METABOLICALLY PROGRAMMED METAL CHELATORS AND USES THEREOF

Abstract

The present invention provides compounds of Formula (I), which are metabolically programmed metal chelators, e.g., lipophilic, absorbable (e.g., orally absorbable), and effective metal chelators that are converted in vivo to their hydrophilic, nontoxic metabolites. The present invention also provides compounds of Formula (II), which are also metabolically programmed metal chelators. The invention also provides pharmaceutical compositions, kits, methods, and uses that include a compound described herein. The compounds, pharmaceutical compositions, kits, and methods may be useful in treating or preventing a disease (e.g., metal overload, oxidative stress, diabetes, liver disease, heart disease, cancer, radiation injury, neurological or neurodegenerative disorder, Friedreich's ataxia (FRDA), macular degeneration, closed head injury, irritable bowel disease, reperfusion injury, metal poisoning, or infectious disease).

Claims

1. A compound of Formula (I): ##STR00164## or a pharmaceutically acceptable salt thereof, wherein: R.sup.1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, an oxygen protecting group, ##STR00165## each instance of R is independently hydrogen, substituted or unsubstituted alkyl, or an oxygen protecting group; each instance of 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 independently an 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; q is 0 or 1, provided that when q is 0, then R.sup.1 is of the formula: ##STR00166## each instance of R.sup.2 is independently CH.sub.2OR.sup.2a, CH.sub.2OH, C()OH, or C(O)OR.sup.2a, wherein each instance of R.sup.ea is independently substituted or unsubstituted alkyl or an oxygen protecting group; each instance of R.sup.3 is independently halogen, substituted or unsubstituted alkyl, or OR.sup.8, wherein each instance of R.sup.8 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, an oxygen protecting group, ##STR00167## k is 0, 1, 2, 3, or 4; R.sup.4 is hydrogen or substituted or unsubstituted alkyl; R.sup.5 is hydrogen or substituted or unsubstituted alkyl; R.sup.6 is hydrogen or substituted or unsubstituted alkyl; Z is O or S; and R.sup.9 is hydrogen, substituted or unsubstituted alkyl, ##STR00168## an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom; provided that the moiety ##STR00169## at the 3,4,5, or 6-position of the phenyl ring is not of the formula: ##STR00170##

2-3. (canceled)

4. The compound of claim 1, wherein when each instance of x is 1, 2, 3, or 4, each instance of n is 2, and each instance of y is 0, then each instance of R.sup.2 is CH.sub.2OH, C(O)OH, or C(O)OR.sup.2a.

5. The compound of claim 1, wherein the compound is of the formula: ##STR00171## or a pharmaceutically acceptable salt thereof.

6. The compound of claim 5, wherein the compound is of the formula: ##STR00172## or a pharmaceutically acceptable salt thereof.

7. The compound of claim 5, wherein the compound is of the formula: ##STR00173## or a pharmaceutically acceptable salt thereof.

8. The compound of claim 5, wherein the compound is of the formula: ##STR00174## or a pharmaceutically acceptable salt thereof.

9. The compound of claim 5, wherein the compound is of the formula: ##STR00175## or a pharmaceutically acceptable salt thereof.

10-26. (canceled)

27. The compound of claim 1, wherein the compound is of the formula: ##STR00176## or a pharmaceutically acceptable salt thereof.

28-46. (canceled)

47. The compound of claim 1, wherein each of x and y is 0.

48. The compound of claim 1, wherein each instance of x is 1, 2, 3, or 4; each instance of n is 2; and each instance of y is 0.

49. The compound of claim 1, wherein at least one instance of p is 1, 2, 3, 4, or 5.

50. The compound of claim 1, wherein at least one instance of R.sup.2 is CH.sub.2OR.sup.2a.

51. (canceled)

52. The compound of claim 1, wherein at least one instance of R.sup.2 is CH.sub.2OH.

53. The compound of claim 1, wherein at least one instance of R.sup.2 is C()OH.

54. The compound of claim 1, wherein at least one instance of R.sup.2 is C(O)OR.sup.2a.

55-69. (canceled)

70. The compound of claim 1, wherein the compound is of the formula: ##STR00177## or a pharmaceutically acceptable salt thereof.

71. The compound of claim 1, wherein the pharmaceutically acceptable salt is a pharmaceutically acceptable alkali or alkaline earth metal salt.

72. (canceled)

73. A compound of Formula (II): ##STR00178## or a pharmaceutically acceptable salt thereof, wherein: each instance of R.sup.C1 is independently (CH.sub.2).sub.hOR.sup.A1, or (CH.sub.2).sub.hC(O)OR.sup.A1, wherein each instance of R.sup.A1 is independently hydrogen, substituted or unsubstituted alkyl, or an oxygen protecting group, provided that h is not 0 and R.sup.A1 is not hydrogen when R.sup.C1 is (CH.sub.2).sub.hC(O)OR.sup.A1; each instance of R.sup.C2 is independently hydrogen, halogen, substituted or unsubstituted C.sub.1-6 alkyl, CN, NO.sub.2, OR.sup.X, or N(R.sup.Y).sub.2; each instance of R.sup.D is independently hydrogen, alkyl, or an oxygen protecting group; R.sup.X is hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or oxygen protecting group; each instance of R.sup.Y is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, a nitrogen protecting group, or optionally two R.sup.Y 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; and each instance of j is independently 0, 1, 2, 3, or 4.

74-95. (canceled)

96. A pharmaceutical composition comprising a compound of claim 1 and optionally a pharmaceutically acceptable excipient.

97. (canceled)

98. A method of treating a disease in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of claim 1, wherein the disease is iron overload, aluminum overload, lanthanide overload, actinide 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, reperfusion injury, an infectious disease, or metal poisoning.

99-112. (canceled)

113. A method of reducing the formation of biofilms in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of claim 1.

114-115. (canceled)

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0117] FIG. 1 shows the structures of some iron chelators evaluated clinically in humans.

[0118] FIGS. 2A-2B show the tissue metabolism/distribution of compounds 2 and 4-7 in rat liver. The rats (n=3 per group) were given the compounds subcutaneously at a dose of 300 mol/kg. The concentration data of the compounds (y-axis) are expressed as nmol/g wet weight of the liver. Admin. Cmpd.: administered compound.

[0119] FIG. 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).

[0120] FIG. 4 shows the a putative metabolism of compound 7 into compounds 8 and 9, and the lipophilicity (log P.sub.app) of compounds 7 to 9.

[0121] FIG. 5A shows the tissue metabolism/distribution of compounds 7 and 8 in rat plasma, liver, kidney, heart, and pancreas. FIG. 5B shows the tissue metabolism/distribution of compounds 7 and 8 in rat plasma. FIG. 5C shows the tissue metabolism/distribution of compounds 7 and 8 in rat liver. FIG. 5D shows the tissue metabolism/distribution of compounds 7 and 8 in rat kidney. FIG. 5E shows the tissue metabolism/distribution of compounds 7 and 8 in rat heart. FIG. 5F shows the tissue metabolism/distribution of compounds 7 and 8 in rat pancreas. The rats (n=3 per group) were given the compounds subcutaneously at a dose of 300 mol/kg. The concentration data (y-axis) of the compounds are expressed as nmol/g wet weight of the organ (e.g., liver, kidney, heart, pancreas), or as M (plasma). Admin. Cmpd.: administered compound.

[0122] FIG. 6 shows a putative metabolism of compound 11 into compounds 12 to 14, and the lipophilicity (log P.sub.app) of the compounds 11 to 14.

[0123] FIG. 7A shows the tissue metabolism/distribution of compound 11 in rat heart. FIG. 7B shows the tissue metabolism/distribution of compound 11 in rat plasma. FIG. 7C shows the tissue metabolism/distribution of compound 11 in rat liver. FIG. 7D shows the tissue metabolism/distribution of compound 11 in rat kidney. FIG. 7E shows the tissue metabolism/distribution of compound 11 in rat pancreas. The rats (n=3 per group) were given compound 11 subcutaneously at a dose of 300 mol/kg. 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 M (plasma). Admin. Cmpd.: administered compound.

[0124] FIG. 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.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION

[0125] 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. The 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. In certain embodiments, 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. In certain embodiments, the disease is metal poisoning. In certain embodiments, the disease is an infectious disease (e.g., malaria).

Compounds

[0126] Desferrithiocin (DFT) 1 is a natural product iron chelator isolated from Streptomyces antibioticus (Naegeli et al., Metabolites of Microorganisms. Part 193. Ferrithiocin. Helv. Chim. Acta 1980, 63, 1400-1406). It forms a 2:1 complex with Fe(III) with a cumulative formation constant of 410.sup.29 M.sup.1 (Hahn et al., Coordination Chemistry of Microbial Iron Transport. 42. Structural and Spectroscopic Characterization of Diastereomeric Cr(III) and Co(III) Complexes of Desferriferrithiocin. J. Am. Chem. Soc. 1990, 112, 1854-1860; Anderegg et al., Metal Complex Formation of a New Siderophore Desferrithiocin and of Three Related Ligands. J. Chem. Soc., Chem. Commun. 1990, 1194-1196). Although the compound was shown to be an excellent deferration agent when administered orally (po) to rats (Bergeron et al., Evaluation of Desferrithiocin and Its Synthetic Analogs as Orally Effective Iron Chelators. J. Med. Chem. 1991, 34, 2072-2078) and primates (Bergeron et al., A Comparative Evaluation of Iron Clearance Models. Ann. N.Y. Acad. Sci. 1990, 612, 378-393; Wolfe et al., A Non-Human Primate Model for the Study of Oral Iron Chelators. Br. J. Haematol. 1989, 72, 456-461), it caused severe nephrotoxicity in rats (Bergeron et al., A Comparative Study of the Iron-Clearing Properties of Desferrithiocin Analogs with Desferrioxamine B in a Cebus Monkey Model. Blood 1993, 81, 2166-2173). However, the compound's oral activity spurred SAR studies focused on DFT aimed at identifying an orally active and safe DFT analog (Bergeron et al., Effects of C-4 Stereochemistry and C-4 Hydroxylation on the Iron Clearing Efficiency and Toxicity of Desferrithiocin Analogs. J. Med. Chem. 1999, 42, 2432-2440; Bergeron et al., Methoxylation of Desazadesferrithiocin Analogs: Enhanced Iron Clearing Efficiency. J. Med. Chem. 2003, 46, 1470-1477; Bergeron et al., Desazadesmethyldesferrithiocin Analogs as Orally Effective Iron Chelators. J. Med. Chem. 1999, 42, 95-108). Various desazadesferrithiocin analogs have been developed that effectively chelate and remove metals from biological systems. See International PCT Application Publications, WO 1997/036885, published Oct. 9, 1997; WO 2000/016763, published Mar. 30, 2000; WO 2000/012493, published Mar. 9, 2000; WO 2004/017959, published Mar. 4, 2004; WO 2005/034949, published Apr. 21, 2005; WO 2005/023310, published Mar. 17, 2005; WO 2006/107626, published Oct. 12, 2006; WO 2008/130395, published Oct. 30, 2008; WO 2008/115433, published Sep. 25, 2008; WO 2011/028255, published Mar. 10, 2011; WO 2013/090750, published Jun. 20, 2013; and WO 2013/090766, published Jun. 20, 2013; each of which is incorporated herein by reference. Also see U.S. Pat. No. 5,840,739; U.S. Pat. No. 6,864,270; U.S. Pat. No. 7,144,904; U.S. Pat. No. 7,879,886, US Reissue 39,132; U.S. Pat. No. 6,083,966; U.S. Pat. No. 6,521,652; U.S. Pat. No. 6,525,080; U.S. Pat. No. 6,559,315; U.S. Pat. No. 8,278,458; and U.S. Pat. No. 8,324,397; each of which is incorporated herein by reference. Also see U.S. Patent Application Publications, US 2004/044220, US 2004/132789, US 2005/234113, US 2008/255081, US 2006/211746, US 2006/211773, US 2008/096974, US 2013/030028, US 2010/137346, US 2013/210870, and US 2012/184586, each of which is incorporated herein by reference.

[0127] Removal of the pyridine nitrogen of 1 provided la, the parent compound of the desazadesferrithiocin (DADFT) series (Bergeron et al., Desazadesmethyldesferrithiocin Analogs as Orally Effective Iron Chelators. J. Med. Chem. 1999, 42, 95-108). Interestingly, although la was not overtly nephrotoxic, it elicited serious gastrointestinal (GI) problems (Bergeron et al., A Comparative Study of the Iron-Clearing Properties of Desferrithiocin Analogs with Desferrioxamine B in a Cebus Monkey Model. Blood 1993, 81, 2166-2173; Bergeron et al., Effects of C-4 Stereochemistry and C-4 Hydroxylation on the Iron Clearing Efficiency and Toxicity of Desferrithiocin Analogs. J. Med. Chem. 1999, 42, 2432-2440; Bergeron et al., Desazadesmethyldesferrithiocin Analogs as Orally Effective Iron Chelators. J. Med. Chem. 1999, 42, 95-108). In spite of its GI toxicity, the compound's excellent iron-clearing efficiency (ICE) and the absence of nephrotoxicity prompted further SAR studies predicated on this pharmacophore. This led to the discovery that the lipophilicity (partition between octanol and water, expressed as the log of the fraction in the octanol layer, logP.sub.app) (Sangster, Octanol-Water Partition Coefficients: Fundamentals and Physical Chemistry; John Wiley and Sons: West Sussex, England, 1997; Vol. 2) of DADFT analogs could have a profound effect on a compound's ICE, organ distribution, and toxicity profile (Bergeron et al., Effects of C-4 Stereochemistry and C-4 Hydroxylation on the Iron Clearing Efficiency and Toxicity of Desferrithiocin Analogs. J. Med. Chem. 1999, 42, 2432-2440; Bergeron et al., Iron Chelators and Therapeutic Uses. In: Abraham, ed. Burger's Medicinal Chemistry. 6th. Wiley; N.Y.: 2003. pp. 479-561; Bergeron et al., Desferrithiocin Analogs and Nephrotoxicity. J. Med. Chem. 2008, 51, 5993-6004). Desferrithiocin analogs have been reported to chelate and remove iron or other metals. See International PCT Application Publications, WO 1997/036885, published Oct. 9, 1997; WO 2000/016763, published Mar. 30, 2000; WO 2000/012493, published Mar. 9, 2000; and WO 2004/017959, published Mar. 4, 2004; each of which is incorporated herein by reference. Also see U.S. Pat. No. 5,840,739; U.S. Pat. No. 6,864,270; U.S. Pat. No. 7,144,904; U.S. Pat. No. 7,879,886; U.S. Reissue 39,132; U.S. Pat. No. 6,083,966; U.S. Pat. No. 6,521,652; U.S. Pat. No. 6,525,080; and U.S. Pat. No. 6,559,315; each of which is incorporated herein by reference. Also see U.S. Patent Application Publications, US 2004/044220, US 2004/132789, US 2005/234113, and US 2008/255081, each of which is incorporated herein by reference.

[0128] The toxicity associated with excess iron derives from its interaction with reactive oxygen species, for instance, endogenous hydrogen peroxide (H.sub.2O.sub.2)..sup.20-22 In the presence of Fe(II), H.sub.2O.sub.2 is reduced to the hydroxyl radical (HO.) and HO.sup., a process known as the Fenton reaction (shown below). 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..sup.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.

Fe(II)+H.sub.2O.sub.2 Fe(III)+HO.+HO.sup.

Fe(III)+O.sub.2..sup. Fe(II)+H.sub.2O.sub.2

[0129] In the majority of patients with thalassemia major or other transfusion-dependent refractory anemias, treatment with a chelating agent capable of sequestering iron and permitting its excretion from the body is the only therapeutic option available. Current choices (FIG. 1) include Desferal, the mesylate.sup.24 salt of desferrioxamine B (DFO), 1,2-dimethyl-3-hydroxypyridin-4-one (deferiprone, L1),.sup.25,26 and 4-[3,5-bis(2-hydroxyphenyl)-1,2,4-triazol-1-yl]benzoic acid (deferasirox, ICL670A)..sup.27,28 Each has shortcomings.sup.29 and in some cases, serious toxicity issues. DFO, a hexacoordinate hydroxamate iron chelator produced by Streptomyces pilosus,.sup.30 a siderophore, is not orally active and is best administered subcutaneously (sc) by continuous infusion over long periods of time,.sup.31 which presents a patient compliance issue. Deferiprone, while orally active, does not remove enough iron to keep patients in a negative iron balance, and has been associated with agranulocytosis (Ferriprox Prescribing Information, Apotex Inc., Toronto, Ontario, Canada, April, 2015; www.ferriprox.com/us/pdf/ferriprox_full_pi.pdf). Novartis's drug deferasirox did not show noninferiority to DFO, is associated with a number of serious side effects, and, unfortunately, has a narrow therapeutic window..sup.28,33 Our pursuit of an efficient orally active iron chelator with an acceptable toxicity profile began with desferrithiocin, (S)-4,5-dihydro-2-(3-hydroxy-2-pyridinyl)-4-methyl-4-thiazolecarboxylic acid (DFT, 1, Table 1). DFT is a tridentate siderophore.sup.34,35 excreted by Streptomyces antibioticus.sup.34 that forms a stable 2:1 complex with Fe(III); the cumulative formation constant is 410.sup.29..sup.35 Initial animal trials with DFT in rodents.sup.36 and primates.sup.37-39 revealed it to be orally active and highly efficient at removing iron. Its iron clearing efficiency (ICE) was 5.53.2% in rodents,.sup.36 and 16.18.5% in primates.sup.38 (Bergeron et al., Ann N.Y. Acad. Sci. 612 (1990, 612,) 378-393; Wolfe et al., Br. J. Hematol. 72 (1989, 72,) 456-461) (Table 1). ICE is calculated as (ligand-induced iron excretion/theoretical iron excretion)100, expressed as a percent. However, DFT has unacceptable renal toxicity in rats..sup.40,41 Nevertheless, the ligand's remarkable oral bioavailability and ICE drove a successful structure-activity study aimed at ameliorating DFT-induced nephrotoxicity..sup.37,42-45 The outcome revealed that removal of the desferrithiocin aromatic nitrogen, providing (S)-4,5-dihydro-2-(2-hydroxyphenyl)-4-methyl-4-thiazolecarboxylic acid (desazadesferrithiocin, DADFT), and introduction of a hydroxyl at either the 4-aromatic to yield (S)-2-(2,4-dihydroxyphenyl)-4,5-dihydro-4-methyl-4-thiazolecarboxylic acid.sup.37 [(S)-4-(HO)-DADFT, deferitrin, 2] or the 3-aromatic to afford (S)-2-(2,3-dihydroxyphenyl)-4,5-dihydro-4-methyl-4-thiazolecarboxylic acid.sup.37 [(S)-3-(OH)-DADFT, 3] led to chelators with good ICE values (Table 1) and a remarkable reduction in toxicity. Deferitrin (2, FIG. 1), 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,.sup.46 and iron clearance levels were approaching the requisite 450 g/kg/d..sup.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 terminated..sup.48 Nevertheless, the results were attractive enough to compel us to reengineer deferitrin in an attempt to ameliorate the its toxicity.

[0130] The redesign of 2 was predicated on the observation that both ligands 2 and 3 were orally active iron chelators in rodents and primates (Table 1), and that when the 4-(OH) of 2 was methylated, providing (S)-4,5-dihydro-2-(2-hydroxy-4-methoxyphenyl)-4-methyl-4-thiazolecarboxylic acid.sup.43 [(S)-4-(CH.sub.3O)-DADFT, 4], there was a remarkable enhancement in both ICE and lipophilicity (log P.sub.app). The log P.sub.app data are expressed as the log of the fraction of the chelator seen in the octanol layer; measurements were done in TRIS buffer, pH 7.4, using a shake flask direct method..sup.49 The more negative the log P.sub.app, the less chelator is in the octanol phase, the less lipophilic. Unfortunately, the increase in ICE of 4 came with a concomitant increase in toxicity..sup.50 Thus, the delicate balance between the increase in ICE and toxicity with enhanced lipophilicity needed to be understood and exploited. It was determined that introducing polyether fragments at the 4-(OH) of 2 to produce (S)-4,5-dihydro-2-[2-hydroxy-4-(3,6,9-trioxadecyloxy)phenyl]-4-methyl-4-thiazolecarboxylic acid.sup.50 [(S)-4-(HO)-DADFT-PE, 5] or the 3-(OH) of 3, yielding (S)-4,5-dihydro-2-[2-hydroxy-3-(3,6,9-trioxadecyloxy)phenyl]-4-methyl-4-thiazolecarboxylic acid.sup.51 [(S)-3-(HO)-DADFT-PE, 6] led to less lipophilic, e.g., lower log P.sub.app, remarkably efficient iron chelators (Table 1). Unlike deferitrin, there was no renal toxicity, seen with either 5 or 6, even when the chelators were administered b.i.d..sup.50,52

[0131] A magnesium salt of ligand 6 (SPD602, deferitazole magnesium, CAS # 1173092-59-5) was evaluated in clinical trials by Shire..sup.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.sup.53,54 derive from the magnesium itself..sup.55-57 All of our studies with 6 were conducted with the monosodium salt..sup.41,51,52,58 It remains to be seen how well the magnesium salt will perform in patients.

[0132] There were two properties of the (S)-3-(HO)-DADFT-PE (6) that needed attention. The parent drug was an oil, and the dose response curve in rats plateaued very quickly. For example, when 6 was given orally (po) to bile duct-cannulated rats at a dose of 150 mol/kg, the drug decorporated 0.7820.121 mg/kg of iron; the ICE was 18.72.9%..sup.45,58 However, when the dose of the chelator was further increased to 300 mol/kg, the quantity of iron excreted, 0.8870.367 mg/kg, was within error of that induced by the drug at 150 mol/kg (p>0.05), and the ICE was 10.64.4%..sup.45,58 Thus, the deferration induced by 6 was saturable over a fairly narrow dose range. Additional structure activity relationship (SAR) studies were carried out to search for a chelator that had better physicochemical properties, e.g., a solid that retained its ICE over a wider range of doses. The answer would come with a simple structural modification of (S)-4-(HO)-DADFT-PE (5): the 3,6,9-trioxadecyloxy polyether moiety was replaced with a 3,6-dioxaheptyloxy function, providing (S)-4,5-dihydro-2-[2-hydroxy-4-(3,6-dioxaheptyloxy)phenyl]-4-methyl-4-thiazolecarboxylic acid.sup.58,59 [(S)-4-(HO)-DADFT-norPE, 7]. Both acid 7 (Table 1) and its ester precursor.sup.59 were crystalline solids and could be given very effectively in capsules to both rodents and primates. Ligand 7 has excellent ICE properties (26%) in rodents and primates. It also has a much better dose response in rodents than 6..sup.58

[0133] Because of the problems with b.i.d. deferitrin, the toxicity issue of most concern with 7 was related to renal proximal tubule damage. A series of tolerability studies focusing on (S)-4-(HO)-DADFT-norPE's impact on renal function were carried out..sup.58 The drug was given orally to rats s.i.d. for 28 d (56.9, 113.8, or 170.7 mol/kg/day); s.i.d. for 10 d (384 mol/ kg/d), and b.i.d. at 237 mol/kg/dose (474 mol/kg/d)7 d..sup.58 Blood was collected immediately prior to sacrifice and was submitted for a complete blood count (CBC) and serum chemistries, including the determination of the animals' blood urea nitrogen (BUN) and serum creatinine (SCr). No drug-related abnormalities were found, and the rats' BUN and SCr levels were within the normal range..sup.59 In addition, an assessment of the drug's effect on urinary kidney injury molecule-1 (Kim-1).sup.60,61 excretion was determined. Kim-1 is a type 1 transmembrane protein located in the epithelial cells of proximal tubules..sup.60,61 The ectodomain of the Kim-1 proximal tubule protein is released into the urine very early after exposure to a nephrotoxic agent or ischemia; it appears far sooner than increases in BUN or SCr are detected in the serum..sup.62,63 Administration of 7 to rats for up to 28 days did not elicit any increases in urinary Kim-1 excretion..sup.58 Extensive tissues were submitted for histopathology; no drug-related abnormalities were identified. This SAR success set the stage for a closer look at how best to further exploit the relationship between lipophilicity, ICE, and ligand toxicity. The design strategies would weigh heavily on how a chelator's substituents are potentially metabolized.

[0134] Although 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.

[0135] One aspect of the present disclosure relates to compounds of Formula (I):

##STR00005##

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, wherein:

[0136] R.sup.1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, an oxygen protecting group,

##STR00006##

[0137] each instance of R is independently hydrogen, substituted or unsubstituted alkyl, or an oxygen protecting group;

[0138] each instance of n is independently an integer from 1 to 8, inclusive;

[0139] each instance of x is independently an integer between 0 and 8, inclusive;

[0140] each instance of m is independentlyan integer from 1 to 8, inclusive;

[0141] each instance of y is independently an integer from 0 to 8, inclusive;

[0142] each instance of p is independently an integer between 1 and 10, inclusive;

[0143] q is 0 or 1, provided that when q is 0, then R.sup.1 is of the formula:

##STR00007##

[0144] each instance of R.sup.2 is independently CH.sub.2OR.sup.2a, CH.sub.2OH, C()OH, or C(O)OR.sup.2a, wherein each instance of R.sup.2a is independently substituted or unsubstituted alkyl or an oxygen protecting group;

[0145] each instance of R.sup.3 is independently halogen, substituted or unsubstituted alkyl, or OR.sup.8, wherein each instance of R.sup.8 is independently hydrogen, substituted or unsubstituted

alkyl, substituted or unsubstituted acyl, an oxygen protecting group,

##STR00008##

[0146] k is 0, 1, 2, 3, or 4;

[0147] R.sup.4 is hydrogen or substituted or unsubstituted alkyl;

[0148] R.sup.5 is hydrogen or substituted or unsubstituted alkyl;

[0149] R.sup.6 is hydrogen or substituted or unsubstituted alkyl;

[0150] Z is O or S; and

[0151] R.sup.9 is hydrogen, substituted or unsubstituted alkyl,

##STR00009##

[0152] an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom.

[0153] Formula (I) includes sub stituent OR.sup.1 at the 2-position of the phenyl ring. In certain embodiments, R.sup.1 is H. In certain embodiments, R.sup.1 is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C.sub.1-6 alkyl). In certain embodiments, R.sup.1 is Me. In certain embodiments, R.sup.1 is Et, Pr, Bu, unsubstituted pentyl, or unsubstituted hexyl. In certain embodiments, R.sup.1 is substituted methyl (e.g., CF.sub.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). In certain embodiments, R.sup.1 is substituted or unsubstituted acyl. In certain embodiments, R.sup.1 is C(O)R.sup.a, optionally wherein R.sup.a is substituted or unsubstituted C.sub.1-6 alkyl (e.g., Me). In certain embodiments, R.sup.1 is C(O)OR.sup.a, optionally wherein R.sup.a is H, substituted or unsubstituted C.sub.1-6 alkyl (e.g., Me), or an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl). In certain embodiments, R.sup.1 is C(O)N(R.sup.a).sub.2, optionally wherein each instance of R.sup.a is independently H, substituted or unsubstituted C.sub.1-6 alkyl (e.g., Me), or a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts). In certain embodiments, R.sup.1 is an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl). In certain embodiments, R.sup.1 is

##STR00010##

[0154] In certain embodiments, R.sup.1 is

##STR00011##

[0155] In certain embodiments, R.sup.1 is

##STR00012##

[0156] In certain embodiments, R.sup.1 is

##STR00013##

[0157] In certain embodiments, R.sup.1 is of the formula:

##STR00014##

[0158] In certain embodiments, OR.sup.1 is of the formula:

##STR00015##

[0159] In certain embodiments, OR.sup.1 is of the formula:

##STR00016##

[0160] In certain embodiments, OR.sup.1 is of the formula:

##STR00017##

[0161] In certain embodiments, OR.sup.1 is of the formula:

##STR00018##

[0162] In certain embodiments, OR.sup.1 is of the formula:

##STR00019##

[0163] In certain embodiments, OR.sup.1 is of the formula:

##STR00020##

[0164] In certain embodiments, OR.sup.1 is of the formula:

##STR00021##

[0165] In certain embodiments, OR.sup.1 is of the formula:

##STR00022##

[0166] In certain embodiments, OR.sup.1 is of the formula:

##STR00023##

[0167] In certain embodiments, OR.sup.1 is of the formula:

##STR00024##

[0168] Formula (I) may include one or more instances of substituent R. When Formula (I) includes two or more instances of R, any two instances of R.sup.a may independently be the same or different from each other. In certain embodiments, at least one instance of R is H. In certain embodiments, each instance of R is H. In certain embodiments, at least one instance of R is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C.sub.1-6 alkyl). In certain embodiments, at least one instance of R is Me. In certain embodiments, at least one instance of R is Et, Pr, Bu, unsubstituted pentyl, or unsubstituted hexyl. In certain embodiments, at least one instance of R is substituted methyl (e.g., CF.sub.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). In certain embodiments, at least one instance of R is an oxygen protecting group (e.g., acyl, silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl).

[0169] Formula (I) may include moiety

##STR00025##

at the 3,4,5, or 6-position of the phenyl ring. In certain embodiments, q is 0. In certain embodiments, q is 1. When Formula (I) includes two or more instances of n, any two instances of n may independently be the same or different from each other. In certain embodiments, at least one instance of n is 1. In certain embodiments, at least one instance of n is 2. In certain embodiments, each instance of n is 2. In certain embodiments, at least one instance of n is 3, 4, 5, 6, 7, or 8.

[0170] When Formula (I) includes two or more instances of x, any two instances of x may independently be the same or different from each other. In certain embodiments, 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.

[0171] When Formula (I) includes two or more instances of m, any two instances of m may independently be the same or different from each other. In certain embodiments, at least one instance of m is 1. In certain embodiments, at least one instance of m is 2. In certain embodiments, each instance of m is 2. In certain embodiments, at least one instance of m is 3, 4, 5, 6, 7, or 8.

[0172] When Formula (I) includes two or more instances of y, any two instances of y may independently be the same or different from each other. In certain embodiments, 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.

[0173] In certain embodiments, 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.

[0174] When Formula (I) includes two or more instances of p, any two instances of p may independently be the same or different from each other. In certain embodiments, at least one instance of p is 1. In certain embodiments, at least one instance of p is 2. In certain embodiments, at least one instance of p is 3. In certain embodiments, at least one instance of p is 4. In certain embodiments, at least one instance of p is 5. In certain embodiments, at least one instance of p is 6, 7, 8, 9, or 10.

[0175] In certain embodiments, each of x and 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 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. In certain embodiments, 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.

[0176] In certain embodiments, R.sup.1 is not of the formula:

##STR00026##

and q is 1. In certain embodiments, R.sup.1 is hydrogen; and q is 1. In certain embodiments, R.sup.1 is of the formula:

##STR00027##

and q is 1.

[0177] In certain embodiments, at least one moiety

##STR00028##

is at the 3-position of the phenyl ring. In certain embodiments, at least one moiety

##STR00029##

is at the 4-position of the phenyl ring. In certain embodiments, at least one moiety

##STR00030##

is at the 5-position of the phenyl ring. In certain embodiments, at least one moiety

##STR00031##

is at the 6-position of the phenyl ring. In certain embodiments, the moiety

##STR00032##

at the 3, 4,5, or 6-position of the phenyl ring is of the formula:

##STR00033##

[0178] In certain embodiments, the moiety

##STR00034##

at the 3,4,5, or 6-position of the phenyl ring is of the formula:

##STR00035##

[0179] In certain embodiments, the moiety

##STR00036##

at the 3,4,5, or 6-position of the phenyl ring is of the formula:

##STR00037##

[0180] In certain embodiments, the moiety

##STR00038##

at the 3,4,5, or 6-position of the phenyl ring is of the formula:

##STR00039##

[0181] In certain embodiments, the moiety

##STR00040##

at the 3,4,5, or 6-position of the phenyl ring is of the formula:

##STR00041##

[0182] In certain embodiments, the moiety

##STR00042##

at the 3,4,5, or 6-position of the phenyl ring is of the formula:

##STR00043##

[0183] In certain embodiments, the moiety

##STR00044##

at the 3,4,5, or 6-position of the phenyl ring is of the formula:

##STR00045##

[0184] In certain embodiments, the moiety

##STR00046##

at the 3,4,5, or 6-position of the phenyl ring is of the formula:

##STR00047##

[0185] In certain embodiments, the moiety

##STR00048##

at the 3,4,5, or 6-position of the phenyl ring is of the formula:

##STR00049##

[0186] In certain embodiments, the moiety

##STR00050##

at the 3,4,5, or 6-position of the phenyl ring is of the formula:

##STR00051##

[0187] When Formula (I) includes two or more instances of R.sup.2, any two instances of R.sup.2 may independently be the same or different from each other. In certain embodiments, at least one instance of R.sup.2 is CH.sub.2OR.sup.2a. In certain embodiments, at least one instance of R.sup.2 is CH.sub.2OR.sup.2a, wherein R.sup.2a is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C.sub.1-6 alkyl). In certain embodiments, at least one instance of R.sup.2 is CH.sub.2OMe. In certain embodiments, at least one instance of R.sup.2 is CH.sub.2OEt, CH.sub.2OPr, CH.sub.2OBu, CH.sub.2O(unsubstituted pentyl), or CH.sub.2O(unsubstituted hexyl). In certain embodiments, at least one instance of R.sup.2 is CH.sub.2O(substituted methyl) (e.g., CH.sub.2OCF.sub.3 or CH.sub.2OBn), CH.sub.2O(substituted ethyl) (e.g., CH.sub.2O(perfluoroethyl)), CH.sub.2O(substituted propyl) (e.g., CH.sub.2O(perfluoropropyl)), CH.sub.2O(substituted butyl) (e.g., CH.sub.2O(perfluorobutyl)), CH.sub.2O(substituted pentyl) (e.g., CH.sub.2O(perfluoropentyl)), or CH.sub.2O(substituted hexyl) (e.g., CH.sub.2O(perfluorohexyl)). In certain embodiments, at least one instance of R.sup.2 is CH.sub.2OR.sup.2a, wherein R.sup.2a is an oxygen protecting group (e.g., acyl, silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl).

[0188] In certain embodiments, at least one instance of R.sup.2 is CH.sub.2OH

[0189] In certain embodiments, at least one instance of R.sup.2 is C()OH.

[0190] In certain embodiments, at least one instance of R.sup.2 is C(O)OR.sup.2a. In certain embodiments, at least one instance of R.sup.2 is C(O)OR.sup.2a, wherein R.sup.2a is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C.sub.1-6 alkyl). In certain embodiments, at least one instance of R.sup.2 is C()OMe. In certain embodiments, at least one instance of R.sup.2 is C()OEt, C()OPr, C()OBu, C()O(unsubstituted pentyl), or C(O)O (unsubstituted hexyl). In certain embodiments, at least one instance of R.sup.2 is C(O)O (substituted methyl) (e.g., C()OCF.sub.3 or C()OBn), C()O(substituted ethyl) (e.g., C()O(perfluoroethyl)), C()O(substituted propyl) (e.g., C(O)O (perfluoropropyl)), C()O(substituted butyl) (e.g., C()O(perfluorobutyl)), C(O)O (substituted pentyl) (e.g., C()O(perfluoropentyl)), or C()O(substituted hexyl) (e.g., C()O(perfluorohexyl)). In certain embodiments, at least one instance of R.sup.2 is C(O)OR.sup.2a, wherein R.sup.2a is an oxygen protecting group (e.g., acyl, silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl).

[0191] Formula (I) may include one or more substituents R.sup.3 at the 3,4,5, and/or 6-position of the phenyl ring. When Formula (I) includes two or more instances of R.sup.3, any two instances of R.sup.3 may independently be the same or different from each other.

[0192] In certain embodiments, at least one instance of R.sup.3 is halogen (e.g., F, Cl, Br, or I). In certain embodiments, at least one instance of R.sup.3 is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C.sub.1-6 alkyl). In certain embodiments, at least one instance of R.sup.3 is Me. In certain embodiments, at least one instance of R.sup.3 is Et, Pr, Bu, unsubstituted pentyl, or unsubstituted hexyl. In certain embodiments, at least one instance of R.sup.3 is substituted methyl (e.g., CF.sub.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). In certain embodiments, at least one instance of R.sup.3 is OR.sup.8. In certain embodiments, at least one instance of R.sup.3 is OH. In certain embodiments, no instance of R.sup.3 is OH.

[0193] In certain embodiments, at least one instance of R.sup.3 is OR.sup.8, wherein R.sup.8 is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C.sub.1-6 alkyl). In certain embodiments, at least one instance of R.sup.3 is OMe. In certain embodiments, no instance of R.sup.3 is OMe. In certain embodiments, at least one instance of R.sup.3 is OEt, OPr, OBu, O (unsubstituted pentyl), or O(unsubstituted hexyl). In certain embodiments, at least one instance of R.sup.3 is O(substituted methyl) (e.g., OCF.sub.3 or OBn), O(substituted ethyl) (e.g., O (perfluoroethyl)), O(substituted propyl) (e.g., O(perfluoropropyl)), O(substituted butyl) (e.g., O(perfluorobutyl)), O(substituted pentyl) (e.g., O(perfluoropentyl)), or O (substituted hexyl) (e.g., O(perfluorohexyl)). In certain embodiments, at least one instance of R.sup.3 is substituted or unsubstituted acyl. In certain embodiments, at least one instance of R.sup.3 is C(O)R.sup.a, optionally wherein R.sup.a is substituted or unsubstituted C.sub.1-6 alkyl (e.g., Me). In certain embodiments, at least one instance of R.sup.3 is C(O)OR.sup.a, optionally wherein R.sup.a is H, substituted or unsubstituted C.sub.1-6 alkyl (e.g., Me), or an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl). In certain embodiments, at least one instance of R.sup.3 is C(O)N(R.sup.a).sub.2, optionally wherein each instance of R.sup.a is independently H, substituted or unsubstituted C.sub.1-6 alkyl (e.g., Me), or a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts). In certain embodiments, at least one instance of R.sup.3 is OR.sup.8, wherein R.sup.8 is an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl). In certain embodiments, at least one instance of R.sup.3 is OR.sup.8, wherein R.sup.8 is

##STR00052##

[0194] In certain embodiments, at least one instance of R.sup.3 is OR.sup.8, wherein R.sup.8 is

##STR00053##

[0195] In certain embodiments, at least one instance of R.sup.3 is OR.sup.8, wherein R.sup.8 is

##STR00054##

In certain embodiments, at least one instance of R.sup.3 is OR.sup.8, wherein R.sup.8 is

##STR00055##

[0196] In certain embodiments, 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.

[0197] Formula (I) includes substituent R.sup.4 at the 5-position of the thiazolinyl ring. In certain embodiments, R.sup.4 is H. In certain embodiments, R.sup.4 is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C.sub.1-6 alkyl). In certain embodiments, R.sup.4 is Me. In certain embodiments, R.sup.4 is Et, Pr, Bu, unsubstituted pentyl, or unsubstituted hexyl. In certain embodiments, R.sup.4 is substituted methyl (e.g., CF.sub.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).

[0198] Formula (I) includes substituent R.sup.5 at the 5-position of the thiazolinyl ring. In certain embodiments, R.sup.5 is H. In certain embodiments, R.sup.5 is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C.sub.1-6 alkyl). In certain embodiments, R.sup.5 is Me. In certain embodiments, R.sup.5 is Et, Pr, Bu, unsubstituted pentyl, or unsubstituted hexyl. In certain embodiments, R.sup.5 is substituted methyl (e.g., CF.sub.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).

[0199] In certain embodiments, each of R.sup.4 and R.sup.5 is hydrogen. In certain embodiments, each of R.sup.4 and R.sup.5 is independently substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C.sub.1-6 alkyl). In certain embodiments, each of R.sup.4 and R.sup.5 is Me.

[0200] Formula (I) includes sub stituent R.sup.6 at the 4-position of the thiazolinyl ring. In certain embodiments, R.sup.6 is H. In certain embodiments, R.sup.6 is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C.sub.1-6 alkyl). In certain embodiments, R.sup.6 is Me. In certain embodiments, R.sup.6 is Et, Pr, Bu, unsubstituted pentyl, or unsubstituted hexyl. In certain embodiments, R.sup.6 is substituted methyl (e.g., CF.sub.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).

[0201] In certain embodiments, each of R.sup.4 and R.sup.5 is hydrogen, and R.sup.6 is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C.sub.1-6 alkyl). In certain embodiments, each of R.sup.4 and R.sup.5 is hydrogen, and R.sup.6 is Me.

[0202] In certain embodiments, Z is O. In certain embodiments, Z is S.

[0203] In certain embodiments, R.sup.9 is H. In certain embodiments, R.sup.9 is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C.sub.1-6 alkyl). In certain embodiments, R.sup.9 is Me. In certain embodiments, R.sup.9 is Et, Pr, Bu, unsubstituted pentyl, or unsubstituted hexyl. In certain embodiments, R.sup.9 is substituted methyl (e.g., CF.sub.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). In certain embodiments, R.sup.9 is

##STR00056##

[0204] In certain embodiments, R.sup.9 is

##STR00057##

[0205] In certain embodiments, R.sup.9 is

##STR00058##

[0206] In certain embodiments, R.sup.9 is

##STR00059##

[0207] In certain embodiments, R.sup.9 is an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl) when attached to an oxygen atom. In certain embodiments, R.sup.9 is a sulfur protecting group (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl) when attached to a sulfur atom.

[0208] In certain embodiments, ZR.sup.9 is OH. In certain embodiments, ZR.sup.9 is O (unsubstituted C.sub.1-6 alkyl).

[0209] Formula (I) includes a chiral carbon atom (the carbon atom labeled with *) at the 4-position of the thiazolinyl ring. In certain embodiments, the carbon atom labeled with * is of the S configuration. In certain embodiments, the carbon atom labeled with * is of the R configuration.

[0210] In certain embodiments, the moiety

##STR00060##

at the 3,4,5, or 6-position of the phenyl ring is not of the formula:

##STR00061##

[0211] In certain embodiments, when the moiety

##STR00062##

at the 3,4,5, or 6-position of the phenyl ring is of the formula:

##STR00063##

R.sup.2a is not Me. In certain embodiments, when the moiety

##STR00064##

at the 3,4,5, or 6-position of the phenyl ring is of the formula:

##STR00065##

R.sup.2a is not substituted or unsubstituted methyl. In certain embodiments, when the moiety

##STR00066##

at the 3,4, 5, or 6-position of the phenyl ring is of the formula:

##STR00067##

R.sup.2a is not unsubstituted C.sub.1-6 alkyl. In certain embodiments, when each instance of x is 1, 2, 3, or 4, each instance of n is 2, and each instance of y is 0, then each instance of R.sup.2 is CH.sub.2OH, C()OH, or C(O)OR.sup.2a. In certain embodiments, when the 4-position of the phenyl ring is substituted with the moiety

##STR00068##

R.sup.2 is CH.sub.2OR.sup.2a, C()OH, or C(O)OR.sup.2a.

[0212] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00069##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0213] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00070##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0214] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00071##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0215] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00072##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0216] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00073##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0217] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00074##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0218] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00075##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0219] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00076##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0220] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00077##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0221] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00078##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0222] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00079##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0223] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00080##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0224] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00081##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0225] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00082##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein x is 1, 2, 3, 4, 5, 6, 7, or 8.

[0226] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00083##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein x is 1, 2, 3, 4, 5, 6, 7, or 8.

[0227] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00084##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein x is 1, 2, 3, 4, 5, 6, 7, or 8.

[0228] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00085##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein x is 1, 2, 3, 4, 5, 6, 7, or 8.

[0229] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00086##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein x is 1, 2, 3, 4, 5, 6, 7, or 8.

[0230] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00087##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein x is 1, 2, 3, 4, 5, 6, 7, or 8.

[0231] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00088##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein x is 1, 2, 3, 4, 5, 6, 7, or 8.

[0232] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00089##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein x is 1, 2, 3, 4, 5, 6, 7, or 8.

[0233] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00090##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein x is 1, 2, 3, 4, 5, 6, 7, or 8.

[0234] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00091##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0235] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00092##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0236] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00093##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0237] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00094##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0238] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00095##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0239] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00096##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0240] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00097##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0241] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00098##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0242] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00099##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0243] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00100##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0244] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00101##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0245] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00102##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0246] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00103##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0247] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00104##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein x is 1, 2, 3, 4, 5, 6, 7, or 8.

[0248] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00105##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein x is 1, 2, 3, 4, 5, 6, 7, or 8.

[0249] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00106##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein x is 1, 2, 3, 4, 5, 6, 7, or 8.

[0250] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00107##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein x is 1, 2, 3, 4, 5, 6, 7, or 8.

[0251] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00108##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein x is 1, 2, 3, 4, 5, 6, 7, or 8.

[0252] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00109##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein x is 1, 2, 3, 4, 5, 6, 7, or 8.

[0253] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00110##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein x is 1, 2, 3, 4, 5, 6, 7, or 8.

[0254] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00111##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein x is 1, 2, 3, 4, 5, 6, 7, or 8.

[0255] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00112##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein x is 1, 2, 3, 4, 5, 6, 7, or 8.

[0256] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00113##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0257] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00114##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0258] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00115##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0259] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00116##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0260] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00117##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0261] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00118##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0262] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00119##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0263] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00120##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0264] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00121##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0265] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00122##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0266] Exemplary compounds of Formula (I) include, but are not limited to:

##STR00123##

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof.

[0267] Additional exemplary compounds of Formula (I) include, but are not limited to:

##STR00124##

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof.

[0268] Additional exemplary compounds of Formula (I) include, but are not limited to:

##STR00125##

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof.

[0269] Additional exemplary compounds of Formula (I) include, but are not limited to:

##STR00126##

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof.

[0270] Additional exemplary compounds of Formula (I) include, but are not limited to:

##STR00127##

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof.

[0271] The compounds of the invention may be provided in various salts forms. In certain embodiments, the inventive compounds are provided as alkali metal salts. In certain embodiments, the inventive compounds are provided as alkaline earth metal salts. In certain embodiments, when a compound described herein includes one or more C()OH or C(O)SH moieties (e.g., ZR.sub.9 is OH or SH, R.sup.2 is C()OH), the compound may be provided as a carboxylate salt or thiocarboxylate salt with a base. In certain embodiments, the base is betaine, choline hydroxide, diethanolamine, diethylamine, ethanolamine, hydroxyethylmorpholine, 4-(2-hydroxyethyl morpholine), 1-(2-hydroxyethyl pyrrolidine), 1-(2-hydroxyethyl)-piperidine, hydroxyethyl pyrroldine, imidazone, lysine (e.g., L-lysine), arginine (e.g., L-arginine), histidine (e.g., L-histidine), N-methyl-D-glucamine (NMG), N,N-dibenzyl-ethylenediamine, N, N-diethyl-ethanolamine, triethanolamine, tromethamine, Ca(OH).sub.2, Mg(OH).sub.2, magnesium acetate, LiOH, KOH, potassium 2-ethylhexanoate, NaOH, sodium acetate, sodium 2-ethylhexanoate, Zn(OH).sub.2, zinc acetate, a mixture of Zn(OH).sub.2 and Mg(OH).sub.2, or piperazine. In certain embodiments, a salt described herein is a lithium salt (e.g., mono-lithium salt or di-lithium salt). In certain embodiments, a salt described herein is a sodium salt (e.g., mono-sodium salt or di-sodium salt). In certain embodiments, a salt described herein is a potassium salt (e.g., mono-potassium salt or di-potassium salt). In certain embodiments, a salt described herein is a zinc salt (e.g., hemi-zinc salt or mono-zinc salt). In certain embodiments, a salt described herein is a magnesium salt (e.g., hemi-megnesium salt or mono-magnesium salt). In certain embodiments, a salt described herein is a calcium salt (e.g., hemi-calcium salt or mono-calcium salt).

[0272] The cation (e.g., Li.sup.+, Na.sup.+, K.sup.+, Mg.sup.2+, Mg(OH).sup.+, Ca.sup.2+, Ca(OH).sup.+, Zn.sup.2+, or Zn(OH).sup.+) and anion (e.g., a compound described herein that includes one or more C()OH or C(O)SH moieties (e.g., ZR.sub.9 is OH or SH, R.sup.2 is C()OH)) in 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 (cation:anion)) are also possible, as long as the sum of the formal charges of the cation and anion in the salt is about zero.

[0273] Additional exemplary compounds of Formula (I) include, but are not limited to:

##STR00128## ##STR00129##

and pharmaceutically acceptable solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof.

[0274] Additional exemplary compounds of Formula (I) include, but are not limited to:

##STR00130## ##STR00131##

and pharmaceutically acceptable solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof.

[0275] Additional exemplary compounds of Formula (I) include, but are not limited to:

##STR00132## ##STR00133##

and pharmaceutically acceptable solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof.

[0276] Additional exemplary compounds of Formula (I) include, but are not limited to:

##STR00134## ##STR00135##

and pharmaceutically acceptable solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof.

[0277] Additional exemplary compounds of Formula (I) include, but are not limited to:

##STR00136##

and pharmaceutically acceptable solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof.

[0278] Additional exemplary compounds of Formula (I) include, but are not limited to:

##STR00137##

and pharmaceutically acceptable solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof.

[0279] In certain embodiments, 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. In certain embodiments, a compound described herein is a compound of Formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof. In certain embodiments, a compound described herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0280] Another aspect of the present disclosure relates to compounds of Formula (II):

##STR00138##

or a pharmaceutically acceptable salt thereof, wherein:

[0281] each instance of R.sup.C1 is independently (CH.sub.2).sub.hOR.sup.A1, or (CH.sub.2).sub.hC(O)OR.sup.A1, wherein each instance of R.sup.A1 is independently hydrogen, substituted or unsubstituted alkyl, or an oxygen protecting group, provided that h is not 0, and R.sup.A1 is not hydrogen when R.sup.C1 is (CH.sub.2).sub.hC(O)OR.sup.A1; [0282] each instance of R.sup.C2 is independently hydrogen, halogen, substituted or unsubstituted C.sub.1-6 alkyl, CN, NO.sub.2, OR.sup.X, or N(R.sup.Y).sub.2; [0283] each instance of R.sup.C3 is independently hydrogen, alkyl, or an oxygen protecting group; [0284] R.sup.X is hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or oxygen protecting group; [0285] each instance of R.sup.Y is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, a nitrogen protecting group, or optionally two R.sup.Y are taken together with the intervening atoms to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; [0286] each instance of h is independently 0, 1, 2, 3, 4, 5, 6, 7, or 8; and [0287] each instance of j is independently 0, 1, 2, 3, or 4.

[0288] Formula (II) includes one or more instances of substituent R.sup.C1. In certain embodiments, at least one instance of R.sup.C1 is of the formula: (CH.sub.2).sub.hOR.sup.A1, wherein each instance of R.sup.A1 is independently hydrogen, substituted or unsubstituted alkyl, or an oxygen protecting group. In certain embodiments, at least one instance of R.sup.C1 is (CH.sub.2).sub.hOH, wherein: h is 0, 1, 2, 3, 4, 5, 6, 7, or 8. In certain embodiments, h is 0. In certain embodiments, 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.sup.C1 is OH. In certain embodiments, R.sup.A1is hydrogen. In certain embodiments, R.sup.A1is substituted or unsubstituted C.sub.1-6 alkyl (e.g., methyl or ethyl). In certain embodiments, at least one instance of R.sup.A1is methyl. In certain embodiments, at least one instance of R.sup.A1is substituted methyl (e.g., CF.sub.3, CH.sub.2OH, or Bn). In certain embodiments, at least one instance of R.sup.A1 is unsubstituted ethyl, substituted ethyl (e.g., perfluoroethyl), unsubstituted propyl (e.g., n-Pr or i-Pr), substituted propyl (e.g., perfluoropropyl), unsubstituted butyl, or substituted butyl (e.g., perfluorobutyl). In certain embodiments, at least one instance of R.sup.C1 is OMe or OEt. In certain embodiments, R.sup.A1 is an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl). In certain embodiments, at least one instance of R.sup.C1 is of the formula: (CH.sub.2).sub.hC(O)OR.sup.A1, wherein each instance of R.sup.A1 is independently hydrogen, substituted or unsubstituted alkyl, or an oxygen protecting group, provided that h is not 0, and R.sup.A1 is not hydrogen when R.sup.C1 is (CH.sub.2).sub.hC(O)OR.sup.A1. In certain embodiments, at least one instance of R.sup.A1 is (CH.sub.2)C(O)OR.sup.A1 (e.g., (CH.sub.2)C(O)OH, (CH.sub.2)C(O)O(substituted or unsubstituted C.sub.1-6 alkyl) (e.g., OMe, OCF.sub.3, OEt, OPr, OBu, or OBn), or (CH.sub.2)C(O)O (substituted or unsubstituted phenyl) (e.g., (CH.sub.2)C(O)OPh)). In certain embodiments, at least one instance of R.sup.C1 is (CH.sub.2)C(O)OMe. In certain embodiments, at least one instance of R.sup.C1 is (CH.sub.2)C(O)OEt.

[0289] Formula (II) includes one or more instances of substituent R.sup.C2. In certain embodiments, 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 instance of R.sup.C2 is hydrogen. In certain embodiments, at least one instance of R.sup.C2 is halogen (e.g., F, Cl, Br, or I). In certain embodiments, at least one instance of R.sup.C2 is F. In certain embodiments, at least one instance of R.sup.C2 is Cl. In certain embodiments, at least one instance of R.sup.C2 is substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.C2 is methyl. In certain embodiments, at least one instance of R.sup.C2 is substituted methyl (e.g., CF.sub.3, CH.sub.2OH, or Bn). In certain embodiments, at least one instance of R.sup.C2 is unsubstituted ethyl, substituted ethyl (e.g., perfluoroethyl), unsubstituted propyl (e.g., n-Pr or i-Pr), substituted propyl (e.g., perfluoropropyl), unsubstituted butyl, or substituted butyl (e.g., perfluorobutyl). In certain embodiments, at least one instance of R.sup.C2 is CN. In certain embodiments, at least one instance of R.sup.C2 is NO.sub.2. In certain embodiments, at least one instance of R.sup.C2is OR.sup.X (e.g., OH, O(substituted or unsubstituted C.sub.1-6 alkyl) (e.g., OMe, OCF.sub.3, OEt, OPr, OBu, or OBn), or O(substituted or unsubstituted phenyl) (e.g., OPh)), wherein R.sup.x is hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or oxygen protecting group. In certain embodiments, at least one instance of R.sup.C2 is OH. In certain embodiments, at least one instance of R.sup.C2 is OMe. In certain embodiments, at least one instance of R.sup.C2 is OEt. In certain embodiments, at least one instance of R.sup.C2 is N(R.sup.Y).sub.2 (e.g., NH.sub.2, NH(substituted or unsubstituted C.sub.1-6 alkyl) (e.g., NHMe), or N(substituted or unsubstituted C.sub.1-6 alkyl)-(substituted or unsubstituted C.sub.1-6 alkyl) (e.g., NMe.sub.2)), wherein each instance of R.sup.Y is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, a nitrogen protecting group, or optionally two R.sup.Y are taken together with the intervening atoms to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl. In certain embodiments, at least one instance of R.sup.C2 is NMe.sub.2. In certain embodiments, at least one instance of R.sup.C2 is NEt.sub.2. In certain embodiments, two instances of R.sup.Y 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.

[0290] Formula (II) includes one or more instances of substituent R.sup.C3. In certain embodiments, at least one instance of R.sup.C3 is hydrogen. In certain embodiments, at least one instance of R.sup.C3 is substituted or unsubstituted alkyl. In certain embodiments, at least one instance of R.sup.C3 is substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.C3 is Me. In certain embodiments, at least one instance of R.sup.C3 is substituted methyl (e.g., CF.sub.3, CH.sub.2OH, or Bn). In certain embodiments, at least one instance of R.sup.C3 is Et, substituted ethyl (e.g., perfluoroethyl), Pr (e.g., n-Pr or i-Pr), substituted propyl (e.g., perfluoropropyl), Bu, or substituted butyl (e.g., perfluorobutyl). In certain embodiments, at least one instance of R.sup.D is an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl).

[0291] In certain embodiments, the compound of Formula (II) is of the formula:

##STR00139##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0292] In certain embodiments, the compound of Formula (II) is of the formula:

##STR00140##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0293] Exemplary compounds of Formula (II) include, but are not limited to:

##STR00141##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0294] Exemplary compounds of Formula (II) include, but are not limited to:

##STR00142## ##STR00143##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0295] In certain embodiments, 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. In certain embodiments, a compound described herein is a compound of Formula (II), or a pharmaceutically acceptable salt or stereoisomer thereof. In certain embodiments, a compound described herein is a compound of Formula (II), or a pharmaceutically acceptable salt thereof.

Pharmaceutical Compositions, Kits, and Administration

[0296] 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. In certain embodiments, the compound of the present invention is a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is a compound of Formula (II), or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is provided in an effective amount in the pharmaceutical composition. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactically effective amount.

[0297] Pharmaceutical 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.

[0298] 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.

[0299] Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and/or any additional ingredients in a pharmaceutical composition 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. By way of example, the composition may comprise between 0.1% and 100% (w/w) active ingredient.

[0300] Pharmaceutically acceptable excipients 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.

[0301] 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.

[0302] 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.

[0303] 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., carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g., carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), 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, and Solutol), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor), 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, Poloxamer188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and/or mixtures thereof.

[0304] 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, 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.

[0305] Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and other preservatives.

[0306] Exemplary 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.

[0307] 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. Exemplary 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.

[0308] 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.

[0309] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.

[0310] 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.

[0311] Other preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus, Phenonip, methylparaben, Germall 115, Germaben II, Neolone, Kathon, and Euxyl. In certain embodiments, the preservative is an anti-oxidant. In other embodiments, the preservative is a chelating agent.

[0312] 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 saline, Ringer's solution, ethyl alcohol, and mixtures thereof.

[0313] 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.

[0314] 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, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, and wheat germ oils. 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.

[0315] Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredients, 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. Besides inert diluents, the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. In certain embodiments for parenteral administration, the conjugates of the invention are mixed with solubilizing agents such as CremophorTM, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.

[0316] 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. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0317] 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.

[0318] In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

[0319] 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.

[0320] While it may be possible for the compounds disclosed herein, or pharmaceutically acceptable salts, tautomers, stereoisomers, solvates, hydrates, or polymorphs thereof, to be administered orally as they are, it is also possible to present them as a pharmaceutical formulation or dosage. Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, 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 (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may comprise buffering agents.

[0321] 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.

[0322] 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. In such solid dosage forms 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. In the case of capsules, tablets and pills, 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. Examples of embedding compositions which can be used include polymeric substances and waxes.

[0323] 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. Generally, 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. Additionally, 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. Alternatively or additionally, 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.

[0324] 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. Alternatively or additionally, 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.

[0325] 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.

[0326] Low boiling propellants generally include liquid propellants having a boiling point of below 65 F. at atmospheric pressure. Generally 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).

[0327] Pharmaceutical 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.

[0328] 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.

[0329] 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 administration. Such 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. Alternately, 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.

[0330] 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.

[0331] Although the descriptions of pharmaceutical compositions provided herein 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.

[0332] Compounds provided 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.

[0333] 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. Specifically contemplated routes are oral administration, intravenous administration (e.g., systemic intravenous injection), regional administration via blood and/or lymph supply, and/or direct administration to an affected site. The 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. In general 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).

[0334] The exact amount of a compound required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound, mode of administration, and the like. An effective amount may be included in a single dose (e.g., single oral dose) or multiple doses (e.g., multiple oral doses). In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, any two doses of the multiple doses include different or substantially the same amounts of a compound described herein. In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, 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. In certain embodiments, 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. In certain embodiments, 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. In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, 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. In certain embodiments, the duration between the first dose and last dose of the multiple doses is three months, six months, or one year. In certain embodiments, the duration between the first dose and last dose of the multiple doses is the lifetime of the subject, tissue, or cell. In certain embodiments, 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. In certain embodiments, 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.

[0335] It will be appreciated that dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult. The amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult. In certain embodiments, a dose described herein is a dose to an adult human whose body weight is 70 kg.

[0336] 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. In certain embodiments, 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.

[0337] 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. Pharmaceutical 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. In certain embodiments, 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). 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. In general, 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 lower than those utilized individually.

[0338] The additional pharmaceutical agents include, but are not limited to, anti-proliferative 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. In certain embodiments, the additional pharmaceutical agent is an anti-proliferative agent. In certain embodiments, the additional pharmaceutical agent is an anti-cancer agent. In certain embodiments, the additional pharmaceutical agent is an anti-viral agent. In certain embodiments, the additional pharmaceutical agent is a binder or inhibitor of a protein kinase. In certain embodiments, 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. In certain embodiments, the additional pharmaceutical agent is an iron chelator (e.g., desferrioxamine (DFO, DFX, deferoxamine, deferoxamine mesylate, desferrioxamine B, Desferal), deferasirox (Exjad), deferiprone (L1, Ferriprox), or Feralex-G). In certain embodiments, the compounds described herein or pharmaceutical compositions can be administered in combination with an anti-cancer therapy including, but not limited to, surgery, radiation therapy, transplantation (e.g., stem cell transplantation, bone marrow transplantation), immunotherapy, and chemotherapy.

[0339] Also encompassed by the invention are 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). In some embodiments, the kit further includes a second container comprising a pharmaceutical excipient for, e.g., dilution or suspension of an inventive compound or pharmaceutical composition. In some embodiments, the inventive compound or pharmaceutical composition provided in the first container and the second container are combined to form one unit dosage form.

[0340] The 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. In certain embodiments, 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 pharmaceutical composition to the subject, instructions for contacting the cell, tissue, or biological sample with the compound or pharmaceutical composition). A kit 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.

Methods of Treatment and Uses

[0341] 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.

[0342] The compounds of the invention are thought to be metal chelators. The compounds 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) typically cannot easily pass the cell membrane and/or are poorly absorbable (e.g., orally absorbable). Lipophilic compounds (e.g., compounds of Formula (I) or Formula (II) that include zero or one carboxyl group) 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 metabolically programing the 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.

[0343] In certain embodiments, 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., Tl(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., Cu(I) or Cu(II)), zinc, silver (e.g., Ag(I)), sodium, potassium, cadmium (e.g., Cd(II)), mercury (e.g., Hg(I) or Hg(II)), lead (e.g., Pb(II) or Pb(IV)), antimony (e.g., Sb(III) or Sb(V)), molybdenum (e.g., Mo(III) or Mo(VI)), tungsten (e.g., W(VI)), a lanthanide (e.g., cerium, such as Ce(III) or Ce(IV)), or an actinide (e.g., uranium, such as U(VI)). In certain embodiments, the metal is a trivalent metal (e.g., Fe(III) or aluminum). In certain embodiments, the trivalent metal is Tl(III), Cr(III), Co(III), Sb(III), Mo(III), or Ce(III). In certain embodiments, the metal is a monovalent metal (e.g., Tl(I), Cu(I), Ag(I), Na(I), K(I), or Hg(I)). In certain embodiments, 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)). In certain embodiments, 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)).

[0344] In another aspect, provided herein are methods of chelating a metal (e.g., iron or another metal) in a subject, the methods including administering to the subject an effective amount (e.g., therapeutically effective amount) of a compound or pharmaceutical composition described herein.

[0345] In another aspect, provided herein are methods of chelating a metal (e.g., iron or another metal) in a cell, tissue, or biological sample, the methods including contacting the cell, tissue, or biological sample with an effective amount of a compound or pharmaceutical composition described herein.

[0346] In another aspect, provided herein are methods of treating a disease in a subject in need thereof, the methods including administering to the subject an effective amount (e.g., therapeutically effective amount) of a compound or pharmaceutical composition described herein.

[0347] In another aspect, provided herein are methods of preventing a disease in a subject in need thereof, the methods including administering to the subject an effective amount (e.g., prophylactically effective amount) of a compound or pharmaceutical composition described herein.

[0348] In another aspect, provided herein are methods of treating a disease in a subject in need thereof, the methods 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.

[0349] In another aspect, provided herein are methods of preventing a disease in a subject in need thereof, the methods 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.

[0350] 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). In certain embodiments, the mixture is administered intravenously to the subject.

[0351] In another aspect, provided are 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).

[0352] In another aspect, provided are the pharmaceutical 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).

[0353] The present invention stems from the recognition that the pathogenesis of various diseases. In certain embodiments, 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, Friedreich's ataxia (FRDA), macular degeneration, closed head injury, irritable bowel disease, or reperfusion injury. These diseases involve free iron and the generation of reactive oxygen species (ROS), including superoxide anion, hydrogen peroxide, hypochlorous acid, and hydroxyl radicals, and other longer lived, free radicals. Such radicals are now realized to be important contributors to these diseases. Free iron is known to contribute to the formation of reactive oxygen species. For example, Fe.sup.+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. Furthermore, superoxide anions or a biological reductant (e.g., ascorbic acid) can reduce the resulting Fe.sup.+3 ion back to Fe.sup.+2 for continued peroxide reduction, thus a problematic cycle.

[0354] Therefore, diseases that lead to bleeding and/or an inflammatory response involve the possibility that reactive oxygen species will come in contact with Fe.sup.+2 ions to produce highly reactive and damaging hydroxyl radicals. That is, the iron released from red blood cells react with oxygen species produced by inflammatory cells such as neutrophils to produce hydroxyl radicals that cause cell and tissue injury. The solution, therefore, is chelation and removal of the unmanaged iron.

[0355] In certain embodiments, 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.

[0356] In certain embodiments, the cell is in vitro. In certain embodiments, the cell is in vivo.

[0357] 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.

[0358] In certain embodiments, the tissue is a target tissue (e.g., heart, lungs, liver, pancreas, kidneys, brain, or spleen).

[0359] In certain embodiments, 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). Iron is an oxidant as well as a nutrient for many microorganisms. To survive and replicate, microbial pathogens must acquire iron from their host. 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 of the infectious diseases caused by microbes. In certain embodiments, the infectious disease is responsive to the chelation or sequestration of a metal. In certain embodiments, the disease that is treated and/or prevented by the compounds, pharmaceutical compositions, and methods of the invention is a viral infection. In certain embodiments, the disease is a bacterial infection. In certain embodiments, 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, Enterococcus, Bacillus, Clostridium, Lactobacillus, Listeria, Erysipelothrix, Propionibacterium, Eubacterium, and Corynebacterium. In certain embodiments, the Gram-positive bacterium is a bacterium of the phylum Firmicutes. In certain embodiments, 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. raffinosus. In certain embodiments, the Enterococcus infection is an E. faecalis infection. In certain embodiments, the Enterococcus infection is an E. faecium infection. In certain embodiments, 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. haemolyticus, S. hominis, S. hyicus, S. intermedius, S. kloosii, S. leei, S. lenus, S. lugdunesis, S. lutrae, S. lyticans, S. massiliensis, S. microti, S. muscae, S. nepalensis, S. pasteuri, S. penttenkoferi, S. piscifermentans, S. psuedointermedius, S. psudolugdensis, S. pulvereri, S. rostri, S. saccharolyticus, S. saprophyticus, S. schleiferi, S. sciuri, S. simiae, S. simulans, S. stepanovicii, S. succinus, S. vitulinus, S. warneri, and S. xylosus. In certain embodiments, the Staphylococcus infection is an S. aureus infection. In certain embodiments, the Staphylococcus infection is an S. epidermis infection. In certain embodiments, the Gram-positive bacterium is selected from the group consisting of Staphylococcus aureus, Staphylococcus auricularis, Staphylococcus capitis, Staphylococcus cohnii, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus lugdanensis, Staphylococcus saccharolyticus, Staphylococcus saprophyticus, Staphylococcus schleiferi, Staphylococcus similans, Staphylococcus warneri, Staphylococcus xylosus, Streptococcus agalactiae, Streptococcus anginosus, Streptococcus bovis, Streptococcus canis, Streptococcus equi, Streptococcus milleri, Streptococcus mitior, Streptococcus mutans, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus salivarius, Streptococcus sanguis, Bacillus anthracis, Clostridium botulinum, Clostridium perfringens, Clostridium tetani, Corynebacterium diphtheriae, Corynebacterium jeikeium, Enterococcus faecalis, Enterococcus faecium, Erysipelothrix rhusiopathiae, Gardnerella vaginalis, Gemella morbillorum, Mycobacterium abcessus, Mycobacterium chelonae, Mycobacterium fortuitum, Mycobacterium haemophilium, Mycobacterium kansasii, Mycobacterium leprae, Mycobacterium marinum, Mycobacterium scrofulaceum, Mycobacterium smegmatis, Mycobacterium terrae, Mycobacterium tuberculosis, Mycobacterium ulcerans, and Peptococcus niger.

[0360] In certain embodiments, the bacterial infection is an infection caused by a Gram-negative bacterium. Exemplary 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, Porphyromonas gingivalis, Helicobacter pylori, Francisella tularensis, Yersinia pestis, Morganella morganii, Edwardsiella tarda, and Haemophilus influenzae. In certain embodiments, the Gram-negative bacteria species is Pseudomonas. In certain embodiments, the Gram-negative bacteria species is Pseudomonas aeruginosa.

[0361] 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. For example, a chronic middle ear infection, or otitis media, can occur when the Eustachian tube becomes blocked repeatedly due to allergies, multiple infections, ear trauma, or swelling of the adenoids. The definition of 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, infectious kidney stones (e.g., infectious kidney stones caused by Proteus mirabilis), bacterial endocarditis, and sinus infection.

[0362] In certain embodiments, 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). In certain embodiments, the bacterial infection is caused by a methicillin-resistant (MR) organism. In certain embodiments, the bacterial infection is caused by methicillin-resistant S. aureus (MRSA). In certain embodiments, the bacterial infection is caused by methicillin-resistant Staphylococcus epidermidis (MRSE). In certain embodiments, the bacterial infection is caused by penicillin-resistant Streptococcus pneumonia. In certain embodiments, the bacterial infection is caused by quinolone-resistant Staphylococcus aureus (QRSA). In certain embodiments, the bacterial infection is caused by multi-drug resistant Mycobacterium tuberculosis.

[0363] In some embodiments, 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. In certain embodiments, the infectious diseases is pneumonia, urinary tract infection, complicated intra-abdominal infection, or complicated skin/skin structure infection. In certain embodiments, 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. In certain embodiments, 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.In certain embodiments, 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. In certain embodiments, the disease is a multicellular-parasitic infection. In certain embodiments, the disease is a fungal infection.

[0364] In certain embodiments, 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) may be elevated in the subject (e.g., in the serum or in a cell), such as when there is insufficient storage capacity for the metal or an abnormality in the metal storage system that leads to metal release. In certain embodiments, the metal overload is iron overload (e.g., Fe(III) overload or Fe(II) overload).

[0365] 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. 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. In certain embodiments, the disease that is treated and/or prevented by a method described herein is global iron overload. In certain embodiments, the disease is focal iron overload. In certain embodiments, the disease is primary hemochromatosis. In certain embodiments, the disease is secondary hemochromatosis. In certain embodiments, the disease is Bantu siderosis.

[0366] In 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. In certain embodiments, the disease is a neurological or neurodegenerative disorder. In certain embodiments, the disease is Parkinson's disease, Alzheimer's disease, Huntington's disease, neuroferritinopathy, amyotrophic lateral sclerosis, or multiple sclerosis.

[0367] While humans have a highly efficient iron management system in which they absorb and excrete about 1 mg of iron daily, there is no conduit for the excretion of excess metal. Transfusion-dependent anemias, like thalassemia, lead to a buildup of iron in the liver, heart, pancreas, and elsewhere resulting in (i) liver disease that may progress to cirrhosis (Angelucci et al., Hepatic Iron Concentration and Total Body Iron Stores in Thalassemia Major. N. Engl. J. Med. 2000, 343, 327-331; Bonkovsky et al., Iron-Induced Liver Injury. Clin. Liver Dis. 2000, 4, 409-429; Peitrangelo, Mechanism of Iron Toxicity. Adv. Exp. Med. Biol. 2002, 509, 19-43), (ii) 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 Haemochromatosis: Assessment by Oral Glucose Tolerance Test. Eur. J. Pediatr. 2004, 162, 139-146; Wojcik et al., Natural History of C282Y Homozygotes for Haemochromatosis. Can. J. Gastroenterol. 2002, 16, 297-302), and (iii) heart disease. Relative excess iron has been associated with increased risk of heart disease. Cardiac failure is still the leading cause of death in thalassemia major and related forms of transfusional iron overload (Brittenham, Disorders of Iron Metabolism: Iron Deficiency and Overload. In: Hoffman et al., editors. Hematology: Basic Principles and Practice. 3. Churchill Livingstone; New York: 2000. pp. 397-428; Brittenham et al., Efficacy of Deferoxamine in Preventing Complications of Iron Overload in Patients with Thalassemia Major. N. Engl. J. Med. 1994, 331, 567-573; Zurlo et al., Survival and Causes of Death in Thalassemia Major. Lancet. 1989, 2, 27-30). There is a strong correlation between serum ferritin levels, inflammatory biomarkers such as C-reactive protein and interleukin-1, and mortality is a subset of patients with peripheral arterial disease; phlebotomy and iron chelation has been used to mitigate that risk. Treatment with an iron chelator would reduce iron stores, reduce serum ferritin and potentially reduce the incidence of heart disease and stroke. In certain embodiments, the disease that is treated and/or prevented by a method described herein is transfusional iron overload. In certain embodiments, the disease is transfusion-dependent anemia. In certain embodiments, the disease is thalassemia. In certain embodiments, 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. In certain embodiments, the disease is diabetes.

[0368] Moreover, 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. In certain embodiments, 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). In certain embodiments, the metal overload is trivalent metal overload. In certain embodiments, the metal overload is aluminum overload. In certain embodiments, the trivalent metal overload is Cr(III) overload, Mo(III) overload, or Co(III) overload). In certain embodiments, 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). In certain embodiments, 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). In certain embodiments, 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).

[0369] In certain embodiments, 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. For example, 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. Even more significantly, 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. In certain embodiments, 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). In certain embodiments, the metal poisoning is iron poisoning (e.g., Fe(II) poisoning or Fe(III) poisoning). In certain embodiments, the metal poisoning is aluminum poisoning. In certain embodiments, 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). In certain embodiments, the metal poisoning is monovalent metal poisoning (e.g., Tl(I) poisoning, Cu(I) poisoning, Ag(I) poisoning, Na(I) poisoning, K(I) poisoning, or Hg(I) poisoning). In certain embodiments, 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). In certain embodiments, the metal poisoning is tetravalent metal poisoning (e.g., Pb(IV) or Ce(IV) poisoning). In certain embodiments, the metal poisoning is pentavalent metal poisoning (e.g., Sb(V) poisoning). In certain embodiments, the metal poisoning is hexavalent metal poisoning (e.g., Cr(VI) poisoning, Mo(VI) poisoning, W(VI) poisoning, or U(VI) poisoning).

[0370] In certain embodiments, the disease that is treated or prevented by a method described herein is oxidative stress. In a subject who suffers from oxidative stress and thus needs oxidative stress reduction, 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 dehydrogenase, cytochrome c oxidase), and 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 longer-lasting ischemic episode, a stroke, involves irreversible brain damage, where the type and severity of symptoms depend on the location and extent of brain tissue whose access to blood circulation has been compromised. 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.

[0371] A subject in need of oxidative stress reduction can be suffering from inflammation 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. Not wishing to be bound by any theory, it is believed that the compounds of the invention derive their ability to reduce oxidative stress through various mechanisms. In one mechanism, 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. In another mechanism, the compound stabilizes the metal in a particular oxidation state, such that it is less likely to undergo redox cycling. In yet another mechanism, the compound itself has antioxidant activity (e.g., free radical scavenging, scavenging of reactive oxygen or nitrogen species). Desferrithiocin and desazadesferrithiocin, and their derivatives and analogs, are known to have intrinsic antioxidant activity, as described in U.S. Application Publication No. 2004/0044220, published Mar. 4, 2004 and now abandoned; U.S. Application Publication No. 2004/0132789 and now abandoned, published Jul. 8, 2004; International PCT Application Publication No. WO 2004/017959, published Mar. 4, 2004; U.S. Application Publication No. 2005/0234113, published Oct. 20, 2005 and now abandoned; U.S. Application Publication No. 2008/0255081, published Oct. 16, 2008 and now abandoned; U.S. Application Publication No. 2003/0236417, published Dec. 25, 2003 and now abandoned; U.S. Patent Application Ser. No. 61/576,920, filed Dec. 16, 2011; U.S. Patent Application Ser. No. 61/576,913, filed Dec. 16, 2011; and U.S. Pat. Nos. 6,083,966, 6,559,315, 6,525,080, 6,521,652, 7,126,004, 7,531,563, and 8,008,502; each of which are incorporated herein by reference. The compounds of the invention can be used to treat these diseases. In certain embodiments, the disease that is treated or prevented by a method described herein is oxidative stress. In certain embodiments, oxidative stress is reduced by a method described herein. In certain embodiments, the disease is radiation injury. In certain embodiments, the disease is inflammation.

[0372] In certain embodiments, the disease that is treated or prevented by a method described herein is macular degeneration. Without wishing to be bound by a particular theory, the compounds and pharmaceutical compositions described herein are able to get into the eye. See, e.g., U.S. Patent Application Ser. No. 61/576,920, filed Dec. 16, 2011; U.S. Patent Application Ser. No. 61/576,913, filed Dec. 16, 2011, International PCT Application Publication No. WO 2013/090750, published Jun. 20, 2013; and International PCT Application Publication No. WO 2013/090766, published Jun. 20, 2013. The compounds of the invention are then able to chelate and remove iron from the eye thereby preventing Fe.sup.+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. In the treatment of macular degeneration, the compound or pharmaceutical composition described herein may be administered systemically or ocularly. In certain embodiments, the compound or pharmaceutical composition is administered orally. In other embodiments, the compound or pharmaceutical composition is administered to the eye using eye drops or an ointment suitable for ocular administration.

[0373] In certain embodiments, 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. Without wishing to be bound by any particular theory, 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. In the case of head injury resulting in bleeding into the central nervous system where the vasculature has been compromised a compound being used may or may not have the ability to cross the blood brain barrier. In certain embodiments, the compound being used to treat a head injury in a subject is able to cross the blood brain barrier. In other embodiments, the compounds are not able to cross the blood brain barrier. Certain compounds of the invention have been found in the CSF after systemic administration (orally and subcutaneously).

[0374] Head injuries come in various forms and results from various causes. In certain embodiments, the head injury is an injury to the head that penetrates the skull. In other embodiments, 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. In certain embodiments, 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. In the treatment or prevention of closed head injury, the compound or pharmaceutical composition described herein may be administered systemically, for example, parenterally (e.g., intravenously) or orally.

[0375] Reactive oxygen species have been implicated in the pathogenesis of inflammatory bowel disease (IBD). Grisham et al., 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 diseasefacts and fashion. Klin. Wochenschr. 69:1001-1003, 1991; Ymamada et al. Role of neutrophil-derived oxidants in the pathogenesis of intestinal inflammation. Klin. Wocheschr. 69:988-944, 1991; Babbs, Oxygen radicals in ulcerative colitis. Free Radic. Biol. Med. 13:169-181, 1992. 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 Ser. No. 61/576,920, filed Dec. 16, 2011; U.S. Patent Application Ser. No. 61/576,913, filed Dec. 16, 2011; Bergeron et al., Prevention of Acetic Acid-Induced Colitis by Desferrithiocin Analgos in a Rat Model. Digestive Diseases and Sciences, 48(2):399-407, February 2003. The compounds and pharmaceutical compositions described herein are thought to prevent or eliminate the generation of reactive oxygen species or other longer-lived, more stable radicals that may be responsible for the tissue damage and inflammation seen in subjects with IBD. Another possible mechanism of action of the compounds useful in the invention is the chelation of metal, such as iron, which may contribute to the generation of reactive oxygen species, such as hydroxyl radicals and hydrogen peroxide, that cause cell damage. 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. In certain embodiments, treatment with a compound or pharmaceutical composition described herein leads to reduced levels of reactive oxygen species in the intestines, specifically the intestinal mucosa. In the treatment of IBD, the compound or pharmaceutical composition may be administered systemically, for example, parenterally (e.g., intravenously), orally, or rectally.

[0376] In certain embodiments, 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. In the treatment of an ischemic 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. In hemorrhagic stroke, 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. In certain embodiments, when the subject has been diagnosed with an ischemic stroke, the compound used in the treatment can pass through the blood brain barrier.

[0377] Moreover, 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. In certain embodiments, 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.

[0378] In certain embodiments, 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. In certain embodiments, the reperfusion injury being treated occurs in the heart. In other embodiments, 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. In the treatment and/or prevention of reperfusion injury, a compound or pharmaceutical composition described herein is administered to a subject who is suffering from ischemia of a tissue or organ. Without wishing to be bound by any particular theory, 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.

[0379] The present invention may be useful in treating a subject after the subject has been diagnosed with ischemia of a particular organ or tissue. In certain embodiments, the compound or pharmaceutical composition described herein is administered as quickly as possible after a subject has been diagnosed with ischemia. In certain embodiments, the compound or pharmaceutical composition is administered to the subject at risk of ischemia. In certain embodiments, 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). In certain embodiments, the compound or pharmaceutical composition is used to prevent reperfusion injury in a transplanted organ. In certain embodiments, the compound or pharmaceutical composition is used to perfuse an isolated organ being prepared for donation. In the prevention or treatment of reperfusion injury, the compound or pharmaceutical composition may be administered systemically, for example, parenterally (e.g., intravenously) or orally. In certain embodiments, the compound or pharmaceutical composition is administered locally to the organ or tissue suffering from ischemia.

[0380] In certain embodiments, the disease that is treated or prevented by a method described herein is a neoplastic disease or preneoplastic condition. In certain embodiments, the disease is a benign neoplastic disease. In certain embodiments, the disease is cancer. In certain embodiments, the disease is a preneoplastic disease.

[0381] 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. Typically, 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 .sup.241Am, .sup.51Cr, .sup.60Co, .sup.57Co, .sup.58Co, .sup.64Cu, .sup.153Gd, .sup.67Ga, .sup.198Au, .sup.113mIn, .sup.111In, .sup.59Fe, .sup.55Fe, .sup.197Hg, .sup.99mTc, .sup.201Ti, and .sup.169Yb, again preferably when the metal is present as a trivalent cation.

[0382] In another aspect, 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. In certain embodiments, the method of treating or preventing biofilm formation treats, cleans, or disinfects a wound. In certain embodiments, 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.

[0383] In another aspect, 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. In certain embodiments, the provided methods inhibit, reduce, or remove biofilms on or in an object. In certain embodiments, the provided method inhibits or removes the biofilm on the surface of the object. In certain embodiments, the surface is a hard, rigid surface. In certain embodiments, the surface is selected from the group consisting of a drainpipe, glaze ceramic, porcelain, glass, metal, wood, chrome, plastic, vinyl, and formica. In certain embodiments, the surface is a soft, flexible surface. In certain embodiments, the surface is selected from the group consisting of shower curtains and liners, upholstery, laundry, and carpeting. In certain embodiments, the surface is a food preparation surface, such as a kitchen counter, cutting board, sink, stove, refrigerator surface, or on a sponge. In certain embodiments, the surface is a bathroom surface such as a toilet, sink, bathtub, shower, or drain. In certain embodiment, the surface is a medical device surface.

[0384] In some embodiment, the contacting of the compound or pharmaceutical composition described herein with the object is carried out by wiping, sponging, or soaking, or laundering means.

[0385] In some embodiments, 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. In some embodiments, 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. In some embodiments, 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.

[0386] In certain embodiments, 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.

[0387] In some embodiments, the compound or pharmaceutical composition is administered with one or more additional pharmaceutical agents (e.g., biocides, e.g., antimicrobials, e.g., antibiotics).

EXAMPLES

[0388] In order that the invention described herein may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope.

Design of the Compounds

[0389] 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. Early metabolic studies with (S)-4-(CH.sub.3O)-DADFT (4), in which the ligand was given subcutaneously to rats at a dose of 300 mol/kg, revealed that it was demethylated in the liver (Kem et al., Mol. Pharmacol. 65 (2004) 56-67), producing (S)-4-(HO)-DADFT (2, FIG. 2)..sup.42 At 2 hours post drug exposure, about 30% of the (S)-4-(CH.sub.3O)-DADFT (4) is demethylated to 2, and the metabolite remains at fairly high levels through the 8-hour time point (FIG. 2). This observation encouraged a similar assessment of the polyethers (S)-4-(HO)-DADFT-PE (5) and (S)-3-(HO)-DADFT-PE (6). If, for example, 5 were converted to 2 to any great extent, this would preclude it being given b.i.d. as renal toxicity might be expected over a long-term exposure. The lack of toxicity of 5 and 6, even when given b.i.d., suggests that cleavage to 2 was either absent or very modest. Accordingly, chelators 5 and 6 were given to rats subcutaneously at a dose of 300 mol/kg. The tissues that were evaluated included the plasma, liver, kidney, heart, and pancreas. The only organ that presented with any 4- or 3-polyether cleavage was the liver (FIG. 2). At 2 hours, 2% of 5 was converted to 2, and 2.6% of 6 was metabolized to the corresponding 3. The metabolites were not detected at the 4 and 8 hours time points..sup.45

[0390] When 7 was given subcutaneously to rats under the same experimental protocol as described for 5 and 6, there was no cleavage to 2 (FIG. 2). However, based on studies with other drugs, e.g., glycodiazine, in which of ether fragments were appended,.sup.64-68 there was a need to determine whether or not the terminal methyl of 7 was being cleaved.

[0391] With glycodiazine (FIG. 3), the methyl ether was dealkylated to an alcohol (metabolite I) (Platzer et al., Europ. J. Clin. Pharmacol. 14 (1978) 293-299), which was oxidized to a carboxylic acid (metabolite II). If this were the case with 7, for example, this would lead first to the corresponding alcohol (S)-4,5-dihydro-2-[2-hydroxy-4-(5-hydroxy-3-oxapentyloxy)phenyl]-4-methyl-4-thiazolecarboxylic acid [(S)-4-(HO)-DADFT-PEA, 8] and then to the acid (S)-4,5-dihydro-2-[2-hydroxy-4-(4-carboxy-3-oxabutyloxy)phenyl]-4-methyl-4-thiazolecarboxylic acid [(S)-4-(HO)-DADFT-PEAA, 9], FIG. 4. Both of these metabolic products would be expected to be very hydrophilic. This increase in hydrophilicity, based on previous studies, would further be expected to minimize ligand toxicity..sup.37,43,45 If indeed such a demethylation-oxidation scenario is occurring with 7, it could support a novel approach to metabolically programmed iron chelators, e.g., highly lipophilic, orally absorbable ligands that are quickly converted to hydrophilic, likely nontoxic metabolites.

[0392] The two putative metabolites of (S)-4-(HO)-DADFT-norPE (7), the alcohol (S)-4-(HO)-DADFT-PEA (8) and the carboxylic acid (S)-4-(HO)-DADFT-PEAA (9), were assembled. These two synthetic chelators allowed us to develop an analytical high-pressure liquid chromatography (HPLC) method to follow the potential conversion of 7 to its metabolites in the organs of animals treated with the parent chelator 7. Furthermore, it provided an opportunity to evaluate the lipophilicity (log P.sub.app), and the ICE values of 8 and 9 when the chelators were given to the rats and primates orally and/or subcutaneously.

Preparation of the Compounds

[0393] 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.

[0394] Exemplary materials and methods employed in Examples 1 to 2 are shown below. Reagents were purchased from Aldrich Chemical Co. (Milwaukee, Wis.). Fisher Optima grade solvents were routinely used. DMF was dried over 4 A molecular sieves. Potassium carbonate was flame activated and cooled in a desiccator over Drierite. Reactions were run under a nitrogen atmosphere, and organic extracts were dried with sodium sulfate and filtered. Silica gel 40-63 from SiliCycle, Inc. (Quebec City, Quebec, Canada) was used for column chromatography. Glassware that was presoaked in 3 N HCl for 15 minutes, washed with distilled water and distilled EtOH, and oven-dried was used during the isolation of 8-14. Melting points are uncorrected. Optical rotations were run at 589 nm (sodium D line) and 20 C. on a Perkin-Elmer 341 polarimeter, with c being concentration in grams of compound per 100 mL of solution (CHCl.sub.3 not indicated). NMR spectra were obtained at 400 MHz (.sup.1H) or 100 MHz (.sup.13C). Chemical shifts () for .sup.1H spectra are given in parts per million downfield from tetramethylsilane for organic solvents (CDCl.sub.3 not indicated) or sodium 3-(trimethylsilyl)propionate-2,2,3,3-d.sub.4 for D.sub.2O. Chemical shifts () for .sup.13C spectra are given in parts per million referenced to CH.sub.3OH ( 49.50) in D.sub.2O or to the residual solvent resonance in CDCl.sub.3 ( 77.16) (not indicated) or DMSO-d.sub.6 ( 39.52). The base peaks are reported for the ESI-FTICR mass spectra. Elemental analyses were performed by Atlantic Microlabs (Norcross, Ga.) and were within 0.4% of the calculated values. The purity of all compounds was confirmed by elemental analysis. Furthermore, the purity of 8-14 was 95% by HPLC analysis.

Example 1

Synthesis of Compounds 8 and 9

[0395] Assembly of alcohol 8 and the carboxylic acid 9 (Scheme 1) began with alkylation of deferitrin ethyl ester (15) at the 4-hydroxyl..sup.52 Specifically, reaction of 15 with 2-(2-chloroethoxy)ethanol (16), K.sub.2CO.sub.3 and KI in DMF at 100 C. provided the alcohol ester 17 in 62% yield. Treatment of 17 with 50% NaOH in CH.sub.3OH led to the alcohol 8 in 97% yield. Alkylating 15 with ethyl 2-chloroethoxyacetate (18).sup.69 under the above conditions gave the diester 19 in 35% yield. Saponification of 19 furnished the diacid 9 as its monosodium salt in 98% yield.

##STR00144##

[0396] Scheme 1. Synthesis of (S)-4,5-dihydro-2-[2-hydroxy-4-(5-hydroxy-3-oxapentyloxy)phenyl]-4-methyl-4-thiazolecarboxylic acid (8) and (S)-4,5-dihydro-2-[2-hydroxy-4-(4-carboxy-3-oxabutyloxy)phenyl]-4-methyl-4-thiazolecarboxylic acid (9).sup.a aReagents and conditions: (a) K.sub.2CO.sub.3 (2.0 equiv), KI, DMF, 100 C., 1 d, 62%; (b) K.sub.2CO.sub.3 (2.1 equiv), NaI, DMF, 95 C., 22 hours, 35%; (c) 50% NaOH (aq), CH.sub.3OH, 97% (8), 98% (9 as its monosodium salt).

[0397] Ethyl (5)-4,5-Dihydro-2-[2-hydroxy-4-(5-hydroxy-3-oxapentyloxy)phenyl]-4-methyl-4-thiazolecarboxylate (17). Potassium carbonate (2.76 g, 20.0 mmol) and KI (200 mg, 1.2 mmol) were added to a mixture of 15 (Bergeron et al., 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. After cooling to room temperature, H.sub.2O (100 mL) was added followed by extraction with EtOAc (2100 mL). Organic layers were combined, washed with H.sub.2O (100 mL) and 6 M NaCl (100 mL), and solvent was removed in vacuo. Column chromatography using 30% EtOAc/CH.sub.2Cl.sub.2 furnished 2.30 g of 17 (62%) as a viscous oil: [] +48.0 (c 0.15). .sup.1H NMR 12.70 (br s, 1H), 7.30 (d, J=8.8 Hz, 1H), 6.50 (d, J=2.4 Hz, 1H), 6.47 (dd, J=8.8, 2.4 Hz, 1H), 4.24 (dq, J=7.6, 1.6 Hz, 2H), 4.15-4.17 (m, 2H), 3.83-3.88 (m, 3H), 3.76-3.79 (m, 2H), 3.66-3.69 (m, 2H), 3.20 (d, J=10.8 Hz, 1H), 1.66 (s, 3H), 1.3 (t, J=7.2 Hz, 3H). .sup.13C NMR 172.96, 170.92, 162.95, 161.32, 131.87, 110.14, 107.39, 101.51, 83.25, 72.73, 69.54, 67.61, 62.05, 61.89, 39.98, 24.61,14.23. HRMS m/z calcd for C.sub.17H.sub.24NO.sub.6S, 370.1319 (M+H); found, 370.1323. Anal. Calc'd for C.sub.17H.sub.23NO.sub.6S: C, 55.27; H, 6.28; N, 3.79. Found: C, 54.99; H, 6.24; N, 3.75.

[0398] Ethyl (S)-4,5-Dihydro-2-[2-hydroxy-4-[(4-ethoxycarbonyl)-3-oxabutyloxy]-phenyl]-4-methyl-4-thiazolecarboxylate (19). Sodium iodide (0.5527 g, 3.69 mmol) and K.sub.2CO.sub.3 (5.1304 g, 37.12 mmol) were added to 15 (5.08 g, 18.1 mmol) and 18.sup.69 (3.31 g, 19.9 mmol) in DMF (46 mL), and the reaction mixture was heated at 95 C. for 22 hours. The mixture was cooled, filtered, washing the solids with acetone (100 mL, 250 mL). Solvents were removed in vacuo, and the concentrate was treated with 1:1 0.5 N HCl/6 M NaCl (120 mL) followed by extraction with EtOAc (100 mL, 250 mL). Organic layers were combined, washed with 1% NaHSO.sub.3 (75 mL), H.sub.2O (75 mL) and 6 M NaCl (55 mL), and solvent was removed by rotary evaporation. Flash column chromatography using 8.4:25:66.5 EtOAc/petroleum ether/CH.sub.2Cl.sub.2 gave 2.574 g of 19 (35%) as a yellow oil: [] +41.0 (c 0.68).

[0399] .sup.1H NMR 12.70 (s, 1H), 7.29 (d, J=8.6 Hz, 1H), 6.50 (d, J=2.3 Hz, 1H), 6.47 (dd, J=8.8, 2.5 Hz, 1H), 4.17-4.28 (m +s, 8H), 3.92-3.97 (m, 2H), 3.84 (d, J=11.3 Hz, 1H), 3.20 (d, J=11.3 Hz, 1H), 1.66 (s, 3H), 1.298 (t, J=7.2 Hz, 3H), 1.290 (t, J=7.0 Hz, 3H). .sup.13C NMR 172.96, 170.92, 170.42, 162.88, 161.29, 131.84, 110.13, 107.34, 101.52, 83.25, 69.94, 69.02, 67.71, 62.05, 61.10, 39.97, 24.60, 14.33,14.22. HRMS m/z calcd for C.sub.19H.sub.26NO.sub.7S, 412.1424 (M+H); found, 412.1440. Anal. Calc'd for C.sub.19H.sub.25NO.sub.7S: C, 55.46; H, 6.12; N, 3.40. Found: C, 55.66; H, 6.21; N, 3.44.

[0400] (S)-4,5-Dihydro-2-[2-hydroxy-4-(5-hydroxy-3-oxapentyloxy)phenyl]-4-methyl-4-thiazolecarboxylic Acid (8). A solution of 50% (w/w) NaOH (3.0 mL, 57 mmol) in CH.sub.3OH (25 mL) was added slowly to a solution of 17 (2.0 g, 5.4 mmol) in CH.sub.3OH (50 mL) at 0 C. The reaction mixture was stirred at room temperature for 16 hours, and the bulk of the solvent was removed under reduced pressure. The residue was dissolved in dilute NaCl (50 mL) and was extracted with Et.sub.2O (230 mL). The aqueous layer was cooled in ice, acidified with cold 6 N HCl to pH=2, and extracted with EtOAc (830 mL). The combined EtOAc layers were concentrated in vacuo to furnish 1.78 g of 8 (97%) as a yellow oil: [] +25.3 (c 0.88). .sup.1H NMR 7.9 (br s, 1H), 7.21 (d, J=8.8 Hz, 1H), 6.50 (d, J=2.4 Hz, 1H), 6.47 (dd, J=8.8, 2.4 Hz, 1H), 4.15-4.19 (m, 2H), 3.74-3.92 (m, 5H), 3.65-3.70 (m, 2H), 3.20 (d, J=10.8 Hz, 1H), 1.68 (s, 3H). .sup.13C NMR 176.29, 171.96, 163.02, 161.32, 131.97, 109.79, 107.69, 101.49, 82.68, 72.57, 69.19, 67.56, 61.78, 39.78, 24.61. HRMS m/z calc'd for C.sub.15H.sub.20NO.sub.6S, 342.1006 (M+H), C.sub.15H.sub.19NNaO.sub.6S, 364.0825 (M+Na); found, 342.1014, 364.0826. Anal. Calc'd for C.sub.15H.sub.19NO.sub.6S: C, 52.78; H, 5.61; N, 4.10. Found: C, 52.93; H, 5.83; N, 4.02.

[0401] (S)-4,5-Dihydro-2-[2-hydroxy-4-(4-carboxy-3-oxabutyloxy)phenyl]-4-methyl-4-thiazolecarboxylic Acid (9). A solution of 50% (w/w) NaOH (2.88 mL, 55.1 mmol) in CH.sub.3OH (30 mL) was added to a mixture of 19 (2.27 g, 5.52 mmol) in CH.sub.3OH (62 mL) over 5 min at 0 C. The reaction mixture was stirred at room temperature for 17 hours, and the bulk of the solvent was removed by rotary evaporation. The residue was dissolve in 3 M NaCl (70 mL) and was extracted with Et.sub.2O (340 mL). The aqueous layer was cooled in ice, treated with cold 2 N HCl (30 mL) and extracted with EtOAc (100 mL, 450 mL). Organic layers were combined, washed with 6 M NaCl (80 mL) and concentrated by rotary evaporation. The residue was combined with H.sub.2O (43 mL) and 0.1050 N NaOH (52.76 mL, 5.540 mmol), heated on the steam bath and hot suction filtered, washing with H.sub.2O (18 mL). The filtrate was diluted with H.sub.2O (34 mL) and lyophilized. Solid was dried under high vacuum at 72 C., furnishing 2.05 g of 9 as its sodium salt (98%) as an amorphous yellow solid: [] +124.3 (c 0.73, H.sub.2O). .sup.1H NMR (D.sub.2O) 7.57 (d, J=9.0 Hz, 1H), 6.61 (dd, J=9.0, 2.3 Hz, 1H), 6.52 (d, J=2.3 Hz, 1H), 4.26-4.30 (m, 2H), 4.06 (s, 2H), 3.90-3.95 (m, 3H), 3.53 (d, J=11.7 Hz, 1H), 1.74 (s, 3H). .sup.13C NMR (D.sub.2O) 178.94, 177.92, 177.62, 166.41, 162.21, 134.11, 109.15, 107.12, 102.09, 78.41, 70.23, 69.43, 68.45, 39.67, 23.98. HRMS m/z calcd for C.sub.15H.sub.15NNaO.sub.7S, 376.0472 (MH), C.sub.15H.sub.16NO.sub.7S, 354.0653 (MNa); found, 376.0479, 354.0663. A sample (1.00 g) was recrystallized from EtOH (aq) to give 0.631 g of 9 (Na salt). Anal. Calc'd for C.sub.15H.sub.16NNaO.sub.7S: C, 47.75; H, 4.27; N, 3.71. Found: C, 47.82; H, 4.43; N, 3.75.

Example 2

Synthesis of Deferitrin Hexamethylene Methyl Ether, (S)-4-(HO)-DADFT-HXME (10), the Corresponding Alcohol Analogue, (S)-4-(HO)-DADFT-HXA (11), and its Putative Metabolites 12, 13, and 14

[0402] Synthesis of the methyl ether-containing chelator 10 required first generating 6-iodo-1-methoxyhexane (21).sup.70 from 1,6-diiodohexane (20) in 28% yield by employing 25% NaOCH.sub.3 (1 equivalent) in DMF at 63 C. (Scheme 2). Alkylation of deferitrin ethyl ester (15) with 21 using K.sub.2CO.sub.3 in DMF at 62 C., generated intermediate 22 in 59% yield. Alkaline cleavage of ester 22 provided (S)-4-(HO)-DADFT-HXME (10) in 97% yield. The synthesis of alcohol 11 involved first alkylating the ester of deferitrin (15) with 6-iodohexyl acetate (23).sup.71 utilizing K.sub.2CO.sub.3 in DMF at 70 C., giving diester 24 in 53% yield (Scheme 2). Alkaline hydrolysis of 24 provided the final product 11 in 91% recrystallized yield.

[0403] Synthesis of the anticipated metabolites of alcohol 11 (12-14) followed methodology similar to that of polyether acid 9 (Scheme 3). The DADFT ester 15 was selectively alkylated with one of three ethyl -bromoalkanoates (25, 26, or 27) in DMF in the presence of K.sub.2CO.sub.3 and catalytic iodide salt. The corresponding diesters 28, 29, and 30 were obtained in 61, 72, and 66% yields. Once again, these diesters were cleaved in 50% NaOH in CH.sub.3OH, giving the required acids 12, 13, and 14 in 99, 90, and 98% yields, respectively.

##STR00145##

[0404] Scheme 2. Synthesis of (S)-4,5-dihydro-2-[2-hydroxy-4-(6-methoxyhexyloxy)phenyl]-4-methyl-4-thiazolecarboxylic acid (10) and (S)-4,5-dihydro-2-[2-hydroxy-4-(6-hydroxyhexyloxy)phenyl]-4-methyl-4-thiazolecarboxylic acid (11).sup.a aReagents and conditions: (a) 25% NaOCH.sub.3 (1.0 equiv), DMF, 63 C., 17 hours, 28%; (b) K.sub.2CO.sub.3 (2.0 equiv), DMF, 62 C., 22 hours, 59%; (c) 50% NaOH (aq), CH.sub.3OH, 97% (10) (d) K.sub.2CO.sub.3 (1.9 equiv), DMF, 70 C., 18 hours, 53%; (c) 50% NaOH (aq), CH.sub.3OH, 91% (11).

[0405] 1-Iodo-6-methoxyhexane (21). Sodium methoxide (25 weight %, 5.5 mL, 24.1 mmol) was added by syringe to 20 (4.0 mL, 24.3 mmol) in DMF (10 mL) over 20 minutes. The reaction solution was heated at 63 C. for 17 hours. After cooling to 0 C., the reaction solution was treated with 3:1 cold 0.5 N HCl/6 M NaCl (200 mL) and was extracted with EtOAc (2150 mL, 50 mL). The organic extracts were washed with 1% NaHSO.sub.3 (150 mL), H.sub.2O (2150 mL) and 6 M NaCl (100 mL), and solvent was removed by rotary evaporation. Flash column chromatography using 4% then 6% EtOAc/petroleum ether furnished 1.61 g of 21.sup.70 (28%) as a liquid: .sup.1H NMR 3.37 (t, J=6.4 Hz, 2H), 3.33 (s, 3H), 3.19 (t, J=7.0 Hz, 2H), 1.83 (quintet, J=7.1 Hz, 2H), 1.54-1.62 (m, 2H), 1.33-1.46 (m, 4H). .sup.13C NMR 72.78, 58.72, 33.58, 30.46, 29.57, 25.26, 7.25. HRMS m/z calc'd for C.sub.7H.sub.19INO, 260.0506 (M+NH.sub.4); found, 260.0515. Anal. Calcd for C.sub.7H.sub.15IO: C, 34.73; H, 6.25. Found: C, 34.44; H, 6.19.

[0406] Ethyl (S)-4,5-Dihydro-2-[2-hydroxy-4-(6-methoxyhexyloxy)phenyl]-4-methyl-4-thiazolecarboxylate (22). Potassium carbonate (1.81 g, 13.1 mmol) was added to 15 (1.77 g, 6.29 mmol) and 21 (1.56 g, 6.44 mmol) in DMF (32 mL), and the reaction mixture was heated at 62 C. for 22 hours. After cooling in an ice bath, cold 0.5 N HCl (100 mL) was added followed by extraction with EtOAc (120 mL, 250 mL). Organic layers were combined and washed with 1% NaHSO.sub.3 (100 mL), H.sub.2O (3100 mL) and 6 M NaCl (80 mL), and solvent was removed by rotary evaporation. Flash column chromatography using 10% EtOAc/petroleum ether then 1:3:6 EtOAc/petroleum ether/CH.sub.2Cl.sub.2 gave 1.47 g of 22 (59%) as a viscous yellow oil: [] +43.3 ( 0.72). .sup.1H NMR 12.68 (s, 1H), 7.28 (d, J=8.6 Hz, 1H), 6.47 (d, J=2.3 Hz, 1H), 6.43 (dd, J=8.8, 2.5 Hz, 1H), 4.18-4.29 (m, 2H), 3.97 (t, J=6.6 Hz, 2H), 3.83 (d, J=11.3 Hz, 1H), 3.38 (t, J=6.4 Hz, 2H), 3.34 (s, 3H), 3.19 (d, J=11.3 Hz, 1H), 1.75-1.83 (m, 2H), 1.65 (s, 3H), 1.56-1.64 (m, 2H), 1.37-1.53 (m, 4H), 1.30 (t, J=7.0 Hz, 3H). .sup.13C NMR 173.02, 170.92, 163.50, 161.34, 131.77, 109.71, 107.40, 101.36, 83.23, 72.86, 68.19, 62.02, 58.70, 39.96, 29.69, 29.14, 26.03, 25.99, 24.61,14.22. HRMS m/z calcd for C.sub.20H.sub.30NO.sub.5S, 396.1839 (M+H); found, 396.1858. Anal. Calc'd for C.sub.20H.sub.29NO.sub.5S: C, 60.74; H, 7.39; N, 3.54. Found: C, 60.59; H, 7.29; N, 3.60.

[0407] Ethyl (S)-4,5-Dihydro-2-[2-hydroxy-4-(6-acetoxyhexyloxy)phenyl]-4-methyl-4-thiazolecarboxylate (24). Potassium carbonate (3.42 g, 24.8 mmol) was added to 15 (3.255 g, 11.57 mmol) and 23 [75] (3.44 g, 12.7 mmol) in DMF (60 mL), and the mixture was heated at 70 C. for 21 hours. After cooling to 0 C., cold 0.5 M HCl (150 mL) was added followed by extraction with EtOAc (150 mL, 280 mL). Organic layers were combined, washed with 1% NaHSO.sub.3 (150 mL), H.sub.2O (3150 mL) and 6 M NaCl (100 mL), and solvent was removed by rotary evaporation. Flash column chromatography using 1:3:6 EtOAc/petroleum ether/CH.sub.2Cl.sub.2 gave 2.60 g of 24 (53%) as a white solid: mp 58.5-60 C., [] +40.1 (c 0.98). .sup.1H NMR 12.69 (s, 1H), 7.29 (d, J=9.0 Hz, 1H), 6.47 (d, J=2.3 Hz, 1H), 6.43 (dd, J=8.8, 2.5 Hz, 1H), 4.20-4.28 (m, 2H), 4.07 (t, J=6.6 Hz, 2H), 3.97 (t, J=6.4 Hz, 2H), 3.84 (d, J=11.3 Hz, 1H), 3.19 (d, J=11.3 Hz, 1H), 2.05 (s, 3H), 1.76-1.84 (m, 2H), 1.62-1.70 (m, 2H), 1.66 (s, 3H), 1.38-1.54 (m, 4H), 1.30 (t, J=7.0 Hz, 3H). .sup.13C NMR 173.01, 171.39, 170.93, 163.45, 161.36, 131.79, 109.76, 107.40, 101.35, 83.23, 68.10, 64.58, 62.03, 39.98, 29.07, 28.66, 25.84, 25.83, 24.62, 21.16, 14.23. HRMS m/z calc'd for C.sub.21H.sub.30NO.sub.6S, 424.1788 (M+H); found, 424.1798. Anal. Calc'd for C.sub.21H.sub.29NO.sub.6S: C, 59.56; H, 6.90; N, 3.31. Found: C, 59.71; H, 6.81; N, 3.33.

[0408] (S)-4,5-Dihydro-2-[2-hydroxy-4-(6-methoxyhexyloxy)phenyl]-4-methyl-4-thiazolecarboxylic Acid (10). A solution of 50% (w/w) NaOH (1.87 mL, 35.8 mmol) in CH.sub.3OH (40 mL) was added over 4 min to a solution of 22 (1.41 g, 3.56 mmol) in CH.sub.3OH (80 mL) at 0 C. The reaction mixture was stirred at room temperature for 15 hours, and the bulk of the solvent was removed under reduced pressure. The residue was diluted in 2 M NaCl (120 mL) and was extracted with Et.sub.2O (350 mL). The aqueous layer was cooled in ice, acidified with cold 2 N HCl (30 mL), and extracted with EtOAc (100 mL, 350 mL). The combined EtOAc extracts were washed with 6 M NaCl (60 mL) and concentrated in vacuo to generate 1.275 g of 10 (97%) as a waxy, light tan solid: mp 68-68.5 C., [] +48.8 (c 0.80, DMF). .sup.1H NMR (DMSO-d.sub.6) 13.17 (s, 1H), 12.74 (s, 1H), 7.31 (d, J=8.6 Hz, 1H), 6.52 (dd, J=2.3, 8.6 Hz, 1H), 6.50 (d, J=2.3 Hz, 1H), 4.00 (t, J=6.6 Hz, 2H), 3.79 (d, J=11.3 Hz, 1H), 3.36 (d, J=11.3 Hz, 1H), 3.30 (t, J=6.4 Hz, 2H), 3.21 (s, 3H), 1.66-1.74 (m, 2H), 1.58 (s, 3H), 1.47-1.54 (m, 2H),1.29-1.45 (m, 4H). .sup.13C NMR (DMSO-d.sub.6) 173.73, 170.03, 162.96, 160.49, 131.57, 108.97, 107.27, 101.13, 82.45, 71.82, 67.80, 57.79, 28.97, 28.47, 25.42, 25.28, 24.11. HRMS m/z calcd for C.sub.18H.sub.26NO.sub.5S, 368.1526 (M+H); found, 368.1540.

[0409] Anal. Calc'd for C.sub.18H.sub.25NO.sub.5S: C, 58.84; H, 6.86; N, 3.81. Found: C, 58.55; H, 6.81; N, 3.80.

[0410] (S)-4,5-Dihydro-2-[2-hydroxy-4-(6-hydroxyhexyloxy)phenyl]-4-methyl-4-thiazole-carboxylic Acid (11). A solution of 50% (w/w) NaOH (3.12 mL, 59.7 mmol) in CH.sub.3OH (95 mL) was added to a mixture of 24 (2.53 g, 5.97 mmol) in CH.sub.3OH (100 mL) over 32 min at 0 C. The reaction mixture was stirred at room temperature for 1 d, and the bulk of the solvent was removed under reduced pressure. The residue was treated with 2 M NaCl (150 mL) and was extracted with Et.sub.2O (350 mL). The aqueous layer was cooled in ice, treated with cold 2 N HCl (50 mL) and extracted with EtOAc (2100 mL, 50 mL). Organic layers were combined, washed with 6 M NaCl (65 mL) and concentrated by rotary evaporation. The residue was recrystallized from EtOAc/hexanes. Solid was collected and dried under high vacuum at 58 C., providing 1.917 g of 11 (91%) as pale yellow crystals: mp 116-116.5 C., [] +50.1 (c 0.83, DMF). .sup.1H NMR (DMSO-d.sub.6) 13.20 (s, 1H), 12.73 (s, 1H), 7.32 (d, J=9.0 Hz, 1H), 6.52 (dd, J=8.6, 2.3 Hz, 1H), 6.50 (d, J=2.3 Hz, 1H), 4.35 (br s, 1H), 4.00 (t, J=6.4 Hz, 2H), 3.79 (d, J=11.3 Hz, 1H), 3.36-3.42 (m, 2H), 3.36 (d, J=11.3 Hz, 1H), 1.66-1.75 (m, 2H), 1.58 (s, 3H), 1.29-1.48 (m, 6H). .sup.13C NMR (DMSO-d.sub.6) 173.76, 170.04, 162.97, 160.50, 131.59, 108.97, 107.28, 101.13, 82.45, 67.85, 60.64, 32.48, 28.56, 25.35, 25.27, 24.12. HRMS m/z calcd for C.sub.17H.sub.24NO.sub.5S, 354.1370 (M+H); found, 354.1384. Anal. Calc'd for C.sub.17H.sub.23NO.sub.5S: C, 57.77; H, 6.56; N, 3.96. Found: C, 57.94; H, 6.50; N, 3.93.

##STR00146##

[0411] Scheme 3. Synthesis of (S)-4,5-dihydro-2-[2-hydroxy-4-(5-carboxypentyloxy)phenyl]-4-methyl-4-thiazolecarboxylic acid (12), (S)-4,5-dihydro-2-[2-hydroxy-4-(3-carboxypropyloxy)phenyl]-4-methyl-4-thiazolecarboxylic acid (13), and (S)-4,5-dihydro-2-[2-hydroxy-4-(carboxymethoxy)phenyl]-4-methyl-4-thiazolecarboxylic acid (14).sup.a aReagents and conditions: (a) K.sub.2CO.sub.3 (1.3 equiv), NaI, DMF, 65 C., 5 d, 61% (28); K.sub.2CO.sub.3 (1.3 equiv), NaI, DMF, 100 C., 2 d, 72% (29); K.sub.2CO.sub.3 (2.1 equiv), NaI, DMF, 70 C., 20 hours, 66% (30); (b) 50% NaOH (aq), CH.sub.3OH, 99% (12), 90% (13), 98% (14).

[0412] Ethyl (5)-4,5-Dihydro-2-[2-hydroxy-4-[5-(ethoxycarbonyl)pentyloxy]phenyl]-4-methyl-4-thiazolecarboxylate (28). Potassium carbonate (3.19 g, 23.1 mmol), NaI (0.351 g, 2.34 mmol), and a solution of 25 (4.46 g, 20.0 mmol) in DMF (25 mL) were added to a solution of 15 (5.0 g, 17.8 mmol) in DMF (100 mL). The reaction mixture was heated at 65 C. for 5 days. After cooling to room temperature, the solvent was removed by rotary evaporation. The residue was treated with cold 0.5 M HCl (200 mL) and was extracted with EtOAc (150 mL, 250 mL). The organic extracts were washed with 1% NaHSO.sub.3 (100 mL), H.sub.2O (100 mL), 6 M NaCl (50 mL), and solvent was removed in vacuo. Column chromatography using 30% EtOAc/petroleum ether furnished 4.586 g of 28 (61%) as an off-white solid: mp 61-62 C., [] +40.94 (c 0.171). .sup.1H NMR 12.68 (s, 1H), 7.28 (d, J=8.4 Hz, 1H), 6.47 (d, J=2.4 Hz, 1H), 6.42 (dd, J=8.8, 2.4 Hz, 1H), 4.24 (dq, J=7.2, 2.0 Hz, 2H), 4.13 (q, J=7.2 Hz, 2H), 3.97 (t, J=6.4 Hz, 2H), 3.84 (d, J=11.2 Hz, 1H), 3.19 (d, J=11.2 Hz, 1H), 2.33 (t, J=7.6 Hz, 2H), 1.77-1.84 (m, 2H), 1.67-1.73 (m, 2H), 1.66 (s, 3H), 1.46-1.54 (m, 2H), 1.30 (t, J=7.2 Hz, 3H), 1.26 (t, J=7.2 Hz, 3H). .sup.13C NMR 173.70, 172.96, 170.88, 163.38, 161.31, 131.75, 109.73, 107.32, 101.33, 83.20, 67.93, 61.99, 60.37, 39.93, 34.31, 28.85, 25.68, 24.78, 24.58, 14.36, 14.20. HRMS m/z calcd for C.sub.21H.sub.30NO.sub.6S, 424.1788 (M+H); found, 424.1784. Anal. Calc'd for C.sub.21H.sub.29NO.sub.6S: C, 59.56; H, 6.90; N, 3.31. Found: C, 59.69; H, 6.78; N, 3.24.

[0413] Ethyl (S)-4,5-Dihydro-2-[2-hydroxy-4-[3-(ethoxycarbonyl)propyloxy]phenyl]-4-methyl-4-thiazolecarboxylate (29). Potassium carbonate (4.41 g, 32.0 mmol) and NaI (182 mg, 1.2 mmol) were added to a mixture of 15 (6.90 g, 24.5 mmol) and 26 (5.27 g, 27.0 mmol) in DMF (150 mL). The reaction mixture was stirred at room temperature for 6 hours and then heated at 100 C. for 48 hours. After cooling to room temperature, the solvent was removed by rotary evaporation under high vacuum, and the residue was treated with 0.2 M HC1/6 M NaCl (50 mL) followed by extraction with EtOAc (430 mL). The organic extracts were washed with 1% NaHSO.sub.3 (150 ml), H.sub.2O (150 mL) and 6 M NaCl (150 mL), and solvent was removed in vacuo. Column chromatography using 30% EtOAc/CH.sub.2Cl.sub.2 gave 6.94 g of 29 (72%) as a light yellow viscous oil: [] +44.35 (c 0.372). .sup.1H NMR 12.65 (s, 1H), 7.28 (d, J=8.4 Hz, 1H), 6.47 (d, J=2.4 Hz, 1H), 6.42 (dd, J=8.8, 2.0 Hz, 1H), 4.24 (dq, J=7.2, 1.6 Hz, 2H), 4.15 (q, J=7.6 Hz, 2H), 4.03 (t, J=6.4 Hz, 2H), 3.84 (d, J=11.2 Hz, 1H), 3.19 (d, J=11.2 Hz, 1H), 2.51 (t, J=7.6 Hz, 2H), 2.11 (quintet, J=6.2 Hz, 2H), 1.66 (s, 3H), 1.30 (t, J=7.6 Hz, 3H), 1.26 (t, J=7.2 Hz, 3H). .sup.13C NMR 173.21, 172.98, 170.90, 163.15, 161.32, 131.81, 109.91, 107.24, 101.44, 83.23, 67.02, 62.02, 60.63, 39.96, 30.84, 24.60, 24.55, 14.35, 14.22. HRMS m/z calcd for C.sub.19H.sub.26NO.sub.6S, 396.1475 (M+H); found, 396.1475. Anal. Calc'd for C.sub.19H.sub.25NO.sub.6S: C, 57.71; H, 6.37; N, 3.54. Found: C, 57.72; H, 6.23; N, 3.52.

[0414] Ethyl (S)-4,5-Dihydro-2-[2-hydroxy-4-(ethoxycarbonylmethoxy)phenyl]-4-methyl-4-thiazolecarboxylate (30). Potassium carbonate (5.29 g, 38.3 mmol) and NaI (0.498 g, 3.32 mmol) were added to 15 (5.035 g, 17.90 mmol) in DMF (75 mL). The mixture was stirred for several minutes, 27 (2.2 mL, 19.8 mmol) was introduced, and the contents were heated at 70 C. for 3.5 d. After cooling to 0 C., cold 0.5 M HCl (200 mL) was added followed by extraction with EtOAc (200 mL, 2100 mL). Organic layers were combined, washed with 1% NaHSO.sub.3 (200 mL), H.sub.2O (2200 mL) and 6 M NaCl (130 mL) and solvent was removed in vacuo. Flash column chromatography using 1% EtOAc/CH.sub.2Cl.sub.2 then 6% acetone/CH.sub.2Cl.sub.2 generated 4.37 g of 30 (66%) as a viscous yellow oil: [] +45.1 (c 0.88). .sup.1H NMR 12.73 (s, 1H), 7.32 (d, J=8.6 Hz, 1H), 6.50 (d, J=2.7 Hz, 1H), 6.47 (dd, J=6.8, 2.5 Hz, 1H), 4.63 (s, 2H), 4.20-4.31 (m, 4H), 3.84 (d, J=11.3 Hz, 1H), 3.20 (d, J=11.3 Hz, 1H), 1.66 (s, 3H), 1.305 (t, J=7.2 Hz, 3H), 1.298 (t, J=7.0 Hz, 3H). .sup.13C NMR 172.89, 170.92, 168.39, 161.91, 161.29, 132.00, 110.74, 107.18, 101.71, 83.28, 65.27, 62.07, 61.68, 40.00, 24.59, 14.28, 14.22. HRMS m/z calcd for C.sub.17H.sub.22NO.sub.6S, 368.1162 (M+H); found, 368.1172. Anal. Calc'd for C.sub.17H.sub.21NO.sub.6S: C, 55.57; H, 5.76; N, 3.81. Found: C, 55.72; H, 5.72; N, 3.82.

[0415] (S)-4,5-Dihydro-2-[2-hydroxy-4-(5-carboxypentyloxy)phenyl]-4-methyl-4-thiazolecarboxylic Acid (12). A solution of 50% (w/w) NaOH (5.00 mL, 95.6 mmol) in CH.sub.3OH (50 mL) was added to a mixture of 28 (4.434 g, 10.47 mmol) in CH.sub.3OH (120 mL) over 7 min at 0 C. The reaction mixture was stirred at room temperature for 2 d, and the bulk of the solvent was removed under reduced pressure. The residue was dissolved in 3 M NaCl (110 mL) and was extracted with Et.sub.2O (2100 mL). The aqueous layer was cooled in ice, treated with cold 2 N HCl (54 mL) and extracted with EtOAc (150 mL, 260 mL). Organic layers were combined, washed with 6 M NaCl (100 mL), and concentrated by rotary evaporation. The residue was dried under high vacuum at 57 C. for 16 hours to afford 3.80 g of 12 (99%) as light colored crystals: mp 153.5-155 C., [] +47.5 (c 0.76, DMF). .sup.1H NMR (DMSO-d.sub.6) 12.72 (s, 2H), 7.31 (d, J=8.6 Hz, 1H), 6.52 (dd, J=8.6, 2.3 Hz, 1H), 6.49 (d, J=2.3 Hz, 1H), 4.00 (t, J=6.4 Hz, 2H), 3.79 (d, J=11.3 Hz, 1H), 3.36 (d, J=11.3 Hz, 1H), 2.23 (t, J=7.2 Hz, 2H), 1.66-1.75 (m, 2H), 1.58 (s, 3H), 1.51-1.60 (m, 2H), 1.36-1.45 (m, 2H). .sup.13C NMR (DMSO-d.sub.6) 174.46, 173.76, 170.05, 162.96, 160.50, 131.60, 108.98, 107.29, 101.16, 82.46, 67.76, 33.61, 28.26, 25.08, 24.25, 24.12. HRMS m/z calcd for C.sub.17H.sub.22NO.sub.6S, 368.1162 (M+H); found, 368.1169. Anal. Calc'd for C.sub.17H.sub.21NO.sub.6S: C, 55.57; H, 5.76; N, 3.81. Found: C, 55.58; H, 5.79; N, 3.78.

[0416] (S)-4,5-Dihydro-2-[2-hydroxy-4-(3-carboxypropyloxy)phenyl]-4-methyl-4-thiazolecarboxylic Acid (13). A solution of 50% (w/w) NaOH (6.34 mL, 0.121 mol) in CH.sub.3OH (100 mL) was added dropwise to a solution of 29 (6.56 g, 16.6 mmol) in CH.sub.3OH (50 mL) at 0 C. The reaction mixture was stirred at room temperature for 36 hours, and the bulk of the solvent was removed under reduced pressure. The residue was dissolved in dilute NaCl (150 mL) and was washed with Et.sub.2O (2100 mL). The aqueous layer was cooled at 0 C., acidified with 6 N HCl to pH=2. Solid was filtered and washed with cold water. Crystallization in hot CH.sub.3OH and EtOAc afforded 5.06 g of 13 (90%) as a white solid: mp 202-204 C., [] +22.1 (c 0.086, CH.sub.3OH). .sup.1H NMR (DMSO-d.sub.6) 7.32 (d, J=8.4 Hz, 1H), 6.53 (dd, J=8.4, 2.0 Hz, 1H), 6.50 (d, J=2.4 Hz, 1H), 4.03 (t, J=6.4 Hz, 2H), 3.79 (d, J=11.2 Hz, 1H), 3.35 (d, J=11.2 Hz, 1H), 2.38 (t, J=7.2 Hz, 2H), 1.93 (quintet, J=7.2 Hz, 2H), 1.57 (s, 3H). .sup.13C NMR (DMSO-d.sub.6) 177.42, 177.11, 173.34, 166.13, 163.85, 135.00, 112.48, 110.60, 104.58, 85.86, 70.38, 33.42, 27.51, 27.43. HRMS m/z calcd for C.sub.15H.sub.18NO.sub.6S, 340.0849 (M+H); found, 340.0849. Anal. Calcd for C.sub.15H.sub.17NO.sub.6S: C, 53.09; H, 5.05; N, 4.13. Found: C, 52.81; H, 5.17; N, 4.09.

[0417] (S)-4,5-Dihydro-2-[2-hydroxy-4-(carboxymethoxy)phenyl]-4-methyl-4-thiazole-carboxylic Acid (14). A solution of 50% (w/w) NaOH (5.60 mL, 0.107 mol) in CH.sub.3OH (75 mL) was added to a solution of 30 (4.32 g, 11.76 mmol) in CH.sub.3OH (120 mL) over 10 min at 0 C. The reaction mixture was stirred at room temperature for 2 d, and the bulk of the solvent was removed under reduced pressure. The residue was dissolved in H.sub.2O (120 mL) and was extracted with Et.sub.2O (2100 mL). The aqueous layer was cooled in ice, treated with 2 N HCl (60 mL) and extracted with EtOAc (150 mL, 2100 mL). Organic layers were combined, washed with 6 M NaCl (100 mL) and concentrated by rotary evaporation. The residue was dried under high vacuum to afford 3.589 g of 14 (98%) as a pale yellow solid: mp 206-206.5 C. (dec), [] +56.3 (c 0.76, DMF). .sup.1H NMR (DMSO-d.sub.6) 13.14 (s, 2H), 12.75 (s, 1H), 7.34 (d, J=8.6 Hz, 1H), 6.53 (dd, J=8.6, 2.3 Hz, 1H), 6.47 (d, J=2.3 Hz, 1H), 4.75 (s, 2H), 3.79 (d, J=11.3 Hz, 1H), 3.37 (d, J=11.3 Hz, 1H), 1.58 (s, 3H). .sup.13C NMR (DMSO-d.sub.6) 173.71, 170.04, 169.72, 161.94, 160.33, 131.62, 109.52, 107.17, 101.46, 82.47, 64.57, 39.34, 24.09. HRMS m/z calcd for C.sub.13H.sub.14NO.sub.6S, 312.0536 (M+H); found, 312.0546. Anal. Calcd for C.sub.13H.sub.13NO.sub.6S: C, 50.16; H, 4.21; N, 4.50. Found: C, 50.06; H, 4.38; N, 4.41.

Biological Assays of the Compounds

[0418] Exemplary materials and methods employed in Examples 3 to 10 are shown below.

[0419] Materials. Male Cebus apella monkeys were obtained from World Wide Primates (Miami, Fla.). Male Sprague-Dawley rats were procured from Harlan Sprague-Dawley (Indianapolis, IN). Ultra-pure salts were obtained from Johnson Matthey Electronics (Royston, UK). All hematological and biochemical studies were performed by Antech Diagnostics (Tampa, Fla.). Histopathological analysis was carried out by Florida Vet Path (Bushnell, Fla.). Atomic absorption (AA) measurements were made on a Perkin-Elmer model 5100 PC (Norwalk, Conn.).

[0420] Biological Methods. All animal experimental treatment protocols were reviewed and approved by the University of Florida's Institutional Animal Care and Use Committee.

[0421] Cannulation of Bile Duct in Non Iron-Overloaded Rats. The cannulation has been described previously..sup.38,40 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..sup.38,40

[0422] Iron Loading of Cebus apella Monkeys. The monkeys (3.5-6.5 kg) were iron overloaded with intravenous iron dextran as specified in earlier publications to provide about 500 mg of iron per kg of body weight; the serum transferrin iron saturation rose to between 70 and 80%..sup.38,40 At least 20 half-lives, 60 days, elapsed before any of the animals were used in experiments evaluating iron-chelating agents.

[0423] Primate Fecal and Urine Samples. Fecal and urine samples were collected at 24 hours intervals and processed as described previously.sup.38,40,74 Briefly, the collections began 4 days prior to the administration of the test drug and continued for an additional 5 days after the drug was given. Iron concentrations were determined by flame absorption spectroscopy as presented in other publications..sup.38.sup.40

[0424] Drug Preparation and Administration. In the iron clearing experiments, the rats were given 8-14 orally at a dose of 300 mol/kg. Ligand 9 and 12-14 were also given subcutaneously at the same dose. The primates were given 8-9 and 11-14 orally at a dose of 75 mol/kg. Ligand 9 and 12-14 were also given subcutaneously at the same dose. The chelators were administered as their monosodium salts (prepared by the addition of 1 equiv of NaOH to a suspension of the free acid in distilled water).

[0425] Calculation of Chelator Iron Clearing Efficiency (ICE). The term ICE is used as a measure of the amount of iron excretion induced by a chelator. The ICE, expressed as a percent, is calculated as (ligand-induced iron excretion/theoretical iron excretion)100. To illustrate, the theoretical iron excretion after administration of 1 mmol of DFO, a hexadentate chelator that forms a 1:1 complex with Fe(III), is 1 milli-g-atom of iron. The theoretical iron outputs of the chelators were generated on the basis of a 2:1 ligand:iron complex. The efficiencies in the rats and monkeys were calculated as set forth elsewhere..sup.37 Data are presented as the meanthe standard error of the mean; p-values were generated via a one-tailed Student's t-test in which the inequality of variances was assumed, and a p-value of <0.05 was considered significant. The p-values for the monkeys that were given 9 and 12-14 orally and subcutaneously were generated via a one-tailed, paired Student's t-test; a p-value of <0.05 was considered significant.

[0426] Collection of Chelator Tissue Distribution Samples from Rodents. Male Sprague-Dawley rats (250-350 g) were given a single subcutaneously injection of the monosodium salts of 8 and 11 prepared as described above at a dose of 300 mol/kg. At times 0.5, 1, 2, 4 and 8 hours after dosing (n=3 rats per time point), the animals were euthanized by exposure to CO.sub.2 gas. Blood was obtained via cardiac puncture into vacutainers containing sodium citrate. The blood was centrifuged, and the plasma was separated for analysis. The liver, kidney, heart, and pancreas were removed from the animals and frozen.

[0427] Tissue Analytical Methods. Tissue samples of animals treated with 8 were prepared for HPLC analysis by homogenizing them in H.sub.2O at a ratio of 1:1 (w/v). Then, as a rinse, CH.sub.3OH 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.sub.2O, vortexed, and filtered with a 0.2 m membrane. Analytical separation was performed on a Supelco Discovery RP Amide C16 HPLC system with UV detection at 310 nm as described previously..sup.44,75 Mobile phase and chromatographic conditions were as follows: solvent A, 5% CH.sub.3CN/95% buffer (25 mM KH.sub.2PO.sub.4+2.5 mM 1-octanesulfonic acid, pH 3.0); solvent B, 60% CH.sub.3CN/40% buffer.

[0428] Tissue samples of animals treated with 11 were prepared for HPLC analysis by homogenizing them in 0.5 N HClO.sub.4 at a ratio of 1:3 (w/v). Then, as a rinse, CH.sub.3OH 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.sub.2PO.sub.4, pH 3.0)/5% CH.sub.3CN, vortexed, and filtered with a 0.2 p.m 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.

[0429] 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 m and was reproducible and linear over a range of 1-1000 n. Tissue distribution data are presented as the mean; p-values were generated via a one-tailed student's t-test, in which the inequality of variances was assumed; a p-value of <0.05 was considered significant.

[0430] Toxicity Assessment of (S)-4-(HO)-DADFT-HXA (11) in Rats. A 10-day toxicity trial on ligand 11 was performed in rodents. Male Sprague-Dawley rats (n=5, 375-400 g) were given the drug, administered as its monosodium salt, orally once daily for 10 days at a dose of 384 mol/kg/day. Note that this dose is equivalent to 100 mg/kg/day of DFT (1) as its sodium salt. The rats were housed in individual metabolic cages and were weighed each day. A baseline (day 0) urine sample was collected and assessed for its Kim-1 content (Bergeron et al., J. Med. Chem. 57 (2014) 9259-9291; Bergeron et al., Biometals 24 (2011) 239-258); each animal served as its own control. Chilled urine was collected from the metabolic cages at 24-hour intervals as previously described (Bergeron et al., Biometals 24 (2011) 239-258) to allow for the determination of Kim-1 levels. The rats were fasted overnight and were given the chelator first thing in the morning. The rodents were fed 3 hours post-drug and had access to food for 5 hours before being fasted overnight. The animals were euthanized one day post drug (day 11). Blood was collected for the performance of a routine CBC and serum chemistries (Bergeron et al., Blood 79 (1992) 1882-1890). Extensive tissues (Bergeron et al., J. Med. Chem. 42 (1999) 2432-2440) were collected and submitted to an outside laboratory for histopathological analysis. Additional age-matched rats served as untreated controls for the CBC and serum chemistries and histopathology. No urine was collected from these animals. The studies were performed on rats with normal iron stores.

Example 3

Tissue Distribution/Metabolism of (S)-4-(HO)-DADFT-norPE (7)

[0431] As described above, when 7 was given subcutaneously to rats at a dose of 300 mol/kg, there was no cleavage to 2 (FIG. 2). When the tissues were subjected to further analysis via HPLC for the presence of 8 or 9, cleavage of the terminal methyl of 7 to the corresponding alcohol 8 did occur (FIG. 5). However, carboxylic acid 9 was not detected, probably because the extent of the metabolism of the parent 7 to 8 was so minor. In order to verify that conversion of the alcohol 8 to the acid 9 could occur efficiently, rodents were given synthetic alcohol 8 subcutaneously at a dose of 300 mol/kg. The rats were euthanized 0.5, 1, 2, 4, and 8 hours post drug. The animals' plasma, liver, kidney, heart and pancreas were removed and assessed for the presence of 8 and its putative metabolite 9. The extent and rapidity of oxidation of 8 to 9 that unfolded was surprising (FIG. 5). In the plasma at 0.5 hour post drug, nearly 60% of 8 had been converted to 9. At 2 hour post dosing, 88% of the drug is in the form of the metabolite. Neither the parent 8 nor the metabolite 9 was found at the 8 hour time point. A similar story unfolds in the liver (FIG. 5). At 0.5 hour post drug, only 53% of the drug (parent+metabolite) is in the form of the parent 8. At 1 hour, the metabolite 9 comprises 59% of the total. 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 (FIG. 5).

Example 4

Chelator-Induced Iron Clearance of 2 and 7-9 in Non-iron-Overloaded, Bile Duct-Cannulated Rodents

[0432] The ICE values for compounds 2 and 7 (Table 2) are historical and included for comparative purposes. The chelators were given to the rats orally at a dose of 300 mol/kg; 9 was also given subcutaneously at the same dose. Compound 2 (log P.sub.app=1.05) was the least effective ligand, with an ICE of 1.10.8%..sup.50 Analogue 7 (log P.sub.app=0.89) was the most effective, with an ICE of 26.74.7%..sup.59 Ligands 8 (log P.sub.app=0.53) and 9 (log P.sub.app=1.63), the two putative metabolites of 7, were significantly less active than the parent drug 7 when given orally. The ICE of 8 was 15.45.6% (p<0.02), while the ICE of 9 was and 6.21.7% (p<0.005). As ligand 9 is very hydrophilic (log P.sub.app=1.63) the lack of activity on orally administration was likely due to its poor oral absorption. Indeed, when 9 was given to the rats subcutaneously at a dose of 300 mol/kg, its ICE, 11.33.4%, was nearly twice that when the drug was dosed orally (p<0.05).

TABLE-US-00001 TABLE 1 Iron Clearing Efficiency of Iron Chelators given to Rats and Cebus apella Primates, and the Log P.sub.app of the Compounds .sup.aLog .sup.bRodent .sup.dPrimate Compound Route P.sub.app ICE (%) ICE (%) [00147] sc <3.2 2.5 0.7 [74/26] 5.5 0.9 [45/55] Desferrioxamine (DFO) [00148] po 1.77 5.5 3.2 [93/7] 16.1 8.5 [78/22] (S)-Desferrithiocin (1) [00149] po 1.05 1.1 0.8 [100/0] 16.8 7.2 [88/12] (S)-4-(HO)-DADFT (2) [00150] po 1.17 4.6 0.9 [98/2] 23.1 5.9 [83/17] (S)-3-(HO)-DADFT (3) [00151] po 0.70 6.6 2.8 [98/2] 24.4 10.8 [91/9] (S)-4-(CH.sub.3O)-DADFT (4) [00152] po 1.10 5.5 1.9 [90/10] 25.4 7.4 [96/4] (S)-4-(HO)-DADFT-PE (5) [00153] po 1.22 10.6 4.4.sup.c [95/5] 23.0 4.1 [95/5] (S)-3-(HO)-DADFT-PE (6) [00154] po 0.89 26.7 4.7.sup.c [97/3] 26.3 9.9.sup.e [93/7] 28.7 12.4.sup.f [83/17] (S)-4-(HO)-DADFT-norPE (7) .sup.aData are expressed as the log of the fraction of the chelator seen in the octanol layer (log P.sub.app); measurements were done in TRIS buffer, pH 7.4, using a shake flask direct method. .sup.bIn the rodents n = 3 (7), 4 (3-6), 5 (1), 6 (DFO) or 8 (2). The drugs were given orally (po) or subcutaneously (sc) as indicated in the table at a dose of 150 (Desferal and 1) or 300 mol/kg (2-7) The drugs were solubilized in 40% Cremophor RH-40/water (DFO and 1), distilled water (5), administered in capsules (7), or were given as their monosodium salts, prepared by the addition of 1 equiv of NaOH to a suspension of the free acid in distilled water (2-4, 6). The efficiency of each compound was calculated by subtracting the iron excretion of control animals from the iron excretion of the treated animals. The number was then divided by the theoretical output; the result is expressed as a percent. .sup.cICE is based on a 48 hour sample collection period. The relative percentages of the iron excreted in the bile and urine are in brackets. .sup.dIn the primates n = 3 (6), 4 (1, 3-5, 7 in capsules.sup.d), 5 (DFO), or 7 (2, 7 as its monosodium salt.sup.e). The chelators were given orally or subcutaneously at a dose of 75 (7) or 150 mol/kg (DFO, 1-6). The ligands were solubilized in 40% Cremophor RH-40/water (1, 3, 4), distilled water (DFO, 5), administered in capsules (7.sup.d), or were given as their monosodium salts, prepared by the addition of 1 equiv of NaOH to a suspension of the free acid in distilled water (2, 6, 7.sup.f). The ICE was calculated by averaging the iron output for 4 days before the drug, subtracting these numbers from the 2-day iron clearance after the administration of the drug, and then dividing by the theoretical output; the result is expressed as a percent. The relative percentages of the iron excreted in the feces and urine are in brackets.

TABLE-US-00002 TABLE 2 Iron Clearing Efficiency of Iron Chelators given to Rats and Cebus apella Primates, and the Log P.sub.app of the Compounds Log .sup.bRat ICE (%) Rat .sup.dCebus ICE (%) Primate .sup.gPerformance Compound P.sub.app [bile/urine] n = [bile/urine] n = Ratio (PR) [00155] 1.05 1.1 0.8 [100/0] 8 16.8 7.2 [88/12] 7 15.3 2 [00156] 0.89 26.7 4.7.sup.c [97/3] 3 26.3 9.9.sup.e [93/7] 28.7 12.4.sup.f [83/17] 4 6 1.0 1.1 7 [00157] 0.53 15.4 5.6 [98/2] 8 9.8 3.4 [54/46] 4 0.6 8 [00158] 1.63 6.2 1.7 (po) [100/0] 11.3 3.4 (sc) [99/1] 3 3 1.7 1.4 (po) [51/49] 17.4 9.7 (sc) [84/16] 4 4 0.3 1.5 9 [00159] 0.95 15.8 3.7 (po) [99/1] 4 Toxic in Rats 10 [00160] 0.21 9.9 0.8 (po) [96/4] 4 21.9 3.6 (po) [90/10] 3 2.2 11 [00161] 1.90 8.8 1.8 (po) [94/6] 6.5 1.5 (sc) [96/4] 5 4 10.6 4.0 (po) [82/18] 18.8 8.7 (sc) [69/31] 4 4 1.2 4.4 12 [00162] 2.21 3.7 1.7 (po) [89/11] 4.3 1.1 (sc) [95/5] 5 4 5.4 1.5 (po) [97/3] 18.1 7.5 (sc) [78/22] 4 4 1.5 4.2 13 [00163] 1.98 2.6 1.6 (po) [89/11] 6.0 1.9 (sc) [94/6] 3 3 3.0 2.7 (po) [60/40] 15.9 4.3 (sc) [53/47] 4 4 1.2 2.7 14 .sup.aData are expressed as the log of the fraction of the chelator seen in the octanol layer (log P.sub.app); measurements were done in TRIS buffer, pH 7.4, using a shake flask direct method. .sup.bIn the rodents the drugs were given orally (po) or subcutaneously (sc) at a dose of 300 mol/kg. The drugs were administered in capsules (7), or were given as their monosodium salts, prepared by the addition of 1 equiv of NaOH to a suspension of the free acid in distilled water (2, 8-14). The efficiency of each compound was calculated by subtracting the iron excretion of control animals from the iron excretion of the treated animals. The number was then divided by the theoretical output; the result is expressed as a percent. .sup.cICE is based on a 48 hour sample collection period. The relative percentages of the iron excreted in the bile and urine are in brackets. .sup.dIn the primates the chelators were given orally or subcutaneously at a dose of 75 mol/kg (7-9, 11-14) or 150 mol/kg (2). The drugs were administered in capsules (2.sup.e), or were given as their monosodium salts, prepared by the addition of 1 equiv of NaOH to a suspension of the free acid in distilled water (2.sup.f). The efficiency was calculated by averaging the iron output for 4 days before the drug, subtracting these numbers from the 2-day iron clearance after the administration of the drug, and then dividing by the theoretical output; the result is expressed as a percent. The relative percentages of the iron excreted in the feces and urine are in brackets. .sup.gPerformance ratio (PR) is defined as the mean ICE.sub.primates/ICE.sub.rodents.

Example 5

Chelator-Induced Iron Clearance of 2 and 7-9 in Iron-Overloaded Primates

[0433] The primate iron clearance data are provided in Table 2. The ICE values for compounds 2 and 7 are historical and included for comparative purposes. The chelators were given to the monkeys orally at a dose of 75 (7-9) or 150 mol/kg (2); 9 was also given to the primates subcutaneously at a dose of 75 mol/kg. The ICE of ligand 2 was 16.87.2%..sup.50 As with the rats, compound 7 was the most effective iron decorporation agent, with an ICE of 26.39.9% when it was given orally in capsules, and an ICE of 28.712.4% when it was administered orally as its monosodium salt..sup.59 Although 8, the putative metabolite of 7, is more lipophilic than 7, log P.sub.app=0.53 vs -0.89, its ICE was lower, 9.83.4% (p<0.003, Table 2). The ICE of 9 given orally was even lower, only 1.71.4%. When 9 was administered subcutaneously to the same group of monkeys that had been given the drug orally, the ICE increased by more than 10-fold, to 17.49.7% (p<0.03). This is in keeping with the idea that highly charged ligands like 9 (log P.sub.app=1.63) do not make it across the intestinal mucosa, but hydrophilic metabolic precursors do.

Example 6

Metabolically Programmed Iron Chelators

[0434] The design of metabolically programmed iron chelators is thus derived from the observation that alcohol 8 is very efficiently oxidized to carboxylic acid 9 (FIGS. 4 and 5). The corollary to all of this is that the replacement of the 3,6-dioxaheptyl group of the parent polyether (S)-4-(HO)-DADFT-norPE (7) with a long chain alcohol should provide a highly lipophilic chelator with good oral absorption. Once absorbed, the ligand is likely to be metabolized to its less lipophilic, less toxic acid counterparts. This metabolic programming represents an innovative way to exploit the delicate balance seen between enhanced chelator lipophilicity and ICE, and ameliorate the concomitant increase in toxicity usually associated with increases in lipophilicity.

[0435] Accordingly, five different ligands predicated on the (S)-4-(HO)-DADFT platform were assembled (Schemes 2 and 3): 1) the hexamethylene analogue of 7, (S)-4,5-dihydro-2-[2-hydroxy-4-(6-methoxyhexyloxy)phenyl]-4-methyl-4-thiazolecarboxylic acid RS)-4-(HO)-DADFT-HXME, 10]; 2) the corresponding alcohol of 10, (S)-4,5-dihydro-2-[2-hydroxy-4-(6-hydroxyhexyloxy)phenyl]-4-methyl-4-thiazolecarboxylic acid [(S)-4-(HO)-DADFT-HXA, 11]; 3) the putative first metabolite of 11, (S)-4,5-dihydro-2-[2-hydroxy-4-(5-carboxypentyloxy)phenyl]-4-methyl-4-thiazolecarboxylic acid [(S)-4-(5-carboxypentyloxy)-DADFT, 12]; 4) the -oxidation product of 11, (S)-4,5-dihydro-2-[2-hydroxy-4-(3-carboxypropyloxy)phenyl]-4-methyl-4-thiazolecarboxylic acid [(S)-4-(3 -carboxypropyloxy)-DADFT, 13], and 5) the second -oxidation product of 11, (S)-4,5-dihydro-242-hydroxy-4-(carboxymethoxy)phenyl1-4-methyl-4-thiazolecarboxylic acid [(S)-4-(carboxymethoxy)-DADFT, 14]. The conversion of the parent alcohol 11 to its putative metabolites 12-14 (FIG. 6) was assessed in rats given 11 subcutaneously at a dose of 300 mol/kg. In addition, the ligands were evaluated for their log P.sub.app, and their ICE in rats and primates (Table 2).

Example 7

Tissue Distribution/Metabolism of (S)-4-(HO)-DADFT-HXA (ll): A Metabolically Programmed Ligand

[0436] In order to verify that conversion of the alcohol 11 to its putative metabolites 12-14 (FIG. 6) was occurring in vivo, rats were given the parent alcohol 11 subcutaneously at a dose of 300 mol/kg. The rats were euthanized 0.5, 1, 2, 4, and 8 hours post drug. The conversion of 11.fwdarw.12-14 was assessed in the animals' plasma, liver, kidney, heart and pancreas. Significant conversion of 11.fwdarw.12-14 was found in all of the tissues examined (FIG. 7). The extent and rapidity of metabolism of 11.fwdarw.12-14 that unfolded was surprising. Chelator 11 and its metabolites achieve a concentration of 400 M in the plasma at 0.5 hour post drug. This tissue concentration is very similar to that seen with the 4-norpolyether 7 (FIG. 5). However, with 7, the parent represented 95% of the total drug concentration, while its metabolite (8) only accounted for 5% of the total drug. In the case of 11 in the plasma at 0.5 hour, only 22% of the total (parent+metabolites) was in the form of the parent 11 (FIG. 7). The first -oxidation product 13 comprised 62% of the total, while the second -oxidation product 14 represented 16% of the total. The ratio of the parent 11 to its metabolites 13 and 14 was similar at the 1 and 2 hour time points. By 4 hours post dosing, the parent 11 was no longer detectable, and metabolites 13 and 14 each accounted for 50% of the total. At 8 hours post dosing, the total plasma drug concentration had decreased to 23 M. Metabolite 13 accounted for 65% of this quantity, while the remainder was in the form of metabolite 14. None of the first oxidation product of alcohol 11, the dicarboxylic acid 12, was detected in the plasma.

[0437] Significant conversion of 11.fwdarw.12-14 also occurred in the liver (FIG. 7). Interestingly, the parent 11 was not found in the liver at any of the time points. However, unlike the plasma, small quantities of first oxidation product of alcohol 11, the dicarboxylic acid 12, were found in the liver 0.5 and 1 hour post drug. At 0.5 hour, 12 represented 11% of the total drug (parent+metabolites); the first -oxidation product 13 comprised 71% of the total, while the second -oxidation product 14 represented 18% of the total. At 1 hour post dosing, the concentration of metabolites 12 and 13 in the liver had decreased to 2% and 59% of the total, respectively, while the proportion of 14 had increased to 39% (FIG. 7). Ligand 12 was not detected in the liver 2, 4, or 8 hours post dosing. Metabolite 13 accounted for 66% of the total drug (metabolites) at 2 hours, and 70% of the total at 4 hours. By 8 hours post dosing, no 13 remained in the liver, and only trace amounts of 14 were detected.

[0438] The parent drug 11 was found in the kidney in trace amounts 0.5 hour post drug, and the carboxylic acid 12 was found at 0.5 and 1 hour post drug. Metabolite 13, the first -oxidation product, achieves very high levels in the kidney, 300 nmol/g wet weight at 0.5 and 1 hour, but is not detectable 8 hours post dosing. Metabolite 14, the second -oxidation product, also reached high levels in the kidney at 0.5, 1, and 2 hours, 156, 201, and 161 nmol/g wet weight, respectively, but had decreased to only 5 nmol/g wet weight at 8 hours.

[0439] The parent drug 11 was found in the heart at 0.5 hour post drug, 26 nmol/g wet weight. The dicarboxylic acid 12 was not found in the cardiac tissue at any of the time points. The concentration of metabolite 13 in the heart was 46 nmol/g wet weight 0.5 and 1 hour post drug, but was not found in the later time points. Metabolite 14 was found in the heart 0.5 and 1 hour post dosing, 17 and 23 nmol/g wet weight, respectively, but was not found in the 2-8 hour time points (FIG. 7).

[0440] In the pancreas, the parent 11 was only found 0.5 hour post drug, <5 nmol/g wet weight. Metabolite 12 was not found at any of the time points. Ligand 13 was present in the 0.5 and 1 hour samples, 19 and 23 nmol/g wet weight, respectively (FIG. 7). Trace amounts of 14 were found at 0.5, 1, and 2 hours post dosing. Ligands 11-14 were not detected in the pancreas at 4 or 8 hours post drug.

Example 8

Chelator-Induced Iron Clearance of 10-14 in Non-iron-Overloaded, Bile Duct-Cannulated Rodents

[0441] Ligands 10-14 were administered to the rats orally at a dose of 300 mol/kg; 12-14 were given to the animals subcutaneously at the same dose. The first chelator evaluated in the rats was 10, the methyl ether analogue of 11. Ligand 10 is very lipophilic (log P.sub.app=0.95), and is also profoundly toxic. When it was given orally to bile duct-cannulated rats, one of animals died about 22 hours post drug. The remaining rodents were euthanized 24 hours post dosing due to their rapidly deteriorating condition. We had seen this same scenario with (S)-2-(4-butoxy-2-hydroxyphenyl)-4,5-dihydro-4-thiazolecarboxylic acid, the 4-butoxy analogue of 2 (log P.sub.app=1.02), with deaths occurring within 24 hours..sup.72 Nonetheless, 10 was a very active decorporation agent. The baseline iron output for rats treated with 10 was 5 g/kg of iron. The drug-induced iron excretion peaked 6 hours post drug, 300 g/kg of iron, and was still 80 g/kg of iron when the rodents were euthanized 24 hours post dosing. The ICE of the drug was 15.83.7% (Table 2), and clearly would have been higher had the animals survived. The ICE of 10 was not assessed in the primates due to the overt toxicity seen with the rodents. The ICE and toxicity of 10 is in keeping with the molecule's lipophilicity. Next, 11, the O-demethylated, metabolically labile analog of 10 was evaluated.

[0442] An alkanol, e.g., a 6-(HO) hexyl fragment, was fixed to the 4-(HO) position of 15 leading to 11 (Scheme 2). This resulted in a less lipophilic, log P.sub.app=0.21, less toxic ligand than 10. Chelator 11 was given to the rats orally at a dose of 300 mol/kg. The drug was well absorbed, had an ICE of 9.90.8%, and did not present with any overt toxicity. As described above, when ligand 11 was given to rats subcutaneously, it was quickly converted to the corresponding hydrophilic metabolites, carboxylic acid (12, log P.sub.app=1.90),.sup.64,66 with -oxidations.sup.73 to acids 13 log P.sub.app=2.21 and acid 14 log P.sub.app=1.98 (FIG. 6). The ICEs of 12-14 were determined in rodents given the drugs orally and subcutaneously at a dose of 300 mol/kg. The oral ICE of the putative first metabolite, 12, was similar to that of 11, 8.81.8% (p>0.05). However, the oral ICEs of 13 and 14 were significantly less than 11, 3.71.7% (p<0.001) and 2.61.6% (p<0.005), respectively. When 12 and 13 were given to the rats subcutaneously, their ICEs were within error of when the drugs were dosed orally (Table 2). In contrast, the ICE of 14 given subcutaneously (6.01.9%) was more than twice that of when the drug was given orally (2.61.6%, p<0.05).

Example 9

Chelator-Induced Iron Clearance of 11-14 in Iron-Overloaded Primates

[0443] Ligand 11 was administered to the primates orally at a dose of 75 mol/kg; 12-14 were given orally and subcutaneously at the same dose. Ligand 11, in which a 6-(HO)-hexyl fragment was fixed to the 4-(HO) position of 2, was very lipophilic (log P.sub.app=0.21). The ICE of this compound given to the monkeys orally was 21.93.6% (Table 2). The ICEs of the much more hydrophilic metabolites of 11, 12-14, given orally to the monkeys, were all significantly less than the parent. The first oxidation product of alcohol 11, the dicarboxylic acid 12 (log P.sub.app=1.90), had an ICE of 10.64.0% in primates when it was given orally (p<0.01). The first and second -oxidation products, 13 (log P.sub.app=2.21) and 14 (log P.sub.app=1.98), were also significantly less effective than 11 when they were administered orally, 5.4 1.5% (p<0.005) and 3.02.7% (p<0.002), respectively. Again, the reason for the substantial reduction in the efficacy of 12-14 dosed orally was likely due to the poor GI absorption of the dicarboxylic acids because of their charge: they are dianions at physiological pH. In order to confirm this, ligands 12-14 were given to the primates subcutaneously. In each case, the same animals that had been given the drugs orally were also given the chelators subcutaneously.

[0444] The oral ICE of 12 in the monkeys was 10.64.0%; the ICE increased to 18.88.7% when the ligand was given subcutaneously, but the increase was not significant (p=0.06). The ICE of 13 increased significantly in the primates, from 5.41.5% when it was dosed orally to 18.17.5% when it was administered subcutaneously (p<0.03). Finally, the ICE of the second -oxidation product 14 in the primates was 3.02.7% when it was given orally. The ICE increased significantly, to 15.94.3%, when it was given to the same animals subcutaneously (p<0.001). Thus, the importance of ligand charge, log P.sub.app, takes on a much more significant role in the primate model.

Example 10

ICE Observations

[0445] Several generalizations can be derived from Table 2. The performance ratio (PR), ICE.sub.primate/ICE.sub.rodent, show that although 8 and 9 (orally) were more effective at iron decorporation in the rats than in primates, the remaining ligands 11-14 are either as effective or better at iron clearance in the primates. In the rodents, 9 and 14 were approximately twice as effective subcutaneously as when they were dosed orally. There was also a dramatic difference in the subcutaneously vs oral ICEs of 9, 13, and 14 in the primates: their subcutaneously ICEs were 10.2, 3.4, and 5.3 times higher, respectively. The ICE of 12 was also increased upon subcutaneously dosing, but the increase was not significant (p=0.06).

Example 11

Toxicology Profile of (S)-4-(HO)-DADFT-HXA (11), A Metabolically Programmed Chelator

[0446] The concept behind the development of metabolically programmed iron chelators is predicated on the administration of highly lipophilic drugs that will be well absorbed orally, present with excellent ICE properties, and, to minimize potential toxicity, must be quickly metabolized to less lipophilic but still active deferration agents. For example, deferitrin analog 10 (Table 2), with a non-metabolizable terminal methyl ether, was highly lipophilic and was an effective iron clearing agent in the bile duct-cannulated rats. Unfortunately, the chelator was profoundly toxic. Conversely, the corresponding demethylated compound, alcohol 11, which is also lipophilic, had excellent ICE properties in rodents and primates and did not display any overt toxicity. As described above, ligand 11 was well absorbed, and, in a tissue distribution/metabolism study, was shown to be quickly converted to the corresponding hydrophilic acids 12, 13, and 14 (FIG. 6).

[0447] Aten-day toxicity trial of 11 was carried out in male Sprague-Dawley rats. The animals were housed in individual metabolic cages. Ligand 11 was given orally by gavage once daily for ten days at a dose of 384 mol/kg/day. Note that this dose is equivalent to 100 mg/kg/day of DFT (1) as its sodium salt. Urine was collected from the metabolic cages at 24-hour intervals and assessed for its Kim-1 content. The studies were performed on rats with normal iron stores; each animal served as its own control. Additional age-matched rats served as untreated controls for the CBC and serum chemistry assessments and histopathology.

[0448] All of the rats treated with 11 survived the exposure to the drug. The animals were bright, alert and responsive at the beginning of the study and remained that way throughout the course of the experiment. The rodents' baseline urinary Kim-1 excretion was <20 ng/kg/24 hours and did not exceed this level at any time during the 10-day exposure to the chelator. The rats were sacrificed 24 hours post drug. Blood was submitted for routine CBC and serum chemistry analysis. The BUN of the treated rats, 204 mg/dl, was within error of that of the untreated controls, 212 mg/dl (p>0.05). In addition, the SCr for both groups was 0.50.1 mg/dl (p>0.05). Note that these values are well within the normal range for this species: 9-30 mg/dl for BUN, and 0.4-1.0 mg/dl for SCr (Antech Diagnostics (2015), www.antechdiagnostics.com, accessed April 2015). Extensive tissues (25/rat) were submitted to an outside lab for assessment of histopathology. The pathologist did not identify any drug-related abnormalities.

[0449] Taken together, these results demonstrate that metabolically programmed ligands that are highly effective deferration agents can be successfully designed. As predicted, the parent in this case, a lipophilic alcohol, 11, was well absorbed and was quickly metabolized to hydrophilic ligands that, collectively, have excellent ICEs with little to no discernable toxicity.

Conclusions

[0450] A number of notable outcomes derived from the metabolic studies of (S)-4-(HO)-DADFT-norPE (7). First, ligand 7 does not sustain metabolic cleavage at the 4-(HO) to yield 2 (FIG. 2). However, what remained unclear is whether or not the terminal methyl on the polyether fragment of 7 is metabolically labile. If this were the case, it would likely be converted first to the corresponding alcohol, 8, and then to the carboxylic acid, 9, FIG. 4. Both of these metabolic products would be expected to be very hydrophilic. This increase in hydrophilicity, based on previous studies, could further be expected to minimize ligand toxicity..sup.37,43,45 If indeed such a demethylation-oxidation scenario is occurring with 7, it could support a novel approach to metabolically programmed iron chelators, e.g., highly lipophilic chelators that would be absorbed well orally, but would then be quickly metabolized to hydrophilic, nontoxic ligands.

[0451] The putative metabolites of 7, 8 and 9, were assembled. The alcohol 8 has a 3-oxa-5-hydroxypentyl fragment fixed to the 4-(HO); the acid 9 has a 3-oxa-4-carboxybutyl group on the 4-(HO). These two synthetic chelators allowed us to develop an analytical HPLC method to follow the potential metabolism of 7. When the tissues of rats treated with 7 subcutaneously were subjected to further analysis via HPLC for the presence of 8 or 9, cleavage of the terminal methyl of 7 to the corresponding alcohol 8 did occur (FIG. 5). However, carboxylic acid 9 was not detected, probably because the extent of the metabolism of the parent 7 to 8 was so minor. However, when synthetic alcohol 8 was given subcutaneously to rats, it was very efficiently converted to acid 9.

[0452] Rodents were administered the synthetic alcohol 8 subcutaneously at a dose of 300 mol/kg. Indeed, alcohol 8 was very quickly oxidized to 9 (FIG. 5).

[0453] When given orally to rodents and primates, neither of the synthetic metabolites of 7, alcohol 8 nor the acid 9, had ICE values as high as the parent ligand. The acid 9, given orally, was particularly ineffective. However, when given subcutaneously, the ICE of 9 doubled in rodents, and was 10 times higher in primates than when it was given to the same monkeys orally (Table 2). This is in keeping with the idea that highly charged ligands do not make it across the intestinal mucosa. Taken collectively, the data suggested that fixing a lipophilic alcohol fragment to the 4-(HO) of 2 would provide a chelator that should be lipophilic, orally absorbed, and quickly converted to hydrophilic acid metabolites.

[0454] Initially, a 6-methoxyhexyl group was appended to the 4-(HO) of 2, providing methyl ether 10. This ligand was very lipophilic (log P.sub.app=0.95), had an ICE of 15.83.7% in the rats, and was very toxic. We had seen this scenario before with a 4-butoxy analogue of 2 (log P.sub.app=1.02), with deaths occurring within 24 hours..sup.72 Nevertheless, this ligand did serve to identify the upper boundary of the lipophilicity/toxicity relationship for this structural family.

[0455] Subsequently, a metabolizable 6-hydroxyhexyl group was fixed to the 4-(HO) of 2, providing alcohol 11 (Table 2). Ligand 11 is still very lipophilic, log P.sub.app=0.21, but it did not elicit any signs of overt toxicity. As predicted, each of the metabolites of 11 (12, 13, and 14) are very hydrophilic, moving from a log P.sub.app=0.21 for the parent to 1.90 for acid 12, 2.21 for acid 13, and 1.98 for acid 14 (FIG. 6). When given to rats subcutaneously, 11 is very quickly converted to the corresponding acid (12), and by (3-oxidation to acid 13 and finally to acid 14 (FIG. 7).

[0456] The oral ICE of ligand 11 in the rats is 9.90.8%. The oral ICE of 12 was similar, while the oral ICEs of 13 and 14 were significantly less. In the primates, the oral ICE of the parent 11 was 21.93.6%. The oral ICEs of the hydrophilic metabolites, 12-14, were all significantly less in the monkeys than the parent alcohol 11 (Table 2). Again, this is in keeping with the idea that highly charged ligands do not make it across the intestinal mucosa. To confirm this, ligands 12-14 were given subcutaneously to the rodents and primates. In the rats, the subcutaneously ICEs of 12 and 13 were within error of their oral values, while that of 14 subcutaneously was significantly greater than when the drug was given orally. In the monkeys, the subcutaneously ICE of 12 did increase vs oral dosing, but the increase was not significant. In contrast, the subcutaneously ICEs of 13 and 14 were 3.4 and 5.3 times greater, respectively, than when the drugs were given to the same animals orally (Table 2). The most notable finding was the lack of toxicity with ligand 11 when given to rodents once daily for 10 days at a dose of 384 mol/kg/day. The toxicity difference between 10 and 11 was profound. This substantiates the idea that the lipophilic parent chelator is quickly converted to hydrophilic, nontoxic deferration metabolites. Thus, the concept of developing metabolically programmed chelators, e.g., highly lipophilic, orally absorbable and effective molecules that are quickly converted to their hydrophilic counterparts, is indeed a credible approach in the design of highly effective iron chelators. FIG. 8 illustrates the concept established in this study.

REFERENCES

[0457] (1) Mladenka, P.; Hrdina, R.; HM, M.; Simunek, T. The Fate of Iron in the Organism and Its Regulatory Pathways. Acta Medica. 2005, 48, 127-135.

[0458] (2) Bauer, I.; Knolker, H-J. Iron Complexes in Organic Chemistry. In Iron Catalysis in Organic Chemistry. Plietker, B. Ed. Wiley-VCH: Weinheim, 2008; pp. 1-28.

[0459] (3) Saha, R.; Saha, N.; Donofrio, R. S.; Bestervelt, L. L. Microbial Siderophores: A Mini Review. J. Basic Microbiol. 2013, 53, 303-317.

[0460] (4) Abergel, R. J.; Wilson, M. K.; Arceneaux, J. E. L.; Hoette, T. M.; Strong, R. K.; Byers, B. R. Anthrax Pathogen Evades the Mammalian Immune System Through Stealth Siderophore Production. Proc. Nat. Acad. Sci., 2006, 103, 18499-18503.

[0461] (5) Raymond, K. N.; Dertz, E. A.; Kim, S. S. Enterobactin: An Archetype for Microbial Iron Transport. Proc. Natl. Acad. Sci. 2003, 100, 3584-3588.

[0462] (6) Gkouvatsos, K.; Papanikolaou, G.; Pantopoulos, K. Regulation of Iron Transport and the Role of Transferrin. Biochim. Biophys. Acta. 2012, 1820, 188-202.

[0463] (7) Li, L.; Fang, C. J.; Ryan, J. C.; Niemi, E. C.; Lebron, J. A.; Bjorkman, P. J.; Arase, H.; Torti, F. M.; Torti, S. V.; Nakamura, M. C.; Seaman, W. E. Binding and Uptake of H-ferritin are Mediated by Human Transferrin Receptor-1. Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 3505-3510.

[0464] (8) Andrews, N. C.; Schmidt, P. J. Iron Homeostasis. Annu. Rev. Physiol. 2007, 69, 69-85.

[0465] (9) Whittington, C. A.; Kowdley, K. V. Review Article: Haemochromatosis. Aliment Pharmacol. Ther. 2002, 16, 1963-1975.

[0466] (10) Peters, M.; Heijboer, H.; Smiers, F.; Giordano, P. C. Diagnosis and Management of Thalassemia. B. M. J. 2012, 344:e228. doi: 10.1136/bmj.e228.

[0467] (11) Cappellini, M. D.; Cohen, A. R.; Eleftheriou, A.; Piga, A.; Porter, J.; Taher, A. T. Guidelines for the Clinical Management of Thalassemia. 2.sup.nd Ed. Thalassemia International Foundation, 2008.

[0468] (12) Conrad, M. E.; Umbreit, J. N.; Moore, E. G. Iron Absorption and Transport. Am. J. Med. Sci. 1999, 318, 213-229.

[0469] (13) Lieu, P. T.; Heiskala, M.; Peterson, P. A.; Yang, Y. The Roles of Iron in Health and Disease. Mol. Aspects Med. 2001, 22, 1-87.

[0470] (14) Bonkovsky, H. L.; Lambrecht, R. W. Iron-Induced Liver Injury. Clin. Liver Dis. 2000, 4, 409-429, vi-vii.

[0471] (15) Wojcik, J. P.; Speechley, M. R.; Kertesz, A. E.; Chakrabarti, S.; Adams, P. C. Natural History of C282Y Homozygotes for Haemochromatosis. Can. J. Gastroenterol. 2002, 16, 297-302

[0472] (16) Brittenham, G. M. Disorders of Iron Metabolism: Iron Deficiency and Overload. In Hematology: Basic Principles and Practice, 3rd Edn.; Hoffman, R.; Benz, E. J.; Shattil, S. J.; Furie, B.; Cohen, H. J., Eds.; Churchill Livingstone: New York, 2000; pp 397-428.

[0473] (17) Brissot, P.; Ropert, M.; Le Lan, C.; Loreal, O. Non-Transferrin Bound Iron: A Key Role in Iron Overload and Iron Toxicity. Biochim. Biophys. Acta. 2012, 1820, 403-410.

[0474] (18) Chua, A. C. G.; Olynyk, J. K.; Leedman, P. J.; Trinder, D. Nontransferrin-Bound Iron Uptake by Hepatocytes is Increased in the Hfe Knockout Mouse Model of Hereditary Hemochromatosis. Blood 2004, 104, 1519-1525.

[0475] (19) Bolli, R.; Patel, B. S.; Jeroudi, M. O.; Li, X. Y.; Triana, J. F.; Lai, E. K.; McCay, P. B. Iron-Mediated Radical Reactions upon Reperfusion Contributes to Myocardial Stunning Am. J. Physiol. 1990, 259, 1901-1911.

[0476] (20) Milia, M.; Sobrino, T.; Arenillas, J. F.; Rodriguez-Ya{acute over ()}ez, M.; Garcia, M.; Nombela, F.; Castellanos, M.; de la Ossa, N. P.; Cuadras, P.; Serena, J.; Castillo, J.; Da{acute over (v)}alos, A. 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.

[0477] (21) Carr, A.; Frei, B. Does Vitamin C Act as a Pro-Oxidant Under Physiological Conditions? FASEB J. 1999, 13, 1007-1024.

[0478] (22) Jomova, K.; Valko, M. Advances in Metal-Induced Oxidative Stress and Human Disease. Toxicology, 2011, 283, 65-87.

[0479] (23) Hazen, S. L.; d'Avignon, A.; Anderson, M. M.; Hsu, F. F.; Heinecke, J. W. Human Neutrophils Employ the Myeloperoxidase- Hydrogen Peroxide- Chloride System to Oxidize -Amino Acids to a Family of Reactive Aldehydes. Mechanistic Studies Identifying Labile Intermediates along the Reaction Pathway. J. Biol. Chem. 1998, 273, 4997-5005.

[0480] (24) Bergeron, R. J.; Wiegand, J.; McManis, J. S.; Perumal, P. T. Synthesis and Biological Evaluation of Hydroxamate-Based Iron Chelators. J. Med. Chem. 1991, 34, 3182-3187.

[0481] (25) Balfour, J. A. B.; Foster, R. H. Deferiprone A Review of its Clinical Potential in Iron Overload in -Thalassemia Major and Other Transfusion-Dependent Diseases. Drugs. 1999, 58, 553-578.

[0482] (26) Richardson, D. R. The Controversial Role of Deferiprone in the Treatment of Thalassemia. J. Lab. Clin. Med. 2001, 137, 324-329.

[0483] (27) Nick, H.; Wong, A.; Acklin, P.; Faller, B.; Jin, Y. Lattmann, R.; Sergejew, T.; Hauffe, S.; Thomas, H.; Schnebli, H. P. ICL670A: Preclinical Profile. Adv. Exp. Med. Biol. 2002, 509, 185-203.

[0484] (28) Yacobovich, J.; Stark, P.; Barzilai-Birenbaum, S.; Krause, I.; Yaniv, I.; Tamary, H. Acquired Proximal Renal Tubular Dysfunction in Beta-Thalassemia Patients Treated with Deferasirox. J. Pediatr. Hematol. Oncol. 2010, 32, 564-567.

[0485] (29) Cappellini, M. D.; Pattoneri, P. Oral Iron Chelators. Annu. Rev. Med. 2009, 60, 25-38.

[0486] (30) Bergeron, R. J.; Pegram, J. J. An Efficient Total Synthesis of Desferrioxamine B. J. Org. Chem. 1988, 53, 3131-3134.

[0487] (31) Cunningham, M. J.; Nathan, D. G. New Developments in Iron Chelators. Curr. Opin. Hematol. 2005, 12, 129-134.

[0488] (32) Olivieri, N. F.; Koren, G.; Hermann, C.; Bentur, Y.; Chung, D.; Klein, J.; St Louis, P.; Freedman, M. H.; McClelland, R. A.; Templeton, D. M. Comparison of Oral Iron Chelator L1 and Desferrioxamine in Iron-Loaded Patients. Lancet 1990, 336, 1275-1279.

[0489] (33) Exjade Prescribing Information; Novartis Pharmaceuticals Corporation: East Hanover, N.J., December, 2014; www.pharma.us. novartis.com/product/pi/pdf/exjade.pdf.

[0490] (34) Naegeli, H.-U.; Zahner, H. Metabolites of Microorganisms. Part 193. Ferrithiocin. Helv. Chim. Acta 1980, 63, 1400-1406.

[0491] (35) Anderegg, G.; Rber, M. Metal Complex Formation of a New Siderophore Desferrithiocin and of Three Related Ligands. J. Chem. Soc., Chem. Commun. 1990, 1194-1196.

[0492] (36) Bergeron, R. J.; Wiegand, J.; Dionis, J. B.; Egil-Karmakka, M.; Frei, J.; Huxley-Tencer, A.; Peter, H. H. Evaluation of Desferrithiocin and its Synthetic Analogues as Orally Effective Iron Chelators. J. Med Chem. 1991, 34, 2072-2078.

[0493] (37) Bergeron R. J.; Wiegand, J.; McManis, J. S.; McCosar, B. H.; Weimar, W. R.; Brittenham, G. W.; Smith, R. E. Effects of C-4 Stereochemistry and C-4 Hydroxylation on the Iron Clearing Efficiency and Toxicity of Desferrithiocin Analogues. J. Med. Chem. 1999, 42, 2432-2440.

[0494] (38) Bergeron, R. J.; Streiff, R. R.; Wiegand, J.; Vinson, J. R. T.; Luchetta, G.; Evans, K. M.; Peter, H.; Jenny, H-B. A Comparative Evaluation of Iron Clearance Models. Ann N.Y. Acad. Sci. 1990, 612, 378-393.

[0495] (39) Wolfe, L. C.; Nicolosi, R. J.; Renaud, M. M.; Finger, J.; Hegsted, M.; Peter, H.; Nathan, D. G. A Non-Human Primate Model for the Study of Oral Iron Chelators. Br. J. Hematol. 1989, 72, 456-461.

[0496] (40) Bergeron, R. J.; Streiff, R. R.; Creary, E. A.; Daniels, R. D. Jr.; King, W.; Luchetta, G.; Wiegand, J.; Moerker, T.; Peter, H. H. A Comparative Study of the Iron-Clearing Properties of Desferrithiocin Analogues with Desferrioxamine B in a Cebus Monkey Model. Blood 1993, 81, 2166-2173.

[0497] (41) Baker, E.; Wong, A.; Peter, H.; Jacobs, A. Desferrithiocin is an Effective Iron Chelator in vivo and in vitro but Ferrithiocin is Toxic. Br. J. Haematol. 1992, 81, 424-431.

[0498] (42) Bergeron, R. J.; Wiegand, J.; McManis, J. S.; Weimar, W. R.; Park, J. H.; Eiler-McManis, E.; Bergeron, J.; Brittenham, G. M. Partition-Variant Desferrithiocin Analogues: Organ Targeting and Increased Iron Clearance. J. Med. Chem. 2005, 48, 821-831.

[0499] (43) Bergeron, R. J.; Wiegand, J.; McManis, J. S.; Bussenius, J.; Smith, R. E.; Weimar, W. R. Methoxylation of Desazadesferrithiocin Analogues: Enhanced Iron Clearing Efficiency. J. Med. Chem. 2003, 46, 1470-1477.

[0500] (44) Bergeron, R. J.; Wiegand, J.; Weimar, W. R.; McManis, J. S.; Smith, R.E.; Abboud, K. A. Iron Chelation Promoted by Desazadesferrithiocin Analogs: An Enantioselective Barrier. Chirality 2003, 15, 593-599.

[0501] (45) Bergeron, R. J.; Wiegand, J.; McManis, J. S.; Bharti, N. Desferrithiocin: A Search for Clinically Effective Iron Chelators. J. Med. Chem. 2014, pubs.acs.org/doi/pdf/10.1021/jm500828f.

[0502] (46) Donovan, J. M.; Plone, M.; Dagher, R.; Bree, M.; Marquis, J. Preclinical and Clinical Development of Deferitrin, a Novel, Orally Available Iron Chelator. Ann. N.Y. Acad. Sci. 2005, 1054, 492-494.

[0503] (47) Brittenham, G. M. Pyridoxal Isonicotinoyl Hydrazone (PIH): Effective Iron Chelation after Oral Administration. Ann. N.Y. Acad. Sci. 1990, 612, 315-326.

[0504] (48) Galanello, R.; Forni, G.; Jones, A.; Kelly, A.; Willemsen, A.; He, X.; Johnston, A.; Fuller, D.; Donovan, J.; Piga, A. A Dose Escalation Study of the Pharmacokinetics, Safety, and Efficacy of Deferitrin, an Oral Iron Chelator in Beta Thalassaemia Patients. ASH Annu. Meet. Abstr. 2007, 110, 2669.

[0505] (49) Sangster, J. Octanol-Water Partition Coefficients: Fundamentals and Physical Chemistry; John Wiley and Sons: West Sussex, England, 1997; Vol. 2.

[0506] (50) Bergeron, R. J.; Wiegand, J.; McManis, J. S.; Vinson, J. R. T.; Yao, H.; Bharti, N.; Rocca, J. R. (S)-4,5-Dihydro-2-(2-hydroxy-4-hydroxyphenyl)-4-methyl-4-thiazolecarboxylic Acid Polyethers: A Solution to Nephrotoxicity. J. Med. Chem. 2006, 49, 2772-2783.

[0507] (51) Bergeron, R. J.; Wiegand, J.; Bharti, N.; Singh, S.; Rocca, J. R. Impact of the 3,6,9-Trioxadecyloxy Group on Desazadesferrithiocin Analogue Iron Clearance and Organ Distribution. J. Med. Chem. 2007, 50, 3302-3313.

[0508] (52) Bergeron, R. J.; Wiegand, J.; McManis, J. S.; Bharti, N.; Singh, S. Design, Synthesis, and Testing of Non-Nephrotoxic Desazadesferrithiocin Polyether Analogues. J. Med. Chem. 2008, 51, 3913-3923.

[0509] (53) Rienhoff, H. Y. Jr.; Virakasit, V.; Tay, L.; Harmatz, P.; Vichinsky, E.; Chirnomas, D.; Kwiatkowski, J. L.; Tapper, A.; Kramer, W.; Porter, J. B.; Neufeld, E. J. A Phase-1 Dose-Escalation Study: Safety, Tolerability, and Pharmacokinetics of FBS0701, a Novel Oral Iron Chelator for the Treatment of Transfusional Overload. Haematologica. 2011, 96, 521-525.

[0510] (54) Neufeld, E. J.; Galanello, R.; Viprakasit, V.; Aydinok, Y.; Piga, A.; Harmatz, P.; Forni, G. L.; Shah, F. T.; Grace, R E. F.; Porter, J. B.; Wood, J. C.; Peppe, J. Jones, A.; Rienhoff, H. Y. Jr. A Phase 2 Study of the Safety, Tolerability, and Pharmacodynamics of FBS0701, a Novel Oral Iron Chelator, in Transfusional Iron Overload. Blood 2012, 119, 3263-3268.

[0511] (55) Suk, O. J. Paradoxical Hypomagnesemia Caused by Excessive Ingestion of Magnesium Hydroxide. Am. J. Emerg. Med. 2008, 26, 837.e1-837.e2.

[0512] (56) Durlach, J.; Durlach, V.; Bac, P.; Bara, M.; Guiet-Bara, A. Magnesium and Therapeutics. Magnes. Res. 1994, 7, 313-328.

[0513] (57) Randall, R. E. Jr. Magnesium Toxicity. Ann. Intern. Med. 1963, 58, 744.

[0514] (58) Bergeron, R. J.; Wiegand, J.; Bharti, N.; McManis, J. S.; Singh, S. Desferrithiocin Analogue Iron Chelators: Iron Clearing Efficiency, Tissue Distribution, and Renal Toxicity. Biometals 2011, 24, 239-258.

[0515] (59) Bergeron, R. J.; Bharti, N.; Wiegand, J.; McManis, J. S.; Singh, S.; Abboud, K. A. The Impact of Polyether Chain Length on the Iron Clearing Efficiency and Physiochemical Properties of Desferrithiocin Analogues. J. Med. Chem. 2010, 53, 2843-2853.

[0516] (60) Han, W. K.; Bailly, V.; Abichandani, R.; Thadhani, R.; Bonventre, J. V. Kidney Injury Molecule-1 (KIM-1): A Novel Biomarker for Human Renal Proximal Tubule Injury. Kidney Int. 2002, 62, 237-244.

[0517] (61) Bonventre, J. V. Kidney Injury Molecule-1 (KIM-1): A Urinary Biomarker and Much More. Nephrol. Dial. Transpl. 2009, 24, 3265-3268.

[0518] (62) Zhou, Y.; Vaidya, V. S.; Brown, R. P.; Zhang, J.; Rosenzweig, B.A.; Thompson, K. L.; Miller, T. J.; Bonventre, J. V.; Goering, P. L. Comparison of Kidney Injury Molecule-1 and Other Nephrotoxicity Biomarkers in Urine and Kidney Following Acute Exposure to Gentamicin, Mercury, and Chromium. Toxicol. Sci. 2008, 101, 159-170.

[0519] (63) Vaidya, V. S.; Ramirez, V.; Ichimura, T.; Bobadilla, N. A.; Bonventre, J. V. Urinary Kidney Injury Molecule-1: A Sensitive Quantitative Biomarker for Early Detection of Kidney Tubular Injury. Am. J. Physiol. Renal Physiol. 2006, 290, F517-F529.

[0520] (64) Rosse, G. Metabolites of the Pyrimidine Amine Preladenant as Adenosine A2a Receptor Antagonists. ACS Med. Chem. Lett. 2013, 4, 5-6.

[0521] (65) Zhao, M.; He, P.; Rudek, M. A.; Hidalgo, M.; Baker, S. D. Specific Method for Determination of OSI-774 and its Metabolite OSI-420 in Human Plasma by Using Liquid Chromatography-Tandem Mass Spectrometry. J. Chromatogr. 2003, 793, 413-420.

[0522] (66) Platzer, R.; Galeazzi, R. L.; Karlaganis, G.; Bircher, J. Rate of Drug Metabolism in Man Measured by .sup.14CO.sub.2-Breath Analysis. Europ. J. Clin. Pharmacol. 1978, 14, 293-299.

[0523] (67) Li, X.-Q.; Zhong, D.-F.; Huang, H.-H.; Wu, S.-D. Demethylation Metabolism of Roxithromycin in Humans and Rats. Acta Pharmacol. Sin. 2001, 22, 469-474.

[0524] (68) Zeng, Z.; Andrew, N. W.; Halley, B. A. Identification of Cytochrome P4503A as the Major Enzyme Sub-Family Responsible for the Metabolism of 22, 23-Dihydro-13-O-[(2-methoxyethoxy)methyl]-Avermectin B.sub.1 Aglycone by Rat Liver Microsomes. Xenobiotica 1997, 27, 985-994.

[0525] (69) He, H.; Jenkins, K.; Lin, C. A Fluorescent Chemosensor for Calcium with Excellent Storage Stability in Water. Anal. Chim. Acta 2008, 197-204.

[0526] (70) Jouany, M.; Coustal, S.; Frappier, F.; Marquet, A. Novel Synthesis of Dethiobiotin. J. Chem. Research (S) 1982, 114.

[0527] (71) Dolkov, P.; Drans, M.; Fanfrlk, J.; Hol, A. Synthesis of Analogues of Acyclic Nucleoside Diphosphates Containing a (Phosphonomethyl)phosphanyl Moiety and Studies of Their Phosphorylation. Eur. J. Org. Chem. 2009, 1082-1092.

[0528] (72) Bergeron, R. J.; Wiegand, J.; McManis, J. S.; Bharti, N.; Singh, S. Desferrithiocin Analogues and Nephrotoxicity. J. Med. Chem. 2008, 51, 5993-6004.

[0529] (73) Dover, G. J.; Brusilow, S.; Samid, D. Increased Fetal Hemoglobin in Patients Receiving Sodium 4-Phenylbutyrate. N. Engl. J. Med. 1992, 327, 569-570.

[0530] (74) Bergeron, R. J.; Wiegand, J.; Brittenham, G. M. HBED: A Potential Alternative to Deferoxamine for Iron-Chelating Therapy. Blood. 1998, 91, 1446-1452.

[0531] (75) Bergeron, R. J.; Wiegand, J.; Ratliff-Thompson, K.; Weimar, W. R. The Origin of the Differences in (R)- and (S)-Desmethyldesferrithiocin: Iron-Clearing Properties. Ann. N.Y. Acad. Sci. 1998, 850, 202-216.

EQUIVALENTS AND SCOPE

[0532] In the claims articles such as a, an, and the may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include or between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.

[0533] Furthermore, the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is/are referred to as comprising particular elements and/or features, certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements and/or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms comprising and containing are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0534] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present invention that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the invention can be excluded from any claim, for any reason, whether or not related to the existence of prior art.

[0535] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present invention, as defined in the following claims.