EP1465899A1 - Trioxane derivatives - Google Patents

Trioxane derivatives

Info

Publication number
EP1465899A1
EP1465899A1 EP02788077A EP02788077A EP1465899A1 EP 1465899 A1 EP1465899 A1 EP 1465899A1 EP 02788077 A EP02788077 A EP 02788077A EP 02788077 A EP02788077 A EP 02788077A EP 1465899 A1 EP1465899 A1 EP 1465899A1
Authority
EP
European Patent Office
Prior art keywords
compound
iron
compound according
treatment
pharmaceutically acceptable
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP02788077A
Other languages
German (de)
English (en)
French (fr)
Inventor
Paul Michael O'neill
Adrian Peter Higson
Sara Taylor
Edward Irving
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
UFC Ltd
Original Assignee
UFC Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB0129215.0A external-priority patent/GB0129215D0/en
Priority claimed from GB0217723A external-priority patent/GB0217723D0/en
Application filed by UFC Ltd filed Critical UFC Ltd
Publication of EP1465899A1 publication Critical patent/EP1465899A1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
    • C07D493/18—Bridged systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/06—Antimalarials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • 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 certain compounds containing a trioxane moiety that have potent antimalarial activity and antitumour activity.
  • Artemisinin (1) which is also known as qinghaosu, is a tetracyclic 1,2,4-trioxane occurring in Artemisia annua.
  • Artemisinin and its derivatives dihydroartemisinin (DHA) (2), artemether (3) and sodium artesunate (4) are used routinely in the treatment of malaria and have been found to be particularly effective against cerebral malaria.
  • artemisinin derivatives containing a peroxide moiety have also been tested for biological activity other than antimalarial activity.
  • the cytoxicity to Ehrlich ascites tumour cells of artemisinin, dihydroartemisinin, artemisitene, arteether, ethylperoxyartemisitene and an ether dimer of artemisinin has been demonstrated (Beekman et al., Phytother. Res., 1996, 10, 140; Woerdenberg et al., J. Nat. Prod., 1993, 56, 849).
  • DNA binding occurs depends upon the overall structure of the molecule and the nature of the chemical groups contained within the molecule. For instance, the major and minor grooves of the double helical DNA are occupied by water under physiological conditions.
  • certain oligopeptidic compounds such as netropscin and disamycin can displace water molecules and form strong hydrogen bonds with hydrophilic groups along the DNA strands.
  • Intercalators are compounds which insert between the bases of DNA.
  • Intercalators are provided by anthracyclines, such as adriamycin and daunomycin, which are used for the treatment of cancer, and acridines, such as amascrine, which is used for treating acute leukaemia and malignant lymphomas.
  • the antitumour activity is associated with the intercalating property of these compounds.
  • Naturally occurring polyamines such as the tetra-amine spermine (5) and the triamine spermidine (6) occur in cells at micromolar concentrations, and may even rise to millimolar levels in certain cancer cells (Tabor & Tabor, Ann. Rev. Biochem, 1984, 53, 749).
  • the biosynthetic building blocks for these and closely related polyamines are the alpha amino acids ornithine and lysine, affording the diamines putrescine (7) (1,4- diaminobutane) and cadaverine (8) (1,5-diamino pentane) respectively.
  • polyamines and polyamine amides have potential as novel therapeutic lead compounds in the design of anti-tumour agents.
  • Other workers, (Bergeron et al., Med. Chem., 1987, 31, 1183, Bergeron et al., Cancer Res., 1989, 49, 2959) have addressed the usefulness of polyamines in cancer chemotherapy.
  • polyamines have been identified as novel leads for the design of antidiarrhoeal agents and antimalarials and as ion chelators.
  • Polyamines bind to DNA via either the major or the minor groove (Rodger et al., Biopolymers, 1994, 34, 1583, Rogers et al., Bioorg. Med. Chem., 1995, 3, 861) and it is thought that endogenous polyamines also effect chromatin stability and structure (Basu et al., Biochem.]., 1992, 282, 723). Taking these aspects into account when designing polyamme based anticancer agents, there exists a potential uptake mechanism with selectivity for cancer cells (Cohen & Smith, Biochem. Soc. Trans., 1990, 18, 743) and two possible modes of cytotoxicity.
  • This cytotoxicity may be mediated either by DNA binding and hence disruption of transcription (Feuerstein et al., Nucleic Acids Res., 1990, 18, 1271), or by interference with polyamine biosynthetic pathways thereby modulating the cellular concentrations of endogenous polyamines.
  • polyamine or polyamide moeities for example desferrioxamine B (12), are low molecular weight ion chelating compounds. They facilitate iron solublization and transport.
  • Another approach to the development of antitumour compounds is the covalent linking of cytotoxic agents, whose activity is mediated tlirough direct interaction with DNA, to a polyamine.
  • the resulting conjugate will be transported into the cell through the polyamine transport mechanism (if recognised) and the polyamine should further aid DNA binding of the cytotoxic component as its DNA target site.
  • Cullis has demonstrated that polyamines conjugated to the nitrogen mustard chlorambucil increase the efficiency of DNA alkylation at the N7 of guanine by factors in the range of 10 3 to 10 4 (Cullis et al., J. Am. Chem. Soc, 1995, 117, 8033).
  • artemisinin and synthetic trioxane derivatives can be chemically modified by the attachment of a polyamine residue to form analogues of artemisinin and synthetic trioxane derivatives which exhibit antimalarial, cytotoxic and antitumour activity.
  • n an integer of from 1 to 4.
  • A represents a trioxane-containing residue
  • D is linked to A and represents an atom or group selected from the following:
  • E represents a bivalent, optionally substituted organic radical
  • F is linked to C and represents a group selected from the following:
  • C represents a group containing at least two nitrogen atoms.
  • A represents the following trioxane-containing residue:
  • the optionally substituted organic radical E preferably comprises an organic radical of 2-50 carbon atoms, more preferably 1-20 carbon atoms.
  • the optionally substituted organic radical E may comprise, for example, an optionally substituted alkyl, aryl, acyl, heteroalkyl or heteroacyl group.
  • the organic radical E may optionally be substituted by groups including, but not limited to, primary, secondary and tertiary amines; halogen-containing groups, such as bromide, chloride and fluoride; alcohols and derivatives thereof, including ethers and esters; and carboxylic acids and derivatives thereof, including esters and amides.
  • Examples of organic radicals comprising Group E include -CH 2 -CH 2 - j>-phenylene and pyridine.
  • group C this may be, for example, a natural or synthetic polyamine residue and is preferably of 2-50 carbon atoms.
  • group C comprises at least two amino groups, each of which is independently a primary or secondary group, after linking to group F through the same or different amino groups of the polyamine.
  • salts comprising pharmaceutically acceptable salts as referred to herein will be readily apparent to a skilled person.
  • These salts include, but are not limited to acetate, adipate, besylate, bromide, camsylate, chloride, citrate, edisylate, estolate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hyclate, hydrobromide, hydrochloride, iodide, isethionate, lactate, lactobionate, maleate, mesylate, methylbromide, methylsulfate, napsylate, nitrate, oleate, pamoate, phosphate, polygalacturonate, stearate, succinate, sulfate, sulfosalicylate, tannate, tartrate, terephthalate, tosylate, triethiodide, benzathine, calcium, diolamine,
  • chloroquine is a dibasic drug with K a S of 8.1 (quinoline ring nitrogen) and 10.2 (diethylamino side chain) and accumulates in acidic vesicles to the square of the monobasic antimalarials such as mefloquine.
  • K a S of 8.1 quinoline ring nitrogen
  • 10.2 diethylamino side chain
  • the value is around 2.2.
  • Ginsburg and co-workers suggested that chloroquine would be expected to accumulate 2.5 x 10 4 compared with 160 fold for the mono-basic antimalarials such as mefloquine (Ginsburg et al., Biochem. Pharmacol, 1989, 38, 2645).
  • One preferred embodiment of the present invention provides compounds having the structure 13n.
  • a process for the production of a compound of general formula 13 as hereinbefore defined comprising the steps of coupling dihydroartemisinin with benzenedimethanol, converting the resultant alcohol into the corresponding sulfonate by treatment with a sulfonyl halide, and reacting said sulfonate with a diamino nucleophile.
  • the resultant alcohol is converted into the corresponding mesylate by treatment with mesyl chloride.
  • This process is particularly advantageous with regard to the production of trioxane derivatives of the type exemplified by compounds 13a-13j.
  • a process for the production of a compound of general formula 13 as hereinbefore described comprising the steps of coupling dihydroartemisinin with an alcohol methyl ester, hydrolysing the resultant compound to produce the corresponding carboxylic acid, and coupling said carboxylic acid with a polyamine or amine.
  • a further aspect of the invention provides a process for the production of a compound of general formula 13 as hereinbefore described, said process comprising the steps of coupling dihydroartemisinin with an anhydride, forming a carboxylic acid, and coupling said carboxylic acid with a polyamine or amine.
  • coupling of the carboxylic acid and polyamine or amine is carried out at a temperature of between -20 and +40 ° C.
  • the antimalarial activity of the new compounds was assessed using two strains of P. falciparuni from Thailand: (a) the uncloned Kl strain which is known to be CQ resistant and (b) the HB3 strain which is sensitive to all antimalarials.
  • Parasites were maintained in continuous culture using the method of Trager and Jenson (/. Parasitol, 1977, 63, 883-886). Cultures were grown in flasks containing human erythrocytes (2-5%) with parasitemia in the range of 1% to 10% suspended in RPMI 1640 medium supplemented with 25 mM HEPES and 32 mM NaHCO 3 , and 10% human serum (complete medium). Cultures were gassed with a mixture of 3% O 2 , 4% CO 2 and 93% N 2 .
  • Antimalarial activity was assessed with an adaption of the 48-h sensitivity assay of Desjardins et al. (Antimicrob. Agents. Chemother., 1979, 16, 710-718) using [ H]- hypoxanthine incorporation as an assessment of parasite growth.
  • Stock drug solutions were prepared in 100% dimethylsulphoxide (DMSO) and diluted to the appropriate concentration using complete medium.
  • Assays were performed in sterile 96-well microtitre plates, each plate containing 200 ⁇ l of parasite culture (2% parasitemia, 0.5% haematocrit) with or without 10 ⁇ l drug dilutions. Each drug was tested in triplicate and parasite growth was compared to control wells (which constituted 100 % parasite growth).
  • IC 50 values were calculated by interpolation of the probit transformation of the log dose - response curve.
  • Table 2 shows the IC50 of compounds of the invention versus the HB3 strain of P. falciparuni in vitro.
  • the anticancer activity of these compounds of the present invention was also assessed, by NCI 3-cell line anticancer assay.
  • each cell line is inoculated and preincubated on a microtiter plate.
  • Test agents are then added at a single concentration and the culture incubated for 48 hours. End-point determinations are made with sulforhodamine B, a protein-binding dye. Results for each test agent are reported as the percentage of growth of the treated cells when compared to the untreated control cells. Compounds which reduce the growth of any one of the cells lines to 32% or less (negative numbers indicate cell kill) are passed on for evaluation in the full panel of 60 cell lines over a 5-log dose range.
  • a compound of general formula 13 as hereinbefore defined or a pharmaceutically acceptable salt thereof, for use as a medicament.
  • Compounds of the present invention may be used particularly, but not exclusively, as medicaments for the treatment of malaria or cancer. Whilst the currently preferred use of peroxides is for treatment, it cannot be ruled out that these compounds would have a use in the prophylaxis of malaria.
  • a therapeutically effective non-toxic amount of a compound of general formula 13 as hereinbefore defined may be administered in any suitable manner, including orally, parenterally (including subcutaneously, intramuscularly and intravenously), or topically.
  • the administration will generally be carried out repetitively at intervals, for example once or several times a day.
  • the amount of the compound of general formula 13 that is required in order to be effective as an antimalarial or anticancer agent for treating human or animal subjects will of course vary and is ultimately at the discretion of the medical or veterinary practitioner treating the human or animal in each particular case.
  • the factors to be considered by such a practitioner, e.g. a physician include the route of administration and pharmaceutical formulation; the subject's body weight, surface area, age and general condition; and the chemical form of the compound to be administered.
  • the total daily dose may be given as a single dose, multiple doses, e.g. two to six times per day, or by intravenous infusion for any selected duration.
  • the compound of general formula 13 may be presented, for example, in the form of a tablet, capsule, liquid (e.g. syrup) or injection.
  • the compounds of general formula 13 While it may be possible for the compounds of general formula 13 to be administered alone as the active pharmaceutical ingredient, it is preferable to present the compounds in a pharmaceutical composition.
  • a pharmaceutical composition containing a compound of general formula 13 as hereinbefore defined, or a pharmaceutically acceptable salt thereof, as an active ingredient.
  • compositions for medical use will be formulated in accordance with any of the methods well known in the art of pharmacy for administration in any convenient manner.
  • the compounds of the invention will usually be admixed with at least one other ingredient providing a compatible pharmaceutically acceptable additive, carrier, diluent or excipient, and may be presented in unit dosage form.
  • the carrier(s) must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the possible formulations include those suitable for oral, rectal, topical and parenteral (including subcutaneous, intramuscular and intravenous) administration or for administration to the lung or another absorptive site such as the nasal passages.
  • All methods of formulation in making up such pharmaceutical compositions will generally include the step of bringing the compound of general formula 13 into association with a carrier which constitutes one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing the compound of general formula 13 into association with a liquid carrier or with a finely divided solid carrier or with both and then, if necessary, shaping the product into desired formulations.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, tablets or lozenges, each containing a predetermined amount of the compound of general formula 13; as a powder or granules; or a suspension in an aqueous liquid or non-aqueous liquid such as a syrup, an elixir, an emulsion or a draught.
  • the compound of general formula 13 may also be presented as a bolus, electuary or paste.
  • a tablet may be made by compression or moulding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing, in a suitable machine, the compound of general formula 13 in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent.
  • Moulded tablets may be made by moulding, in a suitable machine, a mixture of the powdered compound of general formula 13 with any suitable carrier.
  • a syrup may be made by adding the compound of general formula 13 to a concentrated, aqueous solution of a sugar, for example sucrose, to which may be added any desired accessory ingredient.
  • a sugar for example sucrose
  • Such accessory ingredient(s) may include flavourings, an agent to retard crystallisation of the sugar or an agent to increase the solubility of any other ingredient, such as a polyhydric alcohol, for example glycerol or sorbitol.
  • Formulations for rectal administration may be presented as a suppository with a usual carrier such as cocoa butter.
  • Formulations suitable for parental administration conveniently comprise a sterile aqueous preparation of the compound of general formula 13 which is preferably isotonic with the blood of the recipient.
  • formulations of this invention may include one or more accessory ingredients, for example a diluent, buffer, flavouring agent, binder, surface active agent, thickener, lubricant and/or a preservative (including an antioxidant) or other pharmaceutically inert excipient.
  • accessory ingredients for example a diluent, buffer, flavouring agent, binder, surface active agent, thickener, lubricant and/or a preservative (including an antioxidant) or other pharmaceutically inert excipient.
  • the compounds of this invention may also be made up for administration in liposomal formulations which can be prepared by methods well-known in the art.
  • a further aspect of the present invention provides the use of a compound of general formula 13 as hereinbefore defined, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prophylaxis of malaria.
  • a further aspect of the present invention provides the use of a compound of general formula 13 as hereinbefore defined, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer.
  • a product containing a first compound of general formula 13 as hereinbefore defined, or a pharmaceutically acceptable salt thereof, and a second, iron-containing, compound as a combined preparation for simultaneous, separate or sequential use in the treatment of cancers.
  • the first and second compounds are used sequentially, the second, iron-containing, compound being used first.
  • the first compound may be presented in any of the forms described above.
  • Administration of the first compound may be in any suitable manner, including intravenously, intraarterially, intralesionally, topically, intracavitarily or orally.
  • Any suitable dosage of the compound may be used.
  • a dosage within the range of 0.1 to 500mg/kg body weight is used, more preferably within the range of 0.5 to 300mg/kg body weight, such as 1 to 50 mg/kg body weight.
  • iron-containing compound this may take any suitable form.
  • Preferred agents for enhancing intracellular iron levels for use in the present invention include pharmaceutically acceptable iron salts and iron complexes.
  • Iron salts useful in the present invention include ferrous fumarate, ferrous sulphate, ferrous carbonate, ferrous citrate, ferrous gluconate, ferrous lactate and ferrous maleate.
  • Iron complexes useful in the present invention include ferrocholinate, ferroglycine sulphate, dextran iron complex, peptonized iron, iron sorbitex, saccharated iron, iron complexed with iron binding proteins and glycoproteins such as the holoferritins and holotransferrins.
  • the iron-containing compound may be presented in any of the forms described above in relation to the compound of general formula 13. Administration of the iron- containing compound may be achieved via any of the possible routes of administration of the first compound.
  • the first and second compounds may be administered via the same or different routes.
  • the iron-containing compound may be used ay any appropriate dosage, but is preferably used at a dosage within the range of 0.01 to 1000 mg iron/kg body weight.
  • the product of the invention may further comprise one or more other agents known to be useful in the treatment of tumours.
  • agents may include, for example, androgen inhibitors, antiestrogens, antimetabolites and cytotoxic agents.
  • a method of treatment of malaria which comprises administering to an animal in need of such treatment a therapeutically effective amount of a compound of general formula 13 as hereinbefore defined, or a pharmaceutically acceptable salt thereof.
  • the preferred amount of compounds of the present invention is between lOmg to 5g, preferably 50 to lOOOmg, administered over a period of 2-5 days, alone or in combination with other antimalarial drugs, such as, for example, the class II blood schizonticides or halofantrine (Looaeesuwan, Am. J. Trop. Med., 1999, 60, 238).
  • a method of treatment of cancer which comprises administering to an animal in need of such treatment a therapeutically effective amount of a compound of general formula 13 as hereinbefore defined, or a pharmaceutically acceptable salt thereof.
  • the method may further comprise the simultaneous, separate or sequential administration to the said animal an effective amount of an iron-containing compound as hereinbefore described.
  • Infra red (IR) spectra were recorded in the range 4000-600 cmf 1 using a Perkin Elmer 298 infrared spectrometer. Spectra of liquids were taken as films. Sodium chloride plates (nujol mull) , solution cells (dichloromethane) and KBr discs were used as indicated.
  • This compound was prepared from l-(4-trifluoromethyl phenyl)pi ⁇ erazine using general procedure 2 to give the product as a yellow oil (64 % yield): 1H (300 MHz, CDCI3) ⁇
  • This compound was prepared from methyl 4-hydroxybenzoate using procedure 1 and procedure 2 to give the product as a yellow foam (45 % yield).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
EP02788077A 2001-12-06 2002-12-06 Trioxane derivatives Withdrawn EP1465899A1 (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
GBGB0129215.0A GB0129215D0 (en) 2001-12-06 2001-12-06 Trioxane derivatives
GB0129215 2001-12-06
GB0217723A GB0217723D0 (en) 2002-07-31 2002-07-31 Trioxane derivatives
GB0217723 2002-07-31
PCT/GB2002/005531 WO2003048167A1 (en) 2001-12-06 2002-12-06 Trioxane derivatives

Publications (1)

Publication Number Publication Date
EP1465899A1 true EP1465899A1 (en) 2004-10-13

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Family Applications (1)

Application Number Title Priority Date Filing Date
EP02788077A Withdrawn EP1465899A1 (en) 2001-12-06 2002-12-06 Trioxane derivatives

Country Status (5)

Country Link
EP (1) EP1465899A1 (ja)
JP (1) JP2005515999A (ja)
AU (1) AU2002352357A1 (ja)
CA (1) CA2469224A1 (ja)
WO (1) WO2003048167A1 (ja)

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WO2003048167A1 (en) 2003-06-12

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