WO2024073125A2 - Dérivés de hinokitiol deutérés - Google Patents

Dérivés de hinokitiol deutérés Download PDF

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WO2024073125A2
WO2024073125A2 PCT/US2023/034258 US2023034258W WO2024073125A2 WO 2024073125 A2 WO2024073125 A2 WO 2024073125A2 US 2023034258 W US2023034258 W US 2023034258W WO 2024073125 A2 WO2024073125 A2 WO 2024073125A2
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compound
group
alkyl
cycloalkyl
iron
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Martin D. Burke
Andrew D. BLAKE
Christopher Kolste RAKOWSKI
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The Board Of Trustees Of The University Of Illinois
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/10—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/12—Radicals substituted by oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/703—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups
    • C07C49/717—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups a keto group being part of a seven- to twelve-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/703—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups
    • C07C49/723—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups polycyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/753—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/04—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D309/06—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/18—Systems containing only non-condensed rings with a ring being at least seven-membered

Definitions

  • Hinokitiol a small molecule natural product, has been shown to promote transmembrane iron mobilization by reversibly forming a 3:1 complex with iron. Hinokitiol restores iron homeostasis in a range of different model systems, including divalent metal transporter 1 (DMT1-), mitoferrin 1 (MFRN1-), and ferroportin 1 (FPN1-) deficient cells and animals. Hinokitiol, which is it itself not inherently site- or direction-selective, achieves site- and direction-selective mobilization of iron by leveraging the electrochemical gradient that forms in the absence of iron transport protein function.
  • DMT1- divalent metal transporter 1
  • MFRN1- mitoferrin 1
  • FPN1- ferroportin 1
  • hinokitiol There is, however, a key limitation of hinokitiol, which diminishes its potential for clinical translation.
  • hinokitiol effectively mobilizes iron at low-to-intermediate concentrations, but at higher concentrations, a substantial decrease in transmembrane mobilizing activity was observed.
  • a series of studies was conducted to identify derivatives of hinokitiol, such as those disclosed herein, which mobilize iron over a much wider range of concentrations in vitro. These compounds also mobilize iron and can treat anemia of inflammation in vivo.
  • Deuterium is an isotope of hydrogen which includes a neutron in the nucleus, doubling the atomic weight. This lowers the zero-point energy and decreases the van der Waals radii of deuterated compounds relative to their hydrogenated counterparts.
  • literature concerning the effect of deuteration of pharmaceuticals mostly focuses on harnessing the kinetic isotope effect to improve the pharmacokinetic profile of a drug. Some studies on deuterated materials have reported alterations in boiling point, dimerization behavior, among others. Few, if any, systematic studies exist which explain the relationship between deuteration and altered biophysical behavior of a pharmaceutical agent. Thus, it was unclear whether deuteration would have any impact on this aggregation phenomena, and it was further uncertain whether any impact would be positive or negative. Using substituted tropolones, it was discovered that deuteration of the side chains of tropolonoids can increase both potency and tolerability, thereby improving their potential to act as molecular prosthetics for metal ion transporters.
  • R 1 is selected from the group consisting of H, C 1 -C 5 alkyl, cycloalkyl, heterocycloalkyl, - O-C 1 -C 5 alkyl, -O-cycloalkyl, and -O-heterocycloalkyl;
  • R 2 is selected from the group consisting of H, C 1 -C 5 alkyl, cycloalkyl, heterocycloalkyl, - O-C 1 -C 5 alkyl, -O-cycloalkyl, and -O-heterocycloalkyl;
  • R 3 is selected from the group consisting of H, C 1 -C 5 alkyl, cycloalkyl, heterocycloalkyl, - O-C 1 -C 5 alkyl, -O-cycloalkyl, and -O-heterocycloalkyl;
  • R 4 is selected from the group consisting of H, C 1 -C 5 alkyl, cycloalkyl, heterocycloalkyl, - O-C 1 -C 5 alkyl, -O-cycloalkyl, and -O-heterocycloalkyl;
  • R 5 is selected from the group consisting of H, halo, C 1 -C 5 alkyl, cycloalkyl, heterocycloalkyl, -O-C 1 -C 5 alkyl, -O-cycloalkyl, and -O-heterocycloalkyl; wherein when R 1 , R 2 , R 3 , R 4 , or R 5 is C 1 -C 5 alkyl, cycloalkyl, heterocycloalkyl, -O-C 1 - C 5 alkyl, -O-cycloalkyl, or -O-heterocycloalkyl, at least one hydrogen atom in said C 1 -C 5 alkyl, cycloalkyl, heterocycloalkyl, -O-C 1 -C 5 alkyl, -O-cycloalkyl, or -O-heterocycloalkyl is replaced with a deuterium atom; and wherein at least one of R 1 ,
  • compositions comprising a compound of the disclosure, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier or excipient.
  • provided herein are methods of treating a disease or condition characterized by decreased ferroportin, comprising administering to a subject in need thereof a therapeutically effective amount of a compound or pharmaceutical composition of the disclosure.
  • provided herein are methods of treating a disease or condition characterized by decreased iron transport, comprising administering to a subject in need thereof a therapeutically effective amount of a compound or pharmaceutical composition of the disclosure.
  • provided herein are methods of treating a disease or condition characterized by a defect or deficiency in an iron transporter, comprising administering to a subject in need thereof a therapeutically effective amount of a compound or pharmaceutical composition of the disclosure.
  • provided herein are methods of treating a disease or condition characterized by iron accumulation, comprising administering to a subject in need thereof a therapeutically effective amount of a compound or pharmaceutical composition of the disclosure.
  • provided herein are methods of treating a disease or condition characterized by iron misdistribution, comprising administering to a subject in need thereof a therapeutically effective amount of a compound or pharmaceutical composition of the disclosure.
  • provided herein are methods of treating a neurodegenerative disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound or pharmaceutical composition of the disclosure.
  • Fig. 1 depicts a general synthetic scheme for accessing deuterated tropolone derivatives.
  • Fig. 2A depicts data for an evaluation of methyl-do and methyl-d 3 tropolones. Iron mobilized by deuterated derivatives increases at low concentrations, and remains high at extreme concentrations.
  • Fig. 2B depicts data for an evaluation of methyl-do and methyl-d 3 tropolones. Deuterated derivatives are significantly better tolerated in H9C2 cells.
  • Fig. 2C depicts data for an evaluation of methyl-do and methyl-d 3 tropolones. Deuterated derivatives are better tolerated in K562 cells.
  • Fig. 3A depicts results of treatment of fpn-1.2KO C. elegans with various compounds for neurodegeneration scoring and iron level measurement: Treatment scheme of fpn- 1.2KO;Pdat::GFP worms treated with various concentrations of DFP, Hino, and AMB-1269. Dopaminergic neurodegeneration was scored blinded by phenotypic analyses (below).
  • Fig. 3B depicts dopaminergic neurodegeneration scoring of fpn-1.2KO worms treated with DFP.
  • Fig. 3C depicts dopaminergic neurodegeneration scoring of fpn-1.2KO worms treated with Hino.
  • Fig. 3D depicts dopaminergic neurodegeneration scoring of fpn-1.2KO worms treated with FeM-1269.
  • Fig. 3E depicts a Treatment scheme of fpn-1.2KO;Pftn-l::GFP worms treated with various concentrations of DFP, Hino, and FeM-1269.
  • ASI neurons (below) which expresses GFP-tagged ferritin levels.
  • Fig. 3F depicts Fluorescence levels of fpn-1.2KO worms treated with DFP. * P ⁇ 0.05, ** P ⁇ 0.01, *** P ⁇ 0.001, and **** P ⁇ 0.0001 by one-way ANOVA.
  • FIG. 3G depicts Fluorescence levels of fpn-1.2KO worms treated with Hino. * P ⁇ 0.05, ** P ⁇ 0.01, *** P ⁇ 0.001, and **** P ⁇ 0.0001 by one-way ANOVA.
  • Fig. 3H depicts Fluorescence levels of fpn-1.2KO worms treated with FeM-1269. * P ⁇ 0.05, ** p ⁇ 0.01, *** P ⁇ 0.001, and **** P ⁇ 0.0001 by one-way ANOVA.
  • Fig. 4A depicts data from flatiron mice experiments: Flatiron mice display increased anxiety and reduced exploratory activity. WT and flatiron mice were subjected to elevated plus maze task for assessment of anxiety-like behavior, including total distance traveled in whole maze and average velocity.
  • Fig. 4B depicts data from flatiron mice experiments: Flatiron mice display increased anxiety and reduced exploratory activity. WT and flatiron mice were subjected to elevated plus maze task for assessment of anxiety-like behavior, including time spent in open arms and center zone.
  • Fig. 4C depicts data from flatiron mice experiments: Flatiron mice display increased anxiety and reduced exploratory activity. WT and flatiron mice were subjected to elevated plus maze task for assessment of anxiety-like behavior, including rearing frequency and duration. * P ⁇ 0.05 by Student’s t-test.
  • Fig. 4D depicts ICP-MS measurement of brain iron level in flatiron mice after acute treatment of Hino through intraperitoneal (IP) injection. ** P ⁇ 0.01, *** P ⁇ 0.001 by one-way ANOVA.
  • Fig. 4E depicts ICP-MS measurement of brain iron level in flatiron mice after chronic treatment of Hino through intraperitoneal (IP) injection. ** P ⁇ 0.01, *** P ⁇ 0.001 by one-way ANOVA.
  • Fig. 5 depicts crystallographic data showing hinokitiol forms a 3: 1 complex with Fe(III) for transmembrane mobilization.
  • Hinokitiol in crystal packing structure holds isopropyl sidechains from neighboring complexes in proximity.
  • Fig. 6 depicts a schematic showing deuteration is hypothesized to reduce intercomplex van der Waals interactions, restoring transport ability at higher concentrations for pro- aggregative derivatives.
  • Fig. 7A depicts cell-free iron efflux data showing per-deuteration of hinokitiol promotes higher concentration transport similar to that observed with 3,5,7-tri-methyl tropolone.
  • Fig. 7B depicts dynamic light scattering data showing per-deuteration of hinokitiol reduces aggregation.
  • Fig. 8A depicts crystallographic data for hinokitiol showing isopropyl-isopropyl interaction.
  • Fig. 8B depicts cell-free iron efflux data showing per-deuteration of isopropyl isomer GT does not influence transport at higher concentrations, consistent with limited specific isopropylisopropyl interaction seen in crystal structure.
  • Fig. 9A depicts dynamic light scattering data (deflected count) showing per-deuteration of methyl sidechains does not significantly affect aggregation due to lack of discrete interaction and limited aggregation of the protio parent compound.
  • Fig. 9B depicts dynamic light scattering data (average size) showing per-deuteration of methyl sidechains does not significantly affect aggregation due to lack of discrete interaction and limited aggregation of the protio parent compound.
  • Fig. 10A depicts cell-free iron efflux data showing similar iron mobilization capacity between 3-methyltropolone and 3-methyl-(d3)-tropolone.
  • Fig. 10B depicts cell-free iron efflux data showing similar iron mobilization capacity between 4-methyltropolone and 4-methyl-(d3)-tropolone.
  • Fig. IOC depicts cell-free iron efflux data showing similar iron mobilization capacity between 5-methyltropolone and 5-methyl-(d3)-tropolone.
  • Fig. 10D depicts cell-free iron efflux data showing similar iron mobilization capacity between 3,5-dimethyltropolone and 3,5-dimethyl-(d6)-tropolone.
  • Fig. 11 depicts cell-free iron efflux data showing per-deuteration extends transport window of pro-aggregative 4- «-buytl-(d9)-tropolone compared to 4-n-buytltropolone.
  • Iron is biologically essential, but also potentially toxic; as such it is tightly controlled at cell and systemic levels to prevent both deficiency and overload. Iron overload can manifest in two primary ways: (1) an excess of iron in circulation, and (2) an accumulation of iron in tissues. The latter may also be referred to as iron misdistribution or maldistribution. Iron chelators treat iron overload and enhance iron excretion by binding to iron in the blood, decreasing the amount of iron in circulation. Iron mobilizers pull iron out of tissues, and can therefore redistribute iron from sites of accumulation to sites of deficiency. Such iron mobilizers can collaborate with iron- binding proteins to restore normal iron physiology. Current treatments primarily address excess iron in the blood.
  • Hinokitiol ⁇ -thuj adjin
  • Hinokitiol ⁇ -thuj adjin
  • hinokitiol is predisposed at higher concentrations to form higher- order aggregates, limiting the efficacious mobilization range.
  • the P-substituted isopropyl group of adjacent complexes is proposed to promote aggregation through proximity -driven attractive van der Waals interactions. Reduction of these interactions whilst maintaining adequate lipophilicity for transmembrane mobilization will generally increase mobilization efficacy range, as observed in synthetic design principles for new tropolone derivatives.
  • these new derivatives are usually structurally distinct from aggregative compounds, with no alternative modification means to transition an aggregative compound into one that has a lessened tendency to aggregate but holds the same structural design.
  • KIE Kinetic Isotope Effect
  • hinokitiol-d7 was synthesized utilizing a Negishi coupling of 2-iodopropane-d7 to a modular bromotropolone scaffold.
  • Hinokitiol was utilized as a highly aggregative standard, with hinokitiol-d7 the comparison isotopomer containing a perdeuterated isopropyl sidechain.
  • hinokitiol-d7 had significantly greater iron transport capability at higher concentrations (50-150 pM) when compared to hinokitiol, which begins to aggregate.
  • 4nBu has a shortened effective transmembrane mobilization concentration range due to higher order aggregation, ceasing noticeable transport at 40 pM of compound.
  • 4nBu-d9 similarly to Hinokitiol-d7, maintains transport levels at concentrations when the parent compound suffers from limiting higher order aggregation.
  • further primary alkyl derivatives may be synthesized utilizing commercial per-deuterated halides that are transformed to the corresponding boronic acid through Grignard-promoted addition of trimethyl borane and then utilized in Suzuki-Miyaura cross coupling to the bromotropolone scaffolds.
  • the present disclosure is based on the surprising discovery that deuteration of the side chains of tropolonoids can increase both potency and tolerability, thereby improving their potential to act as molecular prosthetics for metal ion transporters.
  • the compounds of the disclosure are useful for treating diseases caused by iron misdistribution.
  • organic moiety refers to a singly-valent group containing one or more carbon atoms.
  • the organic moiety may be aromatic or may be derived from a hydrocarbon.
  • the organic moiety may comprise one or more heteroatoms, one or more units of unsaturation, and/or one or more functional groups.
  • the organic moiety may be substituted.
  • alkyl as used herein is a term of art and refers to saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups.
  • a straight-chain or branched-chain alkyl has about 30 or fewer carbon atoms in its backbone (e.g., C 1 -C 30 for straight chain, C 3 -C 30 for branched chain), and alternatively, about 20 or fewer, or 10 or fewer.
  • the term “alkyl” refers to a C 1 -C 10 alkyl group.
  • alkyl refers to a C 1 -C 6 alkyl group, for example a C 1 -C 6 straight-chain alkyl group. In certain embodiments, the term “alkyl” refers to a C 3 -C 12 branched- chain alkyl group. In certain embodiments, the term “alkyl” refers to a C 3 -C 8 branched-chain alkyl group.
  • alkyl include, but are not limited to, methyl, ethyl, n- propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and n- hexyl.
  • cycloalkyl means mono- or bicyclic or bridged saturated carbocyclic rings, each having from 3 to 12 carbon atoms. Certain cycloalkyls have from 5-12 carbon atoms in their ring structure, and may have 6-10 carbons in the ring structure. Preferably, cycloalkyl is (C 3 -C 7 )cycloalkyl, which represents a monocyclic saturated carbocyclic ring, having from 3 to 7 carbon atoms.
  • Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.
  • Bicyclic cycloalkyl ring systems include bridged monocyclic rings and fused bicyclic rings.
  • Bridged monocyclic rings contain a monocyclic cycloalkyl ring where two non-adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of between one and three additional carbon atoms (i.e., a bridging group of the form -(CH 2 ) W -, where w is 1, 2, or 3).
  • bicyclic ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane.
  • Fused bicyclic cycloalkyl ring systems contain a monocyclic cycloalkyl ring fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl.
  • the bridged or fused bicyclic cycloalkyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkyl ring.
  • Cycloalkyl groups are optionally substituted.
  • the fused bicyclic cycloalkyl is a 5 or 6 membered monocyclic cycloalkyl ring fused to either a phenyl ring, a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, a 5 or 6 membered monocyclic heterocyclyl, or a 5 or 6 membered monocyclic heteroaryl, wherein the fused bicyclic cycloalkyl is optionally substituted.
  • (cycloalkyl)alkyl refers to an alkyl group substituted with one or more cycloalkyl groups.
  • An example of (cycloalkyl)alkyl is cyclohexylmethyl group.
  • heterocycloalkyl refers to a radical of a non-aromatic ring system, including, but not limited to, monocyclic, bicyclic, and tricyclic rings, which can be completely saturated or which can contain one or more units of unsaturation, for the avoidance of doubt, the degree of unsaturation does not result in an aromatic ring system, and having 3 to 12 atoms including at least one heteroatom, such as nitrogen, oxygen, or sulfur.
  • heterocyclic rings aziridinyl, azirinyl, oxiranyl, thiiranyl, thiirenyl, dioxiranyl, diazirinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, azetyl, oxetanyl, oxetyl, thietanyl, thietyl, diazetidinyl, dioxetanyl, dioxetenyl, dithietanyl, dithietyl, dioxalanyl, ox
  • heterocycloalkylalkyl refers to an alkyl group substituted with one or more heterocycloalkyl (i.e., heterocyclyl) groups.
  • alkenyl as used herein means a straight or branched chain hydrocarbon radical containing from 2 to 10 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens.
  • Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2- heptenyl, 2-methyl-l -heptenyl, and 3-decenyl.
  • the unsaturated bond(s) of the alkenyl group can be located anywhere in the moiety and can have either the (Z) or the (E) configuration about the double bond(s).
  • alkynyl as used herein means a straight or branched chain hydrocarbon radical containing from 2 to 10 carbon atoms and containing at least one carbon-carbon triple bond.
  • Representative examples of alkynyl include, but are not limited, to acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.
  • alkylene is art-recognized, and as used herein pertains to a diradical obtained by removing two hydrogen atoms of an alkyl group, as defined above.
  • an alkylene refers to a disubstituted alkane, i.e., an alkane substituted at two positions with substituents such as halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, fluoroalkyl (such as trifluromethyl), cyano, or the like
  • amino is a term of art and as used herein refers to both unsubstituted and substituted amines, e.g., a moiety that may be represented by the general formulas: wherein R a , R b , and R c each independently represent a hydrogen, an alkyl, an alkenyl, -(CH 2 ) X - R d , or R a and R b , taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure; Rd represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocyclyl or a polycyclyl; and x is zero or an integer in the range of 1 to 8.
  • R a or R b may be a carbonyl, e.g., R a , R b , and the nitrogen together do not form an imide.
  • R a and R b each independently represent a hydrogen, an alkyl, an alkenyl, or -(CH 2 ) X -Rd.
  • the term “amino” refers to -NH 2 .
  • alkylamino refers to -NH(alkyl).
  • dialkylamino refers to -N(alkyl) 2 .
  • acyl is a term of art and as used herein refers to any group or radical of the form RCO- where R is any organic group, e.g., alkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl.
  • R is any organic group, e.g., alkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl.
  • Representative acyl groups include acetyl, benzoyl, and malonyl.
  • aminoalkyl refers to an alkyl group substituted with one or more one amino groups. In one embodiment, the term “aminoalkyl” refers to an aminomethyl group.
  • aminoacyl is a term of art and as used herein refers to an acyl group substituted with one or more amino groups.
  • aminothionyl refers to an analog of an aminoacyl in which the O of RC(O)- has been replaced by sulfur, hence is of the form RC(S)-.
  • phosphoryl is a term of art and as used herein may in general be represented by the formula: wherein Q50 represents S or O, and R59 represents hydrogen, a lower alkyl or an aryl; for example, -P(O)(OMe)- or -P(O)(OH) 2 .
  • the phosphoryl group of the phosphorylalkyl may be represented by the general formulas: wherein Q50 and R59, each independently, are defined above, and Q51 represents O, S or N; for example, -O-P(O)(OH)OMe or -NH-P(0)(0H) 2 .
  • Q50 is S
  • the phosphoryl moiety is a “phosphorothioate. ”
  • aminophosphoryl refers to a phosphoryl group substituted with at least one amino group, as defined herein; for example, -P(0)(0H)NMe 2 .
  • azide or “azido”, as used herein, means an -N 3 group.
  • alkylphosphoryl refers to a phosphoryl group substituted with at least one alkyl group, as defined herein; for example, -P(O)(OH)Me.
  • alkylthio refers to alkyl-S-.
  • (alkylthio)alkyl refers to an alkyl group substituted by an alkylthio group.
  • aryl is a term of art and as used herein refers to includes monocyclic, bicyclic and polycyclic aromatic hydrocarbon groups, for example, benzene, naphthalene, anthracene, and pyrene. Typically, an aryl group contains from 6-10 carbon ring atoms (i.e. , (C 6 -Cio)aryl).
  • the aromatic ring may be substituted at one or more ring positions with one or more substituents, such as halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, fluoroalkyl (such as trifluromethyl), cyano, or the like.
  • substituents such as halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, im
  • aryl also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are “fused rings”) wherein at least one of the rings is an aromatic hydrocarbon, e.g., the other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • the term “aryl” refers to a phenyl group.
  • arylene means a diradical obtained by removing two hydrogen atoms of an aryl group, as defined above.
  • an arylene refers to a disubstituted arene, i.e., an arene substituted at two positions with substituents such as halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, fluoroalkyl (such as trifluoromethyl), cyano, or the like. That is, in certain embodiments, a “substituted arene
  • heteroaryl is a term of art and as used herein refers to a monocyclic, bicyclic, and polycyclic aromatic group having 3 to 12 total atoms including one or more heteroatoms such as nitrogen, oxygen, or sulfur in the ring structure.
  • heteroaryl groups include azaindolyl, benzo(b)thienyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzoxadiazolyl, furanyl, imidazolyl, imidazopyridinyl, indolyl, indolinyl, indazolyl, isoindolinyl, isoxazolyl, isothiazolyl, isoquinolinyl, oxadiazolyl, oxazolyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolyl, pyrrolo[2,3- d]pyrimidinyl, pyrazolo[3,4-d]pyrimidinyl, quinolinyl, quinazolinyl, triazolyl, pyr
  • heteroaryl may be substituted at one or more ring positions with one or more substituents such as halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, fluoroalkyl (such as trifluromethyl), cyano, or the like.
  • substituents such as halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino
  • heteroaryl also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are “fused rings”) wherein at least one of the rings is an aromatic group having one or more heteroatoms in the ring structure, e.g., the other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • heteroarylene means a diradical obtained by removing two hydrogen atoms of a heteroaryl group, as defined above.
  • an heteroarylene refers to a disubstituted heteroarene, i.e., a heteroarene substituted at two positions with substituents such as halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, fluoroalkyl (such as trifluoromethyl), cyano, or the like. That is, in certain embodiments,
  • aralkyl or “arylalkyl” is a term of art and as used herein refers to an alkyl group substituted with an aryl group, wherein the moiety is appended to the parent molecule through the alkyl group.
  • heteroarylkyl or “heteroarylalkyl” is a term of art and as used herein refers to an alkyl group substituted with a heteroaryl group, appended to the parent molecular moiety through the alkyl group.
  • alkoxy as used herein means an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
  • Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.
  • alkoxyalkyl refers to an alkyl group substituted by an alkoxy group.
  • Representative examples of alkoxy carbonyl include, but are not limited to, methoxy carbonyl, ethoxy carbonyl, and tert-butoxy carbonyl.
  • alkylcarbonyl means an alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • Representative examples of alkylcarbonyl include, but are not limited to, acetyl, 1 -oxopropyl, 2,2-dimethyl-l -oxopropyl, 1-oxobutyl, and 1-oxopentyl.
  • arylcarbonyl means an aryl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • Representative examples of arylcarbonyl include, but are not limited to, benzoyl and (2- pyridinyl)carbonyl.
  • alkylcarbonyloxy and “arylcarbonyloxy”, as used herein, means an alkylcarbonyl or arylcarbonyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
  • Representative examples of alkylcarbonyloxy include, but are not limited to, acetyloxy, ethylcarbonyloxy, and tert-butylcarbonyloxy.
  • Representative examples of arylcarbonyloxy include, but are not limited to phenylcarbonyloxy.
  • alkenoxy or “alkenoxyl” means an alkenyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
  • aryloxy as used herein means an aryl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
  • heteroaryloxy as used herein means a heteroaryl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
  • carbocyclyl as used herein means a monocyclic or multi cyclic (e.g., bicyclic, tricyclic, etc.) hydrocarbon radical containing from 3 to 12 carbon atoms that is completely saturated or has one or more unsaturated bonds, and for the avoidance of doubt, the degree of unsaturation does not result in an aromatic ring system (e.g., phenyl).
  • carbocyclyl groups include 1 -cyclopropyl, 1-cyclobutyl, 2-cyclopentyl, 1 -cyclopentenyl, 3-cyclohexyl, 1- cyclohexenyl and 2-cyclopentenylmethyl.
  • cyano is a term of art and as used herein refers to -CN.
  • halo is a term of art and as used herein refers to -F, -Cl, -Br, or -I.
  • haloalkyl refers to an alkyl group, as defined herein, wherein some or all of the hydrogens are replaced with halogen atoms.
  • hydroxy is a term of art and as used herein refers to -OH.
  • hydroxyalkyl means at least one hydroxy group, as defined herein, is appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of hydroxy alkyl include, but are not limited to, hydroxymethyl, 2- hydroxy ethyl, 3-hydroxypropyl, 2,3-dihydroxypentyl, and 2-ethyl-4-hydroxyheptyl.
  • silyl includes hydrocarbyl derivatives of the silyl (HsSi-) group (i.e., (hydrocarbyl) 3 Si-), wherein a hydrocarbyl groups are univalent groups formed by removing a hydrogen atom from a hydrocarbon, e.g., ethyl, phenyl.
  • the hydrocarbyl groups can be combinations of differing groups which can be varied in order to provide a number of silyl groups, such as trimethylsilyl (TMS), tert-butyldiphenylsilyl (TBDPS), tert-butyldimethylsilyl (TBS/TBDMS), triisopropylsilyl (TIPS), and [2-(trimethylsilyl)ethoxy]methyl (SEM).
  • TMS trimethylsilyl
  • TDPS tert-butyldiphenylsilyl
  • TIPS triisopropylsilyl
  • SEM [2-(trimethylsilyl)ethoxy]methyl
  • silyloxy means a silyl group, as defined herein, is appended to the parent molecule through an oxygen atom. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, fragmentation, decomposition, cyclization, elimination, or other reaction.
  • substituted is also contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds.
  • Illustrative substituents include, for example, those described herein above.
  • the permissible substituents may be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds.
  • salts derived from inorganic or organic acids including, for example, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, phosphoric, formic, acetic, lactic, maleic, fumaric, succinic, tartaric, glycolic, salicylic, citric, methanesulfonic, benzenesulfonic, benzoic, malonic, trifluoroacetic, trichloroacetic, naphthalene-2-sulfonic, and other acids.
  • Pharmaceutically acceptable salt forms can include forms wherein the ratio of molecules comprising the salt is not 1:1.
  • the salt may comprise more than one inorganic or organic acid molecule per molecule of base, such as two hydrochloric acid molecules per molecule of compound of Formula I.
  • the salt may comprise less than one inorganic or organic acid molecule per molecule of base, such as two molecules of compound of Formula I per molecule of tartaric acid.
  • carrier and “pharmaceutically acceptable carrier” as used herein refer to a diluent, adjuvant, excipient, or vehicle with which a compound is administered or formulated for administration.
  • pharmaceutically acceptable carriers include liquids, such as water, saline, and oils; and solids, such as gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like.
  • auxiliary, stabilizing, thickening, lubricating, flavoring, and coloring agents may be used.
  • suitable pharmaceutical carriers are described in Remington ’s Pharmaceutical Sciences by E.W. Martin, herein incorporated by reference in its entirety.
  • treat means prevent, halt or slow the progression of, or eliminate a disease or condition in a subject. In one embodiment “treat” means halt or slow the progression of, or eliminate a disease or condition in a subject. In one embodiment, “treat” means reduce at least one objective manifestation of a disease or condition in a subject.
  • an effective amount refers to an amount that is sufficient to bring about a desired biological effect.
  • terapéuticaally effective amount refers to an amount that is sufficient to bring about a desired therapeutic effect.
  • inhibitor means decrease by an objectively measurable amount or extent. In various embodiments, “inhibit” means decrease by at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 95 percent compared to relevant control. In one embodiment, “inhibit” means decrease 100 percent, i.e., halt or eliminate.
  • a subject refers to a mammal.
  • a subject is a mouse, rat, rabbit, cat, dog, pig, sheep, horse, cow, or non-human primate.
  • a subject is a human.
  • any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom.
  • a position is designated specifically as “H” or “hydrogen”, the position is understood to have hydrogen at its natural abundance isotopic composition.
  • a position is designated specifically as “D” or “deuterium”, the position is understood to have deuterium at an abundance that is at least 3340 times greater than the natural abundance of deuterium, which is 0.015% (i.e., at least 50.1% incorporation of deuterium).
  • isotopic enrichment factor means the ratio between the isotopic abundance and the natural abundance of a specified isotope.
  • compounds of this invention have an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).
  • compositions and methods of the present invention may be utilized to treat an individual in need thereof.
  • the individual is a mammal such as a human, or a non-human mammal.
  • the composition or the compound is preferably administered as a pharmaceutical composition comprising, for example, a compound of the invention and a pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters.
  • the aqueous solution is pyrogen-free, or substantially pyrogen-free.
  • the excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs.
  • the pharmaceutical composition can be in dosage unit form such as tablet, capsule (including sprinkle capsule and gelatin capsule), granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like.
  • the composition can also be present in a transdermal delivery system, e.g., a skin patch.
  • the composition can also be present in a solution suitable for topical administration, such as a lotion, cream, or ointment.
  • a pharmaceutically acceptable carrier can contain physiologically acceptable agents that act, for example, to stabilize, increase solubility or to increase the absorption of a compound such as a compound of the invention.
  • physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients.
  • the choice of a pharmaceutically acceptable carrier, including a physiologically acceptable agent depends, for example, on the route of administration of the composition.
  • the preparation or pharmaceutical composition can be a selfemulsifying drug delivery system or a selfmicroemulsifying drug delivery system.
  • the pharmaceutical composition also can be a liposome or other polymer matrix, which can have incorporated therein, for example, a compound of the invention.
  • Liposomes for example, which comprise phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer.
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable carrier means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as com starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydrox
  • a pharmaceutical composition can be administered to a subject by any of a number of routes of administration including, for example, orally (for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, pastes for application to the tongue); absorption through the oral mucosa (e.g., sublingually); subcutaneously; transdermally (for example as a patch applied to the skin); and topically (for example, as a cream, ointment or spray applied to the skin).
  • the compound may also be formulated for inhalation.
  • a compound may be simply dissolved or suspended in sterile water.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration.
  • the amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.
  • Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a compound of the invention, with the carrier and, optionally, one or more accessory ingredients.
  • an active compound such as a compound of the invention
  • the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • Formulations of the invention suitable for oral administration may be in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), lyophile, powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient.
  • Compositions or compounds may also be administered as a bolus, electuary or paste.
  • the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents,
  • pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose
  • compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets, and other solid dosage forms of the pharmaceutical compositions may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres.
  • compositions may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
  • embedding compositions that can be used include polymeric substances and waxes.
  • the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the abovedescribed excipients.
  • Liquid dosage forms useful for oral administration include pharmaceutically acceptable emulsions, lyophiles for reconstitution, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, cyclodextrins and derivatives thereof, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, com, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art,
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • Dosage forms for the topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required.
  • the ointments, pastes, creams and gels may contain, in addition to an active compound, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to an active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body.
  • dosage forms can be made by dissolving or dispersing the active compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.
  • parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrastemal injection and infusion.
  • compositions suitable for parenteral administration comprise one or more active compounds in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.
  • the absorption of the drug in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
  • Injectable depot forms are made by forming microencapsulated matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissue.
  • active compounds can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.
  • Methods of introduction may also be provided by rechargeable or biodegradable devices.
  • Various slow release polymeric devices have been developed and tested in vivo in recent years for the controlled delivery of drugs, including proteinaceous biopharmaceuticals.
  • a variety of biocompatible polymers including hydrogels), including both biodegradable and non-degradable polymers, can be used to form an implant for the sustained release of a compound at a particular target site.
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level will depend upon a variety of factors including the activity of the particular compound or combination of compounds employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound(s) being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound(s) employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required.
  • the physician or veterinarian could start doses of the pharmaceutical composition or compound at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • therapeutically effective amount is meant the concentration of a compound that is sufficient to elicit the desired therapeutic effect. It is generally understood that the effective amount of the compound will vary according to the weight, sex, age, and medical history of the subject. Other factors which influence the effective amount may include, but are not limited to, the severity of the patient's condition, the disorder being treated, the stability of the compound, and, if desired, another type of therapeutic agent being administered with the compound of the invention.
  • a larger total dose can be delivered by multiple administrations of the agent.
  • Methods to determine efficacy and dosage are known to those skilled in the art (Isselbacher et al. (1996) Harrison’s Principles of Internal Medicine 13 ed., 1814-1882, herein incorporated by reference).
  • a suitable daily dose of an active compound used in the compositions and methods of the invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.
  • the effective daily dose of the active compound may be administered as one, two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms.
  • the active compound may be administered two or three times daily. In preferred embodiments, the active compound will be administered once daily.
  • the patient receiving this treatment is any animal in need, including primates, in particular humans; and other mammals such as equines, cattle, swine, sheep, cats, and dogs; poultry; and pets in general.
  • compounds of the invention may be used alone or conjointly administered with another type of therapeutic agent.
  • contemplated salts of the invention include, but are not limited to, alkyl, dialkyl, trialkyl or tetraalkyl ammonium salts.
  • contemplated salts of the invention include, but are not limited to, L-arginine, benenthamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, IH-imidazole, lithium, L-lysine, magnesium, 4-(2- hydroxyethyl)morpholine.
  • contemplated salts of the invention include, but are not limited to, Na, Ca, K, Mg, Zn or other metal salts. In certain embodiments, contemplated salts of the invention include, but are not limited to, 1 -hydroxyl- naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4- acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, 1-ascorbic acid, 1-aspartic acid, benzenesulfonic acid, benzoic acid, (+)-camphoric acid, (+)-camphor-10-sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane
  • the pharmaceutically acceptable acid addition salts can also exist as various solvates, such as with water, methanol, ethanol, dimethylformamide, and the like. Mixtures of such solvates can also be prepared.
  • the source of such solvate can be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or adventitious to such solvent.
  • wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
  • antioxidants examples include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxy anisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alphatocopherol, and the like; and (3) metal-chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxy anisole (BHA), butylated hydroxytoluene (BHT), lec
  • R 1 is selected from the group consisting of H, C 1 -C 5 alkyl, cycloalkyl, heterocycloalkyl, - O-C 1 -C 5 alkyl, -O-cycloalkyl, and -O-heterocycloalkyl;
  • R 2 is selected from the group consisting of H, C 1 -C 5 alkyl, cycloalkyl, heterocycloalkyl, - O-C 1 -C 5 alkyl, -O-cycloalkyl, and -O-heterocycloalkyl;
  • R 3 is selected from the group consisting of H, C 1 -C 5 alkyl, cycloalkyl, heterocycloalkyl, - O-C 1 -C 5 alkyl, -O-cycloalkyl, and -O-heterocycloalkyl;
  • R 4 is selected from the group consisting of H, C 1 -C 5 alkyl, cycloalkyl, heterocycloalkyl, - O-C 1 -C 5 alkyl, -O-cycloalkyl, and -O-heterocycloalkyl;
  • R 5 is selected from the group consisting of H, halo, C 1 -C 5 alkyl, cycloalkyl, heterocycloalkyl, -O-C 1 -C 5 alkyl, -O-cycloalkyl, and -O-heterocycloalkyl; wherein when R 1 , R 2 , R 3 , R 4 , or R 5 is C 1 -C 5 alkyl, cycloalkyl, heterocycloalkyl, -O-C 1 - C 5 alkyl, -O-cycloalkyl, or -O-heterocycloalkyl, at least one hydrogen atom in said C 1 -C 5 alkyl, cycloalkyl, heterocycloalkyl, -O-C 1 -C 5 alkyl, -O-cycloalkyl, or -O-heterocycloalkyl is replaced with a deuterium atom; and wherein at least one of R 1 ,
  • R 1 is selected from the group consisting of methyl, ethyl, propyl, and butyl. In further embodiments, R 1 is selected from the group consisting of CD 3 , C 2 D 5 , C 3 D 7 , and C 4 D 9 . In yet further embodiments, R 1 is: In still further embodiments, R 1 is: In certain embodiments, R 1 is In further embodiments, R 1 i
  • R 1 is: In still further embodiments, R 1 is:
  • R 1 is selected from the group consisting of-OMe, -OEt, -OPr, and -OBu. In further embodiments, R 1 is selected from the group consisting of-OCD 3 , -OC 2 D 5 ,
  • R 1 is In still further embodiments, R 1 is:
  • R 2 is selected from the group consisting of methyl, ethyl, propyl, and butyl. In further embodiments, R 2 is selected from the group consisting of CD 3 , C 2 D 5 , C 3 D 7 , and C 4 D 9 . In yet further embodiments, R 2 is In still further embodiments, R 2 is: In certain embodiments, R 2 is: In further embodiments, R 2 is:
  • R 2 is: In still further embodiments, R 2 is
  • R 2 is selected from the group consisting of-OMe, -OEt, -OPr, and -OBu. In further embodiments, R 2 is selected from the group consisting of-OCD 3 , -OC 2 D 5 ,
  • R 2 is: In still further embodiments,
  • R 3 is selected from the group consisting of methyl, ethyl, propyl, and butyl. In further embodiments, R 3 is selected from the group consisting of CD 3 , C 2 D 5 , C 3 D 7 , and C 4 D 9 . In yet further embodiments, R 3 is: In still further embodiments, R 3 is: In certain embodiments, R 3 is: In further embodiments, R 3 is :
  • R 3 is: In still further embodiments, R 3 is:
  • R 3 is selected from the group consisting of-OMe, -OEt, -OPr, and -OBu. In further embodiments, R 3 is selected from the group consisting of-OCD 3 , -OC 2 D 5 , -OC 3 D 7 , and -OC 4 D 9 . In yet further embodiments, R 3 is: In still further embodiments, R 3 is:
  • R 4 is selected from the group consisting of methyl, ethyl, propyl, and butyl. In further embodiments, R 4 is selected from the group consisting of CD 3 , C 2 D 5 , C 3 D 7 , and C 4 D 9 . In yet further embodiments, R 4 is: In still further embodiments, R 4 is: . In certain embodiments, R 4 is In further embodiments, R 4 is:
  • R 4 is: In still further embodiments, R 4 is
  • R 4 is selected from the group consisting of-OMe, -OEt, -OPr, and -OBu. In further embodiments, R 4 is selected from the group consisting of-OCD 3 , -OC 2 D 5 ,
  • R 4 is: In still further embodiments,
  • R 4 is:
  • R 5 is H. In further embodiments, R 5 is halo. In yet further embodiments, R 5 is F. In still further embodiments, R 5 is selected from the group consisting of methyl, ethyl, propyl, and butyl. In certain embodiments, R 5 is selected from the group consisting of CD 3 , C 2 D 5 , C 3 D 7 , and C 4 D 9 . In further embodiments, R 5 is: . In yet further embodiments, R 5 is: . In still further embodiments, R 5 is In certain embodiments, R 5 is: In further embodiments, R 5 is: In yet further embodiments, R 5 is: In yet further embodiments, R 5 is: In yet further embodiments, R 5 is:
  • R 5 is selected from the group consisting of-OMe, -OEt, -OPr, and -OBu. In further embodiments, R 5 is selected from the group consisting of-OCD 3 , -OC 2 D 5 ,
  • R 5 is: .
  • R 5 is :
  • the compound is selected from the group consisting of: or a pharmaceutically acceptable salt thereof.
  • the compound is selected from the group consisting of:
  • the compound is selected from the group consisting of: or a pharmaceutically acceptable salt thereof.
  • compositions comprising a compound of the disclosure, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier or excipient.
  • the pharmaceutical compositions further comprise an additional therapeutic agent selected from the group consisting of an iron mobilizer and deferiprone.
  • a disease or condition characterized by decreased ferroportin comprising administering to a subject in need thereof a therapeutically effective amount of a compound or pharmaceutical composition of the disclosure.
  • the disease or condition characterized by decreased ferroportin is induced ferroportin disease associated with aging.
  • provided herein are methods of treating a disease or condition characterized by decreased iron transport, comprising administering to a subject in need thereof a therapeutically effective amount of a compound or pharmaceutical composition of the disclosure.
  • provided herein are methods of treating a disease or condition characterized by a defect or deficiency in an iron transporter, comprising administering to a subject in need thereof a therapeutically effective amount of a compound or pharmaceutical composition of the disclosure.
  • kits for treating a disease or condition characterized by iron accumulation comprising administering to a subject in need thereof a therapeutically effective amount of a compound or pharmaceutical composition of the disclosure.
  • the iron accumulation is iron accumulation in the brain.
  • provided herein are methods of treating a disease or condition characterized by iron misdistribution, comprising administering to a subject in need thereof a therapeutically effective amount of a compound or pharmaceutical composition of the disclosure.
  • the iron misdistribution is iron misdistribution in the brain.
  • the disease or condition is selected from the group consisting of anemia of inflammation, iron overload, thalassemia, hemochromatosis, atransferrinemia, myelodysplasia, hypochromic microcytic anemia, ferroportin disease, transfusional iron overload, and aceruloplasminemia.
  • a neurodegenerative disorder comprising administering to a subject in need thereof a therapeutically effective amount of a compound or pharmaceutical composition of the disclosure.
  • the neurodegenerative disorder is selected from the group consisting of Parkinson’s Disease, Alzheimer’s Disease, Amyotrophic lateral sclerosis, Friedrich’s ataxia, Huntington’s Disease, Lewy Body Disease, and Spinal Muscular Atrophy.
  • the neurodegenerative disorder is neurodegeneration with brain iron accumulation (NBIA).
  • the NBIA is selected from the group consisting of Beta-propeller Protein- associated Neurodegeneration (BPAN), Pantothenate Kinase-associated Neurodegeneration (PKAN), PLA2G6-associated Neurodegeneration (PLAN), Mitochondrial-membrane Protein- associated Neurodegeneration (MP AN), Fatty Acid Hydroxylase- Associated Neurodegeneration (FAHN), COASY Protein-Associated Neurodegeneration (CoPAN), Aceruloplasminemia, Kufor-Rakeb Syndrome (also known as Parkinson’s Disease 9 (PARK9)), Neuroferritinopathy, Woodhouse-Sakati Syndrome, and Idiopathic NBIA.
  • BPAN Beta-propeller Protein- associated Neurodegeneration
  • PKAN Pantothenate Kinase-associated Neurodegeneration
  • PLAN PLA2G6-associated Neurodegeneration
  • MP AN Mitochondrial-membrane Protein- associated Neurodegeneration
  • Fatty Acid Hydroxylase- Associated Neurodegeneration Fatty Acid Hydroxylase- Associated Neuro
  • the methods of the disclosure further comprise administering to the subject an effective amount of an additional therapeutic agent selected from the group consisting of an iron mobilizer and deferiprone.
  • the reaction was then heated to 100 °C and stirred vigorously for 3 hours. The reaction was then cooled and poured into an aqueous sodium thiosulfate solution and quenched overnight. The crude was then added to a separatory funnel and extracted 5x with Et20. Organic extracts were washed with saturated aqueous CuSO4 solution, water, and brine before being dried over MgSO4 and concentrated in vacuo. The crude was then purified via flash column chromatography, yielding the desired product 2b as a brown solid.
  • reaction was then quenched with 200 mL of 2M HC 1 , transferred to a separatory funnel, and extracted 3x with DCM. The combined organic layers were then washed three times with water, then once with brine, then dried over MgSO4 and concentrated in vacuo. This mixture containing 2c was then subjected to the next step without purification.
  • the Gamma bromotropolone Scaffold was synthesized following the same procedure as for the Beta Bromotropolone Scaffold while utilizing 1,4-cyclohexadiene in place of 1,3-cyclohexadiene in the first step and resulting in the following intermediates.
  • Benzyl-protected ⁇ -Bromotropolone scaffold was prepared as previously described (4). To a mixture of this scaffold in DMSO was added dried CsF (1.5 equiv.) under N 2 atmosphere. The mixture was stirred at 110 °C under N 2 for 8 hours. The reaction was cooled to 25 °C and brine was added. The aqueous mixture was extracted with EtOAc, combined organic layer was washed with brine and then dried over Na 2 SO 4 . The solution was concentrated and purified via silica gel chromatography yielding product.
  • the intermediate was then reprotected utilizing methyl protection procedure as previously described (4). Briefly, the crude residue was resuspended in MeCN to which K 2 CO 3 (3 equivs.) and 18-crown-6 (0.1 equivs.) were added under N 2 . Mel (4 equivs.) was then added dropwise and the reaction was heated to 85 °C and allowed to run for 12 hours. Following cooling, the mixture was filtered and the residue concentrated under reduced pressure to yield crude product. The crude product was purified via silica gel chromatography to yield the desired methylated fluoro/bromotropolone scaffold. This scaffold was then utilized in GP1 followed by GP2 to give desired ⁇ -fluoro/ ⁇ -substituted derivatives.
  • Methyl-protected ⁇ -Fluoro/ ⁇ -substituted derivatives were acquired as depicted above after GP1.
  • NBS 1.3 equiv.
  • the mixture was heated to 80 °C for 3 hours. After, the mixture was cooled to 25 °C and water was added.
  • the aqueous mixture was extracted with 3x dichloromethane and the combined organics were washed with brine and dried over Na 2 SO 4 . Following filtration, the solution was concentrated to dryness giving the ⁇ -Fluorine/ ⁇ -substituted/ ⁇ -Bromo intermediate which was purified via silica gel chromatography.
  • the purified product was utilized in GP1 followed by GP2 to yield ⁇ -Fluorine/ ⁇ , ⁇ -substituted derivatives.
  • Example 5 General Procedure for Derivatives Containing a'-Fluorine/ ⁇ -Substitution
  • the ⁇ -Bromotropolone scaffold was synthesized as described in Example 2. This scaffold was then utilized in GP1 to acquire the protected coupled product. Following, this product was redissolved in CHCl 3 and NBS (1.3 equiv.) was slowly added at 25 °C under N 2 . The mixture was heated to 80 °C for 3 hours. After, the mixture was cooled to 25 °C and water was added. The aqueous mixture was extracted with 3x dichloromethane and the combined organics were washed with brine and dried over Na 2 SO 4 .
  • LiAlD4 was suspended in THF and refluxed for 30 minutes. Upon cooling to -55 °C utilizing an immersion cooler, a solution of Succinic anhydride-d4 in THF was added dropwise over 30 minutes. The solution was warmed to 25 °C over 90 minutes and then cooled to -15 °C for 15 minutes. 6M HC 1 solution was added slowly and the solution was warmed to 25 °C and stirred for 20 minutes. The reaction mixture was washed with brine and the organics extracted with 3x Et 2 O. the combined organics were dried over Na 2 SO 4 and concentrated under vacuum. The residue was purified via fractional distillation (BP 65 °C) to yield the desired product.
  • BP 65 °C fractional distillation
  • a three-necked flask was charged solution of TsOH in quinoline and a distillation apparatus was assembled, with a 2M aqueous solution of NaOH kept frozen around the bottom of the receiver flask.
  • the quinoline solution was submerged in a 190 °C wax bath and the receiver flask was maintained at -78 °C in a dry ice/ acetone bath.
  • the crude product from the previous step was added dropwise into the quinoline solution and the solution was heated to 210 °C for an hour.
  • the recovered liquid was removed from the apparatus quickly and purified via distillation (BP 54 °C) to yield the final desired product.
  • the enantiomers were separately dissolved in neat TFA and heated to 50 °C for 2 hours with stirring. The reaction mixturs were cooled and then concentrated under vacuum to give the crude products. The residues were purified by preparatory HPLC separately, employing a Nanomicro Kromasil C18 (100 mm * 30 mm, 8 mm) as the stationary phase, to yield the final desired products as pure enantiomers.
  • Bromotropolone scaffolds were synthesized as described above. An Oven-dried 8 mL vial equipped with a stir bar and the vial containing the crude boronic acid were carried into a glove box filled with Ar. In the glovebox, all solid components were first added: Bromotropolone scaffold (0.5 mmol, 1 equiv.), Pd 2 (dba) 3 (0.05 mmol, 0.1 equiv.), P(o-tol) 3 (0.1 mmol, 0.2 equiv.), Ag 2 O (0.75 mmol, 1.5 equiv.).
  • Multibrominated scaffolds utilized reagent equivalents per bromide such that, for example, for the tribromotropolone scaffold, Pd 2 (dba) 3 (0.15 mmol, 0.3 equiv.), P(o-tol) 3 (0.3 mmol, 0.6 equiv.), Ag 2 O (2.25 mmol, 4.5 equiv.) were used in 3 mL total of dried dioxane.
  • Liposomes were prepared as previously described (A. S. Grillo et al. Science, 356, 608- 615 (2017)). Lipid films were generated through addition of 200 ⁇ L of 4 mg/mL recrystallized cholesterol in chloroform to a 960 ⁇ L solution of 25 mg/mL POPC in chloroform (Avanti Polar Lipids 850457C). After evaporation under a stream of nitrogen, films were placed under hi- vacuum for 18 hours to ensure quantitative solvent removal.
  • Lipid films were rehydrated by adding ImL of liposome inside buffer (15 mM FeCh, 125 mM citrate, 50 mM MES/TRIS pH 7.0) to the lipid film and thoroughly vortexing to form a solution of multilamellar vesicles (MLVs).
  • Liposomes were then extruded through an Avanti Lipids extruder (Avanti Polar Lipids 610023) using a .2 mm membrane (Whatman 800281), passing the MLV suspension through the filter 21 times to ensure homogenous large unilamellar vesicles (LUVs).
  • LUVs were subjected to size exclusion chromatography, using a ⁇ 20 cm column of Sephadex® G-50 Medium resin that was hydrated in liposome outside buffer (600 mM sodium ascorbate, 50 mM MES/TRIS pH 7.0). Separation of LUVs from extravesicular Fe could be readily visualized on the column, and the most concentrated portion of LUVs was collected.
  • liposome outside buffer 600 mM sodium ascorbate, 50 mM MES/TRIS pH 7.0
  • Determination of total phosphorous was performed utilizing the Bartlett Assay. Briefly, the LUV suspension was diluted 10-fold in liposome outside buffer, then 10 ⁇ L of this solution was placed in three 7 mL vials along with 10 ⁇ L of liposome outside buffer for background. 450 mL of 8.9 M H2SO4 was then added, and the mixture was heated open to air at 225 °C for 25 minutes. Following cooling, 150 mL of 30% H 2 O 2 was added, and the mixture was further heated open to air at 225 °C for 30 min. The samples were then allowed to fully cool and diluted using 3.9 mL of Milli-Q water.
  • 16 mL of liposome suspension was created with the following components: 160 mL of ferrozine solution (100X stock, 50 mM in liposome outside buffer), LUV suspension (to a final concentration of 1 mM phosphorous), and liposome outside buffer up to 16 mL.
  • 195 mL of liposome suspension was then added to a 96 well plate (NUM) using a multichannel pipettor. The plate was then placed in a plate reader and equilibrated at 37 °C for 5 minutes, then read for a baseline measurement. Following this equilibration, compound was added at the designated concentrations (40X stock in DMSO) using a multichannel pipettor, and the plate was then incubated at 37 °C for 40 min. Reads were taken every minute at A562 and the plate mixed at 220 rpm. Total iron efflux was determined via ferrocene-iron complex signal. These experiments were performed in triplicate, with a minimum of two biological replicates.
  • H9C2 Cells (ATCC CRL-1446) were cultured at 37 °C/5% CO 2 in DMEM media supplemented with 10% FBS (Gemini 900-108), 1% Penicillin Streptomycin (Gibco 15140-122) and 1% MEM Non-Essential Amino Acids (Coming 25-025-C 1 ) in T175 culture flasks (Thermofisher) until at least passage 5. Through centrifugation and dilution of cellular pellet, a 5xl0 5 cells/mL solution was obtained. A 96-well compound plate containing 40x DMSO Solutions of desired test compounds over desired concentration range was created using 100 mM DMSO stock solutions.
  • K562 Cells (ATCC CCL-243) were cultured at 37 °C/5% CO 2 in IMDM (Iscove’s Modified Dulbeco’s Medium, ATCC 30-2005) media supplemented with 10% FBS (Gemini 900-108), 1% Penicillin Streptomycin (Gibco 15140-122) and 1% MEM Non-Essential Amino Acids (Coming 25-025-C 1 ) in T175 culture flasks (Thermofisher) until at least passage 5. Through centrifugation and dilution of cellular pellet, a 1.25 x 10 6 cells/mL solution was obtained.
  • a 96- well compound plate containing 40x DMSO Solutions of desired test compounds over desired concentration range was created using 100 mM DMSO stock solutions. Using a multichannel micropipetor, 3.34 ⁇ L of each stock solution was added to 297 ⁇ L of cell media in a 96 well plate with light mixing via pipetting up and down. To a 96 well plate, 3 x 80 ⁇ L of each created compound solution was added to successive rows, with the top and bottom rows filled with cell media to reduce evaporation. Following, 20 ⁇ L of the 1.25 x 10 6 cell/mL solution was added to each well using a micropipettor so that each well contained 2.5 x 10 4 cells.
  • BY200 and NES277 strains were grown in normal NGM plates.
  • worms were transferred to NGM plates containing vehicle (DMSO) or various concentrations of deferiprone (DFP), hinokitiol (Hino), and FeM-1269. Worms were passaged daily until being used for imaging at day 7 using Zeiss Axiolmager microscope equipped with DIC and fluorescence. Data analysis was done blinded according to a previously described protocol (R. Nass, D. H. Hall, D. M. Miller, R. D. Blakely, Neurotoxin-induced degeneration of dopamine neurons in Caenorhabditis elegans. Proceedings of the National Academy of Sciences 99, 3264-3269 (2002).).
  • GA631 and NES281 strains were grown in normal NGM plates. At age day 1, the worms were transferred to NGM plates containing vehicle (DMSO) or various concentrations of DFP, Hino, and FeM-1269. Worms were passaged daily until being used for imaging at day 5 using Zeiss LSM880 at 20x magnification with focus on the head. Fluorescence intensity was quantified blinded using ImageJ.
  • the elevated plus maze consists of 2 open arms and 2 closed arms that extend from the central zone platform. Each mouse was placed in the center zone, facing an open arm, and was allowed to explore the maze for 5 min. The time spent and the frequency of entries into the three areas of the apparatus, namely an open arm, a closed arm, and the center zone, as well as total distance traveled on the whole maze, rearing frequency, and duration of movement was recorded and analyzed by EthoVision XT (Noldus).
  • ICP-MS Inductively coupled plasma-mass spectrometry
  • Dynamic light scattering was performed on a Malvern Zetasizer Nano using disposable cuvettes. Samples were evaluated in a similar buffer to liposome efflux studies (50 mM MES/TRIS, pH to 7.0 using solutions of 1 M MES or 1 M TRIS). Compound at the specified concentration (from 1000X in DMSO), as well as equimolar FeCl 3 (1000X in .1 M HC 1 ) were added to this buffer. After addition, these compounds were vortexed for 30 sec, sonicated for one min, then further vortexed for 30 sec before a five-minute equilibration in the Zetasizer at 37 °C. All standard parameters were used, with each graph representing a minimum of thirty 10 second measurements. For count rate analysis, the raw count rate was utilized, accounting for any differences in attenuator position between samples.

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Abstract

L'invention concerne des dérivés deutérés de tropolone utiles pour le traitement de maladies ou de troubles, par exemple, en lien avec des déficiences dans le transport du fer.
PCT/US2023/034258 2022-09-30 2023-10-02 Dérivés de hinokitiol deutérés WO2024073125A2 (fr)

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