WO2017201581A1 - Chélateurs de fer non toxiques à potentiel neuroprotecteur - Google Patents

Chélateurs de fer non toxiques à potentiel neuroprotecteur Download PDF

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Publication number
WO2017201581A1
WO2017201581A1 PCT/AU2017/050491 AU2017050491W WO2017201581A1 WO 2017201581 A1 WO2017201581 A1 WO 2017201581A1 AU 2017050491 W AU2017050491 W AU 2017050491W WO 2017201581 A1 WO2017201581 A1 WO 2017201581A1
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Prior art keywords
dfob
compound
present
formula
analogue
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PCT/AU2017/050491
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English (en)
Inventor
Rachel Codd
Michael Philipp GOTSBACHER
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The University Of Sydney
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Priority claimed from AU2016901976A external-priority patent/AU2016901976A0/en
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Publication of WO2017201581A1 publication Critical patent/WO2017201581A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/18—One oxygen or sulfur atom
    • C07D231/20—One oxygen atom attached in position 3 or 5
    • C07D231/22—One oxygen atom attached in position 3 or 5 with aryl radicals attached to ring nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C07D311/70—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with two hydrocarbon radicals attached in position 2 and elements other than carbon and hydrogen in position 6
    • C07D311/72—3,4-Dihydro derivatives having in position 2 at least one methyl radical and in position 6 one oxygen atom, e.g. tocopherols

Definitions

  • the present invention relates to new desferrioxamine B-based compounds that have potential utility for treating neurodegenerative conditions, to their preparation, and to compositions including the compounds.
  • the present invention also relates to the use of the compounds, as well as compositions including the compounds, in the treatment of neurodegenerative disorders (such as Parkinson's disease).
  • Desferrioxamine B is an iron(lll) chelating molecule produced by the bacterium Streptomyces pilosus (S. pilosus) and other Actinomycetes.
  • the bacteria produce DFOB to bind iron in the local environment as an essential requirement for supplying iron to the cell for growth.
  • the structure of DFOB is:
  • DFOB has been used in the clinic to treat patients with secondary iron overload, which can occur as a complication of the treatment of transfusion-dependent blood disorders, including beta-thalassaemia, sickle cell anaemia and myelodysplastic syndromes.
  • Various neurodegenerative diseases are also associated with excess iron.
  • Parkinson's disease is associated with an increase in iron in the substantia nigra brain region (compared to age-matched controls), and this increased iron has been implicated in damage to dopaminergic neurons and aggregation of alpha- synuclein (via the iron-mediated production of damaging free radicals).
  • DFOB is effective at removing iron from plasma and it is non-toxic. However, it has poor Blood-Brain Barrier (BBB) permeability and is inefficient at removing iron stored inside cells. It also has a short plasma half-life (ti /2 10-20 min) due to its high water solubility and low plasma protein binding (about 10%).
  • BBB Blood-Brain Barrier
  • the present inventors have proposed that the issues with current agents used in therapy of neurodegenerative disorders could be overcome by developing an agent that has multiple modes of action. Specifically, the present inventors have sought to develop compounds that have high affinity for iron and antioxidant activity. In addition, the agents should have BBB permeability.
  • the present invention relates to a compound of formula (I):
  • E is a vitamin E analogue or an edaravone analogue.
  • n may be 5.
  • E may be a vitamin E analogue.
  • E may be any vitamin E analogue.
  • E may be any vitamin E analogue.
  • E may be any vitamin E analogue.
  • E may be any vitamin E analogue.
  • E may be any vitamin E analogue.
  • E may be any vitamin E analogue.
  • E may be any vitamin E analogue.
  • E may be any vitamin E analogue.
  • E may be
  • A, B, C and D are independently selected from H and alkyi (e.g. Ci to C3 alkyi), and p is 0, 1 or 2.
  • A, B, C and D may be the same or different.
  • a B, C and D may be alkyi (e.g. methyl).
  • A, B and C may be alkyi (e.g. methyl), and D may be H.
  • a and B may be alkyi (e.g. methyl), and C and D may be H.
  • p maybe 0 or 2.
  • the vitamin E analogue may be selected from:
  • E may be an antioxidant fragment such as an analogue or derivative edaravone, e.g.:
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition including a compound of formula (I) (according to the first aspect of the invention) together with a pharmaceutically acceptable carrier, diluent or excipient.
  • the present invention relates to a method of treating a neurodegenerative disorder in a subject, the method including administering to the subject an effective amount of a compound of formula (I) according to the first aspect of the invention, or a pharmaceutical composition according to the second aspect of the invention.
  • the present invention relates to the use of an effective amount of a compound of formula (I) according to the first aspect of the invention, or a pharmaceutical composition according to the second aspect of the invention, in the manufacture of a medicament for treating a neurodegenerative disorder.
  • the present invention relates to the use of an effective amount of a compound of formula (I) according to the first aspect of the invention, or a pharmaceutical composition according to the second aspect of the invention, for the treatment of a neurodegenerative disorder in a subject.
  • the present invention relates to an effective amount of a compound of formula (I) according to the first aspect of the invention, or a pharmaceutical composition according to the second aspect of the invention, for use in the treatment of a neurodegenerative disorder in a subject.
  • the neurodegenerative disorder to be treated is associated with metal ion (in particular, iron) dyshomeostasis.
  • the neurodegenerative disorder may be selected from Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, Friedreich's ataxia, and Multiple Sclerosis.
  • the compounds of formula (I) may be used in therapy alone or in combination with one or more other therapeutic agents, for example, as part of a combination therapy.
  • Figure 8 Extracted ion chromatogram for the single charged species of DFOB-a- CEHC (m/z 821 .5 [M+H] + ). The sample was run on a 5-95% ACN gradient over 40 min at a 0.4 ml_ min-1 flow rate using an Agilent Eclipse XDB-C18 column.
  • FIG. 11 13 C NMR spectrum (DMSO-d 6 , 100 MHz) of DFOB-a-CEHC.
  • Figure 12. Extracted ion chromatogram for the single charged species of DFOB- a-CEHC (m/z 793.4 [M+H] + ). The sample was run on a 5-95% ACN gradient over 40 min at a 0.4 ml_ min-1 flow rate using an Agilent Eclipse XDB-C18 column.
  • Figure 16 Extracted ion chromatogram for the single charged species of DFOB- y-CEHC (m/z 807.5 [M+H] + ). The sample was run on a 5-95% ACN gradient over 40 min at a 0.4 ml_ min-1 flow rate using an Agilent Eclipse XDB-C18 column.
  • FIG. 21 High resolution mass spectrometry of DFOB-EDA (ESI+) found m/z 783.40121 ([M+Na] + ], CseHseNsO ⁇ Na requires 783.40171.
  • Figure 22 1 H NMR spectrum (DMSO-d 6 , 400 MHz) of DFOB-EDA.
  • FIG. 24 Results for ascorbate (AH 2 ) autoxidation assay.
  • A) and (B) show that DFOB and its derivatives (DFOB-(rac)-TLX, DFOB-(R)-TLX, DFOB-(S)-TLX, DFOB-a- CEHC, DFOB-6-CEHC, DFOB-y-CEHC and DFOB-EDA) are effectively chelating iron and minimising ascorbate autoxidation.
  • Figure 25 Antiradical activity, as determined by the ABTS '+ assay, for selected compounds and standards. DFOB (circle), (rac)-TLX (square) and DFOB-(rac)-TLX (triangle).
  • FIG. 26 Neurons in the substantia nigra (A).
  • TLX represents the compound Trolox (6-hydroxy-2,5,7,8- tewtramethylchrmoan-2-carboxylic acid) and "EDA” represents the 4-(5-hydroxy-3- methyl-1 H-pyrazol-1 -yl) benzoic acid-derived moiety.
  • Compounds are generally described herein using standard nomenclature. For compounds having asymmetric centres, it will be understood that, unless otherwise specified, all of the optical isomers and mixtures thereof are encompassed. Compounds with two or more asymmetric elements can also be present as mixtures of diastereomers.
  • a recited compound is not limited to any one specific tautomer, but rather is intended to encompass all tautomeric forms.
  • Recited compounds are further intended to encompass compounds in which one or more atoms are replaced with an isotope, i.e., an atom having the same atomic number but a different mass number.
  • isotopes of hydrogen include tritium and deuterium and isotopes of carbon include 11 C, 13 C, and 14 C.
  • Compounds according to the formula provided herein, which have one or more stereogenic centres, may have an enantiomeric excess of at least 50%.
  • such compounds may have an enantiomeric excess of at least 60%, 70%, 80%, 85%, 90%, 95%, or 98%.
  • Some embodiments of the compounds have an enantiomeric excess of at least 99%.
  • single enantiomers optically active forms
  • the compounds of the present invention may be racemic mixtures.
  • a "pharmaceutically acceptable salt” of a compound disclosed herein is an acid or base salt that is generally considered in the art to be suitable for use in contact with the tissues of human beings or animals without excessive toxicity or carcinogenicity, and preferably without irritation, allergic response, or other problem or complication.
  • pharmaceutically acceptable salts in accordance with the present invention are those that do not adversely affect the ability of the compound to cross the BBB.
  • Such salts include mineral and organic acid salts of basic residues such as amines, as well as alkali or organic salts of acidic residues such as carboxylic acids.
  • Suitable pharmaceutically acceptable salts include, but are not limited to, salts of acids such as hydrochloric, phosphoric, hydrobromic, malic, glycolic, fumaric, sulfuric, sulfamic, sulfanilic, formic, toluenesulfonic, methanesulfonic, benzenesulfonic, ethane disulfonic, 2-hydroxyethylsulfonic, nitric, benzoic, 2-acetoxybenzoic, citric, tartaric, lactic, stearic, salicylic, glutamic, ascorbic, pamoic, succinic, fumaric, maleic, propionic, hydroxymaleic, hydroiodic, phenylacetic, alkanoic (such as acetic, HOOC-(CH 2 ) n -COOH where n is any integer from 0 to 6, i.e.
  • acids such as hydrochloric, phosphoric, hydrobromic, malic, glyco
  • a pharmaceutically acceptable acid or base salt can be synthesized from a parent compound that contains a basic or acidic moiety by any conventional chemical method. Briefly, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent (such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile), or in a mixture of the two.
  • an organic solvent such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile
  • each compound of formula (I) may, but need not, be present as a hydrate, solvate or non-covalent complex.
  • the various crystal forms and polymorphs are within the scope of the present invention, as are prodrugs of the compounds of formula (I) provided herein.
  • a "prodrug” is a compound that may not fully satisfy the structural requirements of the compounds provided herein, but is modified in vivo, following administration to a subject or patient, to produce a compound of formula (I) provided herein.
  • a prodrug may be an acylated derivative of a compound as provided herein.
  • Prodrugs include compounds wherein hydroxy, carboxy, amine or sulfhydryl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxy, carboxy, amino, or sulfhydryl group, respectively.
  • Examples of prodrugs include, but are not limited to, acetate, formate, phosphate and benzoate derivatives of alcohol and amine functional groups within the compounds provided herein.
  • Prodrugs of the compounds provided herein may be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved in vivo to generate the parent compounds.
  • a "CH 2 substituent” is a moiety such as a halogen or an alkyl group that is covalently bonded to the carbon atom of the CH 2 group.
  • substituted means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated substituents, provided that the designated atom's normal valence is not exceeded, and that the substitution results in a stable compound, i.e., a compound that can be isolated, characterized and tested for biological activity.
  • Suitable substituents are halogen (for example, fluorine, chlorine, bromine or iodine atoms).
  • the compound of formula (I) may not be substituted with one or more halogen atoms.
  • the compound of formula (I) may not be substituted with any additional substituents.
  • a wording defining the limits of a range of length such as, for example, "from 1 to 5" means any integer from 1 to 5, i.e. 1 , 2, 3, 4 and 5.
  • any range defined by two integers explicitly mentioned is meant to comprise and disclose any integer defining said limits and any integer comprised in said range.
  • alkyl refers to a saturated, straight-chain or branched hydrocarbon group. Specific examples of alkyl groups are methyl, ethyl, propyl, /so-propyl, n-butyl, /so-butyl, sec-butyl, fe/f-butyl, n-pentyl, /so-pentyl, n-hexyl and 2,2-dimethylbutyl. As discussed above, the present invention relates to a compound of formula (I):
  • n may be 5.
  • the compounds of the present invention are conjugates of a DFOB-based moiety and an antioxidant.
  • the antioxidant will be any compound that is suitable for reducing oxidative stress that leads, or contributes, to the onset or development of a neurodegenerative disorder.
  • vitamin E is lipophilic and it does not contain a free carboxylic acid group as necessary for conjugation to the free amine group of DFOB using amide chemistry. Therefore, it is difficult to conjugate native vitamin E to another compound, such as a drug.
  • vitamin E analogues have been employed by the present inventors in place of the native vitamin E compound. These analogues are intended to mimic the antioxidant activity of vitamin E and also may have the potential to promote brain uptake of the resulting conjugate via the tocopherol transport protein.
  • native vitamin E in contrast to native vitamin E, they are more water soluble and contain a free carboxylic group, and therefore can be easily conjugated to the DFOB- based moiety.
  • the vitamin E analogue may be , wherein A, B,
  • C and D are independently selected from H and alkyl (e.g. Ci to C3 alkyl), and p is 0, 1 or 2.
  • A, B, C and D may be the same or different.
  • all of A, B, C and D may be alkyl (e.g. methyl).
  • A, B and C may be alkyl (e.g. methyl), and D may be H.
  • a and B may be alkyl (e.g. methyl) and C and D may be H.
  • p maybe 0 or 2.
  • vitamin E analogue that may be used to prepare a compound of formula (I) is 6-hydroxy-2,5,7,8-tetramethylchromane-2-carboxylic acid (“Trolox”), which has the following structure:
  • this compound (or any of the vitamin E analogues intended for use in the present invention) may be used as a racemic mixture, or may be conjugated to the DFOB-based moiety in an enantiomerically-pure form i.e. as the (R)- or (S)-isomer.
  • the vitamin E analogue may be:
  • vitamin E analogue that may be used to prepare a compound of formula (I) is 2,7,8-trimethyl-2-(2-carboxyethyl)-6-hydroxychroman (“ ⁇ -CEHC”)):
  • the vitamin E analogue may be selected from:
  • each of the CEHC compounds may be used as a racemic mixture, or as the enantiomerically-pure form i.e. as the (R)- or (S)- isomer, and it is intended that all of these forms of the compounds of the present invention are covered by formula (I).
  • edavarone which has antioxidant properties, is used for the purpose of aiding neurological recovery following acute brain ischemia and subsequent cerebral infarction.
  • the present inventors believe that the edavarone moiety may carry the additional benefit in reducing oxidative stress in the brain.
  • the compounds of the present invention can be synthesised by any suitable method known to a person skilled in the art.
  • a DFOB-based moiety e.g. compound 6 in Scheme 1 below
  • a carboxyi-bearing vitamin E analogue e.g. compound 7 in Scheme 1 below
  • conjugate 1 i.e. a compound of formula (I).
  • the DFOB-based moiety (e.g. compound 6 in Scheme 1 ) is commercially available.
  • Compound 7 is also available commercially.
  • the process may include the further step of reacting the primary amine group with a suitably-functionalised vitamin E analogue or edavarone analogue (such as those discussed above), to produce the compounds of formula (I) of the present invention.
  • the present inventors hypothesise that the compounds of the present invention have a dual mode of action in relation to mitigating the effects of excess iron in neurodegenerative disorders. Specifically, they may possess antioxidant activity, which may contribute to decreasing the effect that free radicals have on the development of neurodegenerative diseases (as discussed above, excess iron has been implicated in the production of free radicals, which are thought to contribute to these diseases).
  • the DFOB-based portion of the compounds is an efficient iron chelator, further contributing to the sequestration of excess iron.
  • the lipophilic nature of the compounds is also believed to enhance the uptake of the compound of formula (I) into brain tissue, in addition to the fact that the antioxidant moiety may facilitate active transport of the compounds through the BBB by the tocopherol transport protein.
  • the edaravone analogue has established BBB permeability and may act in a Trojan horse capacity to increase uptake of the DFOB- edaravone compound.
  • the therapeutic use of compounds of formula (I), their pharmaceutically acceptable salts, solvates, hydrates, prodrugs and also formulations and pharmaceutical compositions (including mixtures of the compounds of formula (I)) are within the scope of the present invention. Accordingly, the present invention also relates to a pharmaceutical composition including a compound of formula (I):
  • E is a vitamin E analogue or an edaravone analogue; together with a pharmaceutically acceptable carrier, diluent or excipient.
  • a “pharmaceutical carrier, diluent or excipient” includes, but is not limited to, any physiological buffered (i.e., about pH 7.0 to 7.4) medium including a suitable water soluble carrier, conventional solvents, dispersion media, fillers, solid carriers, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents.
  • suitable water soluble carriers include, but are not limited to saline, dextrose, corn oil, dimethylsulfoxide, and gelatin capsules.
  • lactose lactose
  • mannitol corn starch
  • potato starch binders such as crystalline cellulose, cellulose derivatives, acacia, gelatins, disintegrators such as sodium carboxymethylcellulose, and lubricants such as talc or magnesium stearate.
  • binders such as crystalline cellulose, cellulose derivatives, acacia, gelatins
  • disintegrators such as sodium carboxymethylcellulose
  • lubricants such as talc or magnesium stearate.
  • compositions may be formulated for any appropriate route of administration including, for example, topical (for example, transdermal or ocular), oral, buccal, nasal, vaginal, rectal or parenteral administration.
  • parenteral as used herein includes subcutaneous, intradermal, intravascular (for example, intravenous), intramuscular, spinal, intracranial, intrathecal, intraocular, periocular, intraorbital, intrasynovial and intraperitoneal injection, as well as any similar injection or infusion technique.
  • compositions in a form suitable for oral use or parenteral use are preferred.
  • Suitable oral forms include, for example, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • a sterile aqueous solution which is preferably isotonic with the blood of the recipient.
  • Such formulations may be prepared by dissolving solid active ingredient in water containing physiologically compatible substances such as sodium chloride or glycine, and having a buffered pH compatible with physiological conditions to produce an aqueous solution, and rendering said solution sterile.
  • the formulations may be present in unit or multi-dose containers such as sealed ampoules or vials.
  • suitable components are described in Martindale - The Extra Pharmacopoeia (Pharmaceutical Press, London 1993) and Martin (ed.), Remington's Pharmaceutical Sciences.
  • the dose of the biologically- active compound according to the invention may vary within wide limits and may be adjusted to individual requirements.
  • Active compounds according to the present invention are generally administered in a therapeutically effective amount. Preferred doses range from about 0.1 mg to about 140 mg per kilogram of body weight per day (e.g. about 0.5 mg to about 7 g per patient per day).
  • the daily dose may be administered as a single dose or in a plurality of doses.
  • 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. Dosage unit forms will generally contain between about 1 mg to about 500 mg of an active ingredient.
  • the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination (i.e. other drugs being used to treat the patient), and the severity of the particular disorder undergoing therapy. Such treatments may be administered as often as necessary and for the period of time judged necessary by the treating physician.
  • the dosage regime or therapeutically effective amount of the compound of formula (I) to be administered may need to be optimized for each individual.
  • an effective amount of an agent is that amount which causes a statistically significant decrease in the severity of the symptoms of the neurodegenerative disorder, or that slows the progression of the neurodegenerative disorder.
  • the term "neurodegenerative disorder” or “neurodegenerative disease” is intended to refer to a disorder that results in, or is characterized by, degeneration of the nervous system, especially the neurons in the brain.
  • Examples of neurodegenerative disorders contemplated by the present invention include those that have a pathology dependent upon metal ion dyshomeostasis.
  • the neurodegenerative disorders of interest are those associated with an accumulation of iron (i.e. an excess of iron) in the brain, such as Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, Friedreich's ataxia, and Multiple Sclerosis.
  • terapéuticaally effective amount refers to an amount of the compound of formula (I) that results in an improvement or remediation of the symptoms of a neurodegenerative disorder, or slowing the progression of the disease.
  • dosage form and amount of the compounds or pharmaceutical compositions of the present invention can be readily established by reference to known treatment regimens.
  • Preferred compounds of the invention will have certain pharmacological properties. Such properties include, but are not limited to, oral bioavailability and BBB permeability, such that the preferred oral dosage forms discussed above can provide therapeutically effective levels of the compound in vivo and at the desired site of action.
  • the compounds of the present invention are preferably administered to a patient (for example, a human) orally or parenterally, and are present within at least one body fluid or tissue of the patient. Accordingly, the present invention further provides methods for treating patients suffering from neurodegenerative disorders (including Parkinson's disease).
  • a patient for example, a human
  • neurodegenerative disorders including Parkinson's disease
  • treating encompass ameliorating the severity of a neurodegenerative disorder or its associated symptoms and/or slowing disease progression.
  • Patients may include but are not limited to primates, especially humans, domesticated companion animals such as dogs, cats, horses, and livestock such as cattle, pigs, sheep, with dosages as described herein.
  • Compounds and pharmaceutical compositions according to the present invention may be suitable for neurodegenerative therapy. Accordingly, the present invention also relates to a method of treating a neurodegenerative disorder in a patient including administration to the patient of a therapeutically effective amount of a compound of formula (I), or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof.
  • the present invention also relates to the use of a therapeutically effective amount of a compound of formula (I), or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, for treating a neurodegenerative disorder.
  • the present invention also provides a pharmaceutical composition for use in treating a neurodegenerative disorder, in any of the embodiments described in the specification.
  • the present invention also relates to the use of a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, for the manufacture of a medicament for treating a neurodegenerative disorder.
  • the present invention also relates to a compound of formula (I), or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, when used in a method of treating a neurodegenerative disorder.
  • the present invention also relates to a composition having an active ingredient for use in treating a neurodegenerative disorder, wherein the active ingredient is a compound of formula (I), or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.
  • the present invention also relates to the use of a pharmaceutical composition containing a compound of the formula (I), or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, in treating a neurodegenerative disorder, such as described above.
  • the compound of formula (I) is essentially the only active ingredient of the composition.
  • the neurodegenerative disorder is associated with metal ion (in particular, iron) dyshomeostasis.
  • the disorder is selected from Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, Friedreich's ataxia, and Multiple Sclerosis.
  • the compounds may be administered in combination with other agents used in neurodegenerative therapy, such as, resveratrol, donepezil, apomorphine and other dopamine agonists, levodopa as monotherapy or in combination with peripherally acting inhibitors of dopamine decarboxylase (carbidopa, benserazide, and monoamine oxidase B inhibitors (selegiline and rasagiline).
  • agents used in neurodegenerative therapy such as, resveratrol, donepezil, apomorphine and other dopamine agonists, levodopa as monotherapy or in combination with peripherally acting inhibitors of dopamine decarboxylase (carbidopa, benserazide, and monoamine oxidase B inhibitors (selegiline and rasagiline).
  • the present invention relates to a compound of formula (I):
  • E is a vitamin E analogue or an edaravone analogue.
  • the present invention relates to a compound of formula (I) according to the first embodiment, wherein n is 5.
  • the present invention relates to a compound of formula (I) according to the first or second embodiment, wherein p is 0 or 2.
  • the present invention relates to a compound of formula (I) according to the first, second or third embodiments, wherein E is: wherein:
  • A, B, C and D are independently selected from H and alkyl, and p is 0, 1 or 2.
  • the present invention relates to a compound of formula (I) according to the fourth embodiment, wherein alkyl is Ci to C3 alkyl.
  • the present invention relates to a compound of formula (I) according to the fourth or fifth embodiments, wherein A, B, C and D are the same.
  • the present invention relates to a compound of formula (I) according to the sixth embodiment, wherein A, B, C and D are alkyl.
  • the present invention relates to a compound of formula (I) according to the fourth or fifth embodiment, wherein A, B, C and D are different.
  • the present invention relates to a compound of formula (I) according to the eighth embodiment, wherein A, B and C are alkyl, and D is H.
  • the present invention relates to a compound of formula (I) according to the fourth or fifth embodiment, wherein A and B are alkyl and C and D are
  • the present invention relates to a compound of formula (I) according to any of the fourth to tenth embodiments, wherein E is selected from
  • the present invention relates to a compound of formula (I) according to any of the first to third embodiments, wherein E is:
  • the present invention relates to a compound of formula (I) according to any of the first to twelfth embodiments, wherein the compound is selected from the group consisting of:
  • the present invention relates to a pharmaceutical composition including an effective amount of a compound of formula (I):
  • each n is independently selected from 4 and 5; m is 2; and E is a vitamin E analogue or an edaravone analogue; together with a pharmaceutically acceptable carrier, diluent or excipient.
  • the present invention relates to a pharmaceutical composition according to the fourteenth embodiment, wherein the composition is suitable for parenteral or oral administration.
  • the present invention relates to a pharmaceutical composition according to the fourteenth or fifteenth embodiments, wherein n is 5.
  • the present invention relates to a pharmaceutical composition according to any one of the fourteenth to sixteenth embodiments, wherein E is:
  • A, B, C and D are independently selected from H and alkyl, and p is 0, 1 or 2.
  • the present invention relates to a compound of formula (I) according to the seventeenth embodiment, wherein alkyl is Ci to C3 alkyl.
  • the present invention relates to a pharmaceutical composition according to the seventeenth or eighteenth embodiments, wherein A, B, C and D are the same.
  • the present invention relates to a pharmaceutical composition according to the nineteenth embodiment, wherein A, B, C and D are alkyl.
  • the present invention relates to a pharmaceutical composition according to the seventeenth or eighteenth embodiments, wherein A, B, C and D are different.
  • the present invention relates to a pharmaceutical composition according to the twenty-first embodiment, wherein A, B and C are alkyl, and D is H.
  • the present invention relates to a pharmaceutical composition according to the seventeenth or eighteenth embodiments, wherein A and B are alkyl and C and D are H. In a twenty-fourth embodiment, the present invention relates to a pharmaceutical composition according to any one of the seventeenth to twenty-third embodiments, wherein p is 0 or 2.
  • the present invention relates to a pharmaceutical composition according to any one of the seventeenth to twenty-fourth embodiments, wherein the E is selected from:
  • the present invention relates to a pharmaceutical composition according to any one of the fourteenth to sixteenth embodiments, wherein E is:
  • the present invention relates to a pharmaceutical composition according to any one of the fourteenth to twenty-sixth embodiments, wherein the compound is selected from the group consisting of:
  • the present invention relates to a method of treating a neurodegenerative disorder in a patient including administration to the patient of an effective amount of a compound of formula (I):
  • each n is independently selected from 4 and 5; m is 2; and E is a vitamin E analogue or an edaravone analogue.
  • the present invention relates to a method according to the twenty-eight embodiment, wherein the administration is selected from parenteral or oral administration.
  • the present invention relates to a method according to the twenty-eight or twenty-ninth embodiment, wherein the neurodegenerative disorder is selected from Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, Friedreich's ataxia, and Multiple Sclerosis.
  • the neurodegenerative disorder is selected from Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, Friedreich's ataxia, and Multiple Sclerosis.
  • the present invention relates to a method according to any one of the twenty-eighth to thirtieth embodiments, wherein n is 5. In a thirty-second embodiment, the present invention relates to a method according to any one of the twenty-eighth to thirty-first embodiments, wherein E is: wherein:
  • A, B, C and D are independently selected from H and alkyl, and p is 0, 1 or 2.
  • the present invention relates to a method according to the thirty-second embodiment, wherein alkyl is Ci to C3 alkyl.
  • the present invention relates to a method according to the thirty-second or thirty-third embodiment, wherein A, B, C and D are the same.
  • the present invention relates to a method according to the thirty-fourth embodiment, wherein A, B, C and D are alkyl.
  • the present invention relates to a method according to the thirty second or thirty-third embodiment, wherein A, B, C and D are different.
  • the present invention relates to a method according to the thirty-sixth embodiment, wherein A, B and C are alkyl, and D is H.
  • the present invention relates to a method according to the thirty-second or thirty-third embodiment, wherein A and B are alkyl and C and D are H.
  • the present invention relates to a method according to any one of the thirty-second to thirty-eighth embodiments, wherein p is 0 or 2.
  • the present invention relates to a method according to any one of the thirty-second to thirty-ninth embodiments, wherein E is selected from:
  • the present invention relates to a method of any one of the twenty-eighth to thirty-first embodiments, wherein E is:
  • the present invention relates to a method according to any one of the twenty-eighth to forty-first embodiments, wherein the compound is selected from the group consisting of:
  • the present invention relates to a method according to any one of the twenty-eighth to forty-second embodiments, wherein the neurodegenerative disorder is associated with metal ion dyshomeostasis.
  • the present invention relates to a method according to the forty-third embodiment, wherein the neurodegenerative disorder is associated with accumulated brain iron.
  • FOB-(rac)-TLX In selective ion mode (SIM) a search for FOB-(rac)-TLX (m/z 845.5 [M- 3H+Fe(lll)+H] + ) was performed and the integrals derived from SIM for Fe(lll)-free and Fe(lll)-loaded analogues compared ( Figure 5).
  • FOB-(rac)-TLX constituted 1 .8% of the product.
  • the synthetic method used to prepare DFOB-(rac)-TLX was also used to prepare DFOB-(R)-TLX and DFOB-(S)-TLX, in which the (rac)-TLX reagent was replaced with the cognate reagents (R)-TLX, (S)-TLX.
  • Ascorbate autoxidises in aqueous solutions In the presence of Fe 3+ , this oxidation progresses significantly faster. In the presence of Fe 3+ and a metal chelator (e.g. DFOB or DFOB analogues), the oxidation process is reduced to a minimum.
  • the graphs in Figure 24 show that DFOB and its derivatives (DFOB-(rac)-TLX, DFOB-(R)-TLX, DFOB-(S)-TLX, DFOB-a-CEHC, DFOB-6-CEHC, DFOB-y-CEHC and DFOB-EDA) are effectively chelating iron and minimising ascorbate autoxidation.
  • DFOB-(rac)-TLX, DFOB-a- CEHC, DFOB-Y-CEHC, DFOB-5-CEHC showed plasma protein binding ranging between 86-97% (Table 1 ).
  • DFOB unbound fraction 86%) is rapidly cleared in the urine within minutes to an hour, as an additional factor that could compromise BBB uptake.
  • the higher degree of protein binding shown by DFOB-(rac)-TLX, DFOB-a-CEHC, DFOB-Y-CEHC, DFOB-5-CEHC (unbound fraction 3-24%) may increase circulation time to improve bioavailability and systemic distribution to support BBB uptake of the drug via passive mechanisms.
  • Table 1 Measurements of plasma protein binding, and antioxidant activity of DFOB, DFOB-(rac)-TLX, DFOB-(R)-TLX, DFOB-(S)-TLX, DFOB-a-CEHC, DFOB- ⁇ - CEHC, DFOB-5-CEHC, DFOB-EDA and standard compounds, as determined by ascorbic acid autoxidation and ABTS '+ assays.
  • Each of DFOB-(rac)-TLX, DFOB-(R)-TLX, DFOB-(S)-TLX, DFOB-a-CEHC, DFOB- ⁇ - CEHC, DFOB-5-CEHC, DFOB-EDA showed IC50 values similar to, or lower than, (rac)- TLX.
  • These data support an additive antiradical potential for conjugates DFOB-(rac)- TLX, DFOB-(R)-TLX, DFOB-(S)-TLX, DFOB-a-CEHC, DFOB-y-CEHC, DFOB-5-CEHC, DFOB-EDA, compared to the individual parent molecules (i.e. DFOB-(rac)-TLX compared to DFOB and (rac)-TLX), and support that the compounds had antioxidant activity ascribable to the ancillary fragment.
  • the neurotoxin MPTP which recapitulates aspects of Parkinson's disease (PD) including brain iron deposition, 2 was administered to the mice on day 1 and each compound (vehicle, DFOB, DFOB-AdAdMe, DFOB-(rac)-TLX) in diluent (distilled water containing 10% DMSO and 0.5% carboxymethylcellulose (CMC)) was administered by IP injection at a concentration of 40 ⁇ /kg once per day for 20 days post MPTP injection.
  • diluent distilled water containing 10% DMSO and 0.5% carboxymethylcellulose (CMC)
  • Each treatment group contained 15 mice.
  • the first phase of the study used the Pole test to measure the effect of the compounds on the speed of complex movements as the mouse equivalent to bradykinesia (slowness of movement) in people with PD.
  • 3 DFOB-(rac)-TLX significantly reduced the rotarod Turn Time (how long the mice take to turn around on the Pole), compared to vehicle and DFOB (see Figure 25). This correlates with an improvement in motor skills. 2
  • the compounds DFOB-(rac)-TLX and DFOB-AdA d Me were tested in the MPTP- mouse model of PD, which is a widely accepted animal model of PD that recapitulates iron deposition in the substantia nigra.
  • the compounds were administered (i.p.) daily (40 micromol/kg) for 20 days.
  • DFOB was also tested. On day 18-20, the Pole test was performed.
  • mice All mice were culled on day 21 and after appropriate processing, the substantia nigra was cut using a cryostat at 30 micrometers, and stained with 2% Neutral Red solution got 2.5 min and then re-hydrated and cover slipped. Neurons were counted using the Stereo Investigator program.
  • Administration of DFOB to the MPTP-lesioned mouse (40 ⁇ /kg/day for 20 days; i.p. commencing 24 h after the last MPTP injection) did not protect neuronal cells.
  • Administration of DFOB- AdA d e or DFOB-(rac)-TLX to the MPTP-lesioned mouse resulted in significant protection of neurons (up to 89% of the non-lesioned animals), demonstrating the neuroprotective potential of these compounds.

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Abstract

La présente invention concerne de nouveaux composés à base de desferrioxamine B qui peuvent être utilisés pour traiter des maladies neurodégénératives, leur préparation et des compositions comprenant ces composés. La présente invention concerne également l'utilisation de ces composés, ainsi que de compositions comprenant ces composés, pour le traitement de maladies neurodégénératives (par exemple la maladie de Parkinson).
PCT/AU2017/050491 2016-05-25 2017-05-25 Chélateurs de fer non toxiques à potentiel neuroprotecteur WO2017201581A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009055863A1 (fr) * 2007-11-01 2009-05-07 The University Of Sydney Conjugués de la desferrioxamine, dérivés et analogues
WO2015061630A2 (fr) * 2013-10-23 2015-04-30 Miller Marvin J Sidéromycines antibactériennes activées par réduction

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009055863A1 (fr) * 2007-11-01 2009-05-07 The University Of Sydney Conjugués de la desferrioxamine, dérivés et analogues
WO2015061630A2 (fr) * 2013-10-23 2015-04-30 Miller Marvin J Sidéromycines antibactériennes activées par réduction

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
GOTSBACHER, M. ET AL.: "Analogues of desferrioxamine B designed to attenuate iron- mediated neurodegeneration: synthesis, characterisation and activity in the MPTP- mouse model of Parkinson's disease", METALLOMICS, vol. 9, 2017, pages 852 - 864, XP055441139 *
IHNAT, P. ET AL.: "Synthesis and solution properties of deferoxamine amides", JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 89, no. 12, 2000, pages 1525 - 1536, XP008134135 *
LAN, J. ET AL.: "Desferrioxamine and vitamin E protect against iron and MPTP-induced neurodegeneration in mice", JOURNAL OF NEURAL TRANSMISSION, vol. 104, no. 4-5, 1997, pages 469 - 81, XP055441132 *
LIDDELL, J. ET AL.: "Lipophilic adamantyl- or deferasirox-based conjugates of desferrioxamine B have enhanced neuroprotective capacity: implications for Parkinson disease", FREE RADICAL BIOLOGY AND MEDICINE, vol. 60, 2013, pages 147 - 156, XP055408015 *
LIU, J. ET AL.: "Conjugates of Desferrioxamine B (DFOB) with Derivatives of Adamantane or with Orally Available Chelators as Potential Agents for Treating Iron Overload", JOURNAL OF MEDICINAL CHEMISTRY, vol. 53, 2010, pages 1370 - 1382, XP055034732 *
UNEY, J. ET AL.: "Changes in heat shock protein 70 and ubiquitin mRNA levels in C1300 N2A mouse neuroblastoma cells following treatment with iron", JOURNAL OF NEUROCHEMISTRY, vol. 60, no. 2, 1993, pages 659 - 665, XP055441137 *

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