DE102010014411A1 - New iron complexes, useful as carbon monoxide and iron releasing molecules for treating e.g. high blood pressure, cancer, tissue damage by irradiation, post-ischemic injury, atherosclerosis, sepsis, angina and myocardial infarction - Google Patents

New iron complexes, useful as carbon monoxide and iron releasing molecules for treating e.g. high blood pressure, cancer, tissue damage by irradiation, post-ischemic injury, atherosclerosis, sepsis, angina and myocardial infarction Download PDF

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DE102010014411A1
DE102010014411A1 DE102010014411A DE102010014411A DE102010014411A1 DE 102010014411 A1 DE102010014411 A1 DE 102010014411A1 DE 102010014411 A DE102010014411 A DE 102010014411A DE 102010014411 A DE102010014411 A DE 102010014411A DE 102010014411 A1 DE102010014411 A1 DE 102010014411A1
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carboxylic acid
acid derivatives
carbon monoxide
peptide sequence
derivative
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Prof. Dr. Westerhausen Matthias
Robert Kretschmer
Prof. Dr. Heinemann Stefan Herbert
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Friedrich Schiller Universtaet Jena FSU
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic System
    • C07F15/02—Iron compounds
    • C07F15/025—Iron compounds without a metal-carbon linkage
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Abstract

Iron complexes having a structure (I) are new. Iron complexes having a structure of formula (I) are new. R : H, aryl-, acyl-, sugar-residue, amino acid, peptide sequence, heterocycle, alkyl or acyl; and R1a, R2a : H, alkyl, acyl, peptide sequence, amine derivative, ether derivative, carboxylic acid derivative, thioether derivative, OH, NH 2or sulfonic acid derivative. Where (I) exclude: when R and R2a are H and R1a is COOH; and when R is H, R1a is COO-alkyl, and R2a is H. An independent claim is included for the preparation of (I). ACTIVITY : Hypotensive; Cytostatic; Immunosuppressive; Vulnerary; Antiarteriosclerotic; Antibacterial; Antianginal; Cardiant; Vasotropic; Antiinflammatory. MECHANISM OF ACTION : None given.

Description

Die Erfindung betrifft spezielle Kohlenmonoxid und Eisen freisetzende Komplexverbindungen und deren Verwendung als pharmakologische Wirkstoffe.The invention relates to specific carbon monoxide and iron-releasing complex compounds and their use as pharmacological agents.

Kohlenmonoxid stellt sich aufgrund der nachstehenden physiologischen Eigenschaften als breit anwendbares Therapeutikum dar:
So ist Kohlenmonoxid (CO) ein fundamentaler Botenstoff (beispielsweise R. Foresti, R. Motterlini: The heme oxygenase pathway and its interaction with nitric oxide in the control of cellular homeostasis, Free Radic. Res. 1999, 31, 459–475 ), wirkt gefäßerweiternd (z. B. I. A. Sammut, R. Foresti, J. E. Clark, D. J. Exon, M. J. Vesely, P. Sarathchandra, C. J. Green, R. Motterlini: Carbon monoxide is a major contributor to the regulation of vascular tone in aortas expressing high levels of haeme oxygenase-1, British Journal of Pharmacology, 125(7), 1998, 1437–1444 ) und kontrolliert das Wachstum von glatten Muskelzellen ( T. Morita, S. A. Mitsialis, H. Koike, V. Liu, S. Kourembanas: Carbon Monoxide Controls the Proliferation of Hypoxic Vascular Smooth Muscle Cells, Journal of Biological Chemistry, 272, 1997, 32804–32809 ).Carbon monoxide is a broadly applicable therapeutic because of the following physiological properties:
Thus carbon monoxide (CO) is a fundamental messenger substance (for example R. Foresti, R. Motterlini: The heme oxygenase pathway and its interaction with nitric oxide in the control of cellular homeostasis, Free Radic. Res. 1999, 31, 459-475 ), has a vasodilatory effect (eg IA Sammut, R. Foresti, JE Clark, DJ Exon, MJ Vesely, P. Sarathchandra, CJ Green, R. Motterlini: Carbon monoxide is a major contributor to the regulation of vascular tone in aortas expressing high levels of heme oxygenase-1, British Journal of Pharmacology, 125 (7), 1998, 1437-1444 ) and controls the growth of smooth muscle cells ( T. Morita, SA Mitsialis, H. Koike, V. Liu, S. Kourembanas: Carbon Monoxide Controls the Proliferation of Hypoxic Vascular Smooth Muscle Cells, Journal of Biological Chemistry, 272, 1997, 32804-32809 ).

Darüber hinaus unterdrückt Kohlenmonoxid die Abstoßung von transplantierten Organen ( K. Sato, J. Balla, L. Otterbein, R. N. Smith, S. Brouard, Y. Lin, E. Csizmadia, J. Sevigny, S. C. Robson, G. Vercellotti, A. M. Choi, F. H. Bach, M. P. Soares: Carbon Monoxide Generated by Heure Oxygenase-1 Suppresses the Rejection of Mouse-to-Rat Cardiac Transplants, The Journal of Immunology, 166, 2001, 4185–4194 ), besitzt anti-inflammatorische Effekte ( L. E. Otterbein, F. H. Bach, J. Alam, M. Soares, L. H. Tao, M. Wysk, R. J. Davis, R. A. Flavell, A. M. Choi: Carbon monoxide has anti-inflammatory effects involving the mitogen-activated Protein kinase pathway, Nat. Med. 2000, 6, 422–428 ) und fördert den Schutz vor ischämischer Gewebsschädigung ( T. Fujita, K. Toda, A. Karimova, S. F. Van, Y. Naka, S. F. Yet, D. J. Pinsky: Paradoxical rescue from ischemic lung injury by inhaled carbon monoxide driven by derepression of fibrinolysis, Nat. Med. 2001, 7, 598–604 ).In addition, carbon monoxide suppresses the rejection of transplanted organs ( K. Sato, J. Balla, L. Otterbein, RN Smith, S. Brouard, Y. Lin, E. Csizmadia, J. Sevigny, SC Robson, G. Vercellotti, AM Choi, FH Bach, MP Soares: Carbon Monoxide Generated by Heure Oxygenase-1 Suppresses the Rejection of Mouse-to-Rat Cardiac Transplants, The Journal of Immunology, 166, 2001, 4185-4194 ), has anti-inflammatory effects ( LE Otterbein, FH Bach, J. Alam, M. Soares, LH Tao, M. Wysk, RJ Davis, RA Flavell, AM Choi: Carbon monoxide has anti-inflammatory effects involving the mitogen-activated protein kinase pathway, Nat. Med. 2000, 6, 422-428 ) and promotes protection against ischemic tissue damage ( T. Fujita, K. Toda, A. Karimova, SF Van, Y. Naka, SF Yet, DJ Pinsky: Paradoxical rescue from ischemic injury by inhaled carbon monoxide driven by derepression of fibrinolysis, Nat. Med. 2001, 7, 598-604 ).

Die geringe Löslichkeit von ca. 1 mmol/L (20°C) und die mangelnde Selektivität von freiem Kohlenmonoxid machen einen gezielten therapeutischen Einsatz jedoch nahezu unmöglich. Die Erforschung von Kohlenmonoxid freisetzenden Molekülen, den so genannten „CO releasing molecules” (CORMs), welche Kohlenmonoxid gezielt an den Ort der gewünschten Wirkung transportieren und dort freisetzen, ist der entscheidende Schritt bei der Nutzung von Kohlenmonoxid als Therapeutikum. Seit 2002 die ersten potenziellen CORMs publiziert wurden, gewinnt dieses Forschungsgebiet zunehmend an Bedeutung ( R. Motterlini, J. E. Clark, R. Foresti, P. Sarathchandra, B. E. Mann, C. J. Green: Carbon Monoxide-Releasing Molecules: Characterization of Biochemical and Vascular Activities, Circ. Res. 2002, 90, E17–E24 ).The low solubility of about 1 mmol / L (20 ° C) and the lack of selectivity of free carbon monoxide make a targeted therapeutic use, however, almost impossible. The research on carbon monoxide releasing molecules, the so-called "CO releasing molecules" (CORMs), which transport carbon monoxide specifically to the site of the desired effect and release it, is the decisive step in the use of carbon monoxide as a therapeutic agent. Since the first potential CORMs were published in 2002, this field of research is becoming increasingly important ( R. Motterlini, JE Clark, R. Foresti, P. Sarathchandra, BE Mann, CJ Green: Carbon Monoxide Releasing Molecules: Characterization of Biochemical and Vascular Activities, Circ. Res. 2002, 90, E17-E24 ).

Mit Dimangandecacarbonyl (CORM-1) und dem Tricarbonyldichlororuthenium(II)-dimer (CORM-2) wurden 2002 die ersten CORMs publiziert. Die wasserunlöslichen Verbindungen zeigen dabei unterschiedliche Eigenschaften. Während CORM-1 nur unter Bestrahlung mit Licht Kohlenmonoxid entwickelte, setzte CORM-2 gelöst in DMSO sofort CO frei. Des Weiteren konnte gezeigt werden, dass diese CORMs in vitro die Relaxation von Blutgefäßen fördern sowie in vivo koronare Gefäßverengungen abschwächen und die akute Hypertonie senken ( R. Motterlini, J. E. Clark, R. Foresti, P. Sarathchandra, B. E. Mann, C. J. Green: Carbon Monoxide-Releasing Molecules: Characterization of Biochemical and Vascular Activities, Circ. Res. 2002, 90, E17–E24 ).The first CORMs were published in 2002 with dimangandecacarbonyl (CORM-1) and tricarbonyldichlororuthenium (II) dimer (CORM-2). The water-insoluble compounds show different properties. While CORM-1 developed carbon monoxide only under light irradiation, CORM-2 dissolved in DMSO immediately released CO. Furthermore, it has been shown that these CORMs promote the relaxation of blood vessels in vitro and attenuate in vivo coronary vasoconstriction and reduce acute hypertension ( R. Motterlini, JE Clark, R. Foresti, P. Sarathchandra, BE Mann, CJ Green: Carbon Monoxide Releasing Molecules: Characterization of Biochemical and Vascular Activities, Circ. Res. 2002, 90, E17-E24 ).

Mit Tricarbonylchloro(glycinato)ruthenium(II) (CORM-3) stand 2003 erstmals ein wasserlösliches CO releasing molecule zur Verfügung ( J. E. Clark, P. Naughton, S. Shurey, C. J. Green, T. R. Johnson, B. E. Mann, R. Foresti, R. Motterlini: Cardioprotective actions by a water-soluble carbon monoxide-releasing molecule, Circ. Res. 2003, 93, e2–e8 ).With tricarbonylchloro (glycinato) ruthenium (II) (CORM-3), a water-soluble CO releasing molecule was available for the first time in 2003 ( JE Clark, P. Naughton, S. Shurey, CJ Green, TR Johnson, BE Mann, R. Foresti, R. Motterlini: Cardioprotective actions by a water-soluble carbon monoxide-releasing molecule, Circ. Res. 2003, 93, e2-e8 ).

2005 wurde das seit 1967 bekannte Boranocarbonat ( L. J. Malone, R. W. Parry, Inorg. Chem. 1967, 6, 817–822 ) als zweites wasserlösliches CORM-A1 identifiziert ( J. E. Clark, P. Naughton, S. Shurey, C. J. Green, T. R. Johnson, B. E. Mann, R. Foresti, R. Motterlini: Cardioprotective Actions by a Water-Soluble Carbon Monoxide-Releasing Molecule, Circ. Res. 2003, 93, e2–e8 ).In 2005, the borane carbonate known since 1967 ( LJ Malone, RW Parry, Inorg. Chem. 1967, 6, 817-822 ) is identified as the second water-soluble CORM-A1 ( JE Clark, P. Naughton, S. Shurey, CJ Green, TR Johnson, BE Mann, R. Foresti, R. Motterlini: Cardioprotective Actions by a Water-Soluble Carbon Monoxide Releasing Molecule, Circ. Res. 2003, 93, e2-e8 ).

Die vorgenannten CORMs weisen mit Mangan und Ruthenium körperfremde Zentralatome auf. Damit verbunden ist die Ungewissheit über mögliche Nebenreaktionen im Organismus. Bor hingegen fungiert als Nähr- und Spurenelement, jedoch weist es die geringste Spanne zwischen Mangel und Überschuss aller Spurenelemente auf. Es beeinflusst die Zellteilungsrate und wirkt als Neutronenfänger, weshalb Überdosierungen zu toxischen Effekten führen können ( R. Fischer: Unser Organismus benötigt Bor-Komplexverbindungen – Wesentliche Bedeutung von Bor für alle Lebewesen, SANUM-Post 1989, 8, 29–34 ).The aforementioned CORMs have manganese and ruthenium foreign to the central atoms. Associated with this is the uncertainty about possible side reactions in the organism. Boron, on the other hand, acts as a nutrient and trace element, but it has the smallest margin between deficiency and excess of all trace elements. It influences the cell division rate and acts as a neutron catcher, which is why overdoses can lead to toxic effects ( R. Fischer: Our Organism Requires Boron Complex Compounds - Significance of Boron for All Living Things, SANUM-Post 1989, 8, 29-34 ).

Eisen stellt ein essentielles Spurenelement dar und wird im Organismus durch Transferrin und Ferritin, transportiert bzw. gespeichert ( W. Kaim, B. Schwederski, Bioanorganische Chemie, 3, B. G. Teubner Verlag/GWV Fachverlage GmbH, Wiesbaden 2004, 168–178 ). Iron is an essential trace element and is transported or stored in the organism by transferrin and ferritin ( W. Kaim, B. Schwederski, Bioinorganic Chemistry, 3, BG Teubner Verlag / GWV Fachverlage GmbH, Wiesbaden 2004, 168-178 ).

Fairlamb et al. stellten Komplexe von nullwertigem Eisen, welches η4 an 2-Pyronderivate gebunden ist, vor ( I. J. Fairlamb, A. K. Duhme-Klair, J. M. Lynam, B. E. Moulton, C. T. O'Brien, P. Sawle, J. Hammad, R. Motterlini: η4-Pyrone metal carbonyl complexes as effective CO-releasing molecules, Bioorg. Med. Chem. Lett. 2005, 16, 995–998 ).Fairlamb et al. complexes of zero-valent iron bound η 4 to 2-pyrone derivatives IJ Fairlamb, AK Duhme-Klair, JM Lynam, BE Moulton, CT O'Brien, P. Sawle, J. Hammad, R. Motterlini: η4-Pyrone metal carbonyl complexes as effective CO-releasing molecules, Bioorg. Med. Chem. Lett. 2005, 16, 995-998 ).

Aufgrund des bekannten metabolischen Abbaus von 2-Pyronderivaten wurden auch η1-Eisen(II)komplexe untersucht, wobei diese jedoch keine Kohlenmonoxidfreisetzung zeigten ( P. Sawle, J. Hammad, I. J. Fairlamb, B. Moulton, C. T. O'Brien, J. M. Lynam, A. K. Duhme-Klair, R. Foresti, R. Motterlini: Bioactive properties of iron-containing carbon monoxide releasing molecules, J. Pharmacol. Exp. Ther. 2006, 318, 403–410 ).Due to the known metabolic degradation of 2-pyrone derivatives, η 1 -iron (II) complexes were also investigated, but these did not show any carbon monoxide release ( P. Sawle, J. Hammad, IJ Fairlamb, B. Moulton, CT O'Brien, JM Lynam, AK Duhme-Klair, R. Foresti, R. Motterlini: Bioactive properties of iron-containing carbon monoxide releasing molecules, J. Pharmacol , Exp. Ther. 2006, 318, 403-410 ).

Aufgrund der ungünstigen Nebeneffekt von [(η5-C5H5)Fe(CO)3]Cl ( WO 0292075 A2 ), welches neben Kohlenmonoxid auch einen unlöslichen Feststoff freisetzte, was zum Verschluss von Mikroarterien und somit zu medizinischen Komplikationen führen könnte, wurden Verbindungen mit wasserlöslichen Gruppen synthetisiert um dieses Problem zu beheben ( D. Scapens, H. Adams, T. R. Johnson, B. E. Mann, P. Sawle, R. Agil, T. Perrior, R. Motterlini: [(η-C5H4R)Fe(CO)2)X], X = Cl, Br, I, NO3,CO2Me and [(η-C5H4R)Fe(CO)3]+), R = (CH2)nCO2Me (n = 0–2), and CO2CH2CH2OH: a new group of CO-releasing molecules, Dalton Transactions, 2007, 4962–4973 ).Due to the unfavorable side effect of [(η 5 -C 5 H 5 ) Fe (CO) 3 ] Cl ( WO 0292075 A2 ), which in addition to carbon monoxide also released an insoluble solid, which could lead to the occlusion of microarteria and thus to medical complications, compounds with water-soluble groups were synthesized to remedy this problem ( D. Scapens, H. Adams, TR Johnson, BE Mann, P. Sawle, R. Agil, T. Perrior, R. Motterlini: [(η-C5H4R) Fe (CO) 2) X], X = Cl, Br , I, NO3, CO2Me and [(η-C5H4R) Fe (CO) 3] +), R = (CH2) nCO2Me (n = 0-2), and CO2CH2CH2OH: a new group of CO-releasing molecules, Dalton Transactions , 2007, 4962-4973 ).

Zhang et al. untersuchten schließlich eine dritte Klasse von eisenhaltigen CORMs. Dabei versuchten sie, die schnelle Kohlenmonoxidfreisetzung von Diiodotetracarbonyleisen(II) durch Einführung von phosphorhaltigen Liganden zu stabilisieren ( D. Scapens, H. Adams, T. R. Johnson, B. E. Mann, P. Sawle, R. Agil, T. Perrior, R. Motterlini: [(Eta-C5H4R)Fe(CO)2X], X = Cl, Br, I, NO3, CO2Me and [(eta-C5H4R)Fe(CO)3]+, R = (CH2)nCO2Me (n = 0–2), and CO2CH2CH2OH: a new group of CO-releasing molecules, Dalton Trans. 2007, 4962–4973 ). Zhang et al. finally investigated a third class of ferruginous CORMs. They attempted to stabilize the rapid release of carbon monoxide from diiodotetracarbonyl iron (II) by introducing phosphorus ligands ( D. Scapens, H. Adams, TR Johnson, BE Mann, P. Sawle, R. Agil, T. Perrior, R. Motterlini: [(Eta C 5 H 4 R) Fe (CO) 2 X], X = Cl, Br, I , NO3, CO2Me and [(eta-C5H4R) Fe (CO) 3] +, R = (CH2) nCO2Me (n = 0-2), and CO2CH2CH2OH: a new group of CO-releasing molecules, Dalton Trans. 2007, 4962-4973 ).

Eine interessante Verbindungsklasse, welche körperbekannte Liganden und lichtinduzierte Kohlenmonoxidfreisetzung beinhaltet, stellen Schwefelkomplexe, die sich von Cystein ableiten, dar. Cremer berichtete 1929, dass die Kohlenmonoxidabsorption von Eisen- und Cobaltcysteinatkomplexen zu den Verbindungen Dicarbonylbis(cysteinato)eisen(II) sowie Carbonylbis(cysteinato)cobalt(I) führt ( Cremer, Biochem. Z. 1929, 206, 228 ). Außerdem beobachtete er für Eisen ein reversibles Desorptions- bzw. Absorptionsverhalten. Bei Bestrahlung mit sichtbarem Licht gab der Komplex Kohlenmonoxid ab, um es in der Dunkelheit wieder aufzunehmen. Diese Beobachtungen wurden von Tomita et al. 1967 bestätigt und um ein entsprechendes thermisches Verhalten erweitert. So stellten sie eine Kohlenmonoxidfreisetzung bei 90°C fest, welche durch Kühlung mit Eis wieder rückgängig gemacht werden konnte ( A. Tomita, H. Hirai, S. Makishima: Optical Rotatory Dispersion Study an the Iron Complex with L-Cystein and Its Reaction with Carbon Monoxide and Nitric Oxide, Inorg. Chem. 1967, 6, 1746–1749 ). Die auf Cystein basierende Verbindung ist durch die vorhandenen Carboxylgruppen als polar zu betrachten. Dies wirkt sich auf die pharmakokinetischen Eigenschaften, insbesondere der Blut-Hirn-Schranken-Gängigkeit ungünstig aus, weshalb eine weniger polare Verbindung wünschenswert wäre. Beim Abbau von Cystein im Körper bildet sich durch Decarboxylierung das biogene Amin Cysteamin ( J. Koolman, K.-H. Röhm, Taschenatlas der Biochemie, 3. Auflage Georg Thieme Verlag, Stuttgart, New York 2003 ). Dieses sollte komplexgebunden, ähnliche Eigenschaften mit einer geringeren Polarität in Einklang bringen. Die daraus resultierende Verbindung der Formel C6H12FeN2O2S2 wurde 1989 von Takács et al. durch Reaktion von FeSO4·7H2O, Cysteamin, Triethylamin und Kohlenmonoxid in 19,5%iger Ausbeute erhalten. Jedoch wird dort keine Aussage über die strukturelle Anordnung der Liganden getroffen.An interesting class of compounds incorporating known ligands and photoinduced carbon monoxide release represent sulfur complexes derived from cysteine. Cremer reported in 1929 that the carbon monoxide absorption of iron and cobalt cysteinate complexes into the compounds dicarbonylbis (cysteinato) iron (II) and carbonylbis (cysteinato ) cobalt (I) leads ( Cremer, Biochem. Z. 1929, 206, 228 ). He also observed a reversible desorption or absorption behavior for iron. Upon exposure to visible light, the complex released carbon monoxide to resume it in the dark. These observations were reported by Tomita et al. Confirmed in 1967 and extended to a corresponding thermal behavior. Thus, they detected a carbon monoxide release at 90 ° C, which could be reversed by cooling with ice ( A. Tomita, H. Hirai, S. Makishima: Optical Rotatory Dispersion Study on the Iron Complex with L-Cysteine and Its Reaction with Carbon Monoxide and Nitric Oxide, Inorg. Chem. 1967, 6, 1746-1749 ). The cysteine-based compound is considered polar by the carboxyl groups present. This has an unfavorable effect on the pharmacokinetic properties, in particular the blood-brain barrier mobility, and therefore a less polar compound would be desirable. In the decomposition of cysteine in the body decarboxylation forms the biogenic amine cysteamine ( J. Koolman, K.-H. Röhm, Pocket Atlas of Biochemistry, 3rd Edition Georg Thieme Verlag, Stuttgart, New York 2003 ). This should be complexed to reconcile similar properties with less polarity. The resulting compound of formula C 6 H 12 FeN 2 O 2 S 2 was 1989 by Takács et al. by reaction of FeSO 4 .7H 2 O, cysteamine, triethylamine and carbon monoxide in 19.5% yield. However, no statement is made about the structural arrangement of the ligands.

US 5,882,674 A beschreibt die Anwendung von Metallkomplexen, wie Eisenpentacarbonyl und Dieisendodecacarbonyl. Beide Verbindungen sind jedoch toxisch und in Wasser unlöslich. US 5,882,674 A describes the use of metal complexes such as iron pentacarbonyl and dieisene dodecacarbonyl. Both compounds, however, are toxic and insoluble in water.

In WO 98/48848 A1 sind Metallcarbonyle beschrieben, welche auf Radionukliden beruhen und für diagnostische Zwecke vorgesehen sind. Die von den Radionukliden ausgehende Strahlung stellt dabei einen großen Nachteil dar, da somit der therapeutische Ansatz durch eine zusätzliche Kontamination kontrainduziert werden könnte. Des Weiteren ist der Abbau entsprechender Radionuklide nicht vollständig geklärt.In WO 98/48848 A1 are described Metallcarbonyle, which are based on radionuclides and are intended for diagnostic purposes. Radiation emanating from the radionuclides represents a major disadvantage, since the therapeutic approach could be counteracted by additional contamination. Furthermore, the degradation of corresponding radionuclides is not fully understood.

WO 1/01128 A1 sowie WO 91/01301 A1 beschreiben die Anwendung von Polyenestern und dessen Tricarbonyleisenderivaten zur Behandlung von Akne, Hautalterung und Schuppenflechte. Die dabei resultierenden therapeutischen Effekte gehen jedoch von den entsprechenden Polyenestern aus, deren metabolischer Abbau nicht beschrieben wird. WO 1/01128 A1 such as WO 91/01301 A1 describe the use of polyene esters and their tricarbonyl selenium derivatives for the treatment of acne, skin aging and psoriasis. The case However, the resulting therapeutic effects are based on the corresponding polyene esters, whose metabolic degradation is not described.

WO 98/29115 A1 beschreibt das Relaxationsverhalten von glatten Muskelzellen bei Warmblutlern nach Gabe von Metallnitrosylkomplexen. Diese Komplexe können neben Nitrosyl auch CO enthalten, beruhen aber nachteiliger Weise auf Stickstoffmonoxid, was ähnliche Eigenschaften wie Kohlenmonoxid aufweist und daher in Konkurrenz zu diesem treten könnte. WO 98/29115 A1 describes the relaxation behavior of smooth muscle cells in warm-blooded animals after administration of metal-nitrosyl complexes. These complexes can contain CO in addition to nitrosyl, but are disadvantageously based on nitrogen monoxide, which has similar properties as carbon monoxide and therefore could compete with it.

WO 95/05814 A1 , WO 00/56743 A1 und US 7,045,140 B2 beschreiben eine große Vielfalt an möglichen Metallcarbonylen. Unter den dort angeführten Beispielen befinden sich jedoch keine wasserlöslichen CORMs, welche lichtinduziert Kohlenmonoxid freisetzen. Lediglich die bereits bekannten Verbindungen Eisenpentacarbonyl und Dimangandecacarbonyl werden dort beschrieben. Hinweise, wie man zu wasserlöslichen, lichtinduzierten CORMs gelangt oder kommen könnte, finden sich nicht. WO 95/05814 A1 . WO 00/56743 A1 and US 7,045,140 B2 describe a wide variety of possible metal carbonyls. However, under the examples given there are no water-soluble CORMs, which release light-induced carbon monoxide. Only the already known compounds iron pentacarbonyl and dimangandecacarbonyl are described there. There are no hints on how to get to water-soluble, light-induced CORMs.

Der Erfindung liegt die Aufgabe zu Grunde, Kohlenmonoxid und Eisen freisetzende, bioverträgliche und wasserlösliche Moleküle zu schaffen, die mit möglichst geringem Aufwand herstellbar sind, keine Bedenklichkeit hinsichtlich körperfremden Bestandteilen erwecken und weitgehend ohne Risiken als pharmakologische Wirkstoffe eingesetzt werden können.The invention is based on the object to provide carbon monoxide and iron-releasing, biocompatible and water-soluble molecules that can be produced with the least possible effort, raise no concern about alien components and can be used largely without risks as pharmacological agents.

Es werden Kohlenmonoxid und Eisen freisetzende Moleküle mit der erfindungsgemäßen allgemeinen Formel I vorgeschlagen:

Figure 00060001
mit: R: R': R'': H H H H jeglicher Alkylrest H H jeglicher Acylrest H H jegliche Peptidsequenz H H jegliches Aminderivat H H jegliches Etherderivat H H jegliche Carbonsäurederivate H H jegliches Thioethererivat H H OH H H NH2 H H jegliches Sulfonsäurederivat H H H jeglicher Alkylrest H H jeglicher Acylrest H H jegliche Peptidsequenz H H jegliches Aminderivat H H jegliches Etherderivat H H jegliche Carbonsäurederivate H H jegliches Thioethererivat H H OH H H NH2 H H jegliches Sulfonsäurederivat H H H jeglicher Arylrest H H jeglicher Acylrest H H jeglicher Zuckerrest H H jegliche Aminosäure H H jegliche Peptidsequenz H H jeglicher Heterozyklus H H jeglicher Alkylrest jeglicher Alkylrest H jeglicher Acylrest jeglicher Acylrest H jegliche Peptidsequenz jegliche Peptidsequenz H jeglicher Alkylrest jegliche Carbonsäurederivate H jeglicher Arylrest jegliche Carbonsäurederivate H jeglicher Acylrest jegliche Carbonsäurederivate H jeglicher Zuckerrest jegliche Carbonsäurederivate H jegliche Aminosäure jegliche Carbonsäurederivate H jegliche Peptidsequenz jegliche Carbonsäurederivate H jeglicher Heterozyklus jegliche Carbonsäurederivate H jeglicher Alkylrest jegliche Carbonsäurederivate jeglicher Alkylrest jeglicher Acylrest jegliche Carbonsäurederivate jeglicher Acylrest jegliche Peptidsequenz jegliche Carbonsäurederivate jegliche Peptidsequenz wobei die Substituenten R, R' und R'' mindestens einmal und maximal zweimal am jeweiligen Kohlenstoffatom gebunden sind,
ausgenommen R R' R'' H COOH H H COOR*, wobei dieses R* jeglicher Alkylrest ist H Carbon monoxide and iron-releasing molecules having the general formula I according to the invention are proposed:
Figure 00060001
With: R: R ': R '': H H H H any alkyl radical H H any acyl radical H H any peptide sequence H H any amine derivative H H any ether derivative H H any carboxylic acid derivatives H H any thioether derivative H H OH H H NH 2 H H any sulfonic acid derivative H H H any alkyl radical H H any acyl radical H H any peptide sequence H H any amine derivative H H any ether derivative H H any carboxylic acid derivatives H H any thioether derivative H H OH H H NH 2 H H any sulfonic acid derivative H H H any aryl radical H H any acyl radical H H any sugar residue H H any amino acid H H any peptide sequence H H any heterocycle H H any alkyl radical any alkyl radical H any acyl radical any acyl radical H any peptide sequence any peptide sequence H any alkyl radical any carboxylic acid derivatives H any aryl radical any carboxylic acid derivatives H any acyl radical any carboxylic acid derivatives H any sugar residue any carboxylic acid derivatives H any amino acid any carboxylic acid derivatives H any peptide sequence any carboxylic acid derivatives H any heterocycle any carboxylic acid derivatives H any alkyl radical any carboxylic acid derivatives any alkyl radical any acyl radical any carboxylic acid derivatives any acyl radical any peptide sequence any carboxylic acid derivatives any peptide sequence where the substituents R, R 'and R "are bonded at least once and at most twice at the respective carbon atom,
except R R ' R '' H COOH H H COOR *, where R * is any alkyl radical H

Mit den vorgenannten Verbindungen werden wasserlösliche Eisen(II)-komplexe geschaffen, welche Eisen und Kohlenmonoxid lichtinduziert oder durch Kontakt mit Wasser bzw. physiologischen Medien oder Organen abgeben und die entweder ausschließlich körperbekannte Liganden oder solchen Liganden aufweisen, deren pharmakokinetisches Profil unbedenklich für therapeutische Verwendungen erscheint, so dass die mit der allgemeinen Formel I vorgeschlagenen CORMs bioverträglich und weitgehend ohne die bekannten Risiken als pharmakologische Wirkstoffe eingesetzt werden können.The above-mentioned compounds provide water-soluble iron (II) complexes which are light-induced by iron and carbon monoxide or by contact with water or physiological media or organs and which have either exclusively known body ligands or those ligands whose pharmacokinetic profile appears harmless for therapeutic uses so that the CORMs proposed with the general formula I can be used biocompatible and largely without the known risks as pharmacological agents.

Sie sind verfahrenstechnisch einfach und aufwandgering sowie in guten Ausbeuten (d. h. mehr als 50%) darstellbar (vgl. Methode nach Formel II). They are technically simple and aufwandgering and in good yields (ie more than 50%) can be displayed (see method according to formula II).

Figure 00080001
Figure 00080001

Die gemäß Formel II beschriebene Synthese der Derivate geschieht in guter Ausbeute und führt selektiv zum gewünschten Produkt. Der dazu nötige Material- und Energieaufwand ist als gering zu betrachten. Es werden lediglich Trieisendodecacarbonyl, der entsprechende Ligand und ein geeignetes Lösungsmittel, beispielsweise Tetrahydrofuran, Methanol oder Ethanol, benötigt.The synthesis of the derivatives described in accordance with formula II occurs in good yield and leads selectively to the desired product. The necessary material and energy expenditure is considered to be low. All that is required is triene dodecacarbonyl, the corresponding ligand and a suitable solvent, for example tetrahydrofuran, methanol or ethanol.

Die Erfindung soll nachstehend anhand von als Formel III dargestelltes trans-cis-cis-Bis(2-Thiolato-κS-ethylamin-κN)-dicarbonyleisen(II) näher erläutert werden.The invention will be explained in more detail below with reference to formula III trans-cis-cis-bis (2-thiolato-κS-ethylamine-κN) -dicarbonyliron (II).

Figure 00090001
Figure 00090001

Zur Synthese der Verbindung (die Liganden der allgemeinen Formel I entsprechen dem ersten Eintrag in der im Anspruch 1 genannten Ligandentabelle) wurden 1,05 mmol Trieisendodecacarbonyl und 6,09 mmol Cysteamin als 2-Mercaptoethylaminderivat in 2 mL Tetrahydrofuran (THF) als Lösungsmittel suspendiert und 30 min bei Raumtemperatur gerührt. Anschließend wurde zum Rückfluss erhitzt (ca. 66°C), wobei eine heftige Gasentwicklung einsetzte.For the synthesis of the compound (the ligands of the general formula I correspond to the first entry in the ligand table mentioned in claim 1) 1.05 mmol Trieisendodecacarbonyl and 6.09 mmol cysteamine as 2-Mercaptoethylaminderivat in 2 mL tetrahydrofuran (THF) were suspended as solvent and Stirred for 30 min at room temperature. It was then heated to reflux (about 66 ° C), with a vigorous evolution of gas began.

Nach dem Abklingen der Gasentwicklung wurden zwei weitere Portionen THF a 10 mL hinzugegeben und 30 min wiederum unter Rückfluss erhitzt. Anschließend wurde heiß filtriert und der Filterkuchen im Vakuum getrocknet, wobei 387 mg eines orangenfarbigen Feststoffes und eine rote Lösung resultierten. Die Lösung wurde bei 6°C gelagert. Die dabei gebildeten Kristalle (27 mg) wurden röntgenografisch in ihrer Struktur untersucht.
Gesamtausbeute 414 mg = 1,57 mmol = 52% d. Th.
MS-FAB: 265 [M+H]+ (16); 237 [M+H-CO]+ (10); 209 [M+H-2C0]+ (56); 208 [M-2CO]+ (88)
IR [KBr]: 3436 (m); 3210 (s); 3119 (s); 2952 (m); 2922 (m); 2867 (m); 2836 (w); 2364 (w); 2345 (w); 2014 (vs); 1945 (vs); 1584 (m); 1454 (w); 1433 (w); 1303 (w); 1269 (m); 1223 (w); 1120 (m); 1094 (m); 1042 (m); 971 (w); 918 (w); 848 (w); 805 (w); 648 (w); 591 (s); 545 (m); 492 (w) After the evolution of gas subsided, two more portions of THF were added to 10 mL and heated under reflux for 30 min. It was then filtered hot and the filter cake dried in vacuo to give 387 mg of an orange solid and a red solution. The solution was stored at 6 ° C. The resulting crystals (27 mg) were analyzed by X-ray diffraction.
Total yield 414 mg = 1.57 mmol = 52% d. Th.
MS-FAB: 265 [M + H] + (16); 237 [M + H-CO] + (10); 209 [M + H-2C0] + (56); 208 [M-2CO] + (88)
IR [KBr]: 3436 (m); 3210 (s); 3119 (s); 2952 (m); 2922 (m); 2867 (m); 2836 (w); 2364 (w); 2345 (w); 2014 (vs); 1945 (vs); 1584 (m); 1454 (w); 1433 (w); 1303 (w); 1269 (m); 1223 (w); 1120 (m); 1094 (m); 1042 (m); 971 (w); 918 (w); 848 (w); 805 (w); 648 (w); 591 (s); 545 (m); 492 (w)

Die Freisetzung von Kohlenmonoxid wurde durch einen auf Myoglobin basierenden Assay quantifiziert. Dazu wurde von der Verbindung III eine DMSO-Lösung der Konzentration 10 mmol/L hergestellt. 2-mal 10 μL dieser Lösung wurden in 2 Küvetten mit je 2 mL einer Desoxymyoglobinlösung pipettiert. Diese wurde zuvor durch Reduktion von Myoglobinlösung (ca. 59 μmol/L pH 6,8, Phosphatpuffer 0,01 mol/L) mit Natriumdithionit (ca. 01%) erhalten. Der Inhalt beider Küvetten wurde umgehend homogenisiert, eine Küvette im Dunkeln gelagert und die zweite mit einer LED-Reihe (470 ± 10 nm, 10 mW/cm2) bestrahlt. Nach 15 Minuten wurden beiden Proben nacheinander durch UV-VIS-Spektroskopie vermessen und die Myoglobin-CO-Konzentration berechnet.The release of carbon monoxide was quantitated by a myoglobin-based assay. For this purpose, a DMSO solution of concentration 10 mmol / L was prepared from the compound III. 2 × 10 μL of this solution were pipetted into 2 cuvettes with 2 mL each of a deoxymyoglobin solution. This was previously obtained by reduction of myoglobin solution (about 59 μmol / L pH 6.8, phosphate buffer 0.01 mol / L) with sodium dithionite (about 01%). The contents of both cuvettes were immediately homogenized, one cuvette stored in the dark and the second irradiated with an LED array (470 ± 10 nm, 10 mW / cm 2 ). After 15 minutes were measured both samples successively by UV-VIS spectroscopy and calculated the myoglobin CO concentration.

Für die Probe ergab sich dabei im Dunkeln keine signifikante Bildung von Kohlenmonoxid, während durch Bestrahlung eine Myoglobin-CO-Konzentration von 56 μmol/L erhalten wurde. Dies zeigt signifikant die lichtinduzierte Freisetzung von Kohlenmonoxid.For the sample, no significant formation of carbon monoxide was observed in the dark, while irradiation resulted in a myoglobin CO concentration of 56 μmol / L. This significantly demonstrates the light-induced release of carbon monoxide.

ZITATE ENTHALTEN IN DER BESCHREIBUNG QUOTES INCLUDE IN THE DESCRIPTION

Diese Liste der vom Anmelder aufgeführten Dokumente wurde automatisiert erzeugt und ist ausschließlich zur besseren Information des Lesers aufgenommen. Die Liste ist nicht Bestandteil der deutschen Patent- bzw. Gebrauchsmusteranmeldung. Das DPMA übernimmt keinerlei Haftung für etwaige Fehler oder Auslassungen.This list of the documents listed by the applicant has been generated automatically and is included solely for the better information of the reader. The list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions.

Zitierte PatentliteraturCited patent literature

  • WO 0292075 A2 [0012] WO 0292075 A2 [0012]
  • US 5882674 A [0015] US 5882674 A [0015]
  • WO 98/48848 A1 [0016] WO 98/48848 A1 [0016]
  • WO 1/01128 A1 [0017] WO 1/01128 A1 [0017]
  • WO 91/01301 A1 [0017] WO 91/01301 A1 [0017]
  • WO 98/29115 A1 [0018] WO 98/29115 A1 [0018]
  • WO 95/05814 A1 [0019] WO 95/05814 A1 [0019]
  • WO 00/56743 A1 [0019] WO 00/56743 A1 [0019]
  • US 7045140 B2 [0019] US 7045140 B2 [0019]

Zitierte Nicht-PatentliteraturCited non-patent literature

  • R. Foresti, R. Motterlini: The heme oxygenase pathway and its interaction with nitric oxide in the control of cellular homeostasis, Free Radic. Res. 1999, 31, 459–475 [0002] R. Foresti, R. Motterlini: The heme oxygenase pathway and its interaction with nitric oxide in the control of cellular homeostasis, Free Radic. Res. 1999, 31, 459-475 [0002]
  • I. A. Sammut, R. Foresti, J. E. Clark, D. J. Exon, M. J. Vesely, P. Sarathchandra, C. J. Green, R. Motterlini: Carbon monoxide is a major contributor to the regulation of vascular tone in aortas expressing high levels of haeme oxygenase-1, British Journal of Pharmacology, 125(7), 1998, 1437–1444 [0002] IA Sammut, R. Foresti, JE Clark, DJ Exon, MJ Vesely, P. Sarathchandra, CJ Green, R. Motterlini: Carbon monoxide is a major contributor to the regulation of vascular tone in aortas expressing high levels of heme oxygenase-1, British Journal of Pharmacology, 125 (7), 1998, 1437-1444 [0002]
  • T. Morita, S. A. Mitsialis, H. Koike, V. Liu, S. Kourembanas: Carbon Monoxide Controls the Proliferation of Hypoxic Vascular Smooth Muscle Cells, Journal of Biological Chemistry, 272, 1997, 32804–32809 [0002] T. Morita, SA Mitsialis, H. Koike, V. Liu, S. Kourembanas: Carbon Monoxide Controls the Proliferation of Hypoxic Vascular Smooth Muscle Cells, Journal of Biological Chemistry, 272, 1997, 32804-32809 [0002]
  • K. Sato, J. Balla, L. Otterbein, R. N. Smith, S. Brouard, Y. Lin, E. Csizmadia, J. Sevigny, S. C. Robson, G. Vercellotti, A. M. Choi, F. H. Bach, M. P. Soares: Carbon Monoxide Generated by Heure Oxygenase-1 Suppresses the Rejection of Mouse-to-Rat Cardiac Transplants, The Journal of Immunology, 166, 2001, 4185–4194 [0003] K. Sato, J. Balla, L. Otterbein, RN Smith, S. Brouard, Y. Lin, E. Csizmadia, J. Sevigny, SC Robson, G. Vercellotti, AM Choi, FH Bach, MP Soares: Carbon Monoxide Generated by Heure Oxygenase-1 Suppresses the Rejection of Mouse-to-Rat Cardiac Transplants, The Journal of Immunology, 166, 2001, 4185-4194 [0003]
  • L. E. Otterbein, F. H. Bach, J. Alam, M. Soares, L. H. Tao, M. Wysk, R. J. Davis, R. A. Flavell, A. M. Choi: Carbon monoxide has anti-inflammatory effects involving the mitogen-activated Protein kinase pathway, Nat. Med. 2000, 6, 422–428 [0003] LE Otterbein, FH Bach, J. Alam, M. Soares, LH Tao, M. Wysk, RJ Davis, RA Flavell, AM Choi: Carbon monoxide has anti-inflammatory effects involving the mitogen-activated protein kinase pathway, Nat. Med. 2000, 6, 422-428 [0003]
  • T. Fujita, K. Toda, A. Karimova, S. F. Van, Y. Naka, S. F. Yet, D. J. Pinsky: Paradoxical rescue from ischemic lung injury by inhaled carbon monoxide driven by derepression of fibrinolysis, Nat. Med. 2001, 7, 598–604 [0003] T. Fujita, K. Toda, A. Karimova, SF Van, Y. Naka, SF Yet, DJ Pinsky: Paradoxical rescue from ischemic injury by inhaled carbon monoxide driven by derepression of fibrinolysis, Nat. Med. 2001, 7, 598-604 [0003]
  • R. Motterlini, J. E. Clark, R. Foresti, P. Sarathchandra, B. E. Mann, C. J. Green: Carbon Monoxide-Releasing Molecules: Characterization of Biochemical and Vascular Activities, Circ. Res. 2002, 90, E17–E24 [0004] R. Motterlini, JE Clark, R. Foresti, P. Sarathchandra, BE Mann, CJ Green: Carbon Monoxide Releasing Molecules: Characterization of Biochemical and Vascular Activities, Circ. Res. 2002, 90, E17-E24 [0004]
  • R. Motterlini, J. E. Clark, R. Foresti, P. Sarathchandra, B. E. Mann, C. J. Green: Carbon Monoxide-Releasing Molecules: Characterization of Biochemical and Vascular Activities, Circ. Res. 2002, 90, E17–E24 [0005] R. Motterlini, JE Clark, R. Foresti, P. Sarathchandra, BE Mann, CJ Green: Carbon Monoxide Releasing Molecules: Characterization of Biochemical and Vascular Activities, Circ. Res. 2002, 90, E17-E24 [0005]
  • J. E. Clark, P. Naughton, S. Shurey, C. J. Green, T. R. Johnson, B. E. Mann, R. Foresti, R. Motterlini: Cardioprotective actions by a water-soluble carbon monoxide-releasing molecule, Circ. Res. 2003, 93, e2–e8 [0006] JE Clark, P. Naughton, S. Shurey, CJ Green, TR Johnson, BE Mann, R. Foresti, R. Motterlini: Cardioprotective actions by a water-soluble carbon monoxide-releasing molecule, Circ. Res. 2003, 93, e2-e8 [0006]
  • L. J. Malone, R. W. Parry, Inorg. Chem. 1967, 6, 817–822 [0007] LJ Malone, RW Parry, Inorg. Chem. 1967, 6, 817-822 [0007]
  • J. E. Clark, P. Naughton, S. Shurey, C. J. Green, T. R. Johnson, B. E. Mann, R. Foresti, R. Motterlini: Cardioprotective Actions by a Water-Soluble Carbon Monoxide-Releasing Molecule, Circ. Res. 2003, 93, e2–e8 [0007] JE Clark, P. Naughton, S. Shurey, CJ Green, TR Johnson, BE Mann, R. Foresti, R. Motterlini: Cardioprotective Actions by a Water-Soluble Carbon Monoxide Releasing Molecule, Circ. Res. 2003, 93, e2-e8 [0007]
  • R. Fischer: Unser Organismus benötigt Bor-Komplexverbindungen – Wesentliche Bedeutung von Bor für alle Lebewesen, SANUM-Post 1989, 8, 29–34 [0008] R. Fischer: Our Organism Requires Boron Complex Compounds - Significance of Boron for All Living Things, SANUM-Post 1989, 8, 29-34 [0008]
  • W. Kaim, B. Schwederski, Bioanorganische Chemie, 3, B. G. Teubner Verlag/GWV Fachverlage GmbH, Wiesbaden 2004, 168–178 [0009] W. Kaim, B. Schwederski, Bioinorganic Chemistry, 3, BG Teubner Verlag / GWV Fachverlage GmbH, Wiesbaden 2004, 168-178 [0009]
  • I. J. Fairlamb, A. K. Duhme-Klair, J. M. Lynam, B. E. Moulton, C. T. O'Brien, P. Sawle, J. Hammad, R. Motterlini: η4-Pyrone metal carbonyl complexes as effective CO-releasing molecules, Bioorg. Med. Chem. Lett. 2005, 16, 995–998 [0010] IJ Fairlamb, AK Duhme-Klair, JM Lynam, BE Moulton, CT O'Brien, P. Sawle, J. Hammad, R. Motterlini: η4-Pyrone metal carbonyl complexes as effective CO-releasing molecules, Bioorg. Med. Chem. Lett. 2005, 16, 995-998 [0010]
  • P. Sawle, J. Hammad, I. J. Fairlamb, B. Moulton, C. T. O'Brien, J. M. Lynam, A. K. Duhme-Klair, R. Foresti, R. Motterlini: Bioactive properties of iron-containing carbon monoxide releasing molecules, J. Pharmacol. Exp. Ther. 2006, 318, 403–410 [0011] P. Sawle, J. Hammad, IJ Fairlamb, B. Moulton, CT O'Brien, JM Lynam, AK Duhme-Klair, R. Foresti, R. Motterlini: Bioactive properties of iron-containing carbon monoxide releasing molecules, J. Pharmacol , Exp. Ther. 2006, 318, 403-410 [0011]
  • D. Scapens, H. Adams, T. R. Johnson, B. E. Mann, P. Sawle, R. Agil, T. Perrior, R. Motterlini: [(η-C5H4R)Fe(CO)2)X], X = Cl, Br, I, NO3,CO2Me and [(η-C5H4R)Fe(CO)3]+), R = (CH2)nCO2Me (n = 0–2), and CO2CH2CH2OH: a new group of CO-releasing molecules, Dalton Transactions, 2007, 4962–4973 [0012] D. Scapens, H. Adams, TR Johnson, BE Mann, P. Sawle, R. Agil, T. Perrior, R. Motterlini: [(η-C5H4R) Fe (CO) 2) X], X = Cl, Br , I, NO3, CO2Me and [(η-C5H4R) Fe (CO) 3] +), R = (CH2) nCO2Me (n = 0-2), and CO2CH2CH2OH: a new group of CO-releasing molecules, Dalton Transactions , 2007, 4962-4973 [0012]
  • Zhang et al. [0013] Zhang et al. [0013]
  • D. Scapens, H. Adams, T. R. Johnson, B. E. Mann, P. Sawle, R. Agil, T. Perrior, R. Motterlini: [(Eta-C5H4R)Fe(CO)2X], X = Cl, Br, I, NO3, CO2Me and [(eta-C5H4R)Fe(CO)3]+, R = (CH2)nCO2Me (n = 0–2), and CO2CH2CH2OH: a new group of CO-releasing molecules, Dalton Trans. 2007, 4962–4973 [0013] D. Scapens, H. Adams, TR Johnson, BE Mann, P. Sawle, R. Agil, T. Perrior, R. Motterlini: [(Eta C 5 H 4 R) Fe (CO) 2 X], X = Cl, Br, I , NO3, CO2Me and [(eta-C5H4R) Fe (CO) 3] +, R = (CH2) nCO2Me (n = 0-2), and CO2CH2CH2OH: a new group of CO-releasing molecules, Dalton Trans. 2007, 4962-4973 [0013]
  • Cremer, Biochem. Z. 1929, 206, 228 [0014] Cremer, Biochem. Z. 1929, 206, 228 [0014]
  • A. Tomita, H. Hirai, S. Makishima: Optical Rotatory Dispersion Study an the Iron Complex with L-Cystein and Its Reaction with Carbon Monoxide and Nitric Oxide, Inorg. Chem. 1967, 6, 1746–1749 [0014] A. Tomita, H. Hirai, S. Makishima: Optical Rotatory Dispersion Study on the Iron Complex with L-Cysteine and Its Reaction with Carbon Monoxide and Nitric Oxide, Inorg. Chem. 1967, 6, 1746-1749 [0014]
  • J. Koolman, K.-H. Röhm, Taschenatlas der Biochemie, 3. Auflage Georg Thieme Verlag, Stuttgart, New York 2003 [0014] J. Koolman, K.-H. Röhm, Pocket Atlas of Biochemistry, 3rd Edition Georg Thieme Verlag, Stuttgart, New York 2003 [0014]
  • 1989 von Takács et al. [0014] 1989 by Takács et al. [0014]

Claims (3)

Kohlenmonoxid und Eisen freisetzende Moleküle gemäß der allgemeinen Formel I
Figure 00110001
mit: R: R': R'': H H H H jeglicher Alkylrest H H jeglicher Acylrest H H jegliche Peptidsequenz H H jegliches Aminderivat H H jegliches Etherderivat H H jegliche Carbonsäurederivate H H jegliches Thioethererivat H H OH H H NH2 H H jegliches Sulfonsäurederivat H H H jeglicher Alkylrest H H jeglicher Acylrest H H jegliche Peptidsequenz H H jegliches Aminderivat H H jegliches Etherderivat H H jegliche Carbonsäurederivate H H jegliches Thioethererivat H H OH H H NH2 H H jegliches Sulfonsäurederivat H H H jeglicher Arylrest H H jeglicher Acylrest H H jeglicher Zuckerrest H H jegliche Aminosäure H H jegliche Peptidsequenz H H jeglicher Heterozyklus H H jeglicher Alkylrest jeglicher Alkylrest H jeglicher Acylrest jeglicher Acylrest H jegliche Peptidsequenz jegliche Peptidsequenz H jeglicher Alkylrest jegliche Carbonsäurederivate H jeglicher Arylrest jegliche Carbonsäurederivate H jeglicher Acylrest jegliche Carbonsäurederivate H jeglicher Zuckerrest jegliche Carbonsäurederivate H jegliche Aminosäure jegliche Carbonsäurederivate H jegliche Peptidsequenz jegliche Carbonsäurederivate H jeglicher Heterozyklus jegliche Carbonsäurederivate H jeglicher Alkylrest jegliche Carbonsäurederivate jeglicher Alkylrest jeglicher Acylrest jegliche Carbonsäurederivate jeglicher Acylrest jegliche Peptidsequenz jegliche Carbonsäurederivate jegliche Peptidsequenz
wobei die Substituenten R, R' und R'' mindestens einmal und maximal zweimal am jeweiligen Kohlenstoffatom gebunden sind, ausgenommen: R R' R'' H COOH H H COOR*, wobei dieses R* jeglicher Alkylrest ist H
Carbon monoxide and iron-releasing molecules according to the general formula I.
Figure 00110001
With: R: R ': R '': H H H H any alkyl radical H H any acyl radical H H any peptide sequence H H any amine derivative H H any ether derivative H H any carboxylic acid derivatives H H any thioether derivative H H OH H H NH 2 H H any sulfonic acid derivative H H H any alkyl radical H H any acyl radical H H any peptide sequence H H any amine derivative H H any ether derivative H H any carboxylic acid derivatives H H any thioether derivative H H OH H H NH 2 H H any sulfonic acid derivative H H H any aryl radical H H any acyl radical H H any sugar residue H H any amino acid H H any peptide sequence H H any heterocycle H H any alkyl radical any alkyl radical H any acyl radical any acyl radical H any peptide sequence any peptide sequence H any alkyl radical any carboxylic acid derivatives H any aryl radical any carboxylic acid derivatives H any acyl radical any carboxylic acid derivatives H any sugar residue any carboxylic acid derivatives H any amino acid any carboxylic acid derivatives H any peptide sequence any carboxylic acid derivatives H any heterocycle any carboxylic acid derivatives H any alkyl radical any carboxylic acid derivatives any alkyl radical any acyl radical any carboxylic acid derivatives any acyl radical any peptide sequence any carboxylic acid derivatives any peptide sequence
where the substituents R, R 'and R "are bonded at least once and at most twice at the respective carbon atom, except: R R ' R '' H COOH H H COOR *, where R * is any alkyl radical H
Verfahren zur Herstellung der Kohlenmonoxid und Eisen freisetzende Moleküle gemäß Anspruch 1, gekennzeichnet durch den Syntheseweg der allgemeinen Formel II
Figure 00130001
wobei 1 Äquivalent Trieisendodecacarbonyl in einem geeigneten Lösungsmittel, beispielsweise Tetrahydrofuran (THF), Methanol oder Ethanol, suspendiert, mit 6 Äquivalenten eines 2-Mercaptoethylaminderivates versetzt, bei Temperaturen von 0°C bis 160°C gerührt und nach beendeter Reaktion, beispielsweise durch Extraktion, Filtration, Kristallisation, Vakuumdestillation, Sublimation oder Chromatographie, aufgearbeitet wird.Process for the preparation of the carbon monoxide and iron-releasing molecules according to Claim 1, characterized by the synthesis route of the general formula II
Figure 00130001
wherein 1 equivalent of trienedodecacarbonyl in a suitable solvent, for example tetrahydrofuran (THF), methanol or ethanol, suspended, mixed with 6 equivalents of a 2-Mercaptoethylaminderivates, stirred at temperatures of 0 ° C to 160 ° C and after completion of the reaction, for example by extraction, Filtration, crystallization, vacuum distillation, sublimation or chromatography, worked up. Verwendung der Kohlenmonoxid und Eisen freisetzende Moleküle gemäß Anspruch 1 als pharmakologische Wirkstoffe, beispielsweise zur Behandlung jeder Formen von Bluthochdruck, Krebs, Gewebsschädigung durch Bestrahlung, post-ischmämischer Schäden, Arteriosklerose, Sepsis, Angina, Herzinfarkten, Auswirkungen eines hämorrhagischen Schocks, Zelltod, Entzündungen und damit verbundenen Krankheiten sowie zur Gefäßerweiterung, zur unterstützenden Behandlung bei Organtransplantationen und zur Stimulation der Neurotransmission.Use of the carbon monoxide and iron releasing molecules according to claim 1 as pharmacologically active agents, for example for the treatment of any forms of hypertension, cancer, tissue damage by radiation, post-ischemic damage, arteriosclerosis, sepsis, angina, heart attacks, haemorrhagic shock, cell death, inflammation, and associated diseases as well as Vascular dilation, assistive treatment for organ transplantation and stimulation of neurotransmission.
DE102010014411A 2010-04-08 2010-04-08 New iron complexes, useful as carbon monoxide and iron releasing molecules for treating e.g. high blood pressure, cancer, tissue damage by irradiation, post-ischemic injury, atherosclerosis, sepsis, angina and myocardial infarction Withdrawn DE102010014411A1 (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102850403A (en) * 2012-05-29 2013-01-02 嘉兴学院 Water-soluble iron carbonyl compound, and preparation method and application thereof

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991001301A1 (en) 1989-07-25 1991-02-07 Eastman Kodak Company Compound and method for treating skin for acne or psoriasis
WO1995005814A1 (en) 1993-08-25 1995-03-02 Johnson Matthey Public Limited Company Pharmaceutical compositions comprising metal complexes
DE4421433C1 (en) * 1994-06-18 1995-06-08 Lohmann Therapie Syst Lts Transdermal therapeutic system for treatment of, e.g., hypertension
WO1998029115A1 (en) 1993-10-06 1998-07-09 University Of British Columbia Transition-metal nitrosyl compounds as smooth muscle relaxants
WO1998048848A1 (en) 1997-04-25 1998-11-05 Mallinckrodt Inc. Method for the preparation of facial metal tricarbonyl compounds and their use in the labelling of biologically active substrates
WO2000056743A1 (en) 1999-03-19 2000-09-28 Anormed Inc. Pharmaceutical compositions comprising metal complexes
WO2002092075A2 (en) 2001-05-15 2002-11-21 Northwick Park Institute For Medical Research Therapeutic delivery of carbon monoxide
WO2010001128A1 (en) 2008-07-03 2010-01-07 Ucl Business Plc Method for dispersing and separating nanotubes

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991001301A1 (en) 1989-07-25 1991-02-07 Eastman Kodak Company Compound and method for treating skin for acne or psoriasis
WO1995005814A1 (en) 1993-08-25 1995-03-02 Johnson Matthey Public Limited Company Pharmaceutical compositions comprising metal complexes
WO1998029115A1 (en) 1993-10-06 1998-07-09 University Of British Columbia Transition-metal nitrosyl compounds as smooth muscle relaxants
DE4421433C1 (en) * 1994-06-18 1995-06-08 Lohmann Therapie Syst Lts Transdermal therapeutic system for treatment of, e.g., hypertension
US5882674A (en) 1994-06-18 1999-03-16 Lts Lohmann Therapie-Systeme Gmbh Transdermal therapeutic system comprising active substances representing carbon monoxide sources
WO1998048848A1 (en) 1997-04-25 1998-11-05 Mallinckrodt Inc. Method for the preparation of facial metal tricarbonyl compounds and their use in the labelling of biologically active substrates
WO2000056743A1 (en) 1999-03-19 2000-09-28 Anormed Inc. Pharmaceutical compositions comprising metal complexes
WO2002092075A2 (en) 2001-05-15 2002-11-21 Northwick Park Institute For Medical Research Therapeutic delivery of carbon monoxide
US7045140B2 (en) 2001-05-15 2006-05-16 Hemocorm Limited Therapeutic delivery of carbon monoxide
US20060115542A1 (en) * 2001-05-15 2006-06-01 Motterlini Roberto A Therapeutic delivery of carbon monoxide
WO2010001128A1 (en) 2008-07-03 2010-01-07 Ucl Business Plc Method for dispersing and separating nanotubes

Non-Patent Citations (26)

* Cited by examiner, † Cited by third party
Title
1989 von Takács et al.
A. Tomita, H. Hirai, S. Makishima: Optical Rotatory Dispersion Study an the Iron Complex with L-Cystein and Its Reaction with Carbon Monoxide and Nitric Oxide, Inorg. Chem. 1967, 6, 1746-1749
Cremer, Biochem. Z. 1929, 206, 228
CREMER,Werner:Reaktionen des Kohlenoxyds mit Metallverbindungen des Cysteins.In:Biochem.,Z.1929,206,S.228-239 S.230,letz.Abs. *
D. Scapens, H. Adams, T. R. Johnson, B. E. Mann, P. Sawle, R. Agil, T. Perrior, R. Motterlini: [(eta-C5H4R)Fe(CO)2)X], X = Cl, Br, I, NO3,CO2Me and [(eta-C5H4R)Fe(CO)3]+), R = (CH2)nCO2Me (n = 0-2), and CO2CH2CH2OH: a new group of CO-releasing molecules, Dalton Transactions, 2007, 4962-4973
D. Scapens, H. Adams, T. R. Johnson, B. E. Mann, P. Sawle, R. Agil, T. Perrior, R. Motterlini: [(Eta-C5H4R)Fe(CO)2X], X = Cl, Br, I, NO3, CO2Me and [(eta-C5H4R)Fe(CO)3]+, R = (CH2)nCO2Me (n = 0-2), and CO2CH2CH2OH: a new group of CO-releasing molecules, Dalton Trans. 2007, 4962-4973
I. A. Sammut, R. Foresti, J. E. Clark, D. J. Exon, M. J. Vesely, P. Sarathchandra, C. J. Green, R. Motterlini: Carbon monoxide is a major contributor to the regulation of vascular tone in aortas expressing high levels of haeme oxygenase-1, British Journal of Pharmacology, 125(7), 1998, 1437-1444
I. J. Fairlamb, A. K. Duhme-Klair, J. M. Lynam, B. E. Moulton, C. T. O'Brien, P. Sawle, J. Hammad, R. Motterlini: eta4-Pyrone metal carbonyl complexes as effective CO-releasing molecules, Bioorg. Med. Chem. Lett. 2005, 16, 995-998
J. E. Clark, P. Naughton, S. Shurey, C. J. Green, T. R. Johnson, B. E. Mann, R. Foresti, R. Motterlini: Cardioprotective actions by a water-soluble carbon monoxide-releasing molecule, Circ. Res. 2003, 93, e2-e8
J. Koolman, K.-H. Röhm, Taschenatlas der Biochemie, 3. Auflage Georg Thieme Verlag, Stuttgart, New York 2003
K. Sato, J. Balla, L. Otterbein, R. N. Smith, S. Brouard, Y. Lin, E. Csizmadia, J. Sevigny, S. C. Robson, G. Vercellotti, A. M. Choi, F. H. Bach, M. P. Soares: Carbon Monoxide Generated by Heure Oxygenase-1 Suppresses the Rejection of Mouse-to-Rat Cardiac Transplants, The Journal of Immunology, 166, 2001, 4185-4194
L. E. Otterbein, F. H. Bach, J. Alam, M. Soares, L. H. Tao, M. Wysk, R. J. Davis, R. A. Flavell, A. M. Choi: Carbon monoxide has anti-inflammatory effects involving the mitogen-activated Protein kinase pathway, Nat. Med. 2000, 6, 422-428
L. J. Malone, R. W. Parry, Inorg. Chem. 1967, 6, 817-822
P. Sawle, J. Hammad, I. J. Fairlamb, B. Moulton, C. T. O'Brien, J. M. Lynam, A. K. Duhme-Klair, R. Foresti, R. Motterlini: Bioactive properties of iron-containing carbon monoxide releasing molecules, J. Pharmacol. Exp. Ther. 2006, 318, 403-410
R. Fischer: Unser Organismus benötigt Bor-Komplexverbindungen - Wesentliche Bedeutung von Bor für alle Lebewesen, SANUM-Post 1989, 8, 29-34
R. Foresti, R. Motterlini: The heme oxygenase pathway and its interaction with nitric oxide in the control of cellular homeostasis, Free Radic. Res. 1999, 31, 459-475
R. Motterlini, J. E. Clark, R. Foresti, P. Sarathchandra, B. E. Mann, C. J. Green: Carbon Monoxide-Releasing Molecules: Characterization of Biochemical and Vascular Activities, Circ. Res. 2002, 90, E17-E24
SONG,L.-C.,et.al.:Synthesis and Structural Characterization of Metallocrown Ethers Containing Butterfly Fe2 Cluster Cores. Biomimetic Hydrogen Evolution Catalyzed by Fe2(μ- SCH2CH2OCH2CH2S-μ)(CO)6.In:Organomet.,2006,25(24),S. 5724-5729 Abstr.
SONG,L.-C.,et.al.:Synthesis and Structural Characterization of Metallocrown Ethers Containing Butterfly FeCluster Cores. Biomimetic Hydrogen Evolution Catalyzed by Fe(mu- SCHCHOCHCHS-mu)(CO).In:Organomet.,2006,25(24),S. 5724-5729 Abstr. *
SZAKACS-SCHMIDT,Anikó,et.al.:Iron(II) thiolates as reversible carbon monoxide carriers.In:Inorg.Chim.Acta,198-200,(1992),S.401- 405 S.403,Tab.2 *
T. Fujita, K. Toda, A. Karimova, S. F. Van, Y. Naka, S. F. Yet, D. J. Pinsky: Paradoxical rescue from ischemic lung injury by inhaled carbon monoxide driven by derepression of fibrinolysis, Nat. Med. 2001, 7, 598-604
T. Morita, S. A. Mitsialis, H. Koike, V. Liu, S. Kourembanas: Carbon Monoxide Controls the Proliferation of Hypoxic Vascular Smooth Muscle Cells, Journal of Biological Chemistry, 272, 1997, 32804-32809
TAKACS,János,et.al.:Synthesis and Molecular Structure of Carbonyl Derivatives of Iron(II) Thiolates Containing Nitrogen-donor Ligands.In:Inorg.Chim.Acta,1989,166,S.39-46 S.40,li.Sp.2,2.Abs. *
W. Kaim, B. Schwederski, Bioanorganische Chemie, 3, B. G. Teubner Verlag/GWV Fachverlage GmbH, Wiesbaden 2004, 168-178
WANG,J.H.,et.el.:Hemoglobin Studies. I. The Combination of Carbon Monoxide with Hemoglobin and Related Model Compounds.In:J.Am Chem . Soc.,1958,80,S.1109-1113 S.1110,re.Sp.,vorl.Abs.,S.1111,li.Sp. ,letzt.Abs. *
Zhang et al.

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102850403A (en) * 2012-05-29 2013-01-02 嘉兴学院 Water-soluble iron carbonyl compound, and preparation method and application thereof
CN102850403B (en) * 2012-05-29 2015-01-14 嘉兴学院 Water-soluble iron carbonyl compound, and preparation method and application thereof

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