Method for treating a disease

Abstract

Novel therapeutic formulations containing superoxide dismutase (SOD) mimetics for the treatment and / or inhibition of various diseases and conditions are provided. The present invention provides a unit dose formulation comprising at least 50 mg of a superoxide dismutase mimic in a container, the superoxide dismutase mimic having the following formula (GC4419): TIFF2023027289000046.tif6580

Description

Technical Field

[0001] The present invention generally relates to methods for treating (including inhibiting) various diseases and conditions. The methods of the present invention involve the administration of superoxide dismutase (SOD) mimetics.

Background Art

[0002] The enzyme superoxide dismutase catalyzes the conversion of superoxide according to formula (I) to oxygen and hydrogen peroxide (this process is often referred to in this specification and the art as disproportionation).

Chemical Formula

[0003] Reactive oxygen metabolites derived from superoxide have been demonstrated to contribute to the tissue pathology in many inflammatory diseases and disorders, such as reperfusion injury to ischemic myocardium, inflammatory bowel disease, rheumatoid arthritis, osteoarthritis, atherosclerosis, hypertension, metastatic responses, psoriasis, organ transplant rejection, radiation-induced injury, asthma, influenza, stroke, burns, and trauma. See, for example, Simic, M. G., et al., Oxygen Radicals in Biology and Medicine, BASIC LIFE SCIENCES, vol. 49, Plenum Press, New York and London, 1988; Weiss, J, Cell. Biochem., 1991 Suppl. 15C, 216 Abstract C110 (1991); Petkau, A., Cancer Treat. Rev. 13, 17 (1986); McCord, J. Free Radicals Biol. Med., 2, 307 (1986); and Bannister, J.V., et al., Crit. Rev. Biochem., 22, 111 (1987). In certain situations, cells lack native SOD activity. For example, this SOD activity deficiency can occur due to heart attacks, organ transplants, and even cancer (cancer cells often lack SOD). As a result, superoxide concentrations can increase and may cause damage to surrounding tissues.

[0004] Superoxide is involved in the breakdown of endothelium-derived relaxing factor (EDRF), which has been identified as nitric oxide (NO), and it is also known that superoxide dismutase prevents the breakdown of EDRF. This suggests a central role played by superoxide-derived reactive oxygen species in the pathogenesis of hypertension, vasoconstriction, thrombosis, and atherosclerosis. See, for example, Gryglewski, R. J. et al., "Superoxide Anion is Involved in the Breakdown of Endothelium-derived Vascular Relaxing Factor", Nature, Vol. 320, pp. 454-56 (1986) and Palmer, R. M. J. et al., "Nitric Oxide Release Accounts for the Biological Activity of Endothelium Derived Relaxing Factor", Nature, Vol. 327, pp. 523-526 (1987).

[0005] To demonstrate the therapeutic effect of reducing superoxide levels in the above-mentioned conditions, clinical trials and animal experiments using natural, recombinant, and modified superoxide dismutase enzymes have been completed or are in progress. However, several problems have arisen when using this enzyme as a potential therapeutic agent. For example, there are problems such as lack of oral activity (a problem common to polypeptides), short half-life in vivo, immunogenicity of non-human-derived enzymes, and insufficient tissue distribution.

[0006] In attempts to overcome problems associated with the superoxide dismutase enzyme, several investigations have been conducted regarding the design of non-proteinaceous catalysts for the disproportionation of superoxide and their use in superoxide-related mild diseases. One group of catalysts that has shown near-catalytic efficiency to the native superoxide dismutase enzyme are the manganese and iron complexes of pentaazacyclopentadecane ligands, as described in U.S. Patent Nos. 5,610,293, 5,637,578, and 5,874,421. These ligands include a pentaazacyclopentadecane macrocycle that has various substituents on the macrocyclic carbons or has a cyclic or heterocyclic structure attached to the macrocyclic carbons. Some of these complexes have potent catalytic superoxide disproportionation activity, produce anti-inflammatory activity, and prevent oxidative damage in vivo. In addition, these compounds (sometimes referred to as SOD mimetics) have been shown to have an analgesic effect and reduce inflammation and edema in a rat hind paw carrageenan hyperalgesia model (see, for example, U.S. Patent No. 6,180,620).

[0007] One particular compound that has been demonstrated to be an effective catalyst for superoxide disproportionation is the following pentaazacyclopentadecane compound, which has been described in the prior art under the names SC-72325, M40403, KM40403, GC4403 (referred to herein as GC4403).

Chemical formula

[0008] In the formula, X and Y are, independently, a neutral ligand or a negatively charged ligand. Superoxide dismutase mimics are generally known to be usable themselves as anticancer agents (see, for example, Simic, M. G., et al., Weiss, supra, Petkau, A., etc. supra). In addition, it has been reported that the combined therapy of superoxide dismutase mimic KM4403 and interleukin-2 (IL-2) enhances the antitumor effect of IL-2. See Samlowski, W. E., et al., Nature Medicine (2003) 9:750-755.

[0009] GC4403 has been shown to be effective in the treatment of inflammatory conditions such as oral mucositis, but there remains room for other superoxide dismutase mimics and treatment methods.

Summary of the Invention

[0010] Among various aspects of the present disclosure, in particular, there is provided a method for treating various diseases and conditions, including administering to a patient a superoxide dismutase mimic corresponding to formula (GC4419).

Chemical Formula

[0011] In the formula, X and Y are, independently, a neutral ligand or a negatively charged ligand. Pharmaceutical compositions, unit dosage forms, manufactured articles, and kits are also described herein.

[0012] Thus, briefly stated, the present disclosure is directed to a unit dosage form containing at least 50 mg of a superoxide dismutase mimic corresponding to formula (GC4419) in a container.

[0013] Another aspect of the disclosure is directed to a manufactured article. The manufactured article includes packaging material, and the packaging material contains a parenteral formulation for treating a disease or condition or protecting tissue from damage resulting from exposure to cancer treatment in a patient in need thereof. The parenteral formulation includes the unit dose formulation described in the present invention, and the packaging material includes a labeled label or package insert for parenterally administering the dosage to the patient.

[0014] Another aspect of the disclosure is directed to a pharmaceutical composition in solution, the pharmaceutical composition comprising a superoxide dismutase mimetic of about 0.25 mg / mL to about 3.5 mg / mL corresponding to formula (GC4419), wherein the unit dose of the pharmaceutical composition is stored in a container for intravenous administration.

[0015] Also described herein are various methods of treatment involving administration of a superoxide dismutase mimetic corresponding to formula (GC4419).

[0016] Accordingly, another aspect of the disclosure is directed to a method of treating tissue damage in a human patient caused by the application of radiation therapy or chemotherapy to the patient. The method of treatment includes administering to the patient a therapeutically effective amount of a superoxide dismutase mimetic corresponding to formula (GC4419).

[0017] Another aspect of the disclosure is directed to a method of treating tissue damage in a human patient caused by exposure to radiation. The method of treatment includes administering to the patient a therapeutically effective amount of a superoxide dismutase mimetic corresponding to formula (GC4419).

[0018] Another aspect of the present disclosure is directed to a method of treating a disease or condition in a human patient, the method comprising administering to the patient at least 25 mg of a superoxide dismutase mimetic corresponding to formula (GC4419) within a time period of 15 minutes. Another aspect of the present disclosure is directed to a method of treating a disease or condition in a human patient, the method comprising administering to the patient at least 50 mg of a superoxide dismutase mimetic corresponding to formula (GC4419) within a time period of 15 minutes. Another aspect of the present disclosure is directed to a method of treating a disease or condition in a human patient, the method comprising administering to the patient at least 50 mg of a superoxide dismutase mimetic corresponding to formula (GC4419) within a time period of 30 minutes. Another aspect of the present disclosure is directed to a method of treating a disease or condition in a human patient, the method comprising administering to the patient at least 100 mg of a superoxide dismutase mimetic corresponding to formula (GC4419) within a time period of 60 minutes.

[0019] Another aspect of the present disclosure is directed to a method of treating a disease or condition in a human patient, the method comprising administering to the patient a superoxide dismutase mimetic corresponding to formula (GC4419) at a rate of at least 100 mg / hour. For example, at least 25 mg of the superoxide dismutase mimetic may be administered to the patient at a rate of at least 100 mg / hour.

[0020] Another aspect of the present disclosure is directed to a method of treating a disease or condition in a human patient, the method comprising administering to the patient a superoxide dismutase mimetic corresponding to formula (GC4419) and calculating an exposure measured using the area under the curve (AUC) to be at least 4,000 ng-hour / mL from measured values of the superoxide dismutase mimetic concentration in the patient's plasma.

[0021] Other objects and features will become apparent in part and pointed out in the following. BRIEF DESCRIPTION OF THE DRAWINGS

[0022]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Mode for Carrying Out the Invention

[0023] Detailed Description The present disclosure generally relates to methods and pharmaceutical compositions for treating various diseases and conditions. The treatment method involves administering a superoxide dismutase mimetic to a subject in need of treatment, and more preferably, administering a pharmaceutical composition containing the superoxide dismutase mimetic to the subject. In addition, pharmaceutical compositions and formulations (e.g., unit dosage formulations) containing a superoxide dismutase mimetic and optionally also a pharmaceutically acceptable carrier are also described herein. The superoxide dismutase mimetic (e.g., a compound corresponding to formula (GC4419) below) administered according to the methods described herein is structurally similar to certain superoxide dismutase mimetics known in the art. Specifically, the chemical structure of GC4403 (e.g., the dichloro complex form described in Riley, D.P., Schall, O.F., 2007, Advances in Inorganic Chemistry, 59: 233-263) and the compound of formula (GC4419) described herein (e.g., the dichloro complex form of formula (GC4419)) are identical except that they have mirror image chirality, i.e., their enantiomeric structures cannot be superimposed.

Chemical formula

[0024] As shown in the above structure, the dichloro complex form of GC4403 has four chiral carbon centers present in the R-absolute configuration, whereas the dichloro complex form of GC4419 has four chiral carbon atoms in the S-absolute configuration.

[0025] As detailed in the description and examples of this specification, these two compounds have almost identical physicochemical properties (including stability, reactivity with achiral reagents, electronic spectra, solubility in achiral media, and reactivity with superoxide) (see Example 3 below). For example, the in vitro activities such as the anti-proliferative inhibitory activity in cell culture media are also similar between GC4403 and GC4419 (see Example 4 below). However, despite these similarities, unexpectedly, it has been discovered that the compound of formula (GC4419) exhibits an excellent safety profile (about 5-fold improvement) compared to the mirror image compound GC4403. As an example, the compound of formula (GC4419) can be administered to a subject at a dose 5 times higher and at least 2 times faster without any significant adverse events compared to GC4403. Furthermore, since the compound of formula (GC4419) is at least as potent as GC4403, this improved safety does not come at the expense of efficacy (see Examples 5-9 below).

[0026] The production of superoxide can increase in cells (e.g., in tumor cells), and this can lead to a reduction in the expression of native superoxide dismutase by these cells, resulting in an increased accumulation of superoxide. The superoxide dismutase mimetic corresponding to formula (GC4419) can catalyze the conversion of superoxide to hydrogen peroxide, substituting or supplementing native superoxide dismutase, which provides therapeutic or other beneficial effects. As further detailed below, in certain embodiments, administering the superoxide dismutase mimetic corresponding to formula (GC4419) can increase the ability of cells to disproportionate superoxide.

[0027] In various embodiments described herein, the superoxide dismutase mimetic corresponding to formula (GC4419) may be administered alone or in combination with another (e.g., one or more) pharmaceutically active agent or compound. According to certain preferred embodiments, the superoxide dismutase mimetic corresponding to formula (GC4419) is administered to a subject as a single pharmaceutically active agent. Thus, in one embodiment, for example, a pharmaceutical composition or formulation consists essentially of a superoxide dismutase mimetic corresponding to formula (GC4419) and optionally (although preferably) includes a pharmaceutically acceptable carrier or excipient. In other embodiments, the superoxide dismutase mimetic corresponding to formula (GC4419) is administered to a subject in combination with another pharmaceutically active agent or compound. Thus, according to certain methods described herein, a superoxide dismutase mimetic corresponding to formula (GC4419) is administered in combination with an additional pharmaceutically active agent or compound. That is, these may be administered simultaneously (concurrently) or sequentially.

[0028] Superoxide dismutase mimetic The superoxide dismutase mimetic compound administered according to the methods described herein is a non-proteinaceous molecule that catalyzes the conversion of superoxide radical O2 -● to molecular oxygen and hydrogen peroxide. For example, according to one embodiment, a superoxide dismutase mimetic is administered to a subject to increase the ability of cells (e.g., cancer cells) in the subject to disproportionate superoxide.

[0029] The superoxide dismutase mimetics used in the methods, compositions, and formulations disclosed herein have the ability to selectively catalyze the conversion of superoxide to oxygen and hydrogen peroxide and show no significant activity towards hydrogen peroxide. For example, the following selective superoxide dismutase mimetic corresponding to formula (GC4419) shows no detectable activity towards hydrogen peroxide, whereas non-selective superoxide dismutase mimetics such as mangafodipir, copper [II] diisopropylsalicylate (CuDIPS), manganese [III] tetrakis-(5,10,15,20)-benzoic acid porphyrin (MnTBAP), etc. show significant activity towards hydrogen peroxide. Generally, the superoxide dismutase mimetics used in the methods described herein tend to have a decreasing efficacy as the activity of the superoxide dismutase mimetic towards hydrogen peroxide increases. Thus, the ratio of the activity of the superoxide dismutase mimetic towards superoxide to the activity of the superoxide dismutase mimetic towards hydrogen peroxide is preferably at least 10:1 (activity towards superoxide:activity towards hydrogen peroxide). More preferably, the ratio of the activity of the superoxide dismutase mimetic towards superoxide to the activity of the superoxide dismutase mimetic towards hydrogen peroxide is at least 100:1 (activity towards superoxide:activity towards hydrogen peroxide). Even more preferably, the ratio of the activity of the superoxide dismutase mimetic towards superoxide to the activity of the superoxide dismutase mimetic towards hydrogen peroxide is at least 1000:1 (activity towards superoxide:activity towards hydrogen peroxide). In a particularly preferred embodiment, the superoxide dismutase mimetic shows no detectable activity towards hydrogen peroxide.

[0030] Accordingly, in various aspects of the present disclosure, the methods described herein involve the administration of a superoxide dismutase mimetic corresponding to the following formula (GC4419).

Chemical formula

[0031] As described above, X and Y represent a monodentate ligand, a polydentate ligand, or a neutral ligand or a negatively charged suitable ligand derived from a ligand system, or the corresponding anions thereof (for example, benzoic acid or benzoate anion, phenol or phenoxide anion, alcohol or alkoxide anion). For example, X and Y can be independently selected from the group consisting of: halide, oxo, aquo, hydroxo, alcohol, phenol, dioxygen, peroxo, hydroperoxo, alkylperoxo, arylperoxo, ammonia, alkylamino, arylamino, heterocycloalkylamino, heterocycloarylamino, amine oxide, hydrazine, alkylhydrazine, arylhydrazine, nitric oxide, cyanide, cyanate, thiocyanate, isocyanate, isothiocyanate, alkylnitrile, arylnitrile, alkylisonitrile, arylisonitrile, nitrate, nitrite, azide, alkylsulfonic acid, arylsulfonic acid, alkylsulfoxide, arylsulfoxide, alkylarylsulfoxide, alkylsulfenic acid, arylsulfenic acid, alkylsulfinic acid, arylsulfinic acid, alkylthiocarboxylic acid, arylthiocarboxylic acid, alkylthiolthiocarboxylic acid, arylthiolthiocarboxylic acid, alkylcarboxylic acid, arylcarboxylic acid, urea, alkylurea, arylurea, alkylarylurea, thiourea, alkylthiourea, arylthiourea, alkylarylthiourea, sulfate, sulfite, bisulfate, bisulfite, thiosulfate, thiosulfite, hydrosulfite, alkylphosphine, arylphosphine, alkylphosphine oxide, arylphosphine oxide, alkylarylphosphine oxide, alkylphosphine sulfide, arylphosphine sulfide, alkylarylphosphine sulfide, alkylphosphonic acid, arylphosphonic acid, alkylphosphinic acid, arylphosphinic acid, alkylphosphonous acid, arylphosphonous acid, phosphate, thiophosphate, phosphite, pyrophosphite, triphosphate, hydrogen phosphate, dihydrogen phosphate, alkylguanidino, arylguanidino, alkylarylguanidino, alkylcarbamate,Aryl carbamate, alkyl aryl carbamate, alkyl thiocarbamate, aryl thiocarbamate, alkyl aryl thiocarbamate, alkyl dithiocarbamate, aryl dithiocarbamate, alkyl aryl dithiocarbamate, bicarbonate, carbonate, perchlorate, chlorate, chlorite, hypochlorite, perbromate, bromate, bromite, hypobromite, tetrahalomanganate, tetrafluoroborate, hexafluoroantimonate, hypophosphite, iodate, periodate, metaborate, tetraarylborate, tetraalkylborate, tartrate, salicylate, succinate, citrate, ascorbate, saccharinate, amino acid, hydroxamic acid, thiotosylate, and anions of ion exchange resins, or, among other possible ones, in particular, these corresponding anions.,

[0032] In one embodiment, X and Y are independently selected from monodentate ligands. For example, in one preferred embodiment, X and Y are independently selected from the group consisting of aqua ligands, halo ligands (e.g., chloro, iodo, fluoro), carboxylato ligands (e.g., formato, acetato), thiocyanato ligands, and bicarbonato ligands. In another preferred embodiment, X and Y are independently selected from aqua ligands and halo ligands. In another preferred embodiment, X and Y are independently halo ligands, and in this embodiment, more preferably, X and Y are chloro ligands.

[0033] In a particularly preferred embodiment, the superoxide dismutase mimetic used in the methods and compositions described herein corresponds to the dichloro complex form of the following formula (GC4419).

Chemical formula

[0034] When the superoxide dismutase mimetic described in this specification dissolves or disperses in a solution such as water or saline, usually a dynamic and rapid equilibrium is established, where a ligand (e.g., a chloro ligand) dissociates from the axial coordination site occupied by solvent (e.g., water) molecules to form both a mono-aquo (monocationic) complex and a bis-aquo (dicationic) complex. As a result, it becomes difficult to accurately represent the dissolved compound by a single structural formula. This dissociation reaction generally proceeds according to the following reaction scheme (this figure also uses chloro ligands and aquo ligands as illustrative examples). [Chemical formula]

[0035] When the ligand is defined by some specific structure (e.g., X and Y are chloro ligands, X is aquo and Y is chloro, X and Y are aquo, etc.), for clarity, the complex is enclosed in parentheses and the net charge is indicated. The exchange rate of the bound / coordinated water / ligand is measured by NMR relaxation techniques and is very fast (e.g., about 10 +7 s -1 ). It is understood that, at least in part due to the high exchange rate of the X and Y ligands in the solution, the ligands at the positions of X and Y at a given time depend on the ligands initially present at the positions of X and Y of the superoxide dismutase mimetic (e.g., halo such as chloro, carboxylato such as formato or acetato, or bicarbonato), and the ligands present in the solution in which the compound is dissolved (e.g., water (aquo ligand), saline (chloro anion), etc.). Thus, for example, in one embodiment, a solution containing the dichloro complex form of formula (GC4419) dissolved in buffered saline is expected to contain a mixture of at least the following complexes in equilibrium. [Chemical formula]

[0036] As a further example, a solution containing the diacetate complex form of the compound of formula (GC4419) dissolved in buffered saline is expected to contain a mixture of at least the following complexes in equilibrium.

Chem.

[0037] Preferably, the enantiomeric purity of the superoxide dismutase mimetic compound is greater than 95%, more preferably greater than 98%, even more preferably greater than 99%, and most preferably greater than 99.5%. As used herein, the term "enantiomeric purity" refers to the amount of the compound having the indicated absolute stereochemistry expressed as a percentage value relative to the total amount of the indicated compound and its enantiomers. Preferably, the diastereomeric purity of the superoxide dismutase mimetic compound is greater than 98%, more preferably greater than 99%, and most preferably greater than 99.5%. As used herein, the term "diastereomeric purity" refers to the amount of the compound having the indicated absolute stereochemistry expressed as a percentage value relative to the total amount of the indicated compound and its diastereomers. Methods for measuring diastereomeric purity and enantiomeric purity are well known in the art. Measurement of diastereomeric purity can be carried out by any analytical technique (e.g., high performance liquid chromatography (HPLC)) capable of quantitatively distinguishing the compound from its diastereomers. Similarly, measurement of enantiomeric purity can also be carried out by any analytical technique capable of quantitatively distinguishing the compound from its enantiomers. Examples of suitable analytical techniques for measuring enantiomeric purity include, but are not limited to, the rotation of plane-polarized light using a polarimeter and HPLC using a chiral column packing material.

[0038] Also, preferably, the superoxide dismutase mimetic is chemically pure. Preferably, the chemical purity of the superoxide dismutase mimetic compound is greater than 95%, more preferably greater than 98%, and most preferably greater than 99%. Chemical purity can be confirmed, for example, by high pressure liquid chromatography.

[0039] High-dose / mass superoxide dismutase mimics and improvement of pharmacokinetic parameters The actual dosage levels of the active ingredients of the superoxide dismutase mimics in the pharmaceutical compositions and formulations described herein may be varied so as to obtain an effective amount of the active compound effective to achieve the desired therapeutic response for a particular patient, composition, and method of administration. The dosage level selected will generally be determined by, for example, the activity of the particular compound, the route of administration, the severity of the condition to be treated, the condition and prior medical history of the patient being treated. However, it is within the capabilities of those skilled in the art to initiate administration of the compound at a level lower than that required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.

[0040] When used in the above or other treatments, the superoxide dismutase mimic compounds may be administered as a pharmaceutical composition or unit dosage formulation containing the compound of interest, usually in combination with one or more pharmaceutically acceptable carriers. It will be understood that a therapeutically effective amount of the superoxide dismutase mimics (or other compounds described herein) includes a sufficient amount of the compound to treat a disease or condition with a reasonable benefit / risk ratio applicable to any treatment. However, it will be understood that the total daily usage of the compounds and compositions of the present invention will be determined by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dosage levels for a particular subject will be determined by a variety of factors. Examples of such various factors include the disease or disorder to be treated and the severity of the disease or disorder; the activity of the particular compound used; the particular composition used; the age, weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the particular compound used; the duration of treatment; the drugs used in combination with or concurrently with the particular compound used; and other factors of the same type well known in the medical arts. For example, it is within the capabilities of those skilled in the art to initiate administration of the compound at a level lower than that required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.

[0041] Administration of the superoxide dismutase mimetic(s) may occur once or over the entire course of treatment. For example, the superoxide dismutase mimetic may be administered daily (including multiple administrations per day), weekly, every two weeks, or monthly. In the case of treating an acute condition, the course of treatment may be at least several minutes, hours, or days. Depending on the condition, the treatment may extend from several days to several weeks. For example, the treatment period may extend over one week, two weeks, three weeks, etc. In the case of a more chronic condition, the treatment period may extend from several weeks to several months, over one year, or over the lifetime of the subject in need of such treatment. Alternatively, the superoxide dismutase mimetic may be administered daily, weekly, every two weeks, or monthly for several weeks, several months, several years, or over the lifetime of the mammal as a preventive or inhibitory measure.

[0042] As described above, the superoxide dismutase mimetic described herein has unexpectedly been found to be able to be administered at a relatively high dose (including single administration and unit dose) at a high administration rate to a subject in need of administration of the mimetic, for example, compared to compounds of similar structure, such as the enantiomers of the mimetic (e.g., formula (GC4419) when compared to the prior art compound (GC4403)).

[0043] Thus, generally, the methods described herein involve administering a superoxide dismutase mimetic corresponding to formula (GC4419) at a relatively high dose and / or at relatively short time intervals. According to the treatment methods described herein for tissue damage resulting from cancer treatment or other radiation exposure, the superoxide dismutase mimetic may be administered in various amounts (e.g., at least 25 mg, 50 mg, 100 mg, etc., or another amount based on the patient's weight) within a specific time frame, such as within 15 minutes, 30 minutes, 45 minutes, 60 minutes, or a time frame exceeding 60 minutes. Thus, for example, a superoxide dismutase mimetic corresponding to formula (GC4419) of at least 25 mg, at least 50 mg, at least 75 mg, at least 100 mg, at least 125 mg, at least 150 mg, at least 175 mg, at least 200 mg, at least 225 mg, at least 250 mg, at least 275 mg, or at least 300 mg may be administered within a time frame of 15 minutes, 30 minutes, 45 minutes, 60 minutes, or a time frame exceeding 60 minutes.

[0044] For example, in one embodiment, an amount of a superoxide dismutase mimetic corresponding to formula (GC4419) is administered to a patient at a rate of at least 100 mg / hour. According to this embodiment, for example, the above amount may be administered at a rate of at least 150 mg / hour, at least 200 mg / hour, at least 250 mg / hour, at least 300 mg / hour, at least 350 mg / hour, at least 400 mg / hour, at least 450 mg / hour, at least 500 mg / hour, at least 550 mg / hour, or at least 600 mg / hour. Thus, for example, the dosage may be a superoxide dismutase mimetic corresponding to formula (GC4419) of at least 25 mg, at least 50 mg, at least 75 mg, at least 100 mg, at least 125 mg, at least 150 mg, at least 175 mg, at least 200 mg, at least 225 mg, at least 250 mg, at least 275 mg, or at least 300 mg.

[0045] For example, in one embodiment, an amount of a superoxide dismutase mimetic corresponding to formula (GC4419) is administered to a patient within a 15-minute time frame. According to this embodiment, for example, the dosage can be at least 25 mg, at least 50 mg, at least 75 mg, at least 100 mg, at least 125 mg, at least 150 mg, at least 175 mg, at least 200 mg, at least 225 mg, at least 250 mg, at least 275 mg, or at least 300 mg of a superoxide dismutase mimetic corresponding to formula (GC4419). Thus, for example, at least 25 mg can be administered to the patient within a 15-minute time frame; at least 50 mg can be administered to the patient within a 15-minute time frame; at least 75 mg can be administered to the patient within a 15-minute time frame; at least 100 mg can be administered to the patient within a 15-minute time frame; at least 125 mg can be administered to the patient within a 15-minute time frame; or at least 150 mg can be administered to the patient within a 15-minute time frame. According to these embodiments, one suitable superoxide dismutase mimetic is the dichloro complex form of formula (GC4419).

[0046] For example, in another embodiment, an amount of a superoxide dismutase mimetic corresponding to formula (GC4419) is administered to a patient within a 30-minute time frame. According to this embodiment, for example, the dosage can be at least 50 mg, at least 75 mg, at least 100 mg, at least 125 mg, at least 150 mg, at least 175 mg, at least 200 mg, at least 225 mg, at least 250 mg, at least 275 mg, or at least 300 mg of a superoxide dismutase mimetic corresponding to formula (GC4419). Thus, for example, at least 50 mg can be administered to the patient within a 30-minute time frame; at least 75 mg can be administered to the patient within a 30-minute time frame; at least 100 mg can be administered to the patient within a 30-minute time frame; at least 125 mg can be administered to the patient within a 30-minute time frame; at least 125 mg can be administered to the patient within a 30-minute time frame; at least 150 mg can be administered to the patient within a 30-minute time frame; at least 175 mg can be administered to the patient within a 30-minute time frame; at least 200 mg can be administered to the patient within a 30-minute time frame; at least 225 mg can be administered to the patient within a 30-minute time frame; at least 250 mg can be administered to the patient within a 30-minute time frame; at least 275 mg can be administered to the patient within a 30-minute time frame; or at least 300 mg can be administered to the patient within a 30-minute time frame. According to these embodiments, one suitable superoxide dismutase mimetic is the dichloro complex form of formula (GC4419).

[0047] For example, in another embodiment, an amount of a superoxide dismutase mimetic corresponding to formula (GC4419) is administered to a patient within a time frame of 45 minutes. According to this embodiment, for example, the dosage can be at least 50 mg, at least 75 mg, at least 100 mg, at least 125 mg, at least 150 mg, at least 175 mg, at least 200 mg, at least 225 mg, at least 250 mg, at least 275 mg, at least 300 mg, at least 325 mg, at least 350 mg, at least 375 mg, at least 400 mg, at least 425 mg, or at least 450 mg of a superoxide dismutase mimetic corresponding to formula (GC4419). Thus, for example, at least 50 mg can be administered to the patient within a time frame of 45 minutes; at least 75 mg can be administered to the patient within a time frame of 45 minutes; at least 100 mg can be administered to the patient within a time frame of 45 minutes; at least 125 mg can be administered to the patient within a time frame of 45 minutes; at least 125 mg can be administered to the patient within a time frame of 45 minutes; at least 150 mg can be administered to the patient within a time frame of 45 minutes; at least 175 mg can be administered to the patient within a time frame of 45 minutes; at least 200 mg can be administered to the patient within a time frame of 45 minutes; at least 225 mg can be administered to the patient within a time frame of 45 minutes; at least 250 mg can be administered to the patient within a time frame of 45 minutes; at least 275 mg can be administered to the patient within a time frame of 45 minutes; at least 300 mg can be administered to the patient within a time frame of 45 minutes; at least 325 mg can be administered to the patient within a time frame of 45 minutes; at least 350 mg can be administered to the patient within a time frame of 45 minutes; at least 375 mg can be administered to the patient within a time frame of 45 minutes; at least 400 mg can be administered to the patient within a time frame of 45 minutes; at least 425 mg can be administered to the patient within a time frame of 45 minutes; or at least 450 mg can be administered to the patient within a time frame of 45 minutes. According to these embodiments, one suitable superoxide dismutase mimetic is the dichloro complex form of formula (GC4419).

[0048] For example, in another embodiment, an amount of a superoxide dismutase mimetic corresponding to formula (GC4419) is administered to a patient within a time frame of 60 minutes. According to this embodiment, for example, the dosage can be at least 50 mg, at least 75 mg, at least 100 mg, at least 125 mg, at least 150 mg, at least 175 mg, at least 200 mg, at least 225 mg, at least 250 mg, at least 275 mg, at least 300 mg, at least 325 mg, at least 350 mg, at least 375 mg, at least 400 mg, at least 425 mg, at least 450 mg, at least 475 mg, at least 500 mg, at least 525 mg, at least 550 mg, at least 575 mg, or at least 600 mg of a superoxide dismutase mimetic corresponding to formula (GC4419).Thus, for example, at least 50 mg may be administered to a patient within a time frame of 60 minutes; at least 75 mg may be administered to a patient within a time frame of 60 minutes; at least 100 mg may be administered to a patient within a time frame of 60 minutes; at least 125 mg may be administered to a patient within a time frame of 60 minutes; at least 125 mg may be administered to a patient within a time frame of 60 minutes; at least 150 mg may be administered to a patient within a time frame of 60 minutes; at least 175 mg may be administered to a patient within a time frame of 60 minutes; at least 200 mg may be administered to a patient within a time frame of 60 minutes; at least 225 mg may be administered to a patient within a time frame of 60 minutes; at least 250 mg may be administered to a patient within a time frame of 60 minutes; at least 275 mg may be administered to a patient within a time frame of 60 minutes; at least 300 mg may be administered to a patient within a time frame of 60 minutes; at least 325 mg may be administered to a patient within a time frame of 60 minutes; at least 350 mg may be administered to a patient within a time frame of 60 minutes; at least 375 mg may be administered to a patient within a time frame of 60 minutes; at least 400 mg may be administered to a patient within a time frame of 60 minutes; at least 425 mg may be administered to a patient within a time frame of 60 minutes; at least 450 mg may be administered to a patient within a time frame of 60 minutes; at least 475 mg may be administered to a patient within a time frame of 60 minutes; at least 500 mg may be administered to a patient within a time frame of 60 minutes; at least 525 mg may be administered to a patient within a time frame of 60 minutes; at least 550 mg may be administered to a patient within a time frame of 60 minutes; at least 575 mg may be administered to a patient within a time frame of 60 minutes; or at least 600 mg may be administered to a patient within a time frame of 60 minutes. According to these embodiments, one suitable superoxide dismutase mimetic is the dichloro complex form of formula (GC4419).

[0049] For example, in other embodiments, a superoxide dismutase mimetic corresponding to formula (GC4419) at at least 0.67 mg per kg of patient body weight; at least 1.0 mg per kg of patient body weight; at least 1.5 mg per kg of patient body weight; at least 2.0 mg per kg of patient body weight; at least 2.5 mg per kg of patient body weight; at least 3.0 mg per kg of patient body weight; at least 3.5 mg per kg of patient body weight; at least 4.0 mg per kg of patient body weight; at least 5.0 mg per kg of patient body weight; at least 6.0 mg per kg of patient body weight; at least 7.5 mg per kg of patient body weight; or at least 10.0 mg per kg of patient body weight is administered to the patient within a specific time frame (e.g., 15 minutes, 30 minutes, 45 minutes, or 60 minutes). Thus, for example, at least 0.67 mg per kg of patient body weight may be administered to the patient within a 15-minute time frame; at least 1.0 mg per kg of patient body weight may be administered to the patient within a 15-minute time frame; at least 1.5 mg per kg of patient body weight may be administered to the patient within a 15-minute time frame; at least 2.0 mg per kg of patient body weight may be administered to the patient within a 15-minute time frame; at least 2.5 mg per kg of patient body weight may be administered to the patient within a 15-minute time frame; at least 0.67 mg per kg of patient body weight may be administered to the patient within a 30-minute time frame; at least 1.0 mg per kg of patient body weight may be administered to the patient within a 30-minute time frame; at least 1.5 mg per kg of patient body weight may be administered to the patient within a 30-minute time frame; at least 2.0 mg per kg of patient body weight may be administered to the patient within a 30-minute time frame; at least 2.5 mg per kg of patient body weight may be administered to the patient within a 30-minute time frame; at least 3.0 mg per kg of patient body weight may be administered to the patient within a 30-minute time frame; at least 3.5 mg per kg of patient body weight may be administered to the patient within a 30-minute time frame; at least 4.0 mg per kg of patient body weight may be administered to the patient within a 30-minute time frame; at least 5.0 mg per kg of patient body weight may be administered to the patient within a 30-minute time frame; at least 6.0 mg per kg of patient body weight may be administered to the patient within a 30-minute time frame; at least 7.It may be administered to the patient at 5 mg within a time frame of 30 minutes; it may be administered to the patient at at least 0.67 mg per kg of patient body weight within a time frame of 45 minutes; it may be administered to the patient at at least 1.0 mg per kg of patient body weight within a time frame of 45 minutes; it may be administered to the patient at at least 1.5 mg per kg of patient body weight within a time frame of 45 minutes; it may be administered to the patient at at least 2.0 mg per kg of patient body weight within a time frame of 45 minutes; it may be administered to the patient at at least 2.5 mg per kg of patient body weight within a time frame of 45 minutes; it may be administered to the patient at at least 3.0 mg per kg of patient body weight within a time frame of 45 minutes; it may be administered to the patient at at least 3.5 mg per kg of patient body weight within a time frame of 45 minutes; it may be administered to the patient at at least 4.0 mg per kg of patient body weight within a time frame of 45 minutes; it may be administered to the patient at at least 5.0 mg per kg of patient body weight within a time frame of 45 minutes; it may be administered to the patient at at least 6.0 mg per kg of patient body weight within a time frame of 45 minutes; it may be administered to the patient at at least 7.5 mg per kg of patient body weight within a time frame of 45 minutes; it may be administered to the patient at at least 0.67 mg per kg of patient body weight within a time frame of 60 minutes; it may be administered to the patient at at least 1.0 mg per kg of patient body weight within a time frame of 60 minutes; it may be administered to the patient at at least 1.5 mg per kg of patient body weight within a time frame of 60 minutes; it may be administered to the patient at at least 2.0 mg per kg of patient body weight within a time frame of 60 minutes; it may be administered to the patient at at least 2.5 mg per kg of patient body weight within a time frame of 60 minutes; it may be administered to the patient at at least 3.0 mg per kg of patient body weight within a time frame of 60 minutes; it may be administered to the patient at at least 3.5 mg per kg of patient body weight within a time frame of 60 minutes; it may be administered to the patient at at least 4.0 mg per kg of patient body weight within a time frame of 60 minutes; it may be administered to the patient at at least 5.0 mg per kg of patient body weight within a time frame of 60 minutes; it may be administered to the patient at at least 6.0 mg per kg of patient body weight within a time frame of 60 minutes; it may be administered to the patient at at least 7.5 mg per kg of patient body weight within a time frame of 60 minutes; or at least 10. per kg of patient body weight.0 mg may be administered to the patient within a time frame of 60 minutes. According to these embodiments, one suitable superoxide dismutase mimetic is the dichloro complex form of formula (GC4419).

[0050] For example, in other embodiments, the dosage (i.e., the dosage without considering the administration time) is at least 25 mg, at least 50 mg, at least 75 mg, at least 100 mg, at least 125 mg, at least 150 mg, at least 175 mg, at least 200 mg, at least 225 mg, at least 250 mg, at least 275 mg, at least 300 mg, at least 325 mg, at least 350 mg, at least 375 mg, at least 400 mg, at least 425 mg, at least 450 mg, at least 475 mg, at least 500 mg, at least 525 mg, at least 550 mg, at least 575 mg, or at least 600 mg of the superoxide dismutase mimetic corresponding to formula (GC4419). For example, in other embodiments, the dosage (i.e., the dosage without considering the administration time) is at least 0.67 mg per kg of patient body weight; at least 1.0 mg per kg of patient body weight; at least 1.5 mg per kg of patient body weight; at least 2.0 mg per kg of patient body weight; at least 2.5 mg per kg of patient body weight; at least 3.0 mg per kg of patient body weight; at least 3.5 mg per kg of patient body weight; at least 4.0 mg per kg of patient body weight; at least 5.0 mg per kg of patient body weight; at least 6.0 mg per kg of patient body weight; at least 7.5 mg per kg of patient body weight; or at least 10.0 mg per kg of patient body weight; or at least 10.0 mg per kg of patient body weight.

[0051] If desired, the effective dose may be divided into multiple administrations for the purpose of administration. Thus, a single-dose composition may contain the effective dose, or the divided amounts that make up the effective dose.

[0052] In addition, some aspects of the present disclosure relate to an improvement in the pharmacokinetic profile when the superoxide dismutase mimetic described herein is administered to a subject. When a superoxide dismutase mimetic corresponding to formula (GC4419) (e.g., the dichloro complex of formula (GC4419)) is administered, the patient exposure measured using AUC (i.e., the area under the curve of the plasma compound concentration graph over time) is increased compared to a related superoxide dismutase mimetic (e.g., the mirror image compound GC4403 described above), at least partially due to the improved safety profile of the superoxide dismutase mimetic corresponding to formula (GC4419).

[0053] For example, in one embodiment, the method described herein comprises administering a superoxide dismutase mimetic corresponding to formula (GC4419) to a patient, such that the exposure measured using the area under the curve (AUC) is at least 4,000 ng-hour / mL, calculated from the measured value of the superoxide dismutase mimetic concentration in the patient's plasma. Thus, the value of AUC can be calculated from the measured value of the superoxide dismutase mimetic concentration in the patient's plasma and be at least 5,000 ng-hour / mL; at least 7,500 ng-hour / mL; at least 10,000 ng-hour / mL; at least 12,500 ng-hour / mL; at least 15,000 ng-hour / mL; at least 17,500 ng-hour / mL; at least 20,000 ng-hour / mL; at least 22,500 ng-hour / mL; at least 25,000 ng-hour / mL; at least 27,500 ng-hour / mL; at least 30,000 ng-hour / mL; at least 32,500 ng-hour / mL; at least 35,000 ng-hour / mL; at least 37,500 ng-hour / mL; at least 40,000 ng-hour / mL; at least 42,500 ng-hour / mL; at least 45,000 ng-hour / mL; at least 47,500 ng-hour / mL; or at least 50,000 ng-hour / mL. According to these embodiments, one suitable superoxide dismutase mimetic is the dichloro complex form of formula (GC4419).

[0054] Methods and Indications For the purpose of treating various diseases and conditions modulated by tissue injury and / or superoxide, the superoxide dismutase mimetics described herein (e.g., superoxide dismutase mimetics corresponding to formula (GC4419)) can be used. Typically, such tissue injury, diseases, and conditions can be treated by controlling the superoxide level in a subject, and preferably, a compound corresponding to formula (GC4419) can be administered alone or in combination with another active agent, for example, as part of a therapeutic regimen or a prophylactic regimen, to treat such tissue injury, diseases, and conditions. Treatment of the diseases and conditions (including tissue injury) described herein generally not only inhibits the disease in a patient who is experiencing or has been exposed to the pathology or symptoms of the disease or condition (i.e., suppresses further development of the pathology and / or symptoms), but may also involve restoring the disease or condition in a patient who is experiencing or has been exposed to the pathology or symptoms of the disease or condition (i.e., reversing the pathology and / or symptoms). As a result of treating a human patient with respect to a disease or condition described herein (e.g., tissue injury resulting from the application of radiation therapy or chemotherapy or radiation exposure), it will also be possible to inhibit or prevent such injury in a patient who does not necessarily experience or have been exposed to the pathology or symptoms of the disease or condition.

[0055] The methods of the present disclosure can be advantageously used for the purpose of treating (e.g., inhibiting, restoring, or alleviating) various diseases or conditions in various subjects (i.e., patients). The subject can be, for example, a mammal such as a bovine, avian, canine, equine, feline, ovine, porcine, primate (including humans and non-human primates), etc. Also included in the subject are important mammals due to being in crisis, economically important mammals, for example, animals raised on farmland for human consumption, and animals having social importance to humans (e.g., as pets or animals maintained in zoos). Examples of such animals include, but are not limited to, cats, dogs, pigs, ruminants or ungulates such as cows, bulls, sheep, giraffes, deer, goats, bison, camels, horses. In one embodiment, the subject is a bovine, avian, canine, equine, feline, ovine, porcine, or non-human primate. In a preferred embodiment, the subject is a human patient.

[0056] Treatment of tissue damage According to one aspect of the present disclosure, a method of treating tissue damage resulting from cancer treatment (e.g., radiotherapy or chemotherapy) performed on a subject in need of treatment is described herein. According to another aspect of the present disclosure, a method of treating tissue damage in a human patient resulting from radiation exposure is described herein. Thus, for example, in various embodiments, the radiation exposure in various embodiments can be accidental radiation exposure, non-intentional radiation exposure, or intentional radiation exposure. As described above, the treatment of tissue damage described herein can include both inhibition (i.e., prevention) and restoration of tissue damage that can result from some event or activity. Generally, this treatment method involves administering to the subject a therapeutically effective amount of a superoxide dismutase mimetic corresponding to formula (GC4419). In a preferred embodiment, the superoxide dismutase mimetic is in the dichloro complex form of formula (GC4419).

[0057] Treatment of tissue damage resulting from cancer treatment or other radiation exposure by the methods described herein involves administering a therapeutically effective amount of a superoxide dismutase mimetic corresponding to formula (GC4419). Generally, various therapeutically effective amounts may be used, for example, depending on among other factors, the selected compound and its safety and efficacy, the type, location, and severity of the tissue damage, various therapeutically effective amounts may be used.

[0058] In some embodiments, treatment of tissue damage by the methods described herein involves administering a superoxide dismutase mimetic corresponding to formula (GC4419) at a relatively high dose and / or at relatively rapid time intervals. According to the treatment methods described herein for tissue damage resulting from cancer treatment or other radiation exposure, the superoxide dismutase mimetic may be administered in various amounts (e.g., at least 25 mg, 50 mg, 100 mg, etc., or another amount based on the patient's weight) within a specific time frame, for example, within 15 minutes, 30 minutes, 60 minutes, or a time frame greater than 60 minutes. According to these embodiments, one suitable superoxide dismutase mimetic is the dichloro complex form of formula (GC4419).

[0059] For example, in one embodiment, an amount of a superoxide dismutase mimetic corresponding to formula (GC4419) is administered to a patient within a 15-minute time frame. According to this embodiment, for example, the dosage can be at least 25 mg, at least 50 mg, at least 75 mg, at least 100 mg, at least 125 mg, at least 150 mg, at least 175 mg, at least 200 mg, at least 225 mg, at least 250 mg, at least 275 mg, or at least 300 mg of a superoxide dismutase mimetic corresponding to formula (GC4419). Thus, for example, at least 25 mg can be administered to the patient within a 15-minute time frame; at least 50 mg can be administered to the patient within a 15-minute time frame; at least 75 mg can be administered to the patient within a 15-minute time frame; at least 100 mg can be administered to the patient within a 15-minute time frame; at least 125 mg can be administered to the patient within a 15-minute time frame; or at least 150 mg can be administered to the patient within a 15-minute time frame. According to these embodiments, one suitable superoxide dismutase mimetic is the dichloro complex form of formula (GC4419).

[0060] For example, in another embodiment, an amount of a superoxide dismutase mimetic corresponding to formula (GC4419) is administered to a patient within a 30-minute time frame. According to this embodiment, for example, the dosage can be at least 50 mg, at least 75 mg, at least 100 mg, at least 125 mg, at least 150 mg, at least 175 mg, at least 200 mg, at least 225 mg, at least 250 mg, at least 275 mg, or at least 300 mg of a superoxide dismutase mimetic corresponding to formula (GC4419). Thus, for example, at least 50 mg can be administered to the patient within a 30-minute time frame; at least 75 mg can be administered to the patient within a 30-minute time frame; at least 100 mg can be administered to the patient within a 30-minute time frame; at least 125 mg can be administered to the patient within a 30-minute time frame; at least 125 mg can be administered to the patient within a 30-minute time frame; at least 150 mg can be administered to the patient within a 30-minute time frame; at least 175 mg can be administered to the patient within a 30-minute time frame; at least 200 mg can be administered to the patient within a 30-minute time frame; at least 225 mg can be administered to the patient within a 30-minute time frame; at least 250 mg can be administered to the patient within a 30-minute time frame; at least 275 mg can be administered to the patient within a 30-minute time frame; or at least 300 mg can be administered to the patient within a 30-minute time frame. According to these embodiments, one suitable superoxide dismutase mimetic is the dichloro complex form of formula (GC4419).

[0061] For example, in another embodiment, an amount of a superoxide dismutase mimetic corresponding to formula (GC4419) is administered to a patient within a 45-minute time frame. According to this embodiment, for example, the dosage can be at least 50 mg, at least 75 mg, at least 100 mg, at least 125 mg, at least 150 mg, at least 175 mg, at least 200 mg, at least 225 mg, at least 250 mg, at least 275 mg, at least 300 mg, at least 325 mg, at least 350 mg, at least 375 mg, at least 400 mg, at least 425 mg, or at least 450 mg of a superoxide dismutase mimetic corresponding to formula (GC4419). Thus, for example, at least 50 mg can be administered to the patient within a 45-minute time frame; at least 75 mg can be administered to the patient within a 45-minute time frame; at least 100 mg can be administered to the patient within a 45-minute time frame; at least 125 mg can be administered to the patient within a 45-minute time frame; at least 125 mg can be administered to the patient within a 45-minute time frame; at least 150 mg can be administered to the patient within a 45-minute time frame; at least 175 mg can be administered to the patient within a 45-minute time frame; at least 200 mg can be administered to the patient within a 45-minute time frame; at least 225 mg can be administered to the patient within a 45-minute time frame; at least 250 mg can be administered to the patient within a 45-minute time frame; at least 275 mg can be administered to the patient within a 45-minute time frame; at least 300 mg can be administered to the patient within a 45-minute time frame; at least 325 mg can be administered to the patient within a 45-minute time frame; at least 350 mg can be administered to the patient within a 45-minute time frame; at least 375 mg can be administered to the patient within a 45-minute time frame; at least 400 mg can be administered to the patient within a 45-minute time frame; at least 425 mg can be administered to the patient within a 45-minute time frame; or at least 450 mg can be administered to the patient within a 45-minute time frame. According to these embodiments, one suitable superoxide dismutase mimetic is the dichloro complex form of formula (GC4419).

[0062] For example, in another embodiment, an amount of a superoxide dismutase mimetic corresponding to formula (GC4419) is administered to a patient within a time frame of 60 minutes. According to this embodiment, for example, the dosage can be at least 50 mg, at least 75 mg, at least 100 mg, at least 125 mg, at least 150 mg, at least 175 mg, at least 200 mg, at least 225 mg, at least 250 mg, at least 275 mg, at least 300 mg, at least 325 mg, at least 350 mg, at least 375 mg, at least 400 mg, at least 425 mg, at least 450 mg, at least 475 mg, at least 500 mg, at least 525 mg, at least 550 mg, at least 575 mg, or at least 600 mg of a superoxide dismutase mimetic corresponding to formula (GC4419).Thus, for example, at least 50 mg may be administered to a patient within a time frame of 60 minutes; at least 75 mg may be administered to a patient within a time frame of 60 minutes; at least 100 mg may be administered to a patient within a time frame of 60 minutes; at least 125 mg may be administered to a patient within a time frame of 60 minutes; at least 125 mg may be administered to a patient within a time frame of 60 minutes; at least 150 mg may be administered to a patient within a time frame of 60 minutes; at least 175 mg may be administered to a patient within a time frame of 60 minutes; at least 200 mg may be administered to a patient within a time frame of 60 minutes; at least 225 mg may be administered to a patient within a time frame of 60 minutes; at least 250 mg may be administered to a patient within a time frame of 60 minutes; at least 275 mg may be administered to a patient within a time frame of 60 minutes; at least 300 mg may be administered to a patient within a time frame of 60 minutes; at least 325 mg may be administered to a patient within a time frame of 60 minutes; at least 350 mg may be administered to a patient within a time frame of 60 minutes; at least 375 mg may be administered to a patient within a time frame of 60 minutes; at least 400 mg may be administered to a patient within a time frame of 60 minutes; at least 425 mg may be administered to a patient within a time frame of 60 minutes; at least 450 mg may be administered to a patient within a time frame of 60 minutes; at least 475 mg may be administered to a patient within a time frame of 60 minutes; at least 500 mg may be administered to a patient within a time frame of 60 minutes; at least 525 mg may be administered to a patient within a time frame of 60 minutes; at least 550 mg may be administered to a patient within a time frame of 60 minutes; at least 575 mg may be administered to a patient within a time frame of 60 minutes; or at least 600 mg may be administered to a patient within a time frame of 60 minutes. According to these embodiments, one preferred superoxide dismutase mimetic is the dichloro complex form of formula (GC4419).

[0063] In other embodiments, a superoxide dismutase mimetic corresponding to formula (GC4419) is administered to a patient within a specific time frame (e.g., 15 minutes, 30 minutes, 45 minutes, or 60 minutes) at a dose of at least 0.67 mg per kg of patient body weight; at least 1.0 mg per kg of patient body weight; at least 1.5 mg per kg of patient body weight; at least 2.0 mg per kg of patient body weight; at least 2.5 mg per kg of patient body weight; at least 3.0 mg per kg of patient body weight; at least 3.5 mg per kg of patient body weight; at least 4.0 mg per kg of patient body weight; at least 5.0 mg per kg of patient body weight; at least 6.0 mg per kg of patient body weight; at least 7.5 mg per kg of patient body weight; or at least 10.0 mg per kg of patient body weight. Thus, for example, at least 0.67 mg per kg of patient body weight may be administered to the patient within a 15-minute time frame; at least 1.0 mg per kg of patient body weight may be administered to the patient within a 15-minute time frame; at least 1.5 mg per kg of patient body weight may be administered to the patient within a 15-minute time frame; at least 2.0 mg per kg of patient body weight may be administered to the patient within a 15-minute time frame; at least 2.5 mg per kg of patient body weight may be administered to the patient within a 15-minute time frame; at least 0.67 mg per kg of patient body weight may be administered to the patient within a 30-minute time frame; at least 1.0 mg per kg of patient body weight may be administered to the patient within a 30-minute time frame; at least 1.5 mg per kg of patient body weight may be administered to the patient within a 30-minute time frame; at least 2.0 mg per kg of patient body weight may be administered to the patient within a 30-minute time frame; at least 2.5 mg per kg of patient body weight may be administered to the patient within a 30-minute time frame; at least 3.0 mg per kg of patient body weight may be administered to the patient within a 30-minute time frame; at least 3.5 mg per kg of patient body weight may be administered to the patient within a 30-minute time frame; at least 4.0 mg per kg of patient body weight may be administered to the patient within a 30-minute time frame; at least 5.0 mg per kg of patient body weight may be administered to the patient within a 30-minute time frame; at least 6.0 mg per kg of patient body weight may be administered to the patient within a 30-minute time frame; at least 7.It may be administered to the patient at 5 mg within a time frame of 30 minutes; it may be administered to the patient at at least 0.67 mg per kg of patient body weight within a time frame of 45 minutes; it may be administered to the patient at at least 1.0 mg per kg of patient body weight within a time frame of 45 minutes; it may be administered to the patient at at least 1.5 mg per kg of patient body weight within a time frame of 45 minutes; it may be administered to the patient at at least 2.0 mg per kg of patient body weight within a time frame of 45 minutes; it may be administered to the patient at at least 2.5 mg per kg of patient body weight within a time frame of 45 minutes; it may be administered to the patient at at least 3.0 mg per kg of patient body weight within a time frame of 45 minutes; it may be administered to the patient at at least 3.5 mg per kg of patient body weight within a time frame of 45 minutes; it may be administered to the patient at at least 4.0 mg per kg of patient body weight within a time frame of 45 minutes; it may be administered to the patient at at least 5.0 mg per kg of patient body weight within a time frame of 45 minutes; it may be administered to the patient at at least 6.0 mg per kg of patient body weight within a time frame of 45 minutes; it may be administered to the patient at at least 7.5 mg per kg of patient body weight within a time frame of 45 minutes; it may be administered to the patient at at least 0.67 mg per kg of patient body weight within a time frame of 60 minutes; it may be administered to the patient at at least 1.0 mg per kg of patient body weight within a time frame of 60 minutes; it may be administered to the patient at at least 1.5 mg per kg of patient body weight within a time frame of 60 minutes; it may be administered to the patient at at least 2.0 mg per kg of patient body weight within a time frame of 60 minutes; it may be administered to the patient at at least 2.5 mg per kg of patient body weight within a time frame of 60 minutes; it may be administered to the patient at at least 3.0 mg per kg of patient body weight within a time frame of 60 minutes; it may be administered to the patient at at least 3.5 mg per kg of patient body weight within a time frame of 60 minutes; it may be administered to the patient at at least 4.0 mg per kg of patient body weight within a time frame of 60 minutes; it may be administered to the patient at at least 5.0 mg per kg of patient body weight within a time frame of 60 minutes; it may be administered to the patient at at least 6.0 mg per kg of patient body weight within a time frame of 60 minutes; it may be administered to the patient at at least 7.5 mg per kg of patient body weight within a time frame of 60 minutes; or at least 10. per kg of patient body weight.0 mg may be administered to a patient within a time frame of 60 minutes. According to these embodiments, one suitable superoxide dismutase mimetic is the dichloro complex form of formula (GC4419).

[0064] For example, in other embodiments, the dosage (i.e., the dosage without considering the administration time) is at least 25 mg, at least 50 mg, at least 75 mg, at least 100 mg, at least 125 mg, at least 150 mg, at least 175 mg, at least 200 mg, at least 225 mg, at least 250 mg, at least 275 mg, at least 300 mg, at least 325 mg, at least 350 mg, at least 375 mg, at least 400 mg, at least 425 mg, at least 450 mg, at least 475 mg, at least 500 mg, at least 525 mg, at least 550 mg, at least 575 mg, or at least 600 mg of a superoxide dismutase mimetic corresponding to formula (GC4419). For example, in other embodiments, the dosage (i.e., the dosage without considering the administration time) is at least 0.67 mg per kg of patient body weight; at least 1.0 mg per kg of patient body weight; at least 1.5 mg per kg of patient body weight; at least 2.0 mg per kg of patient body weight; at least 2.5 mg per kg of patient body weight; at least 3.0 mg per kg of patient body weight; at least 3.5 mg per kg of patient body weight; at least 4.0 mg per kg of patient body weight; at least 5.0 mg per kg of patient body weight; at least 6.0 mg per kg of patient body weight; at least 7.5 mg per kg of patient body weight; or at least 10.0 mg per kg of patient body weight; or at least 10.0 mg per kg of patient body weight.

[0065] If desired, the effective dosage may be divided into multiple administrations for the purpose of administration. Thus, a single dosage composition may contain the effective dosage, or the divided amounts thereof that make up the effective dosage.

[0066] Moreover, some aspects of the present disclosure relate to an improved pharmacokinetic profile when the superoxide dismutase mimics described herein are administered to a subject. Due at least in part to the improved safety profile of the superoxide dismutase mimics corresponding to formula (GC4419) (e.g., GC4419), when such compounds are administered, the patient exposure measured using AUC (i.e., the area under the curve of the plasma compound concentration graph over time) is increased compared to the relevant superoxide dismutase mimics (e.g., the above-mentioned mirror image compound GC4403).

[0067] For example, in one embodiment, the method described herein comprises administering a superoxide dismutase mimic corresponding to formula (GC4419) to a patient, such that the exposure measured using the area under the curve (AUC) is at least 4,000 ng-hour / mL, calculated from the measured value of the superoxide dismutase mimic concentration in the patient's plasma. Thus, the value of AUC can be at least 5,000 ng-hour / mL; at least 7,500 ng-hour / mL; at least 10,000 ng-hour / mL; at least 12,500 ng-hour / mL; at least 15,000 ng-hour / mL; at least 17,500 ng-hour / mL; at least 20,000 ng-hour / mL; at least 22,500 ng-hour / mL; at least 25,000 ng-hour / mL; at least 27,500 ng-hour / mL; at least 30,000 ng-hour / mL; at least 32,500 ng-hour / mL; at least 35,000 ng-hour / mL; at least 37,500 ng-hour / mL; at least 40,000 ng-hour / mL; at least 42,500 ng-hour / mL; at least 45,000 ng-hour / mL; at least 47,500 ng-hour / mL; or at least 50,000 ng-hour / mL, calculated from the measured value of the superoxide dismutase mimic concentration in the patient's plasma. According to these embodiments, one suitable superoxide dismutase mimic is the dichloro complex form of formula (GC4419).

[0068] Generally, the temporal aspects of the administration of superoxide dismutase mimetics can depend, for example, on a particular compound, the selected radiotherapy or chemotherapy, the type, nature, and / or duration of radiation exposure. Other considerations include the disease or disorder being treated, and the severity of the disease or disorder; the activity of the particular compound being used; the particular composition being used; the age, weight, general health, sex, and diet of the subject; the administration time, route, and excretion rate of the particular compound being used; the treatment period; drugs used in combination with or concurrently with the particular compound being used; and like factors. For example, in various embodiments, the superoxide dismutase mimetic may be administered before, during, and / or after the application of cancer treatment (e.g., radiotherapy or chemotherapy). As another example, in various embodiments, the superoxide dismutase mimetic may be administered before, during, and / or after radiation exposure.

[0069] For example, in one embodiment, the superoxide dismutase mimetic is administered to a patient before or concurrently with cancer treatment. For example, in another embodiment, the superoxide dismutase mimetic is administered to a patient before cancer treatment but not after cancer treatment. In yet another embodiment, the superoxide dismutase mimetic is administered to a patient at least 15 minutes before, 30 minutes before, 45 minutes before, 60 minutes before, 90 minutes before, 180 minutes before, 0.5 days before, 1 day before, 3 days before, 5 days before, 1 week before, 2 weeks before, 3 weeks before, 4 weeks before, 5 weeks before, 6 weeks before, 7 weeks before, 8 weeks before, 9 weeks before, 10 weeks before, 11 weeks before, 12 weeks before, or more before cancer treatment. For example, in still other embodiments, the superoxide dismutase mimetic is administered to a patient after cancer treatment. Thus, for example, the superoxide dismutase mimetic may be administered up to 15 minutes after, 30 minutes after, 45 minutes after, 60 minutes after, 90 minutes after, 180 minutes after, 0.5 days after, 1 day after, 3 days after, 5 days after, 1 week after, 2 weeks after, 3 weeks after, 4 weeks after, 5 weeks after, 6 weeks after, 7 weeks after, 8 weeks after, 9 weeks after, 10 weeks after, 11 weeks after, 12 weeks after, or more after cancer treatment. According to these embodiments, one suitable superoxide dismutase mimetic is the dichloro complex form of formula (GC4419).

[0070] For example, in another embodiment, a superoxide dismutase mimetic is administered to a patient before or simultaneously with radiation exposure. For example, in another embodiment, a superoxide dismutase mimetic is administered to a patient before radiation exposure but not after radiation exposure. In yet another embodiment, a superoxide dismutase mimetic is administered to a patient at least 15 minutes before, 30 minutes before, 45 minutes before, 60 minutes before, 90 minutes before, 180 minutes before, 0.5 days before, 1 day before, 3 days before, 5 days before, 1 week before, 2 weeks before, 3 weeks before, 4 weeks before, 5 weeks before, 6 weeks before, 7 weeks before, 8 weeks before, 9 weeks before, 10 weeks before, 11 weeks before, 12 weeks before, or earlier than that before radiation exposure. For example, in still other embodiments, a superoxide dismutase mimetic is administered to a patient after radiation exposure. Thus, for example, a superoxide dismutase mimetic may be administered from 15 minutes after, 30 minutes after, 45 minutes after, 60 minutes after, 90 minutes after, 180 minutes after, 0.5 days after, 1 day after, 3 days after, 5 days after, 1 week after, 2 weeks after, 3 weeks after, 4 weeks after, 5 weeks after, 6 weeks after, 7 weeks after, 8 weeks after, 9 weeks after, 10 weeks after, 11 weeks after, 12 weeks after, or later than that after radiation exposure. According to these embodiments, one suitable superoxide dismutase mimetic is the dichloro complex form of formula (GC4419).

[0071] For example, in one embodiment, cancer treatment includes the application of radiation therapy (e.g., intentional exposure to radiation). According to this embodiment, by administering to a patient a therapeutically effective amount of a superoxide dismutase mimetic corresponding to formula (GC4419), a safe and effective method is provided for treating radiation damage in a patient in need of treatment and inhibiting or recovering radiation-related cancer or radiation-related tissue damage.

[0072] In another embodiment, the exposure to radiation is accidental or non-intentional exposure. For example, radiation exposure can occur due to a wide variety of commercial and non-commercial activities, such as, but not limited to, public facilities, power, oil / gas petrochemicals, chemicals / plastics, automatic ventilation control (cooking, smoking, etc.), heavy industrial manufacturing, environmental toxicity and remediation, biomedicine, cosmetics / fragrances, pharmaceuticals, transportation, emergency response and law enforcement, military or terrorist activities, detection (e.g., leakage or spillage of harmful substances), etc. in various industries. For example, in one embodiment, exposure to radiation can occur due to the excavation and / or purification of radioactive substances from air, groundwater, surface water, sediment, and / or soil.

[0073] In various embodiments, the radiation source can be electromagnetic radiation (including visible light, ultraviolet light) or nuclear radiation (including alpha rays, beta rays, gamma rays, cosmic rays). The types of damage can include, but are not limited to, various forms of dermatological or mucosal damage such as mucositis, esophagitis, etc., internal cell loss, fibrosis, cyst formation, neuropathy, as well as various benign and malignant tumors.

[0074] Additionally, or alternatively, in another embodiment, cancer treatment includes administration of a chemotherapeutic agent. In the method according to this embodiment, by administering to a patient a therapeutically effective amount of a superoxide dismutase mimetic corresponding to formula (GC4419), a safe and effective method is provided for treating, restoring, or inhibiting the toxicity to normal tissues resulting from chemotherapy in a patient in need of treatment or a patient who has received an accidental or intentional administration of a chemical agent having a toxic component of free radicals. The methods described herein are useful in reducing the toxicity of chemical agents having a free radical component (including, among others, fluoropyrimidines, pyrimidine nucleosides, purines, platinum analogs, anthracyclines, podophyllotoxins, camptothecins, hormones and hormone analogs, enzymes, proteins and antibodies, vinca alkaloids, taxanes, etc.). The toxicity reduction method of the present invention can be applied to any chemotherapeutic agent, but representative examples include irinotecan, FU, paclitaxel, docetaxel, cisplatin, doxorubicin, oxaliplatin, cyclophosphamide, EGF and VGF inhibitors, acemannan, acetaminophen, aclarubicin, aldesleukin, alemtuzumab, alitretinoin, altretamine, amifostine, aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole, ANCER, ansetim, ARGLABIN, arsenic acid, BAM 002 (Novelos), bexarotene, bicalutamide, broxuridine, capecitabine, sermolukin, cetrorelix, cladribine, clotrimazole, cytarabine ocfosfate, DA3030 (Dong-A), daclizumab, denileukin diftitox, deslorelin, dexrazoxane, dilazep, docetaxel, docosanol, doxacalciferol, doxifluridine, doxorubicin, bromocriptine, carmustine, cytarabine, fluorouracil, HIT diclofenac, interferon alpha, daunorubicin, tretinoin, edelfosine, edrecolomab, eflornithine, emiteflu, epirubicin, epoetin beta, etoposide phosphate, exemestane, exisulind, fadrozole, filgrastim, finasteride, fludarabine phosphate, formestane, fotemustine, gemcitabine, gemtuzumab zogamicin (gemtuzumab zogamicin), gimeracil / oteracil / tegafur combination drug, glycopine, goserelin, heptaplatin, human chorionic gonadotropin, human fetal alpha-fetoprotein, ibandronate, idarubicin, IL-2, imiquimod, interferon alpha, interferon alpha, natural type, interferon alpha-2, interferon alpha-2a, interferon alpha-2b, interferon alpha-N1, interferon alpha-n3, interferon alfacon-1, interferon alpha, natural type, interferon beta, interferon beta-1a, interferon beta-1b, interferon gamma, natural type interferon gamma-1a, interferon gamma-1b, interleukin-1beta, iobenguane, irinotecan, irsogladine, lanreotide, LC9018 (Yakult), Leflunomide, Lenograstim, Lentinan Sulfate, Letrozole, Leukocyte α - Interferon, Leuprorelin, Levamisole + Fluorouracil, Rialozole, Lobaplatin, Lonidamine, Lovastatin, Masoprocol, Mercaptopropionylglycine, Metoclopramide, Mifepristone, Miltefosine, Muramostim, Inappropriate Double - stranded RNA, Mitoguazone, Mitolactol, Mitoxantrone, Molgramostim, Nafarelin, Naloxone + Pentazocine, Nartograstim, Nedaplatin, Nilutamide, Noscapine, Novel Erythropoiesis - Promoting Protein, NSC631570 Octreotide, Oprelvekin, Osaterone, Oxaliplatin, Paclitaxel, Pamidronic Acid, Pegaspargase, Peg Interferon α - 2b, Pentosan Polysulfate Sodium, Pentostatin, Picibanil, Pirarubicin, Rabbit Anti - Thymocyte Polyclonal Antibody, Polyethylene Glycol Interferon α - 2a, Porfimer Sodium, Raloxifene, Raltitrexed, Rasburicase, Rhenium Re186 Etidronate, RII Retinamid, Rituximab, Romurtide, Lexidronam Samarium (153 Sm), Sargramostim, Schizophyllan, Sobuzoxan, Sonermin, Strontium Chloride - 89, Suramin, Tasermin, Tazarotene, Tegafur, Temoporfin, Temozolomide, Teniposide, Tetrachlorodecaoxide, Thalidomide, Timalphasin, Thyroid - Stimulating Hormone α, Topotecan, Toremifene, Tositumomab - Iodine 131, Trastuzumab, Treosulfan, Tretinoin, Trilostane, Trimethoprim, Triptorelin, Tumor Necrosis Factor α, Native Type, Ubenimex, Bladder Cancer Vaccine, Maruyama Vaccine, Melanoma Lysate Vaccine, Valrubicin, Verteporfin, Vinorelbine, VIRULIZIN, Dinostatin Stimalamer, or Zoledronic Acid; Abarelix; AE941 (Eternacept), Ambamustine, Antisense Oligonucleotide, bcl - 2 (Genentech), APC8015 (dendron), cetuximab, decitabine, dexaminoglutethimide, diacontin, EL532 (Elan), EM800 (Androscience), eniluracil, etanidazole, fenretinide, filgrastim SDO1 (Amgen), fulvestrant, galocitabine, gastrin 17 immunogen, HLA-17 gene therapy (Vical), granulocyte macrophage colony-stimulating factor, histamine dihydrochloride, ibritumomab tiuxetan, iromostat, IM862 (Cytel), interleukin-2, ibuprofen, LDI200 (Millhouse), leridistim, lenzilumab, CA 125 MAb (BioMira), cancer MAb (Japan Drug Development), HER-2 and Fc MAb (Medarex), idiotypic 105AD7 MAb (CRC Technologies), idiotypic CEA MAb (Trileix), LYM-1-iodine 131 MAb (Techniclone), polymorphic epithelial mucin-itrim 90 MAb (Antisoma), marimastat, menogaril, mitsumomab, motexafin, gadolinium, MX6 (Galderma), nelarabine, nolatrexed, P30 protein, pegvisomant, pemetrexed, porfiromycin, prinomastat, RL0903 (Shire), rubitecan, satraplatin, sodium phenylacetate, strontium ranelate, SRL172 (SR Pharma), SU5416 (Sugen), SU6668 (Sugen), TA077 (Tanabe), tetrathiomolybdate, taliblastine, thrombopoietin, ethyl ethiopurpurin tin, tirapazamine, cancer vaccine (BioMira), melanoma vaccine (New York University), melanoma vaccine (Memorial Sloan-Kettering Cancer Center), melanoma tumor lysate vaccine (New York Medical College), viral melanoma cell lysate vaccine (Royal Victoria Infirmary), and valspodar.

[0075] Treatment of diseases and conditions Described herein are methods of treatment according to another aspect of the present disclosure for various diseases and conditions modulated by superoxide in a subject in need of treatment. As noted above, treatment of the diseases and conditions described herein can include both inhibition (i.e., prevention) and restoration of the disease or condition. Generally, the method of treatment involves administering to the subject a therapeutically effective amount of a superoxide dismutase mimetic corresponding to formula (GC4419). In a preferred embodiment, the superoxide dismutase mimetic is the dichloro complex of formula (GC4419).

[0076] Treatment of diseases and conditions by the methods described herein involves administering a superoxide dismutase mimetic corresponding to formula (GC4419) at a relatively high dose and / or at relatively rapid time intervals. According to the methods of treatment described herein for tissue damage resulting from cancer treatment or other radiation exposure, the superoxide dismutase mimetic can be administered in various amounts (e.g., at least 25 mg, 50 mg, 100 mg, etc., or another amount based on the patient's weight) within a specific time frame, such as within 15 minutes, 30 minutes, 45 minutes, 60 minutes, or a time frame greater than 60 minutes.

[0077] For example, in one embodiment, an amount of a superoxide dismutase mimetic corresponding to formula (GC4419) is administered to a patient within a 15-minute time frame. According to this embodiment, for example, the dosage can be at least 25 mg, at least 50 mg, at least 75 mg, at least 100 mg, at least 125 mg, at least 150 mg, at least 175 mg, at least 200 mg, at least 225 mg, at least 250 mg, at least 275 mg, or at least 300 mg of the superoxide dismutase mimetic corresponding to formula (GC4419). Thus, for example, at least 25 mg can be administered to the patient within a 15-minute time frame; at least 50 mg can be administered to the patient within a 15-minute time frame; at least 75 mg can be administered to the patient within a 15-minute time frame; at least 100 mg can be administered to the patient within a 15-minute time frame; at least 125 mg can be administered to the patient within a 15-minute time frame; or at least 150 mg can be administered to the patient within a 15-minute time frame. According to these embodiments, one suitable superoxide dismutase mimetic is the dichloro complex form of formula (GC4419).

[0078] For example, in another embodiment, an amount of a superoxide dismutase mimetic corresponding to formula (GC4419) is administered to a patient within a 30-minute time frame. According to this embodiment, for example, the dosage can be at least 50 mg, at least 75 mg, at least 100 mg, at least 125 mg, at least 150 mg, at least 175 mg, at least 200 mg, at least 225 mg, at least 250 mg, at least 275 mg, or at least 300 mg of the superoxide dismutase mimetic corresponding to formula (GC4419). Thus, for example, at least 50 mg can be administered to the patient within a 30-minute time frame; at least 75 mg can be administered to the patient within a 30-minute time frame; at least 100 mg can be administered to the patient within a 30-minute time frame; at least 125 mg can be administered to the patient within a 30-minute time frame; at least 125 mg can be administered to the patient within a 30-minute time frame; at least 150 mg can be administered to the patient within a 30-minute time frame; at least 175 mg can be administered to the patient within a 30-minute time frame; at least 200 mg can be administered to the patient within a 30-minute time frame; at least 225 mg can be administered to the patient within a 30-minute time frame; at least 250 mg can be administered to the patient within a 30-minute time frame; at least 275 mg can be administered to the patient within a 30-minute time frame; or at least 300 mg can be administered to the patient within a 30-minute time frame. According to these embodiments, one suitable superoxide dismutase mimetic is the dichloro complex form of formula (GC4419).

[0079] For example, in another embodiment, an amount of a superoxide dismutase mimetic corresponding to formula (GC4419) is administered to a patient within a 45-minute time frame. According to this embodiment, for example, the dosage can be at least 50 mg, at least 75 mg, at least 100 mg, at least 125 mg, at least 150 mg, at least 175 mg, at least 200 mg, at least 225 mg, at least 250 mg, at least 275 mg, at least 300 mg, at least 325 mg, at least 350 mg, at least 375 mg, at least 400 mg, at least 425 mg, or at least 450 mg of a superoxide dismutase mimetic corresponding to formula (GC4419). Thus, for example, at least 50 mg can be administered to the patient within a 45-minute time frame; at least 75 mg can be administered to the patient within a 45-minute time frame; at least 100 mg can be administered to the patient within a 45-minute time frame; at least 125 mg can be administered to the patient within a 45-minute time frame; at least 125 mg can be administered to the patient within a 45-minute time frame; at least 150 mg can be administered to the patient within a 45-minute time frame; at least 175 mg can be administered to the patient within a 45-minute time frame; at least 200 mg can be administered to the patient within a 45-minute time frame; at least 225 mg can be administered to the patient within a 45-minute time frame; at least 250 mg can be administered to the patient within a 45-minute time frame; at least 275 mg can be administered to the patient within a 45-minute time frame; at least 300 mg can be administered to the patient within a 45-minute time frame; at least 325 mg can be administered to the patient within a 45-minute time frame; at least 350 mg can be administered to the patient within a 45-minute time frame; at least 375 mg can be administered to the patient within a 45-minute time frame; at least 400 mg can be administered to the patient within a 45-minute time frame; at least 425 mg can be administered to the patient within a 45-minute time frame; or at least 450 mg can be administered to the patient within a 45-minute time frame. According to these embodiments, one suitable superoxide dismutase mimetic is the dichloro complex form of formula (GC4419).

[0080] For example, in another embodiment, an amount of a superoxide dismutase mimetic corresponding to formula (GC4419) is administered to a patient within a time frame of 60 minutes. According to this embodiment, for example, the dosage can be at least 50 mg, at least 75 mg, at least 100 mg, at least 125 mg, at least 150 mg, at least 175 mg, at least 200 mg, at least 225 mg, at least 250 mg, at least 275 mg, at least 300 mg, at least 325 mg, at least 350 mg, at least 375 mg, at least 400 mg, at least 425 mg, at least 450 mg, at least 475 mg, at least 500 mg, at least 525 mg, at least 550 mg, at least 575 mg, or at least 600 mg of a superoxide dismutase mimetic corresponding to formula (GC4419).Thus, for example, at least 50 mg may be administered to a patient within a time frame of 60 minutes; at least 75 mg may be administered to a patient within a time frame of 60 minutes; at least 100 mg may be administered to a patient within a time frame of 60 minutes; at least 125 mg may be administered to a patient within a time frame of 60 minutes; at least 125 mg may be administered to a patient within a time frame of 60 minutes; at least 150 mg may be administered to a patient within a time frame of 60 minutes; at least 175 mg may be administered to a patient within a time frame of 60 minutes; at least 200 mg may be administered to a patient within a time frame of 60 minutes; at least 225 mg may be administered to a patient within a time frame of 60 minutes; at least 250 mg may be administered to a patient within a time frame of 60 minutes; at least 275 mg may be administered to a patient within a time frame of 60 minutes; at least 300 mg may be administered to a patient within a time frame of 60 minutes; at least 325 mg may be administered to a patient within a time frame of 60 minutes; at least 350 mg may be administered to a patient within a time frame of 60 minutes; at least 375 mg may be administered to a patient within a time frame of 60 minutes; at least 400 mg may be administered to a patient within a time frame of 60 minutes; at least 425 mg may be administered to a patient within a time frame of 60 minutes; at least 450 mg may be administered to a patient within a time frame of 60 minutes; at least 475 mg may be administered to a patient within a time frame of 60 minutes; at least 500 mg may be administered to a patient within a time frame of 60 minutes; at least 525 mg may be administered to a patient within a time frame of 60 minutes; at least 550 mg may be administered to a patient within a time frame of 60 minutes; at least 575 mg may be administered to a patient within a time frame of 60 minutes; or at least 600 mg may be administered to a patient within a time frame of 60 minutes. According to these embodiments, one suitable superoxide dismutase mimetic is the dichloro complex form of formula (GC4419).

[0081] In other embodiments, for example, a superoxide dismutase mimetic corresponding to formula (GC4419) of at least 0.67 mg per kg of patient body weight; at least 1.0 mg per kg of patient body weight; at least 1.5 mg per kg of patient body weight; at least 2.0 mg per kg of patient body weight; at least 2.5 mg per kg of patient body weight; at least 3.0 mg per kg of patient body weight; at least 3.5 mg per kg of patient body weight; at least 4.0 mg per kg of patient body weight; at least 5.0 mg per kg of patient body weight; at least 6.0 mg per kg of patient body weight; at least 7.5 mg per kg of patient body weight; or at least 10.0 mg per kg of patient body weight is administered to the patient within a specific time frame (e.g., 15 minutes, 30 minutes, 45 minutes, or 60 minutes). Thus, for example, at least 0.67 mg per kg of patient body weight may be administered to the patient within a 15-minute time frame; at least 1.0 mg per kg of patient body weight may be administered to the patient within a 15-minute time frame; at least 1.5 mg per kg of patient body weight may be administered to the patient within a 15-minute time frame; at least 2.0 mg per kg of patient body weight may be administered to the patient within a 15-minute time frame; at least 2.5 mg per kg of patient body weight may be administered to the patient within a 15-minute time frame; at least 0.67 mg per kg of patient body weight may be administered to the patient within a 30-minute time frame; at least 1.0 mg per kg of patient body weight may be administered to the patient within a 30-minute time frame; at least 1.5 mg per kg of patient body weight may be administered to the patient within a 30-minute time frame; at least 2.0 mg per kg of patient body weight may be administered to the patient within a 30-minute time frame; at least 2.5 mg per kg of patient body weight may be administered to the patient within a 30-minute time frame; at least 3.0 mg per kg of patient body weight may be administered to the patient within a 30-minute time frame; at least 3.5 mg per kg of patient body weight may be administered to the patient within a 30-minute time frame; at least 4.0 mg per kg of patient body weight may be administered to the patient within a 30-minute time frame; at least 5.0 mg per kg of patient body weight may be administered to the patient within a 30-minute time frame; at least 6.0 mg per kg of patient body weight may be administered to the patient within a 30-minute time frame; at least 7.It is acceptable to administer 5 mg to the patient within a 30-minute time frame; it is acceptable to administer at least 0.67 mg per kg of patient body weight to the patient within a 45-minute time frame; it is acceptable to administer at least 1.0 mg per kg of patient body weight to the patient within a 45-minute time frame; it is acceptable to administer at least 1.5 mg per kg of patient body weight to the patient within a 45-minute time frame; it is acceptable to administer at least 2.0 mg per kg of patient body weight to the patient within a 45-minute time frame; it is acceptable to administer at least 2.5 mg per kg of patient body weight to the patient within a 45-minute time frame; it is acceptable to administer at least 3.0 mg per kg of patient body weight to the patient within a 45-minute time frame; it is acceptable to administer at least 3.5 mg per kg of patient body weight to the patient within a 45-minute time frame; it is acceptable to administer at least 4.0 mg per kg of patient body weight to the patient within a 45-minute time frame; it is acceptable to administer at least 5.0 mg per kg of patient body weight to the patient within a 45-minute time frame; it is acceptable to administer at least 6.0 mg per kg of patient body weight to the patient within a 45-minute time frame; it is acceptable to administer at least 7.5 mg per kg of patient body weight to the patient within a 45-minute time frame; it is acceptable to administer at least 0.67 mg per kg of patient body weight to the patient within a 60-minute time frame; it is acceptable to administer at least 1.0 mg per kg of patient body weight to the patient within a 60-minute time frame; it is acceptable to administer at least 1.5 mg per kg of patient body weight to the patient within a 60-minute time frame; it is acceptable to administer at least 2.0 mg per kg of patient body weight to the patient within a 60-minute time frame; it is acceptable to administer at least 2.5 mg per kg of patient body weight to the patient within a 60-minute time frame; it is acceptable to administer at least 3.0 mg per kg of patient body weight to the patient within a 60-minute time frame; it is acceptable to administer at least 3.5 mg per kg of patient body weight to the patient within a 60-minute time frame; it is acceptable to administer at least 4.0 mg per kg of patient body weight to the patient within a 60-minute time frame; it is acceptable to administer at least 5.0 mg per kg of patient body weight to the patient within a 60-minute time frame; it is acceptable to administer at least 6.0 mg per kg of patient body weight to the patient within a 60-minute time frame; it is acceptable to administer at least 7.5 mg per kg of patient body weight to the patient within a 60-minute time frame; or at least 10. per kg of patient body weight.0 mg may be administered to the patient within a time frame of 60 minutes. According to these embodiments, one suitable superoxide dismutase mimetic is the dichloro complex form of formula (GC4419).

[0082] For example, in other embodiments, the dosage (i.e., the dosage without considering the administration time) is at least 25 mg, at least 50 mg, at least 75 mg, at least 100 mg, at least 125 mg, at least 150 mg, at least 175 mg, at least 200 mg, at least 225 mg, at least 250 mg, at least 275 mg, at least 300 mg, at least 325 mg, at least 350 mg, at least 375 mg, at least 400 mg, at least 425 mg, at least 450 mg, at least 475 mg, at least 500 mg, at least 525 mg, at least 550 mg, at least 575 mg, or at least 600 mg of the superoxide dismutase mimetic corresponding to formula (GC4419). In other embodiments, for example, the dosage (i.e., the dosage without considering the administration time) is at least 0.67 mg per kg of patient body weight; at least 1.0 mg per kg of patient body weight; at least 1.5 mg per kg of patient body weight; at least 2.0 mg per kg of patient body weight; at least 2.5 mg per kg of patient body weight; at least 3.0 mg per kg of patient body weight; at least 3.5 mg per kg of patient body weight; at least 4.0 mg per kg of patient body weight; at least 5.0 mg per kg of patient body weight; at least 6.0 mg per kg of patient body weight; at least 7.5 mg per kg of patient body weight; or at least 10.0 mg per kg of patient body weight; or at least 10.0 mg per kg of patient body weight.

[0083] If desired, the effective dosage may be divided into multiple administrations for the purpose of administration. Thus, a single-dose composition may contain the effective dosage, or the divided amounts that make up the effective dosage.

[0084] In addition, some aspects of the present disclosure relate to an improved pharmacokinetic profile when the superoxide dismutase mimics described herein are administered to a subject. Due at least in part to the improved safety profile of superoxide dismutase mimics corresponding to formula (GC4419) (e.g., the dichloro complex of formula (GC4419)), when such compounds are administered, the patient exposure measured using AUC (i.e., the area under the curve of the plasma compound concentration graph over time) is increased compared to the relevant superoxide dismutase mimics (e.g., the mirror image compound GC4403 described above).

[0085] For example, in one embodiment, the method described herein comprises administering a superoxide dismutase mimic corresponding to formula (GC4419) to a patient to obtain an exposure amount, measured using the area under the curve (AUC), of at least 4,000 ng-hour / mL calculated from the measured value of the superoxide dismutase mimic concentration in the patient's plasma. Thus, the value of AUC can be at least 5,000 ng-hour / mL; at least 7,500 ng-hour / mL; at least 10,000 ng-hour / mL; at least 12,500 ng-hour / mL; at least 15,000 ng-hour / mL; at least 17,500 ng-hour / mL; at least 20,000 ng-hour / mL; at least 22,500 ng-hour / mL; at least 25,000 ng-hour / mL; at least 27,500 ng-hour / mL; at least 30,000 ng-hour / mL; at least 32,500 ng-hour / mL; at least 35,000 ng-hour / mL; at least 37,500 ng-hour / mL; at least 40,000 ng-hour / mL; at least 42,500 ng-hour / mL; at least 45,000 ng-hour / mL; at least 47,500 ng-hour / mL; or at least 50,000 ng-hour / mL, calculated from the measured value of the superoxide dismutase mimic concentration in the patient's plasma. According to these embodiments, one suitable superoxide dismutase mimic is the dichloro complex form of formula (GC4419).

[0086] Generally, the timing aspects of the administration of superoxide dismutase mimetics can depend, for example, on the particular compound or the disease or condition being treated. Other considerations include the severity of the disease or condition; the activity of the particular compound being used; the particular composition being used; the age, weight, general health, sex, and diet of the subject; the administration time, route, and excretion rate of the particular compound being used; the treatment period; drugs used in combination with or concurrently with the particular compound being used; and like factors.

[0087] As described above, the disease or condition treated according to the method described herein can be any disease or condition regulated by superoxide. For example, in one embodiment, the disease or condition is selected from cancer, cardiovascular disorders, cerebrovascular disorders, skin disorders, fibrotic disorders, gastrointestinal disorders, immunodeficiency disorders, inflammatory disorders, metabolic disorders, neuropathies, ophthalmic disorders, pulmonary disorders, infections, and combinations thereof. Examples of uses include the treatment of inflammatory and hyperproliferative skin diseases and skin manifestations of immune-mediated diseases, such as psoriasis, atopic dermatitis, contact dermatitis and further eczematous dermatitis, seborrheic dermatitis, lichen planus, pemphigus, pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitis, erythema, cutaneous eosinophilia, lupus erythematosus, acne, and alopecia greata; various ophthalmic diseases (such as autoimmune, etc.), such as keratoconjunctivitis, vernal catarrh, Behçet's disease-related uveitis, keratitis, herpes simplex keratitis, keratoconus, dystrophia epithelialis corneae, corneal leukoma, and ocular pemphigus. In addition, according to the method described herein, reversible obstructive airway diseases can be treated, prevented, and / or recovered, and such reversible obstructive airway diseases include, for example, asthma (such as bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma), especially chronic or refractory asthma (such as late-onset asthma, airway hyperresponsiveness), bronchitis, allergic rhinitis, etc. Other treatable diseases and conditions include, for example, mucosal and vascular inflammation such as gastric ulcer, vascular injury (resulting from ischemic diseases and thrombosis). Furthermore, hyperproliferative vascular diseases, such as intimal smooth muscle cell hyperplasia, restenosis, and vascular occlusion, etc., especially those occurring following biologic or mechanical-mediated vascular injury, can also be treated with the compounds described herein.

[0088] Still other treatable diseases and conditions include heart diseases such as post-myocardial infarction syndrome, changes / reconstruction of pulmonary muscles, lung diseases such as chronic obstructive pulmonary disease (COPD); ischemic bowel diseases, inflammatory bowel diseases, necrotizing enteritis, inflammation / allergies of the small intestine (e.g., celiac disease), proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, and ulcerative colitis; neurological diseases (e.g., polymyositis, Guillain-Barré syndrome, Ménière's disease, polyneuritis, multiple neuritis, mononeuritis, radiculopathy); septic shock and related refractory hypotension; endocrine diseases (e.g., hyperthyroidism, Graves' disease); arthritis (e.g., rheumatoid arthritis, arthritis chronica progrediente, osteoarthritis), and rheumatic diseases; blood diseases (e.g., pure red cell aplasia, aplastic anemia, aplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, erythropoietic hypoplasia); bone diseases (e.g., osteoporosis); respiratory diseases (e.g., sarcoidosis, pulmonary fibrosis, idiopathic interstitial pneumonia); skin diseases (e.g., dermatomyositis, vitiligo vulgaris, ichthyosis vulgaris, photoallergic hypersensitivity, cutaneous T-cell lymphoma); circulatory diseases (e.g., arteriosclerosis, atherosclerotic arteriosclerosis, aortic inflammation syndrome, polyarteritis nodosa, cardiomyopathy); collagen diseases (e.g., scleroderma, Wegener's granulomatosis, Sjögren's syndrome); lipodystrophy; eosinophilic fasciitis; periodontal diseases (e.g., lesions of the gums, periodontal tissues, alveolar bone, and dental cementum); nephrotic syndrome (e.g., glomerulonephritis); male pattern baldness or senile alopecia (treatment by preventing hair loss, promoting hair growth, and / or promoting hair generation and hair growth); muscular dystrophy; impetigo, Sézary syndrome; Addison's disease; reactive oxygen species-mediated diseases, e.g., ischemia-reperfusion injury of organs (e.g., heart, liver, kidney, digestive tract) occurring during preservation, transplantation, (single or multiple) organ failure, or ischemic diseases (e.g., thrombosis, myocardial infarction); movement disorders (e.g., Parkinson's disease, neuroleptic-induced parkinsonism, tardive dyskinesia); bowel diseases (e.g., endotoxin shock, pseudomembranous colitis, colitis caused by drugs or radiation); kidney diseases (e.g., ischemic acute renal failure, chronic renal failure); lung diseases (e.g., poisoning caused by pulmonary oxygen or drugs (e.g., paracort, bleomycin), lung cancer, pulmonary emphysema);Eye diseases (e.g., cataract, siderosis, retinitis, pigmentary degeneration, age-related macular degeneration, vitreous scar, corneal alkali burn); dermatitis (e.g., erythema multiforme, linear IgA bullous dermatosis, cement dermatitis); and other diseases such as gingivitis, periodontal disease, sepsis, pancreatitis, diseases caused by environmental pollution (e.g., air pollution), aging, carcinogenesis, cancer metastasis, altitude sickness, etc.; diseases caused by the release of histamine or leukotriene-C4; Behcet's disease (e.g., intestinal type, vascular type, or neural type Behcet's disease, and in addition, Behcet's disease affecting the oral cavity, skin, eyes, vulva, joints, epididymis, lungs, kidneys, etc.). Further, the compounds of the present invention are useful for the treatment and prevention of immunogenic diseases (e.g., chronic autoimmune liver diseases such as autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, etc.), partial hepatectomy, acute liver necrosis (e.g., necrosis caused by toxins, viral hepatitis, shock, or anoxia), hepatitis B virus, non-A / non-B hepatitis, cirrhosis (e.g., alcoholic cirrhosis), liver failure (fulminant liver failure, late-onset liver failure, "acute in chronic" liver failure (acute liver failure in chronic liver diseases), etc.), and are useful for the treatment of bacterial or viral infections such as influenza, HIV infection, etc. Furthermore, due to useful activities such as an increase in chemotherapeutic effect, cytomegalovirus infection, particularly HCMV infection, and anti-inflammatory activity, they are useful for various diseases, and for sclerotic and fibrotic diseases such as nephrosis, scleroderma, fibrosis (e.g., pulmonary fibrosis including idiopathic fibrotic alveolitis, idiopathic interstitial pneumonia, idiopathic pulmonary fibrosis, idiopathic mediastinal fibrosis, pulmonary fibrosis complicated with antitumor therapy, radiotherapy, and chronic infections including tuberculosis, aspergillosis, and other fungal infections), arteriosclerosis, congestive heart failure, ventricular hypertrophy, postoperative adhesions and scars, stroke, myocardial infarction, and injuries related to ischemia and reperfusion, etc.

[0089] Route of administration The superoxide dismutase mimetic described herein (or a pharmaceutical composition comprising this superoxide dismutase mimetic) can be administered to a subject (e.g., a human and other mammals) according to many suitable routes of administration, and the suitable routes of administration include oral, parenteral (e.g., intravenous, intraarterial, subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intraperitoneal, intrasternal), topical (transnasal, transdermal, buccal, intraocular), intravesical, intrathecal, enteral, intrapulmonary, intralymphatic, intracavitary, intravaginal, rectal, transurethral, intradermal, intraocular, intratympanic, intramammary, local, intratracheal, intralesional, percutaneous, endoscopic, transmucosal, sublingual, and enteral administration. In one embodiment, the superoxide dismutase mimetic is introduced into a patient through oral administration or injection (including intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, intraarterial injection, and intradermal injection). Additionally or alternatively, the superoxide dismutase mimetic described herein (or a pharmaceutical composition comprising the superoxide dismutase mimetic described herein) can be administered to a subject topically (as a patch (e.g., a transdermal patch), powder, lotion, ointment, or as droplets applied to the skin), buccally, or by inhalation (as an oral or nasal spray). The superoxide dismutase mimetic described herein (or a pharmaceutical composition comprising this superoxide dismutase mimetic) may be administered rectally or intravaginally to a human or other mammal. In one embodiment, the superoxide dismutase mimetic (or a pharmaceutical composition or unit dosage form comprising this superoxide dismutase mimetic) is administered parenterally to a subject. Parenteral administration is generally understood to refer to a method of administration including intravenous, intramuscular, intraperitoneal, subcutaneous, and intraarticular. In a preferred embodiment, the superoxide dismutase mimetic (or a pharmaceutical composition or unit dosage form comprising this superoxide dismutase mimetic) is administered intravenously.

[0090] Unit dosage forms and pharmaceutical compositions Another aspect of the present disclosure relates to unit dose formulations and pharmaceutical compositions comprising the compounds described herein, which typically further comprise a pharmaceutically acceptable carrier or excipient and optionally further comprise one or more other pharmaceutically active compounds in combination. The pharmaceutical composition comprises a superoxide dismutase mimetic corresponding to formula (GC4419), which is typically formulated as a pharmaceutical dosage form and optionally formulated in combination with a pharmaceutically acceptable carrier, additive, or excipient. For example, in one embodiment, the pharmaceutical composition comprises a compound of formula (GC4419) and a pharmaceutically acceptable carrier or excipient. The unit dose formulations and pharmaceutical compositions according to the present disclosure may be used, for example, in the treatment of various cancers, cardiovascular disorders, cerebrovascular disorders, skin disorders, fibrosis disorders, gastrointestinal disorders, immunodeficiency disorders, inflammatory disorders, metabolic disorders, neurological disorders, eye disorders, lung disorders, infections, tissue damage, and combinations thereof. Specific diseases and conditions include cancer, fibrosis, inflammatory diseases and conditions (including, for example, inflammatory bowel disease, rheumatoid arthritis, asthma, COPD, pancreatitis, etc.), dermatitis, psoriasis, etc., and additionally include protection against tissue damage resulting from cancer treatment or other radiation exposure.

[0091] A particular aspect of the present disclosure is directed to unit dose formulations comprising a superoxide dismutase mimetic contained in a container as described herein. In one embodiment, the superoxide dismutase mimetic corresponds to formula (GC4419). In a preferred embodiment, the superoxide dismutase mimetic is the dichloro complex form of formula (GC4419).

[0092] Preferably, the unit dosage formulation according to the present disclosure comprises at least 50 mg of a superoxide dismutase mimetic corresponding to formula (GC4419). For example, in various embodiments, the unit dosage formulation comprises at least 50 mg, at least 75 mg, at least 100 mg, at least 125 mg, at least 150 mg, at least 175 mg, at least 200 mg, at least 225 mg, at least 250 mg, at least 275 mg, at least 300 mg, at least 325 mg, at least 350 mg, at least 375 mg, at least 400 mg, at least 425 mg, at least 450 mg, at least 475 mg, at least 500 mg, at least 525 mg, at least 550 mg, at least 575 mg, or at least 600 mg of a superoxide dismutase mimetic corresponding to formula (GC4419). In some of these embodiments, the superoxide dismutase mimetic is in the dichloro complex form of formula (GC4419).

[0093] Another specific aspect of the present disclosure is directed to a pharmaceutical composition in solution form, in which case the pharmaceutical composition is in a unit dosage form for intravenous administration. For example, according to this aspect, the pharmaceutical composition comprises a superoxide dismutase mimetic stored in an IV (intravenous injection) bag for administration to a patient and a pharmaceutically acceptable carrier. A typical unit dosage intravenous injection bag is a glass or plastic container having an inlet means and an outlet means and having a standard volume (e.g., 50 mL, 100 mL, and 150 mL). Usually, a concentrated solution of the reconstituted lyophilized superoxide dismutase mimetic (detailed below) is added to an IV (intravenous injection) container containing a suitable aqueous carrier. Useful carriers are described herein (e.g., sterile water, sterile saline, etc.). Generally, the pharmaceutical composition comprises a superoxide dismutase mimetic (e.g., a superoxide dismutase mimetic corresponding to formula (GC4419)) in an amount of about 0.25 mg / mL to about 3.5 mg / mL as described herein. Alternatively, depending on the purpose of use, considerations regarding packaging and shipping, whether one or more IV bags are used, etc., a higher or lower concentration of the superoxide dismutase mimetic may be present than described above. In one embodiment, a concentrated solution of a certain amount of the lyophilized superoxide dismutase mimetic is added to an intravenous injection bag to form a pharmaceutical composition in solution form. This pharmaceutical composition in solution form comprises a superoxide dismutase mimetic at about 0.25 mg / mL, about 0.5 mg / mL, about 0.75 mg / mL, about 1.0 mg / mL, about 1.25 mg / mL, about 1.5 mg / mL, about 1.75 mg / mL, about 2.0 mg / mL, about 2.25 mg / mL, about 2.5 mg / mL, about 2.75 mg / mL, about 3.0 mg / mL, about 3.25 mg / mL, or about 3.5 mg / mL.

[0094] The above-described superoxide dismutase mimetic may be dispersed in a pharmaceutically acceptable carrier before administration to a mammal. A carrier is known in the art as an excipient, vehicle, adjuvant, or diluent, and generally is a substance that is pharmaceutically inert, provides the appropriate viscosity or form to the composition, and does not decrease the potency of the compound. A carrier that does not produce unacceptable adverse reactions, allergic reactions, or other untoward reactions when administered to a mammal (particularly a human) is generally considered "pharmaceutically or pharmacologically acceptable."

[0095] Also, the pharmaceutically acceptable carrier is selected in part according to the route of administration. The compositions described herein can generally be formulated for any route of administration according to conventional routes of administration of the components (e.g., superoxide dismutase mimetic compounds) as long as the bloodstream is accessible via the route of administration. For example, suitable routes of administration include, but are not limited to, oral, parenteral (e.g., intravenous, intraarterial, subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intraperitoneal, intrasternal), topical (transnasal, transdermal, buccal, intraocular), intravesical, intrathecal, enteral, intrapulmonary, intralymphatic, intracavitary, intravaginal, rectal, transurethral, intradermal, intraocular, intratympanic, intramammary, local, intratracheal, intralesional, transdermal, endoscopic, transmucosal, sublingual, and enteral administration.

[0096] Pharmaceutically acceptable carriers that may be used in combination with the compounds and compositions of the present disclosure are well known to those skilled in the art and are selected based on a number of factors (the particular compound and agent used, its / their concentration, stability, and intended bioavailability; safety; the subject; its age, size, and general condition; as well as the route of administration). Examples of suitable non-aqueous polar solvents that are pharmaceutically acceptable include, but are not limited to, water, alcohols having from 2 to 30 carbon atoms; fatty acid esters of alcohols; amides; esters; ketones; sulfoxides; aliphatic, cycloaliphatic, or aromatic hydrocarbons having from 4 to 30 carbon atoms; mineral oil, vegetable oil, animal oil, essential oil, or synthetic oil.

[0097] In one embodiment, the pharmaceutically acceptable carrier is in solution form. For example, this solution may contain water. As another example, this solution may contain saline. Examples of suitable carriers for formulating liquid dosage forms for parenteral administration include pharmaceutically acceptable non-aqueous polar solvents such as oils, alcohols, amides, esters, ethers, ketones, hydrocarbons, and mixtures thereof, as well as water, physiological saline (e.g., U.S.P. and isotonic saline solutions), dextrose solutions (e.g., D5W), electrolyte solutions, or other aqueous pharmaceutically acceptable liquids. In one preferred embodiment, the pharmaceutical composition is an aqueous solution containing a superoxide dismutase mimetic corresponding to formula (GC4419) and saline (e.g., standard saline, i.e., a sterile solution of 0.9% w / v NaCl in water). In these and other embodiments, for example, the saline is preferably a physiologically buffered saline solution (i.e., buffered saline). Using a buffer provides an appropriate buffering capacity around pH 7 - 8.5, or around pH 7.8, or within the range of pH 7.3 - 8. The buffer is preferably chemically inert and physiologically and pharmaceutically acceptable. Examples of representative buffers include phosphate buffers, carbonate buffers, Tris buffers, amino acid buffers (e.g., arginine, lysine, and other natural amino acids), and citrate buffers. Carbonate buffers (e.g., sodium carbonate buffer, calcium carbonate buffer, or bicarbonate buffer) can be readily available, have high buffering capacity, and are compatible, and thus may be particularly useful in some embodiments. A particular preferred buffer is sodium bicarbonate. For example, in one preferred embodiment, the pharmaceutically acceptable carrier contains a buffered saline solution; in this embodiment, more preferably, the buffered saline solution is a saline solution buffered with carbonated water. In one particularly preferred embodiment, this solution is formulated using 10 mg / mL of GC4419 in an aqueous solution containing 0.9 wt% NaCl, this aqueous solution contains 26 mM of sodium bicarbonate, and the pH range of the solution is 7.6 - 8.3. In one preferred embodiment, the superoxide dismutase mimetic is the dichloro complex of formula (GC4419).As described above, when the chloro (or other) ligand of the superoxide dismutase mimetic is in solution, it is understood that it can dissociate from the axial coordination site occupied by the solvent water molecule to form both a mono-aquo (monocationic) complex and a bis-aquo (dicationic) complex. That is, the ligand binding dissociates and exchanges, and may be occupied by other molecules present in the solution (such as solvent water molecules).

[0098] Also, the pharmaceutical formulation is preferably sterile. For example, the injection formulation can be sterilized by filtering it through a bacteria-retaining filter or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injection media immediately before use. The compositions of the present invention may be provided, prepared, stored, or transported in any container suitable for maintaining sterility. The container may incorporate means for dispensing the aqueous composition (such as a pierceable or removable seal). The compositions of the present invention may be dispensed, for example, by withdrawing with a syringe or by injecting the composition directly into a device for patient administration (such as a syringe, IV bag, or machine). Other means for providing, preparing, storing, transporting, and dispensing sterile pharmaceutical compositions are known to those skilled in the art.

[0099] In another embodiment, the superoxide dismutase mimetic may be used as a lyophilized powder and more typically may be stored as a lyophilized powder. One of ordinary skill in the art will recognize that lyophilization is a lyophilization process in which water sublimes from the composition after freezing. The advantages associated with the lyophilization process are, in particular, the ability to dry biopharmaceuticals and formulations without increasing the temperature (thereby eliminating potentially harmful heat effects), and then to store them in a dry state with relatively few (or at least fewer compared to others) stability problems. Methods for providing lyophilized powders or lyophilized particles are known to those of ordinary skill in the art. The use of bulking agents or solidifying agents in lyophilized formulations can be useful, for example, in enhancing the precision of the product and preventing rupture. The bulking agent gives structural strength to the lyophilized cake, and examples of bulking agents include sucrose, trehalose, dextran, lactose, cyclodextrin, chitosan, mannitol, and glycine. In one embodiment, the bulking agent is dextran. For the purpose of affecting the relationship between the compound and the solvent (e.g., water or saline) in the solution, a buffer may be included in the solution before lyophilization, if necessary. Suitable buffers are described elsewhere in this specification and examples include phosphate-based buffers, carbonate-based buffers, tris-based buffers, amino acid-based buffers (e.g., arginine, lysine, other natural amino acids), and citrate-based buffers. Thus, by way of example, the lyophilized forms described herein may include a superoxide dismutase mimetic, a bulking agent, and a buffer, or may include only a superoxide dismutase mimetic and a bulking agent. In one particular example, the lyophilized form includes a superoxide dismutase mimetic and dextran. In another particular example, the lyophilized form includes a superoxide dismutase mimetic, dextran, and arginine (as a buffer). In another particular example, the lyophilized form includes a superoxide dismutase mimetic, dextran, and lysine (as a buffer). In another particular example, the lyophilized form includes a superoxide dismutase mimetic, dextran, and tris (tris (hydroxymethyl)-aminomethane) (as a buffer).

[0100] When the lyophilized form of the superoxide dismutase mimetic described herein is employed (e.g., for storage or shipment), it is usually necessary to reconstitute this lyophilized form before administration to a patient. To reconstitute the lyophilized cake, any pharmaceutically acceptable carrier solution described herein (e.g., water or saline) may be used. If a buffer was included in the solution prior to lyophilization, it is not necessarily required to include a buffer in the reconstituting solution. On the other hand, if no buffer was included in the solution prior to lyophilization, for the reasons described above, it is preferred that the reconstituting solution include a buffer.

[0101] In some embodiments, for example, due to the presence of a large lipophilic moiety, for example for the purpose of dissolving one or more compounds in solution, an oil or a non-aqueous solvent may be used in the formulation. Alternatively, an emulsion, a suspension, or other preparation (e.g., a liposome formulation) may be used. For example, with regard to liposome preparations, any known method for preparing liposomes may be used. See, for example, Bangham et al., J. Mol. Biol, 23: 238-252 (1965) and Szoka et al., Proc. Natl. Acad. Sci 75: 4194-4198 (1978) (these references are incorporated herein by reference). Thus, in one embodiment, one or more compounds are administered in the form of a liposome delivery system (e.g., small unilamellar vesicles, large unilamellar vesicles, multilamellar vesicles). Liposomes can be formed from various phospholipids (e.g., cholesterol, stearylamine, phosphatidylcholine, etc.). For example, a ligand may be conjugated to the liposome for the purpose of targeting these compositions to a particular site of action.

[0102] Other pharmaceutically acceptable solvents used in the pharmaceutical compositions described herein are well known to those skilled in the art and are specified in the following references: The Chemotherapy Source Book (Williams & Wilkens Publishing), The Handbook of Pharmaceutical Excipients, (American Pharmaceutical Association, Washington, D.C., and The Pharmaceutical Society of Great Britain, London, England, 1968), Modern Pharmaceutics, (G. Banker et al., eds., 3d ed.) (Marcel Dekker, Inc., New York, New York, 1995), The Pharmacological Basis of Therapeutics, (Goodman & Gilman, McGraw Hill Publishing), Pharmaceutical Dosage Forms, (H. Lieberman et al., eds.) (Marcel Dekker, Inc., New York, New York, 1980), Remington’s Pharmaceutical Sciences (A. Gennaro, ed., 19th ed.) (Mack Publishing, Easton, PA, 1995), The United States Pharmacopeia 24, The National Formulary 19, (National Publishing, Philadelphia, PA, 2000), and A.J. Spiegel et al., Use of Nonaqueous Solvents in Parenteral Products, Journal of Pharmaceutical Sciences, Vol. 52, No. 10, pp. 917-927 (1963).

[0103] A formulation containing a superoxide dismutase mimetic may be in the form of a solid, semi-solid, lyophilized powder, or liquid dosage form, such as an aerosol, capsule, cream, emulsion, foam, gel / jelly, lotion, ointment, paste, powder, soap, solution, spray, suppository, suspension, sustained release formulation, tablet, tincture, transdermal patch, etc., and preferably takes the form of a unit dosage form suitable for conveniently administering an exact dosage. When formulated as a fixed dosage, such a pharmaceutical composition or formulation preferably uses a superoxide dismutase mimetic within the dosage range described above.

[0104] Generally, specific formulations for superoxide dismutase mimetics are also known in the art and are outlined, for example, in U.S. Pat. Nos. 5,610,293, 5,637,578, 5,874,421, 5,976,498, 6,084,093, 6,180,620, 6,204,259, 6,214,817, 6,245,758, 6,395,725, and 6,525,041 (each of which is incorporated herein by reference in its entirety).

[0105] In certain embodiments, the pharmaceutical composition administered to a subject according to the methods described herein consists essentially of a superoxide dismutase mimetic corresponding to formula (GC4419) and a pharmaceutically acceptable carrier. In other embodiments, the pharmaceutical composition comprises a superoxide dismutase mimetic, a pharmaceutically acceptable carrier, and one or more additional pharmaceutically active agents or compounds. In these embodiments, the pharmaceutical compositions described herein are products obtained as a result of mixing or combining multiple active ingredients, including both fixed and non-fixed combinations of the multiple active ingredients. A fixed combination is a combination in which both active ingredients (e.g., a superoxide dismutase mimetic and another pharmaceutically active agent or compound described herein) are administered to a patient simultaneously in the form of a single entity or single dosage. A non-fixed combination is a combination in which the active ingredients (e.g., a superoxide dismutase mimetic and another pharmaceutically active agent or compound) are administered to a patient as separate entities simultaneously, concurrently, or sequentially without a specific intervening time limit, such that this administration provides effective levels of the two compounds in the patient's body. The latter also applies to cocktail therapies (e.g., administration of three or more active ingredients).

[0106] When co-formulating a superoxide dismutase mimetic with one or more additional pharmaceutically active agents or compounds, it is contemplated that conventional formulation techniques may be used separately for these components, or alternatively, provided that the compatibility and efficacy of the various components exist, these components may be combined and an alternative formulation route may be used.

[0107] Additional pharmaceutically active agents As described above, the above methods and pharmaceutical compositions (pharmaceutical compositions containing superoxide dismutase mimetics) may additionally include the administration of one or more pharmaceutically active agents or ingredients. The superoxide dismutase mimetics described herein may be administered as a single active pharmaceutical, but may also be used in combination with one or more compounds of the present invention or other agents. When administered in combination, the therapeutic agent may be formulated as separate multiple compositions administered simultaneously or sequentially at different times (e.g., 1 to several hours or days later), or the therapeutic agent may be provided as a single composition. Accordingly, the present disclosure is intended to encompass sequential administration of each agent in a regimen that provides the beneficial effects of a combination drug, and also contemplates substantially simultaneous co-administration of these agents (e.g., administration in a single capsule containing these active agents in a fixed ratio, or administration in multiple capsules separated for each agent).

[0108] Suitable examples of pharmaceutically active agents or compounds that may be included in the methods and compositions of the present disclosure include analgesics, anti-arthritis agents, anti-asthma agents, anti-emetics, anesthetics (e.g., local anesthetics), anti-glaucoma agents, anti-malaria agents, antihypertensive agents, anti-anxiety agents, anticoagulants, anti-spasmodics, hypoglycemic agents, decongestants, antihistamines, antitussives, antipyretics, anticholinergics, anti-ulcer agents, anti-cancer agents, beta-blockers, beta2-agonists, beta-agonists, anti-inflammatory agents, antipsychotics, nootropics, cholesterol-lowering agents, anti-obesity agents, autoimmune disorder agents, anti-impotence agents, antibacterial / antifungal agents, anti-migraine agents, antibacterial agents, amoebicidal or trichomonacidal agents, hypnotics, anti-Parkinson's disease agents, anti-Alzheimer's disease agents, antibiotics, anti-parasitic agents, antidepressants, anti-viral agents, bronchodilators, central nervous system acting agents, cardiovascular acting agents, contraceptives, cell growth inhibitors, diuretics, germicides, H-2 blockers, hormonal agents, hypnotics, cardiotonics, muscle relaxants, muscle contractants, physic energizers, sedatives, sympathomimetics, vasodilators, vasoconstrictors, psychotropics, electrolyte adjuvants, vitamins, counterirritants, stimulants, anti-hormonal agents, drug antagonists, lipid regulators, uricosuric agents, cardiac glycosides, expectorants, laxatives, contrast materials, radiopharmaceuticals, imaging agents, peptides, enzymes, growth factors, and the like. As described above, each component of such combinations may be administered sequentially or simultaneously, in the form of separate pharmaceutical formulations or combined pharmaceutical formulations.

[0109] Specific examples of antihypertensive drugs include prazosin, nifedipine, amlodipine besylate, trimazosin, and doxazosin; specific examples of hypoglycemic drugs are glypidide and chlorpropamide; specific examples of anti-impotence drugs are sildenafil and sildenafil citrate; specific examples of anti-cancer drugs include chlorambucil, lomustine, and echinomycin; a specific example of an imidazole-type anti-cancer drug is tubulazole; specific examples of anti-hypercholesterolemia drugs are atorvastatin and atorvastatin calcium; specific examples of anti-anxiety drugs include hydroxyzine hydrochloride and doxepin hydrochloride; specific examples of anti-inflammatory drugs include betamethasone, prednisolone, aspirin, piroxicam, valdecoxib, carprofen, celecoxib, flurbiprofen, and (+)-N-{4-[3-(4-fluorophenoxy)phenoxy]-2-cyclopenten-1-yl}-N-hydroxyurea; a specific example of a barbiturate is phenobarbital; specific examples of antiviral drugs include acyclovir, nelfinavir, and virazole; specific examples of vitamins / nutritional agents include retinol and vitamin E; specific examples of β-blockers include timolol and nadolol; a specific example of an emetic is apomorphine; specific examples of diuretics include chlorthalidone and spironolactone; a specific example of an anticoagulant is dicumarol; specific examples of cardiotonic drugs include digoxin and digitoxin; specific examples of androgens include 17-methyltestosterone and testosterone; a specific example of a mineralocorticoid is desoxycorticosterone; a specific example of a steroid hypnotic / anesthetic is alphaxalone; specific examples of anabolic agents include fluoxymesterone and methanstenolone; specific examples of antidepressants include sulpiride, [3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-(1-ethylpropyl)-amine, 3,5-dimethyl-4-(3’-pentoxy)-2-(2’,4’,6’-trimethylphenoxy)pyridine, pyroxidine, fluoxetine, paroxetine, venlafaxine, and sertraline;Specific examples of antibiotics include carbenicillin indanyl sodium, bacampicillin hydrochloride, troleandomycin, doxycycline hyclate, ampicillin, amoxicillin, and penicillin G; specific examples of anti-infective agents include benzalkonium chloride and chlorhexidine; specific examples of coronary vasodilators include nitroglycerin and mioflazine; a specific example of a hypnotic is etomidate; specific examples of carbonic anhydrase inhibitors include acetazolamide and chlorzolamide; specific examples of antifungal agents include econazole, terconazole, fluconazole, voriconazole, and griseofulvin; a specific example of an antiprotozoal agent is metronidazole; specific examples of anthelmintics include thiabendazole, oxfendazole, and morantel; specific examples of antihistamines include astemizole, levocabastine, cetirizine, decarboethoxyloratadine, and cinnarizine; specific examples of antipsychotics include diprasidone, olanzepine, thiothixene hydrochloride, fluspirilene, risperidone, and penfluridole; specific examples of gastrointestinal agents include loperamide and cisapride; specific examples of serotonin antagonists include ketanserin and mianserin; a specific example of an anesthetic is lidocaine; a specific example of an antidiabetic agent is acetohexamide; a specific example of an antiemetic is dimenhydrinate; a specific example of an antibacterial agent is cotrimoxazole; a specific example of a dopaminergic agent is L-DOPA; specific examples of anti-Alzheimer's disease agents are THA and donepezil; a specific example of an antiulcer agent / H2 antagonist is famotidine; specific examples of sedatives / hypnotics include chlordiazepoxide and triazolam; a specific example of a vasodilator is alprostadil; a specific example of a platelet inhibitor is prostacyclin; specific examples of ACE inhibitors / hypotensive agents include enalaprilic acid, quinapril, and lisinopril; specific examples of tetracycline antibiotics include oxytetracycline and minocycline;Specific examples of macrolide antibiotics include erythromycin, clarithromycin, and spiramycin; a specific example of azalide antibiotics is azithromycin; specific examples of glycogen phosphorylase inhibitors include [R--(R’S’)]-5-chloro-N-[2-hydroxy-3-{methoxymethylamino}-3-oxo-1-(phenylmethyl)propyl-1H-indole-2-carboxamide and 5-chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-(2R)-hydroxy-3-((3R,4S)-dihydroxy-pyrrolidin-1-yl-)-3-o-xypropyl]amide; specific examples of cholesterol ester transfer protein inhibitors include [2R,4S]-4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester, [2R,4S]-4-[3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester, and [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester.;

[0110] As other specific examples, for example, anti-inflammatory drugs such as ibuprofen, indomethacin, naproxen, nalophine, etc.; anti-Parkinson's drugs such as bromocriptine, biperidine, benzhexol, benzotropine, etc.; antidepressants such as imipramine, nortriptyline, pritiptyline, etc.; antibiotics such as clindamycin, erythromycin, fusidic acid, gentamicin, mupirocine, amfomycin, neomycin, metronidazole, sulfamethizole, bacitracin, flamycin, polymyxin B, acitromycin, etc.; antifungal agents such as miconazole, ketoconaxole, clotrimazole, amphotericin B, nystatin, mepyramine, econazole, fluconazole, flucytosine, griseofulvin, bifonazole, amorofine, mycostatin, itrconazole, terbenafine, terconazole, tolnaftate, etc.; antibacterial drugs such as metronidazole, tetracycline, oxytetracycline, penicillin, etc.; antiemetic drugs such as metoclopramide, droperidol, haloperidol, promethazine, etc.; antihistamine drugs such as chlorpheniramine, terfenadine, triprolidine, etc.; anti-migraine drugs such as dihydroergotamine, ergotamine, pizofylline, etc.; vasodilators for coronary vessels, cerebral vessels, or peripheral vessels such as nifedipine, diltiazem, etc.; anti-angina drugs such as glyceryl nitrate, isosorbide dinitrate, molsidomine, verapamil, etc.; calcium channel blockers such as verapamil, nifedipine, diltiazem, nicardipine, etc.; hormonal agents such as estradiol, estrone, estriol, polyestradiol, polyestriol, dienestrol, diethylstilbestrol, progesterone, dihydroprogesterone, cyprosterone, danazol, testosterone, etc.;Contraceptives, such as ethinyl estradiol, lynestrenol, ethynodiol, norethisterone, mestranol, norgestrel, levonorgestrel, desodestrel, medroxyprogesterone, etc.; Antithrombotic drugs, such as heparin, warfarin, etc.; Diuretics, such as hydrochlorothiazide, flunarizine, minoxidil, etc.; Antihypertensive drugs, such as propranolol, metoprolol, clonidine, pindolol, etc.; Adrenal cortical steroids, such as beclomethasone, betamethasone, betamethasone-17-valerate, betamethasone-dipropionate, clobetasol, clobetasol-17-butyrate, clobetasol-propionate, desonide, desoxymethasone, dexamethasone, diflucortolone, flumethasone, flumethasone-pivalte, fluocinonide acetonide, fluocinoide, hydrocortisone, hydrocortisone-17-butyrate, hydrocortisone buteprate, methylprednisolone, triamcinolone acetonide, halcinonide, fluprednide acetate, alklometasone dipropionate, fludrocortisone, fluticasone propionate, mometasone furoate, desoxymethasone, diflurason diacetate, halcinol, clioquinol, chlorquinaldol, fluocinonide acetonide, etc.; Dermatological drugs, such as nitrofurantoin, ditranol, clioquinol, hydroxyquinoline, isotretinoin, methoxsalen, methotrexate, tretinoin, trioxalen, salicylic acid, penicillamine, etc.; Steroid drugs, such as estradiol, progesterone, norethindrone, levonorgestrel, ethynodiol, levonorgestrol, norgestimate, gestanin, desogestrel, 3-keto-desogestrel, demegestone, promestrol, testosterone, spironolactone, esters thereof, etc.;Nitro compounds, such as amyl nitrate, nitroglycerin, isosorbide nitrate, etc.; opioids, such as morphine, buprenorphine, oxymorphone, hydromorphone, codeine, tramadol, etc.; prostaglandins, such as members of the PGA, PGB, PGE, or PGF series like minoprostol, dinoprostone, carboprost, eneprostil, etc.; peptides, such as growth hormone releasing factor, growth factors (e.g., epidermal growth factor (EGF), nerve growth factor (NGF), TGF, PDGF, insulin-like growth factor (IGF), fibroblast growth factor (aFGF, bFGF, etc.)), somatostatin, calcitonin, insulin, vasopressin, interferon, IL-2, etc., urokinase, serratiopeptidase, superoxide dismutase, thyrotropin releasing hormone, luteinizing hormone releasing hormone (LH-RH), corticotropin releasing hormone; growth hormone releasing hormone (GHRH), oxytocin, erythropoietin (EPO), colony stimulating factor (CSF), etc. are included.;

[0111] Further forms of the compound For example, with respect to the compounds described herein, such as superoxide dismutase mimics corresponding to formula (GC4419), and other pharmaceutically active agents or compounds that may be included in pharmaceutical compositions, these compounds may exist in various forms, and each of these forms and other forms are contemplated in the present disclosure.

[0112] Diastereomeric mixtures can be separated into the individual diastereomers based on their physicochemical differences by known methods (e.g., chromatography and / or fractional crystallization). In one embodiment, enantiomers can be separated by a chiral chromatography column. In other embodiments, the enantiomer mixture is converted into a diastereomeric mixture by reaction with a suitable optically active compound (e.g., a salt), the diastereomers are separated, and the individual diastereomers are converted (e.g., hydrolyzed) into the corresponding pure enantiomers, whereby the enantiomers can be separated. As described above, all such isomers (including diastereomers, enantiomers, and mixtures thereof) are considered part of the compounds and compositions described herein.

[0113] Also, the methods and formulations described herein include the use of crystalline forms (also referred to as polymorphs) of the compounds described herein or pharmaceutically acceptable salts, and in addition, the use of active metabolites of these compounds having the same or similar types of activity will be understood to be included. In addition, the compounds described herein may exist in an unsolvated state or may exist in a solvated state with a pharmaceutically acceptable solvent such as water, ethanol, etc. The solvated forms of the compounds shown herein are also considered to be those disclosed herein.

[0114] The compounds described herein also include isotopically labeled compounds. Isotopically labeled compounds are identical to the compounds listed in the various compounds, structures, and formulas herein, except that one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, and chlorine, for example, 2 H, 3 H, 13 C, 14 C, 15 N, and 54 Mn. Certain isotopically labeled compounds described herein, for example,3 H, 14 Compounds incorporating radioisotopes such as C may be useful in drug and / or substrate tissue distribution assays. Further, substitution with isotopes such as deuterium (i.e., 2 H) may result in increased metabolic stability (e.g., increased in vivo half-life or decreased required dosage), providing certain therapeutic advantages.

[0115] When reference is made to pharmaceutically acceptable salts, it should be understood that solvent addition forms or crystal forms, particularly solvates or polymorphs, are included. Solvates contain a stoichiometric or non-stoichiometric amount of solvent and can be formed during the crystallization process using pharmaceutically acceptable solvents (e.g., water, ethanol, etc.). When the solvent is water, hydrates are formed, and when the solvent is alcohol, alcoholates are formed. Solvates of the compounds described herein can be readily prepared during the processes described herein. In addition, the compounds provided herein can exist not only in solvated forms but also in non-solvated states. Generally, in the compounds and methods provided herein, solvated forms are considered equivalent to non-solvated forms. Polymorphs include multiple different crystal packing arrangements of the same elemental composition of a compound. Polymorphs typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal forms, optical and electrical properties, stability, and solubility. Depending on various factors such as the recrystallization solvent, crystallization rate, storage temperature, etc., a single crystal form can become dominant.

[0116] The compounds described herein can also exist in various forms including, but not limited to, amorphous forms, crushed forms, and nanoparticle forms.

[0117] Kit / Manufactured Product Also described are kits and articles of manufacture for use in the therapeutic methods described herein. Such kits may include a carrier, package, or container compartmentalized to receive one or more containers, such as vials, tubes, etc., each of the one or more containers containing one of the individual elements used in the methods described herein (e.g., a superoxide dismutase mimetic, a pharmaceutically acceptable carrier, or an additional pharmaceutically active agent or compound, whether alone or in combination). Examples of suitable containers include bottles, vials, syringes, and test tubes. The containers can be formed from a variety of materials such as glass, plastic, and the like.

[0118] The articles of manufacture provided herein include a packaging material. Packaging materials used in the packaging of pharmaceuticals are well known to those of skill in the art. See, for example, U.S. Patent Nos. 5,323,907, 5,052,558, and 5,033,252 (each of which is incorporated herein by reference). Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for the selected formulation and intended mode of administration and treatment. As noted above, a wide variety of formulations of the compounds and compositions provided herein are contemplated because there are a variety of treatments for diseases, disorders, or conditions for which it is believed that benefits can be obtained by treatment with the superoxide dismutase mimetics described herein.

[0119] Thus, for example, the container may contain one or more of the compounds described herein, optionally in the form of a composition or in combination with other agents disclosed herein. The container may have a sterile access port (e.g., the container can be an intravenous injection bag or a vial with a stopper pierceable by a subcutaneous injection needle). In one embodiment, such a kit includes a compound (e.g., a superoxide dismutase mimetic) with an identifying content display or label, or instructions regarding use in the methods described herein. The kit may further include a pharmaceutically acceptable carrier or diluent for combination with the active compound. For example, in one embodiment, the kit includes a sterile solution containing a superoxide dismutase mimetic corresponding to formula (GC4419). For example, in another embodiment, the kit includes a lyophilized powder of a superoxide dismutase mimetic corresponding to formula (GC4419). In these and other embodiments, the kit may further include a solution (e.g., a sterile saline solution) for diluting the superoxide dismutase mimetic, for example, within an infusion bag (the infusion bag itself may be included in the kit).

[0120] Kits typically include one or more additional containers, each of which has various materials (e.g., optionally concentrated reagents, and / or devices) that are desirable from a commercial and user perspective for using the compounds described herein. Non-limiting examples of such materials include buffers, diluents, filters, needles, syringes; carriers, packages, containers, vials, bags, and / or tube labels listing the contents, and / or instructions for use; and an attached document with instructions for use. Usually, a set of instructions is included in various embodiments, which may be in the form of individual sheets or booklets, or printed on one or more of the packages, containers, or vials (either printed directly or printed on a label as described below).

[0121] The label may be attached to or accompany the kit or one or more containers included in the kit. If the letters, numbers, and other symbolic characters forming the label are attached, molded, or etched onto the container itself, the label may be attached to the container. If the label is present in a receptacle or carrier that further holds the container (e.g., as an accompanying document), the label may accompany the container. The label may be used to indicate that the contents are for a specific therapeutic use. Also, for example, instructions for use or directions for use of the contents may be displayed on the label according to the methods described herein.

[0122] In certain embodiments, the pharmaceutical composition may be presented within a pack or dispenser device capable of holding one or more unit dosage forms containing one or more of the compounds and agents provided herein. The pack may, for example, be capable of holding a metal or plastic foil such as a blister pack. A package insert may be attached to the pack or dispenser device. Also, a notice related to the container may be attached to the pack or dispenser. This notice is prepared in a manner directed by a government agency that regulates the manufacture, use, or sale of pharmaceuticals and represents that the form of the agent to be administered to humans or animals has been approved by the agency. Such a notice may be, for example, a label indication approved by the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMEA) for prescription drugs, or an approved package insert.

[0123] A composition containing one or more of the compounds provided herein formulated in a pharmaceutically acceptable carrier (e.g., a superoxide dismutase mimetic, or another additional pharmaceutically active agent or compound) may be prepared, placed in a suitable container, and labeled for therapeutic use in the indicated condition.

[0124] According to one aspect, a manufactured article includes a packaging material, within which a parenteral formulation is stored. This parenteral formulation is for treating a disease or condition of a patient in need thereof, or for protecting tissue from damage resulting from exposure to cancer treatment of the patient, as described herein. According to this embodiment, this parenteral formulation includes the unit dose formulation described in the present invention, and this packaging material includes a labeled label or package insert for parenterally administering the dosage to a patient. For example, this parenteral formulation may be in solution form and stored in a suitable vial or container.

[0125] Generally, a parenteral solution can contain the superoxide dismutase mimetic described herein in a unit dose form of about 5 mg / mL to about 20 mg / mL in a suitable container. Alternatively, depending on the purpose of use, considerations regarding packaging and shipping, whether one or multiple vials are used, etc., a superoxide dismutase mimetic at a concentration higher or lower than the above may be present. In one embodiment, the parenteral formulation is a solution containing the superoxide dismutase mimetic at about 20 mg / mL, about 17.5 mg / mL, about 15 mg / mL, about 12.5 mg / mL, about 10 mg / mL, about 7.5 mg / mL, or about 5 mg / mL in a single container. In another embodiment, the parenteral formulation is a solution containing the superoxide dismutase mimetic at about 20 mg / mL, about 17.5 mg / mL, about 15 mg / mL, about 12.5 mg / mL, about 10 mg / mL, about 7.5 mg / mL, or about 5 mg / mL in a plurality of containers (e.g., two or more, three or more, four or more, etc.).

[0126] The embodiments listed below are shown to illustrate specific aspects of the present invention and are not intended to limit the scope of the present invention: 1. A unit dose formulation containing at least 50 mg of a superoxide dismutase mimetic in a container, wherein the superoxide dismutase mimetic has the formula (GC4419):

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chem.

Chem.

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0127] The above examples are for illustrative purposes only and do not represent any limitation on the scope of the present invention. Various modifications and combinations of the disclosed features will be apparent to those skilled in the art based on the above disclosure, and they are also within the scope of the present invention.

[0128] It will be apparent that modifications and variations are possible without departing from the scope of the present invention as defined in the appended claims by having described the present invention in detail. Further, it should be understood that all examples of the present disclosure are provided as non-limiting examples.

Examples

[0129] The following non-limiting examples are provided to further illustrate the present invention. Those skilled in the art should understand that the techniques disclosed in the following examples represent the methods that the inventors have found to function well in the practice of the invention, and thus may be considered as constituting examples of the modes of implementation. However, those skilled in the art should understand that, based on the present disclosure, many modifications can be made to the specific embodiments disclosed, and similar or analogous results can still be obtained without departing from the spirit and scope of the present invention.

Example

[0130] Chemical structures and crystal structures of GC4403 and GC4419 As pointed out above, the chemical structures of GC4403 and GC4419 have mirror-image chirality; that is, their enantiomeric structures are identical except that they cannot be superimposed. GC4403 has four chiral carbon centers present in the R-absolute configuration, and GC4419 has four chiral carbon centers in the S-absolute configuration:

Chemical formula

[0131] The single-crystal X-ray structure of GC4403 has already been reported in the literature and is shown in Figure 1. Riley, D.P., Schall, O.F., 2007, Advances in Inorganic Chemistry, 59: 233-263. The single-crystal X structure of GC4419 has also been determined and is shown in Figure 2.

Example

[0132] Synthesis of GC4403 and GC4419 The complex of GC4403 and GC4419 was synthesized by the template method previously reported for GC4403. In the case of GC4403, the complex was synthesized via the template route described in the literature using chiral R,R-1,2-diaminocyclohexane. Salvemini, D., et. al., 1999, Science, 286: 304-6; Aston, K., Rath, N., Naik, A., Slomczynska, U., Schall, O.F., Riley, D.P., 2001, Inorg. Chem., 40(8), 1779-89. For the synthesis of GC4419, the same method was used, except that R,R-1,2-diaminocyclohexane was replaced with chiral S,S-1,2-diaminocyclohexane during the synthesis.

Example

[0133] Physicochemical properties of GC4403 and GC4419 The complexes of GC4403 and GC4419 have the same physicochemical properties, including stability, reactivity with achiral reagents, electronic spectra, solubility in achiral media, and reactivity with superoxide. The relevant physicochemical properties are summarized in Table 1. Table 1. Physical and chemical characteristics of GC4419 and GC4403

Table 1

Example

[0134] Antiproliferative activity (in vitro) Materials and methods: HEK-293 (CRL-1573) cells were obtained from ATCC and cultured according to the ATCC's instructions. The complete growth medium consisted of RPMI 1640 supplemented with 10% fetal bovine serum (FBS). All cell cultures were performed at 37 °C in 95% air: 5% CO2. Two days before the start of the proliferation experiment, 10 3Individual HEK-293 cells were seeded into each well of a 96-well plate. To synchronize cell division, the cells were maintained in complete growth medium for 24 hours, at which point the cell monolayer was washed once with growth medium without FBS and then cultured overnight in medium without FBS. The next morning, GC4419 or GC4403 in complete growth medium, or growth medium alone, was added. After culturing the plates for 72 hours, cell numbers were determined using an LDH assay kit. "Cell number" in Figure 3 represents the absorbance at 490 nm.

[0135] Results: Growth of HEK-293 cells was equally decreased in a dose-dependent manner by both SOD mimetics, namely GC4403 and GC4419 (Figure 3). In addition, there was no significant difference in the anti-proliferative effect between these compounds.

Example

[0136] Animal safety test When compared to GC4403, GC4419 achieved comparable plasma exposure for comparable mass doses and IV infusion rates in animal safety models and human trials while being significantly safer (i.e., significantly more of the compound could be administered in a significantly shorter infusion time).

[0137] Safety test in dogs 7-day IV toxicity of GC4403 GC4403 in 26 mM sodium bicarbonate / 0.9% sodium chloride was administered IV (slow bolus injection over at least 1 minute) to beagle dogs (4 per sex / group) at doses of 0, 1, 3 or 6 mg / kg / day for 7 days. There were no deaths during the study period. Clinical signs were observed immediately after dosing at 3 mg / kg / day and above, and these included scratching behavior, mild or moderate facial swelling, raised areas with redness on the abdominal body surface, and partial closure of the eyes. At 6 mg / kg / day, the animals also had tremors, abnormal posture and gait, inability to stand, and collapse. Generally, the clinical signs resolved by 2 hours after dosing. As the study progressed, some of the clinical signs (tremors, inability to stand, collapse, and abnormal posture and gait) diminished slightly. Initial weight loss with decreased food intake was seen in males at 3 mg / kg / day and above and females at 6 mg / kg / day during the first 3 days of the study. Males and females at 6 mg / kg / day did not show weight gain compared to animals in the other groups where weight gain was clearly seen during the study. At the end of the dosing period, a tendency for decreased red blood cell count, hemoglobin, and hematocrit, and a tendency for decreased total white blood cell count were seen in all treatment groups. The decrease in white blood cell count correlated with a decrease in the absolute numbers of neutrophils and eosinophils at 3 mg / kg / day and above, but these parameters remained within the range of historical normal values. At necropsy, there were no changes in organ weights compared to control animals, and no macroscopic or microscopic changes in any organs, with the exception of fibrosis seen in the hearts of 1 male at 3 mg / kg / day and 1 male at 6 mg / kg / day.

[0138] Based on the results of this study, the no observed toxic event level (NOTEL) for IV administration of GC4403 to dogs by slow bolus injection for 7 days was 3 mg / kg / day.

[0139] 28-Day IV Toxicity of GC4403 GC4403 was evaluated in beagle dogs in a study conducted in accordance with Good Laboratory Practice (GLP) guidelines. GC4403 was administered intravenously (IV) once daily for 28 consecutive days via slow bolus injection. GC4403 was administered IV (0.5 mL / kg) into the cephalic vein at doses of 1.0, 3.0, and 6.0 mg / kg to three groups of dogs (4 animals / sex / group), and the fourth group received vehicle (26 mM sodium bicarbonate in normal saline). In the 6.0 mg / kg group, tremors, abnormal posture and gait, and inability to stand were observed immediately after dosing, but no animals died during the treatment period. These clinical signs were of short duration and the incidence and severity decreased as the study progressed. There were no test substance-related differences in group mean hematological, coagulation, or clinical chemistry parameters or urinalysis parameters at 28 days after treatment in any of the dosing groups. At necropsy on day 29, there were no gross findings overall related to the test substance, nor were there any organ weight differences related to the test substance. There were no histopathological lesions related to the test substance. There were no electrocardiogram (ECG) effects related to the test substance at the evaluation on day 27.

[0140] Based on the results and observations of this study, the No Observed Toxicological Effect Level (NOTEL) for GC4403 following 28 consecutive days of IV administration to beagle dogs was 3.0 mg / kg / day, while the No Observed Adverse Effect Level (NOAEL) was 1 mg / kg / day.

[0141] Repeated Dose Toxicity of GC4419 in Dogs for 14 Days GC4419 was evaluated in beagle dogs in a GLP study. Beagle dogs were administered GC4419 intravenously (IV) once daily for 14 consecutive days over 15 minutes. GC4419 was administered IV (4 mL / kg) into the cephalic vein at doses of 2.5, 5.0, and 7.5 mg / kg to three groups of dogs (4 animals / sex / group), and a fourth group received vehicle (26 mM sodium bicarbonate in normal saline). No animals died during treatment, and there was little effect of GC4419 up to 7.5 mg / kg, although ataxia was observed in one male and one female, and seizures were observed in one female, all in the 7.5 mg / kg group. All animals recovered from these effects. There were no test substance-related differences in group mean hematological, coagulation, or clinical chemistry parameters or urinalysis parameters 14 days after treatment in any of the dosing groups. At necropsy on Day 15, there were no overall macroscopic findings related to the test substance, nor were there any organ weight differences related to the test substance. There were no histopathological lesions related to the test substance.

[0142] Based on the rare clinical signs at 7.5 mg / kg / day, the no-observed-adverse-effect level (NOAEL) was determined to be 5.0 mg / kg / day.

[0143] Safety study in rats 7-day intravenous administration toxicity of GC4403 in rats GC4403 was tested in a GLP toxicity study where GC4403 in 26 mM sodium bicarbonate / 0.9% sodium chloride was administered IV (slow bolus at 1 mL / kg / min) to Sprague-Dawley rats (10 per sex / group) at doses of 0, 1, 3, or 10 mg / kg / day for 7 days (on day 1, 1 / 10 of the male rats given 10 mg / kg / day died). Therefore, on day 2, the dose was reduced to 8 mg / kg / day for all surviving animals to conduct the remaining study, and the original 10 mg / kg / day group was re-planned as an 8 mg / kg / day group. On day 4, 2 female rats also died from the 8 mg / kg / day group. Clinical signs immediately after dosing at 8 mg / kg / day were convulsions, labored breathing, body drop, and collapse. At regular 1-hour observations, the animals appeared normal. A decrease in weight gain was seen in both male and female rats given 8 mg / kg / day, and a decrease in food intake was seen in males only. Compared to the control, rats given 8 mg / kg / day had significantly higher glucose levels, alkaline phosphatase values, as well as ALT and triglyceride values. In males at 3 mg / kg / day and above and females at 8 mg / kg / day, calcium values were significantly higher. Surviving rats were sacrificed, and all sacrificed or found dead rats were necropsied. No organ weight changes related to the compound were noted at necropsy. There were no macroscopic or microscopic findings in any tissue, and from examination of the injection site, the compound was found to be non-irritating.

[0144] Based on the results and observations of this study, the no-observed toxic effect level (NOTEL) for IV administration of GC4403 by slow bolus injection to rats for 7 days was 3 mg / kg / day.

[0145] 28-Day IV Toxicity of GC4403 in Rats GC4403 was evaluated in a 28-day GLP study in Sprague-Dawley rats. GC4403 was administered to rats (10 per sex / group) at doses of 0, 1, 3, or 6 mg / kg / day for 28 days by slow bolus IV injection. The control (zero-dose) group received vehicle (26 mM sodium bicarbonate in normal saline). Evaluation of compound-related effects was based on clinical findings, body weight, food consumption, hematological and clinical chemistry parameters, functional observation battery, organ weights, and gross and microscopic necropsy. There were no compound-related organ weight differences or gross or microscopic lesions. Based on the results and observations of this study, the no-observed toxic effect level (NOTEL) for GC4403 when administered to rats by IV infusion for 28 days was 3 mg / kg / day.

[0146] 7-Day IV Study of GC4419 in Rats A GLP toxicity study was conducted using GC4419 in bicarbonate buffer. GC4419 was administered to rats (5 per sex / group) at 0, 5, 10, or 15 mg / kg for 7 consecutive days as a 15-minute IV injection (4 mL / kg). The control group received bicarbonate buffer. Evaluation of compound-related effects was based on clinical findings, body weight, and food consumption. There were no deaths during the study and no signs of significant compound effects at any dose. A slight weight loss reaching approximately 10% by day 8 was observed in some male rats given 15 mg / kg / day, and a slight decrease in food consumption was also observed. The NOTEL was found to be 15 mg / kg for both males and females.

[0147] 14-Day IV Study of GC4419 in Rats GC4419 was evaluated in rats in a 14-day GLP study. GC4419 was administered to rats (10 per sex / group) as a 15-minute IV injection at doses of 0, 5, 10, or 20 (15) mg / kg / day for 14 days. The control group received vehicle (sodium citrate in normal saline). Due to mortalities at 20 mg / kg / day, the high-dose group was reduced to 15 mg / kg / day on Day 3. The evaluation of compound-related effects was based on clinical findings, body weight, food consumption, hematological and clinical chemistry parameters, functional observation battery, organ weights, and gross and microscopic necropsies. Several rats died on Day 1 or Day 2 at 20 mg / kg, and these deaths were considered compound-related, so the dose level was reduced to 15 mg / kg / day starting on Day 3. There were no compound-related changes in organ weights or macroscopic or microscopic lesions. Based on the results and observations of this study, the NOAEL for GC4419, when administered to rats as a 15-minute IV infusion for 14 days, was 15 mg / kg / day.

Example

[0148] Efficacy of SOD mimetics against radiation-induced oral mucositis GC4403 and GC4419 were tested in a hamster model of oral mucositis (OM). Lesions were induced by radiation of the hamster cheek pouch, which were clinically and histologically similar to OM that occurs clinically and developed and resolved at a rate similar to human radiation-induced OM. Male Syrian golden hamsters (8 per group) were given vehicle, GC4403 (30 mg / kg) or GC4419 (3 - 30 mg / kg) in 26 mM sodium bicarbonate buffered saline by intraperitoneal injection 30 minutes before irradiation and 12 hours after irradiation. The animals were given a local 40 Gy radiation to the everted cheek pouch and the development of inflammation at the irradiated site was evaluated every 2 days. Inflammation was graded on a scale of 0 (normal) to 5 (total ulceration of the cheek) by trained observers blinded to the treatment protocol.

[0149] At all doses of GC4419 administered before irradiation, the onset of grade 3 or higher OM (Figure 4) was prevented. GC4419 at 30 mg / kg reduced OM by only 57%, and GC4403 at 30 mg / kg reduced grade 3 or higher OM by only 52%. All hamsters treated with GC4403 or GC4419 showed weight gain (approximately 15% compared to the vehicle) throughout the experimental period (28 days), probably because the pain and inflammation in the oral cavity decreased, making it easier to eat.

Example

[0150] Efficacy of SOD mimics against TNF-α in plasma in a collagen-induced arthritis model Male Lewis rats (160 - 180 g) were used in this study. Collagen-induced arthritis (CIA) was induced as follows. Bovine type II collagen (CII; Sigma) was dissolved by stirring overnight at 4°C in 0.1 M acetic acid to a concentration of 2 mg / mL. Rats were immunized with an emulsion of 2 mg / mL CII in Freund's incomplete adjuvant (IFA; Sigma). This emulsion was prepared by mixing CII and IFA at a 1:1 ratio and homogenizing at 4°C. On day 1, 100 μL of the emulsion was injected intradermally at the base of the tail of the rats. On day 21, a second injection of CII in IFA was given at the base of the tail. Fresh GC4403 and GC4419 were prepared and dissolved in 26 mM sodium bicarbonate buffered saline (vehicle). All drugs were administered by intraperitoneal injection at 1 mL / kg. The animals were randomly divided into groups (n = 10 per group). GC4403 and GC4419 were administered once a day at 2, 5, and 10 mg / kg from day 25 to day 35.

[0151] According to the time-course test, in the CIA model, it was shown that the plasma level reached a peak on the 35th day and remained elevated for approximately 5 to 6 days. The TNF-α level was measured from plasma on the 35th day. The assay was performed using a chromogenic ELISA kit (Calbiochem-Novabiochem) with a detection limit of 5 pg / mL. The values were averaged over 10 observations and expressed as mean ± standard error. The dataset was verified by Bonferroni post hoc multiple comparison test after one-way ANOVA. A p-value smaller than 0.05 was considered significant.

[0152] On the 35th day, the level of TNF-α was significantly elevated in the plasma of CIA rats treated with vehicle. Both GC4403 and GC4419 similarly attenuated TNF-α production (Figure 5). At a dose of 2 mg / kg, the decrease in TNF-α production was not significant. For both agents, at doses of 5 mg / kg and 10 mg / kg, the production of TNF-α was significantly decreased.

Example

[0153] Human Clinical Safety of GC4419 A human clinical trial entitled "A double-blind, placebo-controlled, single ascending dose study to evaluate the safety and tolerability of M40419 administered as a 15-minute intravenous infusion to healthy subjects and to determine its pharmacokinetics" was conducted in 54 subjects. This was a single-site, randomized, placebo-controlled, sequential panel study of the single-dose safety, tolerability, and pharmacokinetics of GC4419, in which GC4419 was administered as a 75 mL IV infusion over 15 minutes at escalating doses of 10 mg, 15 mg, 22 mg, 33 mg, 50 mg, 75 mg, and 112 mg. The study consisted of two phases: Phase 1 determined the maximum tolerated dose (MTD) by escalating doses using 6 subjects (4 active, 2 placebo) per cohort; Phase 2 confirmed the safety of the MTD, i.e., the highest dose tested, by repeating the MTD dose in 12 subjects (8 active drug, 4 placebo). The study population included 54 healthy male and female subjects (36 males, 18 females) between 18 and 50 years of age who were considered eligible based on inclusion and exclusion criteria. In the dose-escalation phase of the study, there were 4 subjects receiving the active drug and 2 subjects receiving placebo for each dose level, and for confirmation of the MTD phase, there were 8 subjects receiving the active drug and 4 subjects receiving placebo.

[0154] All subjects who received the test article were evaluated for safety. The safety of the drug product was evaluated based on treatment-emergent adverse events (TEAEs), clinical laboratory evaluations, vital signs, 12-lead electrocardiograms (ECGs), and standard ECG parameters such as PR, QRS, QT, and QTc intervals.

[0155] Of the 54 subjects who were randomized to receive the investigational drug, 54 (100%) completed the trial according to the trial protocol. There were no subjects who discontinued the trial early. Protocol deviations were few and none were considered to affect the pharmacokinetic or safety results of the trial. Immediately after visual inspection of the demographic and baseline characteristics data, no clinically relevant differences were seen between the treatment groups.

[0156] A total of 125 treatment-emergent adverse events (TEAEs) occurred in 37 subjects after dosing. Overall, 7 out of 18 subjects (38.9%) who received placebo and 30 out of 36 subjects (83.3%) who received the investigational substance experienced at least one TEAE. TEAEs occurred in 12 body tissues, and the most common ones in subjects who received the investigational substance were nervous system disorders, general disorders, administration site conditions, and gastrointestinal disorders. The most common adverse events in subjects treated with the investigational substance were paresthesia, perioral paresthesia, and nausea (the analysis of the causes of the side effects of paresthesia will be discussed below). The majority of the reported TEAEs were mild in severity (104 out of 125 events, 83.2%). 19 events (19 out of 125 events, 15.2%) were moderate, and 2 events (2 out of 125 events, 1.6%) were severe. The 2 events reported to be severe in intensity were nausea and were reported in the 75 mg and 112 mg treatment groups. Both events resolved spontaneously. Of the 125 total reported TEAEs, 105 events (84.0%) occurred in 37 out of 54 total subjects and were determined by the trial responsible physician to be either of uncertain relevance or probably related to the investigational drug. 7 of these events (5.6%) occurred in subjects treated with placebo, and 99 out of 105 events (94.3%) occurred in subjects treated with the investigational drug.

[0157] A dose of 50 mg was determined to be the MTD after completion of the MTD panel confirmation. Initially, a dose of 75 mg was determined to be the MTD during the dose escalation phase; however, based on the nature and grading of the adverse events that occurred during the MTD phase confirmation, it was decided to define the MTD as 50 mg. Although no formal statistical analysis of the data was performed, upon visual inspection of this data, the incidence of AEs appeared to be correlated with the dose of the test substance.

[0158] No deaths or serious adverse events occurred throughout the duration of the study. No subjects were prematurely discontinued due to adverse events. Two dose-limiting toxicities (DLTs) occurred, each of which prompted the identification of the MTD as one dose lower. These DLTs included nausea in a subject who received 112 mg of the test substance during the dose escalation phase (initially defining the MTD as 75 mg), and nausea with mild hypotension in a subject who received 75 mg of the test substance during the confirmation of the MTD phase (ultimately defining the MTD as 50 mg). Both events were determined by the principal investigator of the study to be probably related to the test drug.

[0159] No clinically significant trends or changes from baseline were revealed from vital signs, ECG, and physical examination data, and no distinguishable differences were found between subjects treated with placebo and those treated with the test substance at any dose of the test drug.

[0160] The overall conclusions of the study are as follows. - GC4419 was excreted unchanged in the urine, and the amount was less than 20% of the administered dose over 48 hours. The renal pathway does not appear to be the major route of GC4419 excretion in humans. - A dose of 50 mg of GC4419 (administered as an intravenous infusion over 15 minutes) was determined to be the maximum no effect tolerated dose. - The adverse events after GC4419 administration were generally mild. The two dose-limiting toxicities reported did not justify discontinuation of dose escalation, but the maximum tolerated dose ultimately resulted in 50 mg. No serious adverse events were reported, and no subjects discontinued due to adverse events. - Overall, single intravenous administrations of GC4419 from 10 mg to 50 mg were safe and showed good tolerance without adverse events. - In this Phase 1 trial, the results showed that single-dose administrations of GC4419 up to 112 mg were tolerated without serious adverse events in healthy subjects.

Example

[0161] Human Clinical Safety of GC4403 In a Phase 1, randomized, double-blind, placebo-controlled, single ascending-dose pharmacokinetic study of safety and tolerance, 54 healthy male and female subjects were administered 2.2 to 25 mg of GC4403 intravenously over 30 minutes. The properties of GC4403 are multi-exponential, and over the dose range studied, as the dose increases, AUC and C max generally follow linear pharmacokinetics that increase proportionally. The elimination half-life of the terminal elimination phase is approximately 1.5 hours. GC4403 was excreted unchanged in the urine, and the amount was approximately 9 to 17% of the administered dose. No significant effects on the cardiovascular system or vital signs, no significant abnormalities on physical examination, and no significant abnormalities in regular clinical laboratory evaluations were observed. Facial stinging, generalized stinging, paresthesia, and facial flushing were reported to occur in response to the dose at GC4403 doses of 16.7 and 25 mg. No adverse events labeled as severe and no serious adverse events were seen in this study.

[0162] Table 2 summarizes the clinical findings for the signs and symptoms of toxicity observed in the subjects in this Phase 1a trial. Although the established MTD was not established in this trial, based on the dose-dependent findings and the range of findings at 25 mg, clinical trials using GC4403 were continued up to a maximum dose of 20 mg infused over 30 minutes.

[0163] In this first Phase 1 trial, the results showed that single doses up to 25 mg of M40403 were tolerated without serious adverse events in healthy subjects. The number of subjects experiencing adverse events in this trial and confirmed for each dose is shown in Table 2, but as described, the maximum tolerated dose (MTD) was not reached. The highest dose administered was 25 mg. No significant effects on the cardiovascular system, no significant abnormalities on physical examination, and no significant abnormalities in the regular clinical laboratory evaluations were observed. No severe or serious adverse events were reported. Conjunctivitis was reported in 1 case (2.2 mg group), drowsiness in 1 case (3.3 mg group), headache in 1 case (16.7 group), and pain at the injection site in 1 case (16.7 mg group), all reported as moderate intensity. All other treatment-induced adverse events were reported as mild intensity. Facial flushing, stinging, stinging in the mouth, and paresthesia were all graded as mild intensity and reported to occur in response to the dose at 16.7 and 25 mg doses. Facial flushing, stinging, stinging in the mouth, and paresthesia typically began during or immediately after injection and lasted up to 3 - 4 hours. [Table 2] Table 3. Plasma Exposure of Mean Area Under the Curve (AUC) in Human Phase 1 Trial [Table 3]

[0164] As part of conducting a Phase 1a clinical trial for GC4403 and GC4419 described in the examples of this specification, plasma samples were collected and the concentrations of the parent compounds (GC4403 and GC4419) after intravenous injection were measured. Table 3 shows the pharmacokinetic parameters indicating the total exposure of the subjects to the drug over time, namely the area under the curve (AUC). Importantly, this result indicates that in humans, essentially equivalent AUC values should be obtained from equivalent mass doses of GC4419 and GC4403. Due to the higher safety of GC4419 than GC4403 (reflecting the safety at even higher doses achieved with GC4419), an approximately 4-fold larger AUC was achieved using GC4419, which was 10350 ng-hour / mL and 2556 ng-hour / mL respectively compared to GC4403.

Claims

**Claim 1** A therapeutic agent for treating a disease treatable with a superoxide dismutase mimetic corresponding to formula (GC441 9) in a human patient suffering from cancer and undergoing radiation exposure or chemotherapy, the method comprising parenterally administering to the patient a unit dosage formulation containing 75 mg to 450 mg of the superoxide dismutase mimetic within 60 minutes, wherein the parenteral administration is intravenous administration, and the superoxide dismutase mimetic corresponds to formula (GC4419): 【Chemical 1】 wherein X and Y are independently neutral or negatively charged ligands, a therapeutic agent. **Claim 2** The therapeutic agent according to claim 1, wherein the superoxide dismutase mimetic is administered to the patient to provide an exposure amount at which an area under the curve (AUC) of at least 4000 ng-hour / mL is measured, calculated from measurement of the concentration of the superoxide dismutase mimetic in the plasma of the patient. **Claim 3** The therapeutic agent according to claim 1, wherein the tissue damage is regulated by superoxide dismutase activity. **Claim 4** The therapeutic agent according to any one of claims 1 to 3, wherein the superoxide dismutase mimetic is administered as a pharmaceutical composition comprising a superoxide dismutase mimetic corresponding to formula (GC4419) and a pharmaceutically acceptable carrier. **Claim 5** The therapeutic agent according to any one of claims 1 to 4, wherein the superoxide dismutase mimetic is dissolved in a solution containing 0.25 mg / mL to 3.5 mg / mL of the superoxide dismutase mimetic and contained in an IV bag. **Claim 6** The therapeutic agent according to any one of claims 1 to 5, wherein X and Y are independently selected from monodentate ligands. **Claim 7** The therapeutic agent according to any one of claims 1 to 6, wherein X and Y are independently selected from the group consisting of aquo ligands, halo ligands, carboxylate ligands, and bicarboxylate ligands. **Claim 8** The therapeutic agent according to any one of claims 1 to 7, wherein X and Y are chloro ligands. **Claim 9** The therapeutic agent according to any one of claims 1 to 8, characterized in that 100 mg to 450 mg of the superoxide dismutase mimetic is administered to the patient.

10. The therapeutic agent according to any one of Claims 1 to 9, characterized in that the superoxide dismutase mimetic of 150 mg to 450 mg is administered to the patient.

11. The therapeutic agent according to any one of Claims 1 to 10, wherein the superoxide dismutase mimetic is administered to the patient before or simultaneously with radiotherapy or chemotherapy.

12. The therapeutic agent according to any one of Claims 1 to 11, wherein the superoxide dismutase mimetic is administered to the patient before but not after radiotherapy or chemotherapy.

13. The therapeutic agent according to any one of Claims 1 to 12, wherein the superoxide dismutase mimetic is administered to the patient at least 30 minutes before radiotherapy or chemotherapy.

14. The therapeutic agent according to any one of Claims 1 to 10, wherein the superoxide dismutase mimetic is administered to the patient after radiotherapy or chemotherapy.

15. The therapeutic agent according to any one of Claims 1 to 10, wherein the superoxide dismutase mimetic is administered to the patient within 12 weeks after radiotherapy or chemotherapy.

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