WO2004019936A1 - Peroxynitrite rearrangement catalysts used for the treatment or prophylaxis of diseases caused by peroxynitrite-mediated reactions - Google Patents

Peroxynitrite rearrangement catalysts used for the treatment or prophylaxis of diseases caused by peroxynitrite-mediated reactions Download PDF

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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
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group
diseases
peroxynitrite
general formula
treatment
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PCT/EP2003/007556
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German (de)
French (fr)
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Gisbert Depke
Margrit Hillmann
Günter Michl
Johannes Platzek
Detlev Sülzle
Roland Neuhaus
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Schering Aktiengesellschaft
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Priority to CA002493199A priority Critical patent/CA2493199A1/en
Priority to JP2004531801A priority patent/JP2006500383A/en
Priority to EP03790798A priority patent/EP1531808A1/en
Priority to AU2003246687A priority patent/AU2003246687A1/en
Publication of WO2004019936A1 publication Critical patent/WO2004019936A1/en

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    • 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
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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.

Abstract

The invention relates to the use of paramagnetic 3, 8-substituted porphyrin derivatives comprising different substituents in positions 13 and 17 of the porphyrin skeleton as peroxynitrite rearrangement catalysts for the treatment and prophylaxis of diseases that are characterized by radically mediated cellular damages.

Description

PEROXYNITRIT-UM AGERUNGSKATALYSATOREN ZUR BEHANDLUNG ODER PROPHYLAXE VON KRANKHEITEN , DIE DURCH PEROXYNITRIT-VERMITTELTE REAKTIONEN VERURSACHT WERDENPEROXYNITRITE-AGING CATALYSTS FOR TREATING OR PROPHYLAXIS OF DISEASES CAUSED BY PEROXYNITRITE-MEDIATED REACTIONS
Die Erfindung betrifft die Verwendung von metallhaltigen Komplexen, die die 5 Umlagerung von Peroxynitrit katalysieren, zur Herstellung von Arzneimitteln zur Behandlung von Erkrankungen.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.
Peroxynitrit wurde schon 1990 von Beckman et al. (Beckman et al., 1990, Proc. Natl. Acad. Sei. USA. 87, 1620-1624) als toxischer Metabolit beschrieben, der durch diePeroxynitrite 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
10 diffusionskontrollierte Reaktion zwischen Stickstoffmonoxid (NO, nitric oxide) und Superoxidanion (02 ") entsteht. Peroxynitrit ist an einer Reihe von inflammatorischen Prozessen beteiligt, die bei Erkrankungen wie beispielsweise der Alzheimerschen Demenz, der Multiplen Sklerose, der Amyotrophen Lateralsklerose eine wichtige Rolle spielen und für den Zelluntergang und der Induktion der Apoptose verantwortlich10 Diffusion-controlled reaction between nitrogen monoxide (NO, nitric oxide) and superoxide anion (0 2 " ) occurs. Peroxynitrite is involved in a number of inflammatory processes which play an important role in diseases such as Alzheimer's dementia, multiple sclerosis, amyotrophic lateral sclerosis and responsible for cell death and induction of apoptosis
15 gemacht werden.15 can be made.
Peroxynitrit reagiert mit einer Vielzahl von Proteinen, indem es Aminosäurereste oxidiert oder nitriert. In Gewebe von Patienten, die an Multipler Sklerose erkrankt sind, finden sich vermehrt Nitrotyrosinreste, da Peroxynitrit die Nitrierung der Tyrosinreste der Filamente der Motoneurone veranlasst. Durch die so gestörte Kontraktion der FilamentePeroxynitrite 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
20 kommt es zu einer neuronalen Dysfunktion (Estevez et al., 1999, Science 286, 2498 - 2500). Eine Ursache für die nach einem Schlaganfall beeinträchtigte Vasokonstriktion besteht in der durch Peroxynitrit induzierten Oxydation der Lipidreste der Zellmembran, bei der es zu Verletzungen des Endotheliums und daraus resultierender Ödem- und Neutrophilbildung kommt.20 there is neuronal dysfunction (Estevez et al., 1999, Science 286, 2498 - 2500). One cause of the impaired vasoconstriction after a stroke is the peroxynitrite-induced oxidation of the lipid residues of the cell membrane, which leads to injuries to the endothelium and the resulting edema and neutrophil formation.
25 Eine pharmakologische Intervention, um die von Peroxynitrit vermittelten Wirkungen zu verhindern, kann auf der Seite der Ausgangstoffe (NO, und 02 ~) oder auf der Seite des Produktes stattfinden.25 Pharmacological intervention to prevent the effects mediated by peroxynitrite can take place on the side of the starting materials (NO, and 0 2 ~ ) or on the side of the product.
Ein Ansatz auf der Seite des Produktes Peroxynitrit wurde erstmals von Salvemini et al., (Salvemini et al., 1998, Proc. Natl. Acad. Sei. USA., 95, 2659 - 2663) beschrieben. BeiAn approach on the peroxynitrite product side was first described by Salvemini et al., (Salvemini et al., 1998, Proc. Natl. Acad. Sci. USA., 95, 2659-2663). at
30 diesem Ansatz wird Peroxynitrit mittels eines Katalysators in unbedenkliche Endprodukte umgelagert. Es ist möglich, mit nur geringen Konzentrationen an Katalysator große Mengen an Peroxynitrit umzuwandeln. Ein Vorteil dieses Ansatzes beruht darauf, dass es so nicht zur Bildung der nachteiligen Dekompositions-Produkte wie beispielsweise der reaktiven Sauerstoffspezies kommen kann und dass es zur Aufhebung der Inhibition derIn this approach, 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
35 Superoxid-Dismutase (SOD) durch Peroxynitrit kommt. Demzufolge hat diese Behandlungsmethode mit neuartigen Verbindungen einen zweifachen Vorteil in der Behandlung der Erkrankungen. So wird zum einen die Rate der Umwandlung von Peroxynitrit beschleunigt und zum anderen die SOD gegenüber Inaktivierung durch Peroxynitrit geschützt.35 superoxide dismutase (SOD) comes from peroxynitrite. As a result, this method of treatment with novel compounds has a double advantage in the treatment of the diseases. For one, the rate of conversion from Peroxynitrite accelerates and on the other hand protects the SOD against inactivation by peroxynitrite.
Als mögliche Umwandlungskatalysatoren sind bisher metallhaltige Komplexe bekannt (WO 95/31197, US 6,245,758, WO 98/04132, US 5,872,124, WO 00/75144, WO 01/26655, US 6,372,727). Die von Salvemini et al. beschriebenen Metalloporphyrine zeigen in Inflammationsmodellen protektive Wirkung, (Salvemini et al., 1998, Proc. Natl. Acad. Sei. USA. 95, 2659 - 2663 und British J. Pharmacol., 1999, 127, 685 - 692). Die gleiche Klasse von Verbindungen wurde von Cuzzocrea et al. in einem Darmarterien- Oklusionsmodell als wirksam beschrieben (Cuzzocrea et al., 2000, FASEB J. 14 (9), 1061 - 1072 und Cuzzocrea et al., 2001, Pharmacology Rev. 53, 135 - 159). Cross et al. demonstrierten die Wirksamkeit dieser Substanz in einem MS-Modell (.experimentelle Autoimmun-Encephalomyelitis' = EAE) in der Maus, (Cross et al., 2000, J. Neuroimmunology 107, 21 - 28). Mackensen et al. zeigten erstmals die Wirksamkeit eines Mangan-haltigen Porphyrins in einem fokalen Ischämie-Modell, der fokalen MCAO (middle cerebral artery occlusion) (Mackensen et al., 2001, J. Neurosci. 21, 4582 - 4592).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. 14 (9), 1061-1072 and Cuzzocrea et al., 2001, Pharmacology Rev. 53, 135-159). Cross et al. demonstrated the effectiveness of this substance in a MS model ("experimental autoimmune encephalomyelitis' = EAE) in the mouse, (Cross et al., 2000, J. Neuroimmunology 107, 21-28). 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).
Über die Nebenwirkungen wie Toxizität und in vivo Verfügbarkeit, sowie die Blut- Hirnschrankenpermeabilität dieser bekannten Umlagerungskatalysatoren ist bisher wenig bekannt. Für die Behandlung und Prophylaxe von Erkrankungen, die ihre Ursache in den von Peroxynitrit vermittelten Reaktionen haben, besteht das dringende Problem, gut verträgliche, chemisch stabile und in vivo verfügbare Substanzen (Katalysatoren) bereitzustellen, um so die Umlagerung von Peroxynitrit in unbedenkliche Produkte zu steigern. Diese in vivo wirksamen Substanzen können zur Entwicklung von Medikamenten zur Behandlung von Erkrankungen verwendet werden.Little is known about the side effects such as toxicity and in vivo availability, as well as the blood-brain barrier permeability of these known rearrangement catalysts. For the treatment and prophylaxis of diseases that are caused by the reactions mediated by peroxynitrite, there is an urgent problem of providing well-tolerated, chemically stable and in vivo available substances (catalysts) in order to increase the rearrangement of peroxynitrite into harmless products , These in vivo active substances can be used for the development of medicaments for the treatment of diseases.
Die vorliegende Erfindung löst das Problem durch Bereitstellung von Porphyrinkomplexen, die als Peroxynitrit-Umlagerungskatalysatoren dienen. Diese Porphyrine zeichnen sich durch ihre gute in vivo Verfügbarkeit sowie durch ihre chemische Stabilität aus. Sie haben bereits als Mittel zur Diagnose von Tumoren Einsatz gefunden und ihre Verwendung für das Nekrose- und Infarkt-Imaging wurde bereits in der WO 00/05235 offenbart.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.
In der vorliegenden Erfindung konnte mittels NMR- und UV/VIS-Spektroskopie gezeigt werden, dass die erfindungsgemäßen Porphyrine der WO 00/05235 die Umlagerung von Peroxynitrit in unbedenkliche Endprodukte, nämlich Nitrat und Nitrit, katalysieren. Mittels eines Modells für Zellschädigungen konnte gezeigt werden, dass die erfindungsgemäßen Porphyrine protektiv sind und die Zellen vor Peroxynitritschädigungen, induziert durch den Peroxynitritdonor SIN-1, schützen. Die vorliegenden Porphyrine sind bereits sehr gut charakterisiert und es ist bekannt, dass sie keine Nebenwirkungen, gute Wasserlöslichkeit und eine gute in vivo Verfügbarkeit besitzen.In the present invention it could be shown by means of NMR and UV / VIS spectroscopy that the porphyrins according to the invention of WO 00/05235 catalyze the rearrangement of peroxynitrite into harmless end products, namely nitrate and nitrite. Using a model for cell damage it could be shown that 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.
Der Einsatz von Porphyrinkomplexen, die zum einen Peroxynitrit-umlagemde Eigenschaften und zum anderen diagnostische Eigenschaften besitzen, ermöglicht eine gezielte Behandlung der Erkrankungen, die durch Peroxynitrit verursacht werden, und deren Diagnose unter Verwendung bildgebender Verfahren, wie z. B. MRT.The use of 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.
Die vorliegende Erfindung stellt pharmazeutische Mittel für diese gezielte Behandlung bereit und betrifft einen Porphyrinkomplex bestehend aus einem Liganden der allgemeinen Formel IThe present invention provides pharmaceutical agents for this targeted treatment and relates to a porphyrin complex consisting of a ligand of the general formula I.
Figure imgf000004_0001
Figure imgf000004_0001
sowie mindestens einem Ion eines Elementes der Ordnungszahl 20-32, 37-39, 42-51 oder 57-83, worinand at least one ion of an element of atomic number 20-32, 37-39, 42-51 or 57-83, wherein
M für ein paramagnetisches Ion,M for a paramagnetic ion,
1 R für ein Wasserstoffatom, für einen geradkettigen 0,-C8-Alkylrest, einen C6-C12-1 R for a hydrogen atom, for a straight-chain 0, -C 8 -alkyl radical, a C 6 -C 12 -
Aralkylrest oder für eine Gruppe OR' worinAralkylrest or for a group OR 'wherein
R' ein Wasserstoffatom oder ein C^Cj-Alkylrest ist, steht,R 'is a hydrogen atom or a C ^ C j alkyl radical,
R für R , eine Gruppe -CO-Z oder eine Gruppe -(NH)0-(A)q-NH-D steht, worin Z eine Gruppe -OL ist, mit L in der Bedeutung eines anorganischen oder organischen Kations oder eines C^C^Alkylrestes ist,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 eine Phenylenoxy- oder eine durch ein oder mehrere Sauerstoffatome unterbrochene C^C^-Alkylen- oder C7-C12 Aralkylengruppe bedeutet, o und q unabhängig voneinander die Ziffern 0 oder 1 bedeuten undA 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 ein Wasserstoffatom oder eine Gruppe -CO-A-(COOL)0-(H)m bedeutet, mit m gleich 0 oder 1 und unter der Maßgabe, dass die Summe aus m und o gleich 1 ist,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,
R3 für eine Gruppe -(C=Q)(NR4)0-(A)q-(NR5)-K steht, worin Q für ein Sauerstoffatom oder für zwei Wasserstoffatome steht, R eine Gruppe -(A)q-H bedeutet undR 3 represents a group - (C = Q) (NR 4 ) 0 - (A) q - (NR 5 ) -K, where Q represents one oxygen atom or two hydrogen atoms, R represents a group - (A) qH and
K einen Komplexbildner der allgemeinen Formel (lla), (llb), (llc), (lld) oder (lle) bedeutet, wobei R für den Fall, dass K ein Komplexbildner der Formel (lla) ist dieK 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)
4 5 gleiche Bedeutung wie R hat und R für den Fall, dass K ein Komplexbildner der4 5 has the same meaning as R and R if K is a complexing agent of
Formel (llb), (llc), (lld) oder (lle) ist, die gleiche Bedeutung wie D hat, mit der Maßgabe, dass eine direkte Sauerstoff-Stickstoff Bindung nicht zugelassen ist, und K für einen Komplexbildner der allgemeinen Formel (lla), (llb), (llc), (lld), (lle) oder (llf)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)
(lla)(IIa)
Figure imgf000005_0001
Figure imgf000005_0001
Figure imgf000006_0001
Figure imgf000006_0001
Figure imgf000006_0002
Figure imgf000006_0002
(lld), (IId)
Figure imgf000007_0001
Figure imgf000007_0001
(He),(He),
Figure imgf000007_0002
Figure imgf000007_0002
steht, worin q die oben angegebene Bedeutung hat, A die für A angegebene Bedeutung hat,where q has the meaning given above, A has the meaning given for A,
R6 für ein Wasserstoffatom, eine geradkettige oder verzweigte Cn- C7-Alkylgruppe, eine Phenyl- oder Benzylgruppe,R 6 represents a hydrogen atom, a straight-chain or branched C n - C 7 alkyl group, a phenyl or benzyl group,
A2 für eine Phenylen-, -CH2-NHCO-CH2-CH (CH2COOH) -C6H4-ß-, -C6H4-O-(CH2)0. 5-ß, -C6H4-(OCH2CH2)o.ι-N(CH2COOH)-CH2-ß oder eine gegebenenfalls durch ein oder mehrere Sauerstoffatome, 1 bis 3-NHCO-, 1 bis 3 -CONH-gruppen unterbrochene und/oder mit 1 bis 3-(CH2)o.5COOH-Gruppen substituierte C C12-Alkylen- oder C7-C12-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.ι-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 -
Alkylengruppe, wobei ß für die Bindungsstelle an X steht, X für eine -CO- oder NHCS-gruppe undAlkylene group, where ß stands for the binding site on X, X for a -CO or NHCS group and
2 3 4 2 3 4
L , L , L und L unabhängig voneinander für ein Wasserstoffatom oder einL, L, L and L independently represent a hydrogen atom or a
Metallionenäquivalent eines Elements der oben genannten Ordnungszahl steht, unter den Maßgaben, dass mindestens zwei dieser Substituenten für Metallionenäquivalente stehen, und dass zum Ausgleich gegebenenfalls vorhandener Ladungen im Metalloporphyrin weitere Anionen vorhanden sind und worin freie, nicht zur Komplexierung benötigte Carbonsäuregruppen auch als Salze mit physiologisch verträglich anorganischen und/oder organischen Kationen oder als Ester oder als A ide vorliegen können, und der darüberhinaus auch noch die Umlagerungsrate von Peroxynitrit in unbedenkliche Produkte steigern und so für die Herstellung eines Arzneimittels zur Behandlung und Prophylaxe radikal-vermittelter Zellschädigungen verwendet werden können.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.
Mittels NMR- und UVΛ/IS-Spektroskopie konnte gezeigt werden, dass die erfindungsgemäßen Verbindungen die Umlagerung von Peroxynitrit in unbedenkliche Endprodukte, nämlich Nitrat und Nitrit, katalysieren. Peroxynitrit ist ein starkes Oxidans, das durch die Reaktion von Stickoxid (NO) und Superoxid-Anion (02 ~) entsteht. Es konnte gezeigt werden, dass NO in vielen Zellen generiert wird wie beispielsweise in Makrophagen, in neutrophilen Zellen, Hepatocyten und Endothelzellen. Die direkte Reaktion von NO und 02 " resultiert in der Bildung von Peroxynitrit-Ion, das unter physiologischen Bedingungen schnell zu oxidierenden Intermediaten zerfällt. Diese Oxidationszwischenstufen sind für die Schädigungen der biologischen Targets verantwortlich.Using NMR and UVΛ / IS spectroscopy it could be shown that the compounds according to the invention catalyze the rearrangement of peroxynitrite into harmless end products, namely nitrate and nitrite. 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.
Die Folgen dieser Schädigungen können assoziiert sein mit pathologischen Konsequenzen einschließlich der Oxidation und Nitrierung von Proteinen, Lipiden und DNA. Peroxynitrit kann mit einer deutlich höheren Geschwindigkeit als andere Oxidantien Zellmembranen passieren, und selbst in Anwesenheit einer biologischen Membran kann Peroxynitrit schnell in das Zellinnere dringen. Peroxynitrit ist für die Nitrierung von Tyrosinresten in Proteinen bekannt, es oxidiert Sulfhydrylreste, Methionine und Makromoleküle wie beispielsweise Metallenzyme, DNA und Lipide.The consequences of this damage can be associated with pathological consequences including the oxidation and nitration of proteins, lipids and DNA. 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.
Wegen seiner hohen Reaktivität wurde Peroxynitrit mit vielen Erkrankungen in Verbindung gebracht. Die Erfindung betrifft die Verwendung der erfindungsgemäßen Verbindungen zur Herstellung eines Arzneimittels zur Behandlung und Prophylaxe Radikal-vermittelter Zellschädigungen. Dazu zählen neurodegenerative Erkrankungen, inflammatorische Erkrankungen, Autoimmunerkrankungen, Herz-Kreislauf- Erkrankungen.Because of its high reactivity, peroxynitrite has been associated with many diseases. 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. These include neurodegenerative diseases, inflammatory diseases, autoimmune diseases, cardiovascular diseases.
Beispielsweise seien genannt: Cerebrale Ischaemie, ischämische Reperfusionserkrankung, Hypoxie und andere neurodegenerative Erkrankungen, die mit Entzündungen in Verbindung gebracht werden, wie Multiple Sklerose, ALS (Amyotrophe Lateralsklerose) und vergleichbare skierotische Erkrankungen, Morbus Parkinson, Huntington's Disease, Korksakoffs Disease, Epilepsie, Erbrechen, Schlafstörungen, Schizophrenie, Depression, Stress, Schmerz, Migräne, Hypoglykämie, Demenz wie z.B. Alzheimersche Krankheit, HIV- Demenz und Präsenile Demenz.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.
Ferner eignen sie sich zur Behandlung von Krankheiten des Herz-Kreislauf-Systems wie Arteriosklerose und zur Behandlung autoimmuner und/oder inflammatorischer Erkrankungen wie Hypotension, ARDS (adult respiratory distress syndrome), Sepsis oder Septischer Schock, Rheumatoider Arthritis, Osteoarthritis, von insulinabhängiger Diabetes Mellitus (IDDM), entzündlicher Erkrankung des Beckens/Darms (bowel disease), von Meningitis, Glomerulonephritis, akute und chronische Lebererkrankungen, Erkrankungen durch Abstoßung (beispielsweise allogene Herz-, Nieren- oder Lebertransplantationen) oder entzündlichen Hautkrankheiten wie Psoriasis und andere.They are also suitable for the treatment of diseases of the cardiovascular system such as arteriosclerosis and for the treatment of 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), 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.
Die erfindungsgemäßen Porphyrin-Komplexe enthalten als paramagnetisches Ion im Porphyringerüst das Eisen(lll)-, Mangan(lll)-, Kupfer(ll)-, Cobalt(lll), Chrom(lll)-, Nickel(ll)- oder Vanadyl(ll)-lon, wobei die drei erstgenannten bevorzugt sind.The 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.
Sofern eines der im Porphyrin gebundenen Ionen in einer höheren Oxidationsstufe als +2 vorliegt, wird (werden) die überschüssige(n) Ladung(en) z.B. durch Anionen von organischen oder anorganischen Säuren, bevorzugt durch Acetat-, Chlorid-, Sulfat-, Nitrat-, Tartrat-, Succinat-, und Maleat-Ionen oder durch die in R2 und/oder R3 vorhandenen negativen Ladungen ausgeglichen.If one of the ions bound in the porphyrin is in a higher oxidation state than +2, 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 .
Gewünschtenfalls können die Carboxylgruppen, die nicht für die Komplexierung der Metallionen benötigt werden, als Ester, als Amide oder als Salze anorganischer oder organischer Basen vorliegen. Geeignete Esterreste sind solche mit 1 bis 6 C-Atomen vorzugsweise die Ethylester; geeignete anorganische Kationen sind beispielsweise das Lithium- und das Kalium-Ion und insbesondere das Natrium-Ion. Geeignete Kationen organischer Basen sind solche von primären, sekundären oder tertiären Aminen, wie zum Beispiel Ethanolamin, Diethanolamin, Morpholin, Glucamin, N, N-Dimethylglucamin, insbesondere das Meglumin. Als Komplexbildnerrest K seien vorzugsweise Derivate derIf desired, 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
Diethylentriaminpentaessigsaure und der 1, 4,7,10-Tetraazacyclododecan-1 ,4,7- tnessigsaure genannt, die über einen linker an das jeweilige Prophyrin gebunden sind.Diethylenetriaminepentaacetic acid and 1, 4,7,10-tetraazacyclododecane-1, 4,7-Tnesigsaure called, which are linked via a linker to the respective propyrin.
Die Herstellung der Komplexverbindungen der allgemeinen Formel I erfolgt nach literaturbekannten Methoden ( s z B DE 4232925 für II a und II b, s. z B. DE 19507822, DE 19580858 und DE 19507819 für III c, s z B US-5,053,503, WO 96/02669, WO 96/01655, EP 0430863, EP 255471, US-5,277,895, EP 0232751, US-4,885,363 für II d, II e und II f)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)
Die Herstellung der erfindungsgemäßen Verbindung ist bereits in WO 00/17205 beschriebenThe preparation of the compound according to the invention has already been described in WO 00/17205
Die Verbindungen, worin R2 und R3 für CONHNHK-Gruppen stehen, sind bevorzugt Die Synthese des hierfür als Edukt benotigten 3, 3'-(7, 12-Diethyl-3, 8, 13, 17- tetramethyIporphyrin-2, 18-dιyl)di(propanohydrazιd) wird in Z. Physiol Chem 241, 209 (1936) beschriebenThe compounds in which R2 and R3 represent CONHNHK groups are preferred. The synthesis of 3, 3 ' - (7, 12-diethyl-3, 8, 13, 17-tetramethyIporphyrin-2, 18-dιyl) di (propanohydrazιd) is described in Z. Physiol Chem 241, 209 (1936)
Die Einfuhrung der gewünschten Metalle (z.B Mn) in die Porphyrine erfolgt nach literaturbekannten Methoden (z.B. The Porphyrins, ed D Dolphin, Academic Press, New York 1980, Vol. V, 459; DE 4232925), wobei im wesentlichen zu nennen sind. a) die Substitution der pyrrolischen NHs (durch Erwarmen des metallfreien Liganden mit dem entsprechenden Metallsalz, vorzugsweise dem Acetat, gegebenenfalls unter Zusatz von säurepuffernden Mitteln, wie z.B. Natriumacetat, in einem polaren Losungsmittel) oder b) die "Umkomplexierung", bei der ein bereits vom Liganden komplexiertes Metall durch das gewünschte Metall verdrängt wird.The introduction of the desired metals (e.g. Mn) into the porphyrins takes place according to methods known from the literature (e.g. The Porphyrins, ed D Dolphin, Academic Press, New York 1980, Vol. V, 459; DE 4232925). a) 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) or b) the "re-complexation" in which one already metal complexed by the ligand is displaced by the desired metal.
Als Losungsmittel sind vor allem polare Solventien, wie z B Methanol, Eisessig,The main solvents used are polar solvents such as methanol, glacial acetic acid,
Dimethylformamid, Chloroform und Wasser geeignetDimethylformamide, chloroform and water are suitable
Die Einführung des paramagnetischen Metalls M in das Porphyπnsystem kann vor oder nach Anknüpfung des Komplexbildner-Restes K erfolgen. Dadurch wird eine besonders flexible Vorgehensweise für die Synthese der erfindungsgemaßen Verbindungen ermöglicht. Die Chelatisierung des Restes K erfolgt in literaturbekannter Weise (siehe z.B.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.
DE 34 01 052), indem das Metalloxid oder -salz (z B. das Nitrat, Acetat, Carbonat, Chlorid oder Sulfat) des jeweils gewünschten Metalls in polaren Lösungsmitteln wie Wasser oder wässrigen Alkoholen suspendiert oder gelöst wird und mit der entsprechenden Menge des komplexbildenden Liganden umgesetzt wird. Soweit gewünscht, können vorhandene acide Wasserstoffatome oder Säuregruppen durch Kationen anorganischer und / oder organischer Basen oder Aminosäuren substituiert werden.DE 34 01 052) by the metal oxide or salt (e.g. the nitrate, acetate, carbonate, Chloride or sulfate) of the desired metal is suspended or dissolved in polar solvents such as water or aqueous alcohols and reacted with the appropriate amount of the complex-forming ligand. If desired, acidic hydrogen atoms or acid groups present can be substituted by cations of inorganic and / or organic bases or amino acids.
Die Neutralisation erfolgt dabei mit Hilfe anorganischer Basen wie z.B. Alkali- oder Erdalkali-hydroxiden, -carbonaten oder -bicarbonaten und / oder organischer Basen wie unter anderem primärer, sekundärer und tertiärer Amine, wie z.B. Ethanolamin, Morpholin, Glucamin, N-Methyl- und N,N-Dimethylglucamiπ, sowie basischer Aminosäuren, wie z.B. Lysin, Arginin und Ornithin oder von Amiden ursprünglich neutraler oder saurer Aminosäuren.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.
Zur Herstellung der neutralen Komplexverbindungen kann man beispielsweise den sauren Komplexsalzen in wässriger Lösung oder Suspension soviel der gewünschten Basen zusetzen, dass der Neutralpunkt erreicht wird. Die erhaltene Lösung kann anschließend im Vakuum zur Trockne eingeengt werden. Häufig ist es von Vorteil, die gebildeten Neutralsalze durch Zugabe von mit Wasser mischbaren Lösungsmitteln, wie zum Beispiel niederen Alkoholen (z.B. Methanol, Ethanol, Isopropanol), niederen Ketonen (z.B. Aceton), polaren Ethern (z.B. Tetrahydrofuran, Dioxan, 1 ,2- Dimethoxyethan) auszufällen und so leicht zu isolierende und gut zu reinigende Kristallisate zu erhalten. Als besonders vorteilhaft hat es sich erwiesen, die gewünschte Base bereits während der Komplexbildung der Reaktionsmischung zuzusetzen und dadurch einen Verfahrensschritt einzusparen.To produce the neutral complex compounds, for example, 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. It is often advantageous to neutralize the formed salts by adding 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. It has proven to be particularly advantageous to add the desired base already during the complex formation of the reaction mixture and thereby to save one process step.
Enthalten die sauren Komplexverbindungen mehrere freie acide Gruppen, so ist es oft zweckmäßig, neutrale Mischsalze herzustellen, die sowohl anorganische als auch organische Kationen als Gegenionen enthalten.If the 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.
Dies kann beispielsweise geschehen, indem man den komplexbildenden Liganden in wässriger Suspension oder Lösung mit dem Oxid oder Salz des das Zentralion liefernden Elements und der Hälfte des zur Neutralisation benötigten Menge einer organischen Base umsetzt, das gebildete Komplexsalz isoliert, es gewünschtenfalls reinigt und dann zur vollständigen Neutralisation mit der benötigten Menge anorganischer Base versetzt. Die Reihenfolge der Basenzugabe kann auch umgekehrt werden.This can be done, for example, by reacting the complex-forming ligand in aqueous suspension or solution with the oxide or salt of the element providing the central ion and half of the amount of an organic base required for neutralization, isolating the complex salt formed, purifying it if desired and then completing it Neutralization with the required amount inorganic base added. The order of base addition can also be reversed.
Eine andere Möglichkeit, zu neutralen Komplexverbindungen zu kommen, besteht darin, die verbleibenden Säuregruppen im Komplex ganz oder teilweise in Ester zu überführen. Dies kann durch nachträgliche Reaktion am fertigen Komplex geschehen (z.B. durch erschöpfende Umsetzung der freien Carboxy-Gruppen mit Dimethylsulfat).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).
Die Herstellung der erfindungsgemäßen pharmazeutischen Mittel erfolgt ebenfalls in an sich bekannter Weise, indem man die erfindungsgemäßen Komplexverbindungen - gegebenenfalls unter Zugabe der in der Galenik üblichen Zusätze - in wässrigem Medium suspendiert oder löst und anschließend die Suspension oder Lösung gegebenenfalls sterilisiert. Geeignete Zusätze sind beispielsweise physiologisch unbedenkliche Puffer (wie z.B. Tromethamin), geringe Zusätze von Komplexbildnem (wie z. B. Diethylentriaminpentaessigsäure) oder, falls erforderlich, Elektrolyte wie z. B. Natriumchlorid oder, falls erforderlich, Antioxidantien wie z.B. Ascorbinsäure.The pharmaceutical 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.
Prinzipiell ist es auch möglich, die erfindungsgemäßen pharmazeutischen Mittel auch ohne Isolierung der Komplexsalze herzustellen. In jedem Fall muss besondere Sorgfalt darauf verwendet werden, die Chelatbildung so vorzunehmen, dass die erfindungsgemäßen Salze und Salzlösungen praktisch frei sind von nicht komplexierten toxisch wirkenden Metallionen.In principle, it is also possible to prepare the pharmaceutical compositions according to the invention without isolating the complex salts. In any case, special care must be taken to carry out the chelation so that the salts and salt solutions according to the invention are practically free of non-complexed toxic metal ions.
Dies kann beispielsweise mit Hilfe von Farbindikatoren wie Xylenolorange durch Kontrolltitrationen während des Herstellungsprozesses gewährleistet werden. Die Erfindung betrifft daher auch Verfahren zur Herstellung der Komplexverbindungen und ihrer Salze. Als letzte Sicherheit bleibt eine Reinigung des isolierten Komplexsalzes.This can be ensured, for example, with the help of color indicators such as xylenol orange through control titrations during the manufacturing process. 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.
Zur Verwendung der erfindungsgemäßen Verbindungen als Arzneimittel werden diese in die Form eines pharmazeutischen Präparats gebracht, das neben dem Wirkstoff für die enterale oder parenterale Applikation geeignete pharmazeutische, organische oder anorganische inerte Trägermaterialien, wie zum Beispiel, Wasser, Gelatine, Gummi arabicum, Milchzucker, Stärke, Magnesiumstearat, Talk, pflanzliche Öle, Polyalkylenglykole usw. enthält. Die pharmazeutischen Präparate können in fester Form, zum Beispiel als Tabletten, Dragees, Suppositorien, Kapseln oder in flüssiger Form, zum Beispiel als Lösungen, Suspensionen oder Emulsionen vorliegen. Gegebenenfalls enthalten sie darüber hinaus Hilfsstoffe, wie Konservierungs-, Stabilisierungs-, Netzmittel oder Emulgatoren; Salze zur Veränderung des osmotischen Drucks oder Puffer. Diese pharmazeutischen Präparate sind ebenfalls Gegenstand der vorliegenden Erfindung.To use the compounds according to the invention as pharmaceuticals, they are brought into the form of 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. These pharmaceutical preparations are also the subject of the present invention.
Für die parenterale Anwendung sind insbesondere Injektionslösungen oder Suspensionen, insbesondere wässrige Lösungen der aktiven Verbindungen in polyhydroxyethoxyliertem Rizinusöl, geeignet.Injection solutions or suspensions, in particular aqueous solutions of the active compounds in polyhydroxyethoxylated castor oil, are particularly suitable for parenteral use.
Sind für die enterale Verabreichung oder andere Zwecke Suspensionen oder Lösungen der erfindungsgemäßen Mittel in Wasser oder in physiologischer Salzlösung erwünscht, werden sie mit einem oder mehreren in der Galenik üblichen Hilfsstoff(en) (z.B.If 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.)
Methylcellulose, Lactose, Mannit) und/oder Tensid(en) (z.B. Lecithine, Tween®, Myrj®) und/oder Aromastoffen zur Geschmackskorrektur (z.B. etherischen Ölen) gemischt.Methyl cellulose, lactose, mannitol) and / or surfactant (s) (e.g. lecithins, Tween®, Myrj®) and / or flavoring agents for flavor correction (e.g. essential oils) mixed.
Als Trägersysteme können auch grenzflächenaktive Hilfsstoffe wie Salze der Gallensäuren oder tierische oder pflanzliche Phospholipide, aber auch Mischungen davon sowie Liposomen oder deren Bestandteile verwendet werden.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.
Für die orale Anwendung sind insbesondere Tabletten, Dragees oder Kapseln mit Talkum und/oder Kohlenwasserstoffträger oder -binder, wie zum Beispiel Lactose, Maisoder Kartoffelstärke, geeignet. Die Anwendung kann auch in flüssiger Form erfolgen, wie zum Beispiel als Saft, dem gegebenenfalls ein Süßstoff beigefügt ist.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.
Die enteralen, parenteralen und oralen Applikationen sind ebenfalls Gegenstand der vorliegenden Erfindung.The enteral, parenteral and oral applications are also the subject of the present invention.
Die Dosierung der Wirkstoffe kann je nach Verabfolgungsweg, Alter und Gewicht des Patienten, Art und Schwere der zu behandelnden Erkrankung und ähnlichen Faktoren variieren. Die tägliche Dosis beträgt 0,5-1000 mg, vorzugsweise 50-200 mg, wobei die Dosis als einmal zu verabreichende Einzeldosis oder unterteilt in 2 oder mehreren Tagesdosen gegeben werden kann.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.
Die vorliegende Erfindung betrifft auch die Verwendung der erfindungsgemäßen Porphyrinkomplexe nach Formel (1) zur Behandlung und Prophylaxe von Erkrankungen, die verursacht werden durch die von Peroxynitrit-vermittelten Reaktionen und die abgeschwächt und / oder therapiert werden durch die Steigerung der Umwandlungsrate von Peroxynitrit.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.
Die vorliegende Erfindung betrifft insbesondere die Verwendung der erfindungsgemäßen Porphyrinkomplexe der allgemeinen Formel (1) zur Behandlung und Prophylaxe von Erkrankungen, zu denen neurodegenerative Erkrankungen, inflammatorische Erkrankungen, Autoimmunerkrankungen, Herz-Kreislauf-Erkrankungen zählen. Beispielsweise seien genannt: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. Examples include:
Cerebrale Ischämie, ischämische Reperfusionserkrankung, Hypoxie und andere neurodegenerative Erkrankungen, die mit den Entzündungen in Verbindung gebracht werden, wie Multiple Sklerose, Amyotrophe Lateralsklerose und vergleichbare skierotische Erkrankungen, Morbus Parkinson, Huntington-Chorea, Korsakow Syndrom, Epilepsie, Erbrechen, Schlafstörungen, Schizophrenie, Depression, Migräne, Hypoglykämie, Demenz wie z.B. Alzheimerscher Krankheit, HIV-Demenz und präsenile Demenz.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.
Ferner eignen sie sich zur Behandlung von Krankheiten des Herz-Kreislauf Systems und zur Behandlung autoimmuner und / oder inflammatorischer Erkrankungen wie Hypotension, ARDS (adult respiratory distress syndrome), Sepsis oder Septischer Schock, Rheumatoider Arthritis, Osteoarthritis, von insulinabhängiger Diabetes Mellitus (IDDM), entzündlicher Erkrankung des Beckens / Darms (bowel disease), von Meningitis, Glomerulonephritis, akute und chronische Lebererkrankungen, Erkrankungen durch Abstossung (beispielsweise allogene Herz-, Nieren- oder Lebertransplantationen) oder entzündlichen Hautkrankheiten wie Psoriasis und anderen. Auf Grund ihres Wirkprofils eignen sich die erfindungsgemäßen Verbindungen sehr gut zur Umlagerung von Peroxynitrit in unbedenkliche Produkte.They are also suitable for the treatment of diseases of the cardiovascular system and for the treatment of 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. On the basis of their activity profile, the compounds according to the invention are very suitable for the rearrangement of peroxynitrite into harmless products.
Gegenstand der vorliegenden Erfindung ist auch die Verwendung von Verbindungen der allgemeinen Formel (I), dadurch gekennzeichnet, dass M für ein Fe3+, Mn3+, Cu2+, Co3+, VO2+, Cr3+ oder Ni2+-lon steht und die besonders wirksam sind.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.
Im weiteren ist Gegenstand der vorliegenden Erfindung die Verwendung von Porphyrin- Komplex-Verbindungen der allgemeinen Formel I, dadurch gekennzeichnet, dass R2 und R3 jeweils für eine -CONHNHK, -CONH(CH2)2NHK, -CONH(CH2)3NHK, -CONH(CH2)4NHK, -CONH(CH2)20(CH2)2NHK-Gruppe stehen. Ferner ist Gegenstand der vorliegenden Erfindung die Verwendung von Porphyrin- Komplex-Verbindungen der allgemeinen Formel (1), dadurch gekennzeichnet, dass R2 und R3 jeweils für eine -CONHNHK stehen.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.
Ganz besonders wirksam sind diese Verbindungen, wenn K ein Komplexbildner der allgemeinen Formel (lla) istThese compounds are particularly effective when K is a complexing agent of the general formula (IIIa)
Figure imgf000015_0001
Figure imgf000015_0001
Weiterer Gegenstand der vorliegenden Erfindung sind ins besondere Porphyrin- Komplex-Verbindungen gemäß Formel (l), nämlichThe present invention furthermore relates in particular to porphyrin complex compounds of the formula (I), namely
{mu-[{16, 16'-[Chloromangan(lll)-7, 12-diethyl-3, 8, 13, 17-tetramethylporphyrin-2, 18- diyl]-bis[3, 6, 9-tris(carboxymethyl)-11, 14-dioxo-3, 6, 9, 12, 13- pentaazahexadecanoato]}(8-)]}digadolinato(2-),-Dinatrium,{mu - [{16, 16 ' - [Chloromangan (III) -7, 12-diethyl-3, 8, 13, 17-tetramethylporphyrin-2, 18-diyl] -bis [3, 6, 9-tris (carboxymethyl ) -11, 14-dioxo-3, 6, 9, 12, 13-pentaazahexadecanoato]} (8 -)]} digadolinato (2 -), - disodium,
{mu[{16, 16'-[Chloroeisen(lll)-7, 12-diethyl-3, 8, 13, 17-tetramethylporphyrin-2, 18-diyl]- bis[3, 6, 9-tris(carboxymethyl)-11 , 14-dioxo-3, 6, 9, 12, 13-pentaazahexadecanoato]}(8-{mu [{16, 16 ' - [chloro iron (III) -7, 12-diethyl-3, 8, 13, 17-tetramethylporphyrin-2, 18-diyl] - bis [3, 6, 9-tris (carboxymethyl) -11, 14-dioxo-3, 6, 9, 12, 13-pentaazahexadecanoato]} (8-
)]}-digadolinato(2-),-Dinatrium,)]} - digadolinato (2 -) - disodium,
{mu[{16, 16'-[Kupfer(II)-7, 12-diethyl-3, 8, 13, 17-tetramethylpoφhyrin-2, 18-diyl]-bis[3, 6, 9-tris(carboxymethyl)-11 , 14-dioxo-3, 6, 9, 12, 13-pentaazahexadecanoato]}(8-)]}- digadolinato(2-) ,-Dinatrium{mu [{16, 16 '- [copper (II) -7, 12-diethyl-3, 8, 13, 17-tetramethylpoxyrin-2, 18-diyl] -bis [3, 6, 9-tris (carboxymethyl) -11, 14-dioxo-3, 6, 9, 12, 13-pentaazahexadecanoato]} (8 -)]} - digadolinato (2-), -disodium
Die gute Wasserlöslichkeit der erfindungsgemäßen Mittel erlaubt es hochkonzentrierte Lösungen herzustellen, damit die Volumenbelastung des Kreislaufs in vertretbaren Grenzen zu halten und die Verdünnung durch Körperflüssigkeit auszugleichen. Weiterhin weisen die erfindungsgemäßen Mittel nicht nur eine hohe Stabilität in vitro auf, sondern auch eine überraschend hohe Stabilität in vivo, so dass eine Freigabe oder ein Austausch der in den Komplexen nicht konvalent gebundenen - an sich giftigen - Ionen innerhalb der Zeit, in der die Kontrastmittel vollständig wieder ausgeschieden werden, zu vernachlässigen ist. Überraschenderweise zeigen die erfϊndungsgemäßen Komplexe gegenüber den bislang bekannten, strukturell ähnlichen Verbindungen eine deutlich höhere Relaxivität. Da die Relaxivität als ein Maß für die Kontrastmittelwirksamkeit einer Verbindung angesehen werden kann, gelingt bei Verwendung der erfindungsgemäßen Komplexe im Bereich der NMR-Diagnostik eine vergleichbare, positive Signalbeeinflussung schon bei einer niedrigen Dosis. Dadurch vergrößert sich der Sicherheitsabstand signifikant, für den als Richtwert das Produkt aus Relaxivität und Verträglichkeit angesehen werden kann.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. Furthermore, 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. Surprisingly, the complexes according to the invention show a significantly higher relaxivity than the structurally similar compounds known to date. Since 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.
Die vorliegende Erfindung betrifft außerdem die Verwendung der erfindungsgemäßen Porphyrinkomplexe der allgemeinnen Formel 1 nach Anspruch 1 zur Diagnostik von Erkrankungen, die die Gruppe folgender Erkrankungen umfassen: ischämische Reperfusϊonserkrankungen wie z.B. Schlaganfall, Kopftrauma und myokardiale Ischämie, Sepsis, chronische oder akute Inflammation (wie z.B. Arthritis oder inflammatorische Darmerkrankung), adultes respiratorisches Stress-Syndrom, Krebs, Bronchio-pulmonäre Dysplasie, kardiovaskuläre Erkrankungen, Diabetes, Multiple Sklerose, Parkinsonsche Erkrankung, familiäre amyotrophe Lateralsklerose und Kollitis und spezielle neuronale Erkrankungen. 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.
Beschreibung der Abbildungen:Description of the pictures:
Fig. 1 zeigt ein 14NMR- SpektrumFig. 1 shows a 14 NMR spectrum
Fig. 2 zeigt den zeitabhängigen Abbau von Peroxynitrit in An- und Abwesenheit eines Porphyrin-Katalysators, der in einem lOOfachen Unterschuss appliziert wurde 2 shows the time-dependent decomposition of peroxynitrite in the presence and absence of a porphyrin catalyst which was applied in a 100-fold deficit
BeispieleExamples
1. Untersuchung des Zerfalls von Peroxynitrit mit NMR-Spektroskopischen Methoden1. Investigation of the decay of peroxynitrite using NMR spectroscopic methods
Für die Untersuchung werden 3 Proben vorbereitet, wobei eine der Proben die wässrige Original Peroxynitritlösung ohne Zusätze enthält, die anderen enthalten diese Lösung in gleicher Menge aber mit definierten Zusätzen einer Referenzsubstanz bzw. der zu untersuchenden Substanz. Von jeder Probe wird ein 14-N-Spektrum mit den gleichen Aquisitions- und Processingparametern aufgenommen. Die Differenzen der Integrale des Nitratsignals zwischen den behandelten und der unbehandelten Peroxynitritlösung zeigt den Anstieg des Nitrats durch Umlagerung des Peroxynitrits an. Vergleiche der Daten zwischen der zu untersuchenden Substanz und der Referenzverbindung erlaubt eine Quantifizierung dieses Vorganges (Fig. 1).3 samples are prepared for the investigation, one of which contains the aqueous original peroxynitrite solution without additives, the others contain this solution in the same amount but with defined additions of a reference substance or the substance to be examined. A 14 N spectrum of each sample is recorded with the same acquisition and processing parameters. The differences in the integrals of the nitrate signal between the treated and the untreated peroxynitrite solution indicate the increase in nitrate due to rearrangement of the peroxynitrite. Comparing the data between the substance to be investigated and the reference compound allows a quantification of this process (Fig. 1).
2. Messung der Kinetik der Umwandlung von Peroxynitrit zu Nitrat mittels UV- Spektrometrie2. Measurement of the kinetics of the conversion of peroxynitrite to nitrate using UV spectrometry
Benutzt werden: ein UV-Spektrometer eine stopped-flow-Einrichtung mit angeflanschter KüvetteThe following are used: a UV spectrometer, a stopped-flow device with a flanged flask
Laborgeräte für volumetrisches Arbeiten Reagenzien (Puffer, Peroxynitrit-Lösung, Katalysatoren)Laboratory equipment for volumetric work Reagents (buffers, peroxynitrite solution, catalysts)
Aus der konzentrierten Peroxynitrit-Lösung wird der Gehalt an Peroxynitrit bestimmt. Zugrunde gelegt wird ein molarer Extinktionskoeffizient von ε = 1670. Die Lösung wird mit Wasser so verdünnt, dass eine Absorption von etwa 1.6 bei der Beobachtungswellenlänge von 301 nm erreicht wird. Der pH-Wert der so erzeugten Vorratslösung soll nicht unter 11 fallen. Entsprechend der eingestellten Konzentration des Peroxynitrit wird eine Lösung des zu untersuchenden Katalysators in Phosphat-Puffer hergestellt, so dass unter Berücksichtigung der gegebenen Verhältnisse der stopped-Flow-Einrichtung die gewünschten Mengen Katalysatorlösung und Peroxynitrit zur Reaktion zusammengeführt werden können. Der Puffer der Katalysatorlösung muss ausreichend Kapazität haben, um die noch stark alkalische Peroxynitrit-Lösung auf den gewünschten pH-Wert einstellen und halten zu können. Die Katalysatoren werden im lOOfachen Unterschuss zugegeben. Die Dosierspritzen der stopped-flow-Anlage werden mit den beiden Lösungen gefüllt und daraus die im UV-Spektrometer befindliche Küvette gefüllt. Simultan werden die Absorptionswerte bei 301 nm gemessen. Infolge Umlagerung des Peroxynitrits zu Nitrat wird die Absorption abnehmen, um nach einiger Zeit einen gleichbleibenden Wert anzunehmen. Zu diesem Zeitpunkt ist die Umlagerung abgeschlossen, und die Datenregistrierung wird abgebrochen.The content of peroxynitrite is determined from the concentrated peroxynitrite solution. A molar extinction coefficient of ε = 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.
Die Messdaten werden analysiert, aus den sich daraus resultierenden kinetischen Kenndaten der Kurve lässt sich die Peroxynitrit-Konzentration errechnen. Diese Daten dienen zur Charakterisierung des zu untersuchenden Katalysators. Um den Selbstzerfall des Peroxynitrits zu berücksichtigen, wird zu jeder verwendeten Präparation von Peroxynitrit zunächst das Zersetzungsverhalten der Peroxynitrit-Lösung bei Zufügen des Puffers ohne Katalysatorgehalt ermittelt und dessen Kenndaten werden in Beziehung zu denen gesetzt, die aus einer Messung mit Katalysator erhalten werden.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. In order to take into account the self-decay of the peroxynitrite, 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.
relative Eigenzerfall des eingesetzten Peroxynitritsrelative self-decay of the peroxynitrite used
Geschwindigkeits- = bei dem beschriebenen pH Wert konstante katalysierter ZerfallVelocity = constant catalyzed decay at the pH described
(Fig. 2).(Fig. 2).
3. SIN-1 Schädigungs-Assay mit neuronalen Primärkulturen aus dem Kleinhirn neonataler Ratten3. SIN-1 damage assay with neuronal primary cultures from the cerebellum of neonatal rats
Zur in vitro Testung von Substanzen auf Neuroprotektion gegenüber Schädigungen, die durch Peroxynitrit induziert sind, wird eine Primärkultur von Zellen aus dem Kleinhirn neonataler Ratten angelegt. Die Messung des Zelltods bzw. Überlebens von Neuronen in dieser Kultur erfolgt indirekt durch Messung der Umsetzung des Farbstoffs Alamar blue in seine reduzierte fluoreszierende Form. Zur Schädigung wird der Peroxinitrit- Donor SIN-1 (3-Morpholino-sydnonimin) verwendet.For in vitro testing of substances for neuroprotection against damage induced by peroxynitrite, a primary culture of cells from the cerebellum of neonatal rats is created. The cell death or survival of neurons in this culture is measured indirectly by measuring the conversion of the Alamar blue dye into its reduced fluorescent form. The peroxinitrite donor SIN-1 (3-morpholinosydnonimine) is used for damage.
Zur Gewinnung der Zellen werden Wistar Ratten (P8) durch Dekapitation getötet, die Kleinhirne gewonnen, die Meninge vom Kleinhirn entfernt (HBSS (GIBCO, 14025-050) 4°C), zerkleinert und in ein 15 ml Falcon-Röhrchen überführt, der Überstand wird abgesaugt und anschließend werden die Kleinhirne mittels Zugabe von 500 μl Trypsin- EDTA Lsg.( GIBCO #2530-054) / Kleinhirn trypsiniert. Nach einer Inkubation (20 min, 37°C) werden die trypsinierten Kleinhirne 3x mit 10 ml HBSS gewaschen. Es folgt eine Trituation durch Zugabe von 500 μl 0,05%ige DNAsel (BOEHRINGER MANNHEIM, #14953000) pro Kleinhirn. Mittels einer 5 ml-Pipette, dann mit einer feuergeglätteten Pasteurpipette, und zuletzt (falls nötig) mit einer ausgezogenen, feuergeglätteten Pasteurpipette werden die Zellen vereinzelt und mit 10 ml Komplettmedium (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-Stammlsg (MERCK, 1.04936.0500), 1ml L-Glutamin (100x - 200mM) (GIBCO #15140-106) versetzt. Die vereinzelten Zellen werden anschließend abzentrifugiert (10 min bei 600 rpm), 1x mit Komplett-Medium gewaschen und mit 20 ml Komplett-Medium resuspendiert, gezählt und auf 2x108/ml verdünnt. Pro Loch einer 96 Loch- Mikrotiterplatte werden100 μl Komplett-Medium vorgelegt und mit 100 μl Zellsuspension versetzt (=div1 = day 1 in vitro). Die Mikrotiterplatten werden vorher folgendermaßen beschichtet: pro Loch werden 50μl Poly-L-Lysin (MW 70-105kD) (SIGMA #P-6282) appliziert, die Platten werden dann ca. 90 min im Brutschrank inkubiert. Vor dem Ausplatten der Zellen wird die Lösung wieder abgesaugt und 2x mit HBSS bzw. mit sterilem Aqua bidest gewaschen. 24h nach Ausplattierung werden die Zellen durch Zugabe von S1N-1 geschädigt. Testsubstanzen werden 1h vor Zugabe von SIN-1 (Einzelkonzentration 10 bzw. 30 μM, bzw als Konzentrationsreihe, CALBIOCHEM, 567028) appliziert. Die Messung der Zellfunktion erfolgt an div2 (day2 in vitro) mit Alamar blue (10μ7ι well) (BIOSOURCE INT., DAL1100). Nach einer 3 stündigen Inkubation folgt die Messung im Fluoreszenzreader (Victor, Fa. Wallac, Extinktion 544nm / Emmission 590nM). IC50-Werte werden mit dem Excel Plug-in XLfit berechnet. To obtain the cells, 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 μl 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 μl 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), washed once with complete medium and resuspended with 20 ml complete medium, counted and diluted to 2x10 8 / ml 100 μl of complete medium are placed in each well of a 96-well microtiter plate and mixed with 100 μl of cell suspension (= div1 = day 1 in vitro). The microtiter plates are coated beforehand as follows: 50 μl 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 μM, or as a series of concentrations, CALBIOCHEM, 567028). The cell function is measured on div2 (day2 in vitro) with Alamar blue (10μ7ι 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.
ie Ergebnisse aus Beispiel 2 und 3 sind in der folgenden Tabelle angegebenThe results from Examples 2 and 3 are given in the following table
Figure imgf000021_0001
Figure imgf000021_0001

Claims

Patentansprüche claims
1. Verwendung eines Porphyrin-Komplexes bestehend aus einem Liganden der allgemeinen Formel I1. Use of a porphyrin complex consisting of a ligand of the general formula I
Figure imgf000022_0001
Figure imgf000022_0001
sowie mindestens einem Ion eines Elementes der Ordnungszahl 20-32, 37-39, 42-51 oder 57-83, worinand at least one ion of an element of atomic number 20-32, 37-39, 42-51 or 57-83, wherein
M für ein paramagnetisches Ion,M for a paramagnetic ion,
11
R für ein Wasserstoffatom, für einen geradkettigen 0,-C8-Alkylrest, einen C7-C12-R for a hydrogen atom, for a straight-chain 0, -C 8 -alkyl radical, a C 7 -C 12 -
Aralkylrest oder für eine Gruppe OR' worinAralkylrest or for a group OR 'wherein
R' ein Wasserstoffatom oder ein C^C8-Alkylrest ist, steht,R 'is a hydrogen atom or a C 1 -C 8 -alkyl radical,
2 32 3
R für R , eine Gruppe -CO-Z oder eine Gruppe -(NH)0-(A)q-NH-D steht, worinR represents R, a group -CO-Z or a group - (NH) 0 - (A) q-NH-D, wherein
Z eine Gruppe -OL ist, mit L in der Bedeutung eines anorganischen oder organischen Kations oder eines C^C^Alkylrestes ist,Z is a group -OL, with L being an inorganic or organic cation or a C 1 -C 4 alkyl radical,
A eine Phenylenoxy- oder eine durch ein oder mehrere Sauerstoffatome unterbrochene C^C^-Alkylen- oder C7-C12 Aralkylengruppe bedeutet, o und q unabhängig voneinander die Ziffern 0 oder 1 bedeuten und D ein Wasserstoffatom oder eine Gruppe -CO-A-(COOL)0-(H)m bedeutet, mit m gleich 0 oder 1 und unter der Maßgabe, dass die Summe aus m und o gleich 1 ist,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,
R3 für eine Gruppe -(C=Q)(NR )0-(A)q-(NR5)- steht, worin Q für ein Sauerstoffatom oder für zwei Wasserstoffatome steht,R 3 stands for a group - (C = Q) (NR) 0 - (A) q - (NR 5 ) -, in which Q stands for one oxygen atom or for two hydrogen atoms,
44
R eine Gruppe -(A)q-H bedeutet undR is a group - (A) q -H and
K einen Komplexbildner der allgemeinen Formel (lla), (llb), (llc), (lld) oder (lle)K is a complexing agent of the general formula (IIa), (IIb), (IIc), (IIID) or (III)
5 bedeutet, wobei R für den Fall, dass K ein Komplexbildner der Formel (lla) ist die5 means, where R is in the case that K is a complexing agent of the formula (Ila)
4 5 gleiche Bedeutung wie R hat und R für den Fall, dass K ein Komplexbildner der Formel (llb), (llc), (lld) oder (lle) ist, die gleiche Bedeutung wie D hat, mit der Maßgabe, dass eine direkte Sauerstoff-Stickstoff Bindung nicht zugelassen ist, und K für einen Komplexbildner der allgemeinen Formel (lla), (llb), (llc), (lld), (He) oder (llf)4 5 has the same meaning as R and R has the same meaning as D in the case that K is a complexing agent of the formula (IIb), (IIc), (III) or (III), with the proviso that a direct Oxygen-nitrogen bond is not permitted, and K for a complexing agent of the general formula (IIa), (IIB), (IIC), (IIID), (HE) or (IIF)
Figure imgf000023_0001
Figure imgf000023_0001
Figure imgf000023_0002
Figure imgf000024_0001
Figure imgf000023_0002
Figure imgf000024_0001
Figure imgf000024_0002
Figure imgf000024_0002
(lld), (IId)
Figure imgf000025_0001
Figure imgf000025_0001
(He),(He),
Figure imgf000025_0002
Figure imgf000025_0002
steht, worin q die oben angegebene Bedeutung hat,where q has the meaning given above,
A1 die für A angegebene Bedeutung hat,A 1 has the meaning given for A,
Rs für ein Wasserstoffatom, eine geradkettige oder verzweigte C-r C7-Alkylgruppe, eine Phenyl- oder Benzylgruppe,R s represents a hydrogen atom, a straight-chain or branched Cr C 7 alkyl group, a phenyl or benzyl group,
A2 für eine Phenylen-, -CH2-NHC0-CH2-CH (CH2COOH) -C6H4-ß-, -CBH4-0-(CH2)o-A 2 for a phenylene, -CH 2 -NHC0-CH 2 -CH (CH 2 COOH) -C 6 H 4 -ß-, -C B H 4 -0- (CH 2 ) o-
5-ß> -C6H4-(OCH2CH2)o-ι-N(CH2COOH)-CH2-ß oder eine gegebenenfalls durch ein oder mehrere Sauerstoffatome, 1 bis 3-NHCO-, 1 bis 3 -CONH-gruppen unterbrochene und/oder mit 1 bis 3-(CH2)0.5COOH-Gruppen substituierte Cι-C12-Alkylen- oder C7-C12- Alkylengruppe, wobei ß für die Bindungsstelle an X steht, X für eine -CO- oder NHCS-gruppe und 5 -ß > -C 6 H 4 - (OCH 2 CH 2 ) o-ι-N (CH 2 COOH) -CH 2 -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 ) 0 . 5 COOH groups substituted -CC 12 alkylene or C 7 -C 12 alkylene group, where ß stands for the binding site at X, X for a -CO or NHCS group and
L1, L , L und L unabhängig voneinander für ein Wasserstoffatom oder ein Metallionenäquivalent eines Elements der oben genannten Ordnungszahl steht, unter den Maßgaben, dass mindestens zwei dieser Substituenten für Metallionenäquivalente stehen, und dass zum Ausgleich gegebenenfalls vorhandener Ladungen im Metalloporphyrin weitere Anionen vorhanden sind und worin freie, nicht zur Komplexierung benötigte Carbonsäuregruppen auch als Salze mit physiologisch verträglich anorganischen und/oder organischen Kationen oder als Ester oder als Amide vorliegen können, für die Herstellung eines Arzneimittels zur Behandlung und Prophylaxe radikal-vermittelterL 1 , L, L and L independently of one another represent a hydrogen atom or a metal ion equivalent of an element of the above-mentioned atomic number, provided that at least two of these substituents are metal ion equivalents and that additional anions are present in the metalloporphyrin to balance any charges 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 amides, for the production of a medicament for the treatment and prophylaxis of radical-mediated ones
Zellschädigungen.Cell damage.
2. Verwendung der Porphyrinkomplexe nach Anspruch 1 zur Herstellung eines Arzneimittels zur Behandlung und Prophylaxe von Erkrankungen die verursacht werden durch die von Peroxynitrit-vermittelten Reaktionen und die abgeschwächt und / oder therapiert werden durch die Steigerung der Umwandlungsrate von Peroxynitrit.2. Use of the porphyrin complexes according to claim 1 for the manufacture of a medicament for the treatment and prophylaxis of diseases which are caused by the reactions mediated by peroxynitrite and which are weakened and / or treated by increasing the conversion rate of peroxynitrite.
3. Verwendung der Porphyrinkomplexe nach Anspruch 1 oder 2 zur Behandlung und Prophylaxe von Erkrankungen, die die Gruppe folgender Erkrankungen umfassen: ischämische Reperfusionserkrankungen wie z.B. Schlaganfall, Kopftrauma und myokardiale Ischämie, Sepsis, chronische oder akute Inflammation (wie z.B. Arthritis oder inflammatorische Darmerkrankung), adultes respiratorisches Stress-Syndrom, Krebs, Bronchio-pulmonäre Dysplasie, kardiovaskuläre Erkrankungen, Diabetis, Multiple Sklerose, Parkinsonsche Erkrankung, familiäre amyotrophe Lateralsklerose und Kollitis und spezielle neuronale Erkrankungen.3. Use of the porphyrin complexes according to claim 1 or 2 for the treatment and prophylaxis of diseases which include the group of the following diseases: ischemic reperfusion diseases such as e.g. 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 laterals Collitis and special neuronal diseases.
4. Verwendung der Porphyrinkomplexe der allgemeinen Formel 1 nach Anspruch 1, dadurch gekennzeichnet, dass M für ein Fe3+, Mn3+, Cu2+, Co3+, VO24, Cr3* oder Ni2+- Ion steht4. Use of the porphyrin complexes of the general formula 1 according to claim 1, characterized in that M represents an Fe 3+ , Mn 3+ , Cu 2+ , Co 3+ , VO 24 , Cr 3 * or Ni 2+ ion
5. Verwendung von Porphyrin-Komplex-Verbindungen der allgemeinen Formel 1 nach Anspruch 1 oder 4, dadurch gekennzeichnet, dass R2 und R3 jeweils für eine -CONHNHK, -CONH(CH2)2NHK, -CONH(CH2)3NHK, -CONH(CH2)4NHK, -CONH(CH2)20(CH2)2NHK-Gruppe stehen. 5. Use of porphyrin complex compounds of general formula 1 according to claim 1 or 4, characterized in that R 2 and R 3 each for 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.
6. Verwendung der Porphyrinkomplexe nach Anspruch 1, 4 oder 5 dadurch gekennzeichnet, dass R2 und R3 jeweils für eine -CONHNHK stehen,6. Use of the porphyrin complexes according to claim 1, 4 or 5, characterized in that R 2 and R 3 each represent a -CONHNHK,
7. Verbindungen nach Anspruch 6, dadurch gekennzeichnet, dass K ein Komplexbildner der allgemeinen Formel (lla)7. Compounds according to claim 6, characterized in that K is a complexing agent of the general formula (Ila)
Figure imgf000027_0001
Figure imgf000027_0001
8. Verwendung der Porphyrin-Komplex-Verbindungen gemäß Formel 1 von Anspruch8. Use of the porphyrin complex compounds according to formula 1 of claim
1, nämlich1, namely
{mu-[{16, 16'-[Chloromangan(III)-7, 12-diethyl-3, 8, 13, 17-tetramethylporphyrin-2,{mu - [{16, 16 ' - [Chloromangan (III) -7, 12-diethyl-3, 8, 13, 17-tetramethylporphyrin-2,
18-diyl]-bis[3, 6, 9-tris(carboxymethyl)-11 , 14-dioxo-3, 6, 9, 12, 13- pentaazahexadecanoato]}(8-)]}digadoiinato(2-),-Dinatrium, {mu[{16, 16'-[Chloroeisen(lll)-7, 12-diethyl-3, 8, 13, 17-tetramethylporphyrin-2, 18- diyl]-bis[3, 6, 9-tris(carboxymethyl)-11 , 14-dioxo-3, 6, 9, 12, 13- pentaazahexadecanoato]}(8-)]}-digadolinato(2-),-Dinatrium,18-diyl] -bis [3, 6, 9-tris (carboxymethyl) -11, 14-dioxo-3, 6, 9, 12, 13-pentaazahexadecanoato]} (8 -)]} digadoiinato (2 -), - Disodium, {mu [{16, 16 ' - [chloro iron (III) -7, 12-diethyl-3, 8, 13, 17-tetramethylporphyrin-2, 18-diyl] -bis [3, 6, 9-tris ( carboxymethyl) -11, 14-dioxo-3, 6, 9, 12, 13-pentaazahexadecanoato]} (8 -)]} - digadolinato (2 -), - disodium,
{mu[{16, 16'-[Kupfer(ll)-7, 12-diethyl-3, 8, 13, 17-tetramethylporphyrin-2, 18-diyl]- bϊs[3, 6, 9-tris(carboxymethyl)-11 , 14-dioxo-3, 6, 9, 12, 13- pentaazahexadecanoato]}(8-)]}-digadolinato(2-),-Dinatrium{mu [{16, 16 '- [copper (II) -7, 12-diethyl-3, 8, 13, 17-tetramethylporphyrin-2, 18-diyl] - bϊs [3, 6, 9-tris (carboxymethyl) -11, 14-dioxo-3, 6, 9, 12, 13-pentaazahexadecanoato]} (8 -)]} - digadolinato (2 -), - disodium
9. Verwendung der Porphyrinkomplexe der allgemeinen Formel 1 gemäß Anspruch 1 zur Diagnosik von Erkrankungen, die die folgende Gruppe umfassen: a. ischämische Reperfusionserkrankungen b. akute und chronische inflammatorische Erkrankungen c. Autoimmunerkrankungen d. neurodegenerative und neuroregenerative Erkrankungen 9. Use of the porphyrin complexes of the general formula 1 according to claim 1 for the diagnosis of diseases which comprise the following group: a. ischemic reperfusion disorders b. acute and chronic inflammatory diseases c. Autoimmune diseases d. neurodegenerative and neuroregenerative diseases
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005041885A2 (en) * 2003-10-31 2005-05-12 Metaphore Pharmaceuticals, Inc. Compositions and methods for treating, preventing, reversing and inhibiting pain
WO2006054757A1 (en) * 2004-11-16 2006-05-26 Astellas Pharma Inc. Caspase inhibitor
EP2544542A1 (en) * 2010-03-10 2013-01-16 Galleon Pharmaceuticals, Inc. Analgesic compounds, compositions, and uses thereof
CN111848656A (en) * 2020-06-24 2020-10-30 天津大学 Ion-modified protoporphyrin gallium compound and preparation method and application thereof

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100753184B1 (en) 1999-01-25 2007-08-30 내셔날 쥬이쉬 메디칼 앤드 리서치 센터 Substituted Porphyrins
ES2600469T3 (en) 2008-05-23 2017-02-09 National Jewish Health A compound for use in the treatment of lesions associated with exposure to phosgene gas or chlorine gas

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0355041A2 (en) * 1988-08-13 1990-02-21 Schering Aktiengesellschaft Complex porphyrine compounds substituted in position 13,17 by propionic acid and propionic-acid derivatives, process for their preparation and pharmaceutical compositions containing same
WO1995031197A1 (en) * 1994-05-13 1995-11-23 Monsanto Company Methods of use for peroxynitrite decomposition catalysts, pharmaceutical compositions therefor
WO1995031219A1 (en) * 1994-05-11 1995-11-23 Schering Aktiengesellschaft The use of porphyrin-complex or expanded porphyrin-complex compounds as localization diagnosticum for infarction or necrosis
WO1999062512A1 (en) * 1998-06-02 1999-12-09 Schering Aktiengesellschaft 3-, 8-substituted deuteroporphyrin derivatives, pharmaceutical substances containing the same, method for the production and use thereof in photodynamic therapy and mri diagnosis
WO2000005235A1 (en) * 1998-07-24 2000-02-03 Schering Aktiengesellschaft Paramagnetic 3-,8-substituted deuteroporphyrin derivatives, pharmaceutical preparations containing same, method for producing same and their use in magnetic resonance imaging of necrosis and infarction
WO2000075144A2 (en) * 1999-06-03 2000-12-14 The Trustees Of Princeton University Peroxynitrite decomposition catalysts and methods of use thereof
WO2001026655A1 (en) * 1999-10-13 2001-04-19 Uab Research Foundation Metalloporphyrin treatment of neurologic disease
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 (en) * 1992-09-28 1994-03-31 Diagnostikforschung Inst 3-, 8-substituted deuteroporphyrin derivatives, pharmaceutical compositions containing them and process for their preparation

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0355041A2 (en) * 1988-08-13 1990-02-21 Schering Aktiengesellschaft Complex porphyrine compounds substituted in position 13,17 by propionic acid and propionic-acid derivatives, process for their preparation and pharmaceutical compositions containing same
WO1995031219A1 (en) * 1994-05-11 1995-11-23 Schering Aktiengesellschaft The use of porphyrin-complex or expanded porphyrin-complex compounds as localization diagnosticum for infarction or necrosis
WO1995031197A1 (en) * 1994-05-13 1995-11-23 Monsanto Company Methods of use for peroxynitrite decomposition catalysts, pharmaceutical compositions therefor
US6245758B1 (en) * 1994-05-13 2001-06-12 Michael K. Stern Methods of use for peroxynitrite decomposition catalysts, pharmaceutical compositions therefor
WO1999062512A1 (en) * 1998-06-02 1999-12-09 Schering Aktiengesellschaft 3-, 8-substituted deuteroporphyrin derivatives, pharmaceutical substances containing the same, method for the production and use thereof in photodynamic therapy and mri diagnosis
WO2000005235A1 (en) * 1998-07-24 2000-02-03 Schering Aktiengesellschaft Paramagnetic 3-,8-substituted deuteroporphyrin derivatives, pharmaceutical preparations containing same, method for producing same and their use in magnetic resonance imaging of necrosis and infarction
WO2000075144A2 (en) * 1999-06-03 2000-12-14 The Trustees Of Princeton University Peroxynitrite decomposition catalysts and methods of use thereof
WO2001026655A1 (en) * 1999-10-13 2001-04-19 Uab Research Foundation Metalloporphyrin treatment of neurologic disease

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 (en) * 2003-10-31 2005-05-12 Metaphore Pharmaceuticals, Inc. Compositions and methods for treating, preventing, reversing and inhibiting pain
WO2005041885A3 (en) * 2003-10-31 2006-10-12 Metaphore Pharmaceuticals Inc Compositions and methods for treating, preventing, reversing and inhibiting pain
WO2006054757A1 (en) * 2004-11-16 2006-05-26 Astellas Pharma Inc. Caspase inhibitor
EP2544542A1 (en) * 2010-03-10 2013-01-16 Galleon Pharmaceuticals, Inc. Analgesic compounds, compositions, and uses thereof
EP2544542A4 (en) * 2010-03-10 2013-07-24 Galleon Pharmaceuticals Inc Analgesic compounds, compositions, and uses thereof
CN111848656A (en) * 2020-06-24 2020-10-30 天津大学 Ion-modified protoporphyrin gallium compound and preparation method and application thereof
CN111848656B (en) * 2020-06-24 2023-03-14 天津大学 Ion-modified protoporphyrin gallium compound and preparation method and application thereof

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