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WO2017152237A1 - Nouveaux analogues de déféroxamine b (dfob) - Google Patents

Nouveaux analogues de déféroxamine b (dfob) Download PDF

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Publication number
WO2017152237A1
WO2017152237A1 PCT/AU2017/050215 AU2017050215W WO2017152237A1 WO 2017152237 A1 WO2017152237 A1 WO 2017152237A1 AU 2017050215 W AU2017050215 W AU 2017050215W WO 2017152237 A1 WO2017152237 A1 WO 2017152237A1
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Prior art keywords
compound
group
iron
substituted
compounds
Prior art date
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PCT/AU2017/050215
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English (en)
Inventor
Rachel Codd
Thomas James TELFER
Original Assignee
The University Of Sydney
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Publication date
Priority claimed from AU2016900904A external-priority patent/AU2016900904A0/en
Application filed by The University Of Sydney filed Critical The University Of Sydney
Publication of WO2017152237A1 publication Critical patent/WO2017152237A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
    • C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics

Definitions

  • the present invention relates to new desferrioxamine B-based compounds that are useful for iron-chelation therapy, 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 conditions of iron
  • dyshomeostasis such as iron overload
  • 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 growth.
  • the structure of DFOB (1 ) is given below.
  • 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.
  • Transfusion-dependent iron overload is the most common condition of metal toxicity worldwide, with the highest mortality. More generally, derangement of iron homeostasis leading to excessive iron intake and storage is deleterious to several tissues, and has been implicated in cardiac dysfunction and failure, liver dysfunction and cirrhosis, and endocrine abnormalities including hypothyroidism, hypogonadism, and diabetes mellitus.
  • DFOB is effective at removing iron from plasma and it is non-toxic.
  • the administration regimen of the drug is arduous, requiring slow sub-cutaneous infusion over 60 to 70 hours per week. This regimen is necessary due to the short plasma half- life of DFOB (10 to 15 minutes), which requires slow administration to maintain steady- state concentrations of the drug.
  • DFOB has a second shortcoming: it is inefficient at removing iron stored inside cells, which is problematic in the context of the accumulation of iron in major organs, including heart, liver and pancreas.
  • Two synthetic iron chelators desferasirox and deferiprone, are orally active, but have a lower iron binding affinity, are less selective towards iron and have some toxicities, compared to DFOB.
  • the present inventors have proposed that the issues with current agents used in iron- chelation therapy could be overcome by developing an agent that has improved pharmacokinetic properties. Specifically, the present inventors have sought to develop an agent that has a longer plasma half-life, is less prone to degradation by plasma amidases, and has an increased ability to cross cell membranes to access intracellular iron.
  • the present invention relates to a compound of formula (I):
  • each n is independently selected from 4 or 5; m is 2; and one or more of the CH2 groups are substituted with at least one fluorine atom.
  • the primary amine group can be subsequently converted using semi-synthetic reactions to an amide group, a secondary amine group or an azide group. Therefore, the primary amine group may be replaced with a group selected from an amide group, a secondary amine group and an azide group.
  • one CH2 group is substituted with at least one fluorine atom. In another embodiment, two CH2 groups are each substituted with at least one fluorine atom. In another embodiment, three CH2 groups are each substituted with at least one fluorine atom.
  • the present invention relates to 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.
  • a pharmaceutically acceptable carrier diluent or excipient.
  • Compounds and pharmaceutical compositions according to the present invention may be suitable for iron chelation therapy.
  • the present invention relates to a method of treating a condition of iron dyshomeostasis 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 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 condition of iron dyshomeostasis.
  • the present invention relates to the use 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 condition of iron
  • the present invention relates to 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 condition of iron
  • the condition of iron dyshomeostasis may be selected from primary iron overload and secondary iron overload.
  • 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.
  • the present invention relates to a process for making a compound of formula (I) according to the first aspect of the invention, the process including:
  • the fluorinated diamine substrate may be selected from 1 ,4-diamino-2-fluorobutane, or a 1 ,4-diaminobutane or 1 ,5-diaminopentane substituted with at least one fluorine atom, or a salt thereof.
  • the 1 ,4-diamino-2-fluorobutane may be a racemic mixture (i.e. rac-1 ,4-diamino-2- fluorobutane), (R)-1 ,4-diamino-2-fluorobutane or (S)-1 ,4-diamino-2-fluorobutane.
  • the salt may be a hydrochloride salt (e.g. 1 ,4-diamino-2-fluorobutane.2HCI).
  • the concentration of the fluorinated diamine substrate may be about 35 mM or less.
  • the medium may include a further compound that inhibits production of 1 ,4- diaminobutane and/or 1 ,5-diaminopentane.
  • FIG. 1 LC trace with total ion current (TIC) detection mode from semi-purified supernatant of S. pilosus cultured in: (a) base medium, or (b) medium supplemented with rac-1 ,4-diamino-2-fluorobutane (rac-DFB), analyzed as isolated or Fe(lll)-loaded solutions of the base medium system (c) or the rac-DFB supplemented system (d).
  • the gradient in (a) or (c) was the same in (b) or (d), respectively. Peak numbering refers to the structures of the compounds 1 -4 or the equivalent 1 : 1 complexes formed with Fe(lll) (number underlined).
  • Figure 3 The production of iron-binding compounds over time (monitored using an Fe(lll) addition assay) using as a substrate the racemic form, as well as the (R)- and (SJ-isomers, of 1 ,4-diamino-2-fluorobutane to supplement a S. pilosus bacteriological medium.
  • a recited compound is not limited to any one specific tautomer, but rather is intended to encompass all tautomeric forms.
  • Compounds according to the formula provided herein, which have one or more stereogenic centres 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%. It will be apparent that single enantiomers (optically active forms) can be obtained by asymmetric synthesis, synthesis from optically pure precursors,
  • 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 bind iron, and that do not adversely affect the ability of the compound to cross cell membranes to access intracellular iron.
  • Such salts include mineral and organic acid salts of basic residues such as amines.
  • 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
  • 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.
  • prodrugs examples 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 "substituent” as used herein refers to a molecular moiety that is covalently bonded to an atom within a molecule of interest.
  • 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). Particularly preferred is fluorine.
  • 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. In other words, 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.
  • each n is independently selected from 4 or 5; m is 2; and one or more of the CH 2 groups are substituted with at least one fluorine atom.
  • the primary amine group can be subsequently converted using semi-synthetic reactions to an amide group, a secondary amine group or an azide group. Therefore, in the compound of formula (I), the primary amine group may be replaced with a group selected from an amide group, a secondary amine group and an azide group.
  • one, two or three CH 2 groups may be substituted with at least one fluorine atom.
  • one set of CH 2 groups may be substituted with at least one fluorine atom (e.g. as shown in compound 2 below)
  • two sets of CH 2 groups may be substituted with at least one fluorine atom (e.g. as shown in compound 3 below)
  • three sets of CH 2 groups may be substituted with at least one fluorine atom (e.g. as shown in compound 4 below).
  • the compounds of the present invention can be synthesised by any suitable method known to a person skilled in the art.
  • the present inventors have found that precursor- directed biosynthesis can be used to produce the compounds of the present invention. Briefly, a fluorinated diamine substrate (such as 1 ,4-diamino-2-fluorobutane) is introduced into bacteriological medium inoculated with S. pilosus, or another
  • the present invention also relates to a process for making a compound of formula (I):
  • each n is independently selected from 4 or 5; m is 2; and one or more of the CH 2 groups are substituted with at least one fluorine atom, the process including:
  • the fluorinated diamine substrate may be selected from 1 ,4-diamino-2-fluorobutane, or a 1 ,4-diaminobutane or 1 ,5-diaminopentane substituted with one or more fluorine atoms, or a salt thereof.
  • the fluorine atom(s) may be, for example, substituted on any of the two internal CH 2 groups penultimate to the amine groups of the 1 ,4-diaminobutane, or the three internal CH 2 groups penultimate to the amine groups of the 1 ,5- diaminopentane.
  • suitable fluorinated diamine substrates include the following:
  • the 1 ,4-diamino-2-fluorobutane (or any of the other fluorinated diamine substrates) may be used as a racemic mixture (e.g. rac-1 ,4-diamino-2-fluorobutane), as a mixture of enantiomers, or in optically-pure form (e.g. as (R)A ,4-diamino-2-fluorobutane or SJ-1 ,4- diamino-2-fluorobutane).
  • the salt may be a hydrochloride salt (e.g. 1 ,4-diamino-2- fluorobutane.2HCI), or a hydrobromide salt.
  • the concentration of the fluorinated diamine substrate may be about 35 mM or less.
  • Native substrates that are used by S. pilosus to prepare DFOB include 1 ,5- diaminopentane and 1 ,4-diaminobutane. These substrates are produced by the bacterium itself. It may be desirable in the process of the present invention to provide 1 ,5- diaminopentane and 1 ,4-diaminobutane. These substrates are produced by the bacterium itself. It may be desirable in the process of the present invention to
  • the medium may therefore, for example, include a fluorinated diamine substrate (which is intended to be incorporated into the final product) and may also include a compound that inhibits the production of the native diamine substrate.
  • a fluorinated diamine substrate which is intended to be incorporated into the final product
  • a compound that inhibits the production of the native diamine substrate under these conditions, it would be expected that, since the bacterium has a reduced supply of the native substrate, it would be effectively forced to use whatever substrate is available (i.e. the fluorinated diamine substrate). This would lead to an increase in the yield of the fluorinated DFOB derivative.
  • suitable inhibitors include 1 ,4- diamino-2-butanone and 5-hydroxylysine.
  • exogenous compounds in the medium may be about 35 mM or less.
  • concentration used will vary as a function of the culture conditions.
  • the process may also include the further step of converting the primary amine group to a group selected from an amide group, a secondary amine group and an azide group.
  • a person skilled in the art will be aware of suitable methods for carrying out these conversions.
  • the present inventors hypothesise that the compounds of the present invention may have increased plasma protein binding, which in turn may increase the plasma half-life time of the compounds in the body, thereby reducing administration time.
  • the compounds of the present invention may out-perform DFOB on the measure of accessing intracellular iron, due to the reduction in the p a value of the terminal amine group of the compounds of the present invention that arises from the electron
  • a reduced p a value translates to a higher proportion of drug present at physiological pH in neutral form, which is required for the effective passage across cell membranes.
  • an attenuation of plasma degradation may arise due to the presence of the fluorine group proximal to the terminal amine (the region where degradation is thought to be initiated) and/or near the amide bonds for amidase-mediated degradation.
  • compositions are within the scope of the present invention. Accordingly, the present invention also relates to a
  • composition including a compound of formula (I):
  • n is independently selected from 4 or 5; m is 2; and one or more of the CH 2 groups are substituted with at least one fluorine atom, 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,
  • compositions may be formulated for any appropriate route of
  • parenteral 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.
  • tablets, troches, lozenges aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • aqueous or oily suspensions dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • one or more compounds may be combined with a sterile aqueous solution which is preferably isotonic with the blood of the recipient.
  • 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. Examples of suitable components are described in Martindale - The Extra Pharmacopoeia
  • 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
  • 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 level of iron burden in the patient.
  • the patient may have a toxic amount of iron in their body as a result of a hereditary or primary hemochromatosis ("primary iron overload"). Iron overload in this condition results from increased intestinal iron absorption and a further derangement of iron metabolism, which occur as a result of a genetic mutation.
  • the patient may have a toxic amount of iron in their body as a result of high parenteral iron administration ("secondary iron overload”), which is primarily observed in association with transfusion-dependent hereditary or acquired anaemias, or other transfusion-dependent conditions (such as chronic liver disease, Friedreich ataxia, aceruloplasminaemia, and congenital atransferrinaemia).
  • Hereditary anaemias include inherited hemoglobinopathies (e.g. beta-thalassaemia and sickle cell disease), Blackfan-Diamond anaemia, congenital dyserythropoiesis anaemia, and sideroplastic anaemia.
  • Acquired anaemias include myelodysplastic syndromes, myelofibrosis, aplastic anaemia, leukaemia, myeloproliferative disorders, stem cell transplantation, and chronic kidney disease. Increased dietary intake of iron may also contribute, or lead, to secondary iron overload.
  • the terms "therapeutically effective amount” or “effective amount” refer to an amount of the compound of formula (I) that results in an improvement or remediation of the symptoms of iron overload.
  • the 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 cell membrane permeability, such that the preferred oral dosage forms discussed above can provide therapeutically effective levels of the compound in vivo.
  • 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 a condition of iron dyshomeostasis.
  • the terms “treating”, “treatment” and “therapy” are used herein to refer to curative therapy. Therefore, in the context of the present disclosure, the term “treating” encompasses curing and ameliorating the severity of iron overload or its associated symptoms.
  • 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.
  • compositions according to the present invention may be suitable for iron chelation therapy. Accordingly, the present invention also relates to a method of treating a condition of iron dyshomeostasis in a patient including
  • 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 condition of iron dyshomeostasis.
  • the present invention also provides a pharmaceutical composition for use in treating a condition of iron dyshomeostasis, 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 condition of iron dyshomeostasis.
  • 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 condition of iron dyshomeostasis.
  • the present invention also relates to a composition having an active ingredient for use in treating a condition of iron dyshomeostasis, 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 condition of iron dyshomeostasis, such as described above.
  • the compound of formula (I) is essentially the only active ingredient of the composition.
  • the condition of iron dyshomeostasis is primary or secondary iron overload.
  • the compounds may be administered in combination with other agents, for example, deferasirox, deferiprone and Desferal.
  • the invention therefore provides, but is not limited to, the following embodiments:
  • each n is independently selected from 4 or 5; m is 2; and one or more of the CH 2 groups are substituted with at least one fluorine atom.
  • the fluorine atoms may be in various substitution patterns such as mono, vicinal and geminal. In one embodiment, the fluorine atoms are vicinal. In another embodiment, the fluorine atoms are geminal.
  • each n is independently selected from 4 or 5; m is 2; and one or more of the CH 2 groups are substituted with at least one fluorine atom, the process including:
  • the fiuorinated diamine substrate is selected from 1 ,4-diamino-2-fluorobutane, or a 1 ,4-diaminobutane or 1 ,5- diaminopentane substituted with one or more fluorine atoms, or a salt thereof.
  • a pharmaceutical composition including a compound of formula (I):
  • each n is independently selected from 4 or 5; m is 2; and one or more of the CH 2 groups are substituted with at least one fluorine atom, together with a pharmaceutically acceptable carrier, diluent or excipient.
  • composition of embodiment 17, wherein the composition is suitable for parenteral or oral administration.
  • each n is independently selected from 4 or 5; m is 2; and one or more of the CH 2 groups are substituted with at least one fluorine atom.
  • a pre-culture was established by adding an aliquot of a S. pilosus permanent to a 250- ml_ Erienmeyer flask filled with standard treated media (50 mL). This was shaken at 160 rpm and 28 °C for 96 h. The bacteria was withdrawn, spun down on a centrifuge, the supernatant was removed and replaced with fresh media, and were re-suspended before further use.
  • the following enriched medium was prepared that contained per 50 mL: YM broth (2.1 %), KH 2 P0 4 .3H 2 0 (235 mM), Na 2 HP0 4 (1 1 .6 mM), MgS0 4 .7H 2 0 (2.43 mM), CaCI 2 (13.6 mM), ZnS0 4 .7H 2 0 (13.9 ⁇ ), trizma base (35.0 mM), and threonine (0.84 mM).
  • the enriched medium has been optimized for DFOB production.
  • the bacteria were split evenly between two cultures (50 mL) in 250 mL Erienmeyer flasks under the following conditions: enriched media control and racA ,4-diamino-2-fluorobutane.2HCI (10 mM, rac-DFB).
  • the specific conditions were achieved by adding a concentrated, pH adjusted, syringe filtered standard solution of substrate to the media before bacteria addition.
  • the bacteria were shaken at 160 rpm and 28 °C for 8 days, taking 700 ⁇ aliquots of media from each culture on each day. A ferric assay was performed on these aliquot. After the 8 day growth cycle, the bacteria from each culture were collected and were lyophilised to dryness to approximate the bacterial load from each culture. The extracts were purified using conditions described previously. 2 Iron chelation
  • Extracts were analysed using liquid chromatography-mass spectrometry (LC-MS) as described previously. 2 Compared to the native system ( Figure 1 (a)), the extract from the DFB-supplemented system ( Figure 1 (b)) showed signals in the LC that analysed using MS as the fluorinated derivatives 2-4. Compounds were identified from MS patterns that represented the target fluorinated compounds ( Figure 2). These compounds retained function as Fe(lll) chelating molecules ( Figure 3), as shown from analysis in the presence of added Fe(lll). The compounds are racemic mixtures.
  • LC-MS liquid chromatography-mass spectrometry

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Abstract

La présente invention concerne de nouveaux composés à base de déféroxamine B qui sont utilisés pour le traitement par chélation du fer, leur préparation et des compositions comprenant les composés. La présente invention concerne également l'utilisation de ces composés, ainsi que de compositions comprenant ces composés, pour le traitement d'affections liées au dysfonctionnement de l'homéostasie du fer.
PCT/AU2017/050215 2016-03-10 2017-03-10 Nouveaux analogues de déféroxamine b (dfob) WO2017152237A1 (fr)

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AU2016900904A AU2016900904A0 (en) 2016-03-10 Novel analogues of Desferrioxamine B (DFOB)
AU2016900904 2016-03-10

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008116301A1 (fr) * 2007-03-28 2008-10-02 Apotex Technologies Inc. Dérivés fluorés de défériprone
WO2009055863A1 (fr) * 2007-11-01 2009-05-07 The University Of Sydney Conjugués de la desferrioxamine, dérivés et analogues

Patent Citations (2)

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