EP1353655A2 - Methode de traitement de troubles neurodegeneratifs - Google Patents

Methode de traitement de troubles neurodegeneratifs

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Publication number
EP1353655A2
EP1353655A2 EP02703228A EP02703228A EP1353655A2 EP 1353655 A2 EP1353655 A2 EP 1353655A2 EP 02703228 A EP02703228 A EP 02703228A EP 02703228 A EP02703228 A EP 02703228A EP 1353655 A2 EP1353655 A2 EP 1353655A2
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alkyl
aryl
acid
substituted
carbon atoms
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Daniela Salvemini
Dennis P. Riley
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Metaphore Pharmaceuticals Inc
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Metaphore Pharmaceuticals Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • This invention relates to methods of treatment and inhibition of neurodegenerative disorders in a mammal by administering therapeutic amounts of catalysts for the dismutation of superoxide to the mammal. Also provided are pharmaceutical compositions comprising catalysts for the dismutation of superoxide for use in these methods.
  • Neurodegenerative diseases include Parkinson's disease, Huntington's disease, Alzheimer's disease, and multiple sclerosis. Most of the diseases are typified by onset during the middle adult years and lead to rapid degeneration of specific subsets of neurons within the neural system, ultimately resulting in premature death. There is no known cure for any of the stated diseases.
  • Parkinson's disease is a common neurodegenerative disorder which appears in mid to late life. Familial and sporadic cases occur, although familial cases account for only 1-2 percent of the observed cases. The neurological changes which cause this disease are somewhat variable and not fully understood. Patients frequently have nerve cell loss with reactive gliosis and Lewy bodies in the substantia nigra and locus coeruleus of the brain stem. Similar changes are observed in the nucleus basalis of Meynert. As a class, the nigrostriatal dopaminergic neurons seem to be most affected.
  • Parkinson's Disease is a degenerative disease of the nervous system which affects one person in fifty over fifty years of age and one person in twenty over seventy years of age, without gender or social bias. Described by James Parkinson in 1817,the shaking palsy is comprised of a triad of tremor at rest, muscular rigidity and slowness of movement. Accurate description of the disease during the period of the Industrial Revolution has prompted people to speculate that environmental exposure to toxic chemicals precipitates the disease. Exposure to manganese precipitated a Parkinsonian syndrome in miners which also includes schizophreniform behaviors. Some epidemiologic studies have found association between industrial exposure to copper, manganese and copper simultaneously with iron and the incidence of Parkinson's disease, Gorell J.
  • Xenobiotics natural and man made insecticides have also been suggested as candidate agents because they precipitate on occasion motor disturbances in animals and man somewhat akin to Parkinsonism.
  • both inorganic and organic chemicals may contribute to the toxicity mechanism.
  • the disease is progressive though not in all cases. Dementia with Alzheimer type pathological changes follows but does not precede the development of Parkinson's Disease in about one quarter of diagnosed cases.
  • Parkinson's Disease progresses to differing extents in different patients, most commonly over a seven to ten year timeframe from the time of diagnosis. Some patients experience generalized wasting and anorexia, depression and mental changes frequently occur. Approximately one quarter develop Alzheimer type clinical changes in cognitive functioning and measurable Alzheimer pathological changes occur in up to forty percent of cases.
  • gliosis which retards neuronal growth in the brain. Renkawek et al., "Dementia, Gliosis and Expression of the Small Heat Shock Proteins hsp27 and alpha B-crystallin in Parkinson 's Disease " Neuroreport 1999 Aug 2; 10(11):2273-6. Gliosis is a process in which astrocytes form glial scars in the central nervous system. Since minimizing gliosis can both facilitate neuronal regeneration, there is a need for treatments which inhibit gliosis.
  • Parkinson's disease generally develops asymmetrically with tremors in one hand o: leg and progresses into symmetrical loss of voluntary movement. Eventually, the patient becomes incapacitated by rigidity and tremors. In the advanced stages the disease is frequently accompanied by dementia. Diagnosis of Parkinson's disease can only be made after the onset of the disease.
  • Anticholinergic compounds, propranolol, primidone and levodopa are frequently administered to modify neural transmissions and thereby suppress the symptoms of the disease, though there is no known therapy which halts or slows the underlying progression. Deprenyl has shown some therapeutic promise. Clinical and experimental reports have increased interest in the possibility that environmental chemicals, including herbicides, may be related to the development of Parkinson's disease. See Thiruchelvam M. et al, Brain Res, 873(2), 225-34 (Aug 11, 2000); Liou H.H. et al, Neurology, 48(6), 1583-1588 (Jun 1997).
  • ROS reactive oxygen species
  • the herbicide called paraquat is structurally similar to MPP+, and both seem to exert their toxic effects by interfering with the first step of electron transport chain of mitochondria, thus blocking respiration and killing the cells.
  • Iannone et al. "Intra-nigral infusion ofCu-Free Superoxide Dismutase Prevents Paraquat- Induced Behavioural Stimulation and ECoG Epileptogenic Discharges in Rats " Neuropharm. 30, No. 8 893-898 (1991).
  • the hypothesized mechanisms for the neurotoxic effects of these herbicides further involves an impairment of energy metabolism followed by increased free radical generation.
  • This reaction is catalyzed in vitro by the ubiquitous superoxide dismutase enzymes.
  • a particularly effective family of non-peptidic catalysts for the dismutation of superoxide consists of the manganese(II), manganese(III), iron(II) or iron(III) complexes of nitrogen- containing fifteen-membered macrocyclic ligands which catalyze the conversion of superoxide into oxygen and hydrogen peroxide, as described in U.S. Patents Nos. 5,874,421 and 5,637,578, all of which are incorporated herein by reference.
  • non-peptidic catalysts which have been shown to have superoxide dismutating activity are the salen-transition metal cation complexes, as described in U.S. Patent No. 5,696,109 and complexes of porphyrins with iron and manganese cations.
  • BBB blood-brain barrier
  • CNS central nervous system
  • the blood-brain barrier which consists of the endothelium of the brain vessels, the basal membrane and neuroglial cells, acts to limit penetration of substances into the brain.
  • the structure of the BBB is subdivided into two components: the endothelial or capillary barrier and the ependymal barrier Banks, W. A., Kastin, A. J., Barrera, "Delivering peptides to the central nervous system: Dilemmas and strategies," Pharm. Res. 8:1345-1350(1991).
  • an object of the present invention is to provide a method of treating neurodegenerative disorders, the method comprising administering to a subject a therapeutically, prophylactically, pathologically or resuscitative effective amount of a composition comprising a non-proteinaceous catalyst for the dismutation of superoxide anions.
  • Another object of the present invention is to provide a pharmaceutical composition for the treatment of neurodegenerative disorders comprising a non-proteinaceous catalyst for the dismutation of superoxide anions and a pharamaceutically acceptable carrier.
  • a further object of the present invention is to provide a method for treatment of oxidative stress to the components of neurons, the method comprising administering to a subject a therapeutically, prophylactically, pathologically or resuscitative effective amount of a composition comprising a non-proteinaceous catalyst for the dismutation of superoxide anions.
  • Yet another object of the present invention is to provide a method for treatment of gliosis, the method comprising administering to a subject a therapeutically, prophylactically, pathologically or resuscitative effective amount of a composition comprising a catalyst for the dismutation of superoxide anions.
  • Figure 1(a) is a graph of high voltage epileptogenic discharges induced at various times (at 25 minutes, at 60 minutes and at 140 minutes) after infusion of paraquat into the substantia nigra of rats.
  • Figure 1(b) is a graph of high voltage epileptogenic discharges induced after administration of 10 ⁇ g of the SOD mimic M40401 given in the substantia Nigra of rats with administration, 15 minutes later, of paraquat in the subtantia nigra of these rats. The measurements were taken at various times after the administration of the paraquat (at 30 minutes, 60 minutes and 140 minutes).
  • Figure 2(a) is a histopathologic image of the neuropathological effects of a single unilateral injection of Paraquat (50 ⁇ g) into the Substantia Nigra of a vehicle-treated rat.
  • Figure 2(b) is a histopathologic image of the neuropathological effects on the Substantia Nigra from a rat pretreated with 1 ⁇ l of saline, and 15 minutes later, given 50 ⁇ g of Paraquat.
  • Figure 2(c) is a histopathologic image of the neuropathologic effects on the Substantia Nigra from a rat pretreated with 10 ⁇ g of M40401, and 15 minutes later, given 50 ⁇ g of Paraquat. A marked neuroprotection is evident from the image.
  • ROS reactive oxygen species
  • non-peptidic catalysts for the dismutation of superoxide or “non-proteinaceous catalysts for the dismutation of superoxide” mean a low-molecular weight catalyst for the conversion of superoxide anions into hydrogen peroxide and molecular oxygen.
  • These catalysts commonly consist of an organic ligand and a chelated transition metal ion, preferably manganese(II), manganese(III), iron(II) or iron(III).
  • the term may include catalysts containing short-chain polypeptides (under 15 amino acids) or macrocyclic structures derived from amino acids, as the organic ligand.
  • the term explicitly excludes a superoxide dismutase enzyme obtained from any species.
  • substituted means that the described moiety has one or more substituents comprising at least 1 carbon or heteroatom, and further comprising 0 to 22 carbon atoms, more preferably from 1 to 15 carbon atoms, and comprising 0 to 22 heteroatoms, more preferably from 0 to 15 heteroatoms.
  • heteroatom refers to those atoms that are neither carbon nor hydrogen bound to carbon and are selected from the group consisting of: O, S, N, P, Si, B, F, CI, Br, or I. These atoms may be arranged in a number of configurations, creating substituent groups which are unsaturated, saturated, or aromatic.
  • substituents include branched or unbranched alkyl, alkenyl, or alkynyl, cyclic, heterocyclic, aryl, heteroaryl, allyl, polycycloalkyl, polycycloaryl, polycycloheteroaryl, imines, aminoalkyl, hydroxyalkyl, hydroxyl, phenol, amine oxides, thioalkyl, carboalkoxyalkyl, carboxylic acids and their derivatives, keto, ether, aldehyde, amine, amide, nitrile, halo, thiol, sulfoxide, sulfone, sulfonic acid, sulfide, disulfide, phosphonic acid, phosphinic acid, acrylic acid, sulphonamides, amino acids, peptides, proteins, carbohydrates, nucleic acids, fatty acids, lipids, nitro, hydroxylamines, hydroxamic acids, thiocarbonyls,
  • 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- 1-butenyl, 2,3-dimethyl-2-butenyl, 1-pentenyl, 1-hexenyl,
  • alkynyl alone or in combination, means an alkyl radical having one or more triple bonds. Examples of such alkynyl groups include, but are not limited to, ethynyl, propynyl (propargyl), 1-butynyl, 1-octynyl, 9-octadecynyl, 1,3-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.
  • 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,
  • 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- 1 -yhnethyl, 2-( 1 -cyclohexen- 1 -yl)ethyl, 3 -(1 -cyclopenten- 1 -yl)propyl, 1 -(1 -cyclohe; l-(l-cyclopenten-l-yl)hexyl, 6-(l-cyclohexen-l-yl)hexyl, l-(l-cyclopenten-l-yl)nonyl and
  • alkylcycloalkyl and “alkenylcycloalkyl” mean a cycloalkyl radical as 5 defined above which is substituted by an alkyl or alkenyl radical as defined above.
  • alkylcycloalkyl and alkenylcycloalkyl radicals include, but are not limited to, 2-ethylcyclobutyl, 1-methylcyclopentyl, 1-hexylcyclopentyl, 1-methylcyclohexyl, l-(9-octadecenyl)cyclopentyl and l-(9-octadecenyl)cyclohexyl.
  • alkylcycloalkenyl and “alkenylcycloalkenyl” means a cycloalkenyl 0 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-cyclopentyl, l-hexyl-2-cyclopentenyl, l-ethyl-2-cyclohexenyl, l-butyl-2-cyclohexenyl, l-(9-octadecenyl)-2-cyclohexenyl and 1 -(2-pentenyl)-2-cyclohexenyl.
  • aryl alone or in combination, means a phenyl or naphthyl radical which optionally carries one or more substituents selected from alkyl, cycloalkyl, cycloalkenyl, aryl, heterocycle, alkoxyaryl, alkaryl, alkoxy, halogen, hydroxy, amine, cyano, nitro, alkylthio, phenoxy, ether, trifluoromethyl and the like, such as phenyl, p-tolyl, 4-methoxyphenyl, 4-(tert-butoxy)phenyl, 4-fluorophenyl, 4-chlorophenyl, 0 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 contaimng at least one heteroatom 5 within the ring.
  • heteroatom refer to atoms that are neither carbon nor hydrogen bound to a carbon.
  • heterocyclics include, but are not limited to, pyrrolidinyl, piperidyl, imidazolidinyl, tefrahydrofuryl, tetrahydrothienyl, furyl, thienyl, pyridyl, quinolyl, isoquinolyl, pyridazinyl, pyrazinyl, indolyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, pyridinyl, benzoxadiazolyl, benzothiadiazolyl, triazolyl and tetrazolyl 0 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 5 most common of the other kinds of atoms include nitrogen, oxygen and sulfur.
  • the ring structure can also contain more than one ring.
  • saturated, partially saturated or unsaturated ring structure means a ring structure in which one carbon of the ring is also part of the fifteen-membered macrocyclic ligand.
  • the ring structure can contain 3 to 20, preferably 5 to 10, carbon atoms and can also contain nitrogen, oxygen and or sulfur atoms.
  • nitrogen containing heterocycle means ring structures in which 2 carbons and a nitrogen of the ring are also part of the fifteen-membered macrocyclic ligand.
  • the ring structure can contain 2 to 20, preferably 4 to 10, carbon atoms, can be substituted or unsubstituted, partially or fully unsaturated or saturated, and can also contain nitrogen, oxygen and/or sulfur atoms in the portion of the ring which is not also part of the fifteen-membered macrocyclic ligand.
  • organic acid anion refers to carboxylic acid anions having from about 1 to about 18 carbon atoms.
  • halide means chloride, fluoride, iodide, or bromide.
  • R groups means all of the R groups attached to the carbon atoms of the macrocycle, i.e., R, R', R l5 R'êt 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 ,
  • the mammal patient in the methods of the invention is a mammal suffering from Parkinson's disease or other neurodegenerative disorder. It is envisioned that a mammal patient to which the catalyst for the dismutation of superoxide will be administered, in the methods or compositions of the invention, will be a human. However, other mammal patients in veterinary (e.g., companion pets and large veterinary animals) and other conceivable contexts are also contemplated.
  • treatment relate to any treatment of Parkinson's disease and other neurodegenerative disorders and include: (1) preventing Parkinson's disease or other neurodegenerative disorder from occurring in a subject; (2) inhibiting the progression or initiation of neurodegeneration, i.e., arresting or limiting its development; or (3) ameliorating or relieving the symptoms of the disease.
  • neurodegenerative disorder relates to any disease, such as Parkinson's disease, Huntington's disease, multiple sclerosis, and Alzheimer disease, or any other disorder relating to or marked by nervous degeneration related to reactive oxygen species.
  • precursor ligand means the organic ligand of a SOD mimic without the chelated transition metal cation and charge neutralizing anions.
  • terapéuticaally effective amounts means those amounts that, when administered to a particular subject in view of the nature and severity of that subject's disease or condition, will have the desired therapeutic effect, e.g., an amount which will cure, or at least partially arrest or inhibit the disease or condition. All references cited herein are explicitly incorporated by reference.
  • the present invention is directed to methods and compositions for the prevention and treatment of Parkinson's disease and other neurodegenerative disorders comprising administering compositions containing a non-proteinaceous catalyst for dismutation of superoxide.
  • Preferred catalysts include a small molecular weight organic ligand mimics of the superoxide dismutase enzyme (SOD mimetics or SODms).
  • a basis for the present invention is the finding that treatment with a catalyst for the dismutation of superoxide inhibits the progression and initiation of neurodegenerative diseases. It is believed that such neurodegenerative diseases result, in whole or in part, from oxidative stress mediated by overproduction of superoxide anions. See Bogdanov et al., "Increased Oxidative Damage to DNA in ALS Patients " Free Radic Biol Med 2000 Oct. l;29(7):652-8; Olanow, C. W., "An Introduction to the Free Radical Hypothesis in Parkinson 's Disease” Annals of Neurology 32: 52-59 (1992); Albers et al., "Mitochondrial dysfunction and oxidative stress in aging and neurodegenerative disease " J.
  • the compound employed in the method of the present invention will comprise a non-proteinaceous catalyst for the dismutation of superoxide anions ("SOD mimic") as opposed to a native form of the SOD enzyme.
  • SOD mimic means a low-molecular- weight catalyst for the conversion of superoxide anions into hydrogen peroxide and molecular oxygen.
  • These catalysts consist of an organic ligand having a pentaazacyclopentadecane portion and a chelated transition metal ion, preferably manganese or iron.
  • the term may include catalysts containing short-chain polypeptides (under 15 amino acids), or macrocyclic structures derived from amino acids, as the organic ligand.
  • SOD mimics are useful in the method of the present invention as compared to native SOD because of the limitations associated with native SOD therapies such as, solution instability, limited cellular accessibility due to their size, immunogenicity, bell-shaped dose response curves, short half-lives, costs of production, and proteolytic digestion (Salvemini et al, (1999) Science 286: 304-306).
  • native SOD CuZn
  • SOD mimics have an approximate molecular weight of 500 to 600 kD.
  • the compounds employed in the method of the invention must be able to efficiently cross the blood brain barrier to penetrate the cerebral cavity in order to cause the dismutation of superoxide anions. Therefore, the smaller size exhibited by the SOD mimics is particularly advantageous for the present invention because it facilitates passage of the compound through the blood brain barrier and into the cerebral cavity.
  • the SOD mimics utilized in the present invention comprise an organic ligand chelated to a metal ion.
  • Particularly preferred catalysts are pentaaza-macrocyclic ligand compounds, more specifically the manganese(II), manganese (III), iron(II) and iron(III) chelates of pentaazacyclopentadecane compounds.
  • the pentaaza macrocyclic ligand complexes of Mn(II) are particularly advantageous for use in the present invention because, in addition to a low molecular weight, they are highly selective for the dismutation of super oxide anions and possess catalytic rates similar or faster than native SOD counterparts.
  • An example of this class of SOD mimic, M40401 is set forth in the examples below.
  • M is a cation of a transition metal, preferably manganese or iron; wherein R, R', ⁇ > R'u R 2 > R' 2 , R 3 J R' 3 j 45 R' 4 , s> R'SJ Res R' ⁇ ' ⁇ ⁇ '7> R-8> R-'s> ⁇ 9> an( l R-' ⁇ independently represent hydrogen, or substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylcycloalkyl, cycloalkenylalkyl, alkylcycloalkyl, alkylcycloalkenyl, alkenylcycloalkyl, alkenylcycloalkenyl, heterocyclic, aryl and aralkyl radicals; R j or R and R 2 or R' 2 , R 3 or R' 3 and R 4 or R
  • w, x, y and z independently are integers from 0 to 10 and M
  • L and I are independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, alkaryl, alkheteroaryl, aza, amide, ammonium, oxa, thia, sulfonyl, sulfinyl, sulfonamide, phosphoryl, phosphinyl, phosphino, phosphonium, keto, ester, alcohol, carbamate, urea, thiocarbonyl, borates, boranes, boraza, silyl, siloxy, silaza and combinations thereof.
  • M40401 A preferred compound of this class of pentaaza-macrocyclic class is designated M40401 and is represented by the following formula:
  • M40403 Another perferred compound of this class of pentaaza-macrocyclic class is designated M40403 and is represented by the following formula:
  • the catalysts are substituted pentaaza-macrocyclic ligand compounds, which may be represented by the following formula:
  • a nitrogen of the macrocycle and the two adjacent carbon atoms to which it is attached independently form a substituted, unsaturated, nitrogen-containing heterocycle W having 2 to 20 carbon atoms, which may be an aromatic heterocycle, in which case the hydrogen attached to the nitrogen which is both part of the heterocycle and the macrocycle and the R groups attached to the carbon atoms which are both part of the heterocycle and the macrocycle are absent; and wherein R, R l9 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 , Rg, and R' 9 independently represent hydrogen, or substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylcycloalkyl, cycloalkenyl
  • w, x, y and z independently are integers from 0 to 10 and M, L and I are independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, alkaryl, alkheteroaryl, aza, amide, ammonium, oxa, thia, sulfonyl, sulfinyl, sulfonamide, phosphoryl, phosphinyl, phosphino, phosphonium, keto, ester, alcohol, carbamate, urea, thiocarbonyl, borates, boranes, boraza, silyl, siloxy, silaza and combinations thereof; and combinations of any of the above; wherein M is a cation of
  • the substituted pentaaza-macrocyclic ligand set forth above W is a substituted pyridino moiety and U and V are trans- cyclohexanyl fused rings.
  • the pentaaza-macrocyclic or substituted pentaaza-macrocyclic ligand compounds useful in the present invention can have any combinations of substituted or unsubstituted R groups, saturated, partially saturated or unsaturated cyclics, ring structures, nitrogen containing heterocycles, or straps as defined above.
  • 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
  • the "R” groups attached to the carbon atoms of the macrocycle can be in the axial or equatorial position relative to the macrocycle.
  • the "R” group is other than hydrogen or when two adjacent “R” groups, i.e., on adjacent carbon atoms, together with the carbon atoms to which they are attached form a saturated, partially saturated or unsaturated cyclic or a nitrogen containing heterocycle, or when two R groups on the same carbon atom together with the carbon atom to which they are attached form a saturated, partially saturated or unsaturated ring structure, it is preferred that at least some of the "R” groups are in the equatorial position for reasons of improved activity and stability. This is particularly true when the complex contains more than one "R" group which is not hydrogen.
  • the transition metal center of the catalyst is thought to be the active site of catalysis, wherein the manganese or iron ion cycles between the (II) and (III) states.
  • the catalyst will function with a k cat of about 10 "6 to 10 "8 .
  • pentaaza-macrocyclic ligand compound catalysts described have been further described in U.S. Patent No. 5,637,578, PCT application WO98/58636, and copending application USSN 09/398,120, all of which are hereby incorporated by reference.
  • These pentaaza-macrocyclic ligand catalysts may be produced by the methods disclosed in U.S. Patent No. 5,610,293.
  • the pentaaza-macrocyclic ligand compound catalysts used in the present invention be synthesized by the template method described in copending applications USSN 60/136,298 and USSN 09/398,120, incorporated herein by reference.
  • Contemplated equivalents of the general formulas set forth above for the compounds and derivatives as well as the intermediates are compounds otherwise corresponding thereto and having the same general properties such as tautomers of the compounds and such as wherein one or more of the various R groups are simple variations of the substituents as defined therein, e.g. , wherein R is a higher alkyl group than that indicated, or where the tosyl groups are other nitrogen or oxygen protecting groups or wherein the O-tosyl is a halide.
  • Anions having a charge other than 1, e.g., carbonate, phosphate, and hydrogen phosphate can be used instead of anions having a charge of 1, so long as they do not adversely affect the overall activity of the complex.
  • a substituent is designated as, or can be, a hydrogen
  • the exact chemical nature of a substituent which is other than hydrogen at that position e.g., a hydrocarbyl radical or a halogen, hydroxy, amino and the like functional group, is not critical so long as it does not adversely affect the overall activity and/or synthesis procedure.
  • manganese(IL ⁇ ) complexes will be equivalent to the subject manganese(II) complexes.
  • the compounds of the invention can be formulated as pharmaceutical or veterinary compositions.
  • the compounds are formulated in ways consonant with these parameters.
  • the compositions of the present invention comprise a therapeutically or prophylactically effective dosage of a catalyst for the dismutation of superoxide.
  • the catalyst for the dismutation of superoxide is preferably a SOD mimetic, as described in more detail above.
  • the SODms of this invention are preferably used in combination with a pharmaceutically acceptable carrier.
  • compositions of the present invention may be incorporated in conventional pharmaceutical formulations (e.g. injectable solutions) for use in treating humans or animals in need thereof.
  • Pharmaceutical compositions can be administered by subcutaneous, intravenous, or intramuscular injection, or as large volume parenteral solutions and the like.
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques.
  • a parenteral therapeutic composition may comprise a sterile isotonic saline solution containing between 0.1 percent and 90 percent weight to volume of the catalysts for the dismutation of superoxide.
  • a preferred solution contains from about 5 percent to about 20 percent, more preferably from about 5 percent to about 17 percent, more preferably from about 8 to about 14 percent, and most preferably about 10 percent catalysts for dismutation of superoxide in solution (% weight per volume).
  • 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 room temperature 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.
  • adjuvants such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
  • 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. It will be appreciated that the unit content of active ingredients contained in an individual dose of each dosage form need not in itself constitute an effective amount, as the necessary effective amount could be reached by administration of a number of individual doses. The selection of dosage depends upon the dosage form utilized, the condition being treated, and the particular purpose to be achieved according to the determination of those skilled in the art.
  • the dosage regimen for treating a disease condition with the compounds and/or compositions of this invention is selected in accordance with a variety of factors, including the type, age, weight, sex, diet and medical condition of the patient, the route of administration, pharmacological considerations such as the activity, efficacy, pharmacokinetic and toxicology profiles of the particular compound employed, whether a drug delivery system is utilized and whether the compound is administered as part of a drug combination.
  • the dosage regimen actually employed may vary widely and therefore may deviate from the preferred dosage regimen set forth above.
  • compositions of the present invention are preferably administered to a human.
  • these extracts are also useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, avians, and the like. More preferred animals include horses, dogs, cats, sheep, and pigs.

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  • Health & Medical Sciences (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Neurosurgery (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Psychiatry (AREA)
  • Hospice & Palliative Care (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Enzymes And Modification Thereof (AREA)

Abstract

La présente invention concerne des compositions pharmaceutiques et des méthodes dans lesquelles sont utilisées ces compositions pour le traitement de troubles neurodégénératifs. Ces compositions contiennent un catalyseur de dismutation de superoxyde, y compris l'enzyme superoxide dismutase (SOD) et les complexes métalliques dérivés d'un ligand organique de faible poids moléculaire servant de substances mimétiques de l'enzyme (substances mimétiques SOD ou SODms).
EP02703228A 2001-01-26 2002-01-23 Methode de traitement de troubles neurodegeneratifs Withdrawn EP1353655A2 (fr)

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US26449301P 2001-01-26 2001-01-26
US264493P 2001-01-26
PCT/US2002/002108 WO2002058686A2 (fr) 2001-01-26 2002-01-23 Methode de traitement de troubles neurodegeneratifs

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ITTO20040124A1 (it) 2004-03-01 2004-06-01 Medestea Internaz Srl Nuovi impieghi in terapia di derivati di n-piperidina particolarmente per il trattamento di patologie neurodegenerative
EP2056675B1 (fr) 2006-10-12 2019-01-09 Galera Labs, LLC Procédés de traitement de mucosites orales
US9149483B2 (en) 2011-09-26 2015-10-06 Galera Labs, Llc Methods for treatment of diseases
DK3334744T3 (da) 2015-08-11 2020-07-27 Galera Labs Llc Makrocykliske pentaaza-ringkomplekser med oral biotilgængelighed
WO2018098484A1 (fr) 2016-11-28 2018-05-31 Texas Tech University System Cibles médicamenteuses de maladies cérébrales humaines et de vieillissement retardé
CA3053779A1 (fr) * 2017-02-15 2018-08-23 Galera Labs, Llc Complexes de noyaux pentaaza-macrocycliques destines a une administration intestinale locale
IL295620B2 (en) 2017-04-13 2024-01-01 Galera Labs Llc Cancer immunotherapy combined with a macrocyclic ring pentase complex
JP2022551494A (ja) * 2019-10-10 2022-12-09 ガレラ・ラブス・リミテッド・ライアビリティ・カンパニー マンガン含有配位錯体の水性製剤の製造方法、製剤および処置方法

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5426122A (en) * 1989-03-17 1995-06-20 Cedars-Sinai Medical Center Methods for reducing blood pressure with dimercaptosuccinic acid (DMSA)
JP3155552B2 (ja) * 1991-07-19 2001-04-09 モンサント カンパニー 超酸化物の不均斉変化に有効な触媒としての窒素含有−大環状リガンドのマンガン錯体
US5696109A (en) * 1992-12-07 1997-12-09 Eukarion, Inc. Synthetic catalytic free radical scavengers useful as antioxidants for prevention and therapy of disease
US5747026A (en) * 1993-10-15 1998-05-05 University Of Alabama At Birmingham Research Foundation Antioxidants
WO1997033588A1 (fr) * 1996-03-13 1997-09-18 Monsanto Company Complexes ferreux de ligands macrocycliques contenants de l'azote efficaces en tant que catalyseurs de dismutation de superoxyde
US6214817B1 (en) * 1997-06-20 2001-04-10 Monsanto Company Substituted pyridino pentaazamacrocyle complexes having superoxide dismutase activity
US6180620B1 (en) * 1997-06-20 2001-01-30 G.D. Searle & Co. Analgesic methods using synthetic catalysts for the dismutation of superoxide radicals
GB9801398D0 (en) * 1998-01-22 1998-03-18 Anggard Erik E Chemical compounds
GB9824282D0 (en) * 1998-11-05 1998-12-30 Microbiological Research Agenc Delivery of superoxide dismutase to neuronal cells

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
ALBERS ET AL: "Mitochondrial dysfunction and oxidative stress in aging and neurodegenerative disease", J. NEURAL TRANSM. SUPPL., vol. 59, 2000, pages 133 - 154, XP008046819 *
BEERS M.H.; BERKOW R.: "The Merck Manual of Diagnosis and Therapy, seventeenth Edition", 1999, MERCK RESEARCH LABORATORIES, WHITEHOUSE STATION, N.J. *
See also references of WO02058686A3 *

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