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WO1997033588A9 - Complexes ferreux de ligands macrocycliques contenants de l'azote efficaces en tant que catalyseurs de dismutation de superoxyde - Google Patents

Complexes ferreux de ligands macrocycliques contenants de l'azote efficaces en tant que catalyseurs de dismutation de superoxyde

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Publication number
WO1997033588A9
WO1997033588A9 PCT/US1997/003348 US9703348W WO9733588A9 WO 1997033588 A9 WO1997033588 A9 WO 1997033588A9 US 9703348 W US9703348 W US 9703348W WO 9733588 A9 WO9733588 A9 WO 9733588A9
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alkyl
aryl
acid
groups
solution
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PCT/US1997/003348
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English (en)
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WO1997033588A1 (fr
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Priority to JP9532095A priority Critical patent/JP2000507929A/ja
Priority to BR9707978A priority patent/BR9707978A/pt
Priority to IL12599397A priority patent/IL125993A0/xx
Priority to EP97908848A priority patent/EP0888115A1/fr
Priority to AU20656/97A priority patent/AU2065697A/en
Publication of WO1997033588A1 publication Critical patent/WO1997033588A1/fr
Publication of WO1997033588A9 publication Critical patent/WO1997033588A9/fr
Priority to NO984165A priority patent/NO984165L/no

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Definitions

  • the present invention relates to compounds effective as catalysts for dismutating superoxide and, more particularly, relates to iron(II) or iron(III) complexes of nitrogen-containing fifteen-membered
  • the enzyme superoxide dismutase catalyzes the conversion of superoxide into oxygen and hydrogen peroxide according to equation (1) (hereinafter referred to as dismutation).
  • Reactive oxygen metabolites derived from superoxide are postulated to contribute to the tissue pathology in a number of
  • O 2 - + O 2 - + 2H+ ⁇ O2 + H 2 O 2 (1) inflammatory diseases and disorders, such as reperfusion injury to the ischemic myocardium, inflammatory bowel disease, rheumatoid arthritis, osteoarthritis,
  • the iron complexes of nitrogen-containing fifteen-membered macrocyclic ligands that are low molecular weight mimics of superoxide dismutase (SOD) are useful as therapeutic agents and avoid many of the problems associated with SOD enzymes.
  • SOD superoxide dismutase
  • compositions in unit dosage form useful for dismutating superoxide comprising (a) a therapeutically or prophylactically effective amount of an iron complex of the invention and (b) a nontoxic, pharmaceutically acceptable carrier, adjuvant or vehicle.
  • a method of preventing or treating a disease or disorder which is medicated, at least in part, by superoxide comprising administering to a subject in need of such prevention or treatment, a therapeutically or
  • the present invention is directed to iron complexes of nitrogen-containing fifteen-membered macrocyclic ligands which catalyze the conversion of superoxide into oxygen and hydrogen peroxide. These complexes are represented by the formula:
  • heterocycle which does not contain a hydrogen attached to the nitrogen, the hydrogen attached to the nitrogen as shown in the above formula, which nitrogen is also in the macrocyclic ligand or complex, and the R groups attached to the same carbon atoms of the macrocycle are absent.
  • X, Y and Z represent suitable ligands or charge- neutralizing anions which are derived from any
  • 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,
  • alkyl sulfonic acid isonitrile, nitrate, nitrite, azido, alkyl sulfonic acid, aryl sulfonic acid, alkyl sulfoxide, aryl sulfoxide, alkyl aryl sulfoxide, alkyl sulfenic acid, aryl sulfenic acid, alkyl sulfinic acid, aryl sulfinic acid, alkyl thiol carboxylic acid, aryl thiol carboxylic acid, alkyl thiol thiocarboxylic acid, aryl thiol thiocarboxylic acid, alkyl carboxylic acid (such as acetic acid, trifluoroacetic acid, oxalic acid), aryl carboxylic acid (such as benzoic acid, phthalic acid), urea, alkyl urea, aryl urea, alkyl aryl urea,
  • phosphine alkyl phosphine oxide, aryl phosphine oxide, alkyl aryl phosphine oxide, alkyl phosphine sulfide, aryl phosphine sulfide, alkyl aryl phosphine sulfide, alkyl phosphonic acid, aryl phosphonic acid, alkyl phosphinic acid, aryl phosphinic acid, alkyl phosphinous acid, aryl phosphinous acid, phosphate, thiophosphate, phosphite, pyrophosphite, triphosphate, hydrogen
  • hexafluoroantimonate hypophosphite, iodate, periodate, metaborate, tetraaryl borate, tetra alkyl borate, tartrate, salicylate, succinate, citrate, ascorbate, saccharinate, amino acid, hydroxamic acid,
  • thiotosylate and anions of ion exchange resins, or systems where one or more of X, Y and Z are independently attached to one or more of the "R" groups, wherein n is an integer from 0 or 1.
  • the preferred ligands from which X, Y and Z are selected include halide, organic acid, nitrate and bicarbonate anions.
  • 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, trans-2-butenyl, iso-butylenyl, cis-2-pentenyl, trans-2- ⁇ entenyl,
  • 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,
  • 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.
  • 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.
  • examples of cycloalkylalkyl radicals include, but are not limited to, cyclohexylmethyl, cyclopentylmethyl, (4-isopropylcyclohexyl)methyl,
  • cycloalkylcycloalkyl means a cycloalkyl radical as defined above which is substituted by another cycloalkyl radical as defined above.
  • cycloalkylcycloalkyl radicals include, but are not limited to, cyclohexylcyclopentyl and
  • cyclohexylcyclohexyl 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,
  • 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-1- ylmethyl, 1-cyclopenten-1-ylmethyl, 2-(1-cyclohexen-1- yl) ethyl, 3-(1-cyclopenten-1-yl)propyl,
  • alkylcycloalkyl and "alkenylcycloalkyl” mean a
  • alkylcycloalkyl and alkenylcycloalkyl radicals include, but are not limited to,
  • 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, 1-methyl-2-cyclopentyl, 1-hexyl-2-cyclopentenyl, 1-ethyl-2-cyclohexenyl,
  • aryl alone or in combination, means a phenyl or naphthyl radical which optionally carries one or more
  • 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,
  • 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 8 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.
  • 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, preferable 4 to 10 carbon atoms, can be partially or fully unsaturated or saturated and can also contain nitrogen, oxygen and/or sulfur 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 overall charge-type of the complex can be varied from negative to positive by carbon substitution of the appropriate charged groups on the macrocyclic framework.
  • the overall charge on the complex can be adjusted as needed to enhance desired pharmaceutical properties such as osmolality, tissue distribution and non-target clearance. For example, if the complex carries only charge neutral functionality, such as
  • the overall charge on the complex will be determined by the iron center and will be positive.
  • Multi-positive complexes are available via the incorporation of pendant cations such as protonated aminoalkyl groups. These types of complexes can bind to endogenous anions, anionic proteins, cell membranes, and the like. If pendant anionic groups are attached, such as carboxylates, phenolate, phosphonates, sulfonates and the like, the overall charge on the complex can be envisioned as zero or positive, i.e. an anionic complex will result.
  • the pendant groups may be designed to axially chelate and formally displace the axial anions or they may be designed specifically to not chelate but retain a charge type.
  • preferred compounds are those wherein at least one, preferably at least two, of the "R" groups represent alkyl, or alkyl substituted with
  • R 10 and R 11 are independently hydrogen or alkyl, and the remaining R groups represent hydrogen, a saturated, partially saturated or
  • heterocycle more preferably hydrogen or a saturated, partially saturated or unsaturated cyclic; those wherein at least one, preferably at least two, of 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, or R' 9 and R or R' together with the carbon atoms to which they are attached
  • heterocycle .alkyl or alkyl substituted with -OR 10 or -NR 10 R 11 groups, more preferably hydrogen, alkyl or alkyl substituted with -OR 10 or -NR 10 R 11 groups; and those wherein at least one, preferably at least two, of R or R' and R 1 or R' 1 , 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' 8 and R, or R' 9 together with the carbon atoms to which they are attached are bound to form a nitrogen containing
  • R heterocycle having 2 to 20 carbon atoms and all the remaining “R” groups are independently selected from hydrogen, saturated, partially saturated or unsaturated cyclic, alkyl or alkyl substituted with -OR 10 or -NR 10 R 11 groups.
  • R means all of the R groups attached to the carbon atoms of the macrocycle, i.e., R, R', R 1 , R' 1 , R 2 , R' 2 , R 3 , R' 3 , R 4 , R' 4 , R 5 , R' 5 , R 6 , R' 6 , R 7 , R' 7 , R 8 , R' 8 , R 9 and R' 9 .
  • Examples of complexes of the invention include, but are not limited to, compounds having the formulas:
  • the macrocyclic ligand wherein all R's are H can be prepared according to the general synthetic scheme A set forth below utilizing methods known in the art for preparation of certain intermediates and certain
  • tosylated in a suitable solvent system to produce the corresponding tris(N-tosyl) derivative.
  • Such derivative is then treated with a suitable base to produce the corresponding disulfonamide anion.
  • the disulfonamide anion is then reacted with a di-O-tosylated di-N- tosylated diazaalkane diol to produce the corresponding pentatosylpentaazacycloalkane.
  • the tosyl groups are then removed and the resulting compound is reacted with an iron compound under essentially anhydrous and
  • the macrocyclic ligands useful in the complexes of the present invention wherein R 1 , 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 B set forth below.
  • 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., 44, 3101 (1979).
  • the general method See, for example, Veber, D.F. et al., J. Org. Chem., 44, 3101 (1979). The general method
  • 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.
  • a 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
  • pentaazacyclopentadecane with lithium aluminum hydride or borane.
  • the final ligand is then reacted with an iron compound under essentially anaerobic conditions to form the corresponding iron pentaazacyclopentadecane complex.
  • the R groups in the macrocycles produced by the cyclic peptide route 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, poly
  • polycycloheteroaryl imines, aminoalkyl, hydroxyalkyl, hydroxyl, phenol, amine oxides, thioalkyl,
  • 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 disulfonamide 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 ammonium 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
  • 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 bis (haloacetamide) route shown in Scheme D 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.
  • 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.
  • haloacetyl halide e.g., chloroacetyl chloride
  • the macrocyclic ligands useful in the complexes of the present invention wherein R 1 , R , 1 , R 2 , R' 2 are part of a cis- or trans- cycloalkyl ring system 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 E set forth below.
  • a ⁇ is-1,2-Diaminocycloalkane or a trans-(R,R)-1,2- diaminocycloalkane or trans-(S,S)-1,2-diaminocycloalkane can be used in this method in combination with any amino acids.
  • R 1 , R' 1 , R 2 , R 2 and R 5 , R' 5 , R 6 , R' 6 are part of a cis- or trans- cycloalkyl ring system and R 9 , R 9 can be H or any functionality previously described, can be prepared according to the iterative pseudo-peptide method shown in Scheme F set forth below.
  • a cis-1,2-Diaminocycloalkane or a trans- (R,R)-1,2-diaminocycloalkane or trans-(S,S)-1,2- diaminocycloalkane can be used in any combination with each other using this method and in combination with any amino acids. This allows the relative stereochemistry of both cycloalkane fused rings and substituent, R 9 , R 9 , functionality and stereochemistry to be defined in any manner.
  • the (S,S)-1,2-diaminocyclohexyl-N- tosylglycine dipeptide surrogate prepared from (S,S)- 1,2-diaminocyclohexane exactly as in Scheme E in the case of (R,R)-1,2-diaminocyclohexane, can be coupled with a functionalized amino acid ester to afford the corresponding pseudo-tripeptide.
  • TFA cleavage affords the pseudo-tripeptide TFA salt which is coupled with
  • the macrocyclic ligands useful in the complexes of the present invention can also be prepared according to the general procedure shown in Scheme G set forth below.
  • an amino acid amide which is the
  • 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 as previously defined. Most preferred are those wherein R represents hydrogen, alkyl,
  • 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
  • R 9 , and R 2 are alkyl
  • R 3 , R' 3 , R 4 , R' 4 , R s , R , 5 , R 6 , R' 6 , R 7 , R , 7 , R 8 and R' 8 can be alkyl, arylalkyl or cycloalkylalkyl and R or R' and R 1 or R' 1 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 H set forth below utilizing methods known in the art for preparing the iron
  • the macrocyclic ligands useful in the complexes of the present invention can also be prepared by the pyridine diamide route shown in Scheme I as set forth below.
  • a polyamine 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 an compound under essentially anhydrous and anaerobic conditions to form the corresponding substituted pentaazacycloalkane iron complex.
  • 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 an iron compound.
  • 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
  • Still another available method involves synthesis of covalent diastereoisomeric molecules by reacting one or more secondary amine group (s) of the compounds of the
  • the synthesized diastereoisomers can be separated by conventional means such as chromatography, distillation, crystallization or sublimation, and then hydrolyzed to deliver 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 can be utilized to treat numerous inflammatory disease states and disorders that are mediated, at least in part, by superoxide.
  • 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
  • pancreatitis insulin-dependent diabetes mellitus, disseminated intravascular coagulation, fatty embolism, adult and infantile respiratory distress, and
  • the stopped-flow kinetic analysis is suitable for screening compounds for SOD activity and activity of the compounds or complexes of the present invention, as shown by stopped-flow analysis, correlate to treating the above disease states and disorders.
  • 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. Dosage unit 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,
  • 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
  • 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
  • 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,
  • 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.
  • 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 l, so long as they do not adversely affect the overall
  • iron (III) complexes will be equivalent to the subject iron (III) complexes.
  • Cyc represents 1,2- cyclohexanediamine (stereochemistry, i.e. R 1 R or S,S, is indicated as such). This allows three letter code peptide nomenclature to be used in pseudopeptides containing the 1,2-cyclohexanediamine "residue”.
  • the pH was adjusted as before and the solution was allowed to stand at -20 C for 24 h.
  • the pH was readjusted as before and the solution was allowed to warm to 2°C over 24 h. The pH had dropped only slightly.
  • the pH was readjusted as before and the solution was allowed to stand at 2 C for another 24 h after which time the pH had not changed.
  • the solution was divided equally among 6 - 4 1 beakers and H 2 O (1.1 1) was added to each. Then added a total of 5.00 kg mixed-bed ion exchange resin to the solution (divided equally among the 6 beakers) and stirred the mixtures for 6 h. The resin was then filtered and washed with DMF.
  • N-p-Toluenesulfonylglycyl-1R,2R- diaminocyclohexane (1.11 g, 3.42 mmol) and N,
  • N -bis(chloroacetyl)-1R,2R-diaminocyclohexane (0.913 g, 3.42 mmol) were combined in a one liter flask and dry N,N-dimethylacetamide (650 ml) was added. The flask was inerted. After 10 minutes, the sodium hydride was added directly to the homogeneous mixture. The reaction flask was placed in a 70°C oil bath. After the internal temperature reached 45-50°C, gas evolution became constant. The oil bath temperature was stabilized at about 65°C with some excursions from about 60 to 75°C. Overnight, the reaction mixture became homogeneous.
  • the DMF was evaporated and the residue was partitioned between water (500 ml) and ethyl acetate (500 ml).
  • the ethyl acetate solution was washed with IN NaHSO 4 (250 ml), water (250 ml), saturated NaHCO 3 (250 ml), brine (250 ml) and dried over Na 2 SO 4 .
  • the protected dipeptide (31.4 g, 109 mmol) was dissolved in methylene chloride (200 ml) and TFA (66 ml) was added. The resulting solution was allowed to stir for 30 min at RT and concentrated. The residue was coevaporated with methylene chloride (2 x 200 ml), dissolved in ether and oiled out with the addition of excess hexanes.
  • Boc-Ala-Ala-DAla-Ala-DAla-OEt (10.4 g, 18.7 mmol) was dissolved in acetic acid (225 ml) and treated with concentrated hydrochloric acid (75 ml). The resulting solution was allowed to stir at RT for 14 h thereafter.
  • DMSO/superoxide solutions are extremely sensitive to water, heat, air, and extraneous metals.
  • a fresh, pure solution has a very slight yellowish tint.
  • a dilute EDTA solution For example, a
  • 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 M EDTA. This step will remove remaining trace metals from the
  • the 40-cm vertical arm was packed with glass beads and wrapped with
  • 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. Prior to initiating data collection for a
  • 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
  • the catalytic rate constant for dismutation of superoxide by the iron (III) complexes of Examples 1-4 were determined from the linear plot of observed rate constants (k obs ) versus the concentration of the iron (III) complexes. k obs values were obtained from the liner plots of In absorbance at 245 nm versus time for the dismutation of superoxide by the iron (III) complex.
  • the k cat (M -1 sec -1 ) of the iron (III) complexes of Examples 1-4 are shown in Table I.
  • the iron (III) complexes of the nitrogen- containing macrocyclic ligands in Examples 1-4 are effective catalysts for the dismutation of superoxide, as can be seen from the k cat data in Table I.

Abstract

Des compositions pharmaceutiques renfermant des imitateurs de faible masse moléculaire de superoxyde-dismutase (SOD) représentés par la formule (I), dans laquelle 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, et R'9 ainsi que X, Y, Z et n ont la notation ci-définie, sont utiles en tant qu'agents thérapeutiques contre des états et des troubles pathologiques inflammatoires, des lésions ischémiques/de reperfusion, les attaques, l'athérosclérose, les infections intestinales inflammatoires et tout autre état de détérioration ou de lésion tissulaire induite par un oxydant.
PCT/US1997/003348 1996-03-13 1997-03-11 Complexes ferreux de ligands macrocycliques contenants de l'azote efficaces en tant que catalyseurs de dismutation de superoxyde WO1997033588A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
JP9532095A JP2000507929A (ja) 1996-03-13 1997-03-11 ジスムタチンスーパーオキシドの触媒として有効な窒素含有大環状化合物配位子を持つ鉄錯体
BR9707978A BR9707978A (pt) 1996-03-13 1997-03-11 Complexos de ferro de ligantes macrocíclicos contendo nitrogênio eficazes como catalisadores para dismutação de superóxido
IL12599397A IL125993A0 (en) 1996-03-13 1997-03-11 Iron complexes of nitrogen-containing macrocyclic ligands
EP97908848A EP0888115A1 (fr) 1996-03-13 1997-03-11 Complexes ferreux de ligands macrocycliques contenants de l'azote efficaces en tant que catalyseurs de dismutation de superoxyde
AU20656/97A AU2065697A (en) 1996-03-13 1997-03-11 Iron complexes of nitrogen-containing macrocyclic ligands effective as cataly sts for dismutating superoxide
NO984165A NO984165L (no) 1996-03-13 1998-09-10 Jernkomplekser av nitrogen-inneholdende makrocykliske ligander effektive som katalysatorer for dismuterende superoksider

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US61471096A 1996-03-13 1996-03-13
US08/614,710 1996-03-13

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WO1997033588A1 WO1997033588A1 (fr) 1997-09-18
WO1997033588A9 true WO1997033588A9 (fr) 1997-11-06

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EP (1) EP0888115A1 (fr)
JP (1) JP2000507929A (fr)
KR (1) KR19990087783A (fr)
AU (1) AU2065697A (fr)
BR (1) BR9707978A (fr)
CA (1) CA2248964A1 (fr)
CZ (1) CZ277698A3 (fr)
IL (1) IL125993A0 (fr)
NO (1) NO984165L (fr)
WO (1) WO1997033588A1 (fr)

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US6127356A (en) 1993-10-15 2000-10-03 Duke University Oxidant scavengers
ES2198767T3 (es) 1997-11-03 2004-02-01 Duke University Porfirinas sustituidas.
MXPA01007451A (es) 1999-01-25 2004-03-10 Nat Jewish Med & Res Center Porfirinas sustituidas.
ES2240101T3 (es) * 1999-05-27 2005-10-16 Monsanto Company Biomateriales modificados con mimeticos de superoxido dismutasa.
EP1347773B1 (fr) * 2001-01-05 2010-04-14 Metaphore Pharmaceuticals Inc. Compositions et methodes permettant d'ameliorer l'activite d'une cytokine et de traiter l'hypotension associee a l'administration de cytokines
WO2002058686A2 (fr) * 2001-01-26 2002-08-01 Metaphore Pharmaceuticals, Inc. Methode de traitement de troubles neurodegeneratifs
CA2449024A1 (fr) 2001-06-01 2002-12-12 National Jewish Medical And Research Center Capteurs oxydants destines au traitement du diabete ou a etre utilises dans une transplantation ou a induire une tolerance immunitaire
JP2006501163A (ja) 2002-06-07 2006-01-12 デューク・ユニバーシティー 置換ポルフィリン
EP2087439A2 (fr) 2006-11-08 2009-08-12 Sidec Technologies AB Régularisation variable itérée combinée à une régularisation par composantes
ES2464728T3 (es) 2008-05-23 2014-06-03 National Jewish Health Compuestos para su uso en el tratamiento de lesiones asociadas con la exposición a una especie química alquilante

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AU661023B2 (en) * 1991-07-19 1995-07-13 Monsanto Company Manganese complexes of nitrogen-containing macrocyclic ligands effective as catalysts for dismutating superoxide
JPH10500401A (ja) * 1994-04-22 1998-01-13 モンサント カンパニー 金属錯体を用いる診断画像解析法
US6525041B1 (en) * 1995-06-06 2003-02-25 Pharmacia Corporation Manganese or iron complexes of nitrogen-containing macrocyclic ligands effective as catalysts for dismutating superoxide

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