WO2000050431A1 - Composes de platine (ii) - Google Patents

Composes de platine (ii) Download PDF

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Publication number
WO2000050431A1
WO2000050431A1 PCT/GB2000/000686 GB0000686W WO0050431A1 WO 2000050431 A1 WO2000050431 A1 WO 2000050431A1 GB 0000686 W GB0000686 W GB 0000686W WO 0050431 A1 WO0050431 A1 WO 0050431A1
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platinum
teφyridine
thiolate
terpyridine
bis
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PCT/GB2000/000686
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English (en)
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Gordon Lowe
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Isis Innovation Limited
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Priority to CA002364712A priority Critical patent/CA2364712A1/fr
Priority to AU28150/00A priority patent/AU2815000A/en
Priority to EP00906490A priority patent/EP1155025A1/fr
Priority to JP2000601010A priority patent/JP2003526615A/ja
Publication of WO2000050431A1 publication Critical patent/WO2000050431A1/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
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/10—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C323/11—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/12—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/24—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/25—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/52—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C327/00—Thiocarboxylic acids
    • C07C327/58—Derivatives of thiocarboxylic acids, the doubly-bound oxygen atoms being replaced by nitrogen atoms, e.g. imino-thio ethers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
    • C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
    • C07F15/0086—Platinum compounds
    • C07F15/0093—Platinum compounds without a metal-carbon linkage
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H23/00—Compounds containing boron, silicon, or a metal, e.g. chelates, vitamin B12
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
    • C07D213/22—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing two or more pyridine rings directly linked together, e.g. bipyridyl
    • 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 platinum (II) compounds for use in the treatment of the human or animal body.
  • the invention in particular relates to 2,2':6',2"-terpyridine platinum (II) compounds for use as anti-protozoal ⁇ anti- rheumatoid arthritic or anti-tumour agents.
  • the present invention provides a compound which is a complex of formula (I)
  • each X which may be the same or different, is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, aralkyl, alkaryl, acyl, halogen, haloalkyl, haloaryl, hydroxyalkyl, hydroxyaryl, aminoalkyl, aminoaryl, primary, secondary or tertiary amine, hydrazine, alkylhydrazine, alkoxyl, alkylthio, aralkoxyl, nitrile, ester, amide, nitro, azide or aziridino, or is a covalently linked chain which is joined to at least one other complex of formula (I) so as to form a dimeric or oligomeric species, or a covalently linked moiety which provides recognition for a target receptor; and
  • Y is alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aralkyl, heterocyclyl, inorganic oxyacid or inorganic oxyacid derivative, or a covalently linked chain which is joined to at least one other complex of formula (I) so as to form a dimeric or oligomeric species; or a pharmaceutically acceptable salt thereof, for use in a method of treatment of the human or animal body by therapy.
  • alkyl as used herein includes both unsubstituted and substituted, straight and branched chain radicals. Typically it is C r C 6 or C r C g alkyl, preferably Ci - C 4 alkyl, for example methyl, ethyl, i-propyl, n-propyl, t-butyl, s-butyl or n- butyl. It may also be pentyl, hexyl, heptyl, octyl and the various branched chain isomers thereof.
  • alkyl group When the alkyl group is substituted it typically bears one or more substituents selected from aryl, cycloalkyl, halogen, trihaloalkyl such as trifluoromethyl, hydroxy, alkoxy, aralkoxyl, amino, mono or dialkylamino, carbonyl and carboxy.
  • substituents selected from aryl, cycloalkyl, halogen, trihaloalkyl such as trifluoromethyl, hydroxy, alkoxy, aralkoxyl, amino, mono or dialkylamino, carbonyl and carboxy.
  • cycloalkyl typically means a cycloalkyl group having 3 to 8 carbons, for example cyclopropyl and cyclooctyl.
  • a cycloalkyl group may be unsubstituted or substituted as the alkyl groups above.
  • alkenyl as used herein includes unsubstituted and substituted, straight and branched chain radicals having one or more double bonds. Typically it is C 2 - C 6 alkenyl such as, for example, allyl, butenyl, butadienyl, pentenyl or hexenyl. When the alkenyl group is substituted it typically bears one or more substituents as defined above for the alkyl groups.
  • cycloalkenyl typically means a cycloalkenyl group having 4 to 8 carbons, for example cyclopentenyl or cyclooctadiene.
  • alkynyl as used herein includes unsubstituted and substituted, straight and branched chain radicals having one or more triple bonds. Typically it is C 2 - C 6 alkynyl, such as butynyl. When the alkynyl group is substituted it typically bears one or more substituents as defined above for the alkyl groups.
  • aryl as used herein includes both monocyclic and bicyclic aromatic groups which typically contain from 6 to 10 carbons in the ring portion, such as phenyl or naphthyl. The aryl group is unsubstituted or substituted. When it is substituted the aryl group may be substituted by one or more substituents selected from Cj-Cg, alkyl, C C 6 alkoxyl, trihaloalkyl such as tri-fluoromethyl, halogen and hydroxy.
  • heterocyclyl as used herein is typically a 3- to 7-membered, saturated or unsaturated heterocyclic ring containing at least one heteroatom selected from N, O and S and which is optionally fused to a second 5- or 6-membered, saturated or unsaturated heterocyclic ring or to an aryl group as defined above.
  • the heterocyclic ring may be, for example, pyridine, furan, thiophene, pyrrole, pyrimidine, pyrazine, pyridazine, pyrazole or indazole, or a cyclic ether such as glucose.
  • alkyl refers to alkyl groups as previously defined having an aryl substituent, for example benzyl, phenethyl, diphenylmethyl and triphenylmethyl.
  • alkaryl refers to aryl groups as previously defined having an alkyl substituent.
  • acyl as employed herein includes alkyl, aryl and heterocyclyl as described above linked to a carbonyl group.
  • halogen as used herein means fluorine, chlorine, bromine and iodine.
  • alkoxyl or "aralkoxyl” as used herein includes any of the above alkyl, cycloalkyl or aralkyl groups linked to an oxygen atom.
  • X is preferably hydrogen, halogen such as chlorine, alkoxyl such as methoxyl, ethoxyl, propoxyl, butyloxyl, pentyloxyl, hexyloxyl, heptyloxyl or octyloxyl, preferably ethoxyl, butyloxyl, hexyloxyl or octyloxyl, or aryl.
  • a substituent may preferably be at the 4' position of the terpyridine system.
  • Y may be substituted with one or more electron withdrawing groups such as a halogen, hydroxyl, carbonyl, amide or carboxyl and/or one or more electron donating groups.
  • Y is preferably alkyl, for example, (CH 2 ) n OH or (CH 2 ) n NH 3 + wherein n is an integer of 1 to 6, or alkyl substituted by one or more amino or carboxy groups; aralkyl, for example arylCH 2 such as benzyl; heterocyclyl , for example, a 5- or 6- membered saturated heterocyclic ring such as a deoxy-glucose, for instance deoxy- ?- D-glucose or deoxy-glucose substituted by one or more groups such as acyl groups, or a 5- or 6-membered unsaturated heterocyclic ring containing at least one N which may be fused to a 6-membered aryl ring, for example, pyridyl such as 2-pyr
  • Preferred complexes of formula (I) are those wherein:
  • X is hydrogen, halogen such as chlorine, alkoxyl such as methoxyl, ethoxyl, propoxyl, butyloxyl, pentyloxyl, hexyloxyl, heptyloxyl or octyloxyl, preferably ethoxyl, butyloxyl, hexyloxyl or octyloxyl, or aryl; and
  • Y is alkyl, for example, (CH 2 ) n OH or (CH 2 ) n NH 3 + wherein n is an integer of 1 to 6, alkyl substituted by one or more amino or carboxy groups; aralkyl, for example arylCH 2 such as benzyl; heterocyclyl, for example, a 5- or 6-membered saturated heterocyclic ring such as a deoxy-glucose, for instance deoxy- ?-D-glucose or deoxy- glucose substituted by one or more groups such as acyl groups, or a 5- or 6- membered unsaturated heterocyclic ring containing at least one N which may be fused to a 6-membered aryl ring, for example, pyridyl such as 2-pyridyl or 4-pyridyl, pyrimidyl such as 2-pyrimidyl, imidazolyl such as 2-imidazolyl, or benzimidazolyl such as 2-benzimidazo
  • More preferred complexes of formula (I) are: 2-hydroxyethanethiolate-(2,2':6 , ,2"-terpyridine)platinum ( ⁇ ), 2-hydroxyethanethiolate-(4'-chloro-2,2' : 6',2"-terpyridine)platinum (II), 2-hydroxyethanethiolate-(4'-ethoxy-2,2':6',2"-terpyridine)platinum (II),
  • N,S-bis[(2,2':6',2"-te ⁇ yridine)platinum (II)] thioacetimine N,S-bis[(4'-chloro-2,2'-6 , ,2"-te ⁇ yridine)platinum (II)] thioacetimine, diethylphosphorothioato(4'-chloro-2,2':6',2-te ⁇ yridine)platinum (II), succinylthiolatoplatinum (II) 2,2':6',2"-te ⁇ yridine, and l-thio-?-D-glucose(2,2 , :6 , ,2"-te ⁇ yridine)platinum ( ⁇ ).
  • the complexes of formula (I) may be negatively charged, neutral or positively charged. It will be appreciated that Y may be selected to obtain the desired overall charge. For example, when Y is PO 3 2" the overall charge on the compound of formula (I) is -1, when Y is (PO ⁇ 1 ) " wherein R 1 is for example to C 6 alkyl, the compound of formula (I) is neutral and when Y is PO 3 (R 1 ) 2 wherein R is as defined above, the overall charge on the compound of formula (I) is +1.
  • the present invention also includes the salts of the complexes of formula (I).
  • a counterion is present.
  • the counterions are physiologically tolerable counterions and are generally selected to obtain good water solubility.
  • Counterions which may suitably be used include nitrate, sulphate, sulphonate, phosphate, pyrophosphate, phosphate esters and diesters, phosphonate, carbonate, carboxylate and any other non-toxic counterions which retains an appropriate level of solubility with the platinum (II) compound.
  • Stable conjugates with anionic polymers or dendrimers may also be used and may be particularly appropriate for the delivery of the compounds of formula (I) to tumour cells because of the "enhanced cell permeability and retention effect" (EPR) of tumour cells.
  • EPR enhanced cell permeability and retention effect
  • the (2,2':6',2"-te ⁇ yridine)platinum(II) complexes covalently react with human serum albumin and possibly other plasma proteins which can provide a natural and selective mechanism for delivery of these complexes into tumour cells.
  • the plasma protein would be released by a thiol or more especially a selenocysteine dependent intracellular enzyme such as human thioredoxin reductase (see below).
  • the biological activity of the compounds of formula (I) may be affected by the leaving ability of the thiolate ligand which is linked to the pKa of the thiol Y-SH.
  • the pKa of the thiol is not more than 11. In one embodiment the pKa of the thiol is greater than 6.
  • the present invention includes all possible isomers of the compounds of formula (I) and mixtures thereof, including diastereomeric mixtures and racemic mixtures, resulting from the possible combinations of (R) and (S) stereochemistry when stereogenic centres are present.
  • the compounds of formula (I) may be prepared by methods known in the art.
  • the compounds of formula (I) may be prepared from chloro(2,2':6',2"- terpyridine)platinum (II) chloride by treatment with a thiol Y-SH, in one instance the chloro(2,2':6',2"-te ⁇ yridine)platinum (II) chloride may be converted to a suitable salt before treatment with the thiol.
  • the compounds of formula (I) may also be prepared from a complex formed from reacting a platinum complex of 1,5-cyclooctadiene with a 2,2':6',2"-te ⁇ yridine (see, for example, WO97/27202).
  • 2-Hydroxyethanethiolate-(2,2':6',2"-terpyridine)platinum (II) shows a wide range of activities against protozoal parasites. It is effective against Leishmania donovani, Trypanosoma cruzi and Trypanosoma brucei .
  • 2- hydroxyethanethiolate-(2,2':6',2"-te ⁇ yridine)platinum (II) has been shown to irreversibly inactivate the reduced form of human thioredoxin reductase and may therefore have potential as a therapeutic agent for rheumatoid arthritis. It has also been found to have anti-tumour activity against a range of human ovarian tumour cell lines.
  • a human or animal may be treated by administering thereto a non-toxic and therapeutically effective amount of a compound which is a complex of formula (I).
  • the condition of the human or animal may thereby be ameliorated.
  • Protozoal infection, rheumatoid arthritis or tumours can thus be treated.
  • the present invention provides use of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use as an anti-protozoal, anti-rheumatoid arthritic or anti-tumour agent.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, as active ingredient, in association with a pharmaceutically acceptable carrier, excipient or other additive, if necessary.
  • composition containing a compound of formula (I) or salts thereof may be prepared in a conventional way by employing conventional non- toxic pharmaceutical carriers or diluents in a variety of dosage forms and ways of administration.
  • compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such composition may contain one or more agents selected from the group consisting of sweetening agents, flavouring agents, colouring and preserving agents in order to provide elegant and palatable preparations.
  • Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example maize starch or alginic acid; binding agents, for example maize starch, gelatin or acacia, and lubricating agents, for example magnesium stearate or stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and abso ⁇ tion in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such glyceryl monostearate or glyceryl distearate may be employed.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be naturally-occurring phosphatides, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxyacetamol, or condensation products of ethylene oxide with partial esters derived from fatty acids and an hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol anhydrides, for example polyoxysorbitan monooleate.
  • dispersing or wetting agents may be naturally-occurring phosphatides, for example lecithin, or condensation products of an
  • the said aqueous suspension may also contain one or more preservatives, for example ethyl or n-propyl/?-hydroxybenzoate, one or more colouring agents, one or more flavouring agents, one or more sweetening agents such as sucrose or saccharin.
  • preservatives for example ethyl or n-propyl/?-hydroxybenzoate, one or more colouring agents, one or more flavouring agents, one or more sweetening agents such as sucrose or saccharin.
  • An oily suspension may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil, coconut oil or in a mineral oil such as liquid paraffin.
  • the oily suspension may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavouring agents may be added to provide a palatable oral preparation.
  • compositions may be preserved by the addition of an antioxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavouring and colouring agents may also be present.
  • compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of ,these.
  • Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavouring agents. Syrups and elixirs may be formulated with sweetening agents, for example glycerol ⁇ sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, colouring and flavouring agents.
  • compositions may be in the form of a sterile injectable aqueous or olagenous suspensions.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example a solution in 1,3-butanediol.
  • a non-toxic parenterally-acceptable diluent or solvent for example a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oils may be conventionally employed including synthetic mono or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • the daily dose varies according to the activity of the specific compound, the age, weight, and conditions of the subject to be treated, the type and the severity of the disease, and the frequency and route of administration. Typically the daily dose is from 0.1 to 50 mg per kg of body weight.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for oral administration may contain from 5 to 95% of the total composition. Dosage unit forms will generally contain between from 5 to 500 mg of the active compound.
  • the present invention provides a compound which is a complex of formula (I)
  • each X which may be the same or different, is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, aralkyl, alkaryl, acyl, halogen, haloalkyl, haloaryl, hydroxyalkyl, hydroxyaryl, aminoalkyl, aminoaryl, primary, secondary or tertiary amine, hydrazine, alkylhydrazine, alkoxyl, alkylthio, aralkoxyl, nitrile, ester, amide, nitro, azide or aziridino, or is a covalently linked chain which is joined to at least one other complex of formula (I) so as to form a dimeric or oligomeric species, or a covalently linked moiety which provides recognition for a target receptor; and
  • Y is alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aralkyl, heterocyclyl, an inorganic oxyacid or inorganic oxyacid derivative, or a covalently linked chain which is joined to at least one other complex of formula (I) so as to form a dimeric or oligomeric species; or a pharmaceutically acceptable salt thereof, with the proviso that the complex of formula (I) is not 2-hydroxyethanethiolate(2,2':6',2"-te ⁇ yridine)platinum (II) or 2- aminoethanethiolate(2,2':6',2"-te ⁇ yridine)platinum (II).
  • Solvents (A.R. and h.p.l.c. grade) were purchased from Aldrich Chemical Company and Rathburn Chemicals. Diethylamine was dried over potassium hydroxide pellets, distilled from potassium hydroxide and stored under jargon over potassium hydroxide pellets. Water refers to deionised water.
  • Flash chromatography was performed by using h.p.l.c. grade solvents and Merck silica gel 60 (230-400 mesh ASTM). Thin layer chromatography was performed on Merck precoated aluminium t.l.c. plates coated with silica gel 60F 254 (0.2 mm) and visualised by means of ultraviolet light.
  • Electrospray mass spectroscopy was carried out on a NG Biotech Bio-Q spectrometer using a dilute solution of the sample in methanol/water. Antiparasitic Activity
  • Leishmania donovani (strain MHOM/ET/67/L82) amastigotes, derived from the spleen of a golden hamster (Wright's strain) were used to infect mouse peritoneal macrophages from CD1 (Charles River Ltd., Margate, UK) mice at a parasite: macrophage ratio of 10:1.
  • Infected macrophages were maintained in RPMI 1640 medium plus 10% heat inactivated fetal calf serum (hiFCS) (Harlan Sera-Lab., Crawley, UK) in 16-well Labtek chamber slides (Nunc Inc., IL, USA) at 37°C in 5% CO 2 /air mixture.
  • hiFCS heat inactivated fetal calf serum
  • MDCK fibroblasts were used to infect mouse peritoneal macrophages from CD1 mice at a parasite: macrophage ratio of 5: 1.
  • Infected cells were maintained in RPMI 1640 medium plus 10% hiFCS in 16-well Labtek chamber slides at 37°C in 5% CO 2 /air mixture.
  • Infected cultures were exposed to test compounds in medium, in a three-fold dilution series from 30 ⁇ M with quadruplicate cultures at each concentration for 3 days.
  • Nifurtimox (Bayer, Germany) was used as the positive control and had an ED 50 in the range 2.2-4.4 ⁇ M.
  • Activity was determined, after cultures had been methanol fixed and Giemsa stained, from the proportion of infected cells in treated and untreated cultures and dose response curves analysed by linear regression to obtain an ED 50 value where possible.
  • Trypanosoma brucei brucei (strain S427) bloodstream trypomastigotes were cultured in HMI-18 medium containing 20% hiFCS at 37°C in 5% CO 2 /air mixture. Trypomastigotes were exposed to test compounds in medium, in a three-fold drug dilution series from 30 ⁇ M with triplicate culures at each concentration for 72 hours. Pentamidine (Rhone Poulenc Rorer Ltd., Dagenham, UK) was used as the positive control and had an ED 50 of 0.03-0. l ⁇ M. Drug activity was determined by using an MTT-based cytotoxicity assay and dose response curves analysed by linear regression to obtain an ED 50 value where possible. SCREEN 2 - PROTOCOL II
  • the assays follow those outlined in Screen 1- Protocol 1 but include a range of doses in a dilution series from 30 ⁇ M. Dose response curves were analysed by linear regression and ED 50 values determined. T. brucei numbers/ml are determined using a Coulter Counter.
  • Leishmania donovani in vivo protocol.
  • the inoculum is administered i.v. (lateral tail vein).
  • the mice are randomly divided into groups of 5.
  • mice Positive control mice are given Pentostam s.c. x 5 days - 45, 15 and 5 mgSbV/kg.
  • mice are weighed and necropsied. Livers and spleens are dissected and weighed. Impression smears are made, fixed (100% methanol) and Giemsa stained (10% Giemsa' s for 45 minutes) for microscopical examination. The number of amastigotes per 500 nuclei is counted. This figure is then multiplied by the weight of the organ (mg). % inhibition compared with untreated control is calculated. In a dose-response experiment the ED50 is calculated by linear regression analysis (xlfit). The difference in group weight can give an indication of toxicity but this is often obvious.
  • mice monitored daily until death. Untreated control groups die within 14 days post infection. Activity of compound is compared to this.
  • the assay solution contains NADPH (lOO ⁇ M), trypanothione disulphide
  • the hydroxyethanethiolate complex (1) (40 ⁇ M) is not an irreversible inactivator of human glutathione reductase either in the presence or absence of
  • hTrxR Human thioredoxin reductase
  • the other substances for the enzymatic assays were purchased from Boehringer, Serva and Sigma, respectively. All reagents were of the highest purity available. Enzyme assays All assays were conducted at 25°C in a total assay volume of 1 ml.
  • TrxR activity For determining TrxR activity two different assay systems were employed: In the DTNB reduction assay the enzyme was added to an assay mixture consisting of 100 mM potassium phosphate, 2 mM EDTA, pH 7.4 and 3 mM DTNB (100 mM stock solution in DMSO); after initiating the reaction with the addition of NADPH (200 ⁇ M final concentration), the increase in absorbance at 412 nm was monitored. 1 enzyme unit is defined as the NADPH- dependent production of 2 ⁇ mol 2-nitro-5-thiobenzoate ((412nm 13.6 mM-lcm-1) per min.
  • the mixture contained 100 mM potassium phosphate, 2 mM EDTA, pH 7.4, 100 ⁇ M E.coli TrxS2 and 100 ⁇ M NADPH ( ⁇ 340 nm 6.22 mM- lcm-1).
  • the reaction was started with thioredoxin reductase (final concentration 4 nM TrxR subunits) and the decrease in absorbance at 340 nm was monitored during the linear phase.
  • 1 enzyme unit is defined as the consumption of 1 ⁇ mol NADPH per min.
  • the assay mixtures contained varying concentrations of the respective substrates.
  • Glutathione reductase The GR assay consisted of 47 mM potassium phosphate, 1 mM EDTA, 200 mM KCI, pH 6.9, and 100 ⁇ M NADPH; after the addition of hGR the assay was started with 1 mM GSSG and the consumption of NADPH was monitored as the decrease in absorbance at 340 nm.
  • the compounds were exposed to cells for 96 h and growth inhibition assessed using the sulforhodamine B protein staining assay.
  • the IC 50 values (in ⁇ M) are shown in Table 5. Cisplatin and carboplatin are included for comparison. Cell culture conditions
  • glioblastomas and HNSCC head and neck squamous cell carcinoma cells were cultured by dissecting tissue in small pieces of about 1mm and transferring in 75 cm 2 plastic tissue culture flasks (Falcon, Becton Dickinson, Heidelberg, Germany). Cells were cultured routinely in RPMI 1640 supplemented with 60% fetal calf serum and antibiotics at 37°C, 5% CO 2 , and 95% air in a humidified incubator with medium changes twice a week. After reaching confluency cells were harvested by a brief incubation with trypsin/EDTA solution (Viralex, PAA, Linz, Austria) and seeded into a fresh 75 cm 2 plastic tissue culture flask. Tumor cells were characterized for their astrocytic or epithelial origin by the immunhistochemical detection of tissue specific markers like GFAP for glioma cells
  • HCSCC cells head and neck squamous carcinoma cells
  • Proliferation assay The assay was performed as described in U. Maurer et al., European J.
  • Suspension cell cultures A) Timed exposures.
  • Resuspended in HBSS Washed twice Resuspended in growth medium 1 - 2 x 10 3 cells plated into each well of a 96 well plate (8 wells per drug exposure).
  • Silver nitrate (35.7mg, 0.21mmol) was dissolved in aqueous acetone (4: 1 acetone: water, 0.5ml) and added to a suspension of diiodo-l,5-cylooctadienyl platinum (I) (55.7mg, O.lmmol) in aqueous acetone (0.75ml). The mixture was vigourously shaken until the dark yellow colour had subsided then the precipitated silver salt isolated by centrifugation and discarded. The supernatant containing the active platinum species was added to a suspension of 2,2':6 , ,2"-te ⁇ yridine
  • 4'-Chloro-2,2':6',2"-terpyridine is commercially available from Aldrich Chemical Co., UK or Lancaster, UK.
  • the preparation of the title compound was by the general method given above.
  • the product was a dark red powdery solid (23.5mg, 48.8%).
  • 4'-Ethoxy-2,2':6',2"-terpyridine was prepared in excellent yield by ethanolysis of 4'-chloro-2.2':6'.2"-te ⁇ yridine activated by FeCl 2 .4H 2 O or by reaction with sodium ethoxide without activation, m.p. 85-86°C.
  • the mixture was vortexed and sonicated for a few minutes and then centrifuged. The supernatant was removed and discarded. The pellet was washed with acetonitrile/ether (1 :3, 2x1.5 ml) and then dissolved in water (0.75 ml). A solution of 2-mercaptopyridine (15 mg, 0.13 mmol) in methanol/water (1 : 1, 1.0 ml) was added. The mixture was vortexed and then sonicated for 1.5 h. The mixture was added dropwise to ether/acetone (1 : 1, 20 ml) to precipitate the complex.
  • the pellet was washed with acetonitrile/ether (1 :3, 2x1.5 ml) and then dissolved in water (0.75 ml).
  • a solution of 2-mercaptopyridine (15 mg, 0.13 mmol) in methanol/water (1 : 1, 1.0 ml) was added.
  • the mixture was vortexed and then sonicated for 1.5 h.
  • the mixture was added dropwise to ether/acetone (1 : 1, 20 ml) to precipitate the complex.
  • the mixture was vortexed and sonicated for a few minutes and then centrifuged. The supernatant was removed and discarded. The pellet was washed with acetonitrile/ether (1 :3, 2x1.5 ml) and then dissolved in water (0.75 ml). A solution of 2-mercaptoimidazole (6.01 mg, 0.060 mmol) in water (3 ml) was added. The mixture was vortexed and then sonicated for 1.5 h. The mixture was added dropwise to ether/acetone (1 : 1, 20 ml) to precipitate the complex.
  • the solid was washed with ether/acetone (1 : 1, 4x20 ml) and then dried to yield 2-mercaptoimidazole bis[(2,2':6',2"-te ⁇ yridine)platinum(II)] dinitrate (57 mg, 88%) as a crimson solid.
  • the product was purified by dissolving the solid in hot methanol/water (1:1) and re-precipitating from ether/acetone (1 : 1, 25 ml).
  • the product was purified by dissolving the solid in hot methanol/water (1: 1) and re-precipitating from ether/acetone (1 : 1, 25 ml).
  • the pellet was washed with acetonitrile/ether (1 :3, 2x1.5 ml) and then dissolved in water (0.75 ml).
  • a solution of 2-mercaptopyrimidine (8.9 mg, 0.080 mmol) in methanol/water (1 : 1, 1.0 ml) was added.
  • the mixture was vortexed and then sonicated for 1.5 h.
  • the mixture was added dropwise to ether/acetone (1 : 1, 20 ml) to precipitate the complex.
  • the solid was washed with ether/acetone (1 : 1,
  • the product was purified by dissolving the solid in hot methanol/water (1 : 1) and re-precipitating from ether/acetone (1 : 1, 25 ml).
  • the solid was washed with ether/acetone (1 : 1, 4x20 ml) and then dried to yield 6-mercaptopurine bis[(4'-chloro- 2,2':6',2"-terpyridine)platinum(II)] dinitrate (67.1 mg, 93%) as a crimson solid.
  • the product was purified by dissolving the solid in hot methanol/water (1 : 1) and re-precipitating from ether/acetone (1 : 1, 25 ml). ! H n.m.r.
  • the pellet was washed with acetonitrile/ether (1 :3, 2x1.5 ml) and then dissolved in water (0.75 ml).
  • a solution of 1-thio- ⁇ -D-glucose (15.3 mg, 0.070 mmol) in water (2 ml) was added.
  • the mixture was vortexed and sonicated for 45 min and then added dropwise to ether/acetone (1 : 1, 20 ml) to precipitate the complex.
  • the pellet was washed with acetonitrile/ether (1 :3, 2x2.0 ml), dissolved in water (0.75 ml). A solution of thioacetamide (5.41 mg, 0.070 mmol) in water (6 ml) was then added. The mixture was vortexed and then sonicated for 1 h. The mixture was added dropwise to ether/acetone (1 : 1, 25 ml) to precipitate the complex and yielded N,S-bis(2,2':6',2"-te ⁇ yridine)platinum(II) thioacetimine trinitrate as a dark purple- brown solid (52 mg, 67%).
  • the solid was washed with ether/acetone (1: 1, 4x20 ml) and then dried.
  • the solid was purified by dissolving the solid in hot methanol/water (1 : 1) and re-precipitating from ether/acetone (1 : 1, 25 ml). ⁇ n.m.r.
  • ⁇ ,S-bis[(4'-chloro-2,2':6',2"-te ⁇ yridine)platinum (II)] thioacetamide trinitrate (17, 1 26 .3N) may be prepared in an analogous manner. DiethyIphosphorothioato(4*-chloro-2,2 , :6',2"-terpyridine)platinum(H) nitrate (10, 1 27 .N)
  • the title complex was prepared by a method analogous to the preparation of 2-hydroxyethanethiolate-(2,2':6',2"-te ⁇ ydine)platinum (II) nitrate (1, A het .N) but using 4'-chloro-2,2':6',2"-te ⁇ yridine and triethylammonium diethylphosphorothioate on a 0.1 mmol scale. Recrystallisation from acetone and ether afforded the product as a yellow solid (47 mg, 68%). mp >230°C.
  • the title complex was prepared by a method analogous to (l,A het .N) .Yield (110 mg, 83%) (Found: C, 43.5; H, 4.8; N, 8.2. Calc. for C 25 H 32 SN 4 O 5 Pt: C, 43.2; H, 4.6; N, 8.1%).
  • the title complex was prepared by a method analogous to the preparation of 2-hydroxyethanethiolate-(2,2':6',2"-te ⁇ yridine) platinum (II) nitrate (1, A het .N). Yield (100 mg, 75%) (Found: C, 40.4; H, 3.9; N, 11.0. Calc. for C 26 H 28 SN 6 O 7 Pt: C, 40.9; H, 3.7; N, 11.0%).
  • the title complex was prepared by a method analogous to the preparation of 2-hydroxyethanethiolate-(2,2':6',2"-te ⁇ yridine) platinum (II) nitrate. Yield (110 mg, 78%). (Found: C, 42.0; H, 4.4; N, 11.1. Calc. for C 28 H 32 SN 6 O 7 Pt: C, 42.5; H, 4.1; N, 10.6%).
  • ImidazoIe-2-thiolate-bis[(4 , -p-bromophenyl-2,2':6 , ,2"-terpyridine) platinum(II)] trisnitrate The title complex by a method analogous to the preparation of 2- hydroxyethanethiolate-(2,2':6',2"-terpyridine) platinum (II) nitrate. Yield (110 mg, 78%). (Found: C, 36.7; H, 2.5; N, 11.0. Calc. for C 45 H 31 SBr 2 N ⁇ O 9 Pt 2 . H 2 O : C, 36.8; H, 2.3; N, 10.5%).
  • 2-Hydroxyethanethiolato-2,2':6',2"- terpyridine-platinum(II) (1) is even more effective against Trypanosoma cruzi and Trypanosoma brucei (Tables 2 and 3).
  • Trypanothione reductase is an FAD-dependent enzyme which catalyses the reduction of trypanothione using NADPH as co-factor. The enzyme is found in the haemflagellate protozoa from the genera Trypanosoma and Leishmania and is a known target for drugs against these parasites.
  • tryparedoxin a thioredoxin-like protein found in trypanosomes which with trypanothione is an effective reductant of trypanosomal ribonucleotide reductase an enzyme required for the biosynthesis of deoxyribonucleotides in trypanosomes .
  • thiolate-2,2':6',2"-te ⁇ yridine-platinum(II) complexes have considerable potential as antiprotozoal agents.
  • Antirheumatoid Arthritic Activity Human thioredoxin reductase is now considered to be the site of action of organogold compounds such as aurothioglucose (S. Gromer et al, J. Biol. Chem., 1998, 273, 20096-20101) and auranofin which are used in the treatment of rheumatoid arthritis.
  • thiolato-2,2':6',2"-te ⁇ yridine-platinum( ⁇ ) complexes are likely to be agents useful in the treatment of rheumatoid arthritis.
  • the 2,2':6',2"- terpyridine-platinum(II) analogue of aurothioglucose, i.e. (12) has been prepared and at 20 ⁇ M concentration irreversibly inhibits human thioredoxin reductase within 10 min. in the presence of NADPH.
  • Human thioredoxin reductase is also a homodimeric FAD-dependent enzyme and has been recently shown to be a seleno-enzyme. Only two other mammalian enzymes are known to contain selenocysteine, namely, glutathione peroxidases and thyroxine deiodinases. The selenocysteine forms a seleno-sulphide bridge at the active site analogous to the many disulphide oxidoreductases. In its reduced form the enzyme is inhibited by organic gold compounds (e.g. auranofin) used in the treatment of rheumatoid arthritis.
  • organic gold compounds e.g. auranofin
  • 2 nM hTrxR is assay buffer was reduced with 200 ⁇ M NADPH; then, different concentrations of the respective inhibitor were added, the assay was incubated for 5 min at 25°C and started with 3 mM DTNB.
  • IC 50 -values were calculated from the dose-response curves. Since the enzyme has to be reduced for the tight binding inhibition and on the other hand at 3 mM DTNB the competitive component of the inhibition is very weak, the two different experimental setups sufficiently describe the respective component of inhibition.
  • the bis-platinated complexes are interesting as antitumour agents as they may have the ability to intercalate into DNA through the thiolate 2,2':6',2"- terpyridine-platinum(II) complex and platinate DNA through the second platinum complex.
  • the possibility of using thiols with a wide range of pK a s, differing charge and lipophilicity as the fourth ligand in 2,2':6',2"-terpyridine-platinum(II) complexes may make it possible to modulate the biological activity of these systems.
  • dithiophosphate O,O-diesters have low pKa values and their hydrophobicity may be controlled by the nature of the ester groups.
  • the 2,2':6',2"-terpyridine-platinum(II) complexes retain a single positive charge. If thiosulphate is used as the fourth ligand, the complex becomes overall neutral.
  • Thioredoxin is involved in a range of essential cellular regulatory processes the most prominent being the donation of electrons to ribonucleotide reductase and the selenoenzyme human thioredoxin reductase (hTrxR; EC 1.6.4.5) is a possible target for antitumour chemotherapy.
  • Malignant neoplasms of the brain represent the second leading cause of cancer related mortality in children under the age of 15.
  • N,S- bis[(2,2':6',2"-te ⁇ yridine)platinum(II)] thioacetimine trisnitrate the Ki for the competitive component of the inhibition is 4 nM
  • the IC 50 for the tight binding component is 2 nM after an incubation time of 5 min.
  • the closely related but non selenium-containing enzyme human glutathione reductase is much less inhibited (by a factor of >2000).
  • a single dose (10 ⁇ M ) of the above inhibitors reduced proliferation of several highly malignant glioblastoma cell lines by more than 95 % within 3 days (Table 7 and 8).
  • Two of the cell lines are resistant to cisplatin RF is the resistance factor IC 50 resistant line/IC 50 parent line

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Abstract

L'invention porte sur un composé consistant en un complexe de formule (I) dans laquelle chaque X, qui peut être identique ou différent, est hydrogène, alkyle, cycloalkyle, alcényle, cycloalcényle, alkynyle, aryle, hétérocyclyle, aralkyle, alkaryle, acyle, halogène, haloalkyle, haloaryle, hydroxyalkyle, hydroxyaryle, aminoalkyle, aminoaryle, amine primaire, secondaire ou tertiaire, hydrazine, alkylhydrazine, alkoxyle, alkylthio, aralkoxyle, nitrile, ester, amide, nitro, azide ou aziridino, ou est une chaîne liée par covalence et relié à au moins d'autres complexes de formule (I) de manière à former un fragment lié par covalence pouvant reconnaître un récepteur cible; et Y est alkyle, cycloalkyle, alcényle, cycloalcényle, alkynyle, aralkyle, hétérocyclyle, un oxacide minéral ou l'un de ses dérivés, ou une chaîne liée par covalence et relié à au moins d'autres complexes de formule (I) de manière à former un dimère ou un oligomére. L'invention porte également sur un de ses sels pharmacocompatible utilisable dans un procédé de traitement thérapeutique du corps de l'homme ou de l'animal.
PCT/GB2000/000686 1999-02-26 2000-02-25 Composes de platine (ii) WO2000050431A1 (fr)

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EP00906490A EP1155025A1 (fr) 1999-02-26 2000-02-25 Composes de platine (ii)
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WO2011008132A1 (fr) * 2009-07-13 2011-01-20 Закрытое Акционерное Общество "Ива Фарм" Modulateurs d’activité pharmacologique à faible poids moléculaire

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CN113666948B (zh) * 2021-09-28 2023-12-05 广西师范大学 三联吡啶铜配合物及其合成方法和应用

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Publication number Priority date Publication date Assignee Title
CA2005039A1 (fr) * 1989-12-08 1991-06-08 Randell L. Mills Produit pharmaceutique et appareil pour l'obtention d'un diagnostic par necrose selective de tissus

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Publication number Priority date Publication date Assignee Title
CA2005039A1 (fr) * 1989-12-08 1991-06-08 Randell L. Mills Produit pharmaceutique et appareil pour l'obtention d'un diagnostic par necrose selective de tissus

Non-Patent Citations (4)

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Title
CHEMICAL ABSTRACTS, vol. 116, no. 5, 3 February 1992, Columbus, Ohio, US; abstract no. 37120, MILLS, RANDELL L.: "Pharmaceuticals and apparatus based on Moessbauer isotopic resonant absorption of.gamma. emission (MIRAGE) providing diagnosis and selective tissue necrosis" XP002135882 *
LOWE, GORDON ET AL: "Cytotoxicity of (2,2':6',2''-Terpyridine)platinum(II) Complexes to Leishmania donovani, Trypanosoma cruzi, and Trypanosoma brucei", J. MED. CHEM. (1999), 42(6), 999-1006, 1999, XP002135881 *
MCFADYEN, W. DAVID ET AL: "Activity of platinum(II) intercalating agents against murine leukemia L1210", J. MED. CHEM. (1985), 28(8), 1113-16, 1985, XP000670165 *
See also references of EP1155025A1 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011008132A1 (fr) * 2009-07-13 2011-01-20 Закрытое Акционерное Общество "Ива Фарм" Modulateurs d’activité pharmacologique à faible poids moléculaire
CN102482306A (zh) * 2009-07-13 2012-05-30 Ivy药品公司 低分子量药理活性调节剂
US8575382B2 (en) 2009-07-13 2013-11-05 “Ivy Pharm” LLC Low molecular weight pharmacological activity modulators

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