DE102012004132A1 - Carbon monoxide-releasing materials and their use - Google Patents

Carbon monoxide-releasing materials and their use Download PDF

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DE102012004132A1
DE102012004132A1 DE102012004132A DE102012004132A DE102012004132A1 DE 102012004132 A1 DE102012004132 A1 DE 102012004132A1 DE 102012004132 A DE102012004132 A DE 102012004132A DE 102012004132 A DE102012004132 A DE 102012004132A DE 102012004132 A1 DE102012004132 A1 DE 102012004132A1
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carbon monoxide
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Alexander Schiller
Matthias Schnabelrauch
Cindy Altmann
Ralf Wyrwa
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Innovent EV Technologieentwicklung De
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00Medicinal preparations containing inorganic active ingredients
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    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00Cosmetics or similar toiletry preparations
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    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00Cosmetics or similar toiletry preparations
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    • A61K8/19Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K8/72Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/81Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions involving only carbon-to-carbon unsaturated bonds
    • A61K8/8105Compositions of homopolymers or copolymers of unsaturated aliphatic hydrocarbons having only one carbon-to-carbon double bond; Compositions of derivatives of such polymers
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    • AHUMAN NECESSITIES
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    • A61K8/72Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
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    • AHUMAN NECESSITIES
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Abstract

Aufgabe war es, neue Materialien zu schaffen, welche bei ihrer Anwendung auch in Wasser auf möglichst einfache Weise und ohne störende Sekundärwirkung effizient Kohlenstoffmonoxid freisetzen. Erfindungsgemäß ist die CO-emittierende Substanz in ein Polymer eingebettet, beispielsweise entsprechend Schema 1Anwendung finden diese Materialien insbesondere als CO-Donator bzw. CO-Quelle in der Biologie, Medizin, Kosmetik und Pharmazie.The task was to create new materials, which release carbon monoxide efficiently in their application even in water in the simplest possible way and without disturbing secondary action. According to the invention, the CO-emitting substance is embedded in a polymer, for example according to Scheme 1A use, these materials find particular as CO donor or CO source in biology, medicine, cosmetics and pharmacy.

Description

Die Erfindung betrifft Materialien, die durch Lichteinwirkung Kohlenstoffmonoxid freisetzen, und deren Verwendung in der Medizin, Biologie, Medizintechnik, Kosmetik und der pharmazeutischen Industrie.The invention relates to materials which release carbon monoxide by exposure to light and their use in medicine, biology, medical technology, cosmetics and the pharmaceutical industry.

Kohlenstoffmonoxid (CO) kontrolliert wichtige Stoffwechselprozesse in Zellen und Organen des menschlichen Körpers. Aufgrund seiner zentralen Rolle als Signalmolekül wird Kohlenstoffmonoxid unter der Substanzgruppe der „Gasotransmitter” geführt.Carbon monoxide (CO) controls important metabolic processes in cells and organs of the human body. Due to its central role as a signaling molecule carbon monoxide is led under the substance group of the "gasotransmitter".

Weitere wichtige Signalmoleküle, wie Stickstoffmonoxid (NO) und Schwefelwasserstoff (H2S), zählen ebenfalls zu den Gasotransmittern ( B. E. Mann, R. Motterlini: CO and NO in medicine, Chemical Communications, 2007, 4197–4208 ).Other important signaling molecules, such as nitric oxide (NO) and hydrogen sulfide (H 2 S), also belong to the gasotransmitters ( BE Mann, R. Motterlini: CO and NO in Medicine, Chemical Communications, 2007, 4197-4208 ).

Alle Gasotransmitter werden im Körper enzymatisch hergestellt. Im Fall von Kohlenstoffmonoxid spalten Hämoxygenasen (HO-1 und HO-2) mittels Sauerstoff und anderen Kofaktoren CO aus Häm-Verbindungen ab, die vorwiegend aus dem roten Blutfarbstoff Hämoglobin stammen. Während HO-1 in Leber und Milz wirksam sind, wird das Enzym HO-2 hauptsächlich im Gehirn hergestellt.All gasotransmitters are enzymatically produced in the body. In the case of carbon monoxide, heme oxygenases (HO-1 and HO-2) split CO from heme compounds, mainly from the red blood pigment hemoglobin, via oxygen and other cofactors. While HO-1 is active in the liver and spleen, the enzyme HO-2 is mainly produced in the brain.

Ähnlich wie Stickstoffmonoxid agiert Kohlenstoffmonoxid im Nervensystem. Es stellt sich auf Grund der nachstehenden physiologischen Eigenschaften als breit anwendbares Therapeutikum dar:
So ist Kohlenstoffmonoxid (CO) ein fundamentaler Botenstoff ( R. Foresti, R. Motterlini: The heure oxygenase pathway and its interaction with nitric oxide in the control of cellular homeostasis, Free Radical Research 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, vaskulären Muskelzellen ( T. Morita, S. A. Mitsialis, H. Koike, Y. Liu, S. Kourembanas: Carbon Monoxide Controls the Proliferation of Hypoxic Vascular Smooth Muscle Cells, Journal of Biological Chemistry, 272, 1997, 32804–32809 ). Es löst eine cGMP-Kaskade aus (cGMP = zyklisches Guanosinmonophosphat). An neuromuskulären Synapsen aktiviert es cAMP (zyklisches Adenosinmonophosphat) und hemmt gleichzeitig den cAMP-Abbau. Dadurch setzen die Synapsen Acetylcholin frei und verstärken die Muskelkontraktion. Im Hippocampus beeinflusst Kohlenstoffmonoxid auch die Gedächtnisleistung: Hämoxygenase-Blocker hemmen die Langzeitpotenzierung.
Similar to nitric oxide, carbon monoxide acts in the nervous system. It is a widely applicable therapeutic because of the following physiological properties:
So carbon monoxide (CO) is a fundamental messenger ( R. Foresti, R. Motterlini: The novel oxygenase pathway and its interaction with nitric oxide in the control of cellular homeostasis, Free Radical Research 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, vascular muscle cells ( T. Morita, SA Mitsialis, H. Koike, Y. Liu, S. Kourembanas: Carbon Monoxide Controls the Proliferation of Hypoxic Vascular Smooth Muscle Cells, Journal of Biological Chemistry, 272, 1997, 32804-32809 ). It triggers a cGMP cascade (cGMP = cyclic guanosine monophosphate). At neuromuscular synapses it activates cAMP (cyclic adenosine monophosphate) and simultaneously inhibits cAMP degradation. As a result, the synapses release acetylcholine and increase muscle contraction. In the hippocampus, carbon monoxide also affects memory performance: Hemoxygenase blockers inhibit long-term potentiation.

Darüber hinaus unterdrückt Kohlenstoffmonoxid die Abstoßung von transplantierten Herzen ( 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 Heme Oxygenase-1 Suppresses the Rejection of Mouse-to-Rat Cardiac Transplants, The Journal of Immunology, 166, 2001, 4185–4194 ), besitzt antiinflammatorische Effekte ( L. E. Otterbein, F. H. Bach, J. Alam, M. Soores, 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, Nature Medicine, 2000, 6, 422–428 ) und fördert den Schutz vor ischämischer Gewebsschädigung ( T. Fujita, K. Toda, A. Karimova, S. F. Yan, Y. Naka, S. F. Yet, D. J. Pinsky: Paradoxical rescue from ischemic lung injury by inhaled carbon monoxide driven by derepression of fibrinolysis, Nature Medicine, 2001, 7, 598–604 ).In addition, carbon monoxide suppresses the rejection of transplanted hearts ( 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 Heme 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. Soores, LH Tao, M. Wysk, RJ Davis, RA Flavell, AM Choi: Carbon monoxide has anti-inflammatory effects involving the mitogen-activated protein kinase pathway, Nature Medicine, 2000 , 6, 422-428 ) and promotes protection against ischemic tissue damage ( T. Fujita, K. Toda, A. Karimova, SF Yan, Y. Naka, SF Yet, DJ Pinsky: Paradoxical rescue from ischemic injury by inhaled carbon monoxide driven by derepression of fibrinolysis, Nature Medicine, 2001, 7, 598- 604 ).

Kohlenstoffmonoxid reguliert ebenfalls Kalzium-abhängige Kaliumionenkanäle. Diese Ionenkanäle besitzen hohe Relevanz in der Aufrechterhaltung des Herzrhythmus und in der neuronalen Signalverarbeitung bei der embryonalen Entwicklung ( S. Hou, R. Xu, S. H. Heinemann, T. Hoshi: The RCK1 high-affmity Ca2+ sensor confers carbon monoxide sensitivity to Slo1 BK channels, Proceedings of the National Academy of Sciences, 2008, 105, 4039–4043 .)Carbon monoxide also regulates calcium-dependent potassium ion channels. These ion channels are highly relevant in the maintenance of heart rhythm and in neuronal signal processing in embryonic development ( Hou, R. Xu, Heinemann H, T. Hoshi: The RCK1 high-affinity Ca2 + sensor confers carbon monoxide sensitivity to Slo1 BK channels, Proceedings of the National Academy of Sciences, 2008, 105, 4039-4043 .)

Die geringe Löslichkeit Von ca. 1 mmol/l (20°C) in Wasser und die mangelnde Selektivität von freiem Kohlenstoffmonoxid machen einen gezielten sicheren therapeutischen Einsatz des freien Gases jedoch sehr schwierig.The low solubility of about 1 mmol / l (20 ° C) in water and the lack of selectivity of free carbon monoxide make a targeted safe therapeutic use of the free gas but very difficult.

Die Erforschung von Kohlenstoffmonoxid freisetzenden Molekülen, den so genannten „CO releasing molecules” (CORMs), welche Kohlenstoffmonoxid gezielt an den Ort der gewünschten Wirkung transportieren und dort abgeben, ist der entscheidende Schritt bei der Nutzung von Kohlenstoffmonoxid als Therapeutikum. Im Jahr 2002 sind die ersten pharmakologisch aktiven CORMs publiziert worden ( 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 ).Research into carbon monoxide-releasing molecules, the so-called "CO releasing molecules" (CORMs), which specifically transport carbon monoxide to the site of the desired effect and deliver it there, is the decisive step in the use of carbon monoxide as a therapeutic agent. In 2002, the first pharmacologically active CORMs were published ( 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 ).

Eine überschaubare Menge an verschiedenen CO-freisetzenden Molekülen sind daraufhin synthetisiert und untersucht worden. Neben organometallischen Komplexen wurden α,α-Dialkylaldehyde (M. N. De Matos, C. C. Romão, US 2007219120 A1 ), Oxalate, Borcarboxylate ( R. Motterlini, P. Sawle, J. Hammad, R. Alberto, R. Foresti and C. J. Green, FASER Journal, 2005, 19, 284–286 ) und Silacarboxylate ( S. D. Friis, R. H. Taaning, A. T. Lindhardt, T. Skrydstrup: Silacarboxylic Acids as Efficient Carbon Monoxide Releasing Molecules: Synthesis and Application in Palladium-Catalyzed Carbonylation Reactions, Journal of the American Chemical Society, 133, 2011, 18114–18117 ) verwendet. Nur sehr wenige Verbindungen können durch den externen Auslöser Licht Kohlenstoffmonoxid freisetzen ( U. Schatzschneider: PhotoCORMs: Light-triggered release of carbon monoxide from the coordination sphere of transition metal complexes for biological applications, Inorganica Chimica Acta, 2011, 374, 19–23 ). zeigt eine Übersicht bekannter CORM-Systeme, die in der Literatur beschrieben sind. A manageable amount of different CO-releasing molecules have subsequently been synthesized and studied. In addition to organometallic complexes, α, α-dialkyl aldehydes (MN De Matos, CC Romão, US 2007219120 A1 ), Oxalates, boron carboxylates ( R. Motterlini, P. Sawle, J. Hammad, R. Alberto, R. Foresti and CJ Green, FASER Journal, 2005, 19, 284-286 ) and silacarboxylates ( SD Friis, RH Taaning, AT Lindhardt, T. Skrydstrup: Silacarboxylic Acids as Efficient Carbon Monoxide Releasing Molecules: Synthesis and Application in Palladium Catalyzed Carbonylation Reactions, Journal of the American Chemical Society, 133, 2011, 18114-18117 ) used. Very few compounds can release light carbon monoxide through the external trigger ( U. Schatzschneider: PhotoCORMs: Light-triggered release of carbon monoxide from the coordination sphere of transitional metal complexes for biological applications, Inorganica Chimica Acta, 2011, 374, 19-23 ). shows an overview of known CORM systems, which are described in the literature.

Organometallische CO Verbindungen sind die geeignetsten Kandidaten für CORMs. Um den Mechanismus der CO-Abgabe zu untersuchen, wurden viele Kohlenstoffmonoxid-Komplexe mit verschiedenen Metallen, Ligandenumgebungen und variierenden CO-Gehalten synthetisiert ( D. Crespy, K. Landfester, U. S. Schubert, A. Schiller: Potential photoactivated metallopharmaceuticals: from active molecules to supported drugs, Chemical Communications, 2010, 46, 6651–6662 ; U. Schatzschneider: Photoactivated Biological Activity of Transition-Metal Complexes, European Journal of Inorganic Chemistry, 2010, 1451–1467 ). Darunter fallen auch photoaktive Metall-Carbonyl-Komplexe. Diese sind rar und zurzeit ein aktuelles Forschungsfeld ( R. D. Rimmer, A. E. Pierri, P. C. Ford: Photochemically activated carbon monoxide release for biological targets. Toward developing air-stable photoCORMs labilized by visible light, Coordination Chemistry Reviews, 2012, DOI: 10.1016/j.ccr.2011.12.009 ). Allerdings sind unter physiologischen Bedingungen viele CORMs unlöslich; die wenigen wasserlöslichen CORMs erzeugen nach CO-Freisetzung als Nachteil möglicherweise ein biologisch-aktives Metall-Fragment, welches die bestimmungsgemäße Verwendung stören oder zumindest beeinträchtigen kann oder systemisch im Organismus verteilt wird und aufgrund von Zell- und Organtoxizitäten unerwünschte Nebenwirkungen auftreten.Organometallic CO compounds are the most suitable candidates for CORMs. To study the mechanism of CO release, many carbon monoxide complexes with different metals, ligand environments, and varying CO levels have been synthesized ( D. Crespy, K. Landfester, US Schubert, A. Schiller: Potential photoactivated metallopharmaceuticals: from active molecules to supported drugs, Chemical Communications, 2010, 46, 6651-6662 ; U. Schatzschneider: Photoactivated Biological Activity of Transition-Metal Complexes, European Journal of Inorganic Chemistry, 2010, 1451-1467 ). This includes photoactive metal carbonyl complexes. These are rare and currently a current field of research ( RD Rimmer, AE Pierri, PC Ford: Photochemically activated carbon monoxide release for biological targets. Toward developing air-stable photoCORMs labilized by visible light, Coordination Chemistry Reviews, 2012, DOI: 10.1016 / j.ccr.2011.12.009 ). However, under physiological conditions many CORMs are insoluble; the few water-soluble CORMs may cause a CO-release as a disadvantage, possibly a biologically active metal fragment, which may interfere with the intended use or at least impair or systemically distributed in the organism and unwanted side effects occur due to cell and organ toxicity.

Mit Dimangandecacarbonyl (CORM-1) und dem Tricarbonyldichlororuthenium(II)-dimer (CORM-2) wurden 2002 die ersten pharmakologisch aktiven CORMs publiziert. Die wasserunlöslichen Verbindungen zeigen dabei unterschiedliche Eigenschaften. Während CORM-1 nur unter Bestrahlung mit Licht Kohlenstoffmonoxid 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, Circular Research 2002, 90, E17–E24 ).With dimangandecacarbonyl (CORM-1) and tricarbonyldichlororuthenium (II) dimer (CORM-2), the first pharmacologically active CORMs were published in 2002. 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, Circular Research 2002, 90, E17-E24 ).

Mit Tricarbonylchloro(glycinato)ruthenium(II) (CORM-3) stand 2003 erstmals ein wasserlösliches CO freisetzendes Molekül 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, Circular Research 2003, 93, e2–e8 ). CORM-3 lässt sich nur systemisch applizieren; eine lokale Anwendung wäre nicht möglich. Außerdem erzeugt CORM-3 nach CO-Freisetzung wiederum ein nachteiliges biologisch-aktives Metall-Fragment.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, Circular Research 2003, 93, e2-e8 ). CORM-3 can only be applied systemically; a local application would not be possible. In addition, after release of CO, CORM-3 again generates a deleterious biologically active metal fragment.

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, Circular Research 2003, 93, e2–e8 ). Die gleichen Nachteile wie bei CORM-3 sind hier zu erwarten.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, Circular Research 2003, 93, e2-e8 ). The same disadvantages as with CORM-3 are to be expected here.

Eine neue Generation von CORMs wurde 2008 von Schatzschneider et al. eingeführt. Hierbei dienen wasserlösliche Tricarbonylmangan-Komplexe mit Tris(pyrazolyl)methan als Liganden zur photoinduzierten CO-Freisetzung ( U. Schatzschneider: PhotoCORMs: Light-triggered release of carbon monoxide from the coordination sphere of transition metal complexes for biological applications, Inorganica Chimica Acta, 2011, 374, 19–23 ). Die gleichen Nachteile wie bei CORM-3 sind hier zu erwarten.A new generation of CORMs was launched in 2008 by Schatzschneider et al. introduced. Here, water-soluble tricarbonylmanganese complexes with tris (pyrazolyl) methane serve as ligands for photoinduced CO release ( U. Schatzschneider: PhotoCORMs: Light-triggered release of carbon monoxide from the coordination sphere of transitional metal complexes for biological applications, Inorganica Chimica Acta, 2011, 374, 19-23 ). The same disadvantages as with CORM-3 are to be expected here.

Eine interessante Verbindungsklasse, welche körperbekannte Liganden und lichtinduzierte Kohlenstoffmonoxidfreisetzung beinhaltet, stellen Schwefelkomplexe, die sich von Cystein ableiten, dar. Westerhausen et al. beschrieb einen wasserlöslichen Dicarbonylbis(cysteamine)eisen(II)-Komplex (CORM-S1) welcher mit sichtbarem Licht Kohlenstoffmonoxid abspaltet ( R. Kretschmer, G. Gessner, H. Görls, S. H. Heinemann, M. Westerhausen: Dicarbonyl-bis(cysteamine)iron(II): A light induced carbon monoxide releasing molecule based on iron (CORM-S1), Journal of Inorganic Biochemistry, 2011, 105, 6–9 ). Die gleichen Nachteile wie bei CORM-3 sind auch hier zu erwarten.An interesting class of compounds, which includes well-known ligands and light-induced carbon monoxide release, are sulfur complexes derived from cysteine. Westerhausen et al. described a water-soluble dicarbonylbis (cysteamine) iron (II) complex (CORM-S1) which cleaves carbon monoxide with visible light ( R. Kretschmer, G. Gessner, H. Görls, SH Heinemann, M. Westerhausen: Dicarbonyl bis (cysteamine) iron (II): A light induced carbon monoxide releasing molecule based on iron (CORM-S1), Journal of Inorganic Biochemistry, 2011, 105, 6-9 ). The same disadvantages as in CORM-3 are to be expected here.

Ein aktueller Review-Artikel aus der Gruppe von Ford beschreibt die neuesten Errungenschaften im Bereich photoaktiver CORMs ( R. D. Rimmer, A. E. Pierri, P. C. Ford: Photochemically activated carbon monoxide release for biological targets. Toward developing air-stable photoCORMs labilized by visible light, Coordination Chemistry Reviews, 2012, DOI: 10.1016/j.ccr.2011.12.009 ). Ford et al. zählen drei wesentliche Erfordernisse von neuen, innovativen photoaktiven CORMs auf: Stabilität, Wasserlöslichkeit, Vermeidung des Metall-Fragment-Effekts nach CO-Freisetzung, denen jedoch die bekannten CORMs entweder nicht, nicht hinreichend bzw. nicht in der Summe dieser Erfordernisse gerecht werden.A recent review article from the Ford group describes the latest achievements in the field of photoactive CORMs ( RD Rimmer, AE Pierri, PC Ford: Photochemically activated carbon monoxide release for biological targets. Toward developing air-stable photoCORMs labilized by visible light, Coordination Chemistry Reviews, 2012, DOI: 10.1016 / j.ccr.2011.12.009 ). Ford et al. include three essential requirements of new, innovative photoactive CORMs: stability, water solubility, avoidance of the metal fragment effect after CO release, which, however, the well-known CORMs either not, not sufficiently or do not meet the sum of these requirements.

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 Radionuldiden beruhen und für diagnostische Zwecke vorgesehen sind. Die von den Radionuldiden 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 Metallcarbonyle described, which are based on Radionuldiden and intended for diagnostic purposes. The radiation emanating from the Radionuldiden represents a major disadvantage, since thus the therapeutic approach could be counterinduced by an 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. Von einer CO-Freisetzung als Erklärung für die therapeutischen Effekte kann somit nicht ausgegangen werden. 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. However, the resulting therapeutic effects are based on the corresponding polyene esters, whose metabolic degradation is not described. CO release as an explanation for the therapeutic effects can thus not be assumed.

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 keine wasserlöslichen CORMs, welche lichtinduziert Kohlenstoffmonoxid freisetzen. Lediglich die bereits bekannten Verbindungen Eisenpentacarbonyl und Dimangandecacarbonyl werden dort beschrieben. Hinweise, wie man zu in Wasser wirksamen, lichtinduzierten CO-freisetzenden Materialien gelangt oder kommen könnte, finden sich dort nicht. WO 95/05814 A1 . WO 00/56743 A1 and US 7,045,140 B2 describe a wide variety of possible metal carbonyls. Among 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 or in water-effective, light-induced CO-releasing materials there.

Die CO-freisetzenden Moleküle (CORMs) müssen – speziell für Anwendungen in der Medizin, Kosmetik und Pharmazie – besondere Anforderungen erfüllen, wie Wasserlöslichkeit, gesteuerte CO-Abgabe und pharmakologische Unbedenklichkeit der Komplexe sowie ihrer Abbauprodukte. Viele der genannten Verbindungen können die strengen Kriterien der pharmakologischen Unbedenklichkeit jedoch nicht bzw. nicht in der Gänze erfüllen (Aufnahme-, Distribution-, Metabolisierungs- und Exkretions-(ADME)Eigenschaften pharmakologischer Substanzen im Organismus). Neben der Verwendung in Wasser ist die pharmakologische Unbedenklichkeit der CORMs nach CO-Freisetzung noch immer ein oder nicht zufriedenstellend gelöstes Problem.The CO-releasing molecules (CORMs) must - especially for applications in medicine, cosmetics and pharmacy - meet special requirements, such as water solubility, controlled CO release and pharmacological safety of the complexes and their degradation products. However, many of the compounds mentioned can not or do not fully meet the strict criteria of pharmacological safety (absorption, distribution, metabolization and excretion (ADME) properties of pharmacological substances in the organism). Apart from the use in water, the pharmacological safety of the CORMs after CO release is still an unsatisfactorily solved problem.

Wasserlösliche CORMs sind deshalb immer noch eine große Herausforderung in der CORM Forschung. Gegenstand vieler Arbeiten ist es, den Erhalt der CO-Abgabe mit einer guten Wasserlöslichkeit zu kombinieren. Allerdings werden damit drastische Haupt- und Nebenwirkungen des zurückbleibenden Metallfragments nach der CO-Abgabe verifiziert. Die sogenannten toxischen Metaboliten (Metallfragmente nach CO Abgabe) verursachen oftmals stärkere physiologische Reaktionen als das freigewordene CO selbst. Zum Beispiel ist die zytotoxische Wirkung von Tricarbonylmangantris(pyrazolyl)methan-Komplexen auf HT29 Kolon Krebs-Zellen eher auf das Metallfragment als auf die photoinduzierten zwei Äquivalente CO zurückzuführen ( J. Niesel, A. Pinto, H. W. P. N'Dongo, K. Merz, I. Ott, R. Gust, U. Schatzschneider: Photoinduced CO release, cellular uptake and cytotoxicity of a tris(pyrazolyl) methane (tpm) manganese tricarbonyl complex, Chemical Communications, 2008, 1798–1800 ).Water-soluble CORMs are therefore still a major challenge in CORM research. The subject of much work is to combine the receipt of the CO charge with a good water solubility. However, drastic main and side effects of the remaining metal fragment after CO delivery are verified. The so-called toxic metabolites (metal fragments after CO release) often cause stronger physiological reactions than the released CO itself. For example, the cytotoxic effect of tricarbonylmanganetris (pyrazolyl) methane complexes on HT29 colon cancer cells is on the metal fragment rather than the photoinduced two Attributed equivalents of CO ( J. Niesel, A. Pinto, HWP N'Dongo, K. Merz, I. Ott, R. Gust, U. Schatzschneider: Photoinduced CO release, cellular uptake and cytotoxicity of a tris (pyrazolyl) methane (tpm) manganese tricarbonyl complex , Chemical Communications, 2008, 1798-1800 ).

Im Gegensatz zu diesen wasserlöslichen CORMs kann es in Anbetracht der genannten Nachteile in Wasser aktiver CORMs sogar vorteilhaft sein, wasserunlösliche CO-abgebende Materialien (CORMAs) einzusetzen, die nach der CO-Abgabe zusammen mit den Zersetzungsprodukten (Metall-Fragmente als Metaboliten) entfernt werden können.In contrast to these water-soluble CORMs, it may even be advantageous to use water-insoluble CO-emitting materials (CORMAs) in view of the mentioned disadvantages in water-active CORMs, which are removed after the CO release together with the decomposition products (metal fragments as metabolites) can.

2005 wurden von Tyler et al. Polyurethane mit (C5H4R)(CO)3Mo-Mo(CO)3(C5H4R)-Einheiten im Polymerrückgrat modifiziert. Bei Bestrahlung mit Licht konnte das Polymer zerlegt werden und CO Gas wurde freigesetzt. Biologische Wirkungen sind allerdings nicht untersucht worden ( R. Chen, J. Meloy, B. C. Daglen, D. R. Tyler: Photochemically Reactive Polymers. Identification of the Products Formed in the Photochemical Degradation of Polyurethanes That Contain (C5H4R)(CO)3Mo-Mo(CO)3(C5H4R) Units along Their Backbons, Organometallics, 2005, 24, 1495–1500 ). Hier wird das Polymer-Rückgrat unter Bestrahlung mittels CO-Freisetzung zerlegt. Somit werden weitere potenziell toxische Metaboliten erzeugt.In 2005, Tyler et al. Polyurethanes with (C 5 H 4 R) (CO) 3 Mo-Mo (CO) 3 (C 5 H 4 R) units modified in the polymer backbone. Upon irradiation with light, the polymer could be decomposed and CO gas was released. However, biological effects have not been investigated ( R. Chen, J. Meloy, BC Daglen, DR Tyler: Photochemically Reactive Polymers. Identification of the Products Formed in the Photochemical Degradation of Polyurethanes That Contain (C5H4R) (CO) 3 Mo-Mo (CO) 3 (C5H4R) Units along Their Bakes, Organometallics, 2005, 24, 1495-1500 ). Here, the polymer backbone is decomposed under exposure to CO release. Thus, other potentially toxic metabolites are generated.

WO 20 11127218 beschreibt den Einbau von Metallcarbonylen in Silikon-Nanofasern welche als Komposit-Materialien für elektronische Schalter, Sensoren, Photodetektoren und Batterien verwendet werden können. Unter anderen werden hier auch Mn2(CO)10 und Fe(CO)5 eingesetzt, diese werden allerdings nicht mit Licht bestrahlt und dienen nicht der CO-Freisetzung. WO 20 11127218 describes the incorporation of metal carbonyls in silicone nanofibers which can be used as composite materials for electronic switches, sensors, photodetectors, and batteries. Among others, Mn 2 (CO) 10 and Fe (CO) 5 are also used here, but these are not irradiated with light and are not used for CO release.

Zang et al. beschreiben die Einbettung des Rhenium-Carbonyl-Komplexes Re(CO)3(Bphen)Br, (Bphen = 4,7-Diphenyl-1,10-phenanthrolin) in elektroversponnene Fasern und beobachten matrixabhängige Photolumineszenz ( Y. Wang, H.-J. Mao, G.-Q. Zang, Y.-S. Yu, Z.-H. Tang: Photoluminescence properties of Re(I) complex doped composite submicron fibers prepared by electrospinning, Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, 2011, 78, 469–473 ). Ziel dieser Studie war es, eine matrixabhängige Photolumineszenz zu beobachten. Die Materialien dienten nicht zur photoaktiven CO-Freisetzung.Zang et al. describe the embedding of the rhenium carbonyl complex Re (CO) 3 (Bphen) Br, (Bphen = 4,7-diphenyl-1,10-phenanthroline) in electrospun fibers and observe matrix-dependent photoluminescence ( Y. Wang, H.-J. Mao, G.-Q. Zang, Y.-S. Yu, Z.-H. Tang: Photoluminescence properties of Re (I) complex doped composite submicron fibers prepared by electrospinning, Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, 2011, 78, 469-473 ). The aim of this study was to observe a matrix-dependent photoluminescence. The materials did not serve for photoactive CO release.

Lewkowitz-Shpuntoff et al. demonstrierten mit Hilfe von Fe(CO)5 im elektroversponnenen Komposit aus Ethylenvinylacetat und organischen Tonmineralien eine gesteigerte Proliferation von Osteoblasten im Magnetfeld. Magnetische Eisen-Nanokomposite werden als Erklärung dafür genannt. ( H. M. Lewkowitz-Shpuntoff, M. C. Wen, A. Singh, N. Brenner, R. Gambino, N. Pernodet, R. Isseroff, M. Rafailovich, J. Sokolov: The effect of organo clay and adsorbed FeO3 nanoparticles on cells cultured on Ethylen Vinyl Acetate substrates and fibers, Biomaterials, 2009, 30, 8–1 8). Eine CO-Freisetzung im sichtbaren Licht wird nicht erwähnt, da die thermische Behandlung eine Umwandlung von Fe(CO)5 in Eisen-Nanopartikel vorsah.Lewkowitz-Shpuntoff et al. demonstrated an increased proliferation of osteoblasts in the magnetic field with the aid of Fe (CO) 5 in the electrospun composite of ethylene vinyl acetate and organic clay minerals. Magnetic iron nanocomposites are mentioned as an explanation for this. ( HM Lewkowitz-Shpuntoff, MC Wen, A. Singh, N. Brenner, R. Gambino, N. Pernodet, R. Isseroff, M. Rafailovich, J. Sokolov: The effect of organo-clay and adsorbed FeO3 nanoparticles on cells cultured on ethylene Vinyl Acetate substrates and fibers, Biomaterials, 2009, 30, 8-1 8th). A CO release in visible light is not mentioned because the thermal treatment provided for conversion of Fe (CO) 5 to iron nanoparticles.

Die Gruppe um Greiner und Wendorff verwendete ebenfalls ein Metallcarbonyl (Co2(CO)8) als Precursor für magnetische Nanopartikel in elektroversponnenen PMMA-Fasern ( O. Kriha, M. Becker, M. Lehmann, D. Kriha, J. Krieglstein, M. Yosef, S. Schlecht, R. B. Wehrspohn, J. H. Wendorff, A. Greiner: Connection of Hippocampal Neurons by Magnetically Controlled Movement of Short Electrospun Polymer Fibers – A Route to Magnetic Micromanipulators, Advanced Materials, 2007, 19, 2483–2485 ). Co2(CO)8 wurde hier als Precursor für magnetische Nanopartikel eingesetzt und nicht als CORM für eine CO-Freisetzung aus PMMA.The group of Greiner and Wendorff also used a metal carbonyl (Co 2 (CO) 8 ) as precursor for magnetic nanoparticles in electrospun PMMA fibers ( O. Kriha, M. Becker, M. Lehmann, D. Kriha, J. Krieglstein, M. Yosef, S. Schlecht, RB Wehrspohn, JH Wendorff, A. Greiner: Connection of Hippocampal Neurons by Magnetically Controlled Movement of Short Electrospun Polymer Fibers - A Route to Magnetic Micromanipulators, Advanced Materials, 2007, 19, 2483-2485 ). Co 2 (CO) 8 was used here as precursor for magnetic nanoparticles and not as CORM for CO release from PMMA.

In der Literatur sind bis heute lediglich drei nachfolgend aufgeführte Verfahren beschrieben, wie CO-abgebende Metallkomplexe in polymere Systeme kovalent eingebunden wurden. In allen Studien wird die mögliche biologische Anwendung diskutiert oder untersucht. Hubell et al. entwickelte polymere Mizellen, welche Ru(CO)3Cl(aminoacidat) als CO-abgebende Substanz beinhalten. Die Mizellen, mit einem Durchmesser zwischen 30 und 40 nun, bestehen aus Triblock-Copolymeren (Poly(ethylenglycol) – Poly(ornithinacrylamid) – Poly(n-butylacrylamid)) und sind Zellmembran durchgängig. ( U. Hasegawa, A. J. van der Vlies, E. Simeoni, C. Wandrey, J. A. Hubbell: Carbon Monoxide-Releasing Micelles for Immunotherapy, Journal of the American Chemical Society, 2010, 132, 18273–18280 ). Schatzschneider et al. nutzte Siliziumdioxid-Nanopartikel für die Immobilisierung von funktionalisierten [Mn(CO)3(tpm)]+-Komplexen (tpm = Tris(pyrazolyl)methan). Die partikulären PhotoCORMS sind möglicherweise in der Krebstherapie einsetzbar ( G. Döidelmann, H. Pfeiffer, A. Birkner, U. Schatzschneider: Silicium Dioxide Nanoparticles As Carriers for Photoactivatable CO-Releasing Molecules (PhotoCORMs), Inorganic Chemistry, 2011, 50, 4362–4367 ).In the literature, only three methods described below are described to date how CO-donating metal complexes were covalently incorporated into polymeric systems. In all studies the possible biological application is discussed or investigated. Hubell et al. developed polymeric micelles, which include Ru (CO) 3 Cl (aminoacidate) as a CO-donating substance. The micelles, with a diameter of between 30 and 40 mm, consist of triblock copolymers (poly (ethylene glycol) - poly (ornithine acrylamide) - poly (n-butylacrylamide)) and are cell membrane continuous. ( U. Hasegawa, AJ van der Vlies, E. Simeoni, C. Wandrey, JA Hubbell: Carbon Monoxide Releasing Micelles for Immunotherapy, Journal of the American Chemical Society, 2010, 132, 18273-18280 ). Schatzschneider et al. used silica nanoparticles for the immobilization of functionalized [Mn (CO) 3 (tpm)] + complexes (tpm = tris (pyrazolyl) methane). The particulate PhotoCORMS may be useful in cancer therapy ( G. Döidelmann, H. Pfeiffer, A. Birkner, U. Schatzschneider: Silicon Dioxide Nanoparticles As Carriers for Photoactivatable CO-Releasing Molecules (PhotoCORMs), Inorganic Chemistry, 2011, 50, 4362-4367 ).

Kunz et al. immobilisierte kovalent das bekannte photolabile organometallische fac-Mn(CO)3 Fragment über Bis(pyridylmethyl)amin-Liganden an Methacrylat- und Methacrylamidpolymere für eine lichtinduzierte CO-Abgabe ( N. E. Brückmann, M. Wahl, G. J. Reiß, M. Kohns, W. Wätjen, P. C. Kunz: Polymer Conjugates of Photoinducible CO-Releasing Molecules, European Journal of Inorganic Chemistry, 2011, 2011, 4571–4577 ). In allen drei genannten Methoden müssen Liganden für die kovalente Immobilisierung in sehr aufwendiger Weise synthetisiert werden. Außerdem sind die Einbauraten (Gehalt an CO-Komplex im Polymer) sehr gering.Kunz et al. immobilized the known photolabile organometallic fac-Mn (CO) 3 fragment via bis (pyridylmethyl) amine ligands to methacrylate and methacrylamide polymers for a light-induced CO release ( NE Brückmann, M. Wahl, GJ Reiß, M. Kohns, W. Wätjen, PC Kunz: Polymer Conjugates of Photoinducible CO-Releasing Molecules, European Journal of Inorganic Chemistry, 2011, 2011, 4571-4577 ). In all three methods, ligands for covalent immobilization must be synthesized in a very complex manner. In addition, the incorporation rates (content of CO complex in the polymer) are very low.

Ausgehend von den genannten Nachteilen bekannter eingangs beschriebener Systeme besteht die dringende Notwendigkeit mittels prozesstechnisch einfacher Verfahren CO-Release-Systeme zu ermöglichen, um den steigenden Bedarf aus Medizin, Biologie, Medizintechnik sowie der Kosmetik und der pharmazeutischen Industrie zu decken.Based on the disadvantages of known systems described above, there is an urgent need to enable CO-release systems by means of simple process technology in order to meet the increasing demand from medicine, biology, medical technology as well as cosmetics and the pharmaceutical industry.

Der Erfindung liegt daher die Aufgabe zu Grunde, Kohlenstoffmonoxid-freisetzende und bioverträgliche Materialien zu schaffen, die mit möglichst geringem Aufwand herstellbar sind, sowie bei ihrer Anwendung in Wasser auf möglichst einfache Weise und ahne störende Sekundärwirkung Kohlenstoffmonoxid effizient freisetzen.The invention is therefore based on the object to provide carbon monoxide-releasing and biocompatible materials that can be produced with the least possible effort, as well as efficiently release carbon monoxide when used in water in the simplest possible way and without disturbing secondary effect.

Damit sollen die Kohlenstoffnonoxid-freisetzenden Materialien weitgehend ohne Risiken als pharmakologische Wirkstoffträger eingesetzt werden können. Thus, the carbon non-oxide-releasing materials should be able to be used largely without risks as a pharmacological drug carrier.

Diese Aufgabe wird durch Kohlenstoffmonoxid freisetzende Materialien auf Grundlage von CO-abgebenden Substanzen (CORMs), gelöst, indem die zumindest eine CO-abgebende Substanz jeweils in ein Polymer oder ein Polymerblend (Mischung von Polymeren) eingebettet ist, beispielsweise entsprechend Schema 1

Figure 00090001
This object is achieved by carbon monoxide-releasing materials based on CO-releasing substances (CORMs), in which the at least one CO-releasing substance is embedded in each case in a polymer or a polymer blend (mixture of polymers), for example according to Scheme 1
Figure 00090001

Die zumindest eine CO-abgebende Substanz kann dabei im Polymer bzw. Polymerblend homogen gelöst oder partikulär darin eingebettet sein.The at least one CO-releasing substance can be homogeneously dissolved in the polymer or polymer blend or embedded therein particulate.

Zweckmäßig kann sich die zumindest eine CO-abgebende Substanz an der Oberfläche der Polymermaterialien befinden.Suitably, the at least one CO-donating substance may be on the surface of the polymeric materials.

Die CORMs bestehen aus an atomares oder ionisches Metall, wie Fe, Co, Ru, Rh, Re, Ni, Mo, Mn, Os und V, gebundenem Kohlenstoffmonoxid, einem oder mehreren Metallzentren und ggf. weiteren zusätzlichen organischen mono- und multidendaten Liganden, wie Amine, Imine, Carboxamide oder Phosphine.The CORMs consist of atomic or ionic metal, such as Fe, Co, Ru, Rh, Re, Ni, Mo, Mn, Os and V, bound carbon monoxide, one or more metal centers and optionally further organic mono- and multidate ligands, such as amines, imines, carboxamides or phosphines.

Es ist vorteilhaft, wenn als CO-freisetzende Substanz CORM-1 der Formel!

Figure 00100001
in das Polymer oder Polymerblend eingebettet ist.It is advantageous if the CO-releasing substance CORM-1 of the formula!
Figure 00100001
embedded in the polymer or polymer blend.

Vorteilhaft kann auch sein, wenn als Kohlenstoffmonoxid abgebende Substanz Fe(CO)5 der Formel II

Figure 00100002
in das Polymer oder Polymerblend eingebettet ist.It may also be advantageous if Fe (CO) 5 of the formula II as carbon monoxide-releasing substance
Figure 00100002
embedded in the polymer or polymer blend.

Des Weiteren könnten als Kohlenstoffmonoxid freisetzende Substanzen Komplexe der allgemeinen Formeln III oder IV

Figure 00110001
in das Polymer oder Polymerblend eingebettet sein.Furthermore, carbon monoxide-releasing substances could be complexes of the general formulas III or IV
Figure 00110001
embedded in the polymer or polymer blend.

Als Polymer, in welches die Kohlenstoffmonoxid freisetzende Substanz homogen gelöst oder partikulär eingebettet ist, könnten ein organisches Polymer, vorzugsweise aus der Klasse der Polyether, Poly(etherimide) (PEI), Poly(ether-ketone), Polyether-ether-ketone), Poly(ethyleneoxide) (PEO), Poly(vinylalcohole) (PVA), Poly(vinylacetat) (PVAc), Polystyrole (PS), Polyethylene, Polypropylene, Poly(vinylhalogenide), Poly(tetrafluoroethylen), Poly(vinylidenefluoride), Poly(butadiene), Polyacrylnitrile (PAN), Polyester (PE), Poly(hydroxycarbonsäuren (PHC), Polyurethane (PU), Polyamide (PA), Polycarbonate (PC), Polyanhydride, Polysulfone (PS), Poly(ethersulfone), Polymethacrylate, Polyacrylate, Polyvinylbutyrale, Poly(aminosäuren), Poly(organosiloxane), davon abgeleitete Copolymere, Blends dieser Polymere sowie Biopolymere, vorzugsweise Polysaccharide und Polysaccharidderivate, wie Chitosan, Dextran, Chitosan, Celluloseacetat (CA), Proteine, wie Kollagene sowie Mischungen dieser Polymere, Anwendung finden.As a polymer in which the carbon monoxide-releasing substance is homogeneously dissolved or particulate embedded, could be an organic polymer, preferably from the class of polyethers, poly (etherimides) (PEI), poly (ether ketones), polyether ether ketones), Poly (ethylene oxides) (PEO), poly (vinyl alcohol) (PVA), poly (vinyl acetate) (PVAc), polystyrenes (PS), polyethylenes, polypropylenes, poly (vinyl halides), poly (tetrafluoroethylene), poly (vinylidene fluorides), poly ( butadiene), polyacrylonitriles (PAN), polyesters (PE), poly (hydroxycarboxylic acids (PHC), polyurethanes (PU), polyamides (PA), polycarbonates (PC), polyanhydrides, polysulfones (PS), Poly (ether sulfones), polymethacrylates, polyacrylates, polyvinyl butyrals, poly (amino acids), poly (organosiloxanes), copolymers derived therefrom, blends of these polymers and biopolymers, preferably polysaccharides and polysaccharide derivatives, such as chitosan, dextran, chitosan, cellulose acetate (CA), proteins, like collagens, as well as mixtures of these polymers, find application.

Das Polymer oder das Polymerblend mit der zumindest einen eingebetteten CO-abgebender Substanz kann zweckmäßig als Folie bzw. folienartige Beschichtung oder auch als Faser bzw. Faservlies vorliegen, wobei insbesondere die Methode des Electrospinning zur Faserherstellung verwendet werden kann. Mit dieser Methode ist es möglich, eine große Oberfläche und damit eine schnelle und effiziente Kohlenstoffmonoxidfreigabe zu realisieren.The polymer or the polymer blend with the at least one embedded CO-donating substance may expediently be present as a film or film-like coating or else as a fiber or non-woven fabric, wherein in particular the method of electro-spinning can be used for fiber production. With this method it is possible to realize a large surface and thus a fast and efficient carbon monoxide release.

Die erfindungsgemäßen Kohlenstoffmonoxid-freisetzenden Materialien können beispielsweise als CO-Donator, der unter Lichteinwirkung Kohlenstoffmonoxid abgibt, insbesondere als CO-Quelle in der Biologie, Medizin, Kosmetik und Pharmazie, verwendet werden, ohne dies darauf zu beschränken.The carbon monoxide-releasing materials of the present invention can be used, for example, as a CO donor which releases carbon monoxide under the action of light, in particular as a CO source in biology, medicine, cosmetics and pharmacy, without being limited thereto.

Überraschend hat sich gezeigt, dass die vorgeschlagenen Materialien, welche vorteilhaft mit vertretbarem Aufwand herstellbar und bioverträglich sind sowie auch in Wasser Kohlenstoffmonoxid freisetzen. Die Einbauraten an CO-Metallkomplexen sind enorm groß und können bis zu 70 Gew.-% CO-Metallkomplex im Polymer betragen. Dies ermöglicht eine effiziente CO-Abgabe nach Photoaktivierung. Die extreme geringe Wasserlöslichkeit des eingebetteten Metall-CO-Komplexes verhindert das Freisetzen von Komplexen oder eines Metallfragments nach Photoaktivierung. Leaching Raten belaufen sich auf nur 1% innerhalb einer Woche.Surprisingly, it has been found that the proposed materials, which can be produced advantageously with reasonable effort and are biocompatible, as well as release carbon monoxide in water. The incorporation rates of CO metal complexes are enormous and can be up to 70 wt .-% CO metal complex in the polymer. This allows efficient CO delivery after photoactivation. The extremely low water solubility of the embedded metal-CO complex prevents the release of complexes or a metal fragment after photoactivation. Leaching rates amount to only 1% within a week.

Es wurde weiter gefunden, dass besonders unter Anwendung des Electrospinning-Verfahrens organische Polymere gemeinsam mit photolabilen CO-Metallkomplex zu nanofasrigen Vliesen versponnen werden können. Sehr überraschend war dabei das Entstehen hochporöser Fasern. Aus den Fasern mit Durchmessern im Nanometer- und unterem Mikrometerbereich wurde photoinduziert eine gesteuerte CO-Freisetzung nachgewiesen, die aufgrund der hohen Porosität sehr effektiv verläuft. Die erreichte Porosität konnte mit bisherigen Verfahren noch nicht erreicht werden. Derartige Materialkombinationen aus organischem Polymer und CO-Metallkomplexen, die unter Lichteinwirkung in der umgebenden Atmosphäre sowie auch in Wasser CO freisetzen, sind der Fachwelt bisher nicht bekannt. Besonders vorteilhaft ist, dass eine Vielzahl von wasserunlöslichen, photoaktivierbaren Metallcarbonylen an Stelle der Formeln I bis IV verwendet werden kann. Darunter fallen unter anderem V(CO)6, Mo(CO)6, Mn(CO)5X (X = Cl, Br), Fe2(CO)9, Fe3(CO)12, Fe(CO)4X2 (X = Cl, Br, I) Co2(CO)8, Co(CO)4I, Re2(CO)10, Ru(CO)4. Darüber hinaus ist auch eine Anregung von Eisen-Carbonylen mit sichtbarem Licht möglich.It has also been found that, in particular using the electrospinning method, organic polymers can be spun together with photolabile CO metal complex to nanofibrous nonwovens. Very surprising was the emergence of highly porous fibers. From the fibers with diameters in the nanometer and the lower micrometre range, a controlled release of CO was detected photoinduced, which proceeds very effectively due to the high porosity. The achieved porosity could not be achieved with previous methods. Such material combinations of organic polymer and CO metal complexes that release CO under the action of light in the surrounding atmosphere as well as in water, are not known in the art. It is particularly advantageous that a multiplicity of water-insoluble, photoactivatable metal carbonyls can be used instead of the formulas I to IV. These include, but are not limited to, V (CO) 6 , Mo (CO) 6 , Mn (CO) 5 X (X = Cl, Br), Fe 2 (CO) 9 , Fe 3 (CO) 12 , Fe (CO) 4 X 2 (X = Cl, Br, I) Co 2 (CO) 8 , Co (CO) 4 I, Re 2 (CO) 10 , Ru (CO) 4 . In addition, excitation of iron carbonyls with visible light is possible.

Mit der vorliegenden Erfindung können unzählige bekannte und neue Metall-Carbonyl-Komplexe für die Einbettung in Polymere genutzt werden, um auch in Wasser wirksame CO freisetzende Materialien zu generieren. Diese CO-freisetzenden Materialien entsprechen im Gegensatz zu bisher bekannten CORMs auch den eingangs genannten Anforderungen, die Ford et al. (R. D. Rimmer, A. E. Pierri, P. C. Ford: Photochemically activated carbon monoxide release for biological targets. Toward developing air-stable photoCORMs labilized by visible light, Coordination Chemistry Reviews, 2012, DOI: 10.1016/j.ccr.2011.12.009) an neue und innovative CORMs stellen. Mit der vorgeschlagenen Einbettung bekannter und neuer CORMs in Polymere oder Polymerblends kann auch der nachteilige Metall-Fragment-Effekt wirksam unterdrückt werden.With the present invention, innumerable known and new metal-carbonyl complexes can be used for embedding in polymers in order to generate water-releasing CO-releasing materials. These CO-releasing materials correspond in contrast to previously known CORMs also the requirements mentioned above, the Ford et al. (RD Rimmer, AE Pierri, PC Ford: Photochemically activated carbon monoxide release for biological targets. Toward developing air-stable photoCORMs, Labilized by visible light, Coordination Chemistry Reviews, 2012, DOI: 10.1016 / j.ccr.2011.12.009) to new and innovative CORMs. With the proposed embedding of known and new CORMs in polymers or polymer blends, the adverse metal fragment effect can also be effectively suppressed.

Die Erfindung soll nachstehend anhand von in der Zeichnung dargestellten Ausführungsbeispielen näher erläutert werden.The invention will be explained below with reference to exemplary embodiments illustrated in the drawing.

Es zeigen:Show it:

: Übersicht zu an sich bekannten CORM-Systemen : Overview of known CORM systems

: Myoglobin-Assay zum Nachweis von freigesetztem CO : Myoglobin Assay for Detecting Liberated CO

: Grafische Darstellung der Kristallstruktur von [(bpb)Ru(CO)(H2O)] : Graphical representation of the crystal structure of [(bpb) Ru (CO) (H 2 O)]

Zur Herstellung der erfindungsmäßen Kohlenstoffmonoxid freisetzende Materialien wird zunächst in an sich bekannter Weise eine 1–80%ige Polymerlösung in einem geeignetem Lösungsmittel hergestellt. Geeignete Lösungsmittel sind halogenierte Lösungsmittel (wie beispielsweise Chloroform, Methylenchlorid), Ether (wie z. B. Dieethylether, Tetrahydrofuran, Dioxan, tert.-Butylmethylether), Alkohole (wie Methanol, Ethanol, Isopropanol, Hexaflouroisopropanol), Ketone (z. B. Aceton, Ethylmethylketon, Cyclohexanon), organische Säuren und Kohlenwasserstoffe (wie Hexan, Octan) sowie Gemische aus diesen. In diesem Lösungsmittel bzw. Lösungsmittelgemisch wird vorschlagsgemäß ein CO-Metallkomplex gelöst bzw. homogen suspendiert. Der Gehalt an CO-Metallkomplex liegt dabei in Konzentrationsbereich von 0,01–70 Gew.%, bezogen auf das eingesetzte Polymer, vor. Das so hergestellte Polymer/CO-Metallkomplex-Gemisch kann auf an sich bekannte Weise zu Folien, Beschichtungen und Fasern verarbeitet werden. Bevorzugt ist die Folienbildung durch Verdunstung des Lösungsmittels/Lösungsmittelgemisches. Beschichtungen können bevorzugt durch ein- und mehrmaliges Tauchen erzeugt werden. Fasern können zweckmäßig mittels Electrospinning hergestellt werden. Die nachstehenden Beispiele dienen der näheren Erläuterung der Erfindung, ohne den Schutzumfang der Erfindung auf diese Herstellungsbeispiele zu beschränken.To produce the carbon monoxide-releasing materials according to the invention, a 1-80% polymer solution is first prepared in a conventional manner in a suitable solvent. Suitable solvents are halogenated solvents (such as chloroform, methylene chloride), ethers (such as, for example, diethyl ether, tetrahydrofuran, dioxane, tert-butyl methyl ether), alcohols (such as methanol, ethanol, isopropanol, hexafluoroisopropanol), ketones (eg. Acetone, ethyl methyl ketone, cyclohexanone), organic acids and hydrocarbons (such as hexane, octane) and mixtures of these. In accordance with the proposal, a CO metal complex is dissolved or homogeneously suspended in this solvent or solvent mixture. The content of CO metal complex is in the concentration range of 0.01-70 wt.%, Based on the polymer used before. The polymer / CO-metal complex mixture produced in this way can be processed in a manner known per se into films, coatings and fibers. The film formation by evaporation of the solvent / solvent mixture is preferred. Coatings may preferably be produced by dipping once or more. Fibers can be conveniently made by electrospinning. The following examples serve to illustrate the invention without limiting the scope of the invention to these preparation examples.

Beispiel 1:Example 1:

Mn2(CO)10-haltige Poly(L-lactid-co-D/L-lactid)-FolieMn 2 (CO) 10 -containing poly (L-lactide-co-D / L-lactide) film

119 mg Poly(L-lactid-co-D/L-lactid) (M = 1,4 Mio. g/mol, gemessen mit Polystyrol-Standard) werden in 2,5 ml Chloroform gelöst. Zu der Lösung werden 1,2 mg Mn2(CO)10 gegeben. Die Reaktionsmischung wird in der Dunkelheit bis zur Auflösung des Metallkomplexes gerührt. Anschließend wird die Lösung in der Dunkelheit in eine Teflonschale gegossen. Nach Verdunstung des Lösungsmittels erhält man eine Mn2(CO)10-haltige lichtempfindliche Polylactidfolie mit einem Mn2(CO)10-Gehalt von ca. 1 Gew.%.119 mg of poly (L-lactide-co-D / L-lactide) (M = 1.4 million g / mol, measured with polystyrene standard) are dissolved in 2.5 ml of chloroform. 1.2 mg of Mn 2 (CO) 10 are added to the solution. The reaction mixture is stirred in the dark until the metal complex dissolves. Then the solution is poured in the dark in a Teflon dish. After evaporation of the solvent, a Mn 2 (CO) 10 -containing photosensitive Polylactidfolie having a Mn 2 (CO) 10 content of about 1 wt.%.

Beispiel 2:Example 2:

Mn2(CO)10-haltige Poly(L-lactid-co-D/L-lactid)-BeschichtungMn 2 (CO) 10 -containing poly (L-lactide-co-D / L-lactide) coating

Die wie im Beispiel 1 hergestellte Lösung wird direkt für Beschichtungen eingesetzt. In der Dunkelheit oder unter Rotlicht wird ein Glasprobekörper (Scheibe 3 × 8 cm, 1 mm dick) in die Lösung getaucht. Nach dem Verdunsten des Lösungsmittels erhält man eine festhaftende Mn2(CO)10-haltige lichtempfindliche Polylactidbeschichtung mit ca. 1 Gew.% Mn2(CO)10.The solution prepared as in Example 1 is used directly for coatings. In the dark or under red light, a glass specimen (disc 3 × 8 cm, 1 mm thick) is immersed in the solution. After evaporation of the solvent, a firmly adhering Mn 2 (CO) 10 -containing photosensitive Polylactidbeschichtung with about 1 wt.% Mn 2 (CO) 10 .

Beispiel 3 (CORMA-1):Example 3 (CORMA-1):

Mn2(CO)10 haltiges Poly(L-lactid-co-D/L-lactid)-Vlies (1 Gew.-%)Mn 2 (CO) 10- containing poly (L-lactide-co-D / L-lactide) nonwoven (1 wt%)

Die in Beispiel 1 hergestellte Lösung wird in einer Electrospinning-Anlage bestehend aus einer Spritzenpumpe und einem regelbaren Hochspannungsgenerator überführt. Bei einer Flussrate von 1,5 ml/h, 22 kV und einem Elektrodenabstand von 22 cm wird die Polymerlösung unter Ausschluss starker Lichteinwirkung versponnen. Auf dem Kollektor wird das Material als feines elektrogesponnenes lichtempfindliches Polylactid-Vlies abgeschieden, welches ca. 1 Gew.% Mn2(CO)10 enthält.The solution prepared in Example 1 is transferred in an electrospinning system consisting of a syringe pump and a controllable high voltage generator. At a flow rate of 1.5 ml / h, 22 kV and an electrode distance of 22 cm, the polymer solution is spun under the exclusion of strong light. On the collector, the material is deposited as a fine electrospun photosensitive polylactide nonwoven, which contains about 1 wt.% Mn 2 (CO) 10 .

Beispiel 4 (CORMA-1):Example 4 (CORMA-1):

Mn2(CO)10-haltiges Poly(L-lactid-co-D/L-lactid)-Vlies (10 Gew.-%)Mn 2 (CO) 10 -containing poly (L-lactide-co-D / L-lactide) nonwoven (10% by weight)

108 mg Poly(L-lactid-co-D/L-lactid) (M = 1,4 Mio. g/mol, gemessen mit Polystyrol-Standard) werden in 4 ml Chloroform gelöst. Zu der Lösung werden 12 mg Mn2(CO)10 gegeben. Die Reaktionsmischung wird in der Dunkelheit bis zur Auflösung des Metallkomplexes gerührt. Die Lösung wird, wie in Beispiel 3 beschrieben, in einer an sich bekannten Electrospinning-Anlage versponnen (1,5 ml/h, 24 kV, 21 cm). Es ergibt sich ein hellgelbes elektrogesponnenes lichtempfindliches Polylyctidvlies, welches ca. 10 Gew.% Mn2(CO)10 enthält.108 mg of poly (L-lactide-co-D / L-lactide) (M = 1.4 million g / mol, measured with polystyrene standard) are dissolved in 4 ml of chloroform. 12 mg of Mn 2 (CO) 10 are added to the solution. The reaction mixture is stirred in the dark until the metal complex dissolves. The solution is, as described in Example 3, spun in a known electrospinning plant (1.5 ml / h, 24 kV, 21 cm). The result is a light yellow electrospun photosensitive Polylyctidvlies containing about 10 wt.% Mn 2 (CO) 10 contains.

Beispiel 5 (CORMA-1):Example 5 (CORMA-1):

Mn2(CO)10-haltiges Poly(L-lactid-co-D/L-lactid)-Vlies (20 Gew.-%)Mn 2 (CO) 10 -containing poly (L-lactide-co-D / L-lactide) nonwoven (20% by weight)

96 mg Poly(L-lactid-co-D/L-lactid) (M = 1,4 Mio. g/mol, gemessen mit Polystyrol-Standard) werden in 4 ml Chloroform gelöst. Zu der Lösung werden 24 mg Mn2(CO)10 gegeben. Die Reaktionsmischung wird in der Dunkelheit bis zur Auflösung des Metallkomplexes gerührt. Die Lösung wird, wie in den Beispielen 3 und 4 genannt, wiederum in einer Electrospinning-Anlage versponnen (1,5 ml/h, 20 kV, 20 cm). Es ergibt sich ein gelbes elektrogesponnenes lichtempfindliches Polylactidvlies, welches ca. 20 Gew.% Mn2(CO)10 enthält.96 mg of poly (L-lactide-co-D / L-lactide) (M = 1.4 million g / mol, measured with polystyrene standard) are dissolved in 4 ml of chloroform. 24 mg of Mn 2 (CO) 10 are added to the solution. The reaction mixture is stirred in the dark until the metal complex dissolves. The solution is, as mentioned in Examples 3 and 4, again spun in an electrospinning plant (1.5 ml / h, 20 kV, 20 cm). The result is a yellow electrospun photosensitive Polylactidvlies containing about 20 wt.% Mn 2 (CO) 10 contains.

Beispiel 6: Example 6:

Mn2(CO)10-haltiges Polystyrol-VliesMn 2 (CO) 10 -containing polystyrene nonwoven

1,08 g Polystyrol mit einer Molmasse von 195.000 g/mol werden in 1,6 g eines Gemisches aus drei Volumenteilen Chloroform und einem Volumenteil Dimethylformamid (DMF) gelöst. Zu der Lösung werden in der Dunkelheit 120 mg Mn2(CO)10 gegeben und die Mischung bis zur vollständigen Auflösung des Metallkomplexes gerührt. Die Lösung wird, wie in den Beispielen 3, 4 und 5 genannt, wiederum, in eine Electrospinning-Anlage überführt und versponnen (1,5 ml/h, 20 kV, 21 cm). Es ergibt sich ein hellgelbes elektrogesponnenes, lichtempfindliches Polystyrolvlies, welches ca. 10 Gew.% Mn2(CO)10 enthält.1.08 g of polystyrene having a molecular weight of 195,000 g / mol are dissolved in 1.6 g of a mixture of three volumes of chloroform and one part by volume of dimethylformamide (DMF). 120 mg of Mn 2 (CO) 10 are added to the solution in the dark and the mixture is stirred until complete dissolution of the metal complex. The solution is, as mentioned in Examples 3, 4 and 5, in turn, transferred to an electrospinning plant and spun (1.5 ml / h, 20 kV, 21 cm). The result is a light yellow electrospun, photosensitive Polystyrolvlies containing about 10 wt.% Mn 2 (CO) 10 contains.

Beispiel 7:Example 7:

Mn2(CO)10-haltiges Polystyrol-VliesMn 2 (CO) 10 -containing polystyrene nonwoven

1,08 g Polystyrol mit einer Molmasse von 195,000 g/mol werden in 2,5 ml Hexafluoroisoproanol gelöst. Zu der Lösung werden in der Dunkelheit 120 mg Mn2(CO)10 gegeben und die Mischung bis zur vollständigen Auflösung des Metallkomplexes gerührt. Die Lösung wird, wie in den Beispielen 3–6 genannt, in eine Electrospinning-Anlage überführt und versponnen (1,2 ml/h, 20 kV, 21 cm). Es ergibt sich ein hellgelbes elektrogesponnenes lichtempfindliches Polystyrolvlies, welches ca. 10 Gew.% Mn2(CO)10 enthält.1.08 g of polystyrene having a molecular weight of 195,000 g / mol are dissolved in 2.5 ml of hexafluoroisoproanol. 120 mg of Mn 2 (CO) 10 are added to the solution in the dark and the mixture is stirred until complete dissolution of the metal complex. The solution is transferred to an electrospinning plant as described in Examples 3-6 and spun (1.2 ml / h, 20 kV, 21 cm). The result is a light yellow electrospun light-sensitive polystyrene non-woven, which contains about 10 wt.% Mn 2 (CO) 10 .

Beispiel 8:Example 8:

Mn2(CO)10-haltige Polystyrol-FolieMn 2 (CO) 10 -containing polystyrene film

Aus einer entsprechend Beispiel 7 hergestellten Lösung wird, wie unter Beispiel 1 beschrieben, eine hellgelbe lichtempfindliche Polystyrolfolie hergestellt, die ca. 10 Gew.% Mn2(CO)10 enthält.From a solution prepared according to Example 7, as described in Example 1, a light yellow photosensitive polystyrene film is prepared which contains about 10 wt.% Mn 2 (CO) 10 .

Beispiel 9:Example 9:

Mn2(CO)10-haltige Polystyrol-BeschichtungMn 2 (CO) 10 -containing polystyrene coating

Aus einer entsprechend Beispiel 7 hergestellten Lösung wird, wie unter Beispiel 2 beschrieben, eine hellgelbe lichtempfindliche Polystyrolfolie hergestellt, die ca. 10 Gew.% Mn2(CO)10 enthält.From a solution prepared according to Example 7, as described in Example 2, a pale yellow photosensitive polystyrene film is prepared which contains about 10 wt.% Mn 2 (CO) 10 .

Beispiel 10:Example 10:

Mn2(CO)10-haltiges Polymethylmethacrylat-VliesMn 2 (CO) 10 -containing polymethylmethacrylate nonwoven

0,76 g Polymethylmethacrylat (PMMA) mit einer Molmasse von 100.000 g/mol werden in 5,8 ml Hexafluoroisopropanol gelöst. Zu der Lösung werden in der Dunkelheit 40 mg Mn2(CO)10 gegeben und die Mischung bis zur vollständigen Auflösung des Metallkomplexes gerührt. Die Lösung wird, wie in den Beispielen 3–7 genannt, in eine Electrospinning-Anlage überführt und versponnen (1,0 ml/h, 20 kV, 20 cm). Es ergibt sich ein gelbliches elektrogesponnenes lichtempfindliches PMMA-Vlies, welches ca. 5 Gew.% Mn2(CO)10 enthält.0.76 g of polymethyl methacrylate (PMMA) having a molecular weight of 100,000 g / mol are dissolved in 5.8 ml of hexafluoroisopropanol. 40 mg of Mn 2 (CO) 10 are added to the solution in the dark and the mixture is stirred until complete dissolution of the metal complex. The solution is transferred to an electrospinning plant as described in Examples 3-7 and spun (1.0 ml / h, 20 kV, 20 cm). The result is a yellowish electrospun photosensitive PMMA non-woven, which contains about 5 wt.% Mn 2 (CO) 10 .

Beispiel 11:Example 11:

Fe(CO)5-haltige Poly(L-lactid-co-D/L-lactid)-FolieFe (CO) 5 -containing poly (L-lactide-co-D / L-lactide) film

114 mg Poly(L-lactid-co-D/L-lactid) (M = 1,4 Mio. g/mol, gemessen mit Polystyrol-Standard) werden in 2,4 ml Chloroform gelöst. Zu der Lösung werden 6 mg Fe(CO)5 gegeben. Die Reaktionsmischung wird in der Dunkelheit bis zur Auflösung des Metallkomplexes gerührt. Anschließend wird die Lösung in der Dunkelheit in eine Teflonschale gegossen. Nach Verdunstung des Lösungsmittels erhält man eine Polylactidfolie mit ca. 5 Gew.% Fe(CO)5.114 mg of poly (L-lactide-co-D / L-lactide) (M = 1.4 million g / mol, measured with polystyrene standard) are dissolved in 2.4 ml of chloroform. 6 mg of Fe (CO) 5 are added to the solution. The reaction mixture is stirred in the dark until the metal complex dissolves. Then the solution is poured in the dark in a Teflon dish. After evaporation of the solvent gives a Polylactidfolie with about 5 wt.% Fe (CO). 5

Beispiel 12: Example 12:

Fe(CO)5-haltige Poly(L-lactid-co-D/L-lactid)-BeschichtungFe (CO) 5 -containing poly (L-lactide-co-D / L-lactide) coating

Aus einer dem Beispiel 11 entsprechend hergestellten Lösung wird, wie unter Beispiel 1 beschrieben, eine Polylactidbeschichtung erhalten, die ca. 5 Gew.% Fe(CO)5 enthält.From a solution prepared according to Example 11, as described in Example 1, a Polylactidbeschichtung obtained containing about 5 wt.% Fe (CO) 5 .

Beispiel 13:Example 13:

Fe(CO)5-haltiges Poly(L-lactid-co-D/L-lactid)-VliesFe (CO) 5 -containing poly (L-lactide-co-D / L-lactide) nonwoven

Eine aus dem Beispiel 11 analog hergestellte Lösung wird, wie in den Beispielen 3–7 und 10 genannt, in eine Electrospinning-Anlage überführt und versponnen (2 ml/h, 22 kV, 12 cm). Es ergibt sich ein elektrogesponnnenes Polylactid-Vlies, welches ca. 5 Gew.% Fe(CO)5 enthält.A solution prepared analogously from Example 11 is, as mentioned in Examples 3-7 and 10, transferred to an electrospinning plant and spun (2 ml / h, 22 kV, 12 cm). The result is a elektrogesponnnenes polylactide nonwoven, which contains about 5 wt.% Fe (CO) 5 .

Im Folgenden wird die CO-Freisetzung mittels UV-A-Licht der Wellenlänge λ = 366 nm aus einem Mn2(CO)10-haltigen Poly(L-lactid-co-D/L-lactid)-Vlies (10 Gew.-%) beschrieben. Dazu wird der sogenannte Myoglobin-Assay verwendet, der zur Zeit der wichtigste Assay für die CO-Detektion in Wasser ist ( 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, Circulation Research, 2002, 90, e17–24 ). Bei einer Bestrahlung von 40 min mit einer Leistung von 3 mW/cm2 können mikromolare Konzentrationen von CO in Wasser generiert werden. Bei höheren Leistungen können solche Konzentrationen innerhalb weniger Minuten erzeugt werden. Mikromolare Konzentrationen von CO sind für die physiologische Aktivität notwendig. zeigt den Myoglobin-Assay zum Nachweis von freigesetztem CO. Ein Mn2(CO)10-haltiges Poly(L-lactid-co-D/L-lactid)-Vlies (10 Gew.-%) wird 60 min lang mit Licht der Wellelänge λ = 366 nm (3 mW/cm2) bestrahlt. Alle 10 min wird ein UV/Vis Spektrum aufgezeichnet, und der Abbau der Bande bei 560 nm und der Aufbau der Banden bei 548 und 580 nm korreliert eindeutig mit gebundenem CO an Myoglobin.In the following, the release of CO by means of UV-A light of wavelength λ = 366 nm from a Mn 2 (CO) 10 -containing poly (L-lactide-co-D / L-lactide) fleece (10 wt. %). For this purpose, the so-called myoglobin assay is used, which is currently the most important assay for CO detection in water ( R. Motterlini, JE Clark, R. Foresti, P. Sarathchandra, BE Mann, CJ Green: Carbon Monoxide Releasing Molecules: Characterization of Biochemical and Vascular Activities, Circulation Research, 2002, 90, e17-24 ). With an irradiation of 40 min with a power of 3 mW / cm 2 , micromolar concentrations of CO in water can be generated. At higher powers, such concentrations can be generated within a few minutes. Micromolar concentrations of CO are necessary for physiological activity. shows the myoglobin assay for detection of released CO. A Mn 2 (CO) 10 -containing poly (L-lactide-co-D / L-lactide) nonwoven fabric (10% by weight) is irradiated for 60 minutes with wavelength λ = 366 nm (3 mW / cm 2 ) irradiated. A UV / Vis spectrum is recorded every 10 min, and band degradation at 560 nm and band construction at 548 and 580 nm clearly correlate with bound CO on myoglobin.

Die Verwendung der CORMs für die erfindungsgemäßen Materialien beschränkt sich nicht auf die eingangs aufgeführten bekannten CORM-Systeme (vgl. auch 1). Nachfolgend soll die Synthese eines noch nicht der Fachwelt bekannten CORMs [(bpb)Ru(CO)(H2O)] der Formel V beschrieben werden, welcher der im Anspruch 6 angegebenen allgemeinen Formel IV unterliegt:

Figure 00190001
The use of the CORMs for the materials according to the invention is not limited to the known CORM systems mentioned at the outset (cf. 1 ). The synthesis of a CORM [(bpb) Ru (CO) (H2O)] of the formula V which is not yet known to the experts and is subject to the general formula IV given in claim 6 is described below:
Figure 00190001

[Ru3(CO)12] (0,088 g, 0,1376 mmol) und 1,2-Bis(pyridin-2-carboxamido)benzen (0,1305 g, 0,4099 mmol) werden in einem 50 ml Dreihalskolben in 6 ml trockenem Dimethylformamid (DMF) vorgelegt. Die hellrote Lösung wird in einer Stickstoff-Atmosphäre 19 Stunden unter Rückfluss erhitzt. Das Lösungsmittel wird im Vakuum abgezogen und der Rückstand mit Acetonitril umkristallisiert.
Ausbeute: 0,1095 g, 0,2363 mmol, 57,65%.
zeigt grafisch die Kristallstruktur von [(bpb)Ru(CO)(H2O)]. Kreuzungen und Endpunkte stellen die Elektronendichte von Atomen dar. Die Bezeichnungen lauten: C für Kohlenstoff, N für Stickstoff, O für Sauerstoff und Ru für Ruthenium.
[Ru 3 (CO) 12 ] (0.088 g, 0.1376 mmol) and 1,2-bis (pyridine-2-carboxamido) benzene (0.1305 g, 0.4099 mmol) are dissolved in a 50 ml three-necked flask in 6 ml of dry dimethylformamide (DMF) submitted. The bright red solution is refluxed in a nitrogen atmosphere for 19 hours. The solvent is removed in vacuo and the residue recrystallized with acetonitrile.
Yield: 0.1095 g, 0.2363 mmol, 57.65%.
shows graphically the crystal structure of [(bpb) Ru (CO) (H 2 O)]. Crossings and endpoints represent the electron density of atoms. The designations are: C for carbon, N for nitrogen, O for oxygen and Ru for ruthenium.

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.

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Claims (10)

Kohlenstoffmonoxid freisetzende Materialien auf Grundlage von CO-abgebenden Substanzen (CORMs), wobei die CORMs aus an atomares oder ionisches Metall, wie Fe, Co, Ru, Rh, Re, Ni, Mo, Mn, Os und V, gebundenem Kohlenstoffmonoxid, einem oder mehreren Metallatomen und ggf. weiteren zusätzlichen organischen mono- und multidendaten Liganden, wie Amine, Imine, Carboxamide oder Phosphine, bestehen, dadurch gekennzeichnet, dass die zumindest eine CO-abgebende Substanz jeweils in ein Polymer oder ein Polymerblend eingebettet ist.Carbon monoxide-releasing materials based on CO-releasing substances (CORMs), wherein the CORMs of atomic or ionic metal, such as Fe, Co, Ru, Rh, Re, Ni, Mo, Mn, Os and V, bound carbon monoxide, one or a plurality of metal atoms and optionally further additional organic mono- and multidaten ligands, such as amines, imines, carboxamides or phosphines, consist, characterized in that the at least one CO-emitting substance is embedded in each case in a polymer or a polymer blend. Kohlenstoffmonoxid freisetzende Materialien gemäß Anspruch 1, dadurch gekennzeichnet, dass die zumindest eine CO-abgebende Substanz im Polymer homogen gelöst oder partikulär eingebettet ist.Carbon monoxide-releasing materials according to claim 1, characterized in that the at least one CO-releasing substance is homogeneously dissolved or particulate embedded in the polymer. Kohlenstoffmonoxid freisetzende Materialien gemäß Ansprüchen 1 und 2, dadurch gekennzeichnet, dass sich die zumindest eine CO-freisetzende Substanz an der Oberfläche der Polymermaterialien befindet.Carbon monoxide-releasing materials according to claims 1 and 2, characterized in that the at least one CO-releasing substance is located on the surface of the polymer materials. Kohlenstoffmonoxid freisetzende Materialien gemäß einem oder mehreren der Ansprüche 1 bis 3, dadurch gekennzeichnet, dass als CO-abgebende Substanz Dimangandecacarbonyl der Formel I
Figure 00200001
in das Polymer oder Polymerblend eingebettet ist.
Carbon monoxide-releasing materials according to one or more of claims 1 to 3, characterized in that the CO-releasing substance Dimangandecacarbonyl of the formula I.
Figure 00200001
embedded in the polymer or polymer blend.
Kohlenstoffmonoxid freisetzende Materialien gemäß einem oder mehreren der Ansprüche 1 bis 3, dadurch gekennzeichnet, dass als CO-abgebende Substanz Fe(CO)5 der Formel II
Figure 00210001
in das Polymer oder Polymerblend eingebettet ist.
Carbon monoxide-releasing materials according to one or more of claims 1 to 3, characterized in that the CO-releasing substance Fe (CO) 5 of the formula II
Figure 00210001
embedded in the polymer or polymer blend.
Kohlenstoffmonoxid freisetzende Materialien gemäß einem oder mehreren der Ansprüche 1 bis 3, dadurch gekennzeichnet, dass als CO-abgebende Substanzen Komplexe der allgemeinen Formeln III oder IV
Figure 00210002
Figure 00220001
in das Polymer oder Polymerblend eingebettet sind.
Carbon monoxide-releasing materials according to one or more of claims 1 to 3, characterized in that as CO-releasing substances complexes of the general formulas III or IV
Figure 00210002
Figure 00220001
embedded in the polymer or polymer blend.
Kohlenstoffmonoxid freisetzende Materialien gemäß einem oder mehreren der Ansprüche 1 bis 6, dadurch gekennzeichnet, dass als Polymer ein organisches Polymer, vorzugsweise aus der Klasse der Polyether, Poly(etherimide) (PEI), Poly(ether-ketone), Polyether-ether-ketone), Poly(ethyleneoxide) (PEO), Poly(vinylalcohole) (PVA), Poly(vinylacetat) (PVAc), Polystyrole (PS), Polyethylen, Polypropylene, Poly(vinylhalogenide), Poly(tetrafluoroethylen), Poly(vinylidenefluoride), Poly(butadiene), Polyacrylnitrile (PAN), Polyester (PE), Poly(hydroxycarbonsäuren (PHC), Polyurethane (PU), Polyamide (PA), Polycarbonate (PC), Polyanhydride, Polysulfone (PS), Poly(ethersulfone), Polymethacrylate, Polyacrylate, Polyvinylbutyrale, Poly(aminosäuren), Poly(organosiloxane), davon abgeleitete Copolymere, Blends dieser Polymere sowie Biopolymere, vorzugsweise Polysaccharide und Polysaccharidderivate, wie Chitosan, Dextran, Celluloseacetat (CA), Proteine, wie Kollagene sowie Mischungen dieser Polymere, Anwendung finden.Carbon monoxide-releasing materials according to one or more of claims 1 to 6, characterized in that the polymer is an organic polymer, preferably from the class of polyethers, poly (etherimides) (PEI), poly (ether ketones), polyether ether ketones ), Poly (ethylene oxides) (PEO), poly (vinyl alcohol) (PVA), poly (vinyl acetate) (PVAc), polystyrenes (PS), polyethylene, polypropylenes, poly (vinyl halides), Poly (tetrafluoroethylene), poly (vinylidene fluoride), poly (butadiene), polyacrylonitrile (PAN), polyester (PE), poly (hydroxycarboxylic acid (PHC), polyurethanes (PU), polyamides (PA), polycarbonates (PC), polyanhydrides, polysulfones (PS), poly (ether sulfones), polymethacrylates, polyacrylates, polyvinyl butyrals, poly (amino acids), poly (organosiloxanes), copolymers derived therefrom, blends of these polymers and biopolymers, preferably polysaccharides and polysaccharide derivatives, such as chitosan, dextran, cellulose acetate (CA), Proteins, such as collagens and mixtures of these polymers, find application. Kohlenstoffmonoxid freisetzende Materialien gemäß einem oder mehreren der Ansprüche 1 bis 7, dadurch gekennzeichnet, dass das Polymer mit der eingebetteten CO-abgebender Substanz als Folie oder folienartige Beschichtung vorliegt.Carbon monoxide-releasing materials according to one or more of claims 1 to 7, characterized in that the polymer with the embedded CO-donating substance is present as a film or film-like coating. Kohlenstoffmonoxid freisetzende Materialien gemäß einem oder mehreren der Ansprüche 1 bis 7, dadurch gekennzeichnet, dass das Polymer mit der eingebetteten CO-abgebender Substanz als Faser oder Faservlies vorliegt, insbesondere unter Verwendung des Electrospinning zur Faserherstellung.Carbon monoxide-releasing materials according to one or more of claims 1 to 7, characterized in that the polymer with the embedded CO-donating substance is present as a fiber or non-woven fabric, in particular using the electrospinning for fiber production. Verwendung der Kohlenstoffmonoxid freisetzenden Materialien gemäß einem oder mehreren der Ansprüche 1 bis 9 als CO-Donator, der unter Lichteinwirkung Kohlenstoffmonoxid emittiert, insbesondere als CO-Quelle in der Biologie, Medizin, Kosmetik und Pharmazie.Use of the carbon monoxide-releasing materials according to one or more of claims 1 to 9 as a CO donor, which emits carbon monoxide under the action of light, in particular as CO source in biology, medicine, cosmetics and pharmacy.
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