Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
  • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
  • C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
  • C07D277/12—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/425—Thiazoles
  • A61K31/426—1,3-Thiazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P39/00—General protective or antinoxious agents
  • A61P39/02—Antidotes
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/06—Antianaemics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
  • C07C211/43—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
  • C07C211/54—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to two or three six-membered aromatic rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
  • C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
  • C07C215/48—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups
  • C07C215/50—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
  • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
  • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
  • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
  • C07C229/10—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
  • C07C229/16—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of hydrocarbon radicals substituted by amino or carboxyl groups, e.g. ethylenediamine-tetra-acetic acid, iminodiacetic acids

Definitions

• the hydroxyl radical reacts very quickly with a variety of cellular constituents and can initiate free radicals and radical-mediated chain processes that damage DNA and membranes as well as produce carcinogens (Halliwell, "Free Radicals and Antioxidants: A Personal View.” Nutr. Rev. 1994, 52, 253-265); Babbs, "Oxygen Radicals in Ulcerative Colitis.” Free Radical Biol. Med. 1992, 13, 169-181; Hazen et al, "Human Neutrophils Employ the Myeloperoxidase-Hydrogen Peroxide-Chloride System to Oxidize a- Amino Acids to a Family of Reactive Aldehydes. Mechanistic Studies Identifying Labile
• Iron-mediated damage can be focal, as in reperfusion damage (Millan et ah, "Biological Signatures of Brain Damage Associated with High Serum Ferritin Levels in Patients with Acute Ischemic Stroke and Thrombolytic Treatment.” Dis. Markers 2008, 25, 181-188), Parkinson's (Zecca et ah, "Neuromelanin Can Protect Against Iron-Mediated Oxidative Damage in System Modeling Iron Overload of Brain Aging and Parkinson's Disease.” J. Neurochem. 2008, 106, 1866-1875), Friedreich's ataxia (Pietrangelo, "Iron Chelation Beyond Tranfusion Iron Overload.” Am. J. Hematol.
• DFO desferoxamine B mesylate
• Novartis Pharmaceuticals Corporation East Hanover, NJ, 2008; www.pharma.us.novartis.com/product/pi/pdf/desferal.pdf
• 1,2-dimethyl- 3-hydroxy-4-pyridinone deferiprone, LI
• Hoffbrand "Long-Term Trial of Deferiprone in 51 Transfusion-Dependent Iron Overloaded Patients.” Blood 1998, 91, 295-300; Olivieri, “Long-Term Therapy with Deferiprone.” Acta Haematol. 1996, 95, 37-48; Olivieri, "Long- Term Safety and Effectiveness of Iron-Chelation Therapy with Deferiprone from
• ICL670A (Nisbet-Brown et ah, "Effectiveness and Safety of ICL670 in Iron-Loaded Patients with Thalassemia: A Randomised, Double-Blind, Placebo-Controlled, Dose- Escalation Trial.” Lancet, 2003, 361, 1597-1602; Galanello et ah, "Safety, Tolerability, and Pharmacokinetics of ICL670, a New Orally Active Iron-Chelating Agent in Patients with Transfusion-Dependent Iron Overload Due to / ⁇ -Thalassemia.” J. Clin. Pharmacol.
• Desferasirox did not show noninferiority to DFO and is associated with numerous side effects, including some renal toxicity (Nisbet-Brown et ah, "Effectiveness and Safety of ICL670 in Iron-Loaded Patients with Thalassemia: A Randomised, Double-Blind, Placebo-Controlled, Dose-Escalation Trial.” Lancet, 2003, 361, 1597-1602; Galanello et ah, "Safety, Tolerability, and Pharmacokinetics of ICL670, a New Orally Active Iron-Chelating Agent in Patients with Transfusion-Dependent Iron Overload Due to / ⁇ -Thalassemia.” J. Clin. Pharmacol. 2003, 43, 565-572; Cappellini, "Iron-Chelating Therapy with the New Oral Agent ICL670 (Exjade).” Best Pract. Res. Clin. Haematol. 2005, 18, 289-298).
• metal chelating agents with more desirable properties (e.g., metal chelating agents with balanced properties (e.g., lipophilicity, metal clearing efficiency, and toxicity)) for better treatment and/or prevention of pathological conditions in a subject.
• metal chelating agents with balanced properties e.g., lipophilicity, metal clearing efficiency, and toxicity
• the present invention provides desazadesferrithiocin analogs based on
• desferrithiocin (1, shown below) and desazadesferrithiocin (la, shown below).
• the desazadesferrithiocin analogs are compounds of Formula (I), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof.
• desazadesferrithiocin analogs are able to chelate a metal (e.g., iron and other metals).
• the invention also provides compounds of Formula (II), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof.
• the invention provides pharmaceutical compositions, kits, methods, and uses that involve or include a desazadesferrithiocin analog or compounds of Formula (I) or Formula (II) described herein.
• the compounds, pharmaceutical compositions, kits, and methods may be useful in chelating a metal in a subject, cell, tissue, or biological sample, treating a disease in a subject, preventing a disease in a subject, treating, reducing, or preventing the formation of biofilms in a subject, or reducing or preventing the formation of biofilms on or in an object.
• the disease is metal overload, oxidative stress, transfusional iron overload, thalassemia, primary hemochromatosis, secondary hemochromatosis, diabetes, liver disease, heart disease, cancer, radiation injury, neurological or neurodegenerative disorder, Friedreich's ataxia (FRDA), macular degeneration, closed head injury, irritable bowel disease, or reperfusion injury.
• FRDA Friedreich's ataxia
• the disease is metal poisoning.
• the disease is an infectious disease (e.g., malaria).
• Iron is usually a nutrient necessary for the growth of microorganisms. Depriving the organisms of iron by chelating and/or removing iron may contribute to the treatment and/or prevention of infectious diseases.
• R , R , R , R 5 , R 6 , R 9 , Z, x, n, y, m, p, q, and k are as defined herein.
• Exemplary compounds of Formula (I) include, but are not limited to:
• compositions including a compound described herein and optionally a pharmaceutically acceptable excipient.
• a pharmaceutical composition described herein includes an effective amount (e.g., a therapeutically or prophylactically effective amount) of a compound described herein.
• the pharmaceutical compositions may be useful in chelating a metal in a subject, cell, tissue, or biological sample; treating a disease in a subject (e.g., human); preventing a disease in a subject; treating, reducing, or preventing the formation of biofilms in a subject; or reducing or preventing the formation of biofilms on or in an object.
• the subject is a human.
• the cell is in vitro. In certain embodiments, the cell is in vivo.
• one of the metals chelated by the compound described herein is iron.
• other metals such as aluminum, thallium, chromium, magnesium, calcium, strontium, nickel, manganese, cobalt, copper, zinc, silver, sodium, potassium, cadmium, mercury, lead, antimony, molybdenum, tungsten, a lanthanide (e.g., cerium), or an actinide (e.g., uranium) are chelated by the compound.
• the disease is a disease associated with the chelation of a metal.
• the disease is iron overload.
• the disease is transfusional iron overload.
• the disease is thalassemia, primary hemochromatosis, or secondary hemochromatosis.
• the disease is aluminum overload, lanthanide overload, or actinide overload.
• the disease is oxidative stress.
• the disease is diabetes, liver disease, heart disease, cancer, or neurological or neurodegenerative disorder.
• the disease is radiation injury, Friedreich' s ataxia (FRDA), macular degeneration, closed head injury, irritable bowel disease, or reperfusion injury.
• the disease is metal poisoning.
• the disease is an infectious disease.
• kits including a compound or pharmaceutical composition described herein.
• the kit further includes instructions for using (e.g. , administering) the compound or pharmaceutical composition.
• kits for chelating a metal in a subject including administering to the subject an effective amount of a compound or pharmaceutical composition described herein.
• kits for chelating a metal in a cell, tissue, or biological sample including contacting the cell, tissue, or biological sample with an effective amount of a compound or pharmaceutical composition described herein.
• kits for treating a disease in a subject in need thereof including administering to the subject an effective amount of a compound or pharmaceutical composition described herein.
• kits for preventing a disease in a subject in need thereof including administering to the subject an effective amount of a compound or pharmaceutical composition described herein.
• kits for treating a disease in a subject in need thereof including mixing blood or a component thereof (e.g., red blood cells) with an effective amount of a compound or pharmaceutical composition described herein to form a mixture ex vivo; and administering the mixture to the subject.
• a component thereof e.g., red blood cells
• kits for preventing a disease in a subject in need thereof including mixing blood or a component thereof (e.g., red blood cells) with an effective amount of a compound or pharmaceutical composition described herein to form a mixture; and administering the mixture to the subject.
• the present disclosure provides methods of inhibiting the formation of biofilms comprising administering to a subject in need thereof an effective amount (e.g., therapeutically effective amount) of a compound or pharmaceutical composition described herein.
• the present invention provides methods of inhibiting the formation of biofilms comprising administering to a subject in need thereof an effective amount (e.g., therapeutically effective amount) of a compound or pharmaceutical composition described herein and an antimicrobial agent.
• the biofilms are produced by one or more microorganisms selected from the group consisting of bacteria, archaea, protozoa, fungi, and algae.
• the biofilms are produced by bacteria.
• the biofilms are produced by Gram-negative bacteria.
• the biofilms are produced by S. epidermidis, E. faecalis, E. coli, P. mirabilis, P. aeruginosa, K. pneumoniae, S. aureus, S. viridans, K.
• the biofilms are produced by Gram-positive bacteria.
• a method for inhibiting bacterial cell growth comprising contacting bacteria with an effective amount of a compound or pharmaceutical composition described herein.
• hypersusceptibility comprising contacting a bacterium with an effective amount of a compound or pharmaceutical composition described herein.
• Hypersusceptibility refers to a condition of abnormal susceptibility to poisons, infective agents, or agents that are entirely innocuous in the normal subject.
• An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively).
• a chiral compound can exist as either individual enantiomer or as a mixture thereof.
• a mixture containing equal proportions of the enantiomers is called a "racemic mixture.”
• the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer.
• Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley).
• an isomer/enantiomer may, in some embodiments, be provided substantially free of the corresponding enantiomer, and may also be referred to as "optically enriched” or “enantiomerically enriched.”
• “Optically enriched” and “enantiomeric ally enriched” means that a provided compound is made up of a significantly greater proportion of one enantiomer.
• a compound of the present invention is made up of at least about 70% by weight of a preferred enantiomer.
• a compound of the present invention is made up of at least about 80% by weight of a preferred enantiomer.
• a compound of the present invention is made up of at least about 90% by weight of a preferred enantiomer. In other embodiments the compound is made up of at least about 95%, 98%, or 99% by weight of a preferred enantiomer.
• Preferred enantiomers may be isolated from racemic mixtures by any method known to those skilled in the art, including chiral high pressure liquid
• structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
• compounds having the depicted structures that differ only in the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by 13 C or 14 C are within the scope of this invention.
• Such compounds may be useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention.
• CiV is intended to encompass, Ci, C 2 , C 3 , C 4 , C5, C 6 , Ci_6, Ci_5, Ci ⁇ , Ci_ 3 , Ci_2, C2-6, C2-5, C 2 - , C2-3, C 3 _6, C 3 _5, C 3 ⁇ , C4_6, C 4 _5, and Cs_6.
• purified refers to a compound useful in the present invention being free of other, dissimilar compounds with which the compound is normally associated in its natural state, so that the compound comprises at least 0.5%, 1%, 5%, 10%, 20%, 50%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% of the mass, by weight, of a given sample or composition. In one embodiment, these terms refer to the compound comprising at least 95%, 98%, 99%, or 99.9% of the mass, by weight, of a given sample or composition.
• R is hydrogen; halogen; substituted or unsubstituted hydroxyl; substituted or unsubstituted thiol; substituted or unsubstituted amino; substituted or unsubstituted acyl, cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched
• heteroaliphatic cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkyl; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy,
• heteroaryloxy aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, mono- or di- aliphaticamino, mono- or di- heteroaliphaticamino, mono- or di- alkylamino, mono- or di- heteroalkylamino, mono- or di-arylamino, or mono- or
• acyl groups include aldehydes (-CHO), carboxylic acids (-C0 2 H), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas.
• Acyl substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g., aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, oxo, imino, thiooxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphaticamino, heteroaliphaticamino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, acy
• acyloxy refers to a "substituted hydroxyl" of the formula (-OR 1 ), wherein R 1 is an optionally substituted acyl group, as defined herein, and the oxygen moiety is directly attached to the parent molecule.
• aliphatic includes both saturated and unsaturated, nonaromatic, straight chain (e.g., unbranched), branched, acyclic, and cyclic (e.g. , carbocyclic)
• hydrocarbons which are optionally substituted with one or more functional groups.
• aliphatic is intended herein to include, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties.
• alkyl includes straight, branched and cyclic alkyl groups.
• An analogous convention applies to other generic terms such as “alkenyl”, “alkynyl”, and the like.
• alkyl encompass both substituted and unsubstituted groups.
• aliphatic is used to indicate those aliphatic groups (cyclic, acyclic, substituted, unsubstituted, branched or unbranched) having 1-20 carbon atoms.
• Aliphatic group substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g.
• heteroarylthioxy acyloxy, and the like, each of which may or may not be further substituted).
• alkyl refers to saturated, straight- or branched-chain hydrocarbon radicals derived from a hydrocarbon moiety containing between one and twenty carbon atoms by removal of a single hydrogen atom.
• the alkyl group employed in the invention contains 1-20 carbon atoms.
• the alkyl group employed contains 1-15 carbon atoms.
• the alkyl group employed contains 1-10 carbon atoms.
• the alkyl group employed contains 1-8 carbon atoms.
• the alkyl group employed contains 1-5 carbon atoms.
• alkyl radicals include, but are not limited to, methyl (e.g., unsubstituted methyl (Me)), ethyl (e.g., unsubstituted ethyl (Et)), propyl (e.g., unsubstituted propyl (Pr)), n-propyl, isopropyl, butyl (e.g., unsubstituted butyl (Bu)), n-butyl, z ' so-butyl, sec-butyl, sec-pentyl, wo-pentyl, tert- butyl, ft-pentyl, neopentyl, n-hexyl, sec-hexyl, n-heptyl, n-octyl, n-decyl, n-undecyl, dodecyl, and the like, which may bear one or more sustitutents.
• Alkyl group substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g. , aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, oxo, imino, thiooxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphaticamino, heteroaliphaticamino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyloxy,
• heteroalkyloxy aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, and the like, each of which may or may not be further substituted).
• alkenyl denotes a monovalent group derived from a straight- or branched-chain hydrocarbon moiety having at least one carbon-carbon double bond by the removal of a single hydrogen atom.
• the alkenyl group employed in the invention contains 2-20 carbon atoms. In some embodiments, the alkenyl group employed in the invention contains 2-15 carbon atoms. In another embodiment, the alkenyl group employed contains 2-10 carbon atoms. In still other embodiments, the alkenyl group contains 2-8 carbon atoms. In yet other embodiments, the alkenyl group contains 2-5 carbons.
• Alkenyl groups include, for example, ethenyl, propenyl, butenyl, l-methyl-2-buten- 1-yl, and the like, which may bear one or more substituents.
• Alkenyl group substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g., aliphatic, alkyl, alkenyl, alkynyl, hetero aliphatic, heterocyclic, aryl, heteroaryl, acyl, oxo, imino, thiooxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphaticamino, heteroaliphaticamino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyl
• alkynyl refers to a monovalent group derived from a straight- or branched-chain hydrocarbon having at least one carbon-carbon triple bond by the removal of a single hydrogen atom.
• the alkynyl group employed in the invention contains 2-20 carbon atoms. In some embodiments, the alkynyl group employed in the invention contains 2-15 carbon atoms. In another embodiment, the alkynyl group employed contains 2-10 carbon atoms. In still other embodiments, the alkynyl group contains 2-8 carbon atoms. In still other embodiments, the alkynyl group contains 2-5 carbon atoms.
• Representative alkynyl groups include, but are not limited to, ethynyl, 2-propynyl
• Alkynyl group substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g.
• heteroaliphaticoxy alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, and the like, each of which may or may not be further substituted).
• R aa is, independently, selected from CMO alkyl, CMO perhaloalkyl, C 2 _io alkenyl, C 2-1 o alkynyl, heteroCi-io alkyl, heteroC 2 _ioalkenyl, heteroC 2 _ioalkynyl, C 3 _io carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5- 14 membered heteroaryl, or two R aa groups are joined to form a 3- 14 membered heterocyclyl or 5- 14 membered heteroaryl, or two R aa groups are joined to form a 3- 14 membered heterocyclyl or 5- 14 membered heteroaryl, or two R aa groups are joined to form a 3- 14 membered heterocyclyl or 5- 14 membered heteroaryl, or two R aa groups are joined to form a 3- 14 membered heterocyclyl or 5- 14 membered heteroaryl, or two R a
• each instance of R bb is, independently, selected from hydrogen, -OH, -OR aa ,
• each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups; wherein X ⁇ is a counterion;
• each instance of R cc is, independently, selected from hydrogen, Ci_io alkyl, Ci_io perhaloalkyl, C2-10 alkenyl, C 2 _io alkynyl, heteroCi_io alkyl, heteroC 2 _io alkenyl, heteroC 2 _io alkynyl, C 3 _io carbocyclyl, 3-14 membered heterocyclyl, C 6 -i 4 aryl, and 5-14 membered heteroaryl, or two R cc groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups;
• each instance of R ee is, independently, selected from Ci_ 6 alkyl, Ci_ 6 perhaloalkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, heteroCi_ 6 alkyl, heteroC 2 _ 6 alkenyl, heteroC 2 _ 6 alkynyl, C 3 _io
• each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups;
• each instance of R ff is, independently, selected from hydrogen, Ci_ 6 alkyl, Ci_ 6 perhaloalkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, heteroCi_ 6 alkyl, heteroC 2 _ 6 alkenyl, heteroC 2 _ 6 alkynyl, C 3 _io carbocyclyl, 3-10 membered heterocyclyl, C 6 io aryl and 5-10 membered heteroaryl, or two R ff groups are joined to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups; and
• amino refers to a group of the formula (-NH 2 ).
• a "substituted amino” refers either to a mono-substituted amine (-NHR h ) of a disubstituted amine (-NR h 2 ), wherein the R h substituent is any substituent as described herein that results in the formation of a stable moiety (e.g.
• a suitable amino protecting group aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, amino, nitro, hydroxyl, thiol, halo, aliphaticamino, heteroaliphaticamino, alkylamino, heteroalkylamino, arylamino,
• heteroarylamino alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyloxy,
• the R h substituents of the disubstituted amino group(-NR h 2 ) form a 5- to 6-membered heterocyclic ring.
• alkoxy refers to a "substituted hydroxyl" of the formula (-OR 1 ), wherein R 1 is an optionally substituted alkyl group as defined herein, and the oxygen moiety is directly attached to the parent molecule.
• alkylthioxy refers to a "substituted thiol” of the formula (-SR r ), wherein R r is an optionally substituted alkyl group as defined herein, and the sulfur moiety is directly attached to the parent molecule.
• alkylamino refers to a "substituted amino' Of the formula (-NR h 2 ), wherein R h is, independently, a hydrogen or an optionally substituted alkyl group as defined herein, and the nitrogen moiety is directly attached to the parent molecule.
• aryl refer to stable aromatic mono- or polycyclic ring system having 3-20 ring atoms, of which all the ring atoms are carbon, and which may be substituted or unsubstituted.
• aryl refers to a mono, bi, or tricyclic C 4 -C 2 o aromatic ring system having one, two, or three aromatic rings which include, but not limited to, phenyl, biphenyl, naphthyl, and the like, which may bear one or more substituents.
• Aryl substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g.
• arylalkyl refers to an aryl substituted alkyl group, wherein the terms “aryl” and “alkyl” are defined herein, and wherein the aryl group is attached to the alkyl group, which in turn is attached to the parent molecule.
• exemplary arylalkyl groups are benzyl and phenethyl.
• aryloxy refers to a "substituted hydroxyl" of the formula (-OR 1 ), wherein R 1 is an optionally substituted aryl group as defined herein, and the oxygen moiety is directly attached to the parent molecule.
• arylamino refers to a "substituted amino' Of the formula (-NR h 2 ), wherein R h is, independently, a hydrogen or an optionally substituted aryl group as defined herein, and the nitrogen moiety is directly attached to the parent molecule.
• arylthioxy refers to a "substituted thiol” of the formula (-SR r ), wherein R r is an optionally substituted aryl group as defined herein, and the sulfur moiety is directly attached to the parent molecule.
• halo and halogen refer to an atom selected from fluorine (fluoro, - F), chlorine (chloro, -CI), bromine (bromo, -Br), and iodine (iodo, -I).
• heteroaliphatic refers to an aliphatic moiety, as defined herein, which includes both saturated and unsaturated, nonaromatic, straight chain (i.e., unbranched), branched, acyclic, cyclic (e.g.
• heteroaliphatic or polycyclic hydrocarbons, which are optionally substituted with one or more functional groups, and that contain one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms, e.g., in place of carbon atoms.
• heteroaliphatic moieties are substituted by independent replacement of one or more of the hydrogen atoms thereon with one or more substituents.
• heteroaliphatic is intended herein to include, but is not limited to, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl,
• heterocycloalkenyl and heterocycloalkynyl moieties.
• heteroaliphatic includes the terms “heteroalkyl,” “heteroalkenyl”, “heteroalkynyl”, and the like.
• heteroalkyl and the like encompass both substituted and unsubstituted groups.
• heteroaliphatic is used to indicate those heteroaliphatic groups (cyclic, acyclic, substituted, unsubstituted, branched or unbranched) having 1-20 carbon atoms.
• Heteroaliphatic group substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g., aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, sulfinyl, sulfonyl, oxo, imino, thiooxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphaticamino, heteroaliphaticamino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyloxy,
• heteroalkyloxy aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, and the like, each of which may or may not be further substituted).
• heteroalkyl refers to an alkyl moiety, as defined herein, which contain one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms, e.g. , in place of carbon atoms.
• heteroalkenyl refers to an alkenyl moiety, as defined herein, which contain one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms, e.g., in place of carbon atoms.
• heteroalkynyl refers to an alkynyl moiety, as defined herein, which contain one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms, e.g., in place of carbon atoms.
• heteroalkylamino refers to a "substituted amino" of the formula (- NR h 2 ), wherein R h is, independently, a hydrogen or an optionally substituted heteroalkyl group, as defined herein, and the nitrogen moiety is directly attached to the parent molecule.
• heteroalkyloxy refers to a "substituted hydroxyl” of the formula (- OR 1 ), wherein R 1 is an optionally substituted heteroalkyl group, as defined herein, and the oxygen moiety is directly attached to the parent molecule.
• heteroalkylthioxy refers to a "substituted thiol” of the formula (-SR r ), wherein R r is an optionally substituted heteroalkyl group, as defined herein, and the sulfur moiety is directly attached to the parent molecule.
• carbocyclyl refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms ("C 3 _i 4 carbocyclyl") and zero heteroatoms in the non-aromatic ring system.
• a carbocyclyl group has 3 to 10 ring carbon atoms ("C 3 _io carbocyclyl”).
• a carbocyclyl group has 3 to 8 ring carbon atoms (“C 3 _ 8 carbocyclyl”).
• a carbocyclyl group has 3 to 7 ring carbon atoms (“C 3 _7 carbocyclyl”).
• a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3 _6 carbocyclyl”). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms ("C 4 _ 6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“Cs_6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("Cs-io carbocyclyl”).
• Exemplary C 3 _ 6 carbocyclyl groups include, without limitation, cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), and the like.
• Exemplary C 3 _ 8 carbocyclyl groups include, without limitation, the aforementioned C 3 _ 6 carbocyclyl groups as well as cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), cyclooctenyl (C 8 ), bicyclo[2.2.1]heptanyl (C 7 ), bicyclo[2.2.2]octanyl (C 8 ), and the like.
• Exemplary C 3 _io carbocyclyl groups include, without limitation, the
• C 3 _ 8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-lH-indenyl (C9), decahydronaphthalenyl (Cio), spiro[4.5]decanyl (C 10 ), and the like.
• the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can be saturated or can contain one or more carbon-carbon double or triple bonds.
• Carbocyclyl also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system.
• each instance of a carbocyclyl group is independently unsubstituted (an "unsubstituted carbocyclyl") or substituted (a "substituted carbocyclyl”) with one or more substituents.
• the carbocyclyl group is an unsubstituted C 3 _i 4 carbocyclyl.
• the carbocyclyl group is a substituted C 3 _i 4 carbocyclyl.
• “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms ("C 3 _i 4 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms ("C 3 _io cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C 3 _ 8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C 3 _6 cycloalkyl").
• a cycloalkyl group has 4 to 6 ring carbon atoms ("C 4 _6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“Cs_6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("Cs-io cycloalkyl”). Examples of Cs_6 cycloalkyl groups include cyclopentyl (C 5 ) and cyclohexyl (C5).
• C 3 _ 6 cycloalkyl groups include the aforementioned Cs_ 6 cycloalkyl groups as well as cyclopropyl (C 3 ) and cyclobutyl (C 4 ).
• C 3 _ 8 cycloalkyl groups include the aforementioned C 3 _6 cycloalkyl groups as well as cycloheptyl (C 7 ) and cyclooctyl (C 8 ).
• each instance of a cycloalkyl group is independently unsubstituted (an "unsubstituted cycloalkyl") or substituted (a "substituted cycloalkyl") with one or more substituents.
• the cycloalkyl group is an unsubstituted C 3 _i 4 cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C 3 _i 4 cycloalkyl.
• heterocyclic refers to a cyclic heteroaliphatic group.
• a heterocyclic group refers to a non-aromatic, partially unsaturated or fully saturated, 3- to 12-membered ring system, which includes single rings of 3 to 8 atoms in size, and bi- and tri-cyclic ring systems which may include aromatic five- or six-membered aryl or heteroaryl groups fused to a non-aromatic ring.
• These heterocyclic rings include those having from one to three heteroatoms independently selected from oxygen, sulfur, and nitrogen, in which the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized.
• heterocyclic refers to a non-aromatic 5-, 6-, or 7-membered ring or polycyclic group wherein at least one ring atom is a heteroatom selected from O, S, and N (wherein the nitrogen and sulfur heteroatoms may be optionally oxidized), and the remaining ring atoms are carbon, the radical being joined to the rest of the molecule via any of the ring atoms.
• Heterocyclyl groups include, but are not limited to, a bi- or tri-cyclic group, comprising fused five, six, or seven- membered rings having between one and three heteroatoms independently selected from the oxygen, sulfur, and nitrogen, wherein (i) each 5-membered ring has 0 to 2 double bonds, each 6-membered ring has 0 to 2 double bonds, and each 7-membered ring has 0 to 3 double bonds, (ii) the nitrogen and sulfur heteroatoms may be optionally oxidized, (iii) the nitrogen heteroatom may optionally be quaternized, and (iv) any of the above heterocyclic rings may be fused to an aryl or heteroaryl ring.
• heterocycles include azacyclopropanyl, azacyclobutanyl, 1,3-diazatidinyl, piperidinyl, piperazinyl, azocanyl, thiaranyl, thietanyl, tetrahydrothiophenyl, dithiolanyl, thiacyclohexanyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropuranyl, dioxanyl, oxathiolanyl, morpholinyl, thioxanyl, tetrahydronaphthyl, and the like, which may bear one or more substituents.
• Substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g., aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, sulfinyl, sulfonyl, oxo, imino, thiooxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphaticamino, heteroaliphaticamino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyloxy,
• heteroalkyloxy aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, and the like, each of which may or may not be further substituted).
• heteroaryl refer to stable aromatic mono- or polycyclic ring system having 3-20 ring atoms, of which one ring atom is selected from S, O, and N; zero, one, or two ring atoms are additional heteroatoms independently selected from S, O, and N; and the remaining ring atoms are carbon, the radical being joined to the rest of the molecule via any of the ring atoms.
• heteroaryls include, but are not limited to pyrrolyl, pyrazolyl, imidazolyl, pyridinyl (pyridyl), pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, pyyrolizinyl, indolyl, quinolinyl, isoquinolinyl, benzoimidazolyl, indazolyl, quinolinyl, isoquinolinyl, quinolizinyl, cinnolinyl, quinazolynyl, phthalazinyl, naphthridinyl,
• Heteroaryl substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g., aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, sulfinyl, sulfonyl, oxo, imino, thiooxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphaticamino, heteroaliphaticamino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyloxy,
• heteroalkyloxy aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, and the like, each of which may or may not be further substituted).
• heteroarylamino refers to a "substituted amino' Of the (-NR h 2 ), wherein R h is, independently, hydrogen or an optionally substituted heteroaryl group, as defined herein, and the nitrogen moiety is directly attached to the parent molecule.
• heteroaryloxy refers to a "substituted hydroxyl" of the formula (- OR 1 ), wherein R 1 is an optionally substituted heteroaryl group, as defined herein, and the oxygen moiety is directly attached to the parent molecule.
• heteroarylthioxy refers to a "substituted thiol” of the formula (-SR r ), wherein R r is an optionally substituted heteroaryl group, as defined herein, and the sulfur moiety is directly attached to the parent molecule.
• hydroxyl refers to the group -OH.
• nitro refers to a group of the formula (-N0 2 ).
• a "protecting group” is well known in the art and include those described in detail in Greene 's Protective Groups in Organic Synthesis, P. G. M. Wuts and T. W. Greene, 4 th edition, Wiley- Interscience, 2006, the entirety of which is incorporated herein by reference.
• Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms.
• Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, -OH, -OR aa , -N(R CC ) 2 , -CN,
• the substituent present on the nitrogen atom is an nitrogen protecting group (also referred to herein as an "amino protecting group").
• Nitrogen protecting groups such as carbamate groups include, but are not limited to, methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD- Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2- trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), l-(l-adamantyl)-l-
• TBOC 1 -methyl- l-(4-biphenylyl)ethyl carbamate (Bpoc), l-(3,5-di-t-butylphenyl)-l- methylethyl carbamate (t-Bumeoc), 2-(2'- and 4'-pyridyl)ethyl carbamate (Pyoc), 2-(N,N- dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithio carbamate, benz
• Nitrogen protecting groups such as sulfonamide groups include, but are not limited to, p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6- trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb),
• nitrogen protecting groups include, but are not limited to, phenothiazinyl-(10)-acyl derivative, N'-p-toluenesulfonylaminoacyl derivative, N'-phenylaminothioacyl derivative, N- benzoylphenylalanyl derivative, N-acetylmethionine derivative, 4,5-diphenyl-3-oxazolin-2- one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5- dimethylpyrrole, N-l,l,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5- substituted l,3-dimethyl-l,3,5-triazacyclohexan-2-one, 5-substituted l,3-dibenzyl-l,3,5- triazacyclohexan-2-one, 1 -substituted
• Dpp diphenylphosphinamide
• Mpt dimethylthiophosphinamide
• diphenylthiophosphinamide Ppt
• dialkyl phosphoramidates dibenzyl phosphoramidate, diphenyl phosphoramidate
• benzenesulfenamide o-nitrobenzenesulfenamide
• Nps 2,4- dinitrobenzenesulfenamide
• pentachlorobenzenesulfenamide 2-nitro-4- methoxybenzenesulfenamide
• triphenylmethylsulfenamide triphenylmethylsulfenamide
• 3-nitropyridinesulfenamide Npys
• the substituent present on an oxygen atom is an oxygen protecting group (also referred to herein as an "hydroxyl protecting group").
• Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 edition, John Wiley & Sons, 1999, incorporated herein by reference.
• oxygen protecting groups include, but are not limited to, methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4- methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4- pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2- trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl
• DEIPS diethylisopropylsilyl
• TDMS t-butyldimethylsilyl
• TDPS t- butyldiphenylsilyl
• tribenzylsilyl tri-p-xylylsilyl, triphenylsilyl
• DPMS diphenylmethylsilyl
• TMPS t-butylmethoxyphenylsilyl
• formate benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4- oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6- trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate
• the substituent present on a sulfur atom is a sulfur protecting group (also referred to as a "thiol protecting group").
• Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
• a "counterion” or “anionic counterion” is a negatively charged group associated with a positively charged group in order to maintain electronic neutrality.
• An anionic counterion may be monovalent (i.e., including one formal negative charge).
• An anionic counterion may also be multivalent (i.e., including more than one formal negative charge), such as divalent or trivalent.
• Exemplary counterions include halide ions (e.g., F , Cl ⁇ , Br , ⁇ ), N0 3 , C10 4 , OH , H 2 P0 4 , HC0 3 ⁇ HS0 4 , sulfonate ions (e.g., methansulfonate,
• exemplary counterions which may be multivalent include C0 3 , HP0 4 ,
• carboxylate anions e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like
• carboxylate anions e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like
• carboranes e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the
• carbohydrate refers to an aldehydic or ketonic derivative of polyhydric alcohols.
• Carbohydrates include compounds with relatively small molecules (e.g., sugars) as well as macromolecular or polymeric substances (e.g. , starch, glycogen, and cellulose polysaccharides).
• saccharide refers to monosaccharides, disaccharides, or polysaccharides. Monosaccharides are the simplest carbohydrates in that they cannot be hydrolyzed to smaller carbohydrates.
• monosaccharides can be represented by the general formula C y H 2y O y (e.g., C 6 Hi 2 0 6 (a hexose such as glucose)), wherein y is an integer equal to or greater than 3.
• C y H 2y O y e.g., C 6 Hi 2 0 6 (a hexose such as glucose)
• y is an integer equal to or greater than 3.
• Certain polyhydric alcohols not represented by the general formula described above may also be considered monosaccharides.
• deoxyribose is of the formula CsHio0 4 and is a monosaccharide.
• Monosaccharides usually consist of five or six carbon atoms and are referred to as pentoses and hexoses, receptively.
• the monosaccharide contains an aldehyde it is referred to as an aldose; and if it contains a ketone, it is referred to as a ketose.
• Monosaccharides may also consist of three, four, or seven carbon atoms in an aldose or ketose form and are referred to as trioses, tetroses, and heptoses, respectively.
• Glyceraldehyde and dihydroxyacetone are considered to be aldotriose and ketotriose sugars, respectively.
• aldotetrose sugars include erythrose and threose
• ketotetrose sugars include erythrulose.
• Aldopentose sugars include ribose, arabinose, xylose, and lyxose; and ketopentose sugars include ribulose, arabulose, xylulose, and lyxulose.
• aldohexose sugars include glucose (for example, dextrose), mannose, galactose, allose, altrose, talose, gulose, and idose; and ketohexose sugars include fructose, psicose, sorbose, and tagatose.
• Ketoheptose sugars include sedoheptulose.
• the aldohexose D-glucose for example, has the formula C 6 Hi206, of which all but two of its six carbons atoms are stereogenic, making D-glucose one of the 16 (i.e. , 2 4 ) possible stereoisomers.
• the assignment of D or L is made according to the orientation of the asymmetric carbon furthest from the carbonyl group: in a standard Fischer projection if the hydroxyl group is on the right the molecule is a D sugar, otherwise it is an L sugar.
• the aldehyde or ketone group of a straight- chain monosaccharide will react reversibly with a hydroxyl group on a different carbon atom to form a hemiacetal or hemiketal, forming a heterocyclic ring with an oxygen bridge between two carbon atoms. Rings with five and six atoms are called furanose and pyranose forms, respectively, and exist in equilibrium with the straight-chain form.
• the carbon atom containing the carbonyl oxygen becomes a stereogenic center with two possible configurations: the oxygen atom may take a position either above or below the plane of the ring.
• the resulting possible pair of stereoisomers is called anomers.
• an a anomer the -OH substituent on the anomeric carbon rests on the opposite side (trans) of the ring from the - CH 2 OH side branch.
• the alternative form, in which the -C3 ⁇ 4OH substituent and the anomeric hydroxyl are on the same side (cis) of the plane of the ring, is called a ⁇ anomer.
• a carbohydrate including two or more joined monosaccharide units is called a disaccharide or polysaccharide (e.g., a trisaccharide), respectively.
• Exemplary disaccharides include sucrose, lactulose, lactose, maltose, isomaltose, trehalose, cellobiose, xylobiose, laminaribiose, gentiobiose, mannobiose, melibiose, nigerose, and rutinose.
• Exemplary trisaccharides include, but are not limited to, isomaltotriose, nigerotriose, maltotriose, melezitose, maltotriulose, raffinose, and kestose.
• carbohydrate also includes other natural or synthetic stereoisomers of the carbohydrates described herein.
• pharmaceutically acceptable salt refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio.
• Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference.
• salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
• the salts can be prepared during the final isolation and purification of the compounds or separately by reacting the appropriate compound in the form of the free base with a suitable acid.
• Representative acid addition salts include acetate, adipate, alginate, L-ascorbate, aspartate, benzoate, benzenesulfonate
• basic groups in the compounds disclosed herein can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides.
• acids which can be employed to form therapeutically acceptable salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid; and organic acids such as oxalic acid, maleic acid, succinic acid, and citric acid.
• Basic addition salts refer to salts derived from appropriate bases, these salts including alkali metal, alkaline earth metal, and quaternary amine salts. Hence, the present invention contemplates sodium, potassium, magnesium, and calcium salts of the compounds disclosed herein, and the like.
• Basic addition salts can be prepared during the final isolation and purification of the compounds, often by reacting a carboxyl group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation or with ammonia or an organic primary, secondary, or tertiary amine.
• the cations of therapeutically acceptable salts include lithium, sodium (by using, e.g., NaOH), potassium (by using, e.g.
• KOH potassium hydroxide
• calcium by using, e.g. , Ca(OH) 2
• magnesium by using, e.g. , Mg(OH) 2 and magnesium acetate
• zinc by using, e.g. , Zn(OH) 2 and zinc acetate
• aluminum as well as nontoxic quaternary amine cations such as ammonium
• tetramethylammonium tetraethylammonium
• methylamine dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N- methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N- dibenzylphenethylamine, 1-ephenamine, and N,N-dibenzylethylenediamine.
• organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, choline hydroxide, hydroxyethyl morpholine, hydroxyethyl pyrrolidone, imidazole, n-methyl-d-glucamine, ⁇ , ⁇ '- dibenzylethylenediamine, N,A ⁇ -diethylethanolamine, N,A ⁇ -dimethylethanolamine, triethanolamine, and tromethamine.
• Basic amino acids e.g., 1-glycine and 1-arginine
• amino acids which may be zwitterionic at neutral pH e.g. , betaine (N,N,N-trimethylglycine) are also contemplated.
• tautomers refers to two or more interconvertible compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valency (e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa).
• the exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Tautomerizations (i.e., the reaction providing a tautomeric pair) may catalyzed by acid or base.
• Exemplary tautomerizations include keto-to-enol, amide-to-imide, lactam-to-lactim, enamine-to-imine, and enamine-to-(a different enamine) tautomerizations.
• polymorphs refers to a crystalline form of a compound (or a salt, hydrate, or solvate thereof). All polymorphs have the same elemental composition. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate. Various polymorphs of a compound can be prepared by crystallization under different conditions.
• solvate refers to forms of the compound, or a salt thereof, that are associated with a solvent, usually by a solvolysis reaction. This physical association may include hydrogen bonding.
• solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like.
• the compounds of the invention may be prepared, e.g., in crystalline form, and may be solvated.
• Suitable solvates include pharmaceutically acceptable solvates and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of a crystalline solid.
• “Solvate” encompasses both solution-phase and isolable solvates.
• Representative solvates include hydrates, ethanolates, and methanolates.
• hydrate refers to a compound that is associated with water.
• the number of the water molecules contained in a hydrate of a compound is in a definite ratio to the number of the compound molecules in the hydrate. Therefore, a hydrate of a compound may be represented, for example, by the general formula R xH 2 0, wherein R is the compound and wherein x is a number greater than 0.
• a given compound may form more than one type of hydrates, including, e.g., monohydrates (x is 1), lower hydrates (x is a number greater than 0 and smaller than 1, e.g. , hemihydrates (R 0.5H 2 O)), and polyhydrates (x is a number greater than I, e.g., dihydrates (R-2H 2 0) and hexahydrates (R-6H 2 0)).
• the term "subject" refers to any animal.
• the subject is a mammal.
• the subject is a human (e.g., a man, a woman, or a child).
• the human may be of either sex and may be at any stage of development.
• the subject has been diagnosed with the condition or disease to be treated.
• the subject is at risk of developing the condition or disease.
• the subject is an experimental animal (e.g. , mouse, rat, rabbit, dog, pig, or primate).
• the experimental animal may be genetically engineered.
• the subject is a domesticated animal (e.g., dog, cat, bird, horse, cow, goat, sheep).
• administer refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing an inventive compound, or a pharmaceutical composition thereof.
• treatment refers to reversing, alleviating, delaying the onset of, or inhibiting the progress of a "pathological condition” (e.g. , a disease, disorder, or condition, or one or more signs or symptoms thereof) described herein.
• pathological condition e.g. , a disease, disorder, or condition, or one or more signs or symptoms thereof
• treatment may be administered after one or more signs or symptoms have developed or have been observed.
• treatment may be administered in the absence of signs or symptoms of the disease or condition.
• treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.
• condition means "condition,” "pathological condition,” “disease,” and “disorder” are used interchangeably.
• an effective amount of a compound of the invention refers to an amount sufficient to elicit the desired biological response, e.g. , treating the condition.
• the effective amount of a compound of the invention may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject.
• an effective amount is a therapeutically effective amount.
• an effective amount is a prophylactic treatment.
• an effective amount is the amount of a compound described herein in a single dose.
• an effective amount is the combined amounts of a compound described herein in multiple doses.
• a "therapeutically effective amount" of a compound of the present invention or a pharmaceutical composition thereof is an amount sufficient to provide a therapeutic benefit in the treatment of a condition, e.g., iron overload, or to delay or minimize one or more symptoms associated with the condition.
• a therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition.
• the term "therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of the condition, and/or enhances the therapeutic efficacy of another therapeutic agent.
• a therapeutically effective amount is an amount sufficient for chelating a metal described herein.
• a therapeutically effective amount is an amount sufficient for treating a pathological condition described herein.
• a therapeutically effective amount is an amount sufficient for chelating a metal described herein and for treating a pathological condition described herein.
• a prophylactically effective amount of a compound of the present invention is an amount sufficient to prevent a condition, e.g. , iron overload, or one or more symptoms associated with the condition or prevent its recurrence.
• a prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the condition.
• the term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.
• a prophylactically effective amount is an amount sufficient for chelating a metal described herein.
• a prophylactically effective amount is an amount sufficient for preventing a pathological condition described herein. In certain embodiments, a prophylactically effective amount is an amount sufficient for chelating a metal described herein and for preventing a pathological condition described herein.
• tissue samples such as tissue sections and needle biopsies of a tissue
• cell samples e.g., cytological smears (such as Pap or blood smears) or samples of cells obtained by microdissection); samples of whole organisms (such as samples of yeasts or bacteria); or cell fractions, fragments or organelles (such as obtained by lysing cells and separating the components thereof by centrifugation or otherwise).
• Other examples of biological samples include blood, serum, urine, semen, fecal matter, cerebrospinal fluid, interstitial fluid, mucous, tears, sweat, pus, biopsied tissue (e.g. , obtained by a surgical biopsy or needle biopsy), nipple aspirates, milk, vaginal fluid, saliva, swabs (such as buccal swabs), or any material containing biomolecules that is derived from a first biological sample.
• “Chelation,” “chelating,” “sequestration,” or “sequestering” is the formation or presence of two or more separate coordinate bonds between a polydentate (multiple-bonded) compound and a single central atom.
• the polydentate compound is typically an organic compound and referred to as a "chelator,” “chelant,” “chelating agent,” “sequestrator,” “sequestering agent,” or “ligand.”
• the central atom is usually a metal atom or metal ion (e.g.
• a metal atom or metal ion described herein such as iron (e.g., Fe(III)), Al(III), chromium (e.g., Cr(III) or Cr(VI)), and uranium (e.g., U(VI)), etc.).
• the chelator may form a stable complex with the central atom through coordinate bonds, inactivating the central atom so that the central atom is less likely to react with other molecules or atoms.
• metal-clearing efficiency refers to the efficacy of a given concentration of chelator in clearing a metal atom or metal ion (e.g., a metal atom or metal ion described herein, such as iron (e.g. , Fe(III)), Al(III), chromium (e.g. , Cr(III) or Cr(VI)), and uranium (e.g. , U(VI)) from the body or one of its organs or parts.
• Efficaciousness in turn concerns quantity of the metal atom or metal ion removed from a target system (e.g. , a whole body, an organ, or a tissue) in a unit of time.
• Chelators of a metal atom or metal ion are needed in one or more of three clinical situations: (1) for acute metal toxicity from ingestion or infusion of the metal atom or metal ion; (2) to reduce total body metal secondary to transfusion or excess metal absorption; and (3) for the maintenance of metal balance after total body metal has been satisfactorily reduced and only daily dietary metal needs to be excreted.
• the recommendation is that 0.3-0.5 mg/kg/d (i.e. , mg iron per kg body weight of the subject per day) need be excreted.
• 0.25- 1 mg/kg/d is sufficient. Other ranges are also possible.
• the metal-clearing efficiency is iron- clearing efficiency or "ICE.” In certain embodiments, the metal-clearing efficiency is aluminum-clearing efficiency. In certain embodiments, the metal-clearing efficiency is chromium-clearing efficiency. In certain embodiments, the metal-clearing efficiency is uranium-clearing efficiency.
• Focal iron overload refers to any disease or condition that involves the accumulation of unmanaged iron in a tissue or organ. Focal iron overload typically involves less than the subject's whole body but may involve more than one organ or tissue.
• Unmanaged iron in any tissue or organ is typically undesired and can be the focus of the treatments of the present invention.
• the treatment may involve the removal of as much iron as possible from the tissue or organ or may only involve the removal of excess iron.
• focal iron overload examples include, but are not limited to, macular degeneration, IBD, reperfusion injury, stroke including hemorrhagic stroke, and closed head injury; however, any disease or condition of focal iron overload may be treated as described herein.
• focal iron overload does not include diseases or conditions associated with global iron overload (e.g. , global iron overload associated with chronic transfusion therapy, hereditary hemochromatosis, etc.).
• the treatment of focal iron overload may be systemic or local administration of an effective amount of an inventive compound, or a pharmaceutical composition thereof.
• Reactive oxygen species refers to molecules or ions formed by the incomplete reduction of oxygen.
• Reactive oxygen species include superoxide anion (0 2 * ), peroxides such as hydrogen peroxide (H 2 0 2 ), hydroxyl radical (HO * ), and
• hypochlorous acid HCIO
• Reactive oxygen species may be formed by any number of mechanisms (e.g., enzymatically, by ionizing radiation, by reaction oxygen with a metal).
• the reactive oxygen species are formed by the reduction of oxygen by an iron ion, such as Fe +2 .
• Primary hemochromatosis is a genetic disorder characterized by excessive iron accumulation that results in tissue damage. Manifestations include systemic symptoms, liver disorders, cardiomyopathy, diabetes, erectile dysfunction, and arthropathy. Normal total body iron content is about 2.5 g in women and 3.5 g in men. Because symptoms may be delayed until iron accumulation is excessive, hemochromatosis may not be recognized until total body iron content is >10 g, or often several times greater. In women, clinical manifestations are uncommon before menopause because iron loss due to menses (and sometimes pregnancy and childbirth) tends to offset iron accumulation. One mechanism for iron overload is increased iron absorption from the gastrointestinal tract, leading to chronic deposition of iron in the tissues.
• Hepcidin a liver-derived peptide
• Hepcidin is the critical control mechanism for iron absorption. Hepcidin, along with the normal HFE gene, prevents excessive iron absorption and storage in normal people. Tissue injury in a subject with primary hemochromatosis may result from reactive free hydroxyl radicals generated when iron deposition in tissues catalyzes their formation. Other mechanisms may affect particular organs (e.g., skin hyperpigmentation can result from increased melanin as well as iron accumulation).
• Secondary hemochromatosis is a condition acquired as a consequence of another disease that causes iron overload, or blood transfusions, or both, and typically characterized by increased hepatic and total body iron content and unequivocal portal cirrhosis of the liver.
• Secondary hemochromatosis is usually caused by disorders of erythropoiesis (e.g. , thalassemia, sickle cell anemia, X-linked sideroblastic anemia, pyruvate kinase deficiency, hereditary spherocytosis, and congenital dyserythropoietic anemia (CD A)) and the treatment of these diseases with blood transfusions.
• erythropoiesis e.g. , thalassemia, sickle cell anemia, X-linked sideroblastic anemia, pyruvate kinase deficiency, hereditary spherocytosis, and congenital dyserythropoietic anemia (CD A)
• Diabetes or "diabetes mellitus” is a metabolic disorder in which there are high levels of glucose in the blood. Diabetes can be caused by insufficient amount of insulin (a hormone produced by the pancreas to control blood glucose) or resistance to insulin in a subject, or both.
• Type 1 diabetes is usually diagnosed in children and young adults, and was previously known as juvenile diabetes. In Type 1 diabetes, the body does not produce insulin, which may be a result of the destruction of islet cells in the pancreas.
• Type 2 diabetes or non- insulin-dependent diabetes mellitus (NIDDM) or adult-onset diabetes, is the most common form of diabetes.
• NIDDM non- insulin-dependent diabetes mellitus
• Type 2 diabetes is characterized by high blood glucose in the context of insulin resistance and relative insulin deficiency. This is in contrast to Type 1 diabetes in which there is an absolute insulin deficiency. Obesity is thought to be one of the primary causes of Type 2 diabetes in subjects who are genetically predisposed to obesity.
• Gestational diabetes is characterized by high blood glucose that develops during pregnancy in a woman who does not have diabetes prior to the pregnancy. Gestational diabetes may be caused by various pregnancy hormones that may interfere with the body's response to insulin.
• closed head injury refers to any injury to the head that does not penetrate the skull. Closed head injuries may result from falls, blasts, accidents including vehicular accidents, and assaults. Closed head injuries can lead to hemorrhage or brain swelling, which can result in increased intracranial pressure, which can in turn lead to permanent brain damage or even death.
• Various types of closed head injury include concussions, brain contusions, diffuse axonal injury, and hematomas.
• Thalassemia is a group of inherited autosomal recessive blood disorders that originated in the Mediterranean region.
• the genetic defect which could be either mutation or deletion, results in reduced rate of synthesis or no synthesis of one of the globin chains that make up hemoglobin. This can cause the formation of abnormal hemoglobin molecules, thus causing anemia.
• Alpha thalassemia occurs when a gene or genes related to the alpha globin protein are missing or changed (i.e., mutated).
• Beta thalassemia occurs when similar gene defects affect production of the beta globin protein.
• Each of alpha and beta thalassemias includes two forms: thalassemia major and thalassemia minor. Beta thalassemia major is also referred to as Cooley's anemia or Mediterranean anemia.
• Friedreich's ataxia or "FRDA” is an inherited disease that causes progressive damage to the nervous system of a subject resulting in symptoms including muscle weakness, speech problems, and heart disease.
• FRDA FRDA
• the spinal cord and peripheral nerves degenerate and become thinner.
• the cerebellum part of the brain that coordinates balance and movement, also degenerates to a lesser extent. This damage results in awkward, unsteady movements and impaired sensory functions.
• Friedreich's ataxia also causes problems in the heart and spine, and some subjects with the condition develop diabetes. However, this disorder usually does not affect cognitive functions, such as thinking and reasoning.
• Friedreich's ataxia is caused by a defect, which may be a result of mutation, in a gene labeled as FXN.
• This disorder is recessive, meaning it occurs only in someone who inherits two defective copies of the gene, one from each parent.
• Macular degeneration is a disease that affects the retina of a subject.
• the retina is a thin tissue lining the back of the eye.
• Light-sensitive cells in the retina are responsible for converting light into electrical impulses, which are then sent via the optic nerve to the brain for interpretation.
• the macula contains the highest concentration of the light-sensitive cells, called cones, which are responsible for sharp, detailed, and central vision.
• cones the highest concentration of the light-sensitive cells, called cones, which are responsible for sharp, detailed, and central vision.
• macular degeneration cells in the macular region begin to die, which results in blind spots and distorted vision.
• Macular degeneration is the leading cause of vision loss in humans over the age of 60. There are two forms of macular degeneration: dry and wet macular degenerations.
• Dry macular degeneration is the most common type of macular degeneration, in which the photosensitive cells of the macula slowly break down.
• Yellow deposits called drusen extracellular waste products from metabolism
• RPE retinal pigmented epithelium
• Bruch's membrane which supports the retina.
• drusen are associated with deterioration of the macula and the death of RPE and photoreceptor cells, resulting in a blurring or spotty loss of clear, straight- ahead vision. This process does not cause any pain.
• the subject may notice slightly blurry vision.
• neoplasm and “tumor” are used herein interchangeably and refer to an abnormal mass of tissue wherein the growth of the mass surpasses and is not coordinated with the growth of a normal tissue.
• a neoplasm or tumor may be “benign” or “malignant,” depending on the following characteristics: degree of cellular differentiation (including morphology and functionality), rate of growth, local invasion, and metastasis.
• a “benign neoplasm” is generally well differentiated, has characteristically slower growth than a malignant neoplasm, and remains localized to the site of origin.
• a benign neoplasm does not have the capacity to infiltrate, invade, or metastasize to distant sites.
• Exemplary benign neoplasms include, but are not limited to, lipoma, chondroma, adenomas, acrochordon, senile angiomas, seborrheic keratoses, lentigos, and sebaceous hyperplasias.
• certain "benign" tumors may later give rise to malignant neoplasms, which may result from additional genetic changes in a subpopulation of the tumor's neoplastic cells, and these tumors are referred to as "pre-malignant neoplasms.”
• An exemplary pre-malignant neoplasm is a teratoma.
• a malignant neoplasm is generally poorly differentiated (anaplasia) and has characteristically rapid growth accompanied by progressive infiltration, invasion, and destruction of the surrounding tissue. Furthermore, a malignant neoplasm generally has the capacity to metastasize to distant sites.
• the term “metastasis,” “metastatic,” or “metastasize” refers to the spread or migration of cancerous cells from a primary or original tumor to another organ or tissue and is typically identifiable by the presence of a "secondary tumor” or “secondary cell mass” of the tissue type of the primary or original tumor and not of that of the organ or tissue in which the secondary (metastatic) tumor is located.
• a prostate cancer that has migrated to bone is said to be metastasized prostate cancer and includes cancerous prostate cancer cells growing in bone tissue.
• cancer refers to a class of diseases characterized by the development of abnormal cells that proliferate uncontrollably and have the ability to infiltrate and destroy normal body tissues. See, e.g. , Stedman 's Medical Dictionary, 25th ed.; Hensyl ed.; Williams & Wilkins: Philadelphia, 1990.
• Exemplary cancers include, but are not limited to, hematological malignancies. Hematological malignancies are tumors that affect blood, bone marrow, and/or lymph nodes. Exemplary hematological malignancies include, but are not limited to, leukemia, such as acute lymphocytic leukemia (ALL) (e.g.
• ALL acute lymphocytic leukemia
• B-cell ALL B-cell ALL, T-cell ALL
• AML acute myelocytic leukemia
• CML chronic myelocytic leukemia
• CLL chronic lymphocytic leukemia
• lymphoma such as Hodgkin lymphoma (HL) (e.g. , B-cell HL, T-cell HL) and non-Hodgkin lymphoma (NHL) (e.g. , B-cell NHL, such as diffuse large cell lymphoma (DLCL) (e.g.
• DLBCL diffuse large B-cell lymphoma
• ABSCL activated B-cell
• follicular lymphoma chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphoma (e.g. , mucosa-associated lymphoid tissue (MALT) lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, Waldenstrom' s
• WM lymphoplasmacytic lymphoma
• HCL hairy cell leukemia
• CNS central nervous system
• T-cell NHL T-cell NHL
• PTCL peripheral T-cell lymphoma
• CNS central nervous system
• PTCL peripheral T-cell lymphoma
• CCL cutaneous T-cell lymphoma
• lymphoma of an immune privileged site e.g., cerebral lymphoma, ocular lymphoma, lymphoma of the placenta, lymphoma of the fetus, testicular lymphoma
• MM multiple myeloma
• Additional exemplary cancers include, but are not limited to, lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung); kidney cancer (e.g., nephroblastoma, a.k.a. Wilms' tumor, renal cell carcinoma); acoustic neuroma;
• lung cancer e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung
• kidney cancer e.g., nephroblastoma, a.k.a. Wilms' tumor, renal cell carcinoma
• acoustic neuroma e.g., acoustic neuroma
• adenocarcinoma adenocarcinoma
• adrenal gland cancer anal cancer
• angiosarcoma e.g. , lymphangiosarcoma, lymphangioendothelio sarcoma, hemangio sarcoma
• appendix cancer benign monoclonal gammopathy
• biliary cancer e.g. , cholangiocarcinoma
• bladder cancer e.g.
• adenocarcinoma of the breast papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast
• brain cancer e.g., meningioma, glioblastomas, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchus cancer; carcinoid tumor; cervical cancer (e.g. , cervical adenocarcinoma); choriocarcinoma; chordoma;
• colorectal cancer e.g., colon cancer, rectal cancer, colorectal
• adenocarcinoma connective tissue cancer
• epithelial carcinoma connective tissue cancer
• ependymoma connective tissue cancer
• endotheliosarcoma e.g., Kaposi' s sarcoma, multiple idiopathic hemorrhagic sarcoma
• endometrial cancer e.g., uterine cancer, uterine sarcoma
• esophageal cancer e.g. , adenocarcinoma of the esophagus, Barrett' s adenocarcinoma
• Ewing' s sarcoma ocular cancer (e.g., intraocular melanoma, retinoblastoma); familiar hypereosinophilia; gall bladder cancer; gastric cancer (e.g., stomach adenocarcinoma); gastrointestinal stromal tumor (GIST); germ cell cancer; head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)); heavy chain disease (e.g., alpha chain disease, gamm
• HCC hepatocellular cancer
• MMS leiomyosarcoma
• mastocytosis e.g., systemic mastocytosis
• muscle cancer e.g., myelodysplastic syndrome (MDS);
• MPD myeloproliferative disorder
• PV polycythemia vera
• ET essential thrombocytosis
• ALM agnogenic myeloid metaplasia
• CML chronic myelocytic leukemia
• CTL chronic neutrophilic leukemia
• HES hypereosinophilic syndrome
• neurofibromatosis NF
• type 1 or type 2 schwannomatosis
• neuroendocrine cancer e.g., gastroenteropancreatic neuroendocrine tumor (GEP-NET), carcinoid tumor
• osteosarcoma e.g., bone cancer
• ovarian cancer e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma
• papillary adenocarcinoma pancreatic cancer (e.g., pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), Islet cell tumors)
• penile cancer e.g., Paget' s disease of the penis and scrotum
• pinealoma primitive neuroectodermal tumor (PNT); plasma cell neoplasia; paraneoplastic syndromes; intraepithelial neoplasms; prostate cancer (e.
• prostate adenocarcinoma rectal cancer; rhabdomyosarcoma; salivary gland cancer; skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)); small bowel cancer (e.g. , appendix cancer); soft tissue sarcoma (e.g. , malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland carcinoma; small intestine cancer; sweat gland carcinoma; synovioma;
• SCC squamous cell carcinoma
• KA keratoacanthoma
• BCC basal cell carcinoma
• small bowel cancer e.g. , appendix cancer
• soft tissue sarcoma e.g. , malignant fibr
• testicular cancer e.g. , seminoma, testicular embryonal carcinoma
• thyroid cancer e.g. , papillary carcinoma of the thyroid, papillary thyroid carcinoma (PTC), medullary thyroid cancer
• urethral cancer e.g. , vaginal cancer
• vulvar cancer e.g. , Paget' s disease of the vulva
• a "preneoplastic disease” is a disease that precedes the formation of a benign or malignant neoplasm.
• a precancerous lesion typically forms before a malignant neoplasm.
• Preneoplastic diseases include, but are not limited to, photodermatitis, x-ray dermatitis, tar dermatitis, arsenic dermatitis, lupus dermatitis, senile keratosis, Paget disease, condylomata, burn scar, syphilitic scar, fistula scar, ulcus cruris scar, chronic ulcer, varicose ulcer, bone fistula, rectal fistula, Barrett esophagus, gastric ulcer, gastritis, cholelithiasis, kraurosis vulvae, nevus pigmentosus, Bowen dermatosis, xeroderma pigmentosum, erythroplasia, leukoplakia,
• Figure 1 shows the structures of some iron chelators evaluated clinically in humans.
• Figures 2A-2B show the tissue metabolism/distribution of compounds 2 and 4-7 in rat liver.
• the concentration data of the compounds -axis) are expressed as nmol/g wet weight of the liver.
• "Admin. Cmpd.” administered compound.
• Figure 3 shows the dealkylation of the methyl ether of glycodiazine, first to an alcohol (metabolite I), which is then oxidized to a carboxylic acid (metabolite II).
• Figure 4 shows the a putative metabolism of compound 7 into compounds 8 and 9, and the lipophilicity (log P a pp) of compounds 7 to 9.
• Figure 5A shows the tissue metabolism/distribution of compounds 7 and 8 in rat plasma, liver, kidney, heart, and pancreas.
• Figure 5B shows the tissue
• FIG. 5C shows the tissue metabolism/distribution of compounds 7 and 8 in rat liver.
• Figure 5D shows the tissue metabolism/distribution of compounds 7 and 8 in rat kidney.
• Figure 5E shows the tissue metabolism/distribution of compounds 7 and 8 in rat heart.
• Figure 5F shows the tissue metabolism/distribution of compounds 7 and 8 in rat pancreas.
• the concentration data ( -axis) of the compounds are expressed as nmol/g wet weight of the organ (e.g., liver, kidney, heart, pancreas), or as ⁇ (plasma).
• Administration. Cmpd administered compound.
• Figure 6 shows a putative metabolism of compound 11 into compounds 12 to 14, and the lipophilicity (log P a pp) of the compounds 11 to 14.
• Figure 7 A shows the tissue metabolism/distribution of compound 11 in rat heart.
• Figure 7B shows the tissue metabolism/distribution of compound 11 in rat plasma.
• Figure 7C shows the tissue metabolism/distribution of compound 11 in rat liver.
• Figure 7D shows the tissue metabolism/distribution of compound 11 in rat kidney.
• Figure 7E shows the tissue metabolism/distribution of compound 11 in rat pancreas.
• the concentration data (y-axis) of compound 11 are expressed as nmol/g wet weight or the organ (e.g., liver, kidney, heart, pancreas), or as ⁇ (plasma).
• Administration. Cmpd administered compound.
• Figure 8 is a schematic representation of the oral absorption of compound 11, and the rapid metabolism of compound 11 into compounds 12 to 14.
• Compound 11 is highly lipophilic, and compounds 12 to 14 are hydrophilic.
• the present invention provides, in one aspect, compounds of Formula (I), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof.
• desazadesferrithiocin analogs are able to chelate a metal (e.g., iron and other metals).
• the invention also provides pharmaceutical compositions, kits, methods, and uses that involve or include a desazadesferrithiocin analog described herein.
• the present invention provides, in another aspect, compounds of Formula (II), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof.
• the invention also provides pharmaceutical compositions, kits, methods, and uses that involve or include a compound of Formula (I) or Formula (II) described herein.
• the compounds, pharmaceutical compositions, kits, and methods may be useful in chelating a metal in a subject, cell, tissue, or biological sample.
• the compounds, pharmaceutical compositions, kits, and methods may also be useful in treating a disease in a subject, preventing a disease in a subject, treating, reducing, or preventing the formation of biofilms in a subject, or reducing or preventing the formation of biofilms on or in an object.
• the disease is a metal overload, oxidative stress, transfusional iron overload, thalassemia, primary hemochromatosis, secondary hemochromatosis, diabetes, liver disease, heart disease, cancer, radiation injury, neurological or neurodegenerative disorder, Friedreich's ataxia (FRDA), macular degeneration, closed head injury, irritable bowel disease, or reperfusion injury.
• the disease is metal poisoning.
• the disease is an infectious disease (e.g., malaria).
• Desfemthiocin (DFT) 1 is a natural product iron chelator isolated from
• Streptomyces antibioticus (Naegeli et al., "Metabolites of Microorganisms. Part 193.
• H 2 O 2 H 2 O 2
• H 2 O 2 H 2 O 2
• HO * hydroxyl radical
• HO hydroxyl radical
• the hydroxyl radical reacts very quickly with a variety of cellular constituents and can initiate radical-mediated chain processes that damage DNA and membranes, as well as produce carcinogens. 23
• the cyclic nature of the Fenton reaction adds to the potential danger.
• the Fe(III) liberated in this reaction is converted back to Fe(II) via a variety of biological reductants, e.g., ascorbate or glutathione.
• Deferitrin (2, Figure i) was taken into human clinical trials by Genzyme. Chelator 2 was well tolerated in patients at doses of 5, 10, or 15 mg/kg/day once daily (s.i.d) for up to 12 weeks, 46 and iron clearance levels were approaching the requisite 450 ⁇ g/kg/d. 47 However, when the drug was given twice daily (b.i.d) at a dose of 12.5 mg/kg (25 mg/kg/d), unacceptable renal toxicity, e.g., increases in blood urea nitrogen (BUN) and serum creatinine (SCr), were observed in three patients after only 4-5 weeks of treatment and the study was
• a magnesium salt of ligand 6 (SPD602, deferitazole magnesium, CAS # 1173092- 59-5) was evaluated in clinical trials by Shire. 53 ' 54 Since 6 is an oil, and its sodium salt is hygroscopic, dosage form issues may have driven their choice of a magnesium salt. It is interesting to speculate as to whether or not the gastrointestinal (GI) and other side effects observed with the magnesium salt of 6 53 ⁇ 54 derive from the magnesium itself. 55"57 All of our studies with 6 were conducted with the monosodium salt. 41 ' 51 ' 52 ' 58 It remains to be seen how well the magnesium salt will perform in patients.
• GI gastrointestinal
• DFT and DADFT analogs as a class of compounds appear promising as metal chelating agents, work may be done to improve these compounds' physicochemical, pharmacokinetic, pharmacodynamic, and/or toxicological properties, such as absorption, distribution, metal-clearing efficiency, and toxicity, for the purpose of providing safe and effective compounds for a better treatment and/or prevention of pathological conditions in a subject.
• R 1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, an
• each instance of R' is independently hydrogen, substituted or unsubstituted alkyl, oxygen protecting group
• n is independently an integer from 1 to 8, inclusive;
• each instance of x is independently an integer between 0 and 8, inclusive;
• each instance of m is independentlyan integer from 1 to 8, inclusive;
• each instance of y is independently an integer from 0 to 8, inclusive;
• each instance of p is independently an integer between 1 and 10, inclusive;
• R 1 is of the formula:
• each instance of R is independently halogen, substituted or unsubstituted alkyl, or -
• OR 8 wherein each instance of R 8 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, an oxygen protecting group, or
• k 0, 1, 2, 3, or 4;
• R 4 is hydrogen or substituted or unsubstituted alkyl
• R 5 is hydrogen or substituted or unsubstituted alkyl
• R 6 is hydrogen or substituted or unsubstituted alkyl
• Z is -O- or -S-
• R is hydrogen, substituted or unsubstituted alkyl, or
• Formula (I) includes substituent -O-R 1 at the 2'-position of the phenyl ring.
• R 1 is H.
• R 1 is substituted or unsubstituted alkyl (e.g. , substituted or unsubstituted Ci_ 6 alkyl).
• R 1 is Me.
• R 1 is Et, Pr, Bu, unsubstituted pentyl, or unsubstituted hexyl.
• R 1 is substituted methyl (e.g. , -CF 3 , or Bn), substituted ethyl (e.g. ,
• perfluoroethyl substituted propyl (e.g. , perfluoropropyl), substituted butyl (e.g. ,
• R 1 is substituted or unsubstituted acyl.
• R 1 is an oxygen protecting group (e.g.
• R 1 silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, ⁇ -Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl).
• R 1 silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, ⁇ -Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl).
• -O-R 1 is of the formula:
• -O-R 1 is of the formula:
• -O-R 1 is of the formula:
• -O-R 1 is of the formula: . In certain embodiments, -O-R 1 is of the formula:
• Formula (I) may include one or more instances of substituent R'.
• any two instances of R a may independently be the same or different from each other.
• at least one instance of R' is H.
• each instance of R' is H.
• at least one instance of R' is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C 1-6 alkyl).
• at least one instance of R' is Me.
• at least one instance of R' is Et, Pr, Bu, unsubstituted pentyl, or unsubstituted hexyl.
• At least one instance of R' is substituted methyl (e.g., -CF 3 , or Bn), substituted ethyl (e.g. , perfluoroethyl), substituted propyl (e.g. , perfluoropropyl), substituted butyl (e.g. , perfluorobutyl), substituted pentyl (e.g., perfluoropentyl), or substituted hexyl (e.g., perflourohexyl).
• substituted methyl e.g., -CF 3 , or Bn
• substituted ethyl e.g. , perfluoroethyl
• substituted propyl e.g. , perfluoropropyl
• substituted butyl e.g. , perfluorobutyl
• substituted pentyl e.g., perfluoropentyl
• hexyl e.g
• At least one instance of R' is an oxygen protecting group (e.g., acyl, silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, f-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl).
• an oxygen protecting group e.g., acyl, silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, f-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl.
• Formula (I) may include moiety at the 3', 4', 5', or
• any two instances of n may independently be the same or different from each other.
• at least one instance of n is 1.
• at least one instance of n is 2.
• each instance of n is 2.
• at least one instance of n is 3, 4, 5, 6, 7, or 8.
• any two instances of x may independently be the same or different from each other.
• at least one instance of x is 0. In certain embodiments, at least one instance of x is 1. In certain embodiments, at least one instance of x is 2. In certain embodiments, each instance of x is 2. In certain embodiments, at least one instance of x is 3. In certain embodiments, at least one instance of x is 4. In certain embodiments, at least one instance of x is 5, 6, 7, or 8.
• any two instances of m may independently be the same or different from each other.
• at least one instance of m is 1.
• at least one instance of m is 2.
• each instance of m is 2.
• at least one instance of m is 3, 4, 5, 6, 7, or 8.
• any two instances of y may independently be the same or different from each other.
• at least one instance of y is 0. In certain embodiments, at least one instance of y is 1. In certain embodiments, at least one instance of y is 2. In certain embodiments, at least one instance of y is 3. In certain embodiments, at least one instance of y is 4. In certain embodiments, at least one instance of y is 5, 6, 7, or 8.
• each of x and y is 0. In certain embodiments, each instance of x is 1, 2, 3, or 4; each instance of n is 2; and each instance of y is 0. In certain embodiments, each instance of x is 1; each instance of n is 2; and each instance of y is 0. In certain embodiments, each instance of x is 2; each instance of n is 2; and each instance of y is 0. In certain embodiments, each instance of x is 3; each instance of n is 2; and each instance of y is 0. In certain embodiments, each instance of x is 4; each instance of n is 2; and each instance of y is 0.
• any two instances of p may independently be the same or different from each other.
• at least one instance of p is 1.
• at least one instance of p is 2.
• at least one instance of p is 3.
• at least one instance of p is 4.
• at least one instance of p is 5.
• at least one instance of p is 6, 7, 8, 9, or 10.
• each of x and y is 0; and at least one instance of p is 1, 2, 3, 4, or 5.
• each instance of x is 1, 2, 3, or 4; each instance of n is 2; each instance of y is 0; and at least one instance of p is 1, 2, 3, 4, or 5.
• each instance of x is 1; each instance of n is 2; each instance of y is 0; and at least one instance of p is 1, 2, 3, 4, or 5. In certain embodiments, each instance of x is 2; each instance of n is 2; each instance of y is 0; and at least one instance of p is 1, 2, 3, 4, or 5. In certain embodiments, each instance of x is 3; each instance of n is 2; each instance of y is 0; and at least one instance of p is 1, 2, 3, 4, or 5. In certain embodiments, each instance of x is 4; each instance of n is 2; each instance of y is 0; and at least one instance of p is 1, 2, 3, 4, or 5.
• R is not of the formula: and q q is 1. In certain embodiments, R is of the [00136] In certain embodiments, at least one moiety is at the '-position of the phenyl ring. In certain embodiments, at least one moiety of the phenyl ring. In certain embodiments. is at the 5 '-position of the phenyl ring. In certain embodiments, at least one moiety is at the 6'-position of the phenyl ring. In certain embodiments, the moiety at the 3',
• R 2 ⁇ 0— j R 2 ⁇ 0— ⁇ ', 5', or 6'-position of the phenyl ring is of the formula: ? , ? ,
• the moiety at the 3', 4', 5', or 6' posi ⁇ ,ti ⁇ on o f f t rt h.e pattyheny ,l ri ⁇ ng i ⁇ s o f f t,he formul ,a: , * 2a 0
• the moiety at the 3', 4', 5', or 6'-position of the phenyl ring is of the
• the moiety at the 3', 4', 5', or 6'-position of the phenyl ring is of the formula: c ertain embodiments, the moiety at the 3' 4', 5', or 6'-position of the phenyl ring is of the formula:
• the moiety at the 3', 4', 5' In certain embodiments, the moiety
• the moiety ', 4', ', or 6'-position of the phenyl ring is of the
• any two instances of R may independently be the same or different from each other.
• at least one instance of R 2 is -CH 2 OR 2a .
• at least one instance of R 2 is - CH 2 OR 2a , wherein R 2a is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted Ci_6 alkyl).
• at least one instance of R is -CH 2 OMe.
• At least one instance of R is -CH 2 OEt, -CH 2 OPr, -CH 2 OBu, - CH 2 0(unsubstituted pentyl), or -CH 2 0(unsubstituted hexyl).
• At least one instance of R is -CH 2 0(substituted methyl) (e.g., -CH 2 OCF 3 or -CH 2 OBn), - CH 2 0(substituted ethyl) (e.g., -CH 2 0(perfluoroethyl)), -CH 2 0(substituted propyl) (e.g., - CH 2 0(perfluoropropyl)), -CH 2 0(substituted butyl) (e.g., -CH 2 0(perfluorobutyl)), - CH 2 0(substituted pentyl) (e.g., -CH 2 0(perfluoropentyl)), or -CH 2 0(substituted hexyl) (e.g.
• R 2 is -CH 2 OR 2a , wherein R 2a is an oxygen protecting group (e.g., acyl, silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, ⁇ -Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl).
• R 2a is an oxygen protecting group (e.g., acyl, silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, ⁇ -Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl).
• At least one instance of R is -CH 2 OH
• R 2a is an oxygen protecting group (e.g. , acyl, silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, ⁇ -Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl).
• Formula (I) may include one or more substituents R 3 at the 3', 4', 5', and/or 6'- position of the phenyl ring.
• any two instances of R may independently be the same or different from each other.
• at least one instance of R is halogen (e.g., F, CI, Br, or I).
• at least one instance of R is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C 1-6 alkyl).
• R is Me.
• at least one instance of R is Et, Pr, Bu, unsubstituted pentyl, or unsubstituted hexyl.
• at least one instance of R is substituted methyl (e.g. , -CF 3 , or Bn), substituted ethyl (e.g., perfluoroethyl), substituted propyl (e.g., perfluoropropyl), substituted butyl (e.g., perfluorobutyl), substituted pentyl (e.g. , perfluoropentyl), or substituted hexyl (e.g. , perfluorohexyl).
• at least one instance of R is Et, Pr, Bu, unsubstituted pentyl, or unsubstituted hexyl.
• at least one instance of R is substituted methyl (e.g. , -CF 3 , or Bn), substituted ethyl
• R 3 8 3 one instance of R is -OR . In certain embodiments, at least one instance of R is -OH. In certain embodiments, no instance of R is -OH.
• At least one instance of R is -OR , wherein R is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C 1-6 alkyl).
• R is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C 1-6 alkyl).
• At least one instance of R is -OMe. In certain embodiments, no instance of R is -OMe. In certain embodiments, at least one instance of R is -OEt, -OPr, -OBu, - 0(unsubstituted pentyl), or -0(unsubstituted hexyl). In certain embodiments, at least one instance of R is -0(substituted methyl) (e.g. , -OCF 3 or -OBn), -0(substituted ethyl) (e.g.
• R 3 3 of R is substituted or unsubstituted acyl.
• R 3 8 triphenylmethyl, acetyl, or Ts).
• at least one instance of R is -OR , wherein R 8 is an oxygen protecting group (e.g. , silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, ⁇ -Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl).
• at least one instance of R 3 is -OR 8 , wherein R 8 is or
• At least one instance of R is -OR , wherein R
• At least one instance of R 3 is -OR 8 , wherein R 8 is
• k is 0. In certain embodiments, k is 1. In certain embodiments, k is 2. In certain embodiments, k is 3. In certain embodiments, k is 4.
• Formula (I) includes substituent R 4 at the 5-position of the thiazolinyl ring.
• R 4 is H.
• R 4 is substituted or unsubstituted alkyl ⁇ e.g. , substituted or unsubstituted Ci_ 6 alkyl).
• R 4 is Me.
• R 4 is Et, Pr, Bu, unsubstituted pentyl, or unsubstituted hexyl.
• R 4 is substituted methyl ⁇ e.g. , -CF 3 , or Bn), substituted ethyl ⁇ e.g. ,
• perfluoroethyl substituted propyl ⁇ e.g. , perfluoropropyl
• butyl ⁇ e.g. , perfluorobutyl
• substituted pentyl e.g., perfluoropentyl
• substituted hexyl e.g., perflourohexyl
• Formula (I) includes substituent R 5 at the 5-position of the thiazolinyl ring.
• R 5 is H.
• R 5 is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted Ci_ 6 alkyl).
• R 5 is Me.
• R 5 is Et, Pr, Bu, unsubstituted pentyl, or unsubstituted hexyl.
• R 5 is substituted methyl (e.g., -CF 3 , or Bn), substituted ethyl (e.g.,
• perfluoroethyl substituted propyl (e.g. , perfluoropropyl), substituted butyl (e.g.,
• perfluorobutyl substituted pentyl (e.g., perfluoropentyl), or substituted hexyl (e.g., perflourohexyl).
• each of R 4 and R 5 is hydrogen. In certain embodiments, each of R 4 and R 5 is independently substituted or unsubstituted alkyl (e.g. , substituted or unsubstituted Ci_ 6 alkyl). In certain embodiments, each of R 4 and R 5 is Me.
• Formula (I) includes substituent R 6 at the 4-position of the thiazolinyl ring.
• R 6 is H.
• R 6 is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C 1-6 alkyl).
• R 6 is Me.
• R 6 is Et, Pr, Bu, unsubstituted pentyl, or unsubstituted hexyl.
• R 6 is substituted methyl (e.g., -CF 3 , or Bn), substituted ethyl (e.g.,
• perfluoroethyl substituted propyl (e.g. , perfluoropropyl), substituted butyl (e.g.,
• perfluorobutyl substituted pentyl (e.g., perfluoropentyl), or substituted hexyl (e.g., perflourohexyl).
• each of R 4 and R 5 is hydrogen, and R 6 is substituted or unsubstituted alkyl (e.g. , substituted or unsubstituted C 1-6 alkyl). In certain embodiments, each of R 4 and R 5 is hydrogen, and R 6 is Me.
• Z is -0-. In certain embodiments, Z is -S-.
• R 9 is H. In certain embodiments, R 9 is substituted or unsubstituted alkyl (e.g. , substituted or unsubstituted C 1-6 alkyl). In certain embodiments, R 9 is Me. In certain embodiments, R 9 is Et, Pr, Bu, unsubstituted pentyl, or unsubstituted hexyl. In certain embodiments, R 9 is substituted methyl (e.g., -CF 3 , or Bn), substituted ethyl (e.g. , perfluoroethyl), substituted propyl (e.g. , perfluoropropyl), substituted butyl (e.g.,
• R is
• R 9 e.g. ,
• R is
• R 9 is an oxygen protecting group (e.g. , silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, ⁇ -Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl) when attached to an oxygen atom.
• R 9 is a sulfur protecting group (e.g. , acetamidomethyl, ⁇ -Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine- sulfenyl, or triphenylmethyl) when attached to a sulfur atom.
• -Z-R 9 is -OH. In certain embodiments, -Z-R 9 is - 0(unsubstituted Ci_ 6 alkyl).
• Formula (I) includes a chiral carbon atom (the carbon atom labeled with "*") at the 4-position of the thiazolinyl ring.
• the carbon atom labeled with "*” is of the S configuration.
• the carbon atom labeled with "*” is of the R configuration.
• the moiety 4', 5', '- osition of the phenyl ring is not of the for mula: mbodiments, when the moiety r 6'-position of the phenyl ring is of the , R a is not Me. In certain embodiments, when the moiety at the 3', 4', 5', or 6'-position of the phenyl ring is of the formula: , d is not substituted or unsubstituted
• R is not unsubstituted Ci_ 6 alkyl.
• each instance of x is 1, 2, 3, or 4
• the compound of Formula (I) is of the formula:
• the compound of Formula (I) is of the formula:
• the compound of Formula (I) is of the formula:
• the compound of Formula (I) is of the formula:
• the compound of Formula (I) is of the formula:
• the compound of Formula (I) is of the formula:
• the compound of Formula (I) is of the formula:
• the compound of Formula (I) is of the formula:
• the compound of Formula (I) is of the formula:
• the compound of Formula (I) is of the formula:
• the compound of Formula (I) is of the formula:
• the compound of Formula (I) is of the formula:
• the compound of Formula (I) is of the formula:
• the compound of Formula (I) is of the formula:
• the compound of Formula (I) is of the formula:
• the compound of Formula (I) is of the formula:
• the compound of Formula (I) is of the formula:
• the compound of Formula (I) is of the formula:
• the compound of Formula (I) is of the formula:
• the compound of Formula (I) is of the formula:
• the compound of Formula (I) is of the formula:
• the compound of Formula (I) is of the formula:
• the compound of Formula (I) is of the formula:
• the compound of Formula (I) is of the formula:
• the compound of Formula (I) is of the formula:
• the compound of Formula (I) is of the formula:
• the compound of Formula (I) is of the formula:
• the compound of Formula (I) is of the formula:
• the compound of Formula (I) is of the formula:
• the compound of Formula (I) is of the formula:
• the compound of Formula (I) is of the formula:
• the compound of Formula (I) is of the formula:
• the compound of Formula (I) is of the formula:
• the compound of Formula (I) is of the formula:
• the compound of Formula (I) is of the formula:
• the compound of Formula (I) is of the formula:
• the compound of Formula (I) is of the formula:
• the compound of Formula (I) is of the formula:
• the compound of Formula (I) is of the formula:
• the compound of Formula (I) is of the formula:
• the compound of Formula (I) is of the formula:
• the compound of Formula (I) is of the formula:
• the compound of Formula (I) is of the formula:
• the compound of Formula (I) is of the formula:
• the compound of Formula (I) is of the formula:
• the compound of Formula (I) is of the formula:
• the compound of Formula (I) is of the formula:
• the compound of Formula (I) is of the formula:
• the compound of Formula (I) is of the formula:
• the compound of Formula (I) is of the formula:
• the compound of Formula (I) is of the formula:
• the compound of Formula (I) is of the formula:
• the compound of Formula (I) is of the formula:
• the compound of Formula (I) is of the formula:
• Exemplary compounds of Formula (I) include, but are not limited to:
• Additional exemplary compounds of Formula (I) include, but are not limited to:
• Additional exemplary compounds of Formula (I) include, but are not limited to:
• Additional exemplary compounds of Formula (I) include, but are not limited to:
• Additional exemplary compounds of Formula (I) include, but are not limited to:
• the compounds of the invention may be provided in various salts forms.
• the inventive compounds are provided as alkali metal salts.
• the inventive compounds are provided as alkaline earth metal salts.
• the compound may be provided as a carboxylate salt or thiocarboxylate salt with a base.
• the base is betaine, choline hydroxide, diethanolamine, diethylamine, ethanolamine,
• hydroxyethylmorpholine 4-(2-hydroxyethyl morpholine), l-(2-hydroxyethyl pyrrolidine), 1- (2-hydroxyethyl)-piperidine, hydroxyethyl pyrroldine, imidazone, lysine (e.g. , L-lysine), arginine (e.g. , L-arginine), histidine (e.g.
• a salt described herein is a lithium salt (e.g. , mono-lithium salt or di-lithium salt).
• a salt described herein is a sodium salt (e.g. , mono-sodium salt or di-sodium salt).
• a salt described herein is a potassium salt (e.g. , mono-potassium salt or di-potassium salt).
• a salt described herein is a zinc salt (e.g. , hemi-zinc salt or mono-zinc salt).
• a salt described herein is a magnesium salt (e.g. , hemi- magnesium salt or mono-magnesium salt).
• a salt described herein is a calcium salt (e.g. , hemi-calcium salt or mono-calcium salt).
• the cation e.g., Li + , Na + , K + , Mg 2+ , Mg(OH) + , Ca 2+ , Ca(OH) + , Zn 2+ , or Zn(OH) +
• a salt described herein may combine in a 1 : 1 molar ratio.
• Other molar ratios e.g. , 1 : 1.5, 1 :2, 1 :3, and 2: 1
• Additional exemplary compounds of Formula (I) include, but are not limited to:
• Additional exemplary compounds of Formula I) include, but are not limited to:
• Additional exemplary compounds of Formula (I) include, but are not limited to:
• Additional exemplary compounds of Formula (I) include, but are not limited to:
• Additional exemplary compounds of Formula (I) include, but are not limited to:
• Additional exemplary compounds of Formula (I) include, but are not limited to:
• a compound described herein is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
• a compound described herein is a compound of Formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof.
• a compound described herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
• each instance of R is independently hydrogen, alkyl, or an oxygen protecting group
• R is hydrogen, substituted or unsubstituted Ci_6 alkyl, or oxygen protecting group; each instance of R is independently hydrogen, substituted or unsubstituted Ci_ 6 alkyl, a nitrogen protecting group, or optionally two R are taken together with the intervening atoms to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl;
• each instance of h is independently 0, 1, 2, 3, 4, 5, 6, 7, or 8;
• each instance of j is independently 0, 1, 2, 3, or 4.
• Formula (II) includes one or more instances of substituent R .
• at least one instance of R C1 is of the formula: -(CH 2 ) h OR A1 , wherein each instance of R A1 is independently hydrogen, substituted or unsubstituted alkyl, or an oxygen
• At least one instance of R is -(CH 2 ) h OH, wherein: h is 0, 1, 2, 3, 4, 5, 6, 7, or 8. In certain embodiments, h is 0. In certain
• h is 1. In certain embodiments, h is 2. In certain embodiments, h is 3. In certain embodiments, h is 4. In certain embodiments, h is 5. In certain embodiments, h is 6. In certain embodiments, h is 7. In certain embodiments, h is 8. In certain embodiments, at least one instance of R C1 is -OH. In certain embodiments, R A1 is hydrogen. In certain embodiments, R A1 is substituted or unsubstituted Ci_6 alkyl (e.g. , methyl or ethyl). In certain embodiments, at least one instance of R A1 is methyl. In certain embodiments, at least one instance of R A1 is substituted methyl (e.g.
• R A1 is unsubstituted ethyl, substituted ethyl (e.g., perfluoroethyl), unsubstituted propyl (e.g., n-Pr or z ' -Pr), substituted propyl (e.g. , perfluoropropyl), unsubstituted butyl, or
• R A1 is an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, ⁇ -Bu, Bn, allyl, acetyl, pivaloyl, or
• Ci_ 6 alkyl e.g. , -OMe, -OCF 3 , -OEt, -OPr, -OBu, or -OBn
• Formula (II) includes one or more instances of substituent R .
• j is 0. In certain embodiments, j is 1. In certain embodiments, j is 2. In certain embodiments, j is 3. In certain embodiments, j is 4. In certain embodiments, at least one
• C2 C2 instance of R is hydrogen. In certain embodiments, at least one instance of R is halogen
• At least one instance of R is F.
• At least one instance of R is CI. In certain embodiments, at least one instance
• R is substituted or unsubstituted Ci_ 6 alkyl. In certain embodiments, at least one instance
• R is methyl. In certain embodiments, at least one instance of R is substituted methyl
• R is unsubstituted ethyl, substituted ethyl (e.g. , perfluoroethyl), unsubstituted propyl (e.g. , n-Pr or z-Pr), substituted propyl (e.g., perfluoropropyl), unsubstituted butyl, or substituted butyl (e.g. ,
• At least one instance of R is -CN.
• At least one instance of R is -N0 2 . In certain embodiments, at least one
• R is -OR (e.g., -OH, -0(substituted or unsubstituted C 1-6 alkyl) (e.g. , -OMe, - OCF 3 , -OEt, -OPr, -OBu, or -OBn), or -0(substituted or unsubstituted phenyl) (e.g., - OPh)), wherein R is hydrogen, substituted or unsubstituted Ci_ 6 alkyl, or oxygen protecting
• At least one instance of R is -OH. In certain embodiments,
• R is -OMe. In certain embodiments, at least one instance of R is -
• R is -N(R ) 2 (e.g. , -NH 2 , - NH(substituted or unsubstituted Ci_ 6 alkyl) (e.g. , -NHMe), or -N(substituted or unsubstituted Ci-6 alkyl)-(substituted or unsubstituted C 1-6 alkyl) (e.g.
• R is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, a nitrogen protecting group, or optionally two R are taken together with the intervening atoms to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl.
• At least one instance of R is -NMe 2 . In certain embodiments, at least one
• instance of R is -NEt 2 .
• two instances of R are taken together with the intervening atoms to form a substituted or unsubstituted, 5- to 14-membered, monocyclic or bicyclic heterocyclic ring comprising zero, one, or two double bonds in the heterocyclic ring, wherein one, two, or three atoms of the heterocyclic ring are independently nitrogen, oxygen, or sulfur.
• Formula (II) includes one or more instances of substituent R .
• At least one instance of R is hydrogen. In certain embodiments, at least one instance of R is substituted or unsubstituted alkyl. In certain embodiments, at least one
• instance of R is substituted or unsubstituted Ci_ 6 alkyl.
• instance of R is Me. In certain embodiments, at least one instance of R is substituted
• R is Et, substituted ethyl (e.g. , perfluoroethyl), Pr (e.g. , n-Pr or z ' -Pr), substituted propyl (e.g., perfluoropropyl), Bu, or substituted butyl (e.g. , perfluorobutyl).
• at least one instance of R is Et, substituted ethyl (e.g. , perfluoroethyl), Pr (e.g. , n-Pr or z ' -Pr), substituted propyl (e.g., perfluoropropyl), Bu, or substituted butyl (e.g. , perfluorobutyl).
• at least one instance of R is Et, substituted ethyl (e.g. , perfluoroethyl), Pr (e.g. , n-Pr or z ' -Pr), substituted propyl (
• R is an oxygen protecting group (e.g. , silyl, TBDPS, TBDMS, TIPS,
• oxygen protecting group e.g. , silyl, TBDPS, TBDMS, TIPS,
• TES TES, TMS, MOM, THP, ⁇ -Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl).
• the compound of Formula (II) is of the formula:
• the compound of Formula (II) is of the formula:
• Exem lar com ounds of Formula (II) include, but are not limited to:
• Exemplary compounds of Formula (II) include, but are not limited to:
• a compound described herein is a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
• a compound described herein is a compound of Formula (II), or a pharmaceutically acceptable salt or stereoisomer thereof.
• a compound described herein is a compound of Formula (II), or a pharmaceutically acceptable salt thereof.
• the present invention provides pharmaceutical compositions comprising a compound of the invention, and optionally a pharmaceutically acceptable excipient.
• the pharmaceutical compositions may be useful in chelating a metal ⁇ e.g., iron or another metal) in a subject, cell, tissue, or biological sample, treating a disease in a subject thereof, preventing a disease in a subject in need thereof, treating, reducing, or preventing the formation of biofilms in a subject, or reducing or preventing the formation of biofilms on or in an object.
• the compound of the present invention is a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
• the compound of the present invention is a compound of Formula (II), or a pharmaceutically acceptable salt thereof.
• the compound of the present invention is provided in an effective amount in the pharmaceutical composition.
• the effective amount is a therapeutically effective amount.
• the effective amount is a prophylactically effective amount.
• compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include the steps of bringing the compound of the present invention (the "active ingredient") into association with a carrier or excipient, and/or one or more other accessory ingredients, and then, if necessary and/or desirable, shaping, and/or packaging the product into a desired single- or multi-dose unit.
• Pharmaceutical compositions can be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses.
• a "unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage.
• compositions of the invention will vary, depending upon the identity, size, and/or condition of the subject treated and further depending upon the route by which the composition is to be administered.
• the composition may comprise between 0.1% and 100% (w/w) active ingredient.
• compositions used in the manufacture of provided pharmaceutical compositions include inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition.
• Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, and mixtures thereof.
• Exemplary granulating and/or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross- linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.
• crospovidone cross-linked poly(vinyl-pyrrolidone)
• sodium carboxymethyl starch sodium starch glycolate
• Exemplary surface active agents and/or emulsifiers include natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate
• sorbitan fatty acid esters e.g., polyoxyethylene sorbitan monolaurate (Tween 20), polyoxyethylene sorbitan (Tween 60), polyoxyethylene sorbitan monooleate (Tween 80), sorbitan monopalmitate (Span 40), sorbitan monostearate (Span 60), sorbitan tristearate (Span 65), glyceryl monooleate, sorbitan monooleate (Span 80)), polyoxyethylene esters (e.g.
• polyoxyethylene monostearate Myrj 45
• polyoxyethylene hydrogenated castor oil polyethoxylated castor oil
• polyoxymethylene stearate polyoxymethylene stearate
• Solutol sucrose fatty acid esters
• polyethylene glycol fatty acid esters e.g. , CremophorTM
• polyoxyethylene ethers e.g.
• polyoxyethylene lauryl ether (Brij 30)), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F-68, Poloxamerl88, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and/or mixtures thereof.
• Exemplary binding agents include starch (e.g., cornstarch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g. , acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl
• methylcellulose methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and/or mixtures thereof.
• Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and other preservatives.
• antioxidants include alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.
• Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof.
• EDTA ethylenediaminetetraacetic acid
• salts and hydrates thereof e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like
• citric acid and salts and hydrates thereof e.g., citric acid mono
• antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.
• Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.
• Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.
• Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta- carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.
• preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT),
• the preservative is an anti-oxidant. In other embodiments, the preservative is a chelating agent.
• Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D- gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic s
• Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.
• Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury,
• Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.
• Liquid dosage forms for oral and parenteral administration include
• the liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
• inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate,
• the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
• adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
• the conjugates of the invention are mixed with solubilizing agents such as CremophorTM, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.
• Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
• the sterile injectable preparation can be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
• acceptable vehicles and solvents that can be employed are water, Ringer's solution, U.S. P. and isotonic sodium chloride solution.
• sterile, fixed oils are conventionally employed as a solvent or suspending medium.
• any bland fixed oil can be employed including synthetic mono- or di-glycerides.
• fatty acids such as oleic acid are used in the preparation of injectables.
• the injectable formulations can be sterilized, for example, by filtration through a bacterial -retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
• compositions for rectal or vaginal administration are typically suppositories which can be prepared by mixing the conjugates of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.
• suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.
• Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
• the active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolin and bentonite clay, and (a) fillers or
• Solid compositions of a similar type can be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
• the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
• Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.
• the active ingredient can be in micro-encapsulated form with one or more excipients as noted above.
• the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
• the active ingredient can be admixed with at least one inert diluent such as sucrose, lactose or starch.
• Such dosage forms may comprise, as is normal practice, additional substances other than inert diluents, e.g. , tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
• the dosage forms may comprise buffering agents. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
• embedding compositions which can be used include polymeric substances and waxes.
• Dosage forms for topical and/or transdermal administration of a compound of this invention may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants and/or patches.
• the active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier or excipient and/or any needed preservatives and/or buffers as can be required.
• the present invention contemplates the use of transdermal patches, which often have the added advantage of providing controlled delivery of an active ingredient to the body.
• Such dosage forms can be prepared, for example, by dissolving and/or dispensing the active ingredient in the proper medium.
• the rate can be controlled by either providing a rate controlling membrane and/or by dispersing the active ingredient in a polymer matrix and/or gel.
• Suitable devices for use in delivering intradermal pharmaceutical compositions described herein include short needle devices.
• Intradermal compositions can be administered by devices which limit the effective penetration length of a needle into the skin.
• conventional syringes can be used in the classical mantoux method of intradermal administration.
• Jet injection devices which deliver liquid formulations to the dermis via a liquid jet injector and/or via a needle which pierces the stratum corneum and produces a jet which reaches the dermis are suitable.
• Ballistic powder/particle delivery devices which use compressed gas to accelerate the compound in powder form through the outer layers of the skin to the dermis are suitable.
• Formulations suitable for topical administration include, but are not limited to, liquid and/or semi-liquid preparations such as liniments, lotions, oil in water and/or water in oil emulsions such as creams, ointments and/or pastes, and/or solutions and/or suspensions.
• Topically-administrable formulations may, for example, comprise from about 1% to about 10% (w/w) active ingredient, although the concentration of the active ingredient can be as high as the solubility limit of the active ingredient in the solvent.
• Formulations for topical administration may further comprise one or more of the additional ingredients described herein.
• Low boiling propellants generally include liquid propellants having a boiling point of below 65 °F at atmospheric pressure.
• the propellant may constitute 50 to 99.9% (w/w) of the composition, and the active ingredient may constitute 0.1 to 20% (w/w) of the composition.
• the propellant may further comprise additional ingredients such as a liquid non-ionic and/or solid anionic surfactant and/or a solid diluent (which may have a particle size of the same order as particles comprising the active ingredient).
• compositions of the invention formulated for pulmonary delivery may provide the active ingredient in the form of droplets of a solution and/or suspension.
• Such formulations can be prepared, packaged, and/or sold as aqueous and/or dilute alcoholic solutions and/or suspensions, optionally sterile, comprising the active ingredient, and may conveniently be administered using any nebulization and/or atomization device.
• Such formulations may further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, and/or a preservative such as methylhydroxybenzoate.
• the droplets provided by this route of administration may have an average diameter in the range from about 0.1 to about 200 nanometers.
• Formulations described herein as being useful for pulmonary delivery are useful for intranasal delivery of a pharmaceutical composition of the invention.
• Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 to 500 micrometers. Such a formulation is administered by rapid inhalation through the nasal passage from a container of the powder held close to the nares.
• Formulations for nasal administration may, for example, comprise from about as little as 0.1% (w/w) and as much as 100% (w/w) of the active ingredient, and may comprise one or more of the additional ingredients described herein.
• a pharmaceutical composition of the invention can be prepared, packaged, and/or sold in a formulation for buccal
• formulations may, for example, be in the form of tablets and/or lozenges made using conventional methods, and may contain, for example, 0.1 to 20% (w/w) active ingredient, the balance comprising an orally dissolvable and/or degradable composition and, optionally, one or more of the additional ingredients described herein.
• formulations for buccal administration may comprise a powder and/or an aerosolized and/or atomized solution and/or suspension comprising the active ingredient.
• Such powdered, aerosolized, and/or aerosolized formulations when dispersed, may have an average particle and/or droplet size in the range from about 0.1 to about 200 nanometers, and may further comprise one or more of the additional ingredients described herein.
• a pharmaceutical composition of the invention can be prepared, packaged, and/or sold in a formulation for ophthalmic administration.
• Such formulations may, for example, be in the form of eye drops including, for example, a 0.1-1.0% (w/w) solution and/or suspension of the active ingredient in an aqueous or oily liquid carrier or excipient.
• Such drops may further comprise buffering agents, salts, and/or one or more other of the additional ingredients described herein.
• Other opthalmically-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form and/or in a liposomal preparation. Ear drops and/or eye drops are contemplated as being within the scope of this invention.
• compositions are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical
• compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation .
• compositions described herein are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions described herein will be decided by a physician within the scope of sound medical judgment.
• the specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.
• the compounds and compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and/or drops), mucosal, nasal, bucal, sublingual; by intratracheal instillation, bronchial instillation, and/or inhalation; and/or as an oral spray, nasal spray, and/or aerosol.
• enteral e.g., oral
• parenteral intravenous
• intramuscular intra-arterial
• intramedullary intrathecal
• subcutaneous intraventricular
• transdermal transdermal
• interdermal interdermal
• rectal intravaginal
• topical as by powders, ointments, creams, and/or drops
• inventive compounds and compositions may also be mixed with blood ex vivo, and the resulting mixture may be administered (e.g. , intravenously) to a subject.
• administration e.g. , intravenously
• the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), and/or the condition of the subject (e.g. , whether the subject is able to tolerate oral administration).
• any two doses of the multiple doses include different or substantially the same amounts of a compound described herein.
• the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is three doses a day, two doses a day, one dose a day, one dose every other day, one dose every third day, one dose every week, one dose every two weeks, one dose every three weeks, or one dose every four weeks.
• the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is one dose per day. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is two doses per day.
• the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is three doses per day.
• the duration between the first dose and last dose of the multiple doses is one day, two days, four days, one week, two weeks, three weeks, one month, two months, three months, four months, six months, nine months, one year, two years, three years, four years, five years, seven years, ten years, fifteen years, twenty years, or the lifetime of the subject, tissue, or cell.
• the duration between the first dose and last dose of the multiple doses is three months, six months, or one year.
• the duration between the first dose and last dose of the multiple doses is the lifetime of the subject, tissue, or cell.
• a dose (e.g., a single dose, or any dose of multiple doses) described herein includes independently between 0.1 ⁇ g and 1 ⁇ g, between 0.001 mg and 0.01 mg, between 0.01 mg and 0.1 mg, between 0.1 mg and 1 mg, between 1 mg and 3 mg, between 3 mg and 10 mg, between 10 mg and 30 mg, between 30 mg and 100 mg, between 100 mg and 300 mg, between 300 mg and 1,000 mg, or between 1 g and 10 g, inclusive, of a compound described herein.
• a dose described herein includes independently between 1 mg and 3 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 3 mg and 10 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 10 mg and 30 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 30 mg and 100 mg, inclusive, of a compound described herein. [00272] It will be appreciated that dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult.
• a dose described herein is a dose to an adult human whose body weight is 70 kg.
• a compound or composition described herein can be administered in combination with one or more additional pharmaceutical agents (e.g. , therapeutically and/or
• prophylactically active agents The compounds or compositions can be administered in combination with additional pharmaceutical agents that improve their activity (e.g. , activity (e.g., potency and/or efficacy) in treating a disease in a subject in need thereof, in preventing a disease in a subject in need thereof, in reducing the risk to develop a disease in a subject in need thereof, and/or in inhibiting the activity of a protein kinase in a subject or cell), improve bioavailability, improve safety, reduce drug resistance, reduce and/or modify metabolism, inhibit excretion, and/or modify distribution in a subject or cell. It will also be appreciated that the therapy employed may achieve a desired effect for the same disorder, and/or it may achieve different effects.
• a pharmaceutical composition described herein including a compound described herein and an additional pharmaceutical agent shows a synergistic effect that is absent in a pharmaceutical composition including one of the compound and the additional pharmaceutical agent, but not both.
• the compound or composition can be administered concurrently with, prior to, or subsequent to one or more additional pharmaceutical agents, which are different from the compound or composition and may be useful as, e.g. , combination therapies.
• Pharmaceutical agents include therapeutically active agents.
• Pharmaceutical agents also include
• prophylactically active agents include small organic molecules such as drug compounds (e.g., compounds approved for human or veterinary use by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells.
• drug compounds e.g., compounds approved for human or veterinary use by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (CFR)
• CFR Code of Federal Regulations
• peptides e.g., compounds approved for human or veterinary use by the U.S. Food and Drug Administration
• the additional pharmaceutical agent is a pharmaceutical agent useful for treating and/or preventing a disease (e.g. , proliferative disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder).
• a disease e.g. , proliferative disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder.
• Each additional pharmaceutical agent may be administered at a dose and/or on a time schedule determined for that pharmaceutical agent.
• the additional pharmaceutical agents may also be administered together with each other and/or with the compound or composition described herein in a single dose or administered separately in different doses.
• the particular combination to employ in a regimen will take into account compatibility of the compound described herein with the additional pharmaceutical agent(s) and/or the desired therapeutic and/or prophylactic effect to be achieved.
• it is expected that the additional pharmaceutical agent(s) in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be
• the additional pharmaceutical agents include, but are not limited to, antiproliferative agents, anti-cancer agents, anti-angiogenesis agents, anti-inflammatory agents, immunosuppressants, anti-bacterial agents, anti-viral agents, cardiovascular agents, cholesterol-lowering agents, anti-diabetic agents, anti-allergic agents, contraceptive agents, and pain-relieving agents.
• the additional pharmaceutical agent is an anti-proliferative agent.
• the additional pharmaceutical agent is an anti-cancer agent.
• the additional pharmaceutical agent is an anti- viral agent.
• the additional pharmaceutical agent is a binder or inhibitor of a protein kinase.
• the additional pharmaceutical agent is selected from the group consisting of epigenetic or transcriptional modulators (e.g., DNA methyltransferase inhibitors, histone deacetylase inhibitors (HDAC inhibitors), lysine methyltransferase inhibitors), antimitotic drugs (e.g., taxanes and vinca alkaloids), hormone receptor modulators (e.g. , estrogen receptor modulators and androgen receptor modulators), cell signaling pathway inhibitors (e.g., tyrosine protein kinase inhibitors), modulators of protein stability (e.g. , proteasome inhibitors), Hsp90 inhibitors, glucocorticoids, all-trans retinoic acids, and other agents that promote differentiation.
• epigenetic or transcriptional modulators e.g., DNA methyltransferase inhibitors, histone deacetylase inhibitors (HDAC inhibitors), lysine methyltransferase inhibitors
• antimitotic drugs e.g., taxanes and
• the additional pharmaceutical agent is an iron chelator (e.g. , desferoxamine (DFO, DFX, deferoxamine, deferoxamine mesylate, desferoxamine B, Desferal ® ), deferasirox (Exjade ® ), deferiprone (LI, Ferriprox ® ), or Feralex-G).
• an iron chelator e.g. , desferoxamine (DFO, DFX, deferoxamine, deferoxamine mesylate, desferoxamine B, Desferal ® ), deferasirox (Exjade ® ), deferiprone (LI, Ferriprox ® ), or Feralex-G.
• an anti-cancer therapy including, but not limited to, surgery, radiation therapy, transplantation (e.g., stem cell transplantation, bone marrow transplantation), immunotherapy, and chemotherapy.
• kits e.g. , pharmaceutical packs
• the kit may comprise an inventive compound or pharmaceutical composition and a first container (e.g., a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container).
• the kit further includes a second container comprising a pharmaceutical excipient for, e.g. , dilution or suspension of an inventive compound or pharmaceutical composition.
• the inventive compound or pharmaceutical composition provided in the first container and the second container are combined to form one unit dosage form.
• kits may be useful in chelating a metal (e.g. , iron or another metal) in a subject, cell, tissue, or biological sample, treating a disease in a subject thereof, preventing a disease in a subject in need thereof, treating, reducing, or preventing the formation of biofilms in a subject, or reducing or preventing the formation of biofilms on or in an object.
• a metal e.g. , iron or another metal
• the kit includes a compound or pharmaceutical composition described herein (e.g. , in a first container); and instructions for using the compound or pharmaceutical composition (e.g. , instructions for administering the compound or
• kits described herein may also include information as required by a regulatory agency such as the U.S. Food and Drug Administration (FDA). In certain embodiments, the information included in the kits is prescribing information. In certain embodiments, the kits and instructions provide for chelating a metal (e.g., iron or another metal) in a subject, cell, tissue, or biological sample. In certain embodiments, the kits and instructions provide for treating a disease in a subject in need thereof. In certain embodiments, the kits and instructions provide for preventing a disease in a subject in need thereof. In certain embodiments, the kits and instructions provide for treating, reducing, or preventing the formation of biofilms in a subject. In certain embodiments, the kits and instructions provide for reducing or preventing the formation of biofilms on or in an object. A kit described herein may include one or more additional pharmaceutical agents described herein as a separate composition.
• FDA U.S. Food and Drug Administration
• the compounds of Formula (I) or Formula (II), and pharmaceutical compositions described herein may be useful in chelating a metal (e.g. , iron or another metal) in a subject, cell, tissue, or biological sample, treating a disease in a subject thereof, preventing a disease in a subject in need thereof, treating, reducing, or preventing the formation of biofilms in a subject, or reducing or preventing the formation of biofilms on or in an object.
• a metal e.g. , iron or another metal
• metal chelators are advantageous over known metal chelators at least because the compounds described herein are "metabolically programmed" metal chelators, e.g. , lipophilic, absorbable (e.g., orally absorbable), and effective metal chelators that are quickly converted (e.g., converted in vivo) to their hydrophilic, nontoxic counterparts.
• Hydrophilic compounds e.g. , compounds of Formula (I) or Formula (II) that include two or more carboxyl groups
• Lipophilic compounds typically are able to easily pass the cell membrane and/or are absorbable (e.g. , orally absorbable). Moreover, lipophilic compounds are typically more effective in chelating metal than the hydrophilic compounds. However, the lipophilic compounds typically are more toxic than the hydrophilic compounds. Therefore, by
• hydrophilic compounds e.g., structurally modifying the hydrophilic compounds into lipophilic compounds that can easily pass the cell membrane and in turn are metabolically converted back to the hydrophilic compounds, metal chelators with balanced properties, such as being absorbable, effective, and non-toxic, are achieved.
• the metal is iron (e.g., Fe(II) or Fe(III)). In certain embodiments, the metal is not iron. In certain embodiments, the metal is aluminum, thallium (e.g., T1(I) or Tl(III)), chromium (e.g. , Cr(III) or Cr(VI)), magnesium, calcium, strontium, nickel (e.g. , Ni(II)), manganese (e.g. , Mn(II)), cobalt (e.g., Co(II) or Co(III)), copper (e.g.
• iron e.g., Fe(II) or Fe(III)
• the metal is not iron.
• the metal is aluminum, thallium (e.g., T1(I) or Tl(III)), chromium (e.g. , Cr(III) or Cr(VI)), magnesium, calcium, strontium, nickel (e.g. , Ni(II)), manganese (e
• the metal is a trivalent metal (e.g. , Fe(III) or aluminum).
• the metal is a trivalent metal (e.g. , Fe(III) or aluminum).
• the trivalent metal is Tl(III), Cr(III), Co(III), Sb(III), Mo(III), or Ce(III).
• the metal is a monovalent metal (e.g. , T1(I), Cu(I), Ag(I), Na(I), K(I), or Hg(I)).
• the metal is a divalent metal (e.g. , Fe(II), Mg(II), Ca(II), Sr(II),Ni(II), Mn(II), Co(II), Cu(II), Zn(II), Cd(II), Hg(II), or Pb(II)).
• the metal is a tetravalent metal (e.g. , Pb(IV) or Ce(IV)). In certain embodiments, the metal is a pentavalent metal (e.g., Sb(V)). In certain embodiments, the metal is a hexavalent metal (e.g., Cr(VI), Mo(VI), W(VI), or U(VI)).
• a metal e.g., iron or another metal
• methods of chelating a metal including administering to the subject an effective amount (e.g. , therapeutically effective amount) of a compound or pharmaceutical composition described herein.
• a metal e.g., iron or another metal
• methods of chelating a metal including contacting the cell, tissue, or biological sample with an effective amount of a compound or pharmaceutical composition described herein.
• kits for treating a disease in a subject in need thereof including administering to the subject an effective amount (e.g. , therapeutically effective amount) of a compound or pharmaceutical composition described herein.
• kits for preventing a disease in a subject in need thereof including administering to the subject an effective amount (e.g., prophylactically effective amount) of a compound or pharmaceutical composition described herein.
• kits for treating a disease in a subject in need thereof including mixing blood or a component thereof (e.g., red blood cells) with an effective amount (e.g., therapeutically effective amount) of a compound or pharmaceutical composition described herein to form a mixture; and administering the mixture to the subject.
• a component thereof e.g., red blood cells
• an effective amount e.g., therapeutically effective amount
• kits for preventing a disease in a subject in need thereof including mixing blood or a component thereof (e.g., red blood cells) with an effective amount (e.g., prophylactically effective amount) of a compound or pharmaceutical composition described herein to form a mixture; and administering the mixture to the subject.
• a component thereof e.g., red blood cells
• an effective amount e.g., prophylactically effective amount
• the blood may be whole blood or a fluid comprising one or more components of whole blood (e.g., red blood cells, white blood cells, plasma, clotting factors, and platelets).
• the mixture is administered intravenously to the subject.
• the compounds described herein for use in a method described herein (e.g., method of chelating a metal (e.g. , iron or another metal) in a subject, cell, tissue, or biological sample, method of treating a disease in a subject thereof, or method of preventing a disease in a subject in need thereof).
• a metal e.g. , iron or another metal
• compositions described herein for use in a method described herein (e.g., method of chelating a metal (e.g. , iron or another metal) in a subject, cell, tissue, or biological sample, method of treating a disease in a subject thereof, or method of preventing a disease in a subject in need thereof).
• a metal e.g. , iron or another metal
• the present invention stems from the recognition that the pathogenesis of various diseases.
• the disease is oxidative stress, transfusional iron overload, thalassemia, primary hemochromatosis, secondary hemochromatosis, diabetes, liver disease, heart disease, cancer, radiation injury, neurological or neurodegenerative disorder,
• FRDA Friedreich's ataxia
• ROS reactive oxygen species
• free iron is known to contribute to the formation of reactive oxygen species.
• Fe +2 ions in biological systems react with oxygen species to produce highly reactive hydroxyl radicals via the Fenton reaction.
• the hydroxyl radical is a highly effective oxidizing agent, reacting at a diffusion-controlled rate with most organic species, such as nucleic acids, proteins, and lipids.
• superoxide anions or a biological reductant e.g., ascorbic acid
• the subject is a mammal. In certain embodiments, the subject is a human. In certain embodiments, the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a companion animal such as a dog or cat. In certain embodiments, the subject is a livestock animal such as a cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a zoo animal. In another embodiment, the subject is an experimental animal such as a rodent or non-human primate. In certain embodiments, the subject is diagnosed with cystic fibrosis. In certain embodiments, the subject is immunocompromised.
• the cell is in vitro. In certain embodiments, the cell is in vivo. [00294] In certain embodiments, the cell is a blood cell. In certain embodiments, the cell is a liver cell, lung cell, or spleen cell. In certain embodiments, the cell is a cancer cell.
• the tissue is a target tissue (e.g., heart, lungs, liver, pancreas, kidneys, brain, or spleen).
• a target tissue e.g., heart, lungs, liver, pancreas, kidneys, brain, or spleen.
• the disease that is treated or prevented by a method described herein is an infectious disease.
• Infectious diseases are typically caused by microbial pathogens (e.g., viruses, bacteria, parasites (e.g., protozoa and multicellular parasites), and fungi) into the cells ("host cells") of a subject ("host").
• microbial pathogens e.g., viruses, bacteria, parasites (e.g., protozoa and multicellular parasites), and fungi
• host cells e.g., viruses, bacteria, parasites (e.g., protozoa and multicellular parasites), and fungi) into the cells ("host cells") of a subject ("host").
• Iron is an oxidant as well as a nutrient for many microorganisms.
• Highly virulent microbial strains usually possess powerful mechanisms for obtaining iron from their host. Depriving the pathogenic microbes of iron may inhibit their activities and may be useful for the treatment and/or prevention
• the infectious disease is responsive to the chelation or sequestration of a metal.
• the disease that is treated and/or prevented by the compounds, pharmaceutical compositions, and methods of the invention is a viral infection.
• the disease is a bacterial infection.
• the bacterial infection is caused by a Gram-positive bacterium.
• Exemplary Gram-positive bacteria include, but are not limited to, species of the genera Staphylococcus, Streptococcus, Micrococcus, Peptococcus, Peptostreptococcus,
• the Gram- positive bacterium is a bacterium of the phylum Firmicutes.
• the bacterium is a member of the phylum Firmicutes and the genus Enterococcus, i.e., the bacterial infection is an Enterococcus infection.
• Exemplary Enterococci bacteria include, but are not limited to, E. avium, E. durans, E. faecalis, E. faecium, E. gallinarum, E. solitarius, E. casseliflavus, and E. rajfinosus.
• the Enterococcus infection is an E.
• the Enterococcus infection is an E. faecium infection.
• the bacteria is a member of the phylum Firmicutes and the genus Staphylococcus, i.e., the bacterial infection is a Staphylococcus infection.
• Exemplary Staphylococci bacteria include, but are not limited to, S. arlettae, S. aureus, S. auricularis, S. capitis, S. caprae, S. carnous, S. chromogenes, S. cohii, S. condimenti, S. croceolyticus, S. delphini, S. devriesei, S. epidermis, S. equorum, S. felis, S. fluroettii, S. gallinarum, S.
• the Staphylococcus infection is an S. aureus infection.
• the Staphylococcus infection is an S. aureus infection.
• Staphylococcus infection is an S. epidermis infection.
• the Gram- positive bacterium is selected from the group consisting of Staphylococcus aureus,
• Mycobacterium marinum Mycobacterium scrofulaceum, Mycobacterium smegmatis, Mycobacterium terrae, Mycobacterium tuberculosis, Mycobacterium ulcerans, and
• the bacterial infection is an infection caused by a Gram- negative bacterium.
• Gram-negative bacteria include, but are not limited to, Escherchia coli, Caulobacter crescentus, Pseudomonas, Agrobacterium tumefaciens, Branhamella catarrhalis, Citrobacter diversus, Enterobacter aerogenes, Klebsiella pneumoniae, Proteus mirabilis, Salmonella typhimurium, Neisseria meningitidis, Serratia marcescens, Shigella sonnei, Neisseria gonorrhoeae, Acinetobacter baumannii, Salmonella enteriditis, Fusobacterium nucleatum, Veillonella parvula, Bacteroides forsythus,
• Actinobacillus actinomycetemcomitans Aggregatibacter actinomycetemcomitans,
• the Gram-negative bacteria species is Pseudomonas. In certain embodiments, the Gram-negative bacteria species is Pseudomonas aeruginosa. [00298] In certain embodiments, the bacterial infection is a chronic bacterial infection.
• a "chronic bacterial infection” is a bacterial infection that is of a long duration or frequent recurrence.
• a chronic middle ear infection can occur when the Eustachian tube becomes blocked repeatedly due to allergies, multiple infections, ear trauma, or swelling of the adenoids.
• long duration will depend upon the particular infection. For example, in the case of a chronic middle ear infection, it may last for weeks to months.
• Exemplary chronic bacterial infections include, but are not limited to, urinary tract infection (e.g., urinary tract infection caused by Escherichia coli and/or Staphylococcus saprophyticus), gastritis (e.g., gastritis caused by Helicobacter pylori), respiratory infection (e.g., respiratory infection afflicting patents with cystic fibrosis and respiratory infection caused by Pseudomonas aeuroginosa), cystitis (e.g., cystitis caused by Escherichia coli), pyelonephritis (e.g., pyelonephritis caused by Proteus species, Escherichia coli and/or Pseudomonas sp), osteomyelitis (e.g., osteomyelitis caused by Staphylococcus aureus and/or by Escherichia coli), bacteremia, skin infection, rosacea, acne, chronic wound infection,
• the bacterial infection is caused by an organism resistant to one or more antibiotics. In certain embodiments, the bacterial infection is caused by an organism resistant to penicillin. In certain embodiments, the bacterial infection is caused by an organism resistant to vancomycin (VR). In certain embodiments, the bacterial infection is caused by vancomycin-resistant E. faecalis. In certain embodiments, the bacterial infection is caused by vancomycin-resistant E. faecium. In certain embodiments, the bacterial infection is caused by vancomycin-resistant Staphylococcus aureus (VRSA). In certain embodiments, the bacterial infection is caused by vancomycin-resistant Enterococci (VRE).
• VRE vancomycin-resistant Enterococci
• the bacterial infection is caused by a methicillin-resistant (MR) organism.
• the bacterial infection is caused by methicillin-resistant S. aureus (MRS A).
• the bacterial infection is caused by methicillin-resistant Staphylococcus epidermidis (MRSE).
• the bacterial infection is caused by penicillin-resistant Streptococcus pneumonia.
• the bacterial infection is caused by quinolone-resistant Staphylococcus aureus (QRSA).
• the bacterial infection is caused by multi-drug resistant Mycobacterium tuberculosis.
• the bacterial infection is one or more infections selected from the group consisting of urinary tract infection, gastritis, respiratory infection, cystitis, pyelonephritis, osteomyelitis, bacteremia, skin infection, rosacea, acne, chronic wound infection, infectious kidney stones, bacterial endocarditis, and sinus infection.
• the infectious diseases is pneumonia, urinary tract infection, complicated intraabdominal infection, or complicated skin/skin structure infection.
• the infectious diseases is nosocomial pneumonia, community-acquired pneumonia, urinary tract infection, complicated intra-abdominal infection, complicated skin/skin structure infection, infectious exacerbations of cystic fibrosis, sepsis, or melioidosis.
• the bacterial infection is respiratory infection. In certain embodiments, the bacterial infection is upper respiratory infection. In certain embodiments, the bacterial infection is pneumonia. In certain embodiments, the bacterial infection is bronchitis.
• the disease is a parasitic infection. In certain embodiments, the disease is a protozoan infection. In certain embodiments, the disease is malaria.
• Malaria is typically caused by parasites of the genus Plasmodium (phylum Apicomplexa), including, but not limited to, the species P. falciparum, P. malariae, P. ovale, P. vivax, and P. knowlesi.
• the disease is a multicellular-parasitic infection.
• the disease is a fungal infection.
• the disease that is treated or prevented by a method described herein is a metal overload.
• the amount of free metal e.g., a trivalent metal, such as iron(III) or aluminum
• the metal overload is iron overload (e.g., Fe(III) overload or Fe(II) overload).
• Iron overload conditions or diseases can be characterized by global iron overload or focal iron overload.
• Global iron overload conditions generally involve an excess of iron in multiple tissues or excess iron located throughout an organism.
• Global iron overload conditions can result from excess uptake of iron by a subject, excess storage and/or retention of iron, from, for example, dietary iron or blood transfusions.
• One global iron overload condition is primary hemochromatosis, which is typically a genetic disorder.
• a second global iron overload condition is secondary hemochromatosis, which is typically the result of receiving multiple (chronic) blood transfusions. Blood transfusions are often required for subjects suffering from thalassemia or sickle cell anemia.
• Bantu siderosis A type of dietary iron overload is referred to as Bantu siderosis, which is associated with the ingestion of homebrewed beer with high iron content.
• the disease that is treated and/or prevented by a method described herein is global iron overload.
• the disease is focal iron overload.
• the disease is primary hemochromatosis.
• the disease is secondary hemochromatosis.
• the disease is Bantu siderosis.
• focal iron overload conditions the excess iron is limited to one or a few cell types or tissues or a particular organ. Alternatively, symptoms associated with the excess iron are limited to a discrete organ, such as the heart, lungs, liver, pancreas, kidneys, or brain. It is believed that focal iron overload can lead to neurological or neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, Huntington's disease, neuroferritinopathy, amyotrophic lateral sclerosis, and multiple sclerosis. Diseases that benefit from metal chelation are often associated with deposition of the metal in the tissues of a subject.
• Deposition can occur globally or focally.
• the disease is a
• the disease is a neurological or neurodegenerative disorder.
• the disease is a neurological or neurodegenerative disorder.
• the disease is a neurological or neurodegenerative disorder.
• the disease is a neurological or neurodegenerative disorder.
• Parkinson's disease Alzheimer's disease, Huntington's disease, neuroferritinopathy, amyotrophic lateral sclerosis, or multiple sclerosis.
• diabetes related both to iron-induced decreases in pancreatic beta -cell secretion and to increases in hepatic insulin resistance (Cario et al., "Insulin Sensitivity and ⁇ -Cell Secretion in Thalassemia Major with Secondary
• the disease that is treated and/or prevented by a method described herein is transfusional iron overload.
• the disease is transfusion-dependent anemia.
• the disease is thalassemia.
• the disease a liver disease (e.g., hepatitis B, hepatitis C, and liver cirrhosis), heart disease (e.g., cardiomyopathy, coronary heart disease, inflammatory heart disease, ischemic heart disease, valvular heart disease, hypertensive heart disease, and atherosclerosis), or pancreas disease.
• the disease is diabetes.
• the compounds, pharmaceutical compositions, and methods of the present invention may be useful in the treatment and/or prevention of metal overload where the metal is not iron.
• the metal overload is aluminum overload, chromium overload, magnesium overload, calcium overload, strontium overload, nickel overload, manganese overload, cobalt overload, copper overload, zinc overload, silver overload, sodium overload, potassium overload, cadmium overload, mercury overload, lead overload, molybdenum overload, tungsten overload, or actinide overload (e.g., uranium overload).
• the metal overload is trivalent metal overload.
• the metal overload is aluminum overload.
• the trivalent metal overload is Cr(III) overload, Mo(III) overload, or Co(III) overload).
• the metal overload is monovalent metal overload (e.g. , Cu(I) overload, Ag(I) overload, Na(I) overload, K(I) overload, or Hg(I) overload).
• the metal overload is divalent metal overload (e.g. , Mg(II) overload, Ca(II) overload, Sr(II) overload, Ni(II) overload, Mn(II) overload, Co(II) overload, Cu(II) overload, Zn(II) overload, Cd(II) overload, Hg(II) overload, or Pb(II) overload).
• the metal overload is tetravalent metal overload (e.g. , Pb(IV) overload). In certain embodiments, the metal overload is pentavalent metal overload. In certain embodiments, the metal overload is hexavalent metal overload (e.g., Cr(VI) overload, Mo(VI) overload, W(VI) overload, or U(VI) overload).
• the disease that is treated or prevented by a method described herein is metal poisoning.
• Metal poisoning may be caused by metal toxicity to a subject.
• metals with little or no endogenous function may find their way into the body of a subject and cause damage.
• Heavy metal ions such as Hg(II) can replace ions such as Zn(II) in metalloproteins and render them inactive, resulting in serious acute or chronic toxicity that can end in a patient' s death or in birth defects.
• radioactive isotopes of the lanthanide (e.g. , cerium) and actinide e.g.
• uranium series can cause grave illness on an individual exposed to them by mouth, air, or skin contact. Such exposure could result not only from the detonation of a nuclear bomb or a "dirty bomb" composed of nuclear waste, but also from the destruction of a nuclear power facility.
• the metal poisoning is iron poisoning, aluminum poisoning, thallium poisoning, chromium poisoning, magnesium poisoning, calcium poisoning, strontium poisoning, nickel poisoning, manganese poisoning, cobalt poisoning, copper poisoning, zinc poisoning, silver poisoning, sodium poisoning, potassium poisoning, cadmium poisoning, mercury poisoning, lead poisoning, antimony poisoning, molybdenum poisoning, tungsten poisoning, lanthanide poisoning (e.g. , cerium poisoning), or actinide poisoning (e.g. , uranium poisoning).
• the metal poisoning is iron poisoning (e.g. , Fe(II) poisoning or Fe(III) poisoning).
• the metal poisoning is aluminum poisoning.
• the metal poisoning is trivalent metal poisoning (e.g. , Fe(III) poisoning, Al(III) poisoning, Tl(III) poisoning, Cr(III) poisoning, Co(III) poisoning, Sb(III) poisoning, Mo(III) poisoning, or Ce(III) poisoning).
• the metal poisoning is monovalent metal poisoning (e.g. , T1(I) poisoning, Cu(I) poisoning, Ag(I) poisoning, Na(I) poisoning, K(I) poisoning, or Hg(I) poisoning).
• the metal poisoning is divalent metal poisoning (e.g., Fe(II) poisoning, Mg(II) poisoning, Ca(II) poisoning, Sr(II) poisoning, Ni(II) poisoning, Mn(II) poisoning, Co(II) poisoning, Cu(II) poisoning, Zn(II) poisoning, Cd(II) poisoning, Hg(II) poisoning, or Pb(II) poisoning).
• the metal poisoning is tetravalent metal poisoning (e.g., Pb(IV) or Ce(IV) poisoning).
• the metal poisoning is pentavalent metal poisoning (e.g. , Sb(V) poisoning).
• the metal poisoning is hexavalent metal poisoning (e.g., Cr(VI) poisoning, Mo(VI) poisoning, W(VI) poisoning, or U(VI) poisoning).
• the disease that is treated or prevented by a method described herein is oxidative stress.
• the iron released from red blood cells of the subject may react with oxygen species produced by inflammatory cells such as neutrophils to produce hydroxyl radicals that cause cell and tissue injury. Chelation and removal of the unmanaged iron may prevent or impede these harmful reactions and, therefore, reduce oxidative stress.
• a subject in need of oxidative stress reduction can have one or more of the following conditions: decreased levels of reducing agents, increased levels of reactive oxygen species, mutations in or decreased levels of antioxidant enzymes (e.g., Cu/Zn superoxide dismutase, Mn superoxide dismutase, glutathione reductase, glutathione peroxidase, thioredoxin, thioredoxin peroxidase, DT-diaphorase), mutations in or decreased levels of metal-binding proteins (e.g. , transferrin, ferritin, ceruloplasmin, albumin, metallothionein), mutated or overactive enzymes capable of producing superoxide (e.g. , nitric oxide synthase, NADPH oxidases, xanthine oxidase, NADH oxidase, aldehyde oxidase, dihydroorotate
• antioxidant enzymes e.g., Cu/Z
• dehydrogenase cytochrome c oxidase
• radiation injury Increased or decreased levels of reducing agents, reactive oxygen species, and proteins are determined relative to the amount of such substances typically found in healthy persons.
• a subject in need of oxidative stress reduction can be suffering from an ischemic episode. Ischemic episodes can occur when there is mechanical obstruction of the blood supply, such as from arterial narrowing or disruption.
• Myocardial ischemia which can give rise to angina pectoris and myocardial infarctions, results from inadequate circulation of blood to the myocardium, usually due to coronary artery disease. Ischemic episodes in the brain that resolve within 24 hours are referred to as transient ischemic attacks.
• a subject at risk of suffering from an ischemic episode typically suffers from atherosclerosis, other disorders of the blood vessels, increased tendency of blood to clot, or heart disease.
• a subject in need of oxidative stress reduction can be suffering from
• Inflammation is a fundamental pathologic process consisting of a complex of cytologic and chemical reactions that occur in blood vessels and adjacent tissues in response to an injury or abnormal stimulation caused by a physical, chemical, or biologic agent.
• Inflammatory disorders are characterized inflammation that lasts for an extended period (e.g., chronic inflammation) or that damages tissue.
• Such inflammatory disorders can affect a wide variety of tissues, such as respiratory tract, joints, bowels, and soft tissue.
• the compounds or pharmaceutical compositions of the invention can be used to treat these diseases.
• the compounds of the invention derive their ability to reduce oxidative stress through various mechanisms.
• the compound binds to a metal, particularly a redox-active metal (e.g., iron), and fills all of the coordination sites of the metal. When all of the metal coordination sites are filled, it is believed that oxidation and/or reducing agents have a diminished ability to interact with the metal and cause redox cycling.
• the compound stabilizes the metal in a particular oxidation state, such that it is less likely to undergo redox cycling.
• the compound itself has antioxidant activity (e.g. , free radical scavenging, scavenging of reactive oxygen or nitrogen species).
• antioxidant activity e.g. , free radical scavenging, scavenging of reactive oxygen or nitrogen species.
• Desferrithiocin and desazadesfemthiocin, and their derivatives and analogs are known to have intrinsic antioxidant activity, as described in U.S. Application Publication No. 2004/0044220, published March 4, 2004 and now abandoned; U.S. Application Publication No. 2004/0132789 and now abandoned, published July 8, 2004; International PCT Application Publication No. WO 2004/017959, published March 4, 2004; U.S. Application Publication No. 2005/0234113, published
• the disease that is treated or prevented by a method described herein is oxidative stress.
• oxidative stress is reduced by a method described herein.
• the disease is radiation injury.
• the disease is inflammation.
• the disease that is treated or prevented by a method described herein is macular degeneration.
• the compounds and pharmaceutical compositions described herein are able to get into the eye. See, e.g. , U.S. Patent Application, U.S.S.N. 61/576,920, filed December 16, 2011 ; U.S. Patent Application, U.S.S.N. 61/576,913, filed December 16, 2011, International PCT Application Publication No. WO 2013/090750, published June 20, 2013; and International PCT Application Publication No. WO 2013/090766, published June 20, 2013.
• the compounds of the invention are then able to chelate and remove iron from the eye thereby preventing Fe +2 from generating reactive oxygen species.
• the local accumulation of iron is thought to contribute to macular degeneration. Therefore, the removal of iron from the eye (including the retina) can prevent and treat macular degeneration.
• the compound or pharmaceutical composition described herein may be administered systemically or ocularly. In certain embodiments, the compound or
• the pharmaceutical composition is administered orally.
• the compound or pharmaceutical composition is administered to the eye using eye drops or an ointment suitable for ocular administration.
• the disease that is treated or prevented by a method described herein is head injury, such as those involving bleeding into the brain or other parts of the central nervous system.
• head injury such as those involving bleeding into the brain or other parts of the central nervous system.
• the compounds and pharmaceutical compositions described herein are thought to chelate the iron from red blood cells the blood resulting from the head injury, thereby preventing iron ions from generating reactive oxygen species.
• a compound being used may or may not have the ability to cross the blood brain barrier.
• the compound being used to treat a head injury in a subject is able to cross the blood brain barrier.
• the compounds are not able to cross the blood brain barrier.
• the head injury is an injury to the head that penetrates the skull.
• the head injury is a closed head injury, which does penetrate the skull. Closed head injuries results from a variety of causes including accidents including vehicular accidents, falls, and assaults. Types of closed head injuries include concussions, brain contusions, diffuse axonal injury, and hemtoma.
• the closed head injury is closed head injuries that result in blood outside the blood vessels of the brain. The local accumulation of iron from the bleeding is thought to contribute to after effects associated with closed head injury. By assisting the clearance of iron from the brain the effects of the bleeding are minimized.
• the compound or pharmaceutical composition described herein may be administered systemically, for example, parenterally (e.g., intravenously) or orally.
• IBD inflammatory bowel disease
• Grisham et ah "Neutophil-mediated mucosal injury. Role of reactive oxygen metabolites.” Dig. Dis. Sci. 33:6S-15S, 1988; Allgayer “Clinical relevance of oxygen radicals in inflammatory bowel disease— facts and fashion.” Klin.
• the present invention provides for the treatment or preventon of IBD.
• DFO an iron chelator, has been discovered to prevent acetic acid-induced colitis in rats, an animal model of IBD. See, e.g., U.S. Patent Application, U.S.S.N. 61/576,920, filed December 16, 2011; U.S. Patent
• the present invention may also be useful in treating a subject diagnosed with IBD.
• the treatment may be used to treat the subject long term or may be used to treat a subject with a fare up of IBD.
• treatment with a compound or pharmaceutical composition described herein leads to reduced levels of reactive oxygen species in the intestines, specifically the intestinal mucosa.
• the compound or pharmaceutical composition may be administered systemically, for example, parenterally ⁇ e.g., intravenously), orally, or rectally.
• the disease that is treated or prevented by a method described herein is stroke.
• the inventive treatment typically leads to a better and/or faster recovery from stroke.
• the stroke being treated may be either an ischemic stroke or a hemorrhagic stroke.
• a compound or pharmaceutical composition described herein is administered to a subject to prevent or minimize the damage due to reperfusion injury after the blood supply to the affected part of the brain is restored.
• the compound and pharmaceutical composition are thought to prevent the generation of reactive oxygen species by either chelating iron responsible for the generation of such species and/or quenching such radical species when they do occur.
• the compound and pharmaceutical composition are thought to work by similar mechanisms although the sequestering of iron from the blood in the brain is probably the predominate mechanism by which the inventive treatment works.
• the mechanism of action of the compound or pharmaceutical composition is similar to that in the treatment of head injury.
• the compound being used in the treatment may have the ability to cross the blood brain barrier.
• the compound used in the treatment can pass through the blood brain barrier.
• the present invention may be useful in treating a subject after the subject has been diagnosed with having a stroke, or a subject who is susceptible to having a stroke may be administered a compound or pharmaceutical composition thereof to prevent or minimize the stroke's effects.
• the compound or pharmaceutical composition is administered as quickly as possible after a subject has been diagnosed with having a stroke. In certain embodiments, the compound is administered to the subject while the stroke is still occurring. In certain embodiments, the compound or pharmaceutical composition is administered to a subject who has a history of strokes or is susceptible to having a stroke because of the subject' s underlying medical condition. In the treatment of stroke the compound or pharmaceutical composition may be administered systemically, for example, parenterally (e.g., intravenously) or orally.
• the disease that is treated or prevented by a method described herein is reperfusion injury.
• Reperfusion injury may occur in any area of the body where the blood supply has been compromised.
• the reperfusion injury being treated occurs in the heart.
• the reperfusion injury occurs in the brain, for example, as discussed above in the context of a stroke.
• the inventive treatment minimizes reperfusion injury once the blood supply to the affects organ or tissue is restored.
• composition described herein is administered to a subject who is suffering from ischemia of a tissue or organ.
• the compound or pharmaceutical composition is thought to prevent the generation of reactive oxygen species by either chelating iron responsible for the generation of such species and/or quenching such radical species when they do occur.
• the present invention may be useful in treating a subject after the subject has been diagnosed with ischemia of a particular organ or tissue.
• the compound or pharmaceutical composition described herein is administered as quickly as possible after a subject has been diagnosed with ischemia.
• the compound or pharmaceutical composition is administered to the subject at risk of ischemia.
• the compound pharmaceutical composition is administered to a subject who is about to undergo a procedure that may lead to ischemia of an organ or tissue (e.g., cardiac surgery).
• the compound or pharmaceutical composition is used to prevent reperfusion injury in a transplanted organ.
• the compound or pharmaceutical composition is used to perfuse an isolated organ being prepared for donation.
• the compound or pharmaceutical composition may be administered systemically, for example, parenterally (e.g., intravenously) or orally.
• the compound or pharmaceutical composition is administered locally to the organ or tissue suffering from ischemia.
• the disease that is treated or prevented by a method described herein is a neoplastic disease or preneoplastic condition.
• the disease is a benign neoplastic disease.
• the disease is cancer.
• the disease is a preneoplastic disease.
• Imaging or examining one or more organs, tissues, tumors, or a combination thereof can be conducted after a metal salt of a compound or pharmaceutical composition described herein is administered to a subject.
• the methods of imaging and examining are intended to encompass various instrumental techniques used for diagnosis, such as x-ray methods (including CT scans and conventional x-ray images), magnetic imaging (magnetic resonance imaging, electron paramagnetic resonance imaging) and radiochemical methods.
• the metal salts used in imaging or examining serve as a contrast agent. Therefore in one embodiment the metal complexes or metal salts of compounds of the present invention can be used as contrast agents for example in imaging or examining one or more organs, for example, the gastrointestinal tract.
• Metals that can serve as contrast agents include gadolinium, iron, manganese, chromium, dysprosium, technetium, scandium, barium, aluminum and holmium, preferably as trications.
• Radioactive metal salts can be made from isotopes including 241 Am, 51 Cr, 60 Co, 57 Co, 58 Co, 64 Cu, 153 Gd, 67 Ga, 198 Au, 113 "Tn, m ln, 59 Fe, 55 Fe, 197 Hg, 203 Hg, 99m Tc, 201 T1, and 169 Yb, again preferably when the metal is present as a trivalent cation.
• the present disclosure provides methods of treating or preventing biofilm formation comprising administering to a subject in need thereof a therapeutically effective amount of a compound or pharmaceutical composition described herein.
• the method of treating or preventing biofilm formation treats, cleans, or disinfects a wound.
• the wound is a chronic wound, acute wound, surgical wound, surgical site, second or third degree burn, stasis ulcer, tropic lesion, decubitus ulcer, severe cut, or abrasion.
• the present disclosure provides methods of reducing or preventing biofilm formation comprising contacting object with an effective amount of a compound jor pharmaceutical composition described herein.
• the provided methods inhibit, reduce, or remove biofilms on or in an object.
• the provided method inhibits or removes the biofilm on the surface of the object.
• the surface is a hard, rigid surface.
• the surface is selected from the group consisting of a drainpipe, glaze ceramic, porcelain, glass, metal, wood, chrome, plastic, vinyl, and formica.
• the surface is a soft, flexible surface.
• the surface is selected from the group consisting of shower curtains and liners, upholstery, laundry, and carpeting.
• the surface is a food preparation surface, such as a kitchen counter, cutting board, sink, stove, refrigerator surface, or on a sponge.
• the surface is a bathroom surface such as a toilet, sink, bathtub, shower, or drain.
• the surface is a medical device surface.
• the contacting of the compound or pharmaceutical composition described herein with the object is carried out by wiping, sponging, or soaking, or laundering means.
• the provided methods prevent or remove biofilm as a dentifrice, a mouthwash, a compound for the treatment of dental caries, acne treatment, cleaning and disinfecting contact lenses, and medically implanted devices that are permanent such as an artificial heart valve or hip joint, and those that are not permanent such as indwelling catheters, pacemakers, and surgical pins.
• the provided methods prevent or remove biofilm in situations involving bacterial infection of a subject, for example, in a topical dressing for burn patients. An example of such a situation is the infection by P. aeruginosa of superficial wounds such as those found in burn patients or in the lung of a subject with cystic fibrosis.
• the provided methods control or prevent the development of biofilm in the process of manufacturing integrated circuits, circuit boards, or other electronic or microelectronic devices.
• the bacterium is contacted with the compound or pharmaceutical composition in vitro. In certain embodiments, the bacterium is contacted with the compound or pharmaceutical composition in vivo. In certain embodiments, the bacterium is subsequently contacted with an antibiotic.
• the compound or pharmaceutical composition is administered with one or more additional pharmaceutical agents ⁇ e.g., biocides, e.g., antimicrobials, e.g., antibiotics).
• additional pharmaceutical agents e.g., biocides, e.g., antimicrobials, e.g., antibiotics.
• the design concept is to fix a lipophilic fragment to a chelator that will promote its gastrointestinal absorption. Once absorbed, it should be quickly converted to its hydrophilic, nontoxic counterpart.
• the metabolic profiles of the current chelators will thus set the structural boundary conditions for the future design strategies.
• the compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. Where typical or preferred process conditions ⁇ e.g., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by those skilled in the art by routine optimization procedures.
• Potassium carbonate (2.76 g, 20.0 mmol) and KI (200 mg, 1.2 mmol) were added to a mixture of 15 (Bergeron et ah, J. Med. Chem. 48 (2005) 4120- 4137) (2.81 g, 10 mmol) in DMF (100 mL).
• a solution of 16 (1.24 g, 10 mmol) in DMF (10 mL) was added to the reaction mixture, which was heated at 100 °C for 24 hours.
• the DADFT ester 15 was selectively alkylated with one of three ethyl ⁇ -bromoalkanoates (25, 26, or 27) in DMF in the presence of K 2 CO 3 and catalytic iodide salt.
• the corresponding diesters 28, 29, and 30 were obtained in 61, 72, and 66% yields.
• these diesters were cleaved in 50% NaOH in CH 3 OH, giving the required acids 12, 13, and 14 in 99, 90, and 98% yields, respectively.
• Bile samples were collected from male Sprague-Dawley rats (400-450 g) at 3 hours intervals for up to 48 hours. The urine sample(s) was taken at 24 hours intervals. Sample collection and handling are as previously described. 38 ' 40
• ICE Chelator Iron Clearing Efficiency
• Tissue samples of animals treated with 8 were prepared for HPLC analysis by homogenizing them in H 2 0 at a ratio of 1: 1 (w/v). Then, as a rinse, CH 3 OH at a ratio of 1:3 (w/v) was added, and the mixture was stored at -20°C for 30 min. This homogenate was centrifuged. The supernatant was diluted with H 2 0, vortexed, and filtered with a 0.2 ⁇ membrane. Analytical separation was performed on a Supelco
• Tissue samples of animals treated with 11 were prepared for HPLC analysis by homogenizing them in 0.5 N HC10 4 at a ratio of 1:3 (w/v). Then, as a rinse, CH 3 OH at a ratio of 1:3 (w/v) was added, and the mixture was stored at -20°C for 30 min. This homogenate was centrifuged. The supernatant was diluted with 95% buffer (25 mM KH 2 P0 4 , pH 3.0)/5% CH 3 CN, vortexed, and filtered with a 0.2 ⁇ membrane. Analytical separation was performed on a Supelco Ascentis Express RP- Amide HPLC system with UV detection at 310 nm as described previously [47,80]. Mobile phase and chromatographic conditions were as for 8.
• Ligand concentrations were calculated from the peak area fitted to calibration curves by nonweighted least-squares linear regression with Shimadzu Class- VP 7.4 software. The method had a detection limit of 0.25 ⁇ and was reproducible and linear over a range of 1-1000 ⁇ . Tissue distribution data are presented as the mean; / ⁇ -values were generated via a one-tailed student's t-test, in which the inequality of variances was assumed; a /?-value of ⁇ 0.05 was considered significant.
• the parent vs metabolite ratio is similar at the 2 and 4 hour time points. At 8 hours, very little parent alcohol 8 and no metabolite 9 remains. The kidney, heart and pancreas also demonstrated a similar and significant conversion of 8 to 9 (Figure 5).
• ICE values for compounds 2 and 7 are historical and included for comparative purposes.
• the chelators were given to the rats orally at a dose of 300 ⁇ /kg; 9 was also given subcutaneously at the same dose.
• the ICE of 8 was 15.4 + 5.6% p ⁇ 0.02), while the ICE of 9 was and 6.2 + 1.7% p ⁇ 0.005).

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