WO1997033877A1 - Bioconjugues de complexes de manganese ou de fer de ligands macrocycliques contenant de l'azote, efficaces comme catalyseurs pour la dismutation du superoxyde - Google Patents

Bioconjugues de complexes de manganese ou de fer de ligands macrocycliques contenant de l'azote, efficaces comme catalyseurs pour la dismutation du superoxyde Download PDF

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WO1997033877A1
WO1997033877A1 PCT/US1997/002566 US9702566W WO9733877A1 WO 1997033877 A1 WO1997033877 A1 WO 1997033877A1 US 9702566 W US9702566 W US 9702566W WO 9733877 A1 WO9733877 A1 WO 9733877A1
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alkyl
aryl
groups
attached
acid
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PCT/US1997/002566
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English (en)
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William L. Neumann
Dennis P. Riley
Randy H. Weiss
Susan L. Henke
Patrick J. Lennon
Karl W. Aston
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Monsanto Company
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Priority claimed from PCT/US1996/012767 external-priority patent/WO1997006824A2/fr
Application filed by Monsanto Company filed Critical Monsanto Company
Priority to BR9708179A priority Critical patent/BR9708179A/pt
Priority to JP9532611A priority patent/JP2000508625A/ja
Priority to AU19624/97A priority patent/AU1962497A/en
Priority to IL12588997A priority patent/IL125889A0/xx
Priority to EP97907685A priority patent/EP0891338A1/fr
Publication of WO1997033877A1 publication Critical patent/WO1997033877A1/fr
Priority to NO984164A priority patent/NO984164L/no

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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
    • C07F13/00—Compounds containing elements of Groups 7 or 17 of the Periodic System
    • C07F13/005—Compounds without a metal-carbon linkage
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D259/00—Heterocyclic compounds containing rings having more than four nitrogen atoms as the only ring hetero atoms
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic System
    • C07F15/02—Iron compounds
    • C07F15/025—Iron compounds without a metal-carbon linkage

Definitions

  • This present invention relates to compounds effective as catalysts for dismutating superoxide.
  • This invention relates to manganese or iron complexes of nitrogen-containing fifteen-membered macrocyclic ligands which catalytically dismutate superoxide.
  • this invention relates to manganese or iron complexes of nitrogen-containing fifteen-membered macrocyclic ligands which are conjugated to a targeting biomolecule.
  • the enzyme superoxide dismutase catalyzes the conversion of superoxide into oxygen and hydrogen peroxide according to equation (1) (hereinafter referred to as dis utation) .
  • Reactive oxygen metabolites derived from superoxide are postulated to contribute to the tissue pathology in a number of
  • inflammatory diseases and disorders such as reperfusion injury to the ischemic myocardium, inflammatory bowel disease, rheumatoid arthritis, osteoarthritis, atherosclerosis, hypertension, metastasis, psoriasis, organ transplant rejections, radiation-induced injury, asthma, influenza, stroke, burns and trauma.
  • reperfusion injury to the ischemic myocardium, inflammatory bowel disease, rheumatoid arthritis, osteoarthritis, atherosclerosis, hypertension, metastasis, psoriasis, organ transplant rejections, radiation-induced injury, asthma, influenza, stroke, burns and trauma.
  • Reactive oxygen metabolites and reperfusion injury aberrant triggering of reticuloendothelial function, The Lancet , Vol. 34 4 , pp. 934-36, October l, 1994; Grisham, M.B.
  • the macrocycles or manganese or iron complexes of the present invention can be attached, i.e. conjugated, to one or more targeting biomolecule(s) via a linker group to form a targeting bioraolecule-macrocycle or targeting bio olecule- manganese complex conjugate.
  • MRI magnetic resonance imaging
  • bioconjugates of manganese or iron complexes of nitrogen-containing fifteen-membered macrocyclic ligands that can be targeted to a specific site in the body.
  • bioconjugates of manganese or iron complexes of nitrogen-containing fifteen-membered macrocyclic ligands are provided wherein (1) one to five of the "R" groups are attached to biomolecules via a linker group, (2) one of X, Y and Z is attached to a biomolecule via a linker group, or (3) one to five of the "R” groups and one of X, Y and Z are attached to biomolecules via a linker group; and biomolecules are independently selected from the group consisting of steroids, carbohydrates, fatty acids, amino acids, peptides, proteins, antibodies, vitamins, lipids, phospholipids, phosphates, phosphonates, nucleic acids, enzyme substrates, enzyme inhibitors and enzyme receptor substrates and the linker group is derived from
  • the present invention is directed to bioconjugates of manganese or iron complexes of nitrogen-containing fifteen-membered macrocyclic ligands which catalyze the conversion of superoxide into oxygen and hydrogen peroxide.
  • These complexes can be represented by the formula:
  • R, R', R,, R,', R 2 , R 2 ', R 3 , R 3 ', R 4 , R 4 ', R $ , R 5 ', R 6 , R 6 ', R 7 , R 7 ', R 8 , R 8 ', R, and R,' independently represents hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylcycloalkyl, cycloalkenylalkyl, alkylcycloalkyl, alkenylcycloalkyl, alkylcycloalkenyl, alkenylcycloalkenyl, alkenylcycloalkenyl, heterocyclic, aryl and aralkyl radicals and radicals attached to the ⁇ -carbon of ⁇ -amino acids; or R, or R'i and R 2 or R' 2 , R 3 or R'
  • X, Y and Z represent suitable ligands or charge- neutralizing anions which are derived from any monodentate or polydentate coordinating ligand or ligand system or the corresponding anion thereof (for example benzoic acid or benzoate anion, phenol or phenoxide anion, alcohol or alkoxide anion) .
  • X, Y and Z are 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 sulfonic acid, aryl sulfonic acid, alkyl sulfoxide, aryl sulfoxide, alkyl aryl sulfoxide, al
  • linker groups are derived from the specified functional groups attached to the "R” groups or X, Y and Z, and function to link the biomolecule to the "R” groups or X, Y and Z.
  • the functional groups are selected from the group consisting of -NH 2 , -NHR 10 , -SH, -OH, -COOH, -COOR 10/ -CONH 2 , -NCO, -NCS, -COOX", alkenyl, alkynyl, halide, tosylate, mesylate, tresylate, triflate and phenol wherein R 10 is alkyl, aryl, or alkaryl and X" is a halide.
  • the preferred alkenyl group is ethenyl and the preferred alkynyl group is ethynyl.
  • the functional groups on the "R" groups or X, Y and Z are reactive with the biomolecule, i.e. reactive with a functional group on the steroids, carbohydrates, fatty acids, amino acids, peptides, proteins, antibodies, vitamins, lipids, phospholipids, phosphates, phosphonates, nucleic acids, enzyme substrates, enzyme inhibitors, enzyme receptor substrates and other targeting biomolecules of interest.
  • the functional group attached to the "R" groups or X, Y and Z reacts with the biomolecule, the functional group is modified and it is this derived functional group which is the linker.
  • linker when an -NH 2 functional group attached to an "R" group is reacted with a steroid such as in Example l, the linker is -NH-.
  • the exact structure of specific linker groups will be readily apparent to those of ordinary skill in the art and will depend on the specific functional group and biomolecule selected.
  • the specific reaction conditions for reacting a functional group attached to "R" groups or X, Y and Z with a biomolecule will be readily apparent to those of ordinary skill in the art.
  • the functional group useful to form the linker defined herein as a "linker precursor" may be present on the "R" groups at the time the macrocycle is prepared or it may be added or modified after preparation of the macrocycle or manganese complex thereof.
  • the linker precursor can be present on an axial ligand, i.e. X, Y or Z, when the manganese or iron complex is prepared or an exchange reaction of the axial ligands is conducted to exchange the axial ligands present in the manganese or iron complex.
  • the macrocycle of the present invention can be complexed with manganese or iron either before or after conjugation with the targeting biomolecule depending on the specific biomolecule utilized.
  • the conjugate of the macrocyclic complex and the targeting biomolecule is defined herein as a "bioconjugate".
  • Targeting of drugs is well known to those of ordinary skill in the art. See, for example, J. A. Katzenellenbogen et al, Journal of Nuclear Medicine , Vol. 33, No. 4, 1992, 558, and J.A. Katzenellenbogen et al, Bioconjugate Chemistry, 1991, 2, 353.
  • Targeting agents are typically biomolecules.
  • the biomolecules of the invention are biologically active molecules that are site specific, i.e. known to concentrate in the particular organ or tissue of interest.
  • the biomolecules are selected to direct the tissue distribution of the bioconjugate via receptor binding, membrane association, membrane solubility, and the like.
  • These biomolecules include, for example, steroids, carbohydrates (including monosaccharides, disaccharides and polysaccharides) , fatty acids, amino acids, peptides, proteins, antibodies (including polyclonal and monoclonal and fragments thereof) , vitamins, lipids, phospholipids, phosphates, phosphonates, nucleic acids, enzyme substrates, enzyme inhibitors and enzyme receptor substrates.
  • the biomolecules also include those biomolecules which are combinations of the above biomolecules, such as a combination of a steroid with a carbohydrate, e.g. digitonin.
  • biomolecules which can be utilized to target a desired organ or tissue are known in the art or it will be readily apparent to those of ordinary skill in the art.
  • the biomolecules of the invention are commercially available or can readily be prepared by one of ordinary skill in the art using conventional methods. It is currently preferred that a maximum of one "R" group attached to the carbon atoms located between nitrogen atoms in the macrocycle has a biomolecule attached via a linker.
  • the preferred compounds are those which have one to five, most preferably one to two, of the "R" groups attached to biomolecules and none of X, Y and Z attached to a biomolecule, or those which have one of X, Y and Z attached to a biomolecule and none of the "R” groups attached to a biomolecule.
  • the preferred compounds are those wherein at least one, more preferably at least two, of the "R" groups, in addition to the "R" groups which are attached to a biomolecule, represent alkyl, cycloalkyl alkyl and aralkyl radicals and the remaining "R” groups not attached to a biomolecule represent hydrogen, a saturated, partially saturated or unsaturated cyclic or a nitrogen containing heterocycle.
  • R, or R', 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 and R 9 or R' 9 and R or R' together with the carbon atoms to which they are attached represent a saturated, partially saturated or unsaturated cyclic having 3 to 20 carbon atoms and the remaining "R" groups in addition to the "R" groups which are attached to a biomolecule via a linker are hydrogen, nitrogen containing heterocycles or alkyl groups, and those wherein at least one, preferably two, of R or R' and R y or R' 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 , and R 8 or R' g and R 9 or R' 9 together with the carbon
  • R groups means all of the R groups attached to the carbon atoms of the macrocycle, i.e., R, R , R ⁇ , R ⁇ » 2 / 2 / ⁇ 3 R 3 R 4 , R' 4 / R5 R's/ ⁇ 6/
  • Another embodiment of the invention is a pharmaceutical composition in unit dosage form useful for dismutating superoxide comprising (a) a therapeutically or prophylactically effective amount of a complex as described above and (b) a nontoxic, pharmaceutically acceptable carrier, adjuvant or vehicle.
  • the complexes derived from Mn(II) and the general class of C-substituted [15]aneN 5 ligands described herein have been characterized using cyclic voltammetry to measure their redox potential.
  • the manganese-based C-substituted complexes described herein have reversible oxidations of about +0.7 v (SHE). Coulometry shows that this oxidation is a one-electron process; namely it is the oxidation of the Mn(II) complex to the Mn(III) complex.
  • SOD catalysts the Mn(III) oxidation state is involved in the catalytic cycle.
  • Mn(III) complexes of all these ligands are equally competent as SOD catalysts, since it does not matter which form (Mn(II) or Mn(III)) is present when superoxide is present because superoxide will simply reduce Mn(III) to Mn(II) liberating oxygen.
  • the iron-based complexes of the invention are particularly useful due to the unexpectedly enhanced stability of the iron-based complexes compared to the corresponding manganese-based complexes. This enhanced stability could be important in oral administration and where targeted tissue has very low pH, e.g. ischemic tissue.
  • 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 which optionally carries one or more substituents selected from (1) -NR 30 R 3] wherein R 30 and R 31 are independently selected from hydrogen, alkyl, aryl or aralkyl; or R 30 is hydrogen, alkyl, aryl or aralkyl and R 31 is selected from the group consisting of -NR 32 R 33 , -OH, -OR 34 ,
  • R 32 and R 33 are independently hydrogen, alkyl, aryl or acyl, R 34 is alkyl, aryl or alkaryl, Z is hydrogen, alkyl, aryl, alkaryl, -OR 34 , -SR 34 or -NR 40 R 41 wherein R 40 and R 41 are independently selected from hydrogen, alkyl, aryl or alkaryl, Z is alkyl, aryl, alkaryl, -OR 34 , -SR 34 or -NR 40 R 41 , R 35 is alkyl, aryl, -OR 34 , or -NR 40 R 41 , R 36 is alkyl, aryl or -NR 40 R 41 R 37 is alkyl, aryl or alkaryl, X is oxygen or sulfur, and R 38 and R 39 are independently selected from hydrogen, alkyl or aryl; (2) -SR 42 wherein R 42 is hydrogen, alkyl, aryl, alkaryl, —SR 3 , —NR 32 R 33 ,
  • R 43 is -OH , -OR 34 or -NR 32 R 33
  • a and B are independently -OR 34 , -SR 34 or -NR 32 R 33 .
  • R 44 is halide, alkyl, aryl, alkaryl, -OH, -OR 34 , -SR 34 or -NR 32 R 33 ;
  • R 45 is hydrogen, alkyl, aryl, alkaryl,
  • R 46 is halide, -OH, -SH, -OR 34 , -SR 34 or -NR 32 R 33 ; or (6) amine oxides of the formula
  • R 30 and R 31 are not hydrogen;
  • F and G are independently -OH, -SH, -OR 34 , -SR 34 or -NR 32 R 33 ; or (8) -0-(-(CH 2 ) a -O) b -R 10 wherein R 10 is hydrogen or alkyl, and a and b an integers independently selected from 1 + 6; or
  • Alkyl, aryl and alkaryl groups on the substituents of the above-defined alkyl groups may contain one additional substituent but are preferably unsubstituted.
  • examples of such radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert- butyl, pentyl, isoamyl, 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, trans- 2-butenyl, iso-butylenyl, cis-2-pentenyl, trans-2- pentenyl, 3-methyl-l-butenyl, 2,3-dimethyl-2-butenyl, 1-pentenyl, 1-hexenyl, 1-octenyl, decenyl, dodecenyl, tetradecenyl, hexadecenyl, cis- and trans- 9-octadecenyl, 1,3-pentadienyl, 2,4-pentadienyl, 2,3-pentadienyl, 1,3-hexadienyl, 2,4-hexadienyl
  • alkynyl alone or in combination, means an alkyl radical having one or more triple bonds.
  • alkynyl groups include, but are not limited to, ethynyl, propynyl (propargyl) , 1-butynyl, 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-isopropylcyclohexyl)methyl, (4-t-buty1-cyclohexy1)methyl,
  • 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.
  • 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,
  • 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, l-methylcyclopentyl, 1-hexylcyclopenty1, 1-methylcyclohexyl, l-(9-octadecenyl)cyclopentyl and l-(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, l-methyl-2-cyclopentenyl,
  • 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 other kind of atom, in addition to carbon, in the ring. The most common of the other kinds of atoms include nitrogen, oxygen and sulfur.
  • 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 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 or bromide.
  • the macrocyclic ligands useful in the complexes of the present invention can be prepared according to the general procedure shown in Scheme A set forth below.
  • an amino acid amide which is the corresponding amide derivative of a naturally or non-naturally occurring ⁇ -amino acid, is reduced to form the corresponding substituted ethylenediamine.
  • Such amino acid amide can be the amide derivative of any one of many well known amino acids.
  • Preferred amino acid amides are those represented by the formula:
  • R is derived from the D or L forms of the amino acids Alanine, Aspartic acid, Arginine, Asparagine, Cysteine, Glycine, Glutamic acid, Glutamine, Histidine, Isoleucine, Leucine, Lysine, Methionine, Proline, Phenylalanine, Serine, Tryptophan, Threonine, Tyrosine, Valine and/or the R groups of unnatural ⁇ -amino acids such as alkyl, ethyl, butyl, tert-butyl, cycloalkyl, phenyl, alkenyl, allyl, alkynyl, aryl, heteroaryl, polycycloalkyl, polycycloaryl, polycycloheteroaryl, imines, aminoalkyl, hydroxyalkyl, hydroxyl, phenol, amine oxides, thioalkyl, carboalkoxyalkyl, carboxylic acids and their derivatives, keto, ether
  • R represents hydrogen, alkyl, cycloalkylalkyl, and aralkyl radicals.
  • the diamine is then tosylated to produce the di-N-tosyl derivative which is reacted with a di-O-tosylated tris-N-tosylated triazaalkane diol to produce the corresponding substituted
  • N-pentatosylpentaazacycloalkane N-pentatosylpentaazacycloalkane.
  • the tosyl groups are then removed and the resulting compound is reacted with a manganese(II) or iron (III) compound under essentially anhydrous and anaerobic conditions to form the corresponding substituted manganese(II) or iron (III) pentaazacycloalkane complex.
  • the ligands or charge- neutralizing anions i.e. X, Y and Z
  • the complex with those anions or ligands can be formed by conducting an exchange reaction with a complex that has been prepared by reacting the macrocycle with a manganese or iron compound.
  • the complexes of the present invention wherein R 9 , and R 2 are alkyl, and R 3 , R' 3 , R , R' 4 , R 5 , R' s , R 4 , * , R 7 , R' 7 , R 8 and R' 8 can be alkyl, arylalkyl or cycloalkylalkyl and R or R' and R, or R' ⁇ together with the carbon atoms they are attached to are bound to form a nitrogen containing heterocycle, can also be prepared according to the general procedure shown in Scheme B set forth below utilizing methods known in the art for preparing the manganese(II) or iron (III) pentaazabicyclo[12.3.1]octadecapentaene complex precursor. See, for example, Alexander et al., Inorg. Nucl. Chem. Lett., 6, 445 (1970). Thus a
  • 2,6-diketopyridine is condensed with triethylene tetraamine in the presence of a manganese(II) or iron (III) compound to produce the manganese(II) or iron (III) pentaazabicyclo[12.3.1]octadecapentaene complex.
  • the manganese(II) or iron (III) pentaazabicyclo[12.3.1]octadecapentaene complex is hydrogenated with platinum oxide at a pressure of 10-1000 psi to give the corresponding manganese(II) or iron (III) pentaazabicyclo[12.3.1]octadecatriene complex.
  • the macrocyclic ligands useful in the complexes of the present invention can also be prepared by the diacid dichloride route shown in Scheme C set forth below.
  • a triazaalkane is tosylated in a suitable solvent system to produce the corresponding tris (N-tosyl) derivative.
  • Such a derivative is treated with a suitable base to produce the corresponding disulfona ide anion.
  • the disulfonamide anion is dialkylated with a suitable electrophile to produce a derivative of a dicarboxylic acid.
  • This derivative of a dicarboxylic acid is treated to produce the dicarboxylic acid, which is then treated with a suitable reagent to form the diacid dichloride.
  • the desired vicinal diamine is obtained in any of several ways.
  • One way which is useful is the preparation from an aldehyde by reaction with cyanide in the presence of ammonium chloride followed by treatment with acid to produce the alpha am onium nitrile.
  • the latter compound is reduced in the presence of acid and then treated with a suitable base to produce the vicinal diamine.
  • Condensation of the diacid dichloride with the vicinal diamine in the presence of a suitable base forms the tris(tosyl)diamide macrocycle.
  • the tosyl groups are removed and the amides are reduced and the resulting compound is reacted with a manganese
  • the vicinal diamines have been prepared by the route shown (known as the Strecker synthesis) and vicinal diamines were purchased when commercially available. Any method of vicinal diamine preparation could be used.
  • the macrocyclic ligands useful in the complexes of the present invention can also be prepared by the pyridine diamide route shown in Scheme D as set forth below.
  • a polya ine such as a tetraaza compound, containing two primary amines is condensed with dimethyl 2,6-pyridine dicarboxylate by heating in an appropriate solvent, e.g., methanol, to produce a macrocycle incorporating the pyridine ring as the 2,6-dicarboxamide.
  • the pyridine ring in the macrocycle is reduced to the corresponding piperidine ring in the macrocycle, and then the diamides are reduced and the resulting compound is reacted with a manganese (II) or iron (III) compound under essentially anhydrous and anaerobic conditions to form the corresponding substituted pentaazacycloalkane manganese (II) or iron (III) complex.
  • the macrocyclic ligands useful in the complexes of the present invention can also be prepared by the bis(haloacetamide) route shown in Scheme E set forth below.
  • a triazaalkane is tosylated in a suitable solvent system to produce the corresponding tris (N-tosyl) derivative.
  • Such a derivative is treated with a suitable base to produce the corresponding disulfonamide anion.
  • a bis(haloacetamide) e.g., a bis(chloroacetamide)
  • of a vicinal diamine is prepared by reaction of the diamine with an excess of haloacetyl halide, e.g., chloroacetyl chloride, in the presence of a base.
  • the disulfonamide anion of the tris(N-tosyl) triazaalkane is then reacted with the bis(chloroacetamide) of the diamine to produce the substituted tris(N-tosyl)diamide macrocycle.
  • the tosyl groups are removed and the amides are reduced and the resulting compound is reacted with a manganese (II) or iron (III) compound under essentially anhydrous and anaerobic conditions to form the corresponding substituted pentaazacycloalkane manganese (II) or iron (III) complex.
  • the macrocyclic ligands useful in the complexes of the present invention wherein R R ,, R 2 , R 2 are derived from a diammo starting material and R 5 , R 5 , R 7 , R 7 and R 9 , R 9 can be H or any functionality previously described, can be prepared according to the pseudo- peptide method shown in Scheme F set forth below.
  • R,, R ,, R 2 and R 2 are the substituents on adjacent carbon atoms in the product macrocyclic ligand as set forth above, can be used in this method in combination with any amino acids.
  • the diamine can be produced by any conventional method known to those skilled in the art.
  • R 5 , R 5 , R 7 , R 7 , R 9 and R 9 could be derived from the D or L forms of the amino acids Alanine, Aspartic acid, Arginine, Asparagine, Cysteine, Glycine, Glutamic acid, Glutamine, Histidine, Isoleucine, Leucine, Lysine, Methionine, Proline, Phenylalanine, Serine, Tryptophan, Threonine, Tyrosine, Valine and/or the R groups of unnatural ⁇ -amino acids such as alkyl, ethyl, butyl, tert-butyl, cycloalkyl, phenyl, alkenyl, allyl, alkynyl, aryl, heteroaryl, polycycloalkyl, polycycloaryl, polycycloheteroaryl, imines, aminoalkyl, hydroxyalkyl, hydroxyl, phenol, amine oxides, thioalkyl, carb
  • 1,8-dihydroxy, ,5-diaminooctane is monotosylated and reacted with Boc anhydride to afford the differentiated N-Boc, N-tosyl derivative.
  • the sulfonamide was alkylated with methyl bromoacetate using sodium hydride as the base and saponified to the free acid.
  • the diamine containing N-tosylglycine serves as a dipeptide surrogate in standard solution-phase peptide synthesis.
  • coupling with a functionalized amino acid ester affords the corresponding pseudo-tripeptide.
  • X, Y and Z are anions or ligands that cannot be introduced directly from the manganese or iron compound, the complex with those anions or ligands can be formed by conducting an exchange reaction with a complex that has been prepared by reacting the macrocycle with a manganese or iron compound.
  • the macrocyclic ligands useful in the complexes of the present invention wherein R,, R' 1; R 3 , R' 3 , R 5 , R' 5 , R 7 , R' 7/ R 9 and R' 9 can be H or any functionality as previously described, can be prepared according to the general peptide method shown in Scheme G set forth below.
  • the R groups in the macrocycle derived from substitutents on the ⁇ -carbon of ⁇ -amino acids, i.e. R,, R',, R 3 , R , 3 , R 5 , R' 5 , R 7 , R' 7 , R 9 and R' 9 are defined above in Scheme F.
  • the procedure for preparing the cyclic peptide precursors from the corresponding linear peptides are the same or significant modifications of methods known in the art. See, for example, Veber, D.F. et al., J. Org. Chem. , 4_4, 3101 (1979).
  • the general method outlined in Scheme G below is an example utilizing the sequential solution-phase preparation of the functionalized linear pentapeptide from N-terminus to C-terminus.
  • the reaction sequence to prepare the linear pentapeptide can be carried out by solid-phase preparation utilizing methods known in the art.
  • the reaction sequence could be conducted from C-terminus to N-terminus and by convergent approaches such as the coupling of di- and tri-peptides as needed.
  • Boc-protected amino acid is coupled with an amino acid ester using standard peptide coupling reagents.
  • the new Boc-dipeptide ester is then saponified to the free acid which is coupled again to another amino acid ester.
  • the resulting Boc-tri-peptide ester is again saponified and this method is continued until the Boc-protected pentapeptide free acid has been prepared.
  • the Boc protecting group is removed under standard conditions and the resulting pentapeptide or salt thereof is converted to the cyclic pentapeptide.
  • the cyclic pentapeptide is then reduced to the pentaazacyclopentadecane with lithium aluminum hydride or borane.
  • the final ligand is then reacted with a manganese (II) or iron (III) compound under essentially anaerobic conditions to form the corresponding manganese (II) or iron (III) pentaazacyclopentadecane complex.
  • a manganese (II) or iron (III) compound under essentially anaerobic conditions to form the corresponding manganese (II) or iron (III) pentaazacyclopentadecane complex.
  • the ligands or charge-neutralizing anions e.g. X,Y and Z
  • the complex with those anions or ligands can be formed by conducting an exchange reaction with a complex that has been prepared by reacting the macrocycle with a manganese or iron compound.
  • the following schemes are depicted for preparing the manganese complexes of the invention.
  • the iron complexes of the invention can be prepared by substituting an iron compound for the manganese compound used.
  • the pentaazamacrocycles of the present invention can possess one or more asymmetric carbon atoms and are thus capable of existing in the form of optical isomers as well as in the form of racemic or nonracemic mixtures thereof.
  • the optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example by formation of diastereoisomeric salts by treatment with an optically active acid.
  • appropriate acids are tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric and camphorsulfonic acid and then separation of the mixture of diastereoisomers by crystallization followed by liberation of the optically active bases from these salts.
  • a different process for separation of optical isomers involves the use of a chiral chromatography column optimally chosen to maximize the separation of the enantiomers.
  • Still another available method involves synthesis of covalent diastereoisomeric molecules by reacting one or more secondary amine group(s) of the compounds of the invention with an optically pure acid in an activated form or an optically pure isocyanate.
  • the synthesized diastereoisomers can be separated by conventional means such as chromatography, distillation, crystallization or sublimation, and then hydrolyzed to deliver the enantiomerically pure ligand.
  • the optically active compounds of the invention can likewise be obtained by utilizing optically active starting materials, such as natural amino acids.
  • the compounds or complexes of the present invention are novel and can be utilized to treat numerous inflammatory disease states and disorders.
  • reperfusion injury to an ischemic organ e.g. , reperfusion injury to the ischemic myocardium, surgically-induced ischemia, inflammatory bowel disease, rheumatoid arthritis, osteoarthritis, psoriasis, organ transplant rejections, radiation-induced injury, oxidant- induced tissue injuries and damage, atherosclerosis, thrombosis, platelet aggregation, stroke, acute pancreatitis, insulin-dependent diabetes mellitus, disseminated intravascular coagulation, fatty embolism, adult and infantile respiratory distress, metastasis and carcinogenesis.
  • Total daily dose administered to a host in single or divided doses may be in amounts, for example, from about 1 to about 100 mg/kg body weight daily and more usually about 3 to 30 mg/kg.
  • Unit dosage compositions may contain such amounts of submultiples thereof to make up the daily dose.
  • the amount of active ingredient 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.
  • 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 severity of the disease, 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 compounds of the present invention may be administered orally, parenterally, by inhalation spray, rectally, or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. Topical administration may also involve the use of transdermal administration such as transdermal patches or iontophoresis devices.
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques.
  • sterile 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.
  • Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter and polyethylene glycols which are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
  • Solid dosage forms for oral administration may include capsules, tablets, pills, powders, granules and gels.
  • the active compound may be admixed with at least one inert diluent such as sucrose lactose or starch.
  • Such dosage forms may also comprise, as in normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate.
  • the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
  • Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents. While the compounds of the invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more compounds which are known to be effective against the specific disease state that one is targeting for treatment.
  • the compounds or complexes of the invention can also be utilized as MRI contrast agents.
  • a discussion of the use of contrast agents in MRI can be found in patent application Serial No. 08/397,469, which is incorporated by reference herein.
  • 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 l 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(III) and iron (II) complexes will be equivalent to the subject manganese(II) and iron (III) complexes.
  • Cyc represents 1,2-cyclohexanediamine (stereochemistry, i.e. R,R or S,S, is indicated as such).
  • the pH of the aqueous solution was then adjusted to 2 with 1 N HCI and the product was extracted with ethyl acetate (3 x 1 1) .
  • the extracts were combined, washed with saturated NaCl (500 mL) and dried over MgS0 4 .
  • Boc-(R,R) -Cyc(Ts)-Gly-OH (18.1 g, 43.1 mmol) in DMF (480 mL) was added HOBt»H 2 0 (7.92 g, 51.7 mmol) and
  • Orn(Z) -Cyc(Ts) -Gly-Gly-OEt TFA salt 14.8 g, 19.2 mmol
  • TEA 3.20 mL, 23.0 mmol
  • the DMF was evaporated and the residue was partitioned between water (200 L) and EtOAc (350 mL) .
  • the layers were separated and the EtOAc layer was washed with IN KHS0 4 (150 mL) , water (150 mL) , sat. NaHC0 3 (150 mL) and brine (150 mL) and dried (MgS0 4 ) .
  • DMSO/superoxide solutions are extremely sensitive to water, heat, air, and extraneous metals.
  • a fresh, pure solution has a very slight yellowish tint.
  • Water for buffer solutions was delivered from an in-house deionized water system to a Barnstead Nanopure Ultrapure Series 550 water system and then double distilled, first from alkaline potassium permanganate and then from a dilute EDTA solution.
  • a solution containing 1.0 g of potassium permanganate, 2 liters of water and additional sodium hydroxide necessary to bring the pH to 9.0 were added to a 2-liter flask fitted with a solvent distillation head. This distillation will oxidize any trace of organic compounds in the water.
  • the final distillation was carried out under nitrogen in a 2.5-liter flask containing 1500 ml of water from the first still and 1.0 x 10 6 EDTA. This step will remove remaining trace metals from the ultrapure water.
  • the 40-cm vertical arm was packed with glass beads and wrapped with insulation. This system produces deoxygenated water that can be measured to have a conductivity of less than 2.0 nanomhos/cm 2 .
  • the stopped-flow spectrometer system was designed and manufactured by Kinetic Instruments Inc. (Ann Arbor, MI) and was interfaced to a MAC IICX personal computer.
  • the software for the stopped-flow analysis was provided by Kinetics Instrument Inc. and was written in QuickBasic with MacAdios drivers.
  • Typical injector volumes (0.10 ml of buffer and 0.006 ml of DMSO) were calibrated so that a large excess of water over the DMSO solution were mixed together. The actual ratio was approximately 19/1 so that the initial concentration of superoxide in the aqueous solution was in the range 60-120 ⁇ M.
  • Aqueous solutions to be mixed with the DMSO solution of superoxide were prepared using 80 mM concentrations of the Hepes buffer, pH 8.1 (free acid + Na form).
  • One of the reservoir syringes was filled with 5 ml of the DMSO solution while the other was filled with 5 ml of the aqueous buffer solution.
  • the entire injection block, mixer, and spectrometer cell were immersed in a thermostatted circulating water bath with a temperature of 21.0 ⁇ 0.5°C.
  • a baseline average was obtained by injecting several shots of the buffer and DMSO solutions into the mixing chamber. These shots were averaged and stored as the baseline. The first shots to be collected during a series of runs were with aqueous solutions that did not contain catalyst. This assures that each series of trials were free of contamination capable of generating first-order superoxide decay profiles. If the decays observed for several shots of the buffer solution were second-order, solutions of manganese(II) complexes could be utilized. In general, the potential SOD catalyst was screened over a wide range of concentrations.
  • the manganese(II) complex of the nitrogen- containing macrocyclic ligand in Example 1 is an effective catalyst for the dismutation of superoxide, as can be seen from the k caI above.

Abstract

L'invention concerne des bioconjugués de faible poids moléculaire qui sont des mimétiques de la superoxyde dismutase (SOD) et qui sont représentés par la formule (I), où R, R', R1, R'1, R2, R'2, R3; R'3, R4, R'4, R5, R'5, R6, R'6, R7, R'7, R8, R'8, R9, R'9, X, Y, Z, M et n ont la signification donnée dans la description. Ces bioconjugués sont utiles comme agents thérapeutiques dans les états et les troubles inflammatoires tels que par lésions ischémiques/plaies de reperfusion, accident vasculaire cérébral, athérosclérose, ainsi que toutes les autres pathologies liées à des lésions ou des plaies tissulaires provoquées par des oxydants.
PCT/US1997/002566 1996-03-13 1997-03-04 Bioconjugues de complexes de manganese ou de fer de ligands macrocycliques contenant de l'azote, efficaces comme catalyseurs pour la dismutation du superoxyde WO1997033877A1 (fr)

Priority Applications (6)

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BR9708179A BR9708179A (pt) 1996-03-13 1997-03-04 Bioconjugados de complexos de manganês ou ferro de ligantes macrociclicos contendo nitrogênio eficazes como catalizadores para desmutar superoxidos
JP9532611A JP2000508625A (ja) 1996-03-13 1997-03-04 スーパーオキシドをジスムテートする触媒として有効な窒素含有大環状リガンドのマンガンまたは鉄錯体の生体分子結合体
AU19624/97A AU1962497A (en) 1996-03-13 1997-03-04 Bioconjugates of manganese or iron complexes of nitrogen-containing macrocyclic ligands effective as catalysts for dismutating superoxide
IL12588997A IL125889A0 (en) 1996-03-13 1997-03-04 Bioconjugates of manganese or iron complexes of nitrogen-containing macrocyclic ligands effective as catalysts for dismutating superoxide
EP97907685A EP0891338A1 (fr) 1996-03-13 1997-03-04 Bioconjugues de complexes de manganese ou de fer de ligands macrocycliques contenant de l'azote, efficaces comme catalyseurs pour la dismutation du superoxyde
NO984164A NO984164L (no) 1996-03-13 1998-09-10 Biokonjugater av mangan eller jernkomplekser bestÕende av nitrogen-inneholdende makrocykliske ligander effektive som katalysatorer for dismutering av superoksid

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US1334896P 1996-03-13 1996-03-13
US60/013,348 1996-03-13
USPCT/US96/12767 1996-08-14
PCT/US1996/012767 WO1997006824A2 (fr) 1995-08-17 1996-08-14 Bioconjugues de complexes de manganese et leur application comme catalyseurs

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WO2000054784A1 (fr) * 1999-03-15 2000-09-21 Abdurafik Bakhramovich Akbarov Complexe comprenant le compose de coordination de manganese, ses effets therapeutiques et son procede de production
WO2000072893A2 (fr) * 1999-05-27 2000-12-07 Monsanto Company Biomateriaux modifies par des mimetiques de superoxyde bismuthase
WO2001019823A2 (fr) * 1999-09-16 2001-03-22 Monsanto Company Pyridino pentaazamacrocyle substitue possedant une activite de superoxyde dismutase
US6395725B1 (en) 1997-06-20 2002-05-28 G.D. Searle & Co. Analgesic methods using synthetic catalysts for the dismutation of superoxide radicals
US8217026B2 (en) 1999-01-25 2012-07-10 Aeolus Sciences, Inc. Substituted porphyrins
US8252595B2 (en) 2008-05-13 2012-08-28 University Of Kansas Metal abstraction peptide (MAP) tag and associated methods
US8470808B2 (en) 1999-01-25 2013-06-25 Jon D. Piganelli Oxidant scavengers for treatment of type I diabetes or type II diabetes
US9187735B2 (en) 2012-06-01 2015-11-17 University Of Kansas Metal abstraction peptide with superoxide dismutase activity
US10160719B2 (en) 2001-02-28 2018-12-25 Grunenthal Gmbh Pharmaceutical salts
US11382895B2 (en) 2008-05-23 2022-07-12 National Jewish Health Methods for treating injury associated with exposure to an alkylating species

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WO1993011800A1 (fr) * 1991-12-10 1993-06-24 The Dow Chemical Company Complexes et conjugues a base d'acides bicyclopolyazamacrocyclocarboxylique, leur preparation et utilisation et tant qu'agents de contraste
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WO1996039409A1 (fr) * 1995-06-05 1996-12-12 Nitromed, Inc. Oxydants et reducteurs nitrosyles et nitres de superoxydes
WO1996039396A1 (fr) * 1995-06-06 1996-12-12 Monsanto Company Complexes de manganese ou de fer de coordinats macrocycliques contenant de l'azote, efficaces comme catalyseurs pour la dismutation de superoxydes
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EP0524161A1 (fr) * 1991-07-19 1993-01-20 Monsanto Company Complexes de manganèse avec des ligands macrocycliques contenant de l'azote, effectifs comme catalyseurs pour la dismutation de superoxide
WO1993011800A1 (fr) * 1991-12-10 1993-06-24 The Dow Chemical Company Complexes et conjugues a base d'acides bicyclopolyazamacrocyclocarboxylique, leur preparation et utilisation et tant qu'agents de contraste
WO1995010185A1 (fr) * 1993-10-15 1995-04-20 Duke University Superoxyde-dismutase et ses mimetiques
WO1996039409A1 (fr) * 1995-06-05 1996-12-12 Nitromed, Inc. Oxydants et reducteurs nitrosyles et nitres de superoxydes
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Publication number Priority date Publication date Assignee Title
US6395725B1 (en) 1997-06-20 2002-05-28 G.D. Searle & Co. Analgesic methods using synthetic catalysts for the dismutation of superoxide radicals
US8217026B2 (en) 1999-01-25 2012-07-10 Aeolus Sciences, Inc. Substituted porphyrins
US8946202B2 (en) 1999-01-25 2015-02-03 Aeolus Sciences, Inc. Substituted porphyrins
US8546562B2 (en) 1999-01-25 2013-10-01 James D. Crapo Substituted porphyrins
US8470808B2 (en) 1999-01-25 2013-06-25 Jon D. Piganelli Oxidant scavengers for treatment of type I diabetes or type II diabetes
US9289434B2 (en) 1999-01-25 2016-03-22 Aeolus Sciences, Inc. Substituted porphyrins
WO2000054784A1 (fr) * 1999-03-15 2000-09-21 Abdurafik Bakhramovich Akbarov Complexe comprenant le compose de coordination de manganese, ses effets therapeutiques et son procede de production
JP2003500174A (ja) * 1999-05-27 2003-01-07 フアルマシア・コーポレーシヨン スーパーオキシド・ジスムターゼ模倣体で修飾された生体材料
US7445641B1 (en) 1999-05-27 2008-11-04 Pharmacia Corporation Biomaterials modified with superoxide dismutase mimics
WO2000072893A3 (fr) * 1999-05-27 2001-08-30 Monsanto Co Biomateriaux modifies par des mimetiques de superoxyde bismuthase
WO2000072893A2 (fr) * 1999-05-27 2000-12-07 Monsanto Company Biomateriaux modifies par des mimetiques de superoxyde bismuthase
WO2001019823A3 (fr) * 1999-09-16 2001-09-07 Monsanto Co Pyridino pentaazamacrocyle substitue possedant une activite de superoxyde dismutase
WO2001019823A2 (fr) * 1999-09-16 2001-03-22 Monsanto Company Pyridino pentaazamacrocyle substitue possedant une activite de superoxyde dismutase
US10160719B2 (en) 2001-02-28 2018-12-25 Grunenthal Gmbh Pharmaceutical salts
US8278111B2 (en) 2008-05-13 2012-10-02 University Of Kansas Metal abstraction peptide (MAP) tag and associated methods
US9096652B2 (en) 2008-05-13 2015-08-04 University Of Kansas Metal abstraction peptide (MAP) tag and associated methods
US8975082B2 (en) 2008-05-13 2015-03-10 University Of Kansas Metal abstraction peptide (MAP) tag and associated methods
US8252595B2 (en) 2008-05-13 2012-08-28 University Of Kansas Metal abstraction peptide (MAP) tag and associated methods
US11382895B2 (en) 2008-05-23 2022-07-12 National Jewish Health Methods for treating injury associated with exposure to an alkylating species
US9187735B2 (en) 2012-06-01 2015-11-17 University Of Kansas Metal abstraction peptide with superoxide dismutase activity

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AU1962497A (en) 1997-10-01
IL125889A0 (en) 1999-04-11
CN1225631A (zh) 1999-08-11
NO984164D0 (no) 1998-09-10
EP0891338A1 (fr) 1999-01-20
CA2249011A1 (fr) 1997-09-18
CZ271198A3 (cs) 1999-01-13
KR19990087784A (ko) 1999-12-27
BR9708179A (pt) 1999-07-27

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