WO2004019936A1 - Catalyseurs de transformation du peroxynitrite destines au traitement ou a la prevention de maladies engendrees par des reactions induites par le peroxynitrite - Google Patents

Catalyseurs de transformation du peroxynitrite destines au traitement ou a la prevention de maladies engendrees par des reactions induites par le peroxynitrite Download PDF

Info

Publication number
WO2004019936A1
WO2004019936A1 PCT/EP2003/007556 EP0307556W WO2004019936A1 WO 2004019936 A1 WO2004019936 A1 WO 2004019936A1 EP 0307556 W EP0307556 W EP 0307556W WO 2004019936 A1 WO2004019936 A1 WO 2004019936A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
diseases
peroxynitrite
general formula
treatment
Prior art date
Application number
PCT/EP2003/007556
Other languages
German (de)
English (en)
Inventor
Gisbert Depke
Margrit Hillmann
Günter Michl
Johannes Platzek
Detlev Sülzle
Roland Neuhaus
Original Assignee
Schering Aktiengesellschaft
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Schering Aktiengesellschaft filed Critical Schering Aktiengesellschaft
Priority to EP03790798A priority Critical patent/EP1531808A1/fr
Priority to AU2003246687A priority patent/AU2003246687A1/en
Priority to JP2004531801A priority patent/JP2006500383A/ja
Priority to CA002493199A priority patent/CA2493199A1/fr
Publication of WO2004019936A1 publication Critical patent/WO2004019936A1/fr

Links

Classifications

    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/409—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having four such rings, e.g. porphine derivatives, bilirubin, biliverdine
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/41—Porphyrin- or corrin-ring-containing peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/16—Central respiratory analeptics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • 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
    • 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
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • A61P25/06—Antimigraine agents
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P25/20—Hypnotics; Sedatives
    • 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
    • A61P25/24—Antidepressants
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the invention relates to the use of metal-containing complexes which catalyze the rearrangement of peroxynitrite for the production of medicaments for the treatment of diseases.
  • Peroxynitrite was developed by Beckman et al. (Beckman et al., 1990, Proc. Natl. Acad. Sci. USA. 87, 1620-1624) as a toxic metabolite described by the
  • Peroxynitrite reacts with a variety of proteins by oxidizing or nitrating amino acid residues. Nitrotyrosine residues are found more frequently in the tissue of patients suffering from multiple sclerosis, since peroxynitrite causes the tyrosine residues of the filaments of the motor neurons to nitrate. Because of the disturbed contraction of the filaments
  • peroxynitrite is rearranged into harmless end products using a catalyst. It is possible to convert large amounts of peroxynitrite with only small concentrations of catalyst.
  • An advantage of this approach is that it does not lead to the formation of disadvantageous decomposition products such as the reactive oxygen species and that the inhibition of the
  • Metal-containing complexes have hitherto been known as possible conversion catalysts (WO 95/31197, US 6,245,758, WO 98/04132, US 5,872,124, WO 00/75144, WO 01/26655, US 6,372,727).
  • the by Salvemini et al. Metalloporphyrins described have a protective effect in inflammation models (Salvemini et al., 1998, Proc. Natl. Acad. Sei. USA. 95, 2659-2663 and British J. Pharmacol., 1999, 127, 685-692).
  • the same class of compounds was developed by Cuzzocrea et al. described as effective in an intestinal artery occlusion model (Cuzzocrea et al., 2000, FASEB J.
  • Mackensen et al. first demonstrated the effectiveness of a manganese-containing porphyrin in a focal ischemia model, the focal MCAO (middle cerebral artery occlusion) (Mackensen et al., 2001, J. Neurosci. 21, 4582 - 4592).
  • the present invention solves the problem by providing porphyrin complexes that serve as peroxynitrite rearrangement catalysts.
  • These porphyrins are characterized by their good in vivo availability and by their chemical stability. They have already been used as a means of diagnosing tumors and their use for necrosis and infarct imaging has already been disclosed in WO 00/05235.
  • the porphyrins according to the invention of WO 00/05235 catalyze the rearrangement of peroxynitrite into harmless end products, namely nitrate and nitrite.
  • the Porphyrins according to the invention are protective and protect the cells from peroxynitrite damage induced by the peroxynitrite donor SIN-1.
  • the present porphyrins are already very well characterized and it is known that they have no side effects, good water solubility and good in vivo availability.
  • porphyrin complexes which on the one hand have peroxynitrite-redistributing properties and on the other hand have diagnostic properties, enables targeted treatment of the diseases caused by peroxynitrite and their diagnosis using imaging methods, such as, for. B. MRI.
  • the present invention provides pharmaceutical agents for this targeted treatment and relates to a porphyrin complex consisting of a ligand of the general formula I.
  • R ' is a hydrogen atom or a C ⁇ C j alkyl radical
  • R represents R, a group -CO-Z or a group - (NH) 0 - (A) q-NH-D, wherein Z is a group -OL, with L being an inorganic or organic cation or a C 1 -C 4 alkyl radical,
  • A represents a phenyleneoxy or a C 1 -C 4 -alkylene or C 7 -C 12 aralkylene group interrupted by one or more oxygen atoms, o and q independently of one another denote the numbers 0 or 1 and
  • D represents a hydrogen atom or a group -CO-A- (COOL) 0 - (H) m , where m is 0 or 1 and provided that the sum of m and o is 1,
  • K is a complexing agent of the general formula (IIa), (IIb), (IIc), (IIID) or (III), where R is in the case that K is a complexing agent of the formula (IIA)
  • Formula (llb), (llc), (lld) or (lle) has the same meaning as D, with the proviso that a direct oxygen-nitrogen bond is not permitted, and K for a complexing agent of the general formula (lla ), (llb), (llc), (lld), (lle) or (llf)
  • R 6 represents a hydrogen atom, a straight-chain or branched C n - C 7 alkyl group, a phenyl or benzyl group,
  • a 2 for a phenylene -CH 2 -NHCO-CH 2 -CH (CH 2 COOH) -C 6 H 4 -ß-, -C 6 H 4 -O- (CH 2 ) 0 . 5-ß, -C 6 H 4 - (OCH 2 CH 2 ) o. ⁇ -N (CH 2 COOH) -CH2-ß or one optionally by one or more oxygen atoms, 1 to 3-NHCO-, 1 to 3 - CONH groups interrupted and / or with 1 to 3- (CH 2 ) o. 5 COOH groups substituted CC 12 alkylene or C 7 -C 12 -
  • Alkylene group where ß stands for the binding site on X, X for a -CO or NHCS group and
  • L, L, L and L independently represent a hydrogen atom or a
  • Metal ion equivalent of an element of the atomic number mentioned above provided that at least two of these substituents for metal ion equivalents and that to balance any charges present in the metalloporphyrin, further anions are present and in which free carboxylic acid groups not required for complexation can also be present as salts with physiologically tolerable inorganic and / or organic cations or as esters or as ide, and in addition also increase the rate of redistribution of peroxynitrite into harmless products and can thus be used for the manufacture of a drug for the treatment and prophylaxis of radical-mediated cell damage.
  • Peroxynitrite is a strong oxidant, which is created by the reaction of nitrogen oxide (NO) and superoxide anion (0 2 ⁇ ). It could be shown that NO is generated in many cells such as macrophages, neutrophils, hepatocytes and endothelial cells. The direct reaction of NO and 0 2 " results in the formation of peroxynitrite ion, which decomposes under oxidized conditions to oxidize quickly. These intermediate oxidation states are responsible for the damage to the biological targets.
  • Peroxynitrite can cross cell membranes at a significantly higher rate than other oxidants, and even in the presence of a biological membrane, peroxynitrite can quickly penetrate into the cell interior.
  • Peroxynitrite is known for the nitration of tyrosine residues in proteins; it oxidizes sulfhydryl residues, methionines and macromolecules such as metal enzymes, DNA and lipids.
  • the invention relates to the use of the compounds according to the invention for the manufacture of a medicament for the treatment and prophylaxis of radical-mediated cell damage.
  • diseases include neurodegenerative diseases, inflammatory diseases, autoimmune diseases, cardiovascular diseases.
  • Examples include: Cerebral ischemia, ischemic reperfusion disease, hypoxia and other neurodegenerative diseases associated with inflammation, such as multiple sclerosis, ALS (amyotrophic lateral sclerosis) and comparable skierotic diseases, Parkinson's disease, Huntington's disease, Korksakoffs disease, epilepsy, vomiting, sleep disorders , Depression, stress, pain, migraines, hypoglycemia, dementia such as Alzheimer's disease, HIV dementia and present dementia.
  • ARDS adult respiratory distress syndrome
  • sepsis or septic shock rheumatoid arthritis
  • osteoarthritis and insulin-dependent diabetes mellitus IDDM
  • inflammatory pelvic / bowel disease meningitis, glomerulonephritis, acute and chronic liver diseases, rejection diseases (e.g. allogeneic heart, kidney or liver transplants) or inflammatory skin diseases such as psoriasis and others.
  • porphyrin complexes according to the invention contain iron (III), manganese (III), copper (II), cobalt (III), chromium (III), nickel (II) or vanadyl (II) as paramagnetic ion in the porphyrin structure ) -lon, the first three being preferred.
  • the excess charge (s) are caused, for example, by anions of organic or inorganic acids, preferably by acetate, chloride, sulfate or nitrate -, Tartrate, succinate, and maleate ions or balanced by the negative charges present in R 2 and / or R 3 .
  • the carboxyl groups which are not required for the complexation of the metal ions can be present as esters, as amides or as salts of inorganic or organic bases.
  • Suitable ester residues are those with 1 to 6 carbon atoms, preferably the ethyl esters;
  • Suitable inorganic cations are, for example, the lithium and the potassium ion and in particular the sodium ion.
  • Suitable cations of organic bases are those of primary, secondary or tertiary amines, such as, for example, ethanolamine, diethanolamine, morpholine, glucamine, N, N-dimethylglucamine, in particular meglumine.
  • Derivatives of the complexing agent residue K are preferably
  • the complex compounds of general formula I are prepared by methods known from the literature (see B DE 4232925 for II a and II b, see e.g. DE 19507822, DE 19580858 and DE 19507819 for III c, see B US Pat. No. 5,053,503, WO 96 / 02669, WO 96/01655, EP 0430863, EP 255471, US-5,277,895, EP 0232751, US-4,885,363 for II d, II e and II f)
  • R2 and R3 represent CONHNHK groups are preferred.
  • the synthesis of 3, 3 ' - (7, 12-diethyl-3, 8, 13, 17-tetramethyIporphyrin-2, 18-d ⁇ yl) di (propanohydraz ⁇ d) is described in Z. Physiol Chem 241, 209 (1936)
  • the desired metals e.g. Mn
  • the desired metals e.g. Mn
  • the desired metals e.g. Mn
  • the substitution of the pyrrolic NHs by heating the metal-free ligand with the corresponding metal salt, preferably the acetate, optionally with the addition of acid-buffering agents, such as sodium acetate, in a polar solvent
  • the substitution of the pyrrolic NHs by heating the metal-free ligand with the corresponding metal salt, preferably the acetate, optionally with the addition of acid-buffering agents, such as sodium acetate, in a polar solvent
  • the "re-complexation" in which one already metal complexed by the ligand is displaced by the desired metal.
  • the main solvents used are polar solvents such as methanol, glacial acetic acid,
  • the paramagnetic metal M can be introduced into the porphyry system before or after the complexing agent residue K has been linked. This enables a particularly flexible procedure for the synthesis of the compounds according to the invention.
  • the residue K is chelated in a manner known from the literature (see e.g.
  • metal oxide or salt e.g. the nitrate, acetate, carbonate, Chloride or sulfate
  • metal oxide or salt e.g. the nitrate, acetate, carbonate, Chloride or sulfate
  • polar solvents such as water or aqueous alcohols
  • acidic hydrogen atoms or acid groups present can be substituted by cations of inorganic and / or organic bases or amino acids.
  • the neutralization takes place with the help of inorganic bases such as Alkali or alkaline earth metal hydroxides, carbonates or bicarbonates and / or organic bases such as primary, secondary and tertiary amines, e.g. Ethanolamine, morpholine, glucamine, N-methyl and N, N-dimethylglucamines, as well as basic amino acids, e.g. Lysine, arginine and ornithine or amides of originally neutral or acidic amino acids.
  • inorganic bases such as Alkali or alkaline earth metal hydroxides, carbonates or bicarbonates and / or organic bases
  • primary, secondary and tertiary amines e.g. Ethanolamine, morpholine, glucamine, N-methyl and N, N-dimethylglucamines
  • basic amino acids e.g. Lysine, arginine and ornithine or amides of originally neutral or acidic amino acids.
  • the acidic complex salts in aqueous solution or suspension can be added with enough of the desired bases that the neutral point is reached.
  • the solution obtained can then be evaporated to dryness in vacuo.
  • water-miscible solvents such as lower alcohols (e.g. methanol, ethanol, isopropanol), lower ketones (e.g. acetone), polar ethers (e.g. tetrahydrofuran, dioxane, 1, 2- Precipitate dimethoxyethane) and thus to obtain crystals that are easy to isolate and easy to clean.
  • lower alcohols e.g. methanol, ethanol, isopropanol
  • ketones e.g. acetone
  • polar ethers e.g. tetrahydrofuran, dioxane, 1, 2- Precipitate dimethoxyethane
  • acidic complex compounds contain several free acidic groups, it is often expedient to prepare neutral mixed salts which contain both inorganic and organic cations as counterions.
  • the order of base addition can also be reversed.
  • Another possibility of obtaining neutral complex compounds is to convert all or part of the remaining acid groups in the complex into esters. This can be done by subsequent reaction on the finished complex (e.g. by exhaustive reaction of the free carboxy groups with dimethyl sulfate).
  • compositions according to the invention are likewise prepared in a manner known per se by suspending or dissolving the complex compounds according to the invention - optionally with the addition of the additives customary in galenicals - in an aqueous medium and then, if appropriate, sterilizing the suspension or solution.
  • suitable additives are, for example, physiologically acceptable buffers (such as tromethamine), small additions of complexing agents (such as diethylenetriaminepentaacetic acid) or, if necessary, electrolytes such as e.g. Sodium chloride or, if necessary, antioxidants such as e.g. Ascorbic acid.
  • the invention therefore also relates to processes for the preparation of the complex compounds and their salts.
  • the final security is cleaning the isolated complex salt.
  • a pharmaceutical preparation which, in addition to the active ingredient for enteral or parenteral administration, has suitable pharmaceutical, organic or inorganic inert carrier materials, such as, for example, water, gelatin, gum arabic, lactose, starch , Magnesium stearate, talc, vegetable oils, polyalkylene glycols etc. contains.
  • the pharmaceutical preparations can be in solid form, for example as tablets, dragées, suppositories, capsules or in liquid form, for example as solutions, suspensions or emulsions. Possibly they also contain auxiliaries such as preservatives, stabilizers, wetting agents or emulsifiers; Salts to change the osmotic pressure or buffer.
  • auxiliaries such as preservatives, stabilizers, wetting agents or emulsifiers; Salts to change the osmotic pressure or buffer.
  • Injection solutions or suspensions in particular aqueous solutions of the active compounds in polyhydroxyethoxylated castor oil, are particularly suitable for parenteral use.
  • suspensions or solutions of the agents according to the invention in water or in physiological saline solution are desired for enteral administration or other purposes, they are mixed with one or more adjuvants (e.g.)
  • surfactant e.g. lecithins, Tween®, Myrj®
  • flavoring agents for flavor correction e.g. essential oils
  • Surface-active auxiliaries such as salts of bile acids or animal or vegetable phospholipids, but also mixtures thereof and liposomes or their components can also be used as carrier systems.
  • Tablets, coated tablets or capsules with talc and / or hydrocarbon carriers or binders, such as lactose, corn or potato starch, are particularly suitable for oral use. It can also be used in liquid form, for example as juice, to which a sweetener may be added.
  • enteral, parenteral and oral applications are also the subject of the present invention.
  • the dosage of the active ingredients can vary depending on the route of administration, age and weight of the patient, type and severity of the disease to be treated and similar factors.
  • the daily dose is 0.5-1000 mg, preferably 50-200 mg, whereby the dose can be given as a single dose to be administered once or divided into 2 or more daily doses.
  • the present invention also relates to the use of the porphyrin complexes of the formula (1) according to the invention for the treatment and prophylaxis of diseases which are caused by the reactions mediated by peroxynitrite and are weakened and / or treated by increasing the conversion rate of peroxynitrite.
  • the present invention relates in particular to the use of the porphyrin complexes of the general formula (1) according to the invention for the treatment and prophylaxis of diseases, which include neurodegenerative diseases, inflammatory diseases, autoimmune diseases, cardiovascular diseases.
  • diseases which include neurodegenerative diseases, inflammatory diseases, autoimmune diseases, cardiovascular diseases. Examples include:
  • Cerebral ischemia ischemic reperfusion disease, hypoxia and other neurodegenerative diseases associated with inflammation, such as multiple sclerosis, amyotrophic lateral sclerosis and comparable skierotic diseases, Parkinson's disease, Huntington's chorea, Korsakow syndrome, epilepsy, vomiting, sleep disorders, schizophrenia Depression, migraines, hypoglycemia, dementia such as Alzheimer's disease, HIV dementia and presenile dementia.
  • autoimmune and / or inflammatory diseases such as hypotension, ARDS (adult respiratory distress syndrome), sepsis or septic shock, rheumatoid arthritis, osteoarthritis, and insulin-dependent diabetes mellitus (IDDM) , pelvic / bowel inflammatory disease, meningitis, glomerulonephritis, acute and chronic liver diseases, rejection diseases (e.g. allogeneic heart, kidney or liver transplants) or inflammatory skin diseases such as psoriasis and others.
  • IDDM insulin-dependent diabetes mellitus
  • the compounds according to the invention are very suitable for the rearrangement of peroxynitrite into harmless products.
  • the present invention also relates to the use of compounds of the general formula (I), characterized in that M represents an Fe 3+ , Mn 3+ , Cu 2+ , Co 3+ , VO 2+ , Cr 3+ or Ni 2 + -lon stands and which are particularly effective.
  • the present invention furthermore relates to the use of porphyrin complex compounds of the general formula I, characterized in that R 2 and R 3 each represent a -CONHNHK, -CONH (CH 2 ) 2 NHK, -CONH (CH 2 ) 3 NHK, -CONH (CH 2 ) 4 NHK, -CONH (CH 2 ) 2 0 (CH 2 ) 2 NHK group.
  • the present invention furthermore relates to the use of porphyrin complex compounds of the general formula (1), characterized in that R 2 and R 3 each represent a -CONHNHK.
  • the present invention furthermore relates in particular to porphyrin complex compounds of the formula (I), namely
  • the good water solubility of the agents according to the invention makes it possible to produce highly concentrated solutions, thus keeping the volume load of the circuit within reasonable limits and compensating for the dilution with body fluid.
  • the agents according to the invention not only have a high stability in vitro, but also a surprisingly high stability in vivo, so that a release or an exchange of the ions which are not convexly bound in the complexes - in themselves toxic - within the time in which the Contrast agents are completely excreted again, can be neglected.
  • the complexes according to the invention show a significantly higher relaxivity than the structurally similar compounds known to date.
  • the relaxivity can be regarded as a measure of the contrast agent activity of a compound, when using the complexes according to the invention in the field of NMR diagnostics, a comparable, positive signal influence is achieved even at a low dose. This significantly increases the safety margin, for which the product of relaxivity and tolerance can be regarded as a guideline.
  • the present invention also relates to the use of the porphyrin complexes of general formula 1 according to the invention for the diagnosis of diseases which include the group of the following diseases: ischemic reperfusion diseases such as stroke, head trauma and myocardial ischemia, sepsis, chronic or acute inflammation (such as arthritis or inflammatory bowel disease), adult respiratory stress syndrome, cancer, Bronchio-pulmonary dysplasia, cardiovascular diseases, diabetes, multiple sclerosis, Parkinson's disease, familial amyotrophic lateral sclerosis and collitis and special neuronal diseases.
  • diseases which include the group of the following diseases: ischemic reperfusion diseases such as stroke, head trauma and myocardial ischemia, sepsis, chronic or acute inflammation (such as arthritis or inflammatory bowel disease), adult respiratory stress syndrome, cancer, Bronchio-pulmonary dysplasia, cardiovascular diseases, diabetes, multiple sclerosis, Parkinson's disease, familial amyotrophic lateral sclerosis and collitis and special neuronal diseases.
  • Fig. 1 shows a 14 NMR spectrum
  • the content of peroxynitrite is determined from the concentrated peroxynitrite solution.
  • a molar extinction coefficient of ⁇ 1670 is used as a basis.
  • the solution is diluted with water in such a way that an absorption of about 1.6 is achieved at the observation wavelength of 301 nm.
  • the pH of the stock solution thus produced should not fall below 11.
  • a solution of the catalyst to be investigated is prepared in phosphate buffer in accordance with the set concentration of the peroxynitrite, so that the desired amounts of catalyst solution and peroxynitrite can be combined for the reaction, taking into account the given conditions of the stopped-flow device.
  • the buffer of the catalyst solution must have sufficient capacity to be able to adjust and maintain the still strongly alkaline peroxynitrite solution to the desired pH.
  • the catalysts are added in a 100-fold deficit.
  • the dosing syringes of the stopped-flow system are filled with the two solutions and the cuvette located in the UV spectrometer is filled from them.
  • the absorption values at 301 nm are measured simultaneously. As a result of rearrangement of the peroxynitrite to nitrate, the absorption will decrease in order to assume a constant value after some time. At this point, the migration is complete and data registration is canceled.
  • the measurement data are analyzed and the resulting kinetic characteristic data of the curve can be used to calculate the peroxynitrite concentration. These data are used to characterize the catalyst to be examined.
  • the decomposition behavior of the peroxynitrite solution when the buffer without catalyst content is added is first determined for each preparation of peroxynitrite used, and its characteristics are related to those obtained from a measurement with a catalyst.
  • Wistar rats P8 are killed by decapitation, the cerebellas are extracted, the meninges are removed from the cerebellum (HBSS (GIBCO, 14025-050) 4 ° C), comminuted and transferred to a 15 ml Falcon tube, the supernatant is aspirated and then the cerebellum is removed by adding 500 ⁇ l trypsin EDTA Sol. (GIBCO # 2530-054) / Cerebellum trypsinized. After an incubation (20 min, 37 ° C) the trypsinized cerebellum is washed 3 times with 10 ml HBSS.
  • a tr situation follows by adding 500 ⁇ l of 0.05% DNAsel (BOEHRINGER MANNHEIM, # 14953000) per cerebellum. Using a 5 ml pipette, then with a fire-smoothed Pasteur pipette, and finally (if necessary) with an extended, fire-smoothed Pasteur pipette, the cells are separated and with 10 ml complete medium (100 ml Neurobasal (GIBCO # 21103-049), 1 ml B27 supplement (GIBCO # 17504-044), 0.4 ml pen / strep (10000 lU / ml / 10000 UG / ml) (GIBCO # 15140-106), 0.8 ml KCI stock solution (MERCK, 1.04936.0500), 1 ml L-glutamine ( 100x - 200mM) (GIBCO # 15140-106) The separated cells are then centrifuged off (10 min at 600 rpm), washe
  • microtiter plates are coated beforehand as follows: 50 ⁇ l of poly-L-lysine (MW 70- 105kD) (SIGMA # P-6282), the plates are then incubated for approx. 90 min incubated. Before the cells are flattened out, the solution is suctioned off again and washed twice with HBSS or with sterile Aqua bidest. 24 hours after plating, the cells are damaged by adding S1N-1. Test substances are applied 1 hour before the addition of SIN-1 (single concentration 10 or 30 ⁇ M, or as a series of concentrations, CALBIOCHEM, 567028).
  • the cell function is measured on div2 (day2 in vitro) with Alamar blue (10 ⁇ 7 ⁇ well) (BIOSOURCE INT., DAL1100). After a 3-hour incubation, the measurement is carried out in a fluorescence reader (Victor, Wallac, absorbance 544nm / emission 590nM). IC50 values are calculated with the Excel plug-in XLfit.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Immunology (AREA)
  • Pain & Pain Management (AREA)
  • Diabetes (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Oncology (AREA)
  • Psychiatry (AREA)
  • Epidemiology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Communicable Diseases (AREA)
  • Urology & Nephrology (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Endocrinology (AREA)
  • Emergency Medicine (AREA)
  • Hospice & Palliative Care (AREA)
  • Pulmonology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Virology (AREA)
  • Dermatology (AREA)
  • Psychology (AREA)

Abstract

L'invention concerne l'utilisation de dérivés de porphyrine paramagnétiques substitués en 3 et en 8, avec différents substituants en positions 13 et 17 du squelette de porphyrine, comme catalyseurs de transformation du péroxynitrite pour traiter et prévenir des maladies caractérisées par une détérioration des cellules induite par des radicaux.
PCT/EP2003/007556 2002-08-27 2003-07-12 Catalyseurs de transformation du peroxynitrite destines au traitement ou a la prevention de maladies engendrees par des reactions induites par le peroxynitrite WO2004019936A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP03790798A EP1531808A1 (fr) 2002-08-27 2003-07-12 Catalyseurs de transformation du peroxynitrite destines au traitement ou a la prevention de maladies engendrees par des reactions induites par le peroxynitrite
AU2003246687A AU2003246687A1 (en) 2002-08-27 2003-07-12 Peroxynitrite rearrangement catalysts used for the treatment or prophylaxis of diseases caused by peroxynitrite-mediated reactions
JP2004531801A JP2006500383A (ja) 2002-08-27 2003-07-12 ペルオキシニトライト仲介反応により引き起こされる疾患を治療または予防するためのペルオキシニトライト転移触媒
CA002493199A CA2493199A1 (fr) 2002-08-27 2003-07-12 Catalyseurs de transformation du peroxynitrite destines au traitement ou a la prevention de maladies engendrees par des reactions induites par le peroxynitrite

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10240343A DE10240343A1 (de) 2002-08-27 2002-08-27 Peroxynitrit-Umlagerungskatalysatoren
DE10240343.0 2002-08-27

Publications (1)

Publication Number Publication Date
WO2004019936A1 true WO2004019936A1 (fr) 2004-03-11

Family

ID=31502240

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2003/007556 WO2004019936A1 (fr) 2002-08-27 2003-07-12 Catalyseurs de transformation du peroxynitrite destines au traitement ou a la prevention de maladies engendrees par des reactions induites par le peroxynitrite

Country Status (6)

Country Link
EP (1) EP1531808A1 (fr)
JP (1) JP2006500383A (fr)
AU (1) AU2003246687A1 (fr)
CA (1) CA2493199A1 (fr)
DE (1) DE10240343A1 (fr)
WO (1) WO2004019936A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005041885A2 (fr) * 2003-10-31 2005-05-12 Metaphore Pharmaceuticals, Inc. Compositions et procedes permettant de traiter, empecher, inverser et inhiber la douleur
WO2006054757A1 (fr) * 2004-11-16 2006-05-26 Astellas Pharma Inc. Inhibiteur de la caspase
EP2544542A1 (fr) * 2010-03-10 2013-01-16 Galleon Pharmaceuticals, Inc. Composés analgésiques, compositions en contenant et leurs utilisations
CN111848656A (zh) * 2020-06-24 2020-10-30 天津大学 离子修饰的原卟啉镓化合物及其制备方法和应用

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2385486T3 (es) 1999-01-25 2012-07-25 National Jewish Health Porfirinas sustituidas y su uso terapéutico
EP2732817B1 (fr) * 2008-05-23 2016-08-24 National Jewish Health Composé destiné à être utilisé dans le traitement d'une lésion associée à l'exposition à du phosgène ou du chlore gazeux

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0355041A2 (fr) * 1988-08-13 1990-02-21 Schering Aktiengesellschaft Composés complexes de porphyrine substituée en 13,17 par l'acide propionique et les dérivés d'acide propionique, procédé pour leur préparation et compositions pharmaceutiques les contenant
WO1995031197A1 (fr) * 1994-05-13 1995-11-23 Monsanto Company Procedes d'utilisation de catalyseurs de decomposition deperoxynitrite et compositions pharmaceutiques a cet effet
WO1995031219A1 (fr) * 1994-05-11 1995-11-23 Schering Aktiengesellschaft Utilisation de composes a base d'un complexe de porphyrine ou d'un complexe de porphyrine etendue comme preparation diagnostique pour la localisation d'un infarctus
WO1999062512A1 (fr) * 1998-06-02 1999-12-09 Schering Aktiengesellschaft Derives de deuteroporphyrine substitues en position 3 et 8, substances pharmaceutiques les contenant, procede pour les preparer et leur utilisation dans la therapie photodynamique et le diagnostic par irm
WO2000005235A1 (fr) * 1998-07-24 2000-02-03 Schering Aktiengesellschaft Derives paramagnetiques 3-,8-substitues de deuteroporphyrine, substances pharmaceutiques contenant lesdits derives, procede de preparation desdits derives et leur utilisation dans l'irm de la necrose et de l'infarctus
WO2000075144A2 (fr) * 1999-06-03 2000-12-14 The Trustees Of Princeton University Catalyseurs de decomposition du peroxynitrite et methodes d'utilisation desdits catalyseurs
WO2001026655A1 (fr) * 1999-10-13 2001-04-19 Uab Research Foundation Traitement de maladies neurologiques a l'aide de porphyrines
US6245758B1 (en) * 1994-05-13 2001-06-12 Michael K. Stern Methods of use for peroxynitrite decomposition catalysts, pharmaceutical compositions therefor

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4232925A1 (de) * 1992-09-28 1994-03-31 Diagnostikforschung Inst 3-,8-substituierte Deuteroporphyrinderivate, diese enthaltende pharmazeutische Mittel und Verfahren zu ihrer Herstellung

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0355041A2 (fr) * 1988-08-13 1990-02-21 Schering Aktiengesellschaft Composés complexes de porphyrine substituée en 13,17 par l'acide propionique et les dérivés d'acide propionique, procédé pour leur préparation et compositions pharmaceutiques les contenant
WO1995031219A1 (fr) * 1994-05-11 1995-11-23 Schering Aktiengesellschaft Utilisation de composes a base d'un complexe de porphyrine ou d'un complexe de porphyrine etendue comme preparation diagnostique pour la localisation d'un infarctus
WO1995031197A1 (fr) * 1994-05-13 1995-11-23 Monsanto Company Procedes d'utilisation de catalyseurs de decomposition deperoxynitrite et compositions pharmaceutiques a cet effet
US6245758B1 (en) * 1994-05-13 2001-06-12 Michael K. Stern Methods of use for peroxynitrite decomposition catalysts, pharmaceutical compositions therefor
WO1999062512A1 (fr) * 1998-06-02 1999-12-09 Schering Aktiengesellschaft Derives de deuteroporphyrine substitues en position 3 et 8, substances pharmaceutiques les contenant, procede pour les preparer et leur utilisation dans la therapie photodynamique et le diagnostic par irm
WO2000005235A1 (fr) * 1998-07-24 2000-02-03 Schering Aktiengesellschaft Derives paramagnetiques 3-,8-substitues de deuteroporphyrine, substances pharmaceutiques contenant lesdits derives, procede de preparation desdits derives et leur utilisation dans l'irm de la necrose et de l'infarctus
WO2000075144A2 (fr) * 1999-06-03 2000-12-14 The Trustees Of Princeton University Catalyseurs de decomposition du peroxynitrite et methodes d'utilisation desdits catalyseurs
WO2001026655A1 (fr) * 1999-10-13 2001-04-19 Uab Research Foundation Traitement de maladies neurologiques a l'aide de porphyrines

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CUZZOCREA SALVATORE ET AL: "Antioxidant therapy: A new pharmacological approach in shock, inflammation, and ischemia/reperfusion injury", PHARMACOLOGICAL REVIEWS, vol. 53, no. 1, March 2001 (2001-03-01), pages 135 - 159, XP002258913, ISSN: 0031-6997, Retrieved from the Internet <URL:http://pharmrev.aspetjournals.org> [retrieved on 20031022] *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005041885A2 (fr) * 2003-10-31 2005-05-12 Metaphore Pharmaceuticals, Inc. Compositions et procedes permettant de traiter, empecher, inverser et inhiber la douleur
WO2005041885A3 (fr) * 2003-10-31 2006-10-12 Metaphore Pharmaceuticals Inc Compositions et procedes permettant de traiter, empecher, inverser et inhiber la douleur
WO2006054757A1 (fr) * 2004-11-16 2006-05-26 Astellas Pharma Inc. Inhibiteur de la caspase
EP2544542A1 (fr) * 2010-03-10 2013-01-16 Galleon Pharmaceuticals, Inc. Composés analgésiques, compositions en contenant et leurs utilisations
EP2544542A4 (fr) * 2010-03-10 2013-07-24 Galleon Pharmaceuticals Inc Composés analgésiques, compositions en contenant et leurs utilisations
CN111848656A (zh) * 2020-06-24 2020-10-30 天津大学 离子修饰的原卟啉镓化合物及其制备方法和应用
CN111848656B (zh) * 2020-06-24 2023-03-14 天津大学 离子修饰的原卟啉镓化合物及其制备方法和应用

Also Published As

Publication number Publication date
JP2006500383A (ja) 2006-01-05
EP1531808A1 (fr) 2005-05-25
DE10240343A1 (de) 2004-03-11
CA2493199A1 (fr) 2004-03-11
AU2003246687A1 (en) 2004-03-19

Similar Documents

Publication Publication Date Title
DE3401052C2 (de) Diagnostische Mittel
EP0336879B1 (fr) Complexes composés de méso-tetraphénylporphyrine,procédé pour leur préparation et agents pharmaceutiques les contenant
EP0430863B1 (fr) Formateur de complexe lié à un polymère préparé par étapes, ses complexes et conjugats, procédé de préparation et substances pharmaceutiques les contenant
EP0684948B1 (fr) Composes complexes de meso-tetraphenylporphyrine, leur procede de preparation et agents pharmaceutiques les contenant
DE69813898T2 (de) Substituierte porphyrinen
EP0405704B1 (fr) Dérivés de DTPA-complèxes, compositions pharmaceutiques les contenant, leur utilisation et procédé pour leur fabrication
EP0662972B1 (fr) Derives de deuteroporphyrine substitues en positions 3,8, produits pharmaceutiques les contenant et procede permettant de les preparer
DE60108507T2 (de) Nicht genotoxische metalloporphyrine als synthetische katalytische fänger von reaktiven sauerstoffspezies
EP0993306B1 (fr) Composes oligomeres perfluoralkyles, leur procede de preparation et leur utilisation dans le diagnostic rmn
DE19831217A1 (de) Neue Porphyrinderivate, diese enthaltende pharmazeutische Mittel und ihre Verwendung in der photodynamischen Therapie und MRI-Diagnostik
DE4001655A1 (de) 6-ring enthaltende makrocyclische tetraaza-verbindungen, verfahren zu ihrer herstellung und diese enthaltende pharmazeutische mittel
EP0352218A2 (fr) Composés polyaza macrocycliques, leur procédé de préparation et compositions pharmaceutiques les contenant
DE19744003B4 (de) Kontrastmittel für das Infarkt- und Nekroseimaging
DE3927444A1 (de) Verwendung von amid-komplexverbindungen
WO2004019936A1 (fr) Catalyseurs de transformation du peroxynitrite destines au traitement ou a la prevention de maladies engendrees par des reactions induites par le peroxynitrite
EP1307237B9 (fr) Complexes perfluoroalkyles a residus polaires, leur procede de fabrication et leur utilisation
EP1163231A1 (fr) Perfluoroalkylamide, leur production et leur utilisation dans des diagnostics
EP1102770B1 (fr) Derives paramagnetiques 3-,8-substitues de deuteroporphyrine, substances pharmaceutiques contenant lesdits derives, procede de preparation desdits derives et leur utilisation dans l&#39;irm de la necrose et de l&#39;infarctus
EP2072584B1 (fr) Colorants phthalocyanines, leur préparation et leur utilisation
US20040127479A1 (en) Peroxynitrite rearrangement catalysts
WO1999062512A1 (fr) Derives de deuteroporphyrine substitues en position 3 et 8, substances pharmaceutiques les contenant, procede pour les preparer et leur utilisation dans la therapie photodynamique et le diagnostic par irm
EP0517765A1 (fr) Preparations pour diagnostic rm
DE3633246A1 (de) Amid-komplexe
DE4320307A1 (de) Neue Eisenkomplexe

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 2003790798

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2493199

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 2004531801

Country of ref document: JP

WWP Wipo information: published in national office

Ref document number: 2003790798

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 2003790798

Country of ref document: EP