EP2139522A2 - Auf mitochondrien gerichtete kationische antioxidationsverbindungen zur prävention, therapie oder behandlung von hyperproliferativen erkrankungen, neoplasien und karzinomen - Google Patents

Auf mitochondrien gerichtete kationische antioxidationsverbindungen zur prävention, therapie oder behandlung von hyperproliferativen erkrankungen, neoplasien und karzinomen

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Publication number
EP2139522A2
EP2139522A2 EP08731532A EP08731532A EP2139522A2 EP 2139522 A2 EP2139522 A2 EP 2139522A2 EP 08731532 A EP08731532 A EP 08731532A EP 08731532 A EP08731532 A EP 08731532A EP 2139522 A2 EP2139522 A2 EP 2139522A2
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EP
European Patent Office
Prior art keywords
moieties
independently selected
alkyl
cancer
salt
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP08731532A
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English (en)
French (fr)
Inventor
David A. Zarling
Hirak S. Basu
Balaraman Kalyanaraman
Joy Joseph
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Medical College of Wisconsin
Colby Pharmaceutical Co
Original Assignee
Medical College of Wisconsin
Colby Pharmaceutical Co
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Publication date
Application filed by Medical College of Wisconsin, Colby Pharmaceutical Co filed Critical Medical College of Wisconsin
Publication of EP2139522A2 publication Critical patent/EP2139522A2/de
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/54—Quaternary phosphonium compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/548—Phosphates or phosphonates, e.g. bone-seeking
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
    • C07D211/94—Oxygen atom, e.g. piperidine N-oxide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/572—Five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/576—Six-membered rings
    • C07F9/59—Hydrogenated pyridine rings

Definitions

  • inventions described herein relate to the treatment of various forms of cancer, or related neoplasias, with compounds that comprise one or more quaternary (check spelling) cationic moieties chemically linked to one or more anti-oxidant moieties comprising nitroxide or amine oxide moieties.
  • Oxidative stress has been known to contribute to a variety of human degenerative diseases associated with aging, such as Parkinson's disease and Alzheimer's disease, as well as to Huntington's Chorea, diabetes and Friedreich's Ataxia (Allen, S., et al., J. Biol. Chem. 278:6371-6383,2003; Hirai, K., et al., J. Neurosci. 21:3017-3023, 2001) and to non-specific cellular damage that accumulates with aging.
  • Mitochondria are the intracellular organelles primarily responsible for energy metabolism, and are also the major source of the free radicals and reactive oxygen species ("ROS", such as hydrogen peroxide and the superoxide radical anion (O 2 " )) that cause oxidative stress and/or damage inside most cells (Murphy MP, Smith RA., Ann. Rev Pharmacol Toxicol. 2006 Oct 2; Epub ahead of print). Mitochondria are equipped to detoxify hydrogen peroxide due to the presence of antioxidant enzymes (peroxiredoxins, thioredoxins, and GSH-dependent peroxidases (Chang, T. S., J. Biol. Chem. 279, 41975-41984, 2004).
  • ROS free radicals and reactive oxygen species
  • mitochondrial superoxide O 2
  • MnSOD manganese superoxide dismutase
  • oxidative damage can occur. This damage disrupts mitochondrial function and oxidative phosphorylation and leads to significant cellular damage to mitochondrial, cytoplasmic or nuclear cellular proteins, DNA, RNA and phospholipids and thus induces cell damage, death and/or disease.
  • Superoxide can also react with nitric oxide at a diffusion-controlled reaction rate, forming a highly potent oxidant and peroxynitrite that can modify proteins and DNA through oxidation and nitration reactions (Beckman, J. S., et al., Nature 364, 584, 1993).
  • ROS also act as a redox signaling molecule(s) and promotes cell proliferation, DNA damage repair errors and mutation leading to inflammatory hyper-proliferation, neoplasia and malignancy (see Michikawa et.al., "Aging-dependent large accumulation of point mutations in the human mtDNA control region for replication.” Science. 1999 Oct 22;286(5440):774-9).
  • ROS tissue reactive oxygen species
  • antioxidant therapies To prevent the cellular damage caused by oxidative stress a number of prior art antioxidant therapies have been developed for treating various diseases resulting from oxidative stress. However, most of those inventions are not targeted to other organelles within cells or to the mitochondria and are therefore less than optimally effective.
  • warhead groups are covalently coupled via linker groups to a bulky and/or lipophilic cationic moiety such as a quaternary ammonium or phosphonium cationic moiety. These compounds are initially absorbed and accumulate in the cytoplasmic region of cells in response to the negative plasma membrane potential of 30-60 mV (3).
  • the lipophilic cations with a positive 30-6OmV potential permeate through the mitochondrion's lipid layers and selectively accumulate within mitochondria due to the larger mitochondrial membrane potential of 150-170 mV; (negative inside).
  • Mitochondria-targeted compounds in this class of agents are shown below and include a mitochondria-directed ubiquinone (MitoQ) reported by Murphy and coworkers (U.S. Patent Nos. 6,331,532 and 7,232,809, and EP Patent 1 047 701 Bl, all of which are herein incorporated by reference in their entirety).
  • MitoQ mitochondria-directed ubiquinone
  • MitoQ has shown promise in the treatment of only some, but not all, oxidative stress induced diseases. MitoQ is currently undergoing Phase II clinical trials for the treatment of Parkinson's disease, but it has relatively minor activity against other oxidative stress-induced neurodegenerative diseases such as Amyotrophic Lateral Sclerosis (ALS or Lou Gehrig's Disease). This class of compounds is also disclosed in U.S. Published Application No. U.S. 2008/0032940, herein incorporated by reference in its entirety, in the context of methods for treating cancer.
  • ALS Amyotrophic Lateral Sclerosis
  • mitochondria-targeted compounds include mitochondria-targeted nitroxides, which have been used in method for treating neurodegenerative disorders (see U.S. Published Application No. 2007/0066572, herein incorporated by reference in its entirety) and mitochondria-targeted antioxidants, which have been used in methods for treating cancer (see U.S. Application No. 11/834,799, entitled “Methods for Reducing Anthracycline-Induced Toxicity,” filed August 7, 2007, herein incorporated by reference in its entirety).
  • One aspect of the disclosure relates to methods for treating or inhibiting the occurrence, recurrence, progression or metastasis, of a cancer or a neoplastic or hyper- proliferative precursor thereof, consisting of administering to a mammal diagnosed as having a cancer or precursor neoplasia or hyper-proliferative disorder thereof, in an amount effective to treat the cancer or inhibit the occurrence recurrence, progression, or metastasis of the cancer or precursor hyperplasia or neoplasia thereof, a pharmaceutically acceptable salt comprising one or more cations having the formula:
  • R , 1 wherein a) A is an antioxidant moiety comprising one or more nitroxide or hydroxyl amine moieties, or a pro-drug thereof, having from three to 16 carbon atoms, b) L is an organic linking moiety comprising 4 to 30 carbon atoms, c) E is a nitrogen or phosphorus atom, d) R 1 ' , Ri " , and Rj " ' are each independently selected organic moieties comprising between 1 and 12 carbon atoms, wherein E, Ri', Ri", and Ri'" together form a quaternary ammonium or phosphonium cation; and wherein the salt further comprises one or more X m" pharmaceutically acceptable anions, where m is an integer from 1 to 4, in sufficient quantities to form the pharmaceutically acceptable salt.
  • a related aspect of the disclosure relates to a method for treating, regulating or inhibiting the prostate's inflammation, hyperplasia or enlargement and the occurrence, recurrence, progression or metastasis of prostate cancer, consisting of administering to a mammal diagnosed as having prostate disease or cancer or precursor neoplasia thereof, in an amount effective to treat the cancer or modulate the inflammation, hyperplasia, or enlargement of the prostate or the occurrence, recurrence, progression, or metastasis of prostate cancer or precursor neoplasia thereof, with one or more pharmaceutically acceptable salts having one or more cations having the formula
  • E is a nitrogen or phosphorus atom
  • R f ', Ri", and Rj' are each independently selected organic moieties comprising between 1 and 12 carbon atoms
  • n is an integer between 8 and 12
  • R s ' , Ri " , and R j " ' are each independently selected organic moieties comprising between 1 and 12 carbon atoms, wherein E, R 1 ', Ri", and Ri'" together form a quaternary ammonium or phosphonium cation
  • the salt further comprises one or more pharmaceutically acceptable anions X m" , wherein m is an integer from 1 to 4, in sufficient amount to form the pharmaceutically acceptable salt.
  • E is a nitrogen or phosphorus atom
  • R i ' , R i " , and R 1 '" are each independently selected organic moieties comprising between 1 and 12 carbon atoms
  • n is an integer between 5 and 12
  • E, Ri', R 1 ", and R 1 '" together form a quaternary ammonium or phosphonium cation
  • the salt forther comprises is one or more pharmaceutically acceptable anions X m ⁇ , wherein m is an integer from 1 to 4, in sufficient amount to form the pharmaceutically acceptable salt.
  • Another aspect of the disclosure relates to salts comprising one or more cations having the formula:
  • E is a nitrogen or phosphorus atom
  • R] ', Ri ", and Ri '" are each independently selected organic moieties comprising between 1 and 12 carbon atoms
  • n is an integer between 5 and 12
  • E, Ri', Rj", and Rj '" together form a quaternary ammonium or phosphonium cation
  • the salt further comprises one or more anions X m' in a sufficient amount to form the pharmaceutically acceptable salt.
  • Figure 1 shows the inhibitory effect of varying concentrations of MitoT on the proliferation and growth of human prostate tumor LNCaP and PC-3 cells, as determined by Hoechst dye-DNA fluorescence assays.
  • Figure 2 shows a microscopic picture of DCF fluorescence (green) and Hoechst dye-
  • Figure 3 shows the inhibitory effect of treatment with varying concentrations of MitoT on the oxidative stress levels in LNCaP human prostate tumor cells, as determined by the ratio of DCF fiuorescence/Hoechst dye-DNA fluorescence.
  • FIG. 4 shows that MitoT treatment at sufficient concentrations reduces the ROS level and causes inhibition of cell growth and proliferation in LNCaP human prostate cancer cells
  • A Plot of % control of MTT absorbance at increasing MitoT concentration shows MitoT absorbs mitochondrial electrons.
  • B Plot of the ratio of % of control cell MTT absorbance/DNA fluorescence shows that the decrease in MTT oxidation is related to cell growth arrest.
  • Figure 5 shows that synthetic androgen (Rl 881) treatment-induced oxidative stress in LNCaP human prostate cancer cells, as determined by the ratio of DCF fluorescence/DNA fluorescence, is strongly inhibited by pre-treatment of the ceils with 1 ⁇ M MitoT.
  • Figure 6 shows the pharmacokinetics of MitoT absorption in serum and in kidney tissues of white mice given one intraperitoneal (i.p.) injection of MitoT (5 mg/kg) showing serum clearance and tissue accumulation of the drug with the passage of time.
  • Figure 7 shows pictorial microscopic evidence of Hydroethidine dye fluorescence due to ROS oxidation in kidney tissue of (A) untreated mice and (B) mice treated with 5 mg/kg MitoT for 3 hours.
  • Figure 8 shows the inhibitory effect of varying concentrations of MitoT- 10 on the growth and proliferation of LNCaP and PC-3 human prostate cancer cells, as determined by Hoechst dye-DNA fluorescence assays
  • ranges are expressed herein as from “about” one particular value, and/or to “about” another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent "about,” it will be understood that the particular value forms another embodiment. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint.
  • a cell can be in vitro. Alternatively, a cell can be in vivo and can be found in a subject.
  • a "cell” can be a cell from any organism including, but not limited to, a bacterium or a mammalian cell or a tumor cell.
  • a “subject” is meant an individual.
  • the "subject” can include domesticated animals, such as cats, dogs, etc., livestock (e.g., cattle, horses, pigs, sheep, goats, rabbits, etc.), laboratory animals (e.g., mouse, rabbit, rat, guinea pig, ferret, mink, etc.) and birds.
  • livestock e.g., cattle, horses, pigs, sheep, goats, rabbits, etc.
  • laboratory animals e.g., mouse, rabbit, rat, guinea pig, ferret, mink, etc.
  • the subject is a higher mammal such as a primate or a human.
  • the compounds described herein can be administered to a subject comprising a human or an animal including, but not limited to, a murine, canine, feline, equine, bovine, porcine, caprine or ovine species and the like, that is in need of alleviation or amelioration from a recognized medical condition.
  • references in the specification and concluding claims to parts by weight, of a particular element or component in a composition or article denotes the weight relationship between the element or component and any other elements or components in the composition or article for which a part by weight is expressed.
  • X and Y are present at a weight ratio of 2:5, and are present in such ratio regardless of whether additional components are contained in the compound.
  • a weight percent of a component is based on the total weight of the formulation or composition in which the component is included.
  • moiety defines a carbon containing residue, i.e. a moiety comprising at least one carbon atom, and includes but is not limited to the carbon-containing groups defined hereinabove.
  • Organic moieties can contain various heteroatoms, or be bonded to another molecule through a heteroatom, including oxygen, nitrogen, sulfur, phosphorus, or the like. Examples of organic moieties include but are not limited alkyl or substituted alkyl s, alkoxy or substituted alkoxy, mono or di-substituted amino, amide groups, etc.
  • Organic moieties can preferably comprise 1 to 21 carbon atoms, 1 to 18 carbon atoms, 1 to 15, carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms.
  • alkyl denotes a moiety containing a saturated, straight or branched hydrocarbon residue having from 1 to 18 carbons, or preferably 4 to 14 carbons, 5 to 13 carbons, or 6 to 10 carbons.
  • An alkyl is structurally similar to a non-cyclic alkane compound modified by the removal of one hydrogen from the non-cyclic alkane and the substitution, therefore, with a non-hydrogen group or moiety.
  • Alkyl moieties can be branched or unbranched. Lower alkyl moieties have 1 to 4 carbon atoms.
  • alkyl moieties include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, t-butyl, amyl, t-amyl, n-pentyl and the like.
  • substituted alkyl denotes an alkyl moiety analogous to the above definition that is substituted with one or more organic or inorganic substituent moieties. In some embodiments, 1 or 2 organic or inorganic substituent moieties are employed. In some embodiments, each organic substituent moiety comprises between 1 and 4, or between 5 and 8 carbon atoms.
  • Suitable organic and inorganic substituent moieties include, but are not limited to, hydroxyl, halogens, cycloalkyl, amino, mono -substituted amino, di-substituted amino, acyloxy, nitro, cyano, carboxy, carboalkoxy, alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide, substituted dialkylcarboxamide, alkylsulfonyl, alkylsulfinyl, thioalkyl, thiohaloalkyl, alkoxy, substituted alkoxy, haloalkyl, haloalkoxy, heteroaryl, substituted heteroaryl, aryl or substituted aryl.
  • alkoxy denotes a moiety alkyl, defined above, attached directly to a oxygen to form an ether residue. Examples include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, t-butoxy, iso-butoxy and the like.
  • substituted alkoxy denotes a alkoxy moiety of the above definition that is substituted with one or more groups, but preferably one or two substituent groups including hydroxyl, cycloalkyl, amino, mono -substituted amino, di-substituted amino, acyloxy, nitro, cyano, carboxy, carboalkoxy, alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide, substituted dialkylcarboxamide, alkylsulfonyl, alkylsulfinyl, thioalkyl, thiohaloalkyl, alkoxy, substituted alkoxy or haloalkoxy. When more than one group is present then they can be the same or different.
  • mono-substituted amino denotes an amino (-NH 2 ) group substituted with one group selected from alkyl, substituted alkyl or arylalkyl wherein the terms have the same definitions found throughout.
  • di-substituted amino denotes an amino substituted with two moieties that can be same or different selected from aryl, substituted aryl, alkyl, substituted alkyl or arylalkyl wherein the terms have the same definitions found throughout. Some examples include dimethylamino, methylethylamino, diethylamino and the like.
  • haloalkyl denotes a alkyl moiety, defined above, substituted with one or more halogens, preferably fluorine, such as a trifluoromethyl, pentafluoroethyl and the like.
  • haloalkoxy denotes a haloalkyl, as defined above, that is directly attached to an oxygen to form a halogenated ether residue, including trifluoromethoxy, pentafluoroethoxy and the like.
  • Acyl moieties contain 1 to 8 or 1 to 4 carbon atoms. Examples of acyl moieties include but are not limited to formyl, acetyl, propionyl, butanoyl, iso-butanoyl, pentanoyl, hexanoyl, heptanoyl, benzoyl and like moieties.
  • acyloxy denotes a moiety containing 1 to 8 carbons of an acyl group defined above directly attached to an oxygen such as acetyloxy, propionyloxy, butanoyloxy, iso -butanoyloxy, benzoyloxy and the like.
  • aryl denotes an unsaturated and conjugated aromatic ring moiety containing 6 to 18 ring carbons, or preferably 6 to 12 ring carbons. Many aryl moieties have at least one six-membered aromatic "benzene” moiety therein. Examples of such aryl moieties include phenyl and naphthyl.
  • substituted aryl denotes an aryl ring moiety as defined above that is substituted with or fused to one or more organic or inorganic substituent moieties, which include but are not limited to a halogen, alkyl, substituted alkyl, haloalky, hydroxyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, amino, mono- substituted amino, di-substituted amino, acyloxy, nitro, cyano, carboxy, carboalkoxy, alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide, substituted dialkylcarboxamide, alkylsulfonyl, alkylsulfinyl, thioalkyl, thiohaloalkyl, alkoxy, substituted alkoxy or haloalkoxy, aryl, substituted aryl, heteroaryl, heterocycl
  • Substituted aryl moieties can have one, two, three, four, five, or more substituent moieties.
  • the substituent moieties can be not be of unlimited size or molecular weight, and each organic moiety can comprise 15 or fewer, 10 or fewer, or 4 or fewer carbon atoms unless otherwise expressly contemplated by the claims
  • heteroaryl denotes an aryl ring moiety as defined above, wherein at least one of the carbons of the aromatic ring has been replaced with a heteroatom, which include but are not limited to nitrogen, oxygen, and sulfur atoms.
  • Heteroaryl moieties include 6 membered aromatic ring moieties, and can also comprise 5 or 7 membered aromatic rings, or bicyclic or polycycMc heteroaromatic rings as well. Examples of heteroaryl moieties include pyridyl, bipyridyl, furanyl, and thiofuranyl residues.
  • heteroaryl moieties can optionally be substituted with one or more organic or inorganic substituent moieties bound to the carbon atoms of the heteroaromatic rings, as described hereinabove for substituted aryl moieties.
  • Substituted heteroaryl moieties can have one, two, three, four, five, or more substituent organic or inorganic moieties, in a manner analogous to the substituted aryl moieties defined herein.
  • the substituent moieties cannot be of unlimited size or molecular weight, and each organic substituent moiety can comprise 15 or fewer, 10 or fewer, or four or fewer carbon atoms unless otherwise expressly contemplated by the claims.
  • halo refers to a fluoro, chloro, bromo or iodo atom or ion.
  • heterocycle refers to a moiety having a closed ring structure comprising 3 to 10 ring atoms, in which at least one of the atoms in the ring is an element other than carbon, such as, for example, nitrogen, sulfur, oxygen, silicon, phosphorus, or the like.
  • Heterocyclic compounds having rings with 5, 6, or 7 members are common, and the ring can be saturated, or partially or completely unsaturated.
  • the heterocyclic compound can be monocyclic, bicyclic, or polycyclic. Examples of heterocyclic compounds include but are not limited to pyridine, piperidine, thiophene, furan, tetrahydrofuran, and the like.
  • substituted heterocyclic refers to a heterocyclic moiety as defined above having one or more organic or inorganic substituent moieties bonded to one of the ring atoms.
  • carboxy refers to the - C(O)OH moiety that is characteristic of carboxylic acids.
  • the hydrogen of the carboxy moieties is often acidic and (depending on the pH) often partially or completely dissociates, to form an acid H+ ion and a carboxylate anion (-CO 2 " ), wherein the carboxylate anion is also sometimes referred to as a "carboxy" moiety.
  • a chiral atom is present in a compound disclosed herein, both separated enantiomers, racemic mixtures and mixtures of enantiomeric excess are within the scope of the invention. Separation of such mixtires may be done using techniques known in the art.
  • a racemic mixture is an equal ratio of each of the enantiomers, whereas an enantiomeric excess is when the percent of one enantiomer is greater than the other enantiomer, all percentages are within the scope of the invention. Furthermore, when more than one chiral atom is present in a compound, then the enantiomers, racemic mixtures, mixtures of enantiomeric excess and diastereomic mixtures are within the scope of the invention.
  • the salts comprise a mixture of cations and anions whose total number of positive and negative charges are electrically balanced. More particularly, however, the salts disclosed herein have one or more cations having the Formula (I) illustrated below ⁇
  • A is an antioxidant moiety comprising one or more nitroxide or hydroxylamine moieties, or a prodrug thereof
  • L is an organic linking moiety
  • E is a nitrogen or phosphorus atom
  • Rj ', Ri ", and R 5 '" are each independently selected from organic moieties comprising between 1 and 12 carbon atoms, wherein E, Ri', Ri", and R 1 '" together form a quaternary ammonium or phosphonium cation
  • the salt further comprises is one or more pharmaceutically acceptable anions X m" , wherein m is an integer from 1 to 4, in sufficient amount to form the pharmaceutically acceptable salt.
  • the various genera, subgenera, and species of the compounds of Formula (I) share at least the features disclosed above, and have related functions and utilities, but can differ in specific structural features, as described below.
  • the compounds of the invention all comprise at least one antioxidant moiety "A" which comprises at least one or more nitroxide radial or hydroxyl amine moieties bonded therein or thereto.
  • Nitroxides and relevant hydroxylamines have the chemical structures shown below:
  • the "A" moieties of the salts described herein which comprise one or more nitroxide orhydroxyl amine moieties, can catalyze the dismutation of superoxide radical anions in the cell, to form hydrogen peroxide which can be dealt with by enzymes in the cell, and therefore serve to function as "anti-oxidants.”
  • the nitroxide or hydroxylamine moieties are part of a larger A moiety, which in many embodiments can comprise between 4 and 30 carbon atoms, or, 6 to 24 carbon atoms, or 7 to 18 carbon atoms, or from 8 to 12 carbon atoms.
  • the A moieties have 5 or 6-member rings containing a nitroxide free radical therein having the formulas:
  • R moieties are organic substitutent moieties.
  • the R moieties can be C, -C 4 alkyls, aryls, alkoxides, and the like.
  • the R moieties can be C 1 -C 4 linear or branched alkyl, for example, methyl (C 1 ), ethyl (C 2 ), n-propyl
  • R 2 moieties are all methyl groups as shown below, which are [2,2,5,5-tetramethylpyrrolidinyloxy] free radical having the formula:
  • the "A" moieties are [2,2,6,6-tetramethylpiperidinyloxy] free radical moieties the formula:
  • L g can be any of a variety of moieties that form a bond to the "L" linking group.
  • the L g moieties taken together with nitroxide free radical moieties can provide "Tempol" analog moieties having the formula:
  • the L g moieties taken together with nitroxide free radical moieties can provide "Proxyl" analog moieties having the formula:
  • L moieties serve to connect the quaternary ammonium and/or phosphonium salt moieties with the A moieties.
  • L moieties can comprise a polyalkylene chain having 5 to 30 carbon chain atoms, wherein any one or more of the hydrogens bonded to said carbon chain atoms can be optionally substituted with one or two independently selected hydroxyl, halogen, amino, methylamino, dimethylamino, or C]-C 4 organic moieties selected from alkyl, hydroxyalkyl, alkoxy, alkoxylalkyl, carboxy, or carboxyalkyl moieties.
  • the compounds useful for the methods of the disclosure comprise one or more cationic moieties.
  • the cationic moieties carry a positive charge, which, while not being bound by theory, is believed to cause the desirable selective accumulation of the resultant compounds in the mitochondria, because of the large mitochondrial membrane potential of 150- 170 mV, and the resulting electrostatic attractions.
  • the selective accumulation of the cationic salts disclosed herein is also improved if the cationic moieties comprise relatively large and/or lipophilic organic substitutent moieties, so that the resulting cationic group is relatively lipophilic when considered as a whole.
  • Ri', Ri", and Rj'" are each independently organic moieties comprising from 1 to 32 carbon atoms.
  • the compounds of Formula (I) can have R b , R 1 ", and R 1 "' are each independently selected from alkyl, aryl, heteroaryl, or aralkyl moieties, which may be unsubstituted, or optionally substituted with one or two independently selected substituent moieties, such as those described above, which include but are not limited to hydroxyl, halogen, amino, amino, dimethylamino, alkyl, hydroxyalkyl, alkoxy, alkoxylalkyl, carboxy, or carboxyalkyl moieties.
  • Non-limiting examples of the optional substituents for R 1 ', R 1 ", and R 1 '” include: i) CrC 4 linear branched alkyl; for example, methyl (Cj), ethyl (C 2 ), n-propyl
  • Ci-C 4 linear or branched alkoxy for example, methoxy (Ci), ethoxy (C 2 ), n- propoxy (C 3 ), wo-propoxy (C 3 ), n-butoxy (C 4 ), sec-butoxy (C 4 ), iso-bntoxy (C 4 ), and tert-butoxy (C 4 ) ; iii) halogen; for example, -F, -Cl, -Br, -I, and mixtures thereof; iv) amino and substituted amino; for example, -NH 2 , -NH 2 , -NHCH 3 , -NHCH 3 , and -N(CH 3 ) 2 ; v) hydroxyl; -OH; vi) Ci-C 4 linear or branched hydroxyalkyl; for example, -CH 2 OH, -CH 2 CH 2 OH,
  • Ci-C 4 linear or branched alkoxyalkyl for example, -CHiOCH 3 , -CH 2 CH 2 OCH 3 , -CH 2 CH 2 CH 2 OCH 3 , and -CH 2 CH(OCH 3 )CH 3 ; viii) carboxy or carboxylate, for example, -CO 2 H or the anionic equivalent carboxylate moieties -CO 2 " ; and xi) carboxyalkyl, for example, -CH 2 CO 2 H, -CH 2 CH 2 CO 2 H, -CH 2 CO 2 CH 3 , -CH 2 CH 2 CO 2 CH 3 , and -CH 2 CH 2 CH 2 CO 2 CH 3 .
  • Ri', Ri", and R 1 '" can be each independently selected from alkyl, aryl, or benzyl moieties optionally substituted with one or two independently selected hydroxyl, halogen, amino, diamino, dimethylamino, alkyl, hydroxyalkyl, alkoxy, alkoxylalkyl, carboxy, or carboxyalkyl moieties.
  • R 1 ', R 1 ", and R 1 '" can be independently selected from C4-C 10 alkyl or phenyl moieties, which can optionally be substituted with one or two independently selected substituent moieites, which can include but are not limited to hydroxyl, halogen, amino, diamino, dimethylamino, alkyl, hydroxyalkyl, alkoxy, alkoxylalkyl, cyano,carboxy, or carboxyalkyl moieties.
  • R 1 ', R ! ", and R 1 '" can be independently selected from C4-C1 0 alkyl or phenyl moieties.
  • R 1 ', R 1 ", and R 1 '" are independently selected from C 4 -C 10 alkyl. In yet other related embodiments R 1 ', R 1 ", and R 1 '" are each n-C 4 H 9 moieties.
  • R 1 ', R 1 ", and R 1 '" are each phenyl moieties, to produce triphenyl phosphonium cations having the formula:
  • R 1 ', R 1 ", and R 1 '" are each benzyl moieties, to produce tribenzyl phosphonium cations having the formula:
  • R 1 ', R 1 ", and R 1 '" are each independently selected from alkyl, aryl, heteroaryl, or aralkyl moieties, which can be optionally substituted with one or two independently selected substituent moieties, which include but are not limited to hydroxyl, halogen, amino, dimethylamino, alkyl, hydroxyalkyl, alkoxy, alkoxylalkyl, cyano, carboxy, or carboxyalkyl moieties.
  • substituent moieties include but are not limited to hydroxyl, halogen, amino, dimethylamino, alkyl, hydroxyalkyl, alkoxy, alkoxylalkyl, cyano, carboxy, or carboxyalkyl moieties.
  • Non-limiting examples of the R 1 ', R ! ", and R 1 '" substituents include: i) C]-C 4 linear branched alkyl; for example, methyl (CO, ethyl (C 2 ),
  • C 3 wo- ⁇ ropyl (C 3 ), n-butyl (C 4 ), sec-butyl (C 4 ), iso-bntyl (C4), and tert-butyl (C 4 ); ⁇ ) C 1 -C 4 linear or branched alkoxy; for example, methoxy (Cj), ethoxy (C 2 ), n- propoxy (C 3 ), /so-propoxy (C 3 ), n-butoxy (C 4 ), sec-butoxy (C 4 ), ir ⁇ -butoxy iii) halogen; for example, -F, -Cl, -Br, -I, and mixtures thereof; iv) amino and substituted amino; for example, -NH 2 , -NH 2 , -NHCH 3 , -NHCH 3 , and -N(CH 3 ) 2 ; v) hydroxyl; -OH; vi) Ci-C 4 linear or branched alk
  • R]', Ri", and Ri' are each independently selected from alkyl aryl, or benzyl moieties, which can be optionally substituted with one or two independently chosen substitutent moieties, such as those described above, which include but are not limited hydroxyl, halogen, amino, dimethylamino, alkyl, hydroxyalkyl, alkoxy, alkoxylalkyl, carboxy, or carboxyalkyl moieties.
  • R 1 ', R 1 ", and R 1 "' are independently selected from C 4 -Cj O alkyl or phenyl moieties optionally substituted with one or two independently selected hydroxyl, halogen, amino, dimethylamino, alkyl, hydroxyalkyl, alkoxy, alkoxylalkyl, carboxy, or carboxyalkyl moieties.
  • R 1 ', R 1 ", and R 1 '" are independently selected from C 4 -C JO alkyl or phenyl moieties; and in one further embodiment R 1 ', R 1 ", and R 1 '" are independently selected from C 4 -CiO alkyl.
  • R I ? , R 1 ", and R 1 '" are each n-C 4 Hg moieties.
  • the "L” Linker Moiety The cations of Formula (I) comprise a linker moiety "L", which connects the "A" moiety and the cationic moiety.
  • the exact structure and size of the L moieties can vary considerably, and many variations of the L moieties are within the scope of the inventions disclosed herein. In some the L moieties are often organic moieties, and can comprise a wide variety of structures. In many embodiments it is desirable that the L moiety be of sufficient size and character that it provides some space and/or flexibility in the connection between the A and cation groups, but does not become of such high molecular weight so as to impair the water solubility or trans-membrane absorbability of the resulting cations.
  • the L moiety when considered as a whole, comprises from about 4 and 30 carbon atoms, or from about 4 and 20 carbon atoms. In some embodiments, the L moiety comprises from 6 to 18 carbon atoms, or from 8 to 12 carbon atoms. In some embodiments, the L moieties can comprise only methylene or polymethylene moieties, i.e. -(CHa) n - moieties. Some embodiments provide L having from 5 to 24 carbon chain atoms, for example, -(CHa) n -, wherein the index n is from 5 to 24.
  • Another embodiment relates to L having from 5 to 20 carbon chain atoms, for example, -(CH 2 )H-, wherein the index n is from 5 to 20.
  • a further embodiment relates to L having from 6 to 16 carbon chain atoms, for example, -(CH 2 ) J1 -, wherein the index n is from 6 to 16.
  • a yet further embodiment relates to L having from 7 to 16 carbon chain atoms, for example, - (CH 2 ) n -, wherein the index n is from 7 to 16.
  • a still yet further embodiment relates to L having from 8 to 12 carbon chain atoms, for example, -(CHa) n -, wherein the index n is from 8 to 12.
  • the L moieties can further comprise in the carbon chain from 1 to 10 additional atoms or groups independently selected from -O-, -S-, -S(O)-, -S(O) 2 -NH-, - NCH 3 -, -C(O)-, or -CO 2 - moieties.
  • L can be a polyalkylene glycol moiety, or a polyethylene glycol moiety, having the structure
  • n is an integer from 0 to 3.
  • the L moiety can comprise therein or thereon an additional ionic substituent moiety, so the electrical charge of the cation of Formula (1) could be increased or decreased.
  • the L moiety can comprise an additional one or two quartemary ammonium or phosphonium moiety therein, so that the overall electrical charge of the cation of Formula I could be 2+ or 3+, so as to be a dication, or trication.
  • Such dicationic or tricationic compounds can provide even higher water solubility and/or selectivity of absorption into mitochondria than compounds of Formula (I) that are only monocationic.
  • the salt compounds comprising the cations of Formula(I) also comprise an anion X m , wherein m is an integer from 1 to 4, corresponding to monoanions, di-anions, tri-anions, and tetra-anions.
  • the first iteration of X ' relates to inorganic anion moieties.
  • Mono -anionic inorganic anions include any halide anion, such as fluoride, chloride, bromide, or iodide; nitrate, hydrogen sulfate; dihydrogen phosphate, and the like.
  • Dianionic inorganic cations can include carbonate, sulfate or hydrogenphosphate, and tri-anionic inorganic anions include phosphates.
  • the anions are organic anions.
  • organic anion moieties that can be employed to form the salts from the cations of Formula (I) include organosulphates such as methylsulphonate (mesylate), trifluoromethylsulfonate (inflate), benzenesulphonate, toluenesulphonate (tosylate), or purely organic anions, often formed by the neutralization of organic acids, such as fumarate, maleate, maltolate, succinate, acetate, benzoate, oxalate, citrate, or tartrate anions.
  • organosulphates such as methylsulphonate (mesylate), trifluoromethylsulfonate (inflate), benzenesulphonate, toluenesulphonate (tosylate), or purely organic anions, often formed by the neutralization of organic acids, such as fumarate, maleate, maltolate, succinate, acetate, benzoate, oxalate
  • Step (a) encompasses removal of an H + cation from the starting material with a strong base, with generation of the corresponding 4-alkoxy anion.
  • the proton can be removed by any strong organic or inorganic base which is convenient and which does not affect the R substituents.
  • organic bases include alkyl or aryl lithium reagents, such as phenyl lithium, methyl lithium, n-butyl lithium, tert-butyl lithium, sodium amide, lithium amide, lithium diisopropylamide, lithium dimethylamide, lithium diethylamide, and the like.
  • the formation of the 4-alkoxy anion can be conducted in the cold, i.e. at room temperature or from O 0 C to -78 0 C.
  • Non-limiting examples of inorganic bases include NaOH, KOH, LiOH, Ca(OH) 2 , Na 2 CO 3 , K 2 CO 3 , and the like.
  • One embodiment which is described herein below utilizes NaH as the base.
  • Other hydride bases, inter alia, KH can be utilized especially when low temperature conditions and solvent compatibility cause more reactive bases to be used.
  • strong inorganic bases can be used to form organic bases from polar aprotic solvents, inter alia, dimethyl sulfoxide, ⁇ N-dimethylacetamide, and hexamethylphosphoric triamide, for example, a dimsyl anion from dimethyl sulfoxide. Any non-reactive or aprotic solvent or mixtures of solvents can be used for Step (a).
  • Non-limiting examples of solvents include alkane solvents, inter alia, pentane, iso-pentane, hexane, heptane, octane, isooctane, and the like; aromatic hydrocarbon solvents, inter alia, benzene, toluene, and xylene (all isomers); ethers, inter alia, diethyl ether, tetrahydro-furan, and dioxane; and various fluorinated hydrocarbons.
  • polar aprotic solvents can be used, inter alia, dimethyl sulfoxide, dimethylformamide, AyV-dimethylacetamide, and hexamethylphosphoric triamide.
  • a second co-solvent may be used which enhances the solubility of the reagents used in Step (b) without affecting the formation of the anion.
  • Step (b) encompasses attaching a linker group L to the alkoxide generated in Step (a).
  • the 4-alkoxide is reacted with a linker molecule L having two reactive leaving groups; Z and X.
  • the leaving groups may be the same or different.
  • L is a linking group comprising from 4 to 30 carbon atoms as described herein.
  • Z and X can be any suitable leaving group which is sufficiently reactive to allow attachment of the tether without loss of the free radical moiety.
  • suitable leaving groups include halogens: iodine, bromine, and chlorine; sulphonyl leaving groups, inter alia, methylsulphonyl (mesyl), ethylsulphonyl, benzenesulphonyl, toluenesulphonyl (tosyl), and the like.
  • Non-limiting examples of compounds having two leaving groups that can be used to as reagents in forming the linking group between the free radical portion of the molecule and the quaternary ammonium or phosphonium moiety include: i) ⁇ , ⁇ -di-bromoalkanes, inter alia, 1 ,4-dibromobutane, 1,5-dibromopentane, 1,6- dibromohexane, 1 ,7-dibromoheptane, 1 ,8-dibromooctane, 1,9-di- bromononane, and 1,10-dibromodecane; ii) ⁇ , ⁇ -di-chloroalkanes, inter alia, 1,4-dichlorobutane, 1 ,5-dichloropentane, 1,6- dichlorohexane, 1,7-dichloroheptane, 1,8-dichlorooctane, 1 ,
  • the formulator can take advantage of the differential reactivity of leaving groups when using ⁇ , ⁇ -mixed leaving group alkanes for the formation of the tether. However, the formulator may wish to insert an optional Step (b)(ii) into the process for preparing the compounds of the present invention. For example, the formulator can, once intermediate B is formed, increase the reactivity of leaving group X in order to adjust for any lesser reactivity that the reagent which introduces the quaternary ammonium or phosphonium salt has.
  • step l-iodo-4-chlorobutane is used to attach the first end of the tether to the free radical containing unit taking advantage of the increased reactivity of iodine as a preferred leaving group over chlorine. wherein chlorine is replaced by iodine.
  • Non-limiting examples of solvents which can be used for Step (b), as well as any optional steps, inter alia, Step (b)(i), include alkane solvents, inter alia, pentane, iso-pentane, hexane, heptane, octane, isooctane, and the like; aromatic hydrocarbon solvents, inter alia, benzene, toluene, and xylene (all isomers); ethers, inter alia, diethyl ether, tetrahydro-furan, and dioxane; and various fluorinated hydrocarbons.
  • polar aprotic solvents can be used, inter alia, dimethyl sulfoxide, dimethylformamide, ⁇ yV-dimethylacetamide, and hexamethylphosphoric triamide.
  • Step (c) encompasses forming a quaternary ammonium or phosphonium salt at the end of the linking unit opposite the end which contains the nitroxide or amine oxide moiety.
  • a quaternary ammonium or phosphonium salt for example, formation of a phosphonium salt:
  • Step (c) may optionally be divided into two separate steps, Step (c)(i) and Step (c)(ii), which can be conducted either without isolation of the intermediate C or which can be conducted as two discrete steps, wherein intermediate C is isolated prior to quatemization, for example:
  • the formulator can chose the leaving group X which comprises the alkylating agent in Step (c)(ii) to be the same as the leaving group that is displaced in Step (c)(i) or to take the opportunity to provide a different leaving group which results in the potential source of a different counter ion for the quaternary ammonium ion.
  • the formulator can alternatively choose to provide the final anion by exchanging the anion present as a result of the reaction which occurs in Step (c) with another anion, and this can be done by exposing the final product to a counter ion exchange system, for example, an ion exchange resin.
  • a tri-substituted phosphine can be directly reacted with compounds such as intermediate B to form final compounds. Examples of this reaction are found in Examples 1 and 2 herein below.
  • this phosphonium forming step encompasses the reaction taking place in a refluxing solvent. Because a salt if formed, it is advantageous for the formulator to select a solvent wherein the starting materials have good solubility, but the product which forms is either insoluble or has a reduced solubility. In this way when a stoichiometric excess of one starting reagent is used, the excess will potentially remain in solution while the desired product precipitates as an insoluble material.
  • Step (c) can be conducted in any non-micleophilic solvent which allows for the adequate formation of the desired product.
  • Suitable solvents or mixtures of solvents can be used for Step (c).
  • Non-limiting examples of solvents include alkane solvents, inter alia, pentane, iso-pentane, hexane, heptane, octane, isooctane, and the like; aromatic hydrocarbon solvents, inter alia, benzene, toluene, and xylene (all isomers); ethers, inter alia, diethyl ether, tetrahydro-furan, and dioxane; ketones, inter alia, acetone, methyl ethyl ketone, 3-pentanone; halogenated solvents, inter alia, dichloromethane, chloroform, carbon tetrachloride, 1 , 1 -dichloroethane, 1 ,2- dichloro
  • reactivity may be increased by the addition of a protic solvent, inter alia, water, methanol, ethanol, and the like, which can aid in solvation and separation of ion pairs, however, these adjustments to Step (c) are within the scope of the artisan and can be made without undue experimentation.
  • a protic solvent inter alia, water, methanol, ethanol, and the like, which can aid in solvation and separation of ion pairs, however, these adjustments to Step (c) are within the scope of the artisan and can be made without undue experimentation.
  • Scheme II outlines the preparation of a compound disclosed herein which is further described in detail in Example 1.
  • Reagents and conditions (a) NaH, benzene; reflux, 24 hr.
  • bromide (2) also known as MitoT-10, or CPC-410
  • Tempo 1 (0.01 mol) was added to a three-neck flask containing 100 ml dry benzene that is maintained at nitrogen atmosphere.
  • sodium hydride (0.015 mol) was added and kept refluxed for 24 hrs.
  • the flask was cooled in ice bath and added 1,10- dibromodecane (0.02 mol) in one portion. The refluxing was then resumed for another 72 hrs.
  • the contents of the flask was cooled in ice bath and added 25ml water and transferred to a separatory funnel.
  • the red upper benzene layer was separated , dried over anhydrous magnesium sulfate and solvent removed by rotory evaporation to get a red oil.
  • the oil was purified by column chromatography on silica gel 60.
  • the material was added to the column and eluted first with about 150 ml hexane that removed the excess of dibromodecane.
  • the desired bromodecanoyl ether of Tempol was eluted with a mixture of hexane and ether
  • Scheme IV outlines an example of the preparation of compounds disclosed herein wherein the linking unit is tethered to the free radical portion of the final compound by way of an ester linkage.
  • reaction vessel The contents of the reaction vessel were transferred to a separatory funnel and extracted with water (50 mL), brine (50 mL), then dried over Na 2 SO 4 . The solvent was removed in vacuo to afford the desired product which can be used for the next step without further purification.
  • Reagents and conditions (a) NaI, acetone; reflux, 24 hr.
  • Reagents and conditions (b) triethylamine, dioxane; reflux.
  • reaction is cooled to room temperature after which the reaction is poured into diethyl ether (200 mL). The resulting solution is stirred and the organic layer decanted. The solid that remains is triturated with diethyl ether, the solid collected and dried to afford the desired compound.
  • Step (d) encompasses attaching a tether to the free radical containing portion of the molecule.
  • the 4-amino-2,2, ⁇ , ⁇ -tetraalkylpiperidinyloxy free radical is reacted with a molecule having two reactive leaving groups; Z and X.
  • the leaving groups may be the same or different, however, Z is the group which reacts first to form the 4-acyloxy-2, 2,6,6- tetraalkyl-piperidinyloxy free radical intermediate, D, as depicted in Step (d) of Scheme VI.
  • Step (e) described herein a quaternary ammonium salt or phosphonium salt is formed, it is convenient for the formulator to utilize as a leaving group X, a unit that can form a stable anion and therefore act as the counter ion for the quaternary ammonium or phosphonium salt that is formed.
  • L is a linking group comprising from 4 to 30 carbon atoms as described elsewhere herein
  • Scheme VII outlines an example of the preparation of amide compounds disclosed herein wherein the linking unit is tethered to the free radical portion of the final compound by way of an amide linkage. These compounds can be prepared by the following procedure outlined herein below.
  • Reagents and conditions (a) 4-bromobutyryl chloride, CH 2 Cl 2 ; rt, 48-72 hr.
  • Scheme VIII outlines an example of the preparation of compounds disclosed herein wherein the free radical moiety is derived from a 5-member ring starting material.
  • Reagents and conditions (a) 4-bromobutyryl chloride, CH 2 Cl 2 ; rt, 48-72 hr.
  • reaction vessel After the addition is complete, the solution is allowed to warm to room temperature and stir over night. The contents of the reaction vessel is transferred to a separatory funnel and extracted with water (50 mL), brine (50 mL), then dried over Na 2 SO 4 . The solvent is removed in vacuo to afford the desired product which can be used for the next step without further purification.
  • reaction solution is cooled and the solvent removed under reduced pressure.
  • the residue is treated with diethyl ether (200 mL), the organic layer is decanted and the residue dissolved in CH 2 Cl 2 (10 mL) then added to a flask containing diethyl ether (100 mL).
  • the precipitate is collect, dissolved in CH 2 Cl 2 and re-precipitated with diethyl ether. This procedure is repeated 3 additional times to afford the desired product.
  • the salts described above have been found to be potent compounds in a number of in vitro biological assays that correlate to or are representative of human diseases, especially diseases of uncontrolled inflammation and/or cellular proliferation, including various cancers.
  • the biological activity of the compounds described herein can be measured, screened, and/or optimized by testing the salts for their relative ability to kill or inhibit the growth of various human tumor cell lines and primary tumor cell cultures.
  • Tumor cell lines that can be employed for such tests include, but are not limited to, known cell lines that model cancers and/or diseases of uncontrolled cellular proliferation, such as: • For Leukemia: CCRF-CEM, HL-60 (TB), K-562, MOLT-4, RPMI-8226, and SR.
  • Lung Cancer A549/ATCC, EKVX, HOP-62, HOP-92, NCI-H226, NCI-H23, NCI-H322M, NCI-H460, and NCI-H522.
  • Colon Cancer COLO 205, HCC-2998, HCT-1 16, HCT-15, HT-29, KM-12, and SW- 620.
  • CNS Cancer SF-268, SF-295, SF-539, SNB- 19, SNB-75, U-231 , U-235 and U-251.
  • Renal Cancer 786-0, A-498, ACHN, CAKI-I, RXF-393, RXF-631, SN12C, TK-IO, and UO-31.
  • Prostate Cancer DU-145, PC-3 and LNCaP. • Breast Cancer: MDA-MB-468, MCF 7, MCF7/ADR-RES, MDA-MB-231/ATCC,
  • Pancreatic Cancer PANC-I , Bx-PC3 AsPC-I .
  • the anti-cancer effectiveness can be gauged using a variety of assay procedures known to those of ordinary skill in the art for measuring the number of live cells in the cultures as a function of time.
  • MTT 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide
  • MTT assay procedures have an advantage over an in vivo assay with common laboratory animals such as mice, in that results are obtained within a week as opposed to requiring several weeks or months.
  • MTT anti-cancer activity screening assay provides data regarding the general cytotoxicity of an individual compound.
  • active anticancer compounds can be identified by applying the compounds at a concentration of about 10 ⁇ M to one or more cultured human tumor cell lines, such as for example leukemia, lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer, breast cancer, or pancreatic cancer, so as to kill or inhibit cell growth of the tumor cells.
  • the compounds of the invention are considered to be biologically active for the treatment of a particular cancer if, when they are applied to a culture of one of the above cancer cell lines at a concentration of about 10 ⁇ M or less, for a period of at least about 5 days, the growth of the cancer cells is inhibited, or the cancer cells killed to the extent of about 50% or more, as compared to a control not comprising the compound of the invention.
  • each culture plate was thawed and equilibrated to room temperature under protection from light. Hoechst dye was then added to each well in 200 ⁇ L of high salt TNE buffer (10 mM Tris, ImM EDTA, 2 M NaCl [pH 7.4]) at a final concentration of 6.7 ⁇ g/mL. After further incubation at room temperature for 2 hours under protection from light, culture plates were scanned on the CytoFluor 2350TM scanner using the 360/460 nm filter excitation and emission set. The DNA fluorescence intensity was used as a measure of cell growth.
  • TNE buffer 10 mM Tris, ImM EDTA, 2 M NaCl [pH 7.4]
  • Mito-T drug The effects of varying concentrations of Mito-T drug on the growth of LNCaP and PC-3 cells over a period of 4 days was assayed using the Hoechst dye-DNA fluorescence assay described above. In these and all subsequent cell culture studies described below, each data point and its associated error bar are respectively, an average value and the standard deviation of data obtained from six wells of a 96-well plate run in duplicate in three separate sets of experiments.
  • Mito-T treatment inhibits the growth of both LNCaP and PC-3 cells, with estimated ICgo values of approximately 4 ⁇ M and 60 ⁇ M, respectively.
  • the inhibitory effect of MitoT on the oxidative stress level in LNCaP prostate tumor cells can also be determined by the ratio of DCF fluorescence / Hoechst dye-DNA fluorescence (Ripple MO, Henry WF, Rago RP, Wilding G. Prooxidant-antioxidant shift induced by androgen treatment of human prostate carcinoma cells. J Natl Cancer Inst. 1997 Jan 1 ;89(l):40-8 .
  • DCFH is oxidized to DCF by ROS to yield easily quantifiable ROS levels monitored by the green fluorescence of the DCF (6-carboxy-2 r ,7'-dichlorofiuorescin diacetate) dye, as can be seen in Figure 2.
  • the inhibitory effect of MitoT on the oxidative stress level in LNCaP prostate tumor cells can be determined by the ratio of DCF fluorescence/Hoechst dye-DNA fluorescence.
  • MitoT treatment markedly reduced the oxidative stress in LNCaP cells as determined by DCF fluorescence/DNA fluorescence assay shown in Figure 3. MitoT treatment effectively and reproducibly reduced the ROS levels in LNCaP cells at concentrations at or above about 1-10 ⁇ M. It should be noted that MitoT treatment induced a reduction of oxidative stress determined by DCF assay and mitochondrial function determined by MTT assay, and is parallel to MitoT's effect in the inhibition of prostate tumor cell growth as determined by DNA assay, as shown in Fig. 4, This oxidative stress is probably due to increased lipid peroxidation during apoptotic and/or necrotic cell death (reviewed in 1,2).
  • Figure 6 shows that when animals are treated with MitoT, the serum level of MitoT within the first hour of treatment is between 10-20 ⁇ g/ml, which is 10 - 20 times above the level of MitoT required to block androgen induced oxidative stress in LNCaP cells (Fig. 5) and in the concentration range of completely blocking all oxidative stress in the cancer cells. Also, under these treatment conditions, MitoT markedly reduced the oxidative stress in the prostatic lumen of live animals, as observed by Hydroethidine dye oxidation assay in the animal's prostate. Hydroethidine dye was injected into the tail vein of male mice one hour before sacrifice. Hydroethidine shows a typical red fluorescence upon oxidation by ROS.
  • the compounds described herein can be used to prevent, alleviate or otherwise treat diseases of uncontrolled proliferation in mammals, including humans, such as cancer or precancerous diseases.
  • the compounds described herein can be used for the preparation of medicaments for treating diseases of uncontrolled inflammation, proliferation, cancers, and prostate cancer.
  • the invention relates to methods of treatment for a disease of uncontrolled cellular inflammation, proliferation, wherein the method comprises administering to a mammal diagnosed as having a disease of uncontrolled cellular inflammation and/or proliferation a compound of the invention or a pharmaceutical composition thereof comprising one or more of the compounds of the invention, in an amount that is effective to treat the disease of uncontrolled cellular inflammation and/or proliferation.
  • the disease of uncontrolled cellular inflammation and/or proliferation treated can be a hyperplasia or a carcinoma, lymphoma, leukemia, or sarcoma.
  • the types of diseases treated by methods of the invention include but are not limited to Hodgkin's Disease, myeloid leukemia, polycystic kidney disease, bladder cancer, brain cancer, head and neck cancer, kidney cancer, lung cancer, myeloma, neuroblastoma, glioblastoma, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, liver cancer, melanoma, colon cancer, cervical carcinoma, breast cancer, metastases to the brain or bone, epithelial cancer, and leukemia.
  • compositions can also be used as regulators in diseases of uncontrolled inflammation and/or proliferation and/or precancerous conditions such as cervical and anal dysplasias, other dysplasias, severe dysplasias, hyperplasias, atypical hyperplasias, and neoplasias.
  • the compounds of the invention have been found to particularly effective for the treatment of prostate cancers and related neoplasias, including pancreas adenocarcinomas or prostate adenocarcinomas, and/or inhibiting the growth of prostate hyperplasias (noncancerous) and/or cancers and related neoplasias.
  • the inventions described herein relate to methods for treating or inhibiting the recurrence, progression or metastasis, of a cancer or a neoplasia precursor thereof, consisting of administering to a mammal diagnosed as having a cancer or precursor neoplasia thereof, in an amount effective to treat the cancer or inhibit the recurrence, progression, or metastasis of the cancer or precursor neoplasia thereof, one or more pharmaceutically acceptable salts having a cation having the formula
  • R 1 ' wherein a) A is an antioxidant moiety comprising one or more nitroxide or hydroxylamine moieties, or a prodrug thereof, having from three to 16 carbon atoms, b) L is an organic linking moiety comprising 4 to 30 carbon atoms, c) E is a nitrogen or phosphorus atom, d) Ri', Ri", and R 1 '" are each independently selected organic moieties comprising between 1 and 12 carbon atoms, wherein E, R s ', Ri", and R 1 '" together form a quaternary ammonium or phosphonium cation ; and wherein the salt farther comprises is one or more pharmaceutically acceptable anions X m ⁇ , wherein m is an integer from 1 to 4, in sufficient amount to form the pharmaceutically acceptable salt.
  • the pharmaceutically acceptable salts of the invention have been found to be particularly effective in treating certain forms inflammation, organ enlargement or cancer, including, but not limited to prostate hyperplasia and/or cancer, colorectal cancer, gastric cancer, renal cancer, skin cancer, head and neck cancer, brain cancer, pancreatic cancer, lung cancer, ovarian cancer, uterine cancer, liver cancer, and breast cancer.
  • the invention relates to method for treating, or inhibiting inflammation and benign prostatic hyperplasia or the occurrence, recurrence, progression or metastasis of prostate cancer, consisting of administering to a mammal diagnosed as having prostate disease or cancer or hyperplasia or precursor neoplasia thereof, in an amount effective to treat the disease or cancer or inhibit the occurrence, recurrence, progression, or metastasis of the prostate disease or cancer or precursor neoplasia thereof, one or more pharmaceutically acceptable salts of the invention comprising a cation of Formula (I).
  • the pharmaceutically acceptable salts have a cation having the formula:
  • E is a nitrogen or phosphorus atom
  • Ri', Ri", and Ri' are each independently selected organic moieties comprising between 1 and 12 carbon atoms
  • g) n is an integer between 8 and 12
  • E, Ri ' , Ri " , and Rj " ' together form a quaternary ammonium or phosphonium cation
  • the salt also comprises one or more pharmaceutically acceptable anions X m" wherein m is an integer from 1 to 4, sufficient to form the pharmaceutically acceptable salt.
  • compositions described herein can be administered as pure chemicals either singularly or p rurally, it is preferable to present the active ingredient as a pharmaceutical composition.
  • another embodiment of the invention is the use of a pharmaceutical composition comprising one or more compounds and/or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers thereof and, optionally, other therapeutic and/or prophylactic ingredients.
  • the carrier(s) should be "acceptable" in the sense of being compatible with the other ingredients of the composition and not overly deleterious to the recipient thereof.
  • pharmaceutical composition is administered to an animal diagnosed as in need of treatment for a disease of uncontrolled cellular inflammation and/or proliferation, in an amount effective to treat the disease of uncontrolled cellular inflammation and/or proliferation, such as the various cancers and precancerous conditions described herein.
  • pharmaceutical composition means therapeutically effective amounts of a pharmaceutically effective compound together with suitable combination of one or more pharmaceutically-acceptable carriers, many of which are known in the art, including diluents, preservatives, solubilizers, emulsifiers, and adjuvants, collectively”.
  • the terms "effective amount” and “therapeutically effective amount” refer to the quantity of active therapeutic agent sufficient to yield a desired therapeutic response, without undue adverse side effects, such as toxicity, irritation, or allergic response.
  • the specific "effective amount” will, obviously, vary with such factors as the particular condition being treated, the physical condition of the patient, the type of animal being treated, the duration of the treatment, the nature of concurrent therapy (if any), and the specific formulations employed and the structure of the compounds or its derivatives. In this case, an amount would be deemed therapeutically effective if it resulted in one or more of the following: (a) the prevention of an androgen-mediated or androgen-independent disorder (e. g.
  • prostate cancer prostate cancer
  • reversal or stabilization of an androgen-mediated or androgen-independent disorder e. g., prostate disease and cancer.
  • the optimum effective amounts can be readily determined by one of ordinary skill in the art using routine experimentation .
  • compositions can be liquids or lyophilized or otherwise dried formulations and include diluents of various buffer content (e. g.,Tris-HCI, acetate, phosphate), pH and ionic strength, additives such as albumin or gelatin to prevent absorption to surfaces, detergents (e. g., Tween 20, Tween 80, Pluronic F68, bile acid salts), solubilizing agents (e. g., glycerol, polyethylene glycerol), anti-oxidants (e. g., ascorbic acid, sodium metabisulfite), preservatives (e. g., Thiomersal, benzyl alcohol, parabens), bulking substances or tonicity modifiers (e.
  • buffer content e. g.,Tris-HCI, acetate, phosphate
  • pH and ionic strength additives such as albumin or gelatin to prevent absorption to surfaces
  • additives e. g., Tween 20, T
  • Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media.
  • Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's and fixed oils.
  • Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers such as those based on
  • Ringer's dextrose and the like.
  • Preservatives and other additives may also be present, such as, for example, antimicrobials, antioxidants, collating agents, inert gases and the like.
  • Controlled or sustained release compositions administrable according to the invention include formulation in lipophilic depots (e. g. fatty acids, waxes, oils). Also comprehended by the invention are particulate compositions coated with polymers (e. g. poloxamers or poloxamines) and the compound coupled to antibodies directed against tissue-specific receptors, ligands or antigens or coupled to Hgands of tissue-specific receptors.
  • lipophilic depots e. fatty acids, waxes, oils.
  • particulate compositions coated with polymers e. g. poloxamers or poloxamines
  • compositions administered according to the invention incorporate particulate forms, protective coatings, protease inhibitors or permeation enhancers for various routes of administration, including parenteral, pulmonary, nasal and oral.
  • a pharmaceutical composition can be delivered in a controlled release system.
  • the agent may be administered using intravenous infusion, an implantable osmotic pump, a transdermal patch, liposomes, or other modes of administration.
  • a pump may be used (see Langer, supra; Sefton, CRC Crit Ref. Biomed. Eng. 14: 201 (1987); Buchwald et al., Surgery 88: 507
  • a controlled release system can be placed in proximity to the therapeutic target, i. e., the prostate, thus requiring only a fraction of the systemic dose (see, e. g., Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138 (1984). Other controlled release systems are discussed in the review by Langer (Science 249: 1527-1533 (1990).
  • the pharmaceutical preparation can comprise the anti-androgen compound alone, or can further include a pharmaceutically acceptable carrier, and can be in solid or liquid form such as tablets, powders, capsules, pellets, solutions, suspensions, elixirs, emulsions, gels, creams, or suppositories, including rectal and urethral suppositories.
  • Pharmaceutically acceptable carriers include gums, starches, sugars, cellulosic materials, and mixtures thereof.
  • the pharmaceutical preparation containing the anti-androgen compound can be administered to a patient by, for example, subcutaneous implantation of a pellet.
  • a pellet provides for controlled release of anti-androgen compound over a period of time.
  • the preparation can also be administered by intravenous, intra-arterial, or intramuscular injection of a liquid preparation oral administration of a liquid or solid preparation, or by topical application. Administration can also be accomplished by use of a rectal suppository or a urethral suppository.
  • the active compounds of the invention are administered to achieve peak plasma concentrations of the active compound of from typically about 0.1 to about 100 ⁇ M, about 1 to 50 ⁇ M, or about 2 to about 30 ⁇ M. This can be achieved, for example, by the intravenous injection of a 0.05% to 5% solution of the active ingredient, optionally in saline, or orally administered as a bolus containing about 0.5-500 mg of the active ingredient. Desirable blood levels can be maintained by continuous infusion to provide about 0.01-5.0 mg/kg/hr or by intermittent infusions containing about 0.4-15 mg/kg of the active compounds of the invention.
  • compositions include those suitable for oral, enteral, parental (including intramuscular, subcutaneous and intravenous), topical, nasal, vaginal, ophthalin ⁇ cal, sublingual, nasal or by inhalation administration.
  • the compositions can, where appropriate, be conveniently presented in discrete unit dosage forms and can be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the active compound with liquid carriers, solid matrices, semi-solid carriers, finely divided solid carriers or combination thereof, and then, if necessary, shaping the product into the desired delivery system.
  • the compounds of the invention can have oral bioavailability as exhibited by blood levels after oral dosing, either alone or in the presence of an excipient. Oral bioavailability allows oral dosing for use in chronic diseases, with the advantage of self-administration and decreased cost over other means of administration.
  • Pharmaceutical compositions suitable for oral administration can be presented as discrete unit dosage forms such as hard or soft gelatin capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or as granules; as a solution, a suspension or as an emulsion.
  • the active ingredient can also be presented as a bolus, electuary or paste.
  • Tablets and capsules for oral administration can contain conventional excipients such as binding agents, fillers, lubricants, disintegrants, or wetting agents.
  • the tablets can be coated according to methods well known in the art., e.g., with enteric coatings.
  • Oral liquid preparations can be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or can be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations can contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which can include edible oils), or one or more preservative.
  • the pharmaceutical preparations administrable by the invention can be prepared by known dissolving, mixing, granulating, or tablet-forming processes.
  • the compounds or their physiologically tolerated derivatives such as salts, esters, N-oxides, and the like are mixed with additives customary for this purpose, such as vehicles, stabilizers, or inert diluents, and converted by customary methods into suitable forms for administration, such as tablets, coated tablets, hard or soft gelatin capsules, aqueous, alcoholic or oily solutions.
  • suitable inert vehicles are conventional tablet bases such as lactose, sucrose, or cornstarch in combination with binders such as acacia, cornstarch, gelatin, with disintegrating agents such as cornstarch, potato starch, alginic acid, or with a lubricant such as stearic acid or magnesium stearate.
  • suitable oily vehicles or solvents are vegetable or animal oils such as sunflower oil or fish-liver oil. Preparations can be effected both as dry and as wet granules or supercritically formulated nanoparticles.
  • the compounds can also be formulated for parenteral administration (e.g., by injection, for example, bolus injection or continuous infusion) and can be presented in unit dose form in ampules, pre-filled syringes, small bolus infusion containers or in multi-does containers with an added preservative.
  • the compositions can take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the active ingredient can be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.
  • the compounds or their physiologically tolerated derivatives such as salts, esters, N-oxides, and the like are converted into a solution, suspension, or expulsion, if desired with the substances customary and suitable for this purpose, for example, solubilizers or other auxiliaries.
  • sterile liquids such as water and oils, with or without the addition of a surfactant and other pharmaceutically acceptable adjuvants.
  • Illustrative oils are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, or mineral oil.
  • water, saline, aqueous dextrose and related sugar solutions, and glycols such as propylene glycols or polyethylene glycol are preferred liquid carriers, particularly for injectable solutions.
  • compositions which contain an active component are well understood in the art.
  • Such compositions may be prepared as aerosols delivered to the nasopharynx or as injectables, either as liquid solutions or suspensions; however, solid forms suitable for solution in, or suspension in, liquid prior to injection can also be prepared.
  • the preparation can also be emulsified.
  • the active therapeutic ingredient is often mixed with excipients which are pharmaceutically acceptable and compatible with the active ingredient. Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol, or the like or any combination thereof.
  • composition can contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents which enhance the effectiveness of the active ingredient.
  • auxiliary substances such as wetting or emulsifying agents, pH buffering agents which enhance the effectiveness of the active ingredient.
  • the compounds of the invention comprise cationic anti-oxidants in the form pharmaceutically acceptable salt with pharmaceutically acceptable anions.
  • Pharmaceutically acceptable salts include pharmaceutically acceptable halides such as fluoride, chloride, bromide, or iodide, tribasic phosphate, dibasic hydrogen phosphate, monobasic dihydrogen phosphate, or the anionic forms of pharmaceutically acceptable organic carboxylic acids as acetates, oxalates, tatrates, mandelates, succinates, citrates, and the like.
  • Such pharmaceutically acceptable salts can be readily synthesizes from other salts used for the initial synthesis of the compounds by ion exchange reactions and technologies well known to those of ordinary skill in the art.
  • Salts formed from any free carboxyl groups on the cationic antioxidant moieties can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases asisopropylamine, trimethylamine, 2- ethylamino ethanol, histidine, procaine, and the like.
  • inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases asisopropylamine, trimethylamine, 2- ethylamino ethanol, histidine, procaine, and the like.
  • the salts of the anti-androgen compound may be pharmaceutically acceptable salts.
  • Other salts may, however, be useful in the commercial or laboratory preparation of the compounds according to the invention or of their pharmaceutically acceptable salts.
  • Suitable pharmaceutically acceptable salts of the compounds include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
  • a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
  • the salts described herein may be provided in the form of nutraceutical compositions where the anti-oxidant properties of the salts prevents the onset of or reduces or stabilizes various disorders, e.g., including inhibiting the occurrence of various forms of cancer, including prostate cancer.
  • the term "nutraceutical,” or “nutraceutical composition,” for the purposes of this specification, refers to a food item, or a part of a food item, that offers medical health benefits, including prevention and/or treatment of disease.
  • a nutraceutical composition according to the present invention may contain only a cationic antioxidant compound according to the present invention as an active ingredient or, alternatively, may further comprise, in admixture with the aforesaid cationic antioxidant compound, dietary supplements including vitamins, co-enzymes, minerals, herbs, amino acids and the like which supplement the diet by increasing the total intake of that substance.
  • nutraceutical compositions containing a compound having Formula I or a pharmaceutically acceptable salt thereof.
  • Such compositions generally include a "nutraceutically-acceptable carrier" which, as referred to herein, is any carrier suitable for oral delivery including, but not limited to, the aforementioned pharmaceutically-acceptable carriers.
  • nutraceutical compositions according to the invention comprise dietary supplements which, defined on a functional basis, include immune boosting agents, anti-inflammatory agents, anti-oxidant agents, or mixtures thereof.
  • a suitable dose will, in alternative embodiments, typically be in the range of from about 0.5 to about 10 mg/kg/day, or from about 1 to about 20 mg/kg of body weight per day, or from about 5 to about 50 mg/kg/day.
  • the desired dose can conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day.
  • the sub-dose as necessary by one skilled in the art, can itself be further divided, e.g., into a number of discrete loosely spaced administrations.
  • compositions of matter useful for the treatment of cancer and/or benign prostatic hyperplasia contain, in addition to the aforementioned compounds, an additional therapeutic agent.
  • agents can be chemotherapeutic agents, ablation or other therapeutic hormones, antineoplastic agents, monoclonal antibodies useful against cancers and angiogenesis inhibitors.
  • chemotherapeutic agents can be chemotherapeutic agents, ablation or other therapeutic hormones, antineoplastic agents, monoclonal antibodies useful against cancers and angiogenesis inhibitors.
  • DES diethylstilbestrol
  • leuprolide flutam ⁇ de
  • hydroxyflutamide bicalutamide
  • cyproterone acetate ketoconazole
  • abiraterone acetate amino glutethimide
  • antineoplastic and anticancer agents that can be used in combination with the inventive compounds, 5-fluorouracil, vinblastine sulfate, estramustine phosphate, suramin and strontium-89.
  • Other chemotherapeutics useful in combination and within the scope of the present invention are buserelin, chlorotranisene, chromic phosphate, cisplatin, cyclophosphamide, dexamethasone, doxorubicin, estradiol, estradiol valerate, estrogens conjugated and esterified, estrone, ethinyl estradiol, floxuridine, goserelin, hydroxyurea, melphalan, methotrexate, mitomycin and prednisone.

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US11274114B2 (en) 2014-08-14 2022-03-15 The Medical College Of Wisconsin, Inc. Modified mito-metformin compounds and methods of synthesis and use thereof
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