WO1997033588A1 - Iron complexes of nitrogen-containing macrocyclic ligands effective as catalysts for dismutating superoxide - Google Patents
Iron complexes of nitrogen-containing macrocyclic ligands effective as catalysts for dismutating superoxide Download PDFInfo
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- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic System
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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 macrocyclic ligands which catalytically dismutate superoxide.
- Application Serial No. 08/397,469 is hereby incorporated by reference herein in its entirety.
- 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. See, for example, Bulkley, G.B., Reactive oxygen metabolites and reperfusion injury: aberrant triggering of reticuloendothelial function, The Lancet , Vol. 344, pp.
- 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 prophylactically effective amount of an iron complex of the invention.
- 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:
- 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, aryla ino, 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
- 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-pentenyl, 3-methyl-l-butenyl, 2,3-dimethyl-2-butenyl, l-pentenyl, 1-hexenyl, l-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, 5,8,11,14- eicosatetraenyl, and 9,12,15
- 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) , l-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.
- examples of cycloalkylalkyl radicals include, but are not limited to, cyclohexylmethyl, cyclopentylmethyl, (4-isopropylcyclohexyl)methyl, (4-t-butyl-cyclohexyl)methyl, 3-cyclohexylpropyl, 2-cyclo-hexylmethylpentyl, 3-cyclopentylmethylhexyl, l-(4-neopentylcyclohexyl)methylhexyl, and l-(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.
- 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.
- cycloalkenylalkyl radicals include, but are not limited to, 2-cyclohexen-l- ylmethyl, 1-cyclopenten-l-ylmethyl, 2-(l-cyclohexen-l- yl)ethyl, 3-(l-cyclopenten-l-yl)propyl,
- 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-methylcyclohexy1, 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, 1-methy1-2-cyclopentyl, 1-hexy1-2-cyclopenteny1, 1-ethy1-2-cyclohexeny1, l-butyl-2-cyclohexenyl, l-(9-octadecenyl)-2-cyclohexeny1 and l-(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, phenyl, naphthyl, heterocycle, alkoxyaryl, alkaryl, alkoxy, halogen, hydroxy, amine, cyano, nitro, alkylthio, phenoxy, ether, trifluoromethy1 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 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.
- the complex carries only charge neutral functionality, such as C-alkyl substitution, then 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.
- pendant anionic groups 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 -OR 10 or -NR 10 R n wherein R ⁇ 0 and R n are independently hydrogen or alkyl, and the remaining R groups represent hydrogen, a saturated, partially saturated or unsaturated cyclic, or a nitrogen containing heterocycle, more preferably hydrogen or a saturated, partially saturated or unsaturated cyclic; those wherein at least one, preferably at least two, of Rj or R' x 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' _ , 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 all the remaining "R" groups are hydrogen, nitrogen containing
- R groups means all of the R groups attached to the carbon atoms of the macrocycle, I.e. , R, R' , Rj, R' ⁇ , R 2 , '2/ R 3f R 3 R 4r R 4» 5/ , 5/ R 6 , R' 6 , R 7 , R' 7 , R g , R' 8 , R 9 and R',.
- 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 ligands. See, for example, Rich an et al., J. Am. Chem . Soc , 96, 2268 (1974); Atkins et al. Org. Synth . , 58, 86 (1978); and EP 287 465.
- a triazaalkane is 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 anaerobic conditions to form the corresponding iron pentaazacycloalkane complex.
- the macrocyclic ligands useful in the complexes of the present invention wherein R,, R',, R 3 , R' 3 , R 5 , R's , 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., __ ⁇ , 3101 (1979).
- the general method outlined in Scheme B 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.
- 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 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 an iron compound under essentially anaerobic conditions to form the corresponding iron pentaazacyclopentadecane complex.
- R groups in the macrocycles produced by the cyclic peptide route i.e., R 1; R , j, R 3 , R , 3 , R 5 , R , 5 , R 7 , R' 7 / R?
- 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, a ine oxides, thioalkyl, carboalkoxyalkyl, carboxylic acids and their derivatives
- 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 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 an iron compound under essentially anhydrous and anaerobic conditions to form the corresponding substituted pentaazacycloalkane iron complex.
- 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.
- 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 an iron compound under essentially anhydrous and anaerobic conditions to form the corresponding substituted pentaazacycloalkane iron complex.
- the macrocyclic ligands useful in the complexes of the present invention wherein R,, R ,, R 2 , R 2 are part of a cis- or trans- cycloalkyl ring system and R 5 , i i i
- R 5 , R 7 , R ⁇ 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 cis-l,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. This allows the relative stereochemistry of the
- R 5 , R 5 , R 7 , R 7 , R 9 , R 9 functionality and stereochemistry to be defined in any manner.
- trans-(R,R)-l,2- diaminocyclhexane was 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 cyclohexanediamine containing N-tosylglycine serves as a dipeptide surrogate in standard solution-phase peptide synthesis.
- the macrocyclic ligands useful in the complexes of the present invention wherein R R _ , 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-l,2-Diaminocycloalkane or a trans- (R,R)-l,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.
- 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.
- 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, 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 an iron compound under essentially anhydrous and anaerobic conditions to form the corresponding substituted iron pentaazacycloalkane complex.
- the complexes of the present invention wherein R 9 , and R 2 are alkyl, and R 3 , R' 3/ R 4 , R , 4 , R 5 , R' 5 , R 6 , R' 6 , R 7 , R' 7 , Re and R' 8 can be alkyl, arylalkyl or cycloalkylalkyl and R or R' and R x 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 H set forth below utilizing methods known in the art for preparing the iron pentaazabicyclo[12.3.1]octadecapentaene complex precursor.
- 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 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 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 injuries and damage, atherosclerosis, thrombosis, platelet aggregation, metastasis, stroke, acute pancreatitis, insulin-dependent diabetes mellitus, disseminated intravascular coagulation, fatty embolism, adult and infantile respiratory distress, 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. 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, 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 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.
- 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 l, 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.
- iron (III) complexes will be equivalent to the subject iron (III) complexes.
- Cyc represents 1,2- cyclohexanediamine (stereochemistry, i.e. R,R or SxS, is indicated as such) . This allows three letter code peptide nomenclature to be used in pseudopeptides containing the 1,2-cyclohexanediamine "residue”.
- Example 2B (310 g, 0.841 mole) in anhydrous DMF (3.11 1) at 0 C was added NaH (37.4 g - 60 % in oil, 0.934 mole) in portions and the resulting mixture was stirred for 30 min. Methyl bromoacetate (142 g, 0.925 mole) was then added dropwise over 45 min and the mixture was allowed to warm to room temp while stirring overnight. After stirring for 17 h, the solvent was removed in vacuo and the residue was dissolved in ethyl acetate(3 1) and H 2 0 (1 1) .
- 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 .
- the aqueous solution was then extracted with CH 2 C1 2 (2 x 500 ml) and the extracts and THF layer were combined, washed with saturated NaCl (500 ml) and dried over MgS0 4 . The solvent was removed in vacuo to give a yellow slurry.
- 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 and dried over MgS0 4 .
- 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 0 (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.
- the reaction mixture was placed in a separatory funnel, some additional chloroform added, and the layers were separated.
- the aqueous layer was extracted with another portion of CHC1 3 , and the combined chloroform layers were washed with water, then saturated NaCl, dried (Na 2 S0 4 ) and stripped down to a brownish white solid. This solid was stirred overnight with about 450 ml of ether, then filtered, much of the color staying in the ether, giving a beige solid, 13.68 g, 51.60 mmol, 84.4% yield.
- N-tosylglycine (10.04 g, 43.62 mmol), 1-hydroxybenzotriazole (6.75 g, 44.08 mmol), and l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (8.45 g, 44.05 mmol) were dissolved in dry DMF (150 ml) , and cooled to -10°C under argon. The latter solution was added to the diaminocyclohexane solution at -10°C via cannula. After 2 hours at this temperature, water (8 ml) was added and the reaction was allowed to warm to 0°C over one hour, then to room temperature over the next half hour.
- N-p-Toluenesulfonylglycyl-lR,2R- diaminocyclohexane (l.ll g, 3.42 mmol) and N, N -bis(chloroacetyl)-lR,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. After heating for 17 hours the reaction flask was removed from the bath and allowed to cool. The solvent was removed under reduced pressure, and the yellowish oil was placed on the vacuum line. The residue was treated with dichloromethane (300 ml) and washed with water (40 ml) and twice with saturated sodium chloride (40 ml each) . After combining, the aqueous layers were backwashed with dichloromethane (100 ml) . The combined organic layers were dried over sodium sulfate, filtered, and stripped down to a viscous yellow oil which was placed on the vacuum line, 2.14 g.
- Tetrahydrofuran (thf, 210 ml) was added and stirring was continued for about an hour.
- the thick white suspension was allowed to settle, and was filtered with a filter transfer device (#1 Whatman paper) .
- the filtrate was stripped.
- the white residue was stirred with thf (150 ml) and filtered onto the stripped first filtrate.
- the solvent was removed under reduced pressure, and the residue was placed on the vacuum line.
- the resulting yellow-white solid was extracted with hot dry hexane (initially 70 ml, 65°C; then an additional 15 ml) and filtered through a filter transfer device (#50 Whatman paper) , and the solvent was removed under reduced pressure.
- 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.
- the DMF was evaporated and the residue was dissolved in ethyl acetate (300 ml) and washed with 1 N potassium bisulfate (150 ml), water (150 ml), saturated sodium bicarbonate (150 ml) and brine (150 ml) .
- the ethyl acetate layer was dried (MgS0 4 ) , filtered and concentrated to half volume and crystallization was allowed to proceed.
- the DMF was evaporated and the residue was partitioned between ethyl acetate (300 ml) and water (300 ml) .
- the ethyl acetate layer was washed with 1 N potassium bisulfate (150 ml) , water (150 ml) , saturated sodium bicarbonate (150 ml) and brine (150 ml) .
- 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.
- Stopped-Flow Kinetic Analysis Stopped-flow kinetic analysis has been utilized to determine whether a compound can catalyze the dismutation of superoxide (Riley, D.P., Rivers, W.J. and Weiss, R.H., "Stopped-Flow Kinetic Analysis for Monitoring Superoxide Decay in Aqueous Systems," Anal. Biochem. 196, 344-349 [1991]). For the attainment of consistent and accurate measurements all reagents were biologically clean and metal-free.
- 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* M 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 iron (III) complexes could be utilized. In general, the potential SOD catalyst was screened over a wide range of concentrations.
- k ob 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 ea , (M ⁇ 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 ca . data in Table I. TABLE I
Abstract
Description
Claims
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP9532095A JP2000507929A (en) | 1996-03-13 | 1997-03-11 | Iron Complexes with Nitrogen-Containing Macrocycle Ligands Effective as Catalysts for Dismutatin Superoxide |
EP97908848A EP0888115A1 (en) | 1996-03-13 | 1997-03-11 | Iron complexes of nitrogen-containing macrocyclic ligands effective as catalysts for dismutating superoxide |
BR9707978A BR9707978A (en) | 1996-03-13 | 1997-03-11 | Iron complexes of nitrogen-containing macrocyclic binders effective as catalysts for superoxide dismutation |
IL12599397A IL125993A0 (en) | 1996-03-13 | 1997-03-11 | Iron complexes of nitrogen-containing macrocyclic ligands |
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 (en) | 1996-03-13 | 1998-09-10 | Iron complexes of nitrogen-containing macrocyclic ligands effective as catalysts for dismutating superoxides |
Applications Claiming Priority (2)
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US61471096A | 1996-03-13 | 1996-03-13 | |
US08/614,710 | 1996-03-13 |
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EP (1) | EP0888115A1 (en) |
JP (1) | JP2000507929A (en) |
KR (1) | KR19990087783A (en) |
AU (1) | AU2065697A (en) |
BR (1) | BR9707978A (en) |
CA (1) | CA2248964A1 (en) |
CZ (1) | CZ277698A3 (en) |
IL (1) | IL125993A0 (en) |
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Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000072893A2 (en) * | 1999-05-27 | 2000-12-07 | Monsanto Company | Biomaterials modified with superoxide dismutase mimics |
WO2002053142A2 (en) * | 2001-01-05 | 2002-07-11 | Metaphore Pharmaceuticals, Inc. | Compositions and methods for enhancing cytokine activity and treating hypotension associated with the administration of cytokines |
WO2002058686A2 (en) * | 2001-01-26 | 2002-08-01 | Metaphore Pharmaceuticals, Inc. | Method of treatment of neurodegenerative disorders using pentaaza-macrocyclic ligand complexes |
US8217026B2 (en) | 1999-01-25 | 2012-07-10 | Aeolus Sciences, Inc. | Substituted porphyrins |
US8468189B2 (en) | 2006-11-08 | 2013-06-18 | Okinawa Institute Of Science And Technology Promotion Corporation | Iterated variational regularization combined with componentwise regularization |
US8470808B2 (en) | 1999-01-25 | 2013-06-25 | Jon D. Piganelli | Oxidant scavengers for treatment of type I diabetes or type II diabetes |
US11382895B2 (en) | 2008-05-23 | 2022-07-12 | National Jewish Health | Methods for treating injury associated with exposure to an alkylating species |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
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EP0524161A1 (en) * | 1991-07-19 | 1993-01-20 | Monsanto Company | Manganese complexes of nitrogen containing macrocyclic ligands effective as catalysts for dismutating superoxide |
WO1995028968A1 (en) * | 1994-04-22 | 1995-11-02 | Monsanto Company | Diagnostic image analysis with metal complexes |
WO1996039396A1 (en) * | 1995-06-06 | 1996-12-12 | Monsanto Company | Manganese or iron complexes of nitrogen-containing macrocyclic ligands effective as catalysts for dismutating superoxide |
-
1997
- 1997-03-11 CA CA002248964A patent/CA2248964A1/en not_active Abandoned
- 1997-03-11 JP JP9532095A patent/JP2000507929A/en active Pending
- 1997-03-11 WO PCT/US1997/003348 patent/WO1997033588A1/en not_active Application Discontinuation
- 1997-03-11 IL IL12599397A patent/IL125993A0/en unknown
- 1997-03-11 CZ CZ982776A patent/CZ277698A3/en unknown
- 1997-03-11 AU AU20656/97A patent/AU2065697A/en not_active Abandoned
- 1997-03-11 KR KR1019980707264A patent/KR19990087783A/en not_active Application Discontinuation
- 1997-03-11 EP EP97908848A patent/EP0888115A1/en not_active Withdrawn
- 1997-03-11 BR BR9707978A patent/BR9707978A/en not_active Application Discontinuation
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1998
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0524161A1 (en) * | 1991-07-19 | 1993-01-20 | Monsanto Company | Manganese complexes of nitrogen containing macrocyclic ligands effective as catalysts for dismutating superoxide |
WO1995028968A1 (en) * | 1994-04-22 | 1995-11-02 | Monsanto Company | Diagnostic image analysis with metal complexes |
WO1996039396A1 (en) * | 1995-06-06 | 1996-12-12 | Monsanto Company | Manganese or iron complexes of nitrogen-containing macrocyclic ligands effective as catalysts for dismutating superoxide |
Cited By (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8217026B2 (en) | 1999-01-25 | 2012-07-10 | Aeolus Sciences, Inc. | Substituted porphyrins |
US9289434B2 (en) | 1999-01-25 | 2016-03-22 | 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 |
US7445641B1 (en) | 1999-05-27 | 2008-11-04 | Pharmacia Corporation | Biomaterials modified with superoxide dismutase mimics |
WO2000072893A2 (en) * | 1999-05-27 | 2000-12-07 | Monsanto Company | Biomaterials modified with superoxide dismutase mimics |
WO2000072893A3 (en) * | 1999-05-27 | 2001-08-30 | Monsanto Co | Biomaterials modified with superoxide dismutase mimics |
WO2002053142A3 (en) * | 2001-01-05 | 2002-12-27 | Metaphore Pharmaceuticals Inc | Compositions and methods for enhancing cytokine activity and treating hypotension associated with the administration of cytokines |
WO2002053142A2 (en) * | 2001-01-05 | 2002-07-11 | Metaphore Pharmaceuticals, Inc. | Compositions and methods for enhancing cytokine activity and treating hypotension associated with the administration of cytokines |
WO2002058686A3 (en) * | 2001-01-26 | 2003-02-06 | Metaphore Pharmaceuticals Inc | Method of treatment of neurodegenerative disorders using pentaaza-macrocyclic ligand complexes |
WO2002058686A2 (en) * | 2001-01-26 | 2002-08-01 | Metaphore Pharmaceuticals, Inc. | Method of treatment of neurodegenerative disorders using pentaaza-macrocyclic ligand complexes |
US8468189B2 (en) | 2006-11-08 | 2013-06-18 | Okinawa Institute Of Science And Technology Promotion Corporation | Iterated variational regularization combined with componentwise regularization |
US11382895B2 (en) | 2008-05-23 | 2022-07-12 | National Jewish Health | Methods for treating injury associated with exposure to an alkylating species |
Also Published As
Publication number | Publication date |
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CA2248964A1 (en) | 1997-09-18 |
JP2000507929A (en) | 2000-06-27 |
IL125993A0 (en) | 1999-04-11 |
NO984165L (en) | 1998-11-10 |
BR9707978A (en) | 1999-07-27 |
NO984165D0 (en) | 1998-09-10 |
AU2065697A (en) | 1997-10-01 |
KR19990087783A (en) | 1999-12-27 |
EP0888115A1 (en) | 1999-01-07 |
CZ277698A3 (en) | 1999-02-17 |
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