Targeted nitroxide compounds and uses therefor

Abstract

Provided herein are targeted nitroxide compounds and methods of using the same for treatment of conditions associated with reactive oxygen species, such as ischemia-reperfusion injury associated with myocardial infarction.

Description

Attorney Docket No. 06527-2502274TARGETED NITROXIDE COMPOUNDS AND USES THEREFORCROSS-REFERENCE TO RELATED APPLICATION

[0001] The present application claims priority to U.S. Provisional Patent Application No. 63 / 681 ,377, filed August 9, 2024, the disclosure of which is hereby incorporated by reference in its entirety.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

[0002] This invention was made with government support under HDTRA1 -16-1 - 0041 awarded by the Defense Threat Reduction Agency. The government has certain rights in the invention.BACKGROUND OF THE INVENTIONField of the Invention

[0003] Provided herein are compounds useful for treating conditions, and, more particularly, compounds useful for treating conditions related to oxidative stress in cardiac tissue.Description of Related Art

[0004] Coronary heart disease (CHD) is the leading cause of morbidity and mortality worldwide, accounting for over 370,000 deaths per year in the United States. It is characterized by severe impairment of coronary blood supply, which produces myocardial ischemic injury and is accompanied by a wide range of clinical symptoms. Indeed, timely reperfusion or restoration of coronary perfusion is the only effective therapeutic intervention for protecting the heart against ischemic injury or myocardial infarction. However, although reperfusion salvages viable myocardium, it can also damage the myocardium up to 50% more than ischemia alone, increasing arrhythmia, and infarction size while diminishing myocardial contraction. This phenomenon is known as "reperfusion injury" and is typical of myocardial infarction. Despite continuous intensive studies, including a variety of pharmacological and conditional approaches, there is no effective therapy for preventing cardiac ischemia-reperfusion (IR) injury. Most current cardiovascular / heart attack strategies focus solely on restoring coronary perfusion, not on limiting reperfusion injury. Accordingly, there is a need in the field for improved treatments for oxidative stress related to ischemia / reperfusion injury.166C1902. DOCXAttorney Docket No. 06527-2502274SUMMARY OF THE INVENTION

[0005] Provided herein is a method of treating or preventing a condition selected from one or more of coronary heart disease, ischemia / reperfusion (IR) injury, myocardial infarction, lipid peroxidation of cardiac tissue, a neuroinflammatory disease, or combinations thereof in a patient, including administering to the patient an amount of a composition including a compound having the structure:J effective to prevent or treat the condition, wherein:R is H or -C(O)-X-Ri, wherein Ri is a branched or unbranched Ci-Ce alkyl or a C3-C8 cycloalkyl, wherein the Ci-Ce alkyl or the C3-C8 cycloalkyl is optionally substituted with a phenyl, a substituted phenyl, a heteroaryl, or a substituted heteroaryl, and X is -NH, -O-, or is not present;R2 is a branched or unbranched Ci-Ce alkyl or a C3-C8 cycloalkyl, wherein the Ci-Ce alkyl or the C3-C8 cycloalkyl is optionally substituted with a phenyl, a substituted phenyl, a heteroaryl, or a substituted heteroaryl, or a phenyl, wherein the phenyl is optionally substituted with, independently, 1 , 2, or 3 Cl or F atoms;R3 is H or a C1-C4 alkyl, wherein the C1-C4 alkyl is optionally substituted with a phenyl, a substituted phenyl, a heteroaryl, or a substituted heteroaryl;R4 and R5 are, independently, H, a Ci-Ce alkyl, or a C3-C8 cycloalkyl, wherein the Ci-Ce alky or the C3-C8 cycloalkyl is optionally substituted with a monovalent or divalent benzyl group (-CeH4- or -CeHs) that is optionally substituted with 1 , 2, or 3 halogen atoms, or R4 and R5 together form a cycloalkyl ring or a heterocycloalkyl ring comprising one O, S, or N atom;Re is -C(O)-NH-R7, -NH-C(O)-R?, or -R7, wherein R7 is a nitroxide- containing group;Y is -CH2-, -NH-, or a bond; n is 0 to 6; and the double bond is cis or trans configured, or a pharmaceutically-acceptable salt thereof, including stereoisomers thereof and mixtures of stereoisomers thereof.266C1902. DOCXAttorney Docket No. 06527-2502274

[0006] Further non-limiting embodiments are set forth in the following numbered clauses:

[0007] 1 . A method of treating or preventing a condition selected from one or more of coronary heart disease, ischemia / reperfusion (IR) injury, myocardial infarction, lipid peroxidation of cardiac tissue, a neuroinflammatory disease, or combinations thereof in a patient, comprising administering to the patient an amount of a composition comprising a compound having the structure:effective to prevent or treat the condition, wherein:R is H or -C(O)-X-R1 , wherein R1 is a branched or unbranched C1 -C6 alkyl or a C3 C8 cycloalkyl, wherein the C1 -C6 alkyl or the C3 C8 cycloalkyl is optionally substituted with a phenyl, a substituted phenyl, a heteroaryl, or a substituted heteroaryl, and X is NH, O , or is not present;R2 is a branched or unbranched C1 -C6 alkyl or a C3 C8 cycloalkyl, wherein the C1 - C6 alkyl or the C3 C8 cycloalkyl is optionally substituted with a phenyl, a substituted phenyl, a heteroaryl, or a substituted heteroaryl, or a phenyl, wherein the phenyl is optionally substituted with, independently, 1 , 2, or 3 Cl or F atoms;R3 is H or a C1 -C4 alkyl, wherein the C1 -C4 alkyl is optionally substituted with a phenyl, a substituted phenyl, a heteroaryl, or a substituted heteroaryl;R4 and R5 are, independently, H, a C1 -C6 alkyl, or a C3-C8 cycloalkyl, wherein the C1 -C6 alky or the C3-C8 cycloalkyl is optionally substituted with a monovalent or divalent benzyl group (-C6H4- or -C6H5) that is optionally substituted with 1 , 2, or 3 halogen atoms, or R4 and R5 together form a cycloalkyl ring or a heterocycloalkyl ring comprising one O, S, or N atom;R6 is -C(O)-NH-R7, -NH-C(O)-R7, or -R7, wherein R7 is a nitroxide-containing group;Y is -CH2-, -NH-, or a bond; n is 0 to 6; and the double bond is cis or trans configured, or a pharmaceutically-acceptable salt thereof, including stereoisomers thereof and mixtures of stereoisomers thereof.

[0008] 2. The method of clause 1 , wherein the double bond is trans configured.3 6C1902. DOCXAttorney Docket No. 06527-2502274

[0009] 3. The method of clause 1 or clause 2, wherein the compound has the structure:

[0010] 4. The method of any of clauses 1 -3, wherein the compound has the structure:

[0011] 5. The method of any of clauses 1 to 4, wherein R7 is 2, 2,6,6- tetramethylpiperidin-N-oxyl or 2,2,5,5-tetramethylpyrrolidin-N-oxyl.

[0012] 6. The method of any of clauses 1 to 5, wherein R is 9-fluorenylmethyloxy carbonyl (Fmoc), t-butyloxycarbonyl (Boc), benzhydryloxycarbonyl (Bhoc), benzyloxycarbonyl (Cbz), O-nitroveratryloxycarbonyl (Nvoc), benzyl (Bn), allyloxycarbonyl (alloc), trityl (Trt), l-(4,4-dimethyl-2,6-dioxacyclohexylidene)ethyl (Dde), diathiasuccinoyl (Dts), benzothiazole-2-sulfonyl (Bts), dimethoxytrityl (DMT), or monomethoxytrityl (MMT).

[0013] 7. The method of any of clauses 1 to 6, wherein R is Boc.

[0014] 8. The method of any of clauses 1 to 7, wherein R2 is 2-methylpropyl.

[0015] 9. The method of any of clauses 1 to 8, wherein R3 is H.

[0016] 10. The method of any of clauses 1 to 9, wherein R4 and R5 are each independently a C1 -C6 alkyl substituted with a benzyl group that is substituted with 1 , 2, or 3 halogen atoms.

[0017] 11. The method of any of clause 1 to 10, wherein R4 and R5 are each independently a C2 alkyl substituted with a benzyl group that is substituted with 1 fluorine atom.

[0018] 12. The method any of clauses 1 to 11 , wherein R4 and R5 are each independently 1 -ethyl-4-fluorobenzene.

[0019] 13. The method of any of clauses 1 to 12, wherein R6 is -C(O)-NH-R7 or -NH-C(O)-R7.4 6C1902. DOCXAttorney Docket No. 06527-2502274

[0020] 14. The method of any of clauses 1 to 13, wherein n is 1 to 4.

[0021] 15. The method of any of clauses 1 to 14, wherein n is 2 and R6 is-C(O)-NH-R7 or -NH-C(O)-R7.

[0022] 16. The method of any of clauses 1 to 15, wherein Y is -NH-.

[0023] 17. The method of any of clauses 1 to 16, wherein n is 0 and R6 is -R7, wherein R7 is 2,2,6,6-tetramethylpiperidin-N-oxyl.

[0024] 18. The method of any of clauses 1 to 17, wherein Y is -CH-.

[0025] 19. The method of any of clauses 1 to 18, wherein R4 and R5 are each independently H.

[0026] 20. The method of any of clauses 1 to 19, wherein the compound has the structure:5 6C1902. DOCXAttorney Docket No. 06527-2502274666C1902. DOCXAttorney Docket No. 06527-2502274

[0027] 21 . The method of any of clauses 1 to 20, wherein the compound has the structure:

[0028] 22. The method of any of clauses 1 to 21 , wherein the compound has the structure:7 6C1902. DOCXAttorney Docket No. 06527-2502274

[0029] 23. The method of any of clauses 1 to 22, wherein the compound has the structure:

[0030] 24. The method of any of clauses 1 to 23, wherein the composition further comprises a pharmaceutically-acceptable excipient.

[0031] 25. The method of any of clauses 1 to 24, wherein the composition is administered in a dose of about 1 milligram per kilogram (mg / kg) to about 500 mg / kg of body weight of the patient.

[0032] 26. The method of any of clauses 1 to 25, wherein the composition is administered in a dose of about 10 mg / kg to 200 mg / kg of body weight of the patient.

[0033] 27. The method of any of clauses 1 to 26, wherein the composition is administered over a period of one year or less.

[0034] 28. The method of any of clauses 1 to 27, wherein the composition is administered at least three times per week.

[0035] 29. The method of any of clauses 1 to 28, wherein the composition is administered in a single dose.

[0036] 30. The method of any of clauses 1 to 29, wherein the composition is administered orally, transdermally, topically, through an injection, or combinations thereof.

[0037] 31. The method of any of clauses 1 to 30, wherein the composition is administered through a subcutaneous injection.

[0038] 32. The method of any of clauses 1 to 31 , wherein the composition is administered through an intravenous injection.

[0039] 33. The method of any of clauses 1 to 32, wherein the condition is coronary heart disease.8 6C1902. DOCXAttorney Docket No. 06527-2502274

[0040] 34. The method of any one of clauses 1 to 33, wherein the condition is ischemia / reperfusion (IR) injury.

[0041] 35. The method of any of clauses 1 to 34, wherein the condition is ischemiareperfusion injury following a myocardial infarction.

[0042] 36. The method of any of clauses 1 to 35, wherein the compound is administered once following the myocardial infarction.

[0043] 37. The method of any clauses 1 to 36, wherein the compound is administered prophylactically for up to three times per week, for up to 12 months.BRIEF DESCRIPTION OF THE DRAWINGS

[0044] FIGS. 1A-1 F show structures of various compounds, including compounds falling within the scope of the present disclosure in non-limiting embodiments and the known compounds XJB-5-131 , JP4-039, and ferrostatin-1 .

[0045] FIG. 2 shows the effects of various compounds from FIG. 1 on untreated cells.

[0046] FIGS. 3A-3B show the effects of various compounds from FIG. 1 on TBH- induced cell death.

[0047] FIGS. 4A-4B show the effects of various compounds from FIG. 1 on RSL#- induced cell death (ferroptosis).

[0048] FIGS. 5A-5B shows the effects of various compounds from FIG. 1 on HR- induced cell death.

[0049] FIGS. 6A-6B shows comparative analysis of the antioxidant efficacy of mitochondria-targeting compounds and general antioxidants against oxidative stress- induced cell death in cardiomyocytes. Oxidative stress was induced by TBH (100 pM, an oxidant, A) and in vitro IR (B). To induce IR, the cells were incubated in a controlled Hypoxia Chamber (BioSpherix, Lacona, NY) containing 95% N2 and 5% CO2 at 37 OC for 24 h in glucose- and serum-free culture media (ischemia) followed by incubation in normal culture media in a CO2 incubator (5% CO2 and 95% O2) at 37 0°C for 24 h. All compounds were added before TBH or IR. Mitochondria-targeted compounds: B, D, J, and X, general antioxidants: vitamin C (sodium ascorbate) and N-acetylcysteine (NAC).

[0050] FIG. 7 shows ED50 values (pM) of compounds for oxidative stress induced by TBH, RSL3, and HR.966C1902. DOCXAttorney Docket No. 06527-2502274

[0051] FIG. 8 shows an experimental design for determining the effect of various compounds on ischemia-reperfusion injury.

[0052] FIG. 9 shows the effects of compounds B, D, and J on post-ischemic recovery of cardiac function (A, B) and cell death (C, D) in rat hearts. Functional parameters, including LV systolic pressure (LVSP), end-diastolic pressure (LVEDP), heart rate, the rate of contraction and relaxation (± dP / dt), and aortic pressure were continuously monitored using the Labscribe2 Data Acquisition Software (iWorx 308T, Dover, NH). LV developed pressure (LVDP, A) was calculated as the difference between LVSP and LVEDP (LVDP = LVSP - LVEDP) and presented as a percentage of pre-ischemic values. The rate pressure product (RPP, B) was calculated as the product of LVDP and HR (RPP = LVDP x HR) to estimate cardiac work. LDH activity (C, D) was determined in the coronary effluent at reperfusion as a cell death marker and presented in folds of baseline (C) and AUC (area under curve, D) to estimate cardiac damage. The hearts were perfused with compounds B (0.2 pM), D (5.0 pM), and J (0.2 pM) for 10 min prior to ischemia and throughout the entire reperfusion period. Concentrations of the compounds were established in dose-dependent experiments. N=5-6 per group. *p<0.05; **p<0.01 vs. IR.

[0053] FIG. 10 shows the effects of compounds B, D, and J on mtROS (A) and state 3 respiration rates (B) in rat hearts subjected to ex-vivo IR. The mtROS production rate was measured using Ampliflu™ Red (MilliporeSigma) with a CLARIOstar microplate reader (BMG Labtech). Mitochondrial respiration rate was measured using an Oxygraph (YSI) Model 5300 equipped with a Clark-type oxygen electrode, and respiration charts were recorded and analyzed using Chart5 (PowerLab). The substrates used were 2-oxoglutarate and L-malate and ADP-stimulated respiration (state 3) was measured. N=5-6 per group. *p<0.01 vs. IR.

[0054] FIG. 11 shows that compounds B, D, and J reduced LDH activity at reperfusion.

[0055] FIG. 12 shows that compounds B, D, and J had no effects on mitochondrial respiration but significantly reduced mitochondrial ROS production during cardiac IR.DESCRIPTION OF THE INVENTION

[0056] The use of numerical values in the various ranges specified in this application, unless expressly indicated otherwise, are stated as approximations and the minimum and maximum values within the stated ranges are both preceded by the1066C1902. DOCXAttorney Docket No. 06527-2502274 word "about". In this manner, slight variations above and below the stated ranges can be used to achieve substantially the same results as values within the ranges. Also, unless indicated otherwise, the disclosure of these ranges is intended as a continuous range including every value between the minimum and maximum values. For definitions provided herein, those definitions also refer to word forms, cognates and grammatical variants of those words or phrases.

[0057] As used herein, the terms “comprising,” “comprise” or “comprised,” and variations thereof, in reference to elements of an item, composition, apparatus, method, process, system, claim, etc. are intended to be open-ended, meaning that the item, composition, apparatus, method, process, system, claim, etc. includes those elements and other elements can be included and still fall within the scope / definition of the described item, composition, apparatus, method, process, system, claim, etc. As used herein, "a" or "an" means one or more. As used herein "another" may mean at least a second or more.

[0058] As used herein, the terms "patient" or "subject" refer to members of the animal kingdom, including, but not limited to human beings.

[0059] As used herein, "alkyl" refers to straight, branched chain, or cyclic hydrocarbon groups including, for example, from 1 to about 20 carbon atoms, for example and without limitation C1-3, C1-4, C1-6, C1-10, and C3-8 groups, for example and without limitation, straight, branched chain alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, and the like. An alkyl group can be, for example, a Ci, C2, C3, C4, C5, Ce, C7, Cs, C9, C10, C11 , C12, C13, C14, C15, C16, C17, Cis, C19, C20, C21 , C22, C23, C24, C25, C26, C27, C28, C29, C30, C31 , C32, C33, C34, C35, C36, C37, C38, C39, C40, C41 , C42, C43, C44, C45, C46, C47, C48, C49, or C50 group that is substituted or unsubstituted. Non-limiting examples of straight alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl. Branched alkyl groups comprise any straight alkyl group substituted with any number of alkyl groups. Non-limiting examples of branched alkyl groups include isopropyl, isobutyl, sec-butyl, t-butyl, and 2-methylpropyl. Non-limiting examples of cyclic alkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. Cyclic alkyl groups also comprise fused-, bridged-, and spirobicycles and higher fused-, bridged-, and spiro-systems. A cyclic alkyl group can be substituted with any number of straight, branched, or cyclic alkyl groups. "Substituted alkyl" can include alkyl substituted at 1 or more (e.g., 1 , 2, 3, 4, 5, or even 6) positions,1 166C1902. DOCXAttorney Docket No. 06527-2502274 which substituents are attached at any available atom to produce a stable compound, with substitution as described herein. "Optionally substituted alkyl" refers to alkyl or substituted alkyl. "Alkylene" and "substituted alkylene" can include divalent alkyl and divalent substituted alkyl, respectively, including, without limitation, methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, hepamethylene, octamethylene, nonamethylene, or decamethylene. "Optionally substituted alkylene" can include alkylene or substituted alkylene.

[0060] "Alkene or alkenyl" can include straight, branched chain, or cyclic hydrocarbyl groups including, e.g., from 2 to about 20 carbon atoms, such as, without limitation C2-3, C2-6, C2-10 groups having one or more, e.g., 1 , 2, 3, 4, or 5, carbon-to- carbon double bonds. The olefin or olefins of an alkenyl group can be, for example, E, Z, cis, trans, terminal, or exo-methylene. An alkenyl or alkenylene group can be, for example, a C2, C3, C4, C5, Ce, C7, Cs, C9, C10, C11 , C12, C13, C14, C15, C16, C17, Cis, C19, C20, C21 , C22, C23, C24, C25, C26, C27, C28, C29, C30, C31 , C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, C47, C48, C49, or C50 group that is substituted or unsubstituted. A halo-alkenyl group can be any alkenyl group substituted with any number of halogen atoms. "Substituted alkene" can include alkene substituted at 1 or more, e.g., 1 , 2, 3, 4, or 5 positions, which substituents are attached at any available atom to produce a stable compound, with substitution as described herein. "Optionally substituted alkene" can include alkene or substituted alkene. Likewise, "alkenylene" can refer to divalent alkene. Examples of alkenylene include without limitation, ethylene (-CH=CH-) and all stereoisomeric and conformational isomeric forms thereof. "Substituted alkenylene" can refer to divalent substituted alkene. "Optionally substituted alkenylene" can refer to alkenylene or substituted alkenylene.

[0061] “Aryl," alone or in combination refers to an aromatic ring system such as phenyl or naphthyl. "Aryl" also can include aromatic ring systems that are optionally fused with a cycloalkyl ring. A "substituted aryl" is an aryl that is independently substituted with one or more substituents attached at any available atom to produce a stable compound, wherein the substituents are as described herein. The substituents can be, for example, hydrocarbyl groups, alkyl groups, alkoxy groups, and halogen atoms. "Optionally substituted aryl" refers to aryl or substituted aryl. An aryloxy group can be, for example, an oxygen atom substituted with any aryl group, such as phenoxy. An arylalkoxy group can be, for example, an oxygen atom substituted with any aralkyl group, such as benzyloxy. "Arylene" denotes divalent aryl, and "substituted arylene"1266C1902. DOCXAttorney Docket No. 06527-2502274 refers to divalent substituted aryl. "Optionally substituted arylene" refers to arylene or substituted arylene. A “polycyclic aryl group” and related terms, such as “polycyclic aromatic group” refers to a group composed of at least two fused aromatic rings. “Heteroaryl” or “hetero-substituted aryl” refers to an aryl group substituted with one or more heteroatoms, such as N, O, P, and / or S.

[0062] “Heteroatom" refers to any atom other than carbon or hydrogen, for example, N, O, P, and S. Compounds that contain N or S atoms can be optionally oxidized to the corresponding N-oxide, sulfoxide or sulfone compounds. “Heterosubstituted” refers to an organic compound in any embodiment described herein in which one or more carbon atoms are substituted with any atom other than carbon or hydrogen, for example, N, O, P, or S. Where a cycloalkyl group is substituted with an O, forming one or more ether groups (-C-O-C) within the ring, the group can be referred to as “cycloether,” for example furanyl and tetrahydrofuranyl groups are C4 cycloethers.

[0063] "Substituted" or "substitution" refer to replacement of a hydrogen atom of a molecule with one or more atoms or groups (substituents), such as halogen, alkyl, alkoxy, alkylthio, trifluoromethyl, acyloxy, hydroxy, mercapto, carboxy, aryloxy, aryl, arylalkyl, heteroaryl, amino, alkylamino, dialkylamino, morpholino, piperidino, pyrrolidin-1 -yl, piperazin-1 -yl, nitro, sulfato, or other groups. "Halogen," "halide," and "halo" refers to -F, -Cl, -Br, and / or -I, and “halo-substituted”, refers to substitution of one or more atom or group, such as a hydrogen, with a halide. In aspects or embodiments, substituents may be, independently, and without limitation: Cl, F, or (Ci-C6)alkyl, (Ci-C6)alkoxyl, (Ci-C4)alkyl, (C3-C8)cycloalkyl, or (C2-C7)cycloether optionally substituted with a monovalent or divalent benzyl group (-CeH4- or -CeHs) that is optionally substituted with 1 , 2, or 3 F or Cl atoms.

[0064] Provided herein are compounds and related methods useful for treating conditions related oxidative stress, including at least in cardiac tissue, for example in coronary disease, myocardial infarctions, ischemia / reperfusion injury, lipid peroxidation of cardiac tissue, and / or combinations thereof. In non-limiting embodiments the method may be useful for improving post-infarction recovery of the heart through free radical scavenging, with particular selectivity for mitochondria. The compounds may include a nitroxide-containing group attached to a mitochondria- targeting group that allows the compounds to accumulate in mitochondria. Also, provided are the methods for delivering a compound, amount, and dosage regimen1366C1902. DOCXAttorney Docket No. 06527-2502274 effective to prevent, mitigate or treat cardiac IR injury on cell / animal models in vitro and in vivo.

[0065] In non-limiting embodiments, the compound may be a compound having the structure:J wherein,R is H or an acyl group, such as -C(O)XRi, where R1 is (O-Cejalkyl (e.g., isobutyl or 2-methylpropyl) or (Cs-Csjcycloalkyl, optionally-substituted with phenyl, substituted phenyl, heteroaryl, or substituted heteroaryl, and X is -NH, -O-, or is not present;R2 is (C-i-Cejalkyl (e.g., isobutyl or 2-methylpropyl) or cycloalkyl, optionally-substituted with phenyl, substituted phenyl, heteroaryl, or substituted heteroaryl or phenyl, optionally substituted with, independently, 1 , 2, or 3 Cl or F atoms;R3 is (Ci-Cejalkyl, such as methyl, ethyl, or propyl, optionally-substituted with phenyl, substituted phenyl, heteroaryl, or substituted heteroaryl;R4 and R5 are, independently, H, (Ci-Cejalkyl or (Cs-Csjcycloalkyl, optionally substituted with a monovalent or divalent benzyl group (-CeF - or -CeHs) that is optionally substituted with 1 , 2, or 3 F or Cl atoms, or R4 and R5 together form a cycloalkyl ring or a heterocycloalkyl ring comprising one O, S, or N atom, such as a cycloalkyl ring of 3, 4, 5, 6, 7, or 8 carbons, or a tetrahydropyran ring;Re is optionally substituted -NH-R7, -OR7, or -R7, wherein R7 is a nitroxide-containing group; and the double bond is cis or trans configured, or a pharmaceutically-acceptable salt thereof, including stereoisomers thereof and mixtures of stereoisomers thereof.

[0066] In non-limiting embodiments, the compound may be a compound having the structure:1466C1902. DOCXAttorney Docket No. 06527-2502274wherein:R is H or -C(O)-X-Ri, wherein Ri is a branched or unbranched Ci-Ce alkyl or a C3-C8 cycloalkyl, wherein the Ci-Ce alkyl or the C3-C8 cycloalkyl is optionally substituted with a phenyl, a substituted phenyl, a heteroaryl, or a substituted heteroaryl, and X is -NH, -O-, or is not present;R2 is a branched or unbranched Ci-Ce alkyl or a C3-C8 cycloalkyl, wherein the Ci-Ce alkyl or the C3-C8 cycloalkyl is optionally substituted with a phenyl, a substituted phenyl, a heteroaryl, or a substituted heteroaryl, or a phenyl, wherein the phenyl is optionally substituted with, independently, 1 , 2, or 3 Cl or F atoms;R3 is H or a C1-C4 alkyl, wherein the C1-C4 alkyl is optionally substituted with a phenyl, a substituted phenyl, a heteroaryl, or a substituted heteroaryl;R4 and R5 are, independently, H, a Ci-Ce alkyl, or a C3-C8 cycloalkyl, wherein the Ci-Ce alky or the C3-C8 cycloalkyl is optionally substituted with a monovalent or divalent benzyl group (-CeF - or -CeHs) that is optionally substituted with 1 , 2, or 3 halogen atoms (e.g., F atoms), or R4 and R5 together form a cycloalkyl ring or a heterocycloalkyl ring comprising one O, S, or N atom;Re is -C(O)-NH-R?, -NH-C(O)-R?, or -R7, wherein R7 is a nitroxide- containing group;Y is -CH2-, -NH-, or a bond; n is 0 to 6; and the double bond is cis or trans configured, or a pharmaceutically-acceptable salt thereof, including stereoisomers thereof and mixtures of stereoisomers thereof. In non-limiting embodiments, the bond is trans configured. In non-limiting embodiments, the compound may be combined with a pharmaceutically-acceptable carrier and / or excipient, for example for administration to a patient to treat and / or prevent a condition as described herein.In non-limiting embodiments, the compound has the following structure:1566C1902. DOCXAttorney Docket No. 06527-2502274

[0067] In non-limiting embodiments, the compound has the following structure:In non-limiting embodiments, R7 is(2,2,6,6-tetramethylpiperidin-N oxyl); or-tetramethylpyrrolidin-N-oxyl).

[0068] In non-limiting embodiments, R is a blocking group and / or a protecting group. In non-limiting embodiments, R is R is 9-fluorenylmethyloxy carbonyl (Fmoc), t-butyloxycarbonyl (Boc), benzhydryloxycarbonyl (Bhoc), benzyloxycarbonyl (Cbz), O- nitroveratryloxycarbonyl (Nvoc), benzyl (Bn), allyloxycarbonyl (alloc), trityl (Trt), l-(4,4- dimethyl-2,6-dioxacyclohexylidene)ethyl (Dde), diathiasuccinoyl (Dts), benzothiazole- 2-sulfonyl (Bts), dimethoxytrityl (DMT), or monomethoxytrityl (MMT).

[0069] In non-limiting embodiments, R2 is 2-methylpropyl.

[0070] In non-limiting embodiments, R3 is H.

[0071] In non-limiting embodiments, R4 and R5 are each independently a Ci-Ce alkyl substituted with a benzyl group that is substituted with 1 , 2, or 3 halogen atoms, such as 1 , 2, or 3 F or Cl atoms.

[0072] In non-limiting embodiments, R4 and R5 are each independently a C2 alkyl substituted with a benzyl group that is substituted with 1 fluorine atom.1666C1902. DOCXAttorney Docket No. 06527-2502274

[0073] In non-limiting embodiments, FU and R5 are each independently 1 -ethyl-4- fluorobenzene.

[0074] In non-limiting embodiments, Re is -C(O)-NH-R? or -NH-C(O)-R?.

[0075] In non-limiting embodiments, n is 1 -4.

[0076] In non-limiting embodiments, n is 2 and Re is -C(O)-NH-R? or -NH-C(O)-R?.

[0077] In non-limiting embodiments, Y is -NH-.

[0078] In non-limiting embodiments, n is 0 and Re is -R7, and R7 is:

[0079] In non-limiting embodiments, Y is -CH-.

[0080] In non-limiting embodiments, R4 and R5 are each independently H.

[0081] In non-limiting embodiments, the compound has the structure:1766C1902. DOCXAttorney Docket No. 06527-25022741866C1902. DOCXAttorney Docket No. 06527-2502274

[0082] In non-limiting embodiments, the compound has the structure:

[0083] In non-limiting embodiments, the compound has the structure:1966C1902. DOCXAttorney Docket No. 06527-2502274

[0084] In non-limiting embodiments, the compound has the structure:

[0085] For therapeutic use, salts of the compounds are those wherein the counterion is pharmaceutically acceptable. However, salts of acids and bases which are non- pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.

[0086] The pharmaceutically acceptable acid and base addition salts as mentioned herein are meant to comprise the therapeutically active non-toxic acid and base addition salt forms which the compounds are able to form. The pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the base form with such appropriate acid. Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic (i.e. hydroxybutanedioic acid), tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic,2066C1902. DOCXAttorney Docket No. 06527-2502274 salicylic, p-aminosalicylic, pamoic and the like acids. Conversely the salt forms can be converted by treatment with an appropriate base into the free base form.

[0087] The compounds containing an acidic proton may also be converted into their non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases. Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like. The term "addition salt" as used hereinabove also comprises the solvates which the compounds described herein are able to form. Such solvates are for example hydrates, alcoholates and the like.

[0088] The term "quaternary amine" as used hereinbefore defines the quaternary ammonium salts which the compounds are able to form by reaction between a basic nitrogen of a compound and an appropriate quaternizing agent, such as, for example, an optionally substituted alkylhalide, arylhalide or arylalkylhalide, e.g. methyliodide or benzyliodide. Other reactants with good leaving groups may also be used, such as alkyl trifluoromethanesulfonates, alkyl methanesulfonates, and alkyl p-toluenesulfonates. A quaternary amine has a positively charged nitrogen.

[0089] Pharmaceutically acceptable counterions include chloro, bromo, iodo, trifluoroacetate, and acetate. The counterion of choice can be introduced using ion exchange resins.

[0090] As used herein, unless indicated otherwise, for instance in a structure, all compounds and / or structures described herein comprise all possible stereoisomers, individually or mixtures thereof. The compound and / or structure may be an enantiopure preparation consisting essentially of an (-) or (+) enantiomer of the compound, or may be a mixture of enantiomers in either equal (racemic) or unequal proportions.

[0091] Protected derivatives of the disclosed compounds also are contemplated. Many suitable protecting groups for use with the disclosed compounds are broadly- known in the art. In general, protecting groups are removed under conditions which will not affect the remaining portion of the molecule. These methods are well known in the art and include acid hydrolysis, hydrogenolysis and the like. One method involves the removal of an ester, such as cleavage of a phosphonate ester using Lewis acidic conditions, such as in TMS-Br mediated ester cleavage to yield the free phosphonate.2166C1902. DOCXAttorney Docket No. 06527-2502274A second method involves removal of a protecting group, such as removal of a benzyl group by hydrogenolysis utilizing palladium on carbon in a suitable solvent system such as an alcohol, acetic acid, and the like or mixtures thereof. A t-butoxy-based group, including t-butoxy carbonyl protecting groups can be removed utilizing an inorganic or organic acid, such as HCI or trifluoroacetic acid, in a suitable solvent system, such as water, dioxane and / or methylene chloride. Another exemplary protecting group, suitable for protecting amino and hydroxy functions amino is trityl. Other conventional protecting groups are known and suitable protecting groups can be selected by those of skill in the art in consultation with any of the large number of broadly-available publications. When an amine is deprotected, the resulting salt can readily be neutralized to yield the free amine. Similarly, when an acid moiety, such as a phosphonic acid moiety is unveiled, the compound may be isolated as the acid compound or as a salt thereof.

[0092] According to one aspect, amine side chains are protected using protective groups, for example and without limitation by acylation (See, e.g., U.S. Patent Nos. 7,528,174; 7,718,603; and 9,006,186, and International Patent Publication Nos. WO 2010 / 009405 and WO 2012 / 1 12851 , incorporated herein by reference in their entirety). Protecting groups are known in the art and include, without limitation: 9-fluorenylmethyloxy carbonyl (Fmoc), t-butyloxycarbonyl (Boc), benzhydryloxycarbonyl (Bhoc), benzyloxycarbonyl (Cbz), O-nitroveratryloxycarbonyl (Nvoc), benzyl (Bn), allyloxycarbonyl (alloc), trityl (Trt), l-(4,4-dimethyl-2,6- dioxacyclohexylidene)ethyl (Dde), diathiasuccinoyl (Dts), benzothiazole-2-sulfonyl (Bts), dimethoxytrityl (DMT) and monomethoxytrityl (MMT) groups. A protecting group also includes acyl groups, such as acetyl groups, for example, as described. Nonlimiting examples of acyl groups include: -C(O)XRi, where Ri is (Ci-C6)alkyl (e.g., isobutyl or 2-methylpropyl) or (C3-C8)cycloalkyl, optionally-substituted with phenyl, substituted phenyl, heteroaryl, or substituted heteroaryl, and X is -NH, -O-, or is not present.

[0093] A composition comprising any of the above-described compounds also is provided. The composition is a pharmaceutical composition comprising the compound as described above, in a therapeutically-effective amount, and a pharmaceutically- acceptable excipient. As such, a drug product, dosage form, or unit dosage form comprising the pharmaceutical composition also is provided.2266C1902. DOCXAttorney Docket No. 06527-2502274

[0094] The compounds may be compounded or otherwise manufactured into a suitable composition for use, such as a pharmaceutical dosage form or drug product in which the compound is an active ingredient. Compositions may comprise a pharmaceutically acceptable carrier, or excipient. An excipient is an inactive substance used as a carrier for the active ingredients of a medication. Although “inactive,” excipients may facilitate and aid in increasing the delivery or bioavailability of an active ingredient in a drug product. Non-limiting examples of useful excipients include: antiadherents, binders, rheology modifiers, coatings, disintegrants, emulsifiers, oils, buffers, salts, acids, bases, fillers, diluents, solvents, flavors, colorants, glidants, lubricants, preservatives, antioxidants, sorbents, vitamins, sweeteners, etc., as are available in the pharmaceutical / compounding arts.

[0095] Useful dosage forms may include, without limitation, intravenous, intramuscular, or intraperitoneal solutions, oral tablets or liquids, topical ointments or creams and transdermal devices (e.g., patches). In one embodiment, the compound is a sterile solution comprising the active ingredient (drug, or compound), and a solvent, such as water, saline, lactated Ringer’s solution, or phosphate-buffered saline (PBS). Additional excipients, such as polyethylene glycol, emulsifiers, salts and buffers may be included in the solution.

[0096] Also provided herein are methods of treating or preventing conditions relating to or caused by reactive oxygen species. In non-limiting embodiments, the methods treat and / or prevent coronary heart disease and / or ischemia-reperfusion injury following, for example, myocardial infarction or stroke. In non-limiting embodiments, the methods include administering, to a patient in need thereof, an amount of a composition comprising a compound described herein effective to reduce levels of reactive oxygen species, prevent formation of reactive oxygen species, and / or treat coronary heart disease and / or ischemia-reperfusion injury, for example ischemia-reperfusion injury associated with myocardial infarction or stroke. In nonlimiting embodiments the condition is lipid peroxidation of cardiac tissue. In nonlimiting embodiments the condition is a neuroinflammatory disease.

[0097] In some embodiments, a composition, pharmaceutically acceptable salt thereof, or pharmaceutical formulation comprising a composition or salt thereof described herein can be administered at a dose of from about 1 milligram (mg) to about 1000 mg, from about 5 mg to about 1000 mg, from about 10 mg to about 1000 mg, from about 15 mg to about 1000 mg, from about 20 mg to about 1000 mg, from about2366C1902. DOCXAttorney Docket No. 06527-250227425 mg to about 1000 mg, from about 30 mg to about 1000 mg, from about 35 mg to about 1000 mg, from about 40 mg to about 1000 mg, from about 45 mg to about 1000 mg, from about 50 mg to about 1000 mg, from about 55 mg to about 1000 mg, from about 60 mg to about 1000 mg, from about 65 mg to about 1000 mg, from about 70 mg to about 1000 mg, from about 75 mg to about 1000 mg, from about 80 mg to about 1000 mg, from about 85 mg to about 1000 mg, from about 90 mg to about 1000 mg, from about 95 mg to about 1000 mg, from about 100 mg to about 1000 mg, from about 150 mg to about 1000 mg, from about 200 mg to about 1000 mg, from about 250 mg to about 1000 mg, from about 300 mg to about 1000 mg, from about 350 mg to about 1000 mg, from about 400 mg to about 1000 mg, from about 450 mg to about 1000 mg, from about 500 mg to about 1000 mg, from about 550 mg to about 1000 mg, from about 600 mg to about 1000 mg, from about 650 mg to about 1000 mg, from about 700 mg to about 1000 mg, from about 750 mg to about 1000 mg, from about 800 mg to about 1000 mg, from about 850 mg to about 1000 mg, from about 900 mg to about 1000 mg, or from about 950 mg to about 1000 mg. In some embodiments, a composition, pharmaceutically acceptable salt thereof, or pharmaceutical formulation comprising a composition or salt thereof described herein can be administered at a dose of about 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22,23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45,46, 47, 48, 49, 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68,69, 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 ,92, 93, 94, 95, 96, 97, 98, 99, 100, 101 , 102, 103, 104, 105, 106, 107, 108, 109, 1 10, 1 1 1 , 112, 1 13, 1 14, 1 15, 1 16, 1 17, 1 18, 1 19, 120, 121 , 122, 123, 124, 125, 126, 127,128, 129, 130, 131 , 132, 133, 134, 135, 136, 137, 138, 139, 140, 141 , 142, 143, 144,145, 146, 147, 148, 149, 150, 151 , 152, 153, 154, 155, 156, 157, 158, 159, 160, 161 ,162, 163, 164, 165, 166, 167, 168, 169, 170, 171 , 172, 173, 174, 175, 176, 177, 178,179 180, 181 , 182, 183, 184, 184, 186, 187, 188, 189, 190, 191 , 192, 193, 194, 195,196, 197, 198, 199, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320,330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490,500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660,670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830,840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, or 1000 mg.2466C1902. DOCXAttorney Docket No. 06527-2502274

[0098] In some embodiments, pharmaceutical formulation comprising a composition or pharmaceutically acceptable salt is present at a concentration from at least about 0.01 micrograms per milliliter (pg / mL) to at least about 100 milligrams per milliliter (mg / mL). In some embodiments, the composition or pharmaceutically acceptable salt is present at a concentration from at least about at least about 0.1 mg / mL to at least about 5 mg / mL. In some embodiments, the composition or pharmaceutically acceptable salt is present at a concentration from at least about at least about 0.5 mg / mL to at least about 1 mg / mL. In some embodiments, the composition or pharmaceutically acceptable salt is present at a concentration about 1 mg / mL. In some embodiments, the composition or pharmaceutically acceptable salt is present at a concentration about 2 mg / mL. In some embodiments, the composition or pharmaceutically acceptable salt is present at a concentration about 3 mg / mL. In some embodiments, the composition or pharmaceutically acceptable salt is present at a concentration about 4 mg / mL. In some embodiments, the composition or pharmaceutically acceptable salt is present at a concentration about 5 mg / mL. In some embodiments, the composition or pharmaceutically acceptable salt is present at a concentration about 6 mg / mL. In some embodiments, the composition or pharmaceutically acceptable salt is present at a concentration about 7 mg / mL. In some embodiments, the composition or pharmaceutically acceptable salt is present at a concentration about 8 mg / mL. In some embodiments, the composition or pharmaceutically acceptable salt is present at a concentration about 9 mg / mL. In some embodiments, the composition or pharmaceutically acceptable salt is present at a concentration about 10 mg / mL. In some embodiments, the composition or pharmaceutically acceptable salt is present at a concentration about 20 mg / mL. In some embodiments, the composition or pharmaceutically acceptable salt is present at a concentration about 30 mg / mL. In some embodiments, the composition or pharmaceutically acceptable salt is present at a concentration about 40 mg / mL. In some embodiments, the composition or pharmaceutically acceptable salt is present at a concentration about 50 mg / mL. In some embodiments, the composition or pharmaceutically acceptable salt is present at a concentration about 60 mg / mL. In some embodiments, the composition or pharmaceutically acceptable salt is present at a concentration about 70 mg / mL. In some embodiments, the composition or pharmaceutically acceptable salt is present at a concentration about 80 mg / mL. In2566C1902. DOCXAttorney Docket No. 06527-2502274 some embodiments, the composition or pharmaceutically acceptable salt is present at a concentration about 90 mg / mL

[0099] In some embodiments, the composition or pharmaceutically acceptable salt is present at a concentration about 100 mg / mL. In some embodiments, pharmaceutical formulation comprising a composition or pharmaceutically acceptable salt can exhibit activity at a concentration from at least about 0.01 pg / mL to at least about 0.02 pg / mL, from at least about 0.02 pg / mL to at least about 0.03 pg / mL, from at least about 0.03 pg / mL to at least about 0.04 pg / mL, from at least about 0.04 pg / mL to at least about 0.05 pg / mL, from at least about 0.05 pg / mL to at least about 0.06 pg / mL, from at least about 0.06 pg / mL to at least about 0.07 pg / mL, from at least about 0.07 pg / mL to at least about 0.08 pg / mL, from at least about 0.08 pg / mL to at least about 0.09 pg / mL, from at least about 0.09 pg / mL to at least about 0.1 pg / mL, from at least about 0.1 pg / mL to at least about 0.2 pg / mL, from at least about 0.2 pg / mL to at least about 0.3 pg / mL, from at least about 0.3 pg / mL to at least about 0.4 pg / mL, from at least about 0.4 pg / mL to at least about 0.5 pg / mL, from at least about 0.5 pg / mL to at least about 0.6 pg / mL, from at least about 0.6 pg / mL to at least about 0.7 pg / mL, from at least about 0.7 pg / mL to at least about 0.8 pg / mL, from at least about 0.8 pg / mL to at least about 0.9 pg / mL, from at least about 0.9 pg / mL to at least about 1 pg / mL, from at least about 1 pg / mL to at least about 2 pg / mL, from at least about 2 pg / mL to at least about 3 pg / mL, from at least about 3 pg / mL to at least about 4 pg / mL, from at least about 4 pg / mL to at least about 5 pg / mL, from at least about 5 pg / mL to at least about 6 pg / mL, from at least about 6 pg / mL to at least about 7 pg / mL, from at least about 7 pg / mL to at least about 8 pg / mL, from at least about 8 pg / mL to at least about 9 pg / mL, from at least about 9 pg / mL to at least about 10 pg / mL, from at least about 10 pg / mL to at least about 20 pg / mL, from at least about 20 pg / mL to at least about 30 pg / mL, from at least about 30 pg / mL to at least about 40 pg / mL, from at least about 40 pg / mL to at least about 50 pg / mL, from at least about 50 pg / mL to at least about 60 pg / mL, from at least about 60 pg / mL to at least about 70 pg / mL, from at least about 70 pg / mL to at least about 80 pg / mL, from at least about 80 pg / mL to at least about 90 pg / mL, from at least about 90 pg / mL to at least about 0.1 mg / mL, from at least about 0.1 mg / mL to at least about 0.2 mg / mL, from at least about 0.2 mg / mL to at least about 0.3 mg / mL, from at least about 0.3 mg / mL to at least about 0.4 mg / mL, from at least about 0.4 mg / mL to at least about 0.5 mg / mL, from at least about 0.5 mg / mL to at least about 0.6 mg / mL, from at least about 0.6 mg / mL to at least about 0.7 mg / mL, from at least2666C1902. DOCXAttorney Docket No. 06527-2502274 about 0.7 mg / mL to at least about 0.8 mg / mL, from at least about 0.8 mg / mL to at least about 0.9 mg / mL, from at least about 0.9 mg / mL to at least about 1 mg / mL, from at least about 1 mg / mL to at least about 2 mg / mL, from at least about 2 mg / mL to at least about 3 mg / mL, from at least about 3 mg / mL to at least about 4 mg / mL, from at least about 4 mg / mL to at least about 5 mg / mL, from at least about 5 mg / mL to at least about 6 mg / mL, from at least about 6 mg / mL to at least about 7 mg / mL, from at least about 7 mg / mL to at least about 8 mg / mL, from at least about 8 mg / mL to at least about 9 mg / mL, from at least about 9 mg / mL to at least about 10 mg / mL, from at least about 10 mg / mL to at least about 20 mg / mL, from at least about 20 mg / mL to at least about 30 mg / mL, from at least about 30 mg / mL to at least about 40 mg / mL, from at least about 40 mg / mL to at least about 50 mg / mL, from at least about 50 mg / mL to at least about 60 mg / mL, from at least about 60 mg / mL to at least about 70 mg / mL, from at least about 70 mg / mL to at least about 80 mg / mL, from at least about 80 mg / mL to at least about 90 mg / mL, or from at least about 90 mg / mL to at least about 100 mg / mL.

[0100] In some embodiments, effective amounts of a composition or pharmaceutically acceptable salt can be a concentration from at least about 0.01 pg / mL to at least about 100 mg / mL. In some embodiments, effective amounts of a composition or pharmaceutically acceptable salt is at a concentration from at least about at least about 0.1 mg / mL to at least about 5 mg / mL. In some embodiments, effective amounts of a composition or pharmaceutically acceptable salt is at a concentration from at least about at least about 0.5 mg / mL to at least about 1 mg / mL.

[0101] In some embodiments, effective amounts of a composition or pharmaceutically acceptable salt is at a concentration about 1 mg / mL. In some embodiments, the effective amounts of a composition or pharmaceutically acceptable salt is at a concentration about 2 mg / mL. In some embodiments, the effective amounts of a composition or pharmaceutically acceptable salt is at a concentration about 3 mg / mL. In some embodiments, the effective amounts of a composition or pharmaceutically acceptable salt is at a concentration about 4 mg / mL. In some embodiments, the effective amounts of a composition or pharmaceutically acceptable salt is at a concentration about 5 mg / mL. In some embodiments, the effective amounts of a composition or pharmaceutically acceptable salt is at a concentration about 6 mg / mL. In some embodiments, the effective amounts of a composition or pharmaceutically acceptable salt is at a concentration about 7 mg / mL. In some embodiments, the effective amounts of a composition or pharmaceutically acceptable2766C1902. DOCXAttorney Docket No. 06527-2502274 salt is at a concentration about 8 mg / mL. In some embodiments, the effective amounts of a composition or pharmaceutically acceptable salt is at a concentration about 9 mg / mL. In some embodiments, the effective amounts of a composition or pharmaceutically acceptable salt is at a concentration about 10 mg / mL.

[0102] In some embodiments, effective amounts of a composition or pharmaceutically acceptable salt may be a concentration from at least about 0.01 pg / mL to at least about 0.02 pg / mL, from at least about 0.02 pg / mL to at least about 0.03 pg / mL, from at least about 0.03 pg / mL to at least about 0.04 pg / mL, from at least about 0.04 pg / mL to at least about 0.05 pg / mL, from at least about 0.05 pg / mL to at least about 0.06 pg / mL, from at least about 0.06 pg / mL to at least about 0.07 pg / mL, from at least about 0.07 pg / mL to at least about 0.08 pg / mL, from at least about 0.08 pg / mL to at least about 0.09 pg / mL, from at least about 0.09 pg / mL to at least about 0.1 pg / mL, from at least about 0.1 pg / mL to at least about 0.2 pg / mL, from at least about 0.2 pg / mL to at least about 0.3 pg / mL, from at least about 0.3 pg / mL to at least about 0.4 pg / mL, from at least about 0.4 pg / mL to at least about 0.5 pg / mL, from at least about 0.5 pg / mL to at least about 0.6 pg / mL, from at least about 0.6 pg / mL to at least about 0.7 pg / mL, from at least about 0.7 pg / mL to at least about 0.8 pg / mL, from at least about 0.8 pg / mL to at least about 0.9 pg / mL, from at least about 0.9 pg / mL to at least about 1 pg / mL, from at least about 1 pg / mL to at least about 2 pg / mL, from at least about 2 pg / mL to at least about 3 pg / mL, from at least about 3 pg / mL to at least about 4 pg / mL, from at least about 4 pg / mL to at least about 5 pg / mL, from at least about 5 pg / mL to at least about 6 pg / mL, from at least about 6 pg / mL to at least about 7 pg / mL, from at least about 7 pg / mL to at least about 8 pg / mL, from at least about 8 pg / mL to at least about 9 pg / mL, from at least about 9 pg / mL to at least about 10 pg / mL, from at least about 10 pg / mL to at least about 20 pg / mL, from at least about 20 pg / mL to at least about 30 pg / mL, from at least about 30 pg / mL to at least about 40 pg / mL, from at least about 40 pg / mL to at least about 50 pg / mL, from at least about 50 pg / mL to at least about 60 pg / mL, from at least about 60 pg / mL to at least about 70 pg / mL, from at least about 70 pg / mL to at least about 80 pg / mL, from at least about 80 pg / mL to at least about 90 pg / mL, from at least about 90 pg / mL to at least about 0.1 mg / mL, from at least about 0.1 mg / mL to at least about 0.2 mg / mL, from at least about 0.2 mg / mL to at least about 0.3 mg / mL, from at least about 0.3 mg / mL to at least about 0.4 mg / mL, from at least about 0.4 mg / mL to at least about 0.5 mg / mL, from at least about 0.5 mg / mL to at least about 0.6 mg / mL, from at least about 0.6 mg / mL to2866C1902. DOCXAttorney Docket No. 06527-2502274 at least about 0.7 mg / mL, from at least about 0.7 mg / mL to at least about 0.8 mg / mL, from at least about 0.8 mg / mL to at least about 0.9 mg / mL, from at least about 0.9 mg / mL to at least about 1 mg / mL, from at least about 1 mg / mL to at least about 2 mg / mL, from at least about 2 mg / mL to at least about 3 mg / mL, from at least about 3 mg / mL to at least about 4 mg / mL, from at least about 4 mg / mL to at least about 5 mg / mL, from at least about 5 mg / mL to at least about 6 mg / mL, from at least about 6 mg / mL to at least about 7 mg / mL, from at least about 7 mg / mL to at least about 8 mg / mL, from at least about 8 mg / mL to at least about 9 mg / mL, from at least about 9 mg / mL to at least about 10 mg / mL, from at least about 10 mg / mL to at least about 20 mg / mL, from at least about 20 mg / mL to at least about 30 mg / mL, from at least about 30 mg / mL to at least about 40 mg / mL, from at least about 40 mg / mL to at least about 50 mg / mL, from at least about 50 mg / mL to at least about 60 mg / mL, from at least about 60 mg / mL to at least about 70 mg / mL, from at least about 70 mg / mL to at least about 80 mg / mL, from at least about 80 mg / mL to at least about 90 mg / mL, or from at least about 90 mg / mL to at least about 100 mg / mL.

[0103] In some embodiments, effective amounts of a composition or pharmaceutically acceptable salt may be from at least about 1 microliter (pL) to at least about 2 pL, from at least about 2 pL to at least about 3 pL, from at least about 3 pL to at least about 4 pL, from at least about 4 pL to at least about 5 pL, from at least about 5 pL to at least about 6 pL, from at least about 6 pL to at least about 7 pL, from at least about 7 pL to at least about 8 pL, from at least about 8 pL to at least about 9 pL, from at least about 9 pL to at least about 10 pL, from at least about 10 pL to at least about 20 pL, from at least about 20 pL to at least about 30 pL, from at least about 30 pL to at least about 40 pL, from at least about 40 pL to at least about 50 pL, from at least about 50 pL to at least about 60 pL, from at least about 60 pL to at least about 70 pL, from at least about 70 pL to at least about 80 pL, from at least about 80 pL to at least about 90 pL, from at least about 90 pL to at least about 100 pL, from at least about 100 pL to at least about 200 pL, from at least about 200 pL to at least about 300 pL, from at least about 300 pL to at least about 400 pL, from at least about 400 pL to at least about 500 pL, from at least about 500 pL to at least about 600 pL, from at least about 600 pL to at least about 700 pL, from at least about 700 pL to at least about 800 pL, from at least about 800 pL to at least about 900 pL, from at least about 900 pL to at least about 1 milliliter (mL), from at least about 1 mL to at least about 2 mL, from at least about 2 mL to at least about 3 mL, from at least about 3 mL to at least about 42966C1902. DOCXAttorney Docket No. 06527-2502274 mL, from at least about 4 mL to at least about 5 mL, from at least about 5 mL to at least about 6 mL, from at least about 6 mL to at least about 7 mL, from at least about 7 mL to at least about 8 mL, from at least about 8 mL to at least about 9 mL, from at least about 9 mL to at least about 10 mL, from at least about 10 mL to at least about 20 mL, from at least about 20 mL to at least about 30 mL, from at least about 30 mL to at least about 40 mL, from at least about 40 mL to at least about 50 mL, from at least about 50 mL to at least about 60 mL, from at least about 60 mL to at least about 70 mL, from at least about 70 mL to at least about 80 mL, from at least about 80 mL to at least about 90 mL, from at least about 90 mL to at least about 100 mL, from at least about 100 mL to at least about 200 mL, from at least about 200 mL to at least about 300 mL, from at least about 300 mL to at least about 400 mL, from at least about 400 mL to at least about 500 mL, from at least about 500 mL to at least about 600 mL, from at least about 600 mL to at least about 700 mL, from at least about 700 mL to at least about 800 mL, from at least about 800 mL to at least about 900 mL, from at least about 900 mL to at least about 1 liter (L), from at least about 1 L to at least about 2 L, from at least about 2 L to at least about 3 L, from at least about 3 L to at least about 4 L, from at least about 4 L to at least about 5 L, from at least about 5 L to at least about 6 L, from at least about 6 L to at least about 7 L, from at least about 7 L to at least about 8 L, from at least about 8 L to at least about 9 L, from at least about 9 L to at least about 10 L, from at least about 10 L to at least about 20 L, from at least about 20 L to at least about 30 L, from at least about 30 L to at least about 40 L, from at least about 40 L to at least about 50 L, from at least about 50 L to at least about 60 L, from at least about 60 L to at least about 70 L, from at least about 70 L to at least about 80 L, from at least about 80 L to at least about 90 L, from at least about 90 L to at least about 100 L, from at least about 100 L to at least about 200 L, from at least about 200 L to at least about 300 L, from at least about 300 L to at least about 400 L, from at least about 400 L to at least about 500 L, from at least about 500 L to at least about 600 L, from at least about 600 L to at least about 700 L, from at least about 700 L to at least about 800 L, from at least about 800 L to at least about 900 L, from at least about 900 L to at least about 1 kiloliter (kL), from at least about 1 kL to at least about 2 kL, from at least about 2 kL to at least about 3 kL, from at least about 3 kL to at least about 4 kL, from at least about 4 kL to at least about 5 kL, from at least about 5 kL to at least about 6 kL, from at least about 6 kL to at least about 7 kL, from at least about3066C1902. DOCXAttorney Docket No. 06527-25022747 kL to at least about 8 kL, from at least about 8 kL to at least about 9 kL, or from at least about 9 kL to at least about 10 kL.

[0104] Those of skill in the art will appreciate that any dosing regimen (including frequency and dose) described herein includes all subranges and individua values between the disclosed ranges.

[0105] In non-limiting embodiments, the compound is administered at a dose of about 1 milligram per kilogram (mg / kg) of body weight to 500 mg / kg of body weight, all values and subranges therebetween inclusive. In non-limiting embodiments, the compound is administered at a dose of about 1 mg / kg to about 200 mg / kg, or 10 mg / kg of body weight to 200 mg / kg of body weight, all values and subranges therebetween inclusive.

[0106] In non-limiting embodiments, the compound is administered over a period of one year or less, all values and subranges therebetween inclusive. In non-limiting embodiments, the compound is administered at least three times per week. In nonlimiting embodiments, the compound is administered in a single dose.

[0107] Examples of delivery routes include, without limitation: topical, for example, epicutaneous, inhalational, enema, ocular, otic and intranasal delivery; enteral, for example, orally, by gastric feeding tube and rectally; and parenteral, such as, intravenous, intraarterial, intramuscular, intracardiac, subcutaneous, intraosseous, intradermal, intrathecal, intraperitoneal, transdermal, iontophoretic, transmucosal, epidural and intravitreal, with oral, intravenous, intramuscular and transdermal approaches being preferred in many instances.

[0108] In non-limiting embodiments, the compound is administered orally, topically, through an injection (e.g., subcutaneously, intradermally, and / or intramuscularly), or combinations thereof. In non-limiting embodiments, the compound Is administered intravenously.Example 1

[0109] Objective: Examine the efficacy of newly developed ROS scavengers on cell death induced by oxidative stress in vitro.

[0110] Major activities: The main goal of these studies was to evaluate the efficiency of ROS scavengers (antioxidants). The efficacy of a total of 10 compounds against cell death was assessed in vitro models of oxidative stress in cultured cardiomyocytes. Compounds were labeled as MGL-1049-88 (A), MGL-1049-95 (B), MGL-992-58 (C), MGL-992-59 (D), MGL-992-78 (E), MGL-992-94 (F), MGL-992-953166C1902. DOCXAttorney Docket No. 06527-2502274(G), MGL-1019-1 1 (H), TSM-1005-44 (T), and JP4-039 (J). The well-known antioxidants XJB-5-131 (X) and Ferrostatin-1 (S) were used as positive controls.

[0111] Three models of cell death in vitro were induced by subjecting H9c2 cardiomyocytes to tert-butyl hydroperoxide (TBH, an oxidant), RSL3 (ferroptosis inducer), and hypoxia-reoxygenation (HR). To induce oxidative stress by TBH or RSL3, the cells were incubated with 100 pM TBH or 0.5 pM RSL3 in a CO2 incubator (5% CO2 and 95% O2) at 37 OC for 18 h. Each of the 12 (10 new and 2 positive controls) compounds was present in the incubation media before adding TBH or RSL3. To induce HR in vitro, the cells were incubated in a controlled Hypoxia Chamber (BioSpherix, Lacona, NY) containing 95% N2 and 5% CO2 at 37 0°C for 24 h in glucose- and serum-free culture media (hypoxia) followed by incubation in normal culture media in a CO2 incubator (5% CO2 and 95% O2) at 37 OC for 24 h. All compounds were used at final concentrations of 0, 0.16, 0.31 , 0.63, 1.25, 2.50, 5.0, and 10.0 pM. Cell survival was assessed by the AlamarBlue test, whereas cell death was determined by LDH (lactate dehydrogenase) activity in culture media.

[0112] Compounds were added just prior to addition of TBH (100 pM, RSL3 (0.5 pM), or none (control). Cells were incubated under 5% CO2, at 37eC, for 18 hours. Cell damage was assessed with LDH and cell viability was assessed with AlamarBlue. A sample protocol is shown below.Note: Hypoxic media contained no glucose or serum.

[0113] Safety of the compounds: In the first set of experiments, the safety of the compounds on cells under normal conditions was examined. The cardiomyocytes were cultured for 24 h in the media containing each of the 12 compounds individually3266C1902. DOCXAttorney Docket No. 06527-2502274 at 0, 0.16, 0.31 , 0.63, 1 .25, 2.50, 5.0, and 10.0 pM. No toxic effects of the compounds on cell viability at all concentrations were observed (FIG. 2).

[0114] Anti-death effects of the compounds: In the second set of experiments, the potential protective effects of the compounds on cell death induced by oxidative stress as studied. The results showed that 1 ) the anti-death effects of the compounds are dose-dependent and reach a maximum at their high (5 and 10 pM) concentrations, and 2) the compounds have divergent effects on cell death induced by RSL3 (FIGS.3A-3B) and TBH (FIGS. 4A-4B).

[0115] The results of these experiments demonstrate that the effects of S and X are higher than that of other compounds. Among new compounds, the effect of B is higher than others. Divergencies in the effects of compounds were also observed in cardiomyocytes exposed to HR. All compounds, except S and X, reduced HR-induced cell death with various intensities. The protective effects of B, D, and H were higher at concentrations > 5 pM (FIGS. 5A-5B).

[0116] Comparison of new mitochondria-targeted ROS and free-electron scavengers with generic antioxidants: In the next set of experiments, the efficacy of compounds (B, D, J, and X) were compared with that of two generic antioxidants (vitamin C and N-acetylcysteine (NAC)) on cell death induced by oxidative stress in cultured cardiomyocytes in vitro. Results showed that all four compounds markedly reduced cell death induced by TBH (an oxidant) (FIG. 6A) and in vitro IR (FIG. 6B), with the efficacy reaching a maximum of 10 pM. In contrast, vitamin C and NAC were only partially effective at very high concentrations ranging from 0.1 to 10 mM (FIGS. 6A-6B). These findings provide strong evidence in support of the high efficacy of the mitochondria-targeted ROS and free-electron scavengers.

[0117] Analysis of the efficacy of compounds: Next, the ED50 for all compounds to select the compound(s) with maximum efficacy were calculated. As shown in FIG. 7, B and D among the 10 new compounds involved in these studies have high efficacy (anti-death effects) on oxidative stress, particularly induced by TBH and HR.

[0118] Conclusions of in vitro studies: The effectiveness of the 10 compounds against cell death induced by TBH, RSL3, and HR was tested in cardiomyocytes. Ferrostatin-1 (S, known anti-ferroptotic antioxidant) and XJB-5-131 (X, known mitochondria-targeted ROS and free-electron scavenger) were used as references. All compounds were used at 0, 0.16, 0.31 , 0.63, 1 .25, 2.50, 5.0, 10 uM. All compounds were added just before adding TBH (100 uM), RSL3 (0.5 uM), or beginning of hypoxia.3366C1902. DOCXAttorney Docket No. 06527-2502274Based on ED50 data, compounds B and D exhibited higher than others protective effects against oxidative stress in cardiomyocytes in vitro.Example 2

[0119] Objective: Investigate the cardioprotective effects of novel ROS and free- electron scavengers during ischemia / reperfusion (IR) injury. Based on in vitro studies, the cardioprotective effects of the compounds B and D were examined using an ex vivo model of cardiac IR in rat hearts. For comparison, we also evaluated the efficacy of compound J (JP4-039), which had moderate effects in vitro.

[0120] The protective effects of compounds B, D, and J on post-ischemic recovery of hearts during ex-vivo ischemia-reperfusion (IR) were investigated in Sprague Dawley male rats (225-250 g, Taconic, Hillside, NJ). To induce ex vivo IR, Langendorff-perfused isolated hearts were exposed to 25 min of global normothermic ischemia followed by 30 min of reperfusion, as described in our previous studies (FIG. 8). The compounds B, D, and J were present in the perfusion buffer 10 min before ischemia and throughout the entire reperfusion period. First, optimal concentrations of the compounds that were 0.2 pM, 5.0 pM, and 0.2 pM for B, D, and J, respectively, were identified. In all experiments, cardiac function was monitored throughout the entire period of perfusion. LDH activity in the coronary effluent released from the heart at reperfusion was measured to estimate heart damage. At the end of each experiment, mitochondria were isolated for analysis of oxygen consumption rates and mtROS production.

[0121] The effects of compounds against ex-vivo cardiac IR: Results showed that the compounds affect the post-ischemic recovery of cardiac function differently (FIG. 9, panels A-B). The maximum cardioprotective effects were observed in the presence of compound J (JP4-039). It recovered LVDP and RPP up to 69% and 59% (P<0.01 for both vs. control) of pre-ischemic values, respectively, by the end of reperfusion. In the presence of J, the recovery of LVDP and RPP were ~3 times higher than in control (untreated IR group) hearts. Despite antioxidant effects in vitro, compound D had no effects on post-ischemic recovery of the hearts (FIG. 9, panels A-B). However, all 3 compounds significantly reduced LDH release in the coronary effluent (FIG. 9, panels C-D and FIG. 11). Likewise, mtROS production was reduced in the presence of the compounds (FIG. 10, panel A) with no significant effects on the maximum respiration rate (state 3) of mitochondria (FIG. 10, panel B and FIG. 12).3466C1902. DOCXAttorney Docket No. 06527-2502274

[0122] Conclusions: Compounds B and J significantly improved cardiac functional recovery after IR injury. All three compounds were able to reduce LDH release after IR injury. All three compounds decreased mitochondrial ROS production in IR hearts. Further studies are required to establish the efficacy of different methods for delivering the compounds, optimal amount, and dosage regimen to prevent, mitigate or treat cardiac IR injury.

[0123] Having described this invention above, it will be understood to those of ordinary skill in the art that the same can be performed within a wide and equivalent range of conditions, formulations and other parameters without affecting the scope of the invention or any embodiment thereof. Any document incorporated herein by reference is only done so to the extent of its technical disclosure and to the extent it is consistent with the present document and the disclosure provided herein.3566C1902. DOCX

Claims

Attorney Docket No. 06527-2502274THE INVENTION CLAIMED IS1 . A method of treating or preventing a condition selected from one or more of coronary heart disease, ischemia / reperfusion (IR) injury, myocardial infarction, lipid peroxidation of cardiac tissue, a neuroinflammatory disease, or combinations thereof in a patient, comprising administering to the patient an amount of a composition comprising a compound having the structure:effective to prevent or treat the condition, wherein:R is H or -C(O)-X-Ri, wherein Ri is a branched or unbranched Ci-Ce alkyl or a C3-C8 cycloalkyl, wherein the Ci-Ce alkyl or the C3-C8 cycloalkyl is optionally substituted with a phenyl, a substituted phenyl, a heteroaryl, or a substituted heteroaryl, and X is -NH, -O-, or is not present;R2 is a branched or unbranched Ci-Ce alkyl or a C3-C8 cycloalkyl, wherein the Ci-Ce alkyl or the C3-C8 cycloalkyl is optionally substituted with a phenyl, a substituted phenyl, a heteroaryl, or a substituted heteroaryl, or a phenyl, wherein the phenyl is optionally substituted with, independently, 1 , 2, or 3 Cl or F atoms;R3 is H or a C1-C4 alkyl, wherein the C1-C4 alkyl is optionally substituted with a phenyl, a substituted phenyl, a heteroaryl, or a substituted heteroaryl;R4 and R5 are, independently, H, a Ci-Ce alkyl, or a C3-C8 cycloalkyl, wherein the Ci-Ce alky or the C3-C8 cycloalkyl is optionally substituted with a monovalent or divalent benzyl group (-CeFL- or -CeHs) that is optionally substituted with 1 , 2, or 3 halogen atoms, or R4 and R5 together form a cycloalkyl ring or a heterocycloalkyl ring comprising one O, S, or N atom;Re is -C(O)-NH-R7, -NH-C(O)-R?, or -R7, wherein R7 is a nitroxide- containing group;Y is -CH2-, -NH-, or a bond; n is 0 to 6; and the double bond is cis or trans configured, or a pharmaceutically-acceptable salt thereof, including stereoisomers thereof and mixtures of stereoisomers thereof.3666C1902. DOCXAttorney Docket No. 06527-25022742. The method of claim 1 , wherein the double bond is trans configured.

3. The method of claim 1 , wherein the compound has the structure:

4. The method of claim 1 , wherein the compound has the structure:

5. The method of claim 1 , wherein R? is:

6. The method of claim 1 , wherein R is 9-fluorenylmethyloxy carbonyl (Fmoc), t-butyloxycarbonyl (Boc), benzhydryloxycarbonyl (Bhoc), benzyloxycarbonyl (Cbz), O-nitroveratryloxycarbonyl (Nvoc), benzyl (Bn), allyloxycarbonyl (alloc), trityl (Trt), l-(4,4-dimethyl-2,6-dioxacyclohexylidene)ethyl (Dde), diathiasuccinoyl (Dts), benzothiazole-2-sulfonyl (Bts), dimethoxytrityl (DMT), or monomethoxytrityl (MMT).3766C1902. DOCXAttorney Docket No. 06527-25022747. The method of claim 6, wherein R is Boc.

8. The method of claim 1 , wherein R2 is 2-methylpropyl.

9. The method of claim 1 , wherein R3 is H.

10. The method of claim 1 , wherein R4 and R5 are each independently a Ci-Ce alkyl substituted with a benzyl group that is substituted with 1 , 2, or 3 halogen atoms.

11. The method of claim 10, wherein R4 and R5 are each independently a C2 alkyl substituted with a benzyl group that is substituted with 1 fluorine atom.

12. The method of claim 11 , wherein R4 and R5 are each independently 1 -ethyl-4-fluorobenzene.

13. The method of claim 1 , wherein Re is -C(O)-NH-R? or -NH-C(O)- R7.

14. The method of claim 1 , wherein n is 1 to 4.

15. The method of claim 1 , wherein n is 2 and Re is -C(O)-NH-R7 or -NH-C(O)-R7.

16. The method of claim 1 , wherein Y is -NH-.

17. The method of claim 1 , wherein n is 0 and Re is -R7, wherein R7 is:(2,2,6,6-tetramethylpiperidin-N-oxyl).3866C1902. DOCXAttorney Docket No. 06527-250227418. The method of claim 17, wherein Y is -CH-.

19. The method of claim 17, wherein FU and Rs are each independently H.

20. The method of claim 1 , wherein the compound has the structure:3966C1902. DOCXAttorney Docket No. 06527-25022744066C1902. DOCXAttorney Docket No. 06527-250227421 . The method of claim 1 , wherein the compound has the structure:

22. The method of claim 1 , wherein the compound has the structure:41 C1902. DOCXAttorney Docket No. 06527-250227423. The method of claim 1 , wherein the compound has the structure:

24. The method of claim 1 , wherein the composition further comprises a pharmaceutically-acceptable excipient.

25. The method claim 1 , wherein the composition is administered in a dose of about 1 milligram per kilogram (mg / kg) to about 500 mg / kg of body weight of the patient.

26. The method of claim 1 , wherein the composition is administered in a dose of about 10 mg / kg to 200 mg / kg of body weight of the patient.

27. The method of claim 1 , wherein the composition is administered over a period of one year or less.

28. The method of claim 1 , wherein the composition is administered at least three times per week.

29. The method of claim 1 , wherein the composition is administered in a single dose.

30. The method of claim 1 , wherein the composition is administered orally, transdermally, topically, through an injection, or combinations thereof.4266C1902. DOCXAttorney Docket No. 06527-250227431 . The method of claim 30, wherein the composition is administered through a subcutaneous injection.

32. The method of claim 30, wherein the composition is administered through an intravenous injection.

33. The method of claim 1 , wherein the condition is coronary heart disease.

34. The method of claim 1 , wherein the condition is ischemia / reperfusion (IR) injury.

35. The method of claim 1 , wherein the condition is ischemiareperfusion injury following a myocardial infarction.

36. The method of claim 35, wherein the compound is administered once following the myocardial infarction.

37. The method of claim 1 , wherein the compound is administered prophylactically for up to three times per week, for up to 12 months.4366C1902. DOCX

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