentration. These dUutions were then added to complete ceU culture medium at the rate of 10ml per ml (a d ution of 1 in 100), so that the final concentration of distilled water or DMSO added in every case was constant at 1%, a concentration at which neither DMSO nor distilled water had any effect on virus replication.
  • DHBV DNA standards were used to establish both the detection limit, and prove that the relati tioonnsshhiipp b between the 32 P count and the amount of bound DHBV was linear over the range of interest.
  • the extent of viral repUcation (measured as cpm bound 32 P bound DHBV probe detected) in the presence of test compounds is expressed as a percentage of viral replication in the control cultures; ED50 values were calculated from the dose response curve. The results of the tests are given in Table 7 supra.
  • mice Male white mice (Mus musculus) strain B ALB/ c weighing 20 to 25g per mouse, supplied by the Animal Breeding Unit of the University of N.S.W.
  • the mice were obtained at least one day prior to the test day and acclimatised in the test room (Temp 25°C), where they were held, five to a box and given commercial rat pellets and water ad lib.
  • the compound to be tested was weighed out and dissolved in either olive oU or DMSO to give a stock solution which when injected at the rate of 100 ml per mouse gave a dose of 100 mg/kg. Two further doses of 10 mg/kg and 1.0 mg/kg were prepared from this solution.
  • mice 100 ml of a solution was injected intraperitoneally into each test mouse.
  • Five or ten mice were dosed at each concentration i.e. lOOmg/kg, 50 mg/kg, lOmg/kg and lmg/kg, with five control mice dosed with solvent.
  • the injections were repeated, as above, each day at the same time of day, for the number of days required.
  • the mice were observed at half-hourly intervals and symptoms recorded. Further readings were taken for the next seven days. The results after 7 days are shown in Table 8 below.
  • mice Five mice were given repeated injections of compound at a dose of lOOmg/kg daUy for 5 successive days witiiout ill effects.
  • formulation A may be prepared by wet granulation of the ingredients with a solution of povidone, followed by addition of magnesium stearate and compression.
  • the foUowing 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 9 above and filling into a two-part hard gelatin capsule.
  • Formulation B (infra) may be prepared in a similar manner.
  • the foUowing 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 peUets may then be coated with release-controUing membrane (d) and filled into a two- piece, hard gelatin capsule. mp/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 die 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.
  • the compounds of the present invention 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) was detected by the incorporation of [a- 32 P]GTP.
  • the cells were pelleted by centrifugation and resuspended in 10 mM sodium acetate at a concentration of 2xl0 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 peUet 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 freeze/thawing.
  • the RDRP activity in the cell extract was assayed as previously described witii 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 unis/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 ml) contained 50 mM Tris-HCl pH 8.0, 10 mM magnesium acetate, 7.5 mM potassium acetate, 10 mM 2-mercaptoethanol, 6 mg actinomycin D (AMD), 5 mM phosphoenolpyruvate, 3 units/ml pyruvate kinase, 0.5 mM ATP, 0.5 mM CTP, 0.5 mM UTP, 25 mM GTP, 5 mCi [a- 3 P]GTP (Amersham, specific activity 410 Ci/mmol), 0.5 units/ml RNasin, 30 ml of infected ceU extract and the test compound (from 0.5 to 100 mM).
  • C Electrophoresis of RNA
  • 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 concentration of drug. The concentrations which give > 75% inhibition of RNA synthesis are given in Table 10.

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Abstract

L'invention concerne un traitement prophylactique et/ou curatif d'infections virales consistant à administrer une quantité efficace d'un composé de la formule (I). Dans cette formule, M est un métal capable de former un complexe par six liaisons de coordination, Y est un nombre entier entre 1 et 6, n est égal à 0 ou 1, m est égal à 0 ou 1, A1 à A6 sont NH, N, O et S, R?1 à R14 et R3' à R14'¿ ont différentes significations. Certains de ces composés sont nouveaux.
PCT/AU1995/000283 1994-05-17 1995-05-17 Composes-cages, procedes pour les preparer et leur utilisation en tant qu'agents antiviraux WO1995031202A1 (fr)

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AU24397/95A AU2439795A (en) 1994-05-17 1995-05-17 Cage compounds, processes for their preparation and their use as antiviral agents

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AUPM5656A AUPM565694A0 (en) 1994-05-17 1994-05-17 Antiviral agents
AUPM5720A AUPM572094A0 (en) 1994-05-19 1994-05-19 Antiviral agents

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US6020369A (en) * 1994-09-26 2000-02-01 Schinazi; Raymond F. Method compositions and apparatus for treating and preventing respiratory viral infections
WO2000040585A1 (fr) * 1999-01-05 2000-07-13 Australian Nuclear Science & Technology Organisation Composes cryptates et methodes de diagnostic et de traitement
WO2010063069A1 (fr) * 2008-12-02 2010-06-10 The University Of Melbourne Conjugués macrocycliques contenant de l'azote comme produits radiopharmaceutiques
EP1940385A4 (fr) * 2005-10-24 2010-09-22 Univ Hong Kong Composition pharmaceutique a compose d'oxalate de ruthenium et son procede d'utilisation
US9457107B2 (en) 2011-12-06 2016-10-04 The University Of Melbourne Cage amine ligands for metallo-radiopharmaceuticals

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AU5423590A (en) * 1989-04-07 1990-11-05 Salutar, Inc. Chelants

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CHEMICAL ABSTRACTS, Vol. 102, Abstract No. 16421, GEUE RODNEY J. et al., "Synthesis, Chiroptical Properties and Electron Self-Exchange Reactivity of a Rigid Pentacyclic Metal Ion Cage System With D3 Symmetry"; & J. AM. CHEM. SOC., (1984), 106(26), pages 8282-91. *
CHEMICAL ABSTRACTS, Vol. 107, Abstract No. 108126, BULL DARYL J. et al., "Synthesis and Characterization of Encapsulated Cobalt (III) Hydroxylamine Complexes"; & INORG. CHEM., (1987), 26(18), pages 3040-3. *
CHEMICAL ABSTRACTS, Vol. 112, Abstract No. 190689, GAHAN LAWRENCE R. et al., "Synthesis, X-Ray Crystal Structure and Metal Ion Extraction From a Nitrogen-Sulfur 'Pendant Arm' Encapsulated Complex of Cobalt (III)"; & INORG. CHEM., (1990), 29(7), pages 1451-4. *
CHEMICAL ABSTRACTS, Vol. 114, Abstract No. 134863, HOHN ARTHUR, "A New Strategy for the Metal Template Synthesis of Organic Metal Ion Cages"; & J. CHEM. SOC., CHEM. COMMUN., (1990), (21), pages 1473-5. *
CHEMICAL ABSTRACTS, Vol. 118, Abstract No. 138517, GEUE RODNEY J. et al., "Metal Ion Cages: Capping Reactions With Bifunctional Methylene Compounds and Formaldehyde"; & AUST. J. CHEM., (1992), 45(10), pages 1681-703. *
CHEMICAL ABSTRACTS, Vol. 119, Abstract No. 240294, LAY PETER A. et al., "The Synthesis and Properties of Cobalt Cage Complexes With Nitrogen-Sulfur (N3S3) Donor Sets"; & AUST. J. CHEM., (1993), 46(5), pages 641-661. *
CHEMICAL ABSTRACTS, Vol. 121, Abstract No. 49002, CREASER INGE I. et al., "New Macrocyclic Complex is Derived From Cobalt (III) Cage Complexes"; & AUST. J. CHEM., (1994), 47(3), pages 529-44. *
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Cited By (18)

* 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
WO2000040585A1 (fr) * 1999-01-05 2000-07-13 Australian Nuclear Science & Technology Organisation Composes cryptates et methodes de diagnostic et de traitement
US6869589B1 (en) * 1999-01-05 2005-03-22 Australian Nuclear Science & Technology Organization Cryptate compounds and methods for diagnosis and therapy
EP1940385A4 (fr) * 2005-10-24 2010-09-22 Univ Hong Kong Composition pharmaceutique a compose d'oxalate de ruthenium et son procede d'utilisation
AU2009322081C1 (en) * 2008-12-02 2016-09-01 Clarity Pharmaceuticals Ltd Nitrogen-containing macrocyclic conjugates as radiopharmaceuticals
US9701694B2 (en) 2008-12-02 2017-07-11 The University Of Melbourne Nitrogen-containing macrocyclic conjugates as radiopharmaceuticals
CN102300866B (zh) * 2008-12-02 2015-08-26 墨尔本大学 作为放射性药物的含氮大环共轭物
AU2009322081B2 (en) * 2008-12-02 2016-05-26 Clarity Pharmaceuticals Ltd Nitrogen-containing macrocyclic conjugates as radiopharmaceuticals
WO2010063069A1 (fr) * 2008-12-02 2010-06-10 The University Of Melbourne Conjugués macrocycliques contenant de l'azote comme produits radiopharmaceutiques
US11905301B2 (en) 2008-12-02 2024-02-20 Clarity Pharmaceuticals Ltd. Nitrogen-containing macrocyclic conjugates as radiopharmaceuticals
EP3098225A1 (fr) * 2008-12-02 2016-11-30 The University of Melbourne Conjugués macrocycliques contenant de l'azote comme produits radiopharmaceutiques
JP2012510477A (ja) * 2008-12-02 2012-05-10 ザ ユニバーシティー オブ メルボルン 放射性医用薬剤としての窒素含有大環状結合体
US11111254B2 (en) 2008-12-02 2021-09-07 The University Of Melbourne Nitrogen-containing macrocyclic conjugates as radiopharmaceuticals
US10301326B2 (en) 2008-12-02 2019-05-28 The University Of Melbourne Nitrogen-containing macrocyclic conjugates as radiopharmaceuticals
US10544164B2 (en) 2008-12-02 2020-01-28 The University Of Melbourne Nitrogen-containing macrocyclic conjugates as radiopharmaceuticals
US10870664B2 (en) 2008-12-02 2020-12-22 The University Of Melbourne Nitrogen-containing macrocyclic conjugates as radiopharmaceuticals
US9861714B2 (en) 2011-12-06 2018-01-09 The University Of Melbourne Cage amine ligands for metallo-radiopharmaceuticals
US9457107B2 (en) 2011-12-06 2016-10-04 The University Of Melbourne Cage amine ligands for metallo-radiopharmaceuticals

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