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WO2006037050A2 - Procedes pour traiter l'insuffisance cardiaque congestive - Google Patents

Procedes pour traiter l'insuffisance cardiaque congestive Download PDF

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Publication number
WO2006037050A2
WO2006037050A2 PCT/US2005/034846 US2005034846W WO2006037050A2 WO 2006037050 A2 WO2006037050 A2 WO 2006037050A2 US 2005034846 W US2005034846 W US 2005034846W WO 2006037050 A2 WO2006037050 A2 WO 2006037050A2
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alkyl
aryl
acid
group
independently
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PCT/US2005/034846
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WO2006037050A3 (fr
Inventor
Daniela Salvemini
Yingjie Chen
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Metaphore Pharmaceuticals, Inc.
Regents Of The University Of Minnesota
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Publication of WO2006037050A2 publication Critical patent/WO2006037050A2/fr
Publication of WO2006037050A3 publication Critical patent/WO2006037050A3/fr

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/555Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof

Definitions

  • the invention provides methods for treating heart failure by administering to a subject a therapeutically effective amount of a composition comprising a catalyst for the dismutation of superoxide anions and a peroxynitrite decomposition catalyst.
  • Heart failure means that the heart is not working efficiently enough to keep up with its workload, either during exercise or at rest.
  • the term "failure” indicates that the pumping action of the heart is inadequate to meet the body's needs for oxygen-rich blood. As a result, blood flow to body tissues is reduced and blood returning to the heart accumulates, causing congestion in the veins.
  • the term Congestive Heart Failure (“CHF”) is often synonymous with heart failure but also refers to the build up of body fluid in the lungs and elsewhere in the body that results from the inability of the heart to pump efficiently enough to meet the body's needs.
  • Heart failure usually develops slowly, often overyears as the heart gradually loses its pumping ability. Between 2 to 3 million Americans have heart failure and 400,000 new cases are diagnosed each year. Heart failure causes approximately 39,000 deaths a year and is a contributing factor in another 225,000 deaths.
  • CHF cardiac venous pressure
  • left ventricular failure is secondary to reduced forward flow into the aorta and systemic circulation.
  • systolic dysfunction is characterized by a dilated left ventricle with an inability to contract normally and expel sufficient blood, while diastolic dysfunction occurs in a normal or intact left ventricle with impaired ability to relax and fill normally.
  • the weaker pumping action of the heart means that less blood is sent to the kidneys, which results in fluid build-up by retaining water and salt in the kidneys.
  • classifications for heart failure include high output versus low output failure; acute versus chronic heart failure and right-sided versus left-sided heart failure. While the different classifications may be useful early in the course of the disease, the differences between the classifications and the associated symptoms in the later stages of heart failure and in chronic heart failure often become indistinguishable.
  • Managing CHF generally includes correction of any reversible causes including restrictions of dietary sodium. Diuretics may be prescribed to facilitate the removal of excess water and sodium. Digitalis has been used since the 18th century to strengthen the heart's pumping action and is still a component of modern therapy. Newer drugs for the treatment of heart failure include vasodilators including angiotensin-converting enzyme (ACE). Other drugs used in the treatment of heart failure include calcium-channel blockers, which dilate vessels; beta blockers, which slow the heart; and medications with affect heartbeat irregularities. Surgery is indicated under some circumstances including valve repair or artificial valve replacement. Heart transplants are last resort in treatment and are otherwise generally impractical because of cost and the shortage of organs. Other available options include portable pumps to continuously infuse medications, implanted devices for controlling arrhythmias, or ventricular dynamic cardiomyoplasty.
  • ACE angiotensin-converting enzyme
  • a method for treating congestive heart failure comprising administering to a subject in need thereof a therapeutically effective amount of a superoxide dismutase mimetic.
  • Another aspect provides a method for increasing coronary blood flow in heart failure, the method comprising administering to a subject in need thereof a therapeutically effective amount of a superoxide dismutase mimetic.
  • Yet another aspect provides a method for increasing MVO 2 in heart failure, the method comprising administering to a subject in need thereof a therapeutically effective amount of a superoxide dismutase mimetic.
  • the superoxide dismutase mimetic can comprise an organic ligand chelated to a metal ion including Mn(II), Mn(III), Fe(II), Fe (III), Cu(H)ZZn(ItI), or Cu(lll)/Zn (II).
  • the subject can be a mammal and avian. In particular, the mammal can be a human.
  • the catalyst of the methods above can be a pentaaza- macrocyclic ligand complex or a substituted pentaaza-macrocyclic ligand complex.
  • the pentaaza-macrocyclic ligand complex can be represented by the following formula:
  • R 1 , R'-,, R 2 , R' 2 , R 3 , R 3 , Rt, RU, RS, R'B, Re, R' ⁇ . R?, R'?, Re, R' ⁇ . R ⁇ , R'9, R-io, and R'10 can independently be:
  • (i b ) a moiety independently including alkenyl, alkenylcycloalkenyl, alkenylcycloalkyl, alkyl, alkylcycloalkenyl, alkylcycloalkyl, alkynyl, aralkyl, aryl, cycloalkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylcycloalkyl, cycloalkenylalkyl, or heterocyclyl; or
  • (i G ) a moiety independently including -OR 11 , -NRi 1 R 12 , -COR 11 , -CO 2 Rn, -CONR 11 R 12 , -SR 11 , -SOR 11 , -SO 2 R 11 , -SO 2 NR 11 R 12 , -N(OR 11 )(R 12 ), -P(O)(OR 11 )(OR 12 ), -P(O)(OR 11 )(Ri 2 ), -OP(O)(ORii)(OR 12 ), or substituents attached to the ⁇ -carbon of ⁇ -amino acids, wherein Rn and R 12 can independently include hydrogen or alkyl; and
  • R 10 or R' 1O and R 1 or R'-i, R 2 or R 2 and R 3 or R' 3 , R 4 or R' 4 and R 5 or R 5 , R 6 or R 6 and R 7 or R 7 , or R 8 or R' 8 and R 9 or R 9 together with the carbon atoms to which they can be attached independently can form a substituted or unsubstituted nitrogen containing heterocycle having 3 to 20 carbon atoms, which may be an aromatic heterocycle in which case the hydrogen attached to the nitrogen which can be both part of the heterocycle and the macrocycle and the R groups attached to the carbon atoms which can be both part of the heterocycle and the macrocycle can be absent; and
  • I 1 J 1 K and L independently can be integers from 0 to 10 and Q, R and T can optionally include substituted moieties independently including alkenyl, alkenylcycloalkenyl, alkenylcycloalkyl, alkyl, alkylcycloalkenyl, alkylcycloalkyl, alkynyl, aralkyl, aryl, cycloalkenyl, cycloalkyl, cycloalkylaikyl, cycloalkylcycloalkyl, cycloalkenylalkyl, and heterocyclyl, aza, amide, ammonium, oxa, thia, sulfonyl, sulfinyl, sulfonamide, phosphoryl, phosphinyl, phosphino, phosphonium, keto, ester, alcohol, carbamate, urea, thiocarbonyl, borates, boranes, boraza
  • M can be a transition metal
  • X, Y and Z can independently include halide, oxo, aquo, hydroxo, alcohol, phenol, dioxygen, peroxo, hydroperoxo, alkylperoxo, arylperoxo, ammonia, alkylamino, arylamino, heterocycloalkyl amino, heterocycloaryl amino, amine oxides, hydrazine, alkyl hydrazine, aryl hydrazine, nitric oxide, cyanide, cyanate, thiocyanate, isocyanate, isothiocyanate, alkyl nitrile, aryl nitrile, alkyl isonitrile, aryl isonitrile, nitrate, nitrite, azido, alkyl sulfonic acid, aryl sulfonic acid, alkyl sulfoxide, aryl sulfoxide, alkyl aryl sulfoxide, alkyl aryl
  • X, Y and Z can independently include charge-neutralizing anions which can be derived from any monodentate or polydentate coordinating ligand and a ligand system and the corresponding anion thereof; or
  • X, Y and Z can independently be attached to one or more of R 1 , R'i, R 2 , R' 2 , R3.
  • n can be an integer from 0 to 3.
  • the pentaaza-macrocyclic ligand complex can be represented by the following formula:
  • a nitrogen of the macrocycle and two adjacent carbon atoms to which the nitrogen can be attached can independently form a substituted or unsubstituted, saturated, partially saturated or unsaturated nitrogen-containing heterocycle W having 2 to 20 carbon atoms, which may be an aromatic heterocycle in which case the hydrogen attached to the nitrogen which can be both part of the heterocycle and the macrocycle and the R groups attached to the carbon atoms which can be both part of the heterocycle and the macrocycle can be absent; and
  • R 1 , R 2 , R 2, R3, R 3, R4, R 4, R5, R 5, Re, Re, R?, RV, Ra, R 8 , R9, R'9, and R10 can independently be:
  • (ii b ) a moiety independently including alkenyl, alkenylcycloalkenyl, alkenylcycloalkyl, alkyl, alkylcycloalkenyl, alkylcycloalkyl, alkynyl, aralkyl, aryl, cycloalkenyl, . cycloalkyl, cycloalkylalkyl, cycloalkylcycloalkyl, cycloalkenylalkyl, or heterocyclyl; or
  • (ii c ) a moiety independently selected from the group consisting of -ORn, -NR 11 R 12 , -COR 11 , -CO 2 Ri 1 , -CONR 1I Ri 2 , -SR 11 , -SOR 11 , -SO 2 R 11 , -SO 2 NR 11 R 12 , -N(OR 11 )(R 12 ), -P(O)(OR 11 )(OR 12 ), -P(O)(OR 11 )(R 12 ), -OP(O)(OR 11 )(OR 12 ), or substituents attached to the ⁇ -carbon of ⁇ -amino acids, wherein R 11 and Ri 2 can independently include hydrogen or alkyl; and
  • R 1 and R 2 or R 2 , R 3 or R' 3 and R 4 or R 4 , R 5 or R' 5 and R 6 or R' 6 , R 7 or R' 7 and R 8 or R' 8 , R 9 or R' 9 and R 10 together with the carbon atoms to which they can be attached can independently form a substituted or unsubstituted and saturated, partially saturated, or unsaturated cycle or heterocycle having 3 to 20 carbon atoms; and
  • R 2 and R 2 , R 3 and R' 3l R 4 and R 4 , R 5 and R' 5l R 6 and R 6 , R 7 and R 7 , R 8 and R' 8 , and R 9 and R 9 together with the carbon atom to which they can be attached can independently form a substituted or unsubstituted and saturated, partially saturated, or unsaturated cycle or heterocycle having 3 to 20 carbon atoms; and
  • R 2 or R' 2 and R 3 or R' 3 , R 4 or R 4 and R 5 or R' 5> R 6 or R' 6 and R 7 or R' 7 , or R 8 or R' 8 and R 9 or R' 9 together with the carbon atoms to which they can be attached can independently form a substituted or unsubstituted nitrogen containing heterocycle having 3 to 20 carbon atoms, which may be an aromatic heterocycle in which case the hydrogen attached to the nitrogen which can be both part of the heterocycle and the macrocycle and the R groups attached to the carbon atoms which can be both part of the heterocycle and the macrocycle can be absent; and
  • R 1 , R 2 , R' 2 , Ra, R'3, R 4 , R 4 , Rs, R'5, Re, R'e, R 7 , R 7 , R 8 , Rs, R 9 , Rg, and R 10 together with a different one of R 1 , R 2 , R 2 , R 3 , R' 3 , R 4 , R 4 , R5, R'5, R 6 , R'e, R7, R'7, R ⁇ , R' ⁇ , Rg, R'g, and Ri 0 , which can be attached to a different carbon atom in the macrocyclic ligand may be bound to form a strap represented by the formula:
  • I 1 J 1 K and L independently can be integers from 0 to 10 and Q, R and T can optionally be substituted moieties independently including alkenyl, alkenylcycloalkenyl, alkenylcycloalkyl, alkyl, alkylcycloalkenyl, alkylcycloalkyl, alkynyl, aralkyl, aryl, cycloalkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylcycloalkyl, cycloalkenylalkyl, and heterocyclyl, aza, amide, ammonium, oxa, thia, sulfonyl, sulfinyl, sulfonamide, phosphoryl, phosphinyl, phosphino, phosphonium, keto, ester, alcohol, carbamate, urea, thiocarbonyl, borates, boranes, boraza
  • R 1 , R 2 , R 2 , R 3 , R 3 , R 4 , R 4 , R 5 , R' 5) R 6 , Re, R 7 , R 7 , R 8 , R' ⁇ , Rg, R' 9 , and R 10 may be bound to an atom of heterocycle W to form a strap represented by the formula:
  • I, J, K and L can independently be integers from 0 to 10 and Q, R and T can optionally be substituted moieties independently including alkenyl, alkenylcycloalkenyl, alkenylcycloalkyl, alkyl, alkylcycloalkenyl, alkylcycloalkyl, alkynyl, aralkyl, aryl, cycloalkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylcycloalkyl, cycloalkenylalkyl, and heterocyclyl, aza, amide, ammonium, oxa, thia, sulfonyl, sulfinyl, sulfonamide, phosphoryl, phosphinyl, phosphino, phosphonium, keto, ester, alcohol, carbamate, urea, thiocarbonyl, borates, boranes, boraza
  • M can be a transition metal
  • X, Y and Z can independently include halide, oxo, aquo, hydroxo, alcohol, phenol, dioxygen, peroxo, hydroperoxo, alkylperoxo, arylperoxo, ammonia, alkylamino, arylamino, heterocycloalkyl amino, heterocycloaryl amino, amine oxides, hydrazine, alkyl hydrazine, aryl hydrazine, nitric oxide, cyanide, cyanate, thiocyanate, isocyanate, isothiocyanate, alkyl nitrile, aryl nitrile, alkyl isonitrile, aryl isonitrile, nitrate, nitrite, azido, alkyl sulfonic acid, aryl sulfonic acid, alkyl sulfoxide, aryl sulfoxide, alkyl aryl sulfoxide, alkyl aryl
  • X, Y and Z can independently be charge-neutralizing anions which can be derived from any monodentate or polydentate coordinating ligand and a ligand system and the corresponding anion thereof; or
  • X, Y and Z can independently be attached to one or more of R 1 , R 2 , R' 2 , R 3 , R'3, R4, R'4, R5, R'5, R ⁇ > R F 6> R7.
  • n can be an integer from 0 to 3.
  • the pentaaza-macrocyclic ligand complex can be represented by the following formula:
  • a nitrogen of the macrocycle and two adjacent carbon atoms to which the nitrogen can be attached can independently form a substituted or unsubstituted, saturated, partially saturated or unsaturated nitrogen-containing heterocycle W which can have 2 to 20 carbon atoms, which may be an aromatic heterocycle in which case the hydrogen attached to the nitrogen which can be both part of the heterocycle and the macrocycle and the R groups attached to the carbon atoms which can be both part of the heterocycle and the macrocycle can be absent; and
  • two sets of two adjacent carbon atoms of the macrocycle can independently form substituted or unsubstituted, saturated, partially saturated or unsaturated, cycles or heterocycles U and V having 3 to 20 carbon atoms;
  • Rs, R's, Re, R'e, R 7 , Rs, Rg, Rg, and R 10 can independently be:
  • (iii b ) a moiety independently including alkenyl, alkenylcycloalkenyl, alkenylcycloalkyl, alkyl, alkylcycloalkenyl, alkylcycloalkyl, alkynyl, aralkyl, aryl, cycloalkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylcycloalkyl, cycloalkenylalkyl, or heterocyclyl; or
  • (iii c ) a moiety independently including -OR 11 , -NR 11 R 12 , -COR 11 , -CO 2 R 11 , -CONR 11 R 12 , -SR 11 , -SOR 11 , -SO 2 R 11 , -SO 2 NR 11 R 12 , -N(OR 11 )(R 12 ), -P(O)(OR 11 )(OR 12 ), -P(O)(OR 11 )(R 12 ), -OP(O)(OR 11 )(OR 12 ), or substituents attached to the ⁇ -carbon of ⁇ -amino acids, wherein R 11 and R 12 can independently include hydrogen or alkyl; and
  • R-i and R 2 or R 2 , R 5 or R' 5 and R 6 or R' 6 , R 9 or Rg and R 10 together with the carbon atoms to which they attached can independently form a substituted or unsubstituted and saturated, partially saturated, or unsaturated cycle or heterocycle having 3 to 20 carbon atoms;
  • R 2 and R 2 , R 5 and R' 5 , Re and R' 6 , and R 9 and R g, together with the carbon atom to which they can be attached can independently form a substituted or unsubstituted and saturated, partially saturated, or unsaturated cycle or heterocycle having 3 to 20 carbon atoms;
  • R 2 or R' 2 and R 3 , R 4 and R 5 or R' 5 , R 6 or R' 6 and R 7 , or R 8 and R 9 or R' 9 together with the carbon atoms to which they can be attached can independently form a substituted or unsubstituted nitrogen containing heterocycle having 3 to 20 carbon atoms, which may be an aromatic heterocycle in which case the hydrogen attached to the nitrogen which can be both part of the heterocycle and the macrocycle and the R groups attached to the carbon atoms which can be both part of the heterocycle and the macrocycle can be absent; and
  • I, J, K and L independently can be integers from 0 to 10 and Q, R and T can be optionally substituted moieties independently including alkenyl, alkenylcycloalkenyl, alkenylcycloalkyl, alkyl, alkylcycloalkenyl, alkylcycloalkyl, alkynyl, aralkyl, aryl, cycloalkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylcycloalkyl, cycloalkenylalkyl, and heterocyclyl, aza, amide, ammonium, oxa, thia, sulfonyl, sulfinyl, sulfonamide, phosphoryl, phosphinyl, phosphino, phosphonium, keto, ester, alcohol, carbamate, urea, thiocarbonyl, borates, boranes, boraza
  • R 1 , R 2 , R 2 , R 3 , R 4 , R 5 , R' 5 , R 6 , R 6 , R 7 , R 8 , R 9 , R'g, and R 10 can be individually bound to an atom of heterocycles U, V and W to form a strap represented by the formula:
  • I, J, K and L independently can be integers from 0 to 10 and Q, R and T can be optionally substituted moieties independently including alkenyl, alkenylcycloalkenyl, alkenylcycloalkyl, alkyl, alkylcycloalkenyl, alkylcycloalkyl, alkynyl, aralkyl, aryl, cycloalkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylcycloalkyl, cycloalkenylalkyl, and heterocyclyl, aza, amide, ammonium, oxa, thia, sulfonyl, sulfinyl, sulfonamide, phosphoryl, phosphinyl, phosphino, phosphonium, keto, ester, alcohol, carbamate, urea, thiocarbonyl, borates, boranes, boraza
  • M can be a transition metal
  • X, Y and Z can independently include halide, oxo, aquo, hydroxo, alcohol, phenol, dioxygen, peroxo, hydroperoxo, alkylperoxo, arylperoxo, ammonia, alkylamino, arylamino, heterocycloalkyl amino, heterocycloaryl amino, amine oxides, hydrazine, alkyl hydrazine, aryl hydrazine, nitric oxide, cyanide, cyanate, thiocyanate, isocyanate, isothiocyanate, alkyl nitrile, aryl nitrile, alkyl isonitrile, aryl isonitrile, nitrate, nitrite, azido, alkyl sulfonic acid, aryl sulfonic acid, alkyl sulfoxide, aryl sulfoxide, alkyl aryl sulfoxide, alkyl aryl
  • X, Y and Z can independently include charge-neutralizing anions which can be derived from any monodentate or polydentate coordinating ligand and a ligand system and the corresponding anion thereof; or
  • X, Y and Z can independently be attached to one or more of R-i, R 2 , R' 2 , R 3 , R4, Rs, R's, Re, R'e, R7, Ra, Rg, Rg, and R 10 ; and
  • n can be an integer from 0 to 3.
  • the pentaaza-macrocyclic ligand complex can be represented by the following formulas:
  • W of the pentaaza-macrocyclic ligand complex can be a substituted pyridino moiety.
  • the superoxide dismutase mimetic can be a porphyrin ligand complex or a substituted porphyrin ligand complex.
  • the porphyrin ligand complex can be selected from the group consisting of a manganese (II) porphyrin complex, manganese(lll) porphyrin complex, iron (II) porphyrin complex, and an iron(lll) porphyrin complex.
  • the porphyrin ligand complex can be a 5,10,15, 20-tetrakis (2,4,6- trimethyl-3,5-disulfonatophenyl)-porphyrinato iron (III) (FeTMPS) complex.
  • a method for diagnosing congestive heart failure in a subject comprising obtaining a first coronary blood flow or IVlVO 2 measurement in the subject, administering a superoxide dismutase mimetic to the subject, and obtaining a second coronary blood flow or MVO 2 measurement after administration of the catalyst to the subject, wherein an increase in coronary blood flow or MVO 2 following administration of the superoxide dismutase mimetic is indicative of congestive heart failure.
  • the subject and superoxide dismutase mimetic can be those described above.
  • a method for treating heart failure comprising administering to a subject in need thereof a therapeutically effective amount of a peroxynitrite decomposition catalyst.
  • a method for increasing coronary blood flow in heart failure comprising administering to a subject in need thereof a therapeutically effective amount of a peroxynitrite decomposition catalyst.
  • a method for increasing MVO 2 in heart failure comprising administering to a subject in need thereof a therapeutically effective amount of a peroxynitrite decomposition catalyst.
  • the subject can be selected from the group consisting of a mammal and avian.
  • the mammal can be a human.
  • the peroxynitrite decomposition catalyst can be represented by a formula selected from the group of formulas consisting of:
  • R 3 , R 6 , R 9 or R 12 can independently include H, alkyl, alkenyl, CH 2 , COOH, phenyl, pyridinyl, or N-alkylpyridyl such that phenyl, pyridinyl and N-alkylpyridyl can be: Phenyl
  • phenyl can optionally be substituted by halogen, alkyl, aryl, benzyl, COOH, CONH 2 , SO 3 H, NO 2 , NH 2 , N(R) 3+ or NHCOR 1 wherein R can include hydrogen, alkyl, aryl and alkaryl and R' can be alkyl, and
  • pyridinyl can optionally be substituted by halogen, alkyl, aryl, benzyl, COOH, CONH 2 , SO 3 H, NO 2 , NH 2 , N(R) 3+ or NHCOR 1 wherein R and R 1 can be as defined above, and
  • N-alkylpyridyl can optionally be substituted by halogen, alkyl, aryl, benzyl, COOH, CONH 2 , SO 3 H, NO 2 , NH 2 , N(R) 3+ or NHCOR 1 wherein R and R' can be as defined above; and
  • R 1 , R 2 , R 4 , R 5 , R 7 , R 8 , Rio, or R 11 can independently include H, alkyl, alkenyl, carboxyalkyl, Cl, Br, F, NO 2 , hydroxyalkyl, or SO 3 H, and further wherein R-,R 2 can be taken together to form a ring of from 5 to 8 carbons, and
  • X and Y can be ligands or charge-neutralizing anions which can be derived from any monodentate or polydentate coordinating ligand or ligand system or the corresponding anion thereof and can be independently selected from the group consisting of halide, oxo, aquo, hydroxo, alcohol, phenol, dioxygen, peroxo, hydroperoxo, alkylperoxo, arylperoxo, ammonia, alkylamino, arylamino, heterocycloalkyl amino, heterocycloaryl, amino, amine oxides, hydrazine, alkyl hydrazine, aryl hydrazine, nitric oxide, cyanide, cyanate, thiocyanate, isocyanate, isothiocyanate, alkyl nitrile, aryl nitrile, alkyl isonitrile, aryl isonitrile, nitrate, nitrite, azido, alkyl n
  • M can be selected from the group consisting of Mn, Fe, Ni and V;
  • n can be an integer from 1 to 3; or
  • R' can be CH or N
  • R 7 , Rs, Rg, Rio, Rn, R12, Ri 3 , R14, R15, and R 16 can independently include H, SO 3 H, COOH, NO 2 , NH 2 , and N-alkylamino
  • X, Y, Z, M and n can be as defined above; [0100] Structure III
  • R 1 , R 5 , R 9 , and R 13 can independently include a direct bond and
  • R 2 , R 2 ', R4, R 4 ', Re, Re', R ⁇ , R ⁇ ', R10, R10', Ri2 > Ri 2 1 , Ri4 > R14', R16, and R-i6' can independently include H and alkyl;
  • R 3 , R 7 , R 11 , R 15 can independently include H and alkyl; and [0104] X, Y, Z, M and n can be as defined above;
  • R 1 , Rs, Rs, and Ri 2 can independently include a direct bond
  • R 2 , R 2 1 , R 4 , R 4 1 , R 6 , R 6 1 , R 7 , R 9 , R 9 1 , R 11 , R 11 1 , R 13 , R 13 1 , and R 14 can independently include H and alkyl;
  • R 3 and R 10 can independently include H and alkyl; and [0108] X, Y, Z, M and n can be as defined above;
  • R-i, R 4 , Rs, R 12 can independently include direct bond and CH 2 ;
  • R 2 , R 2 ', R 3 , R 5 , Rs', R7, Rg, Rg', Rn, Rn', R13, R13' and R 14 can independently include H and alkyl;
  • R 10 can be H or alkyl; and [0112] X, Y, Z, M and n can be as defined above;
  • R 1 , R 4 , R 7 and R 10 can independently include direct bond and CH 2 ;
  • R 2 , R 2 ', R 3 , R 5 , R 5 ', R 6 , R 8 , Rs', Rg, Rn, Rn' and R 12 can independently include H and alkyl;
  • X, Y, Z, M and n can be as defined above;
  • R 1 , R 4 , Rs and R- ⁇ can independently include a direct bond
  • R 2 , R 3 , R 3 ', Rs, R 5 ", R?, R/. Rg, Rio> R10 1 , R12, R12 1 and R 13 can independently include H and alkyl;
  • R 6 can be hydrogen or alkyl
  • X, Y, Z, M and n can be as defined above;
  • R 1 , R 4 , R 7 and R 1 0 can independently include H and alkyl
  • R 2 , R 3 , R 3 ', R 5 , Rs', Re, Rs, Rg, Rg', R11, Rn' and R 12 can independently include H and alkyl
  • X, Y, Z, M and n can be as defined above;
  • R-i, R 3 , R 4 and R 6 can independently include H and alkyl;
  • R 2 and R 5 can independently include H, alkyl, SO 3 H, NO 2 , NH 2 , halogen, COOH and N(R) 3+ wherein R can be as defined above; and
  • X, Y, Z, M and n can be as defined above;
  • R 1 , R 2 , R 3 , R 4 can independently include H, alkyl, SO 3 H, NO 2 , NH 2 , halogen, COOH and N(R) 3+ wherein R can be as defined above; and [0127] X, Y, Z, M and n can be as defined above; and [0128] Structure IV
  • R 1 , R 1 ', R 2 , R 2 1 , R 3 , R3 1 , R4, R 4 ', Rs, R5 1 , Re, Re', R 7 and R 7 ' can independently include H, alkyl, alkoxy, NO 2 , aryl, halogen, NH 2 and SO 3 H, wherein R 6 , Re', R 7 and R 7 ' may each be taken together with one other of R 6 , R ⁇ , R 7 and- R 7 ' to form a cyclic group, preferably a 6 carbon cycloalkyl group;
  • M 1 can be selected from the group consisting of Fe, Ni or V;
  • X, Y, Z and n can be as defined above.
  • Figure 1 shows the effect of M40401 'in normal dogs.
  • the relationship between Myocardial 02 consumption (ml/min) and rate pressure product (mm Hg beats/min) were unchanged in normal dogs after taking M40401.
  • FIG 2 shows the effect of M40401 in normal dogs.
  • Coronary blood flow ml/min
  • rate pressure product mm Hg beats/min
  • Figure 3 shows the effect of M40401 and LNA (the nitric oxide synthase inhibitor NG-nitro-l-arginine) on endothelium dependent coronary vasodilation in normal dogs.
  • M40401 and LNA the nitric oxide synthase inhibitor NG-nitro-l-arginine
  • Figure 4 shows the effect of M40401 and LNA (the nitric oxide synthase inhibitor NG-nitro-l-arginine) on endothelium dependent coronary vasodilation in normal dogs. Inhibition of NO production with LNA blunted the increase in coronary flow produced by acetylcholine.
  • Figure 5 shows SOD isoenzyme content. Western analysis shows that norma! extracellular SOD was decreased, while Mn-SOD was increased in the failing heart.
  • LNA the nitric oxide synthase inhibitor NG-nitro-l-arginine
  • ROS reactive oxygen species
  • non-peptidic catalysts for the dismutation of superoxide or “non-proteinaceous catalysts for the dismutation of superoxide” mean a low- molecular weight catalyst for the conversion of superoxide anions into hydrogen peroxide and molecular oxygen.
  • These catalysts commonly consist of an organic ligand and a chelated transition metal ion, preferably copper, manganese(ll), manganese(lll), iron(ll) or iron(lll).
  • the term may include catalysts containing short-chain polypeptides (under 15 amino acids) or macrocyclic structures derived from amino acids, as the organic ligand.
  • the term explicitly excludes a superoxide dismutase enzyme obtained from any species.
  • the term "catalyst for the dismutation of superoxide” is used interchangeable with the term “superoxide dismutase mimetic (SODm)” and means any catalyst for the conversion of superoxide anions into hydrogen peroxide and molecular oxygen.
  • SODm superoxide dismutase mimetic
  • the term explicitly includes a superoxide dismutase enzyme obtained from any species.
  • the superoxide dismutase mimetics can include, generally, those superoxide dismutase mimetics disclosed in U.S. Patent Nos.
  • a mammal patient to which the catalyst for the dismutation of superoxide will be administered, in the methods or compositions of the invention, will be a human.
  • other mammal patients in veterinary e.g., companion pets and large veterinary animals
  • other conceivable contexts are also contemplated.
  • treatment relate to any treatment of heart failure and include: (1) preventing heart failure from occurring in a subject; (2) inhibiting the progression or initiation of heart failure, i.e., arresting or limiting its development; or (3) ameliorating or relieving the symptoms of existing heart failure.
  • terapéuticaally effective amount means those amounts that, when administered to a particular subject in view of the nature and severity of that subject's disease or condition of heart failure, will have the desired therapeutic effect, e.g., an amount which will cure, or at least partially arrest or inhibit the disease or condition or symptoms of heart failure.
  • heart failure is used interchangeably with the term CHF and indicates that the pumping action of the heart is inadequate to meet the body's needs for oxygen-rich blood. As a result, blood flow to body tissues is reduced and blood returning to the heart accumulates, causing congestion in the veins.
  • substituted means that the described moiety has one or more substituents comprising at least 1 carbon or heteroatom, and further comprising 0 to 22 carbon atoms, more preferably from 1 to 15 carbon atoms, and comprising 0 to 22, more preferably from 0 to 15.
  • heteroatom refers to those atoms that are neither carbon nor hydrogen bound to carbon and are selected from the group consisting of O, S, N, P, Si, B, F, Cl, Br, or I. These atoms may be arranged in a number of configurations, creating substituent groups which are unsaturated, saturated, or aromatic.
  • substituents include branched or unbranched alkyl, alkenyl, or alkynyl, cyclic, heterocyclic, aryl, heteroaryl, alkyl, polycycloalkyl, polycycloaryl, polycycloheteroaryl, imines, aminoalkyl, hydroxyalkyl, hydroxyl, phenol, amine oxides, thioalkyl, carboalkoxyalkyl, carboxylic acids and their derivatives, keto, ether, aldehyde, amine, amide, nitrite, halo, thiol, sulfoxide, sulfone, sulfonic acid, sulfide, disulfide, phosphoric acid, phosphonic acid, acrylic acid, sulphonamides, amino acids, peptides, proteins, carbohydrates, nucleic acids, fatty acids, lipids, nitro, hydroxylamines, hydroxamic acids, thiocarbonyls, thio
  • alkyl alone or in combination, means a straight-chain or branched-chain alkyl radical containing from 1 to about 22 carbon atoms, preferably from about 1 to about 18 carbon atoms, and most preferably from about 1 to about 12 carbon atoms.
  • radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, octadecyl and eicosyl.
  • alkenyl alone or in combination, means an alkyl radical having one or more double bonds.
  • alkenyl radicals include, but are not limited to, ethenyl, propenyl, 1-butenyl, cis-2-butenyl, traps-2-butenyl, iso-butylenyl, cis-2-pentenyl, traps-2-pentenyl, 3-methyl-l-butenyl, 2,3-dimethyl-2-butenyl, 1-pentenyl, 1-hexenyl, 1- octenyl, decenyl, dodecenyl, tetradecenyl, hexadecenyl, cis- and traps-9-octadecenyl, 1,3- pentadienyl, 2,4-pentadienyl, 2,3-pentadienyl, 1 ,3-hexadienyl, 2,
  • alkynyl alone or in combination, means an alkyl radical having one or more triple bonds.
  • alkenyl groups include, but are not limited to, ethynyl, propynyl (propargyl), 1-butenyl, 1-octynyl, 9-octadecynyl, 1,3-pentadiynyl, 2,4- pentadiynyl, 1 ,3-hexadiynyl, and 2,4-hexadiynyl.
  • cycloalkyl alone or in combination means a cycloalkyl radical containing from 3 to about 10, preferably from 3 to about 8, and most preferably from 3 to about 6, carbon atoms.
  • examples of such cycloalkyl radicals include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and perhydronaphthyl.
  • cycloalkylalkyl means an alkyl radical as defined above which is substituted by a cycloalkyl radical as defined above.
  • cycloalkylalkyl radicals include, but are not limited to, cyclohexylmethyl, cyclopentylmethyl, (4- iso ⁇ ropylcyclohexyl)methyl, (4-t-butyl-cyclohexyl)methyl, 3-cyclohexylpropyl, 2- cyclohexylmethylpentyl, 3-cyclopentylmethylhexyl, 1 -(4-neopentylcyclohexyl)methylhexyl, and 1 -(4-isopropylcyclohexyl)methylheptyl.
  • cycloalkylcycloalkyl means a cycloalkyl radical as defined above which is substituted by another cycloalkyl radical as defined above.
  • examples of cycloalkylcycloalkyl radicals include, but are not limited to, cyclohexylcyclopentyl and cyclohexylcyclohexyl.
  • cycloalkenyl alone or in combination, means a cycloalkyl radical having one or more double bonds.
  • examples of cycloalkenyl radicals include, but are not limited to, cyclopentenyl, cyclohexenyl, cyclooctenyl, cyclopentadienyl, cyclohexadienyl and cyclooctadienyl.
  • cycloalkenylalkyl means an alkyl radical as defined above which is substituted by a cycloalkenyl radical as defined above.
  • examples of cycloalkenylalkyl radicals include, but are not limited to, 2-cyclohexen-l-ylmethyl, 1-cyclopenten-l-ylmethyl, 2- (1 -cyclohexen-l-yl)ethyl, 3-(1 -cyclopenten-l-yl)propyl, 1 -(1 -cyclohexen-l-ylmethyOpentyl, 1 -(1 - cyclopenten-!-yl)hexyl, 6-(1-cyclohexen-l-yl)hexyl, 1-(1-cyclopenten-l-yl)nonyl and 1-(1- cyclohexen-l-yl)nonyl.
  • alkylcycloalkyl and alkenylcycloalkyl mean a cycloalkyl radical as defined above which is substituted by an alkyl or alkenyl radical as defined above.
  • alkylcycloalkyl and alkenylcycloalkyl radicals include, but are not limited to, 2- ethylcyclobutyl, 1-methylcyclopentyl, 1-hexylcyclopentyl, 1-methylcyclohexyl, 1-(9- octadecenyl)cyc!opentyl and 1-(9-octadecenyl)cyclohexyl.
  • alkylcycloalkenyl and “alkenylcycloalkenyl” means a cycloalkenyl radical as defined above which is substituted by an alkyl or alkenyl radical as defined above.
  • alkylcycloalkenyl and alkenylcycloalkenyl radicals include, but are not limited to, i-methyl-2-cyclopentyl, i-hexyl-2-cyclopentenyl, 1-ethyl-2-cyc(ohexenyl, 1- butyl-2-cyclohexenyl, 1-(9-octadecenyl)-2-cyclohexenyl and 1-(2-pentenyl)-2-cyclohexenyl.
  • aryl alone or in combination, means a phenyl or naphthyl radical which optionally carries one or more substituents selected from alkyl, cycloalkyl, cycloalkenyl, aryl, heterocycle, alkoxyaryl, alkaryl, alkoxy, halogen, hydroxy, amine, cyano, nitro, alkylthio, phenoxy, ether, trifluoromethyl and the like, such as phenyl, p-tolyl, 4- methoxyphenyl, 4-(tert-butoxy)phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-hydroxyphenyl, 1- naphthyl, 2-naphthyl, and the like.
  • aralkyl alone or in combination, means an alkyl or cycloalkyl radical as defined above in which one hydrogen atom is replaced by an aryl radical as defined above, such as benzyl, 2-phenylethyl, and the like.
  • heterocyclic means ring structures containing at least one heteroatom within the ring.
  • heteroatom refers to atoms that are neither carbon nor hydrogen bound to a carbon.
  • heterocyclics include, but are not limited to, pyrrolidinyl, piperidyl, imidazolidinyl, tetrahydrofuryl, tetrahydrothienyl, furyl, thienyl, pyridyl, quinolyl, isoquinolyl, pyridazinyl, pyrazinyl, indolyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, pyridinyl, benzoxadiazolyl, benzothiadiazolyl, triazolyl and tetrazolyl groups.
  • saturated, partially saturated or unsaturated cyclic means fused ring structures in which 2 carbons of the ring are also part of the fifteen-membered macrocyclic ligand.
  • the ring structure can contain 3 to 20 carbon atoms, preferably 5 to 10 carbon atoms, and can also contain one or more other kinds of atoms in addition to carbon. The most common of the other kinds of atoms include nitrogen, oxygen and sulfur.
  • the ring structure can also contain more than one ring.
  • saturated, partially saturated or unsaturated ring structure means a ring structure in which one carbon of the ring is also part of the fifteen-membered macrocyclic ligand.
  • the ring structure can contain 3 to 20, preferably 5 to 10, carbon atoms and can also contain nitrogen, oxygen and/or sulfur atoms.
  • nitrogen containing heterocycle means ring structures in which 2 carbons and a nitrogen of the ring are also part of the fifteen-membered macrocyclic ligand.
  • the ring structure can contain 2 to 20, preferably 4 to 10, carbon atoms, can be substituted or unsubstituted, partially or fully unsaturated or saturated, and can also contain nitrogen, oxygen and/or sulfur atoms in the portion of the ring which is not also part of the fifteen- membered macrocyclic ligand.
  • organic acid anion refers to carboxylic acid anions having from about 1 to about 18 carbon atoms.
  • halide means chloride, fluoride, iodide, or bromide.
  • R groups means ail of the R groups attached to the carbon atoms of the macrocycle, i.e., R, R', R 1 , R ⁇ , R 2 , R' 2> Ra, R's, R 4 , R ! 4, Rs, R' 5 , Re, R'e,
  • the present invention relates to the discovery that superoxide dismutase mimetics and peroxynitrite decompositions are effective in treating CHF and affecting other aspects of the mammalian and avian coronary system.
  • a method for treating CHF comprising administering to a subject in need thereof a therapeutically effective amount of a superoxide dismutase mimetic or a peroxynitrite decomposition catalyst.
  • Another aspect provides a method for increasing coronary blood flow in heart failure, the method comprising administering to a subject in need thereof a therapeutically effective amount of a superoxide dismutase mimetic or a peroxynitrite decomposition catalyst.
  • Yet another aspect provides a method for increasing MVO 2 in CHF, the method comprising administering to a subject in need thereof a therapeutically effective amount of a superoxide dismutase mimetic or a peroxynitrite decomposition catalyst.
  • the superoxide dismutase mimetics and peroxynitrite decomposition catalysts can include, generally, those superoxide dismutase mimetics disclosed in U.S. Patent 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, 6,395,725, and 6,525,041 in addition to those disclosed herein.
  • the superoxide dismutase mimetic can comprise an organic ligand chelated to a metal ion including Mn(II), Mn(III), Fe(II), Fe (III), Cu(ll)/Zn(lll), or Cu(lll)/Zn (II).
  • the subject can be a mammal and avian. In particular, the mammal can be a human.
  • a method for diagnosing congestive heart failure in a subject comprising obtaining a first coronary blood flow or MVO 2 measurement in the subject, administering a superoxide dismutase mimetic or a peroxynitrite decomposition catalyst to the subject, and obtaining a second coronary blood flow or MVO 2 measurement after administration of the catalyst to the subject, wherein an increase in coronary blood flow or MVO 2 following administration of the superoxide dismutase mimetic is indicative of congestive heart failure.
  • the subject and superoxide dismutase mimetic can be those disclosed and incorporated herein.
  • CHF is associated with depressed myocardial oxygen consumption (MVO 2 ), decreased coronary blood flow (CBF), and coronary endothelial dysfunction.
  • MVO 2 myocardial oxygen consumption
  • CBF coronary blood flow
  • O 2 * superoxide
  • CHF left ventricular
  • MVO 2 left ventricular
  • LVEDP LV end-diastolic pressure
  • SOD mimetic M40401 increased CBF (18+5%, p ⁇ 0.01) and MVO 2 (14+6%, p ⁇ 0.01) in CHF dogs at rest and during exercise, and decreased LVEDP from 24+1.3 mmHg to 21+1.1 mmHg (p ⁇ 0.05>.
  • CHF oxidative stress
  • I mitochondria Dhalla et al., Am J Physiol. 266, H1280-285 (1994); Hill et al., Circulation 96, 2414-2420 (1997)).
  • superoxide (O 2 ) production is increased both in myocardial mitochondria (Ide et al., Circ. Res. 85, 357-363 (1999); lde et al., Circ. Res.
  • O 2 " can function as a messenger intermediate involved in signal transduction (Irani et al., Science 275, 1649-1652 (1997); Lander et al., Nature 381, 380-381 (1996)), but high concentrations of O 2 "can result in cell damage and tissue injury.
  • O 2 " reacts avidly with nitric oxide (NO) to form peroxynitrite (ONOO " ), a strong oxidant and nitrating species known to promote oxidative damage (Borutaite et al., Biochim. Biophys. Acta 1459, 405-412 (2000)). But in low concentrations peroxynitrite may play some regulatory role in mitochondrial physiology (Borutaite et al., Biochim Biophys Acta 1459, 405- 412 (2000); Go et al., Am J Physiol 277, H1647-H1653 (1999)). Since O 2 *' has low membrane permeability, reactions with this molecule occur in the compartment in which it is generated.
  • O 2 * produced in vessels can react locally with endothelium derived NO, thereby decreasing NO bioavailability and contributing to the endothelial dysfunction seen in CHF (Bauersachs et al., Circulation 100, 292-298 (1999); Bauersachs et al., Circulation 104, 982-985 (2001); Bauersachs et al., J. Am. Coll. Cardiol. 39, 351-358 (2002)).
  • O 2 ' " produced in mitochondria can react with NO to form ONOO ' which may have the potential to alter mitochondrial respiration both directly by inactivation of mitochondrial complexes I 1 II and V as well as by removing the inhibitory effect of NO on cytochrome c oxidase (Radi et al., Biol. Chem. 383, 401-409 (2002); Borutaite et al., Biochim. Biophys. Acta 1459, 405-412 (2000)).
  • increased O 2 *" production has the potential to alter both vascular reactivity and mitochondrial function in the failing heart.
  • the SOD mimetic M40401 is a novel synthetic low molecular weight S 1 S- dimethyl substituted biscyclohexylpyridine manganese-based superoxide dismutase (SOD) mimetic that is stable in vivo, possesses high activity (at pH 7.4 > 1x10 9 M “1 s "1 which is comparable to the native Cu/Zn SOD enzyme), and is selective for O 2 " with no activity toward hydrogen peroxide (H 2 O 2 ), ONOO " , NO, or hypochlorite (OCI " ) (Salvemini et al., Science 286, 304-306 (1999); Salvemini et al., Br. J. Pharmacol. 127, 685-692 (1999)).
  • SOD superoxide dismutase
  • M40401 The resting redox state of M40401 is the reduced state, Mn(II); as a consequence, the complex has no reactivity for reducing agents until it is oxidized to Mn(III) by O 2 *" (Salvemini et al., Science 286, 304-306 (1999); Salvemini et al., BrJ Pharmacol 127, 685-692 (1999); Cuzzocrea et al., Br J Pharmacol 132, 19-29 (2001)).
  • M40401 is relatively difficult to oxidize (+0.75 v (SHE)) so that many oxidants including NO and oxygen will not oxidize the complex (Salvemini et al., Science 286, 304-306 (1999); Salvemini et al., Br J Pharmacol 127, 685- 692 (1999)). Since M40401 operates via a facile one-electron oxidation pathway, two- electron non-radical oxidants are also not able to oxidize the Mn(II) complex; e.g., 0ONO 2 " , OCr.
  • the myocardial protein content of copper/zinc-containing SOD (CuZn-SOD), mitochondrial manganese SOD (Mn-SOD) and extracellular SOD (EC-SOD) were also measured to determine whether a decrease of these enzymes might contribute to increased oxidative stress in the failing heart.
  • Coronary blood flow responses to acetylcholine are shown in Figures 3 and 4.
  • lntracoronary infusion of acetylcholine in doses of 3.75 to 75 ⁇ g/min had no effect on heart rate or aortic pressure.
  • coronary flow increased from 60 ⁇ 4.9 ml/min at baseline to 190+8.7 ml/min during the maximum acetylcholine dose (75 ⁇ g/min).
  • M40401 had no effect on either resting coronary flow or the increase in flow produced by acetylcholine.
  • Inhibition of NO production with LNA significantly (p ⁇ 0.01) blunted the increase in coronary flow produced by acetylcholine (Figure 4).
  • CHF was associated with increases in resting heart rate and LVEDP, and decreases of aortic pressure, LV systolic pressure (LVSP), LV dp/dt max , CBF and MVO 2 (each p ⁇ 0.05) (Table 2).
  • LVSP LV systolic pressure
  • LV dp/dt max CBF and MVO 2
  • CBF CBF
  • MVO 2 each p ⁇ 0.05
  • M40401 caused a small but significant decrease of LVEDP at rest and during exercise (p ⁇ 0.05), while aortic pressure, LV systolic pressure, LV dP/dt max and rate- pressure product were unchanged. M40401 caused increases (p ⁇ 0.05) in coronary blood flow and MVO2 at rest and during exercise in CHF dogs ( Figures 1 and 2), while the relationship between MVO2 and CBF was unchanged.
  • M40401 significantly augmented the increase of coronary flow produced by acetylcholine (Figure 4), indicating enhanced endothelium-dependent vasodilation.
  • LNA inhibited the increase in coronary flow produced by acetylcholine (p ⁇ 0.01).
  • the compounds of the present methods can comprise a non-proteinaceous catalyst for the dismutation of superoxide anions (an "SOD mimic” or “SODm”) as opposed to a native form of the SOD enzyme and a peroxynitrite decomposition catalyst.
  • the catalysts explicitly exclude a SOD enzyme obtained from any natural sources.
  • SOD mimics can be useful in the method of the present invention as compared to native SOD because of the limitations associated with native SOD therapies. See, e.g., Salvemini et al., Science 286, 304-306 (1999).
  • the best known native SOD, CuZn has a molecular weight of 33,000 kD.
  • SOD mimics have an approximate molecular weight of 400 to 600 Daltons.
  • the catalyst of the methods above can be a pentaaza- macrocyclic ligand complex or a substituted pentaaza-macrocyclic ligand complex.
  • the pentaaza-macrocyclic ligand complex can be represented by the following formula:
  • R 1 , R'-,, R 2 , R' 2 , R 3 , R's, R 4 , R r 4, R 5 , R's, Re, R'e, R 7 , RV, Re, R's, R9, R'g, R10, and R' 1O can independently be:
  • (i b ) a moiety independently including alkenyl, alkenylcycloalkenyl, alkenylcycloalkyl, alkyl, alkylcycloalkenyl, alkylcycloalkyl, alkynyl, aralkyl, aryl, cycloalkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylcycloalkyl, cycloalkenylalkyl, or heterocyclyl; or [0202] (i c ) a moiety independently including -ORn, -NR 11 R 12 , -CORi 1 , -CO 2 Ri 1 , -CONR 11 R 12 , -SRi 1 , -SOR 11 , -SO 2 R 11 , -SO 2 NR 11 R 12 , -N(ORn)(R 12 ), -P(O)(OR 11 )(OR 12 ), -P(O)(
  • R 1 or R'i and R 2 or R 2 , R 3 or R' 3 and R 4 or R f 4 , R 5 or R' 5 and R 6 or R' 6 , R 7 or R' 7 and R 8 or R' 8l R 9 or R' 9 and R 10 or R' 1O together with the carbon atoms to which they can be attached independently can form a substituted or unsubstituted and saturated, partially saturated, or unsaturated cycle or heterocycle having 3 to 20 carbon atoms; and
  • R 1 and R ⁇ , R 2 and R 2 , R 3 and R' 3 , R 4 and R' 4 , R 5 and R' 5 , R 6 and R 6 , R 7 and R' 7 , R 8 and R 8 , R 9 and R 9 , and R 10 and R' 1O together with the carbon atom to which they can be attached independently can form a substituted or unsubstituted and saturated, partially saturated, or unsaturated cycle or heterocycle having 3 to 20 carbon atoms; and
  • R 10 or R' 1O and R 1 or R'i, R 2 or R 2 and R 3 or R 3 , R 4 or R' 4 and R 5 or R 5 , R 6 or R' 6 and R 7 or R 7 , or R 8 or R' 8 and R 9 or R' 9 together with the carbon atoms to which they can be attached independently can form a substituted or unsubstituted nitrogen containing heterocycie having 3 to 20 carbon atoms, which may be an aromatic heterocycle in which case the hydrogen attached to the nitrogen which can be both part of the heterocycle and the macrocycle and the R groups attached to the carbon atoms which can be both part of the heterocycle and the macrocycle can be absent; and
  • I, J, K and L independently can be integers from 0 to 10 and Q, R and T can optionally include substituted moieties independently including alkenyl, alkenylcycloalkenyl, alkenylcycloalkyl, alkyl, alkylcycloalkenyl, alkylcycloalkyl, alkynyl, aralkyl, aryl, cycloalkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylcycloalkyl, cycloalkenylalkyl, and heterocyclyl, aza, amide, ammonium, oxa, thia, sulfonyl, sulfinyl, sulfonamide, phosphoryl, phosphinyl, phosphino, phosphonium, keto, ester, alcohol, carbamate, urea, thiocarbonyl, borates, boranes, boraza
  • M can be a transition metal
  • X, Y and Z can independently include halide, oxo, aquo, hydroxo, alcohol, phenol, dioxygen, peroxo, hydroperoxo, alkylperoxo, arylperoxo, ammonia, alkylamino, arylamino, heterocycloalkyl amino, heterocycloaryl amino, amine oxides, hydrazine, alkyl hydrazine, aryl hydrazine, nitric oxide, cyanide, cyanate, thiocyanate, isocyanate, isothiocyanate, alkyl nitrile, aryl nitrile, alkyl isonitrile, aryl isonitrile, nitrate, nitrite, azido, alkyl sulfonic acid, aryl sulfonic acid, alkyl sulfoxide, aryl sulfoxide, alkyl aryl sulfoxide, alkyl aryl
  • X, Y and Z can independently include charge-neutralizing anions which can be derived from any monodentate or polydentate coordinating ligand and a ligand system and the corresponding anion thereof; or
  • X, Y and Z can independently be attached to one or more of R 1 , R ⁇ , R 2 , R' 2 , R3. R'3. R4. R'4. R5. R'51 Re. R r 6> R71 RV. Rs, R' ⁇ . R9> R'9, R10, or R'10; and
  • n can be an integer from 0 to 3.
  • the pentaaza-macrocyclic ligand complex can be represented by the following formula:
  • a nitrogen of the macrocycle and two adjacent carbon atoms to which the nitrogen can be attached can independently form a substituted or unsubstituted, saturated, partially saturated or unsaturated nitrogen-containing heterocycle W having 2 to 20 carbon atoms, which may be an aromatic heterocycle in which case the hydrogen attached to the nitrogen which can be both part of the heterocycle and the macrocycle and the R groups attached to the carbon atoms which can be both part of the heterocycle and the macrocycle can be absent; and
  • R 1 , R 2 , R' 2 , R 3 , R's, R 4 , R r 4, R 5 , R' ⁇ , R 6 , R' ⁇ , R7, R'/, Rs, R' 8 , R 9 , Rg, and R 10 can independently be:
  • (ii b ) a moiety independently including alkenyl, alkenylcycloalkenyl, alkenylcycloalkyl, alkyl, alkylcycloalkenyl, alkylcycloalkyl, alkynyl, aralkyl, aryl, cycloalkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylcycloalkyl, cycloalkenylalkyl, or heterocyclyl; or
  • (ii c ) a moiety independently selected from the group consisting of -ORi 1 , -NR 11 R 12 , -COR 11 , -CO 2 R 11 , -CONR 11 R 12 , -SR 11 , -SOR 11 , -SO 2 R 11 , -SO 2 NR 11 R 12 , -N(OR 11 )(R 12 ), -P(O)(OR 11 )(OR 12 ), -P(O)(OR 11 )(R 12 ), -OP(O)(OR 11 )(OR 12 ), or substituents attached to the ⁇ -carbon of ⁇ -amino acids, wherein Rn and R 12 can independently include hydrogen or alkyl; and
  • R 1 and R 2 or R 2 , R 3 or R' 3 and R 4 or R' 4 , R 5 or R' 5 and R 6 or R 6 , R 7 or R' 7 and R 8 or R' 8 , Rg or R' 9 and R 10 together with the carbon atoms to which they can be attached can independently form a substituted or unsubstituted and saturated, partially saturated, or unsaturated cycle or heterocycle having 3 to 20 carbon atoms; and
  • R 2 and R 2 , R 3 and R 3 , R 4 and R' 4l R 5 and R 5 , R 6 and R 6 , R 7 and R 7 , Rs and R 8 , and R 9 and R 9 together with the carbon atom to which they can be attached can independently form a substituted or unsubstituted and saturated, partially saturated, or unsaturated cycle or heterocycle having 3 to 20 carbon atoms;
  • R 2 or R' 2 and R 3 or R' 3l R 4 or R' 4 and R 5 or R' 5 , Re or R' 6 and R 7 or R 7 , or R 8 or R' 8 and R 9 or R' 9 together with the carbon atoms to which they can be attached can independently form a substituted or unsubstituted nitrogen containing heterocycle having 3 to 20 carbon atoms, which may be an aromatic heterocycle in which case the hydrogen attached to the nitrogen which can be both part of the heterocycle and the macrocycle and the R groups attached to the carbon atoms which can be both part of the heterocycle and the macrocycle can be absent; and
  • I, J, K and L independently can be integers from 0 to 10 and Q, R and T can optionally be substituted moieties independently including alkenyl, alkenylcycloalkenyl, alkenylcycloalkyl, alkyl, alkylcycloalkenyl, alkylcycloalkyl, alkynyl, aralkyl, aryl, cycloalkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylcycloalkyl, cycloalkenylalkyl, and heterocyclyl, aza, amide, ammonium, oxa, thia, sulfonyl, sulfinyl, sulfonamide, phosphoryl, phosphinyl, phosphino, phosphonium, keto, ester, alcohol, carbamate, urea, thiocarbonyl, borates, boranes, boraza
  • R 1 , R 2 , R 2 , R 3 , R 3 , R 4 , R 4 , R 5 , R 5 , R 6 , R'e, R 7 , R' 7 , Rs, R's, Rg, R'9, and RTM may be bound to an atom of heterocycle W to form a strap represented by the formula:
  • I, J, K and L can independently be integers from 0 to 10 and Q, R and T can optionally be substituted moieties independently including alkenyl, alkenylcycloalkenyl, alkenylcycloalkyl, alkyl, alkylcycloalkenyl, alkylcycloalkyl, alkynyl, aralkyl, aryl, cycloalkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylcycloalkyl, cycloalkenylalkyl, and heterocyclyl, aza, amide, ammonium, oxa, thia, sulfonyl, sulfinyl, sulfonamide, phosphoryl, phosphinyl, phosphino, phosphonium, keto, ester, alcohol, carbamate, urea, thiocarbonyl, borates, boranes, boraza
  • M can be a transition metal
  • X, Y and Z can independently include halide, oxo, aquo, hydroxo, alcohol, phenol, dioxygen, peroxo, hydroperoxo, alkylperoxo, arylperoxo, ammonia, alkylamino, arylamino, heterocycloalkyl amino, heterocycloaryl amino, amine oxides, hydrazine, alkyl hydrazine, aryl hydrazine, nitric oxide, cyanide, cyanate, thiocyanate, isocyanate, isothiocyanate, alkyl nitrile, aryl nitrile, alkyl isonitrile, aryl isonitrile, nitrate, nitrite, azido, alkyl sulfonic acid, aryl sulfonic acid, alkyl sulfoxide, aryl sulfoxide, alkyl aryl sulfoxide, alkyl aryl
  • X, Y and Z can independently be charge-neutralizing anions which can be derived from any monodentate or polydentate coordinating ligand and a ligand system and the corresponding anion thereof; or
  • X, Y and Z can independently be attached to one or more of R 1 , R 2 , R' 2 , R 3 , R'3, R4, R'4, R5, R'5, Re. R'6 > R7. RV. R ⁇ > R' ⁇ . R ⁇ > R'91 and R-io! and
  • n can be an integer from 0 to 3.
  • the pentaaza-macrocyclic ligand complex can be represented by the following formula:
  • a nitrogen of the macrocycle and two adjacent carbon atoms to which the nitrogen can be attached can independently form a substituted or unsubstituted, saturated, partially saturated or unsaturated nitrogen-containing heterocycle W which can have 2 to 20 carbon atoms, which may be an aromatic heterocycle in which case the hydrogen attached to the nitrogen which can be both part of the heterocycle and the macrocycle and the R groups attached to the carbon atoms which can be both part of the heterocycle and the macrocycle can be absent; and
  • two sets of two adjacent carbon atoms of the macrocycle can independently form substituted or unsubstituted, saturated, partially saturated or unsaturated, cycles or heterocycles U and V having 3 to 20 carbon atoms;
  • R 1 , R 2 , R 2, R 3 , R4, R 5 , R's, R 6 , R' ⁇ , R?, Rs, Rg, Rg, and R 10 can independently be:
  • (iii b ) a moiety independently including alkenyl, alkenylcycloalkenyl, alkenylcycloalkyl, alkyl, alkylcycloalkenyl, alkylcycloalkyl, alkynyl, aralkyl, aryl, cycloalkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylcycloalkyl, cycloalkenylalkyl, or heterocyclyl; or
  • (iii c ) a moiety independently including -OR 11 , -NR 11 Ri 2 , -CORi 1 , -CO 2 R 1I , -CONR 11 R 12 , -SR 11 , -SORn, -SO 2 Rn, -SO 2 NRnR 12 , -N(OR 11 )(R 12 ), -P(O)(OR 11 )(OR 12 ), -P(O)(ORi 1 )(R 12 ), -OP(O)(OR 11 )(ORi 2 ), or substituents attached to the ⁇ -carbon of ⁇ -amino acids, wherein Rn and R 12 can independently include hydrogen or alkyl; and
  • R 1 and R 2 or R 2 , R 5 or R' 5 and R 6 or R' 6 , R 9 or R'g and Ri 0 together with the carbon atoms to which they attached can independently form a substituted or unsubstituted and saturated, partially saturated, or unsaturated cycle or heterocycle having 3 to 20 carbon atoms;
  • R 6 and R 6 , and R 9 and R'g, together with the carbon atom to which they can be attached can independently form a substituted or unsubstituted and saturated, partially saturated, or unsaturated cycle or heterocycle having 3 to 20 carbon atoms;
  • R 2 or R' 2 and R 3 , R 4 and R 5 or R' 5 , R 6 or R' 6 and R 7 , or R 8 and R 9 or R' 9 together with the carbon atoms to which they can be attached can independently form a substituted or unsubstituted nitrogen containing heterocycle having 3 to 20 carbon atoms, which may be an aromatic heterocycle in which case the hydrogen attached to the nitrogen which can be both part of the heterocycle and the macrocycle and the R groups attached to the carbon atoms which can be both part of the heterocycle and the macrocycle can be absent; and
  • I 1 J 1 K and L independently can be integers from 0 to 10 and Q 1 R and T can be optionally substituted moieties independently including alkenyl, alkenylcycloalkenyl, alkenylcycloalkyl, alkyl, alkylcycloalkenyl, alkylcycloalkyl, alkynyl, aralkyl, aryl, cycloalkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylcycloalkyl, cycloalkenylalkyl, and heterocyclyl, aza, amide, ammonium, oxa, thia, sulfonyl, sulfinyl, sulfonamide, phosphoryl, phosphinyl, phosphino, phosphonium, keto, ester, alcohol, carbamate, urea, thiocarbonyl, borates, boranes, boraza
  • R 1 , R 2 , R 2 , R 3 , R 4 , R 5 , R 5 , Re, R'e, R 7 , Rs, R 9 , R'g, and R 1O can be individually bound to an atom of heterocycles U, V and W to form a strap represented by the formula:
  • I 1 J 1 K and L independently can be integers from 0 to 10 and Q 1 R and T can be optionally substituted moieties independently including alkenyl, alkenylcycloalkenyl, alkenylcycloalkyl, alkyl, alkylcycloalkenyl, alkylcycloalkyl, alkynyl, aralkyl, aryl, cycloalkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylcycloalkyl, cycloalkenylalkyl, and heterocyclyl, aza, amide, ammonium, oxa, thia, sulfonyl, sulfinyl, sulfonamide, phosphoryl, phosphinyl, phosphino, phosphonium, keto, ester, alcohol, carbamate, urea, thiocarbonyl, borates, boranes, boraza
  • M can be a transition metal
  • X, Y and Z can independently include halide, oxo, aquo, hydroxo, alcohol, phenol, dioxygen, peroxo, hydroperoxo, alkylperoxo, arylperoxo, ammonia, alkylamino, arylamino, heterocycloalkyl amino, heterocycloaryl amino, amine oxides, hydrazine, alkyl hydrazine, aryl hydrazine, nitric oxide, cyanide, cyanate, thiocyanate, isocyanate, isothiocyanate, alkyl nitrile, aryl nitrile, alkyl isonitrile, aryl isonitrile, nitrate, nitrite, azido, alkyl sulfonic acid, aryl sulfonic acid, alkyl sulfoxide, aryl sulfoxide, alkyl aryl sulfoxide, alkyl aryl
  • X, Y and Z can independently include charge-neutralizing anions which can be derived from any monodentate or polydentate coordinating ligand and a ligand system and the corresponding anion thereof; or
  • X, Y and Z can independently be attached to one or more of Ri, R 2 , R 2 , R 3 , R4, R5, R'5, Re, R' ⁇ i R71 Re. R91 R' ⁇ i and R10! and
  • n can be an integer from 0 to 3.
  • the pentaaza-macrocyclic ligand complex can be represented by the following formulas:
  • W of the pentaaza-macrocyclic ligand complex can be a substituted pyridino moiety.
  • the superoxide dismutase mimetic can be a porphyrin ligand complex or a substituted porphyrin ligand complex.
  • the porphyrin ligand complex can be selected from the group consisting of a manganese (II) porphyrin complex, manganese(lll) porphyrin complex, iron (II) porphyrin complex, and an iron(lll) porphyrin complex.
  • the porphyrin ligand complex can be a 5,10,15, 20-tetrakis (2,4,6- trimethyl-3,5-disulfonatophenyl)-porphyrinato iron (III) (FeTMPS) complex.
  • the peroxynitrite decomposition catalyst can be represented by a formula selected from the group of formulas consisting of: [0268] Structure
  • R 3 , R 6 , Rg or R 12 can independently include H, alkyl, alkenyl, CH 2 , COOH, phenyl, pyridinyl, or N-alkylpyridyl such that phenyl, pyridinyl and N-alkylpyridyl can be:
  • phenyl can optionally be substituted by halogen, alkyl, aryl, benzyl, COOH, CONH 2 , SO 3 H, NO 2 , NH 2 , N(R) 3+ or NHCOR' wherein R can include hydrogen, alkyl, aryl and alkaryl and R 1 can be alkyl, and
  • pyridinyl can optionally be substituted by halogen, alkyl, aryl, benzyl, COOH, CONH 2 , SO 3 H, NO 2 , NH 2 , N(R) 3+ or NHCOR' wherein R and R' can be as defined above, and
  • N-alkylpyridyl can optionally be substituted by halogen, alkyl, aryl, benzyl, COOH, CONH 2 , SO 3 H, NO 2 , NH 2 , N(R) 3+ or NHCOR' wherein R and R' can be as defined above; and
  • Ri, R 2 , R4, R 5 , R 7 , Rs, Rio > or R 11 can independently include H, alkyl, alkenyl, carboxyalkyl, Cl, Br, F, NO 2 , hydroxyalkyl, or SO 3 H, and further wherein R 1 R 2 can be taken together to form a ring of from 5 to 8 carbons, and
  • X and Y can be ligands or charge-neutralizing anions which can be derived from any monodentate or polydentate coordinating ligand or ligand system or the corresponding anion thereof and can be independently selected from the group consisting of halide, oxo, aquo, hydroxo, alcohol, phenol, dioxygen, peroxo, hydroperoxo, alkylperoxo, arylperoxo, ammonia, alkylamino, arylamino, heterocycloalkyl amino, heterocycloaryl, amino, amine oxides, hydrazine, alkyl hydrazine, aryl hydrazine, nitric oxide, cyanide, cyanate, thiocyanate, isocyanate, isothiocyanate, alkyl nitrile, aryl nitrile, alkyl isonitrile, aryl isonitrile, nitrate, nitrite, azido, alkyl n
  • M can be selected from the group consisting of Mn, Fe, Ni and V;
  • n can be an integer from 1 to 3;
  • R' can be CH or N
  • Ri5i and R-i ⁇ can independently include H 1 SO 3 H, COOH, NO 2 , NH 2 , and N-alkylamino; and
  • X, Y, Z, M and n can be as defined above; [0282] Structure III
  • R 1 , R 5 , R 9 , and R 13 can independently include a direct bond and
  • R16. and R 16 1 can independently include H and alkyl;
  • R 3 , R 7 , R-n, Ri 5 can independently include H and alkyl; and [0286] X, Y, Z, M and n can be as defined above;
  • R 1 , R 5 , R 8 , and Ri 2 can independently include a direct bond and
  • R 2 , R 2 1 , R 4 , R 4 ', Re, R 6 ', R 7 , R 9 , R 9 ', Rn, Rn', R13, Ru 1 , and R 14 can independently include H and alkyl;
  • R 3 and R 10 can independently include H and alkyl; and [0290] X, Y, Z, M and n can be as defined above;
  • R 1 , R 4 , R 8 , R 12 can independently include direct bond and CH 2 ;
  • R13 1 and R 14 can independently include H and alkyl;
  • R-io can be H or alkyl
  • X, Y, Z, M and n can be as defined above;
  • R 1 , R 4 , R 7 and R 10 can independently include direct bond and CH 2 ;
  • R 2 , R 2 ', R 3 , R 5 , Rs , Re, Rs, Rs', Rg, Rii, Rn' and Ri 2 can independently include H and alkyl;
  • X, Y, Z, M and n can be as defined above;
  • Ri, R 4 , Rs and R 11 can independently include a direct bond and
  • R 2 , R 3 , R 3 1 , R 5 , Rs 1 , R?. R?', Rg, Rio, R-io', R12, R12' and R 13 can independently include H and alkyl;
  • R 6 can be hydrogen or alkyl
  • X, Y, Z, M and n can be as defined above;
  • R 1 , R 4 , R 7 and R 10 can independently include H and alkyl; [0303] R 2 , R 3 , Ra', Rs, R 5 ', Re, Re, Rg, FV. RH , RH 1 and R 12 can independently include H and alkyl; and
  • X, Y, Z, M and n can be as defined above;
  • R 1 , R 3 , R 4 and R 6 can independently include H and alkyl;
  • R 2 and R 5 can independently include H, alkyl, SO 3 H, NO 2 , NH 2 , halogen, COOH and N(R) 3+ wherein R can be as defined above; and
  • X, Y, Z, M and n can be as defined above;
  • R 1 , R 2 , R 3 , R 4 can independently include H, alkyl, SO 3 H, NO 2 , NH 2 , halogen, COOH and N(R) 3+ wherein R can be as defined above; and [0309] X, Y, Z, M and n can be as defined above; and [0310] Structure IV
  • R 1 , R 1 ", R 2 , R 2 ', R 3 , R 3 ', R 4 , R4', Rs, R5', Re, Re 1 , R7 and R 7 ' can independently include H, alkyl, alkoxy, NO 2 , aryl, halogen, NH 2 and SO 3 H, wherein R 6 , Re', R 7 and R 7 ' may each be taken together with one other of R 6 , R 6 ', R 7 and R 7 ' to form a cyclic group, preferably a 6 carbon cycloalkyl group;
  • M 1 can be selected from the group consisting of Fe, Ni or V;
  • X, Y, Z and n can be as defined above.
  • Contemplated equivalents of the general formulas set forth above for the compounds and derivatives as well as the intermediates are compounds otherwise corresponding thereto and having the same general properties such as tautomers of the compounds and such as wherein one or more of the various R groups are simple variations of the substituents as defined therein, e.g., wherein R is a higher alkyl group than that indicated, or where the tosyl groups are other nitrogen or oxygen protecting groups or wherein the O-tosyl is a halide.
  • Anions having a charge other than 1 e.g., carbonate, phosphate, and hydrogen phosphate, can be used instead of anions having a charge of 1 , so long as they do not adversely affect the overall activity of the complex.
  • a substituent is designated as, or can be, a hydrogen
  • the exact chemical nature of a substituent which is other than hydrogen at that position e.g., a hydrocarbyl radical or a halogen, hydroxy, amino and the like functional group, is not critical so long as it does not adversely affect the overall activity and/or synthesis procedure.
  • manganese(lll) complexes will be equivalent to the subject manganese(ll) complexes.
  • the compounds of the invention can be formulated as pharmaceutical or veterinary compositions. Depending on the subject to be treated, the mode of administration, and the type of treatment desired (e.g., inhibition, prevention, prophylaxis, therapy), the compounds can be formulated in ways consonant with these parameters.
  • the compounds of the present invention can comprise a therapeutically or prophylactically effective dosage of a catalyst.
  • the catalyst can be used in combination with a pharmaceutically acceptable carrier, either in the same formulation or in separate formulations.
  • the catalysts of the present invention can be incorporated in conventional pharmaceutical formulations (e.g., injectable solutions) for use in treating humans or animals in need thereof.
  • Pharmaceutical compositions can be administered by subcutaneous, intravenous, or intramuscular injection, or as large volume parenteral solutions and the like.
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrastemal injection, or infusion techniques.
  • a parenteral therapeutic composition may comprise a sterile isotonic saline solution containing between 0.1 percent and 90 percent weight to volume of the catalysts for the dismutation of superoxide.
  • a preferred solution contains from about 5 percent to about 25 weight percent catalysts for dismutation of superoxide in solution (% weight per volume).
  • the dosage of catalyst to be used may vary. A primary consideration for the dosage level of the catalysts is the monitoring of the known side effects in an individual.
  • Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1 ,3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • the preparations may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the catalyst for the dismutation of superoxide.
  • the pack may for example comprise metal or plastic foil, such as a blister pack.
  • the pack or dispenser device may be accompanied by instructions for administration.
  • the amount of catalyst that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. It will be appreciated that the unit content of active ingredients contained in an individual dose of each dosage form need not in itself constitute an effective amount, as the necessary effective amount could be reached by administration of a number of individual doses. The selection of dosage depends upon the dosage form utilized, the condition being treated, and the particular purpose to be achieved according to the determination of those skilled in the art.
  • the dosage regimen for treating a disease condition with the compounds and/or compositions of this invention is selected in accordance with a variety of factors, including the type, age, weight, sex, diet and medical condition of the patient, the route of administration, pharmacological considerations such as the activity, efficacy, pharmacokinetic and toxicology profiles of the particular compound employed, whether a drug delivery system is utilized and whether the compound is administered as part of a drug combination.
  • the dosage regimen actually employed may vary widely and therefore may deviate from the preferred dosage regimen set forth above.
  • the treatment comprises administering to a mammal in need of such treatment an amount of 10 mg/kg or less of a non-proteinaceous catalyst for the dismutation of superoxide anions, or a pharmaceutically acceptable salt, hydrate, solvate, or pro-drug thereof.
  • the amount of a non-proteinaceous catalyst for the dismutation of superoxide anions, or a pharmaceutically acceptable salt, hydrate, solvate, or pro-drug thereof can be between about 0.1 ⁇ g and about 10.0 mg; between about 1.0 ⁇ g and about 1.0 mg; between about 5.0 ⁇ g and about 15.0 ⁇ g; or between about 100.0 ⁇ g and about 300.0 ⁇ g.
  • compositions of the present invention are preferably administered to a human.
  • these extracts are also useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, avians, and the like.
  • alterations in substrate preference in the failing heart with decreased free fatty acid uptake and increased glucose utilization, could contribute to decreased oxygen utilization (Davila- Roman et al., J. Am. Coll. Cardiol.40, 271-277 (2002».
  • NO can modulate mitochondrial respiration and ATP production through reversible binding to the oxygen-binding site of cytochrome oxidase (Borutaite et al., Biochim Biophys Acta 1459, 405-412 (2000)).
  • Blockade of NO production with nonselective NOS inhibitors increased MVO 2 in normal animals at rest and during treadmill exercise (Bernstein et al., Circ. Res. 79, 840-848 (1996); Altman et al., Cardiovasc. Res. 28, 119-124 (1994); Chen et al., Circulation 106, 273-279 (2002)).
  • stimulating endogenous endothelial NO production with bradykinin or administering an NO donor decreased oxygen consumption in isolated crystalloid perfused rat hearts (Poderoso et al., Am J Physiol 274, C112-119 (1998)) and in myocardial tissue slices from normal and failing hearts (Xie et al., Circ Res 79, 381-387 (1996); Xie et al., Circulation 94, 2580-2586 (1996)).
  • Heart failure of several etiologies is associated with increased myocardial free radical formation and increased products of oxygen free radical reactions (such as lipid peroxides) (Ide et al., Circ Res 85, 357-363 (1999); lde et al., Circ Res 8, 152-157 (2000); Dhalla 1996; Hill et al., Circulation 96, 2414-2420 (1997)).
  • oxygen free radical reactions such as lipid peroxides
  • pyrogallol which generates O 2 " through autoxidation, caused respiratory inhibition that was only partially reversible after washout of the pyrogallol (Xie et al., Circ Res 79, 381-387 (1996); Xie et al., Circulation 94, 2580-2586 (1996)).
  • the effect of pyrogallol was inhibited by the O 2 " scavenger tiron, but not the ONOO ' scavenger urate, indicating that O 2 " can directly inhibit respiration without conversion to ONOO ' .
  • Endothelial Dysfunction and Vascular O 2 " in CHF [0336] Endothelial Dysfunction and Vascular O 2 " in CHF [0337] Endothelium-derived NO is an important contributor to acetylcholine- induced vasodilation (Altman et al., Cardiovasc Res 28, 119-124 (1994)>and therefore decreased NO bioavailability could be responsible, at least in part, for the impaired acetylcholine response in heart failure. A decrease of NO bioavailability could result either from decreased production or increased inactivation of NO.
  • Three SOD isozymes have identified in the heart, including CuZn-SOD, which is primarily cytosolic in location, mitochondrial Mn-SOD, and extracellular EC-SOD (Oury, Lab Invest 75, 617-636 (1996); Fukai et al., Cardiovasc Res 55, 239-249 (2002)). Up to one half of the total SOD in vessels is EC-SOD, and EC-SOD has been implicated as a principal regulator of endothelium-derived NO bioavailability (Oury, Lab Invest 75, 617-636 (1996); Fukai et al., J. Clin. Invest.
  • Example 1 Effect Of Superoxide Dismutase Mimetics In The Normal Heart
  • Example 1 was performed in adult mongrel dogs weighing 20-26 kg trained to run on a treadmill. All experiments were performed in accordance with the Guiding Principles in the Care and Use of Laboratory Animals as approved by the council of the American Physiological Society and with prior approval of the University of Minnesota Animal Care Committee.
  • a final catheter was introduced into the right atrial appendage and advanced through the coronary sinus until the tip could be palpated at the origin of the anterior interventricular vein to allow selective sampling of blood draining the myocardium perfused by the left anterior descending coronary artery (LAD).
  • LAD left anterior descending coronary artery
  • a Doppler velocity probe (Craig Hartley, Houston, TX) was positioned on the LAD for measurement of coronary blood flow (CBF) and a silicone catheter (0.3 mm ID) was introduced into the LAD distal to the velocity probe. Catheters were tunneled to exit at the base of the neck; catheters were flushed daily to maintain patency.
  • Postoperative analgesia was provided with butorphanol, 0.4 ⁇ g/kg S.Q. q 4-6 h.
  • CHF was produced by rapid ventricular pacing (Traverse et al., Circ Res 84, 401-408 (1999)). After completion of studies during normal conditions, the pacemaker was activated at 220 beats/min; pacing was continued at this rate or adjusted upward to a maximum of 250 beats/min based on weekly assessments of hemodynamics obtained 30 minutes after deactivating the pacemaker. CHF was deemed to have developed when resting LVEDP was >20 mmHg or visual estimation of ejection fraction by 2-dimensional echocardiography was ⁇ 30%.
  • LV pressure was measured with the micromanometer; the first derivative of LV pressure (dP/dt) was obtained via electrical differentiation. Coronary blood velocity was measured with a Doppler flowmeter (Craig Hartley, Houston, TX). Data were recorded on an eight-channel recorder.
  • Tissue homogenates of left ventricular myocardium were separated on 12% SDS-PAGE, transferred onto nitrocellulose membrane, followed by routine Western blotting.
  • Antibodies against CuZn-SOD and Mn-SOD were purchased from BD Transduction Laboratories and Santa Cruz Biotech, respectively. The anti-extracellular SOD antibody was produced in our laboratory and has been previously reported (Fukai et al., J Clin Invest 101 , 2101-2111 (1998)). °
  • RNA was reverse-transcribed using random hexamers and Moloney murine leukemia virus (MMLV) reverse transcriptase (Life Technologies).
  • Oligonucleotide primers were designed according the corresponding canine cDNA sequences in the NIH gene bank.
  • the primer sequences of CuZn-SOD were: Sense, 5'- AGTGGGCCTGTTGTGGTATC (SEQ ID NO: 1); and antisense, 5'- AGTCACATTGCCCAGGTCTC (PCR-product of 189 bp) (SEQ ID NO: 2).
  • the primer sequences of GAPDH were: sense, 5'-TGCCCCCATGTTTGTGATG (SEQ ID NO: 3), and antisense, 5'-CCAGCCCCAGCGTCAAAGGTG (product of 519 bp) (SEQ ID NO: 4).
  • mRNA levels were compared by quantitative real-time RT-PCR analysis, using the Light Cycler Thermocycler (Roche Diagnostics Corp). Reactions were prepared in the presence of the fluorescent dye SYBR green I for specific detection of double-stranded DNA. Quantification was performed in the log-linear phase of the reaction and cycle numbers obtained at this point were plotted against a standard curve prepared from serially diluted control samples. Results were normalized to GAPDH expression levels.
  • the SOD mimetic M40401 was studied in seven normal dogs 10-14 days after surgery. Resting hemodynamics were recorded and 2 ml of blood was withdrawn from the aortic and coronary venous catheters for blood gas analysis. Subsequently, a 3-stage treadmill exercise protocol was begun (Stage 1: 3.2 km/hr at 0% grade; stage 2: 6.4 km/hr at 0% grade; stage 3: 6.4 km/hr at 5%). Each exercise stage was three minutes in duration; aortic and coronary venous blood samples were withdrawn during the last 30 seconds of each exercise stage. After a 10 minute rest period, M40401 , 1.5 mg/kg i.v. was infused over 10 minutes. Forty minutes after M40401 all measurements were repeated at rest and during exercise.
  • the SODm M40401 caused increases (p ⁇ 0.05) in coronary blood flow and MVO 2 at rest and during exercise in CHF dogs ( Figures 1 and 2), while the relationship between MVO 2 and CBF was unchanged. M40401 did not increase LV dP/dt ma)( in the failing hearts, possibly because any O 2 *" and peroxynitrite-induced protein modifications of the contractile apparatus would require a longer time period to recover. In the present study, the SOD mimetic M40401 caused significant increases of MVO 2 and coronary blood flow at rest and during exercise in animals with CHF suggesting that O 2 " contributed to the depressed MVO 2 in the failing hearts.
  • Example 3 Effects of SODm and Acetycholine (Ach) in Heart Failure
  • the methods for preparing the animals and collecting and analyzing data were the same as for the previous examples, except where specific differences are described.
  • M40401 caused no change of heart rate or mean aortic pressure.
  • M40401 significantly augmented the increase of coronary flow produced by acetylcholine ( Figure 4), indicating enhanced endothelium-dependent vasodilation.
  • Example 4 Effects of SODm and ACh in The Normal Heart
  • the methods for preparing the animals and collecting and analyzing data were the same as for the previous examples, except where specific differences are described.
  • the effects of M40401 on the vasodilator response to acetylcholine were examined in five normal dogs.
  • the increases in CBF produced by intracoronary acetylcholine (3.75 to 75 ⁇ g/min) were observed under control conditions, after M40401 (1.5 mg/kg intracoronary).
  • the SOD mimetic M40401 had no effect on either resting coronary flow or the increase in flow produced by acetylcholine.
  • Example 5 Effect of ACh Alone in The Normal Heart
  • Coronary blood flow responses to acetylcholine are shown in Figures 3 and 4.
  • lntracoronary infusion of acetylcholine in doses of 3.75 to 75 ⁇ g/min had no effect on heart rate or aortic pressure.
  • coronary flow increased from 60+4.9 ml/min at baseline to 190+8.7 ml/min during the maximum acetylcholine dose (75 ⁇ g/min). In the present example there was an increase of coronary flow in response to acetylcholine.
  • Example 9 Effect of SODms and LNA on Endothelium Dependent Coronary Vasodilation in Normal Dogs
  • Example 10 Effect of SODms and LNA on Endothelium-Dependent Coronary Vasodilation in CHF Dogs
  • M40401 caused no change of heart rate or mean aortic pressure. However, M40401 significantly augmented the increase of coronary flow produced by acetylcholine (Figure 4), indicating enhanced endothelium-dependent vasodilation. As expected, LNA inhibited the increase in coronary flow produced by acetylcholine (p ⁇ 0.01).

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Abstract

L'invention concerne un procédé pour traiter l'insuffisance cardiaque congestive par l'administration d'une quantité thérapeutiquement efficace d'un mimétique de dismutase de superoxyde ou d'un catalyseur de décomposition de la péroxynitrite.
PCT/US2005/034846 2004-09-24 2005-09-26 Procedes pour traiter l'insuffisance cardiaque congestive WO2006037050A2 (fr)

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WO2009027965A1 (fr) * 2007-08-28 2009-03-05 Technion Research And Development Foundation Ltd. Complexes de métaux de transition de corroles permettant de prévenir des troubles ou des maladies cardiovasculaires

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NZ315505A (en) * 1995-08-17 2000-01-28 Monsanto Co Methods of diagnostic image analysis using metal complexes of nitrogen-containing macrocyclic ligands
GB9801398D0 (en) * 1998-01-22 1998-03-18 Anggard Erik E Chemical compounds
DE60024588T2 (de) * 1999-01-25 2006-08-17 National Jewish Medical And Research Center, Denver Substituierte porphyrine und deren therapeutische verwendungen

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009027965A1 (fr) * 2007-08-28 2009-03-05 Technion Research And Development Foundation Ltd. Complexes de métaux de transition de corroles permettant de prévenir des troubles ou des maladies cardiovasculaires
AU2008293376B2 (en) * 2007-08-28 2013-07-11 Technion Research & Development Foundation Ltd. Transition metal complexes of corroles for preventing cardiovascular diseases or disorders
US8791099B2 (en) 2007-08-28 2014-07-29 Technion Research And Development Foundation Ltd. Transition metal complexes of corroles for preventing cardiovascular diseases or disorders

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