DE102014008537A1 - Water-soluble manganese-based carbon monoxide releasing molecules, their use and processes for their preparation - Google Patents

Water-soluble manganese-based carbon monoxide releasing molecules, their use and processes for their preparation Download PDF

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DE102014008537A1
DE102014008537A1 DE102014008537.6A DE102014008537A DE102014008537A1 DE 102014008537 A1 DE102014008537 A1 DE 102014008537A1 DE 102014008537 A DE102014008537 A DE 102014008537A DE 102014008537 A1 DE102014008537 A1 DE 102014008537A1
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carbon monoxide
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Matthias Westerhausen
Ralf Mede
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Friedrich Schiller Universtaet Jena FSU
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Abstract

Kohlenstoffmonoxid freisetzende manganhaltige Moleküle, deren Verwendung und Verfahren zu deren Herstellung Aufgabe war es, bioverträgliche und wasserlösliche Moleküle zu schaffen, die mit möglichst geringem Aufwand herstellbar sind, keine Bedenklichkeit hinsichtlich körperfremden Bestandteilen erwecken. Erfindungsgemäß werden Moleküle gemäß der allgemeinen Formel I vorgeschlagen:Die Moleküle können weitgehend ohne Risiken als pharmakologische Wirkstoffe eingesetzt werden.Carbon monoxide-releasing manganese-containing molecules, their use and methods for their production task was to create biocompatible and water-soluble molecules that can be produced with the least possible effort, no concern about alien components. According to the invention, molecules according to the general formula I are proposed: The molecules can be used largely without risks as pharmacological active ingredients.

Description

Die Erfindung betrifft spezielle Kohlenstoffmonoxid freisetzende Komplexverbindungen und deren Verwendung als pharmakologische Wirkstoffe. Kohlenstoffmonoxid stellt sich aufgrund der nachstehenden physiologischen Eigenschaften als breit anwendbares Therapeutikum dar:
So ist Kohlenstoffmonoxid (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 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 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 ). Darüber hinaus unterdrückt Kohlenstoffmonoxid 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 Heme 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, 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 ).The invention relates to specific carbon monoxide-releasing complex compounds and their use as pharmacological agents. 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 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 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 ). 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 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. Soares, 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 caused by derepression of fibrinolysis, Nature Medicine 2001, 7, 598-604 ).

Die geringe Löslichkeit von ca. 1 mmol/L (20°C) und die mangelnde Selektivität von freiem Kohlenstoffmonoxid machen einen gezielten therapeutischen Einsatz jedoch nahezu unmöglich. 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 freisetzen, ist der entscheidende Schritt bei der Nutzung von Kohlenstoffmonoxid als Therapeutikum ( M. A. Gonzales, P. K. Mascharak: Photoactive metal carbonyl complexes as potential agents for targeted CO delivery, Journal of Inorganic Biochemistry 2014, 133, 127–135 ). 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, Circulation Research 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 targeted to the site of the desired effect and release there, is the decisive step in the use of carbon monoxide as a therapeutic agent ( MA Gonzales, PK Mascharak: Photoactive metal carbonyl complexes as potential agents for targeted CO delivery, Journal of Inorganic Biochemistry 2014, 133, 127-135 ). 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, Circulation Research 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 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, Circulation Research 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, Circulation Research 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, Circulation Research 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, Circulation Research 2003, 93, e2-e8 ).

2005 wurde das seit 1967 bekannte Boranocarbonat ( L. J. Malone, R. W. Parry, Inorganic Chemistry 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, Circulation Research 2003, 93, e2–e8 ).In 2005, the borane carbonate known since 1967 ( LJ Malone, RW Parry, Inorganic Chemistry 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, Circulation Research 2003, 93, e2-e8 ).

CORM-2 und CORM-3 weisen mit Ruthenium ein körperfremdes Zentralatom 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 ).CORM-2 and CORM-3 have ruthenium as a foreign central atom. 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 ).

Mangan stellt hingegen ein essentielles Spurenelement dar. ( W. Mertz: The Essential Trace Elements, Science 1981, 213, 1332 ). Manganese, on the other hand, is an essential trace element. ( W. Mertz: The Essential Trace Elements, Science 1981, 213, 1332 ).

In den vergangenen Jahren lieferte vor allem die Arbeitsgruppe um SCHATZSCHNEIDER vielversprechende Ergebnisse auf dem Gebiet der manganhaltigen CORMs. Die Derivate der kationischen Mangan(I)-Verbindung [Mn(CO)3(R-tpm)]+ setzen mittels Lichtinduktion zwei Moleküle CO pro Molekül Komplex frei. Von Vorteil ist dabei das breite Absorptionsmaxium bei 360 nm. Weiterhin besteht hier die Möglichkeit der Anbindung eines Tragerpeptides mittels einer Sonogashira-Kreuzkupplung oder einer Azid-Alkin-Cycloaddition („Click”-Chemie) über die Dreifachbindung (H. Pfeiffer, A. Rojas, J. Niesel, U. Schatzschneider: Sonogashira and ”Click” reactions in the N-terminal and side chain functionalization of peptides with [Mn(CO)3(tpm)]+-based CO releasing molecules (tpm = tris(pyrazolyl)methane), Dalton Transactions 2009, 4292–4298).In recent years, the SCHATZSCHNEIDER working group has provided promising results in the field of manganese-containing CORMs. The derivatives of the cationic manganese (I) compound [Mn (CO) 3 (R-tpm)] + release two molecules of CO per molecule complex by means of light induction. The advantage here is the broad absorption maximum at 360 nm. Furthermore, there is the possibility here of attaching a carrier peptide by means of a Sonogashira cross-coupling or an azide-alkyne cycloaddition ("click" chemistry) via the triple bond (H. Pfeiffer, A. Rojas , J. Niesel, U. Schatzschneider: Sonogashira and "click" reactions in the N-terminal and side chain functionalization of peptides with [Mn (CO) 3 (tpm)] + -based CO releasing molecules (tpm = tris (pyrazolyl) methane), Dalton Transactions 2009, 4292-4298).

Außerdem konnte der Zugang zu weiteren interessanten Tricarbonylmangankomplexen realisiert werden. Hier sind die monokationen PhotoCORMs [Mn(CO)3(2-tip)]+ und [Mn(CO)3(4-tip)iPr]+ zu nennen ( P. C. Kunz, W. Huber, A. Rojas, U. Schatzschneider, B. Spingler: Manganese and rhenium tricarbonyl complexes of imidazol-based phosphane ligands: influence of the substitution pattern on the CO release properties, European Journal of Inorganic Chemistry 2009, 5358–5366 ) und polynuklearen, luft- und wasserstabilen Metallodendrimere [DAB-PPI-{MnBr-(bpyCH3, CH=N)(CO)3}n], ( P. Govender, S. Pai, U. Schatzschneider, G. S. Smith: Next generation PhotoCORMs: Polynuclear tricarbonylmanganese(I)-functionalised polypyridyl metallodendrimers, Inorganic Chemistry 2013, 52, 5470–5478 ).In addition, access to other interesting tricarbonyl manganese complexes could be realized. Here are the monocations PhotoCORMs [Mn (CO) 3 (2-tip)] + and [Mn (CO) 3 (4-tip) iPr] + ( PC Kunz, W. Huber, A. Rojas, U. Schatzschneider, B. Spingler: Manganese and rhenium tricarbonyl complexes of imidazole-based phosphane ligands: influence of the substitution pattern on the CO release properties, European Journal of Inorganic Chemistry 2009, 5358 -5,366 ) and polynuclear, air- and water-stable metallodendrimers [DAB-PPI- {MnBr- ( bpyCH3, CH = N ) (CO) 3 } n ], P. Govender, S. Pai, U. Schatzschneider, GS Smith: Next generation PhotoCORMs: Polynuclear tricarbonyl manganese (I) -functionalized polypyridyl metallodendrimers, Inorganic Chemistry 2013, 52, 5470-5478 ).

Weiterhin ist es gelungen Nanopartikel aus Siliciumdioxid als Trägermaterial für Mangantricarbonylkomplexe zu nutzen ( G. Dördelmann, H. Pfeiffer, A. Birkner, U. Schatzschneider: Silicium Dioxide Nanoparticles As Carriers for Photoactivatable CO-Releasing Molecules (PhotoCORMs), Inorganic Chemistry 2011, 50, 4362–4367 ).Furthermore, it has been possible to use nanoparticles of silicon dioxide as carrier material for manganese tricarbonyl complexes ( G. Dördelmann, H. Pfeiffer, A. Birkner, U. Schatzschneider: Silicon Dioxide Nanoparticles As Carriers for Photoactivatable CO-Releasing Molecules (PhotoCORMs), Inorganic Chemistry 2011, 50, 4362-4367 ).

Auch die Arbeitsgruppe um MASCHARAK beschäftigte sich in den letzten Jahren mit der Synthese von Tricarbonylmanganverbindungen ( M. A. Gonzalez, M. A. Yim, S. Cheng, A. Moyes, A. J. Hobbs, P. K. Mascharak: Manganese Carbonyls Bearing Tripodal Polypyridine Ligands as Photoactive Carbon Monoxide-Releasing Molecules, Inorganic Chemistry 2011, 51, 601–608 ; M. A. Gonzalez, S. J. Carrington, N. L. Fry, J. L. Martinez, P. K. Mascharak: Syntheses, Structures, and Properties of New Manganese Carbonyls as Photoactive CO-Releasing Molecules: Design Strategies That Lead to CO Photolability in the Visible Region, Inorganic Chemistry 2012, 51, 11930–11940 ; S. J. Carrington, I. Chakraborty, P. K. Mascharak: Rapid CO release from a Mn(I) carbonyl complex derived from azopyridine upon exposure to visible light and its phototoxicity toward malignant cells, Chemical Communications 2013, 49, 11254–11256 ).The working group of MASCHARAK has also been involved in the synthesis of tricarbonyl manganese compounds ( MA Gonzalez, MA Yim, S. Cheng, A. Moyes, AJ Hobbs, PK Machash: Manganese Carbonyls Bearing Tripodal Polypyridine Ligands as Photoactive Carbon Monoxide Releasing Molecules, Inorganic Chemistry 2011, 51, 601-608 ; MA Gonzalez, SJ Carrington, NL Fry, JL Martinez, PK Mascharak: Syntheses, Structures, and Properties of New Manganese Carbonyls as Photoactive CO-Releasing Molecules: Design Strategies That Lead to CO Photolability in the Visible Region, Inorganic Chemistry 2012, 51, 11930-11940 ; SJ Carrington, I. Chakraborty, PK Mascharak: Rapid CO release from a Mn (I) carbonyl complex derived from azopyridine upon exposure to visible and its phototoxicity toward malignant cells, Chemical Communications 2013, 49, 11254-11256 ).

Eine interessante Verbindungsklasse, welche körperbekannte Liganden und lichtinduzierte Kohlenstoffmonoxidfreisetzung beinhaltet, stellen Schwefelkomplexe, die sich von Cystein ableiten, dar. Cremer berichtete 1929, dass die Kohlenstoffmonoxidabsorption von Eisen- und Cobaltcysteinatkomplexen zu den Verbindungen Dicarbonylbis(cysteinato)eisen(II) sowie Carbonylbis(cysteinato)cobalt(I) führt ( Cremer, Biochemische Zeitschrift 1929, 206, 228 ). Außerdem beobachtete er für Eisen ein reversibles Desorptions- bzw. Absorptionsverhalten. Bei Bestrahlung mit sichtbarem Licht gab der Komplex Kohlenstoffmonoxid 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 Kohlenstoffmonoxidfreisetzung bei 90°C fest, welche durch Kühlung mit Eis wieder rückgängig gemacht werden konnte ( A. Tomita, H. Hirai, S. Makishima: Optical Rotatory Dispersion Study on the Iron Complex with L-Cystein and Its Reaction with Carbon Monoxide and Nitric Oxide, Inorganic Chemistry 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.An interesting class of compounds, incorporating known ligands and light-induced carbon monoxide release, are 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, Biochemische Zeitschrift 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 made by Tomita et al. 1967 confirmed and extended by 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, Inorganic Chemistry 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.

Die Arbeitsgruppe um Lee hat Mangan(II)-Komplexe der Form [MnII(-SC5H4NO-)3]– hergestellt (W.-F. Liaw, C.-H. Hsieh, S.-M. Peng, G.-H. Lee: S-S Bond-activation of diorganyl disulfide by anionic [Mn(CO)5]–: crystal structures of [MnII(-SC5H4NO-)3]– and [(CO)3Mn(μ-SR)3Co(μ-SR)3Mn(CO)3]– (R=C6H4NHCOPh), Inorganica Chimica Acta 2002, 332, 153–159). Angaben zu CO-Freisetzungseigenschaften und zu Bioverträglichkeiten der offenbarten Mangan(II)-Komplexe gehen aus dieser Literaturstelle nicht hervor.Lee's group has prepared manganese (II) complexes of the form [Mn II (-SC 5 H 4 NO) 3 ] - (W.-F. Liaw, C.-H. Hsieh, S.-M. Peng , G.-H. Lee: SS Bond-activation of diorganyl disulfide by anionic [Mn (CO) 5 ] - : crystal structures of [Mn II (-SC 5 H 4 NO) 3 ] - and [(CO) 3 Mn (μ-SR) 3 Co (μ-SR) 3 Mn (CO) 3 ] - (R = C 6 H 4 NHCOPh), Inorganica Chimica Acta 2002, 332, 153-159). Information on CO release properties and biocompatibilities of the disclosed manganese (II) complexes are not apparent from this reference.

Den Zugang zu einem manganhaltigen wasserlöslichen Schwefelkomplex der Formel [Mn(CO)4{S2CNMe(CH2CO2H)}] konnte der Arbeitskreis um Motterlini realisieren (S. H. Crook, B. E. Mann, A. J. H. M. Meijer, H. Adams, P. Sawle, D. Scapens, R. Motterlini: [Mn(CO)4{S2CNMe(CH2CO2H)}], a new water-soluble CO-releasing molecule, Dalton Transactions 2011, 40, 4230–4235). Dieser Komplex enthält einen Chelatliganden, welcher Metalle bindet und deshalb insbesondere als pharmakologische Wirkstoffe nicht geeignet sind. Weiterhin handelt es sich um einen Tetracarbonylkomplex, welcher im wässrigen Medium Stabilitätsprobleme aufweisen könnte, da sich ein Carbonyl leicht gegen ein Wassermolekül austauschen kann. Access to a manganese-containing water-soluble sulfur complex of the formula [Mn (CO) 4 {S 2 CNMe (CH 2 CO 2 H)}] was realized by the working group around Motterlini (SH Crook, BE Mann, AJHM Meijer, H. Adams, P. Sawle, D. Scapens, R. Motterlini: [Mn (CO) 4 {S 2 CNMe (CH 2 CO 2 H)}], a new water-soluble CO-releasing molecule, Dalton Transactions 2011, 40, 4230-4235) , This complex contains a chelating ligand which binds metals and are therefore not suitable in particular as pharmacological active ingredients. Furthermore, it is a tetracarbonyl complex, which could have stability problems in the aqueous medium, since a carbonyl can easily exchange with a water molecule.

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 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 Kohlenstoffmonoxid 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 may 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 2008/003953 A2 , WO 09/066067 A1 , 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 Kohlenstoffmonoxid freisetzen. Hinweise, wie man zu wasserlöslichen, lichtinduzierten CORMs gelangt oder kommen könnte, finden sich nicht. WO 2008/003953 A2 . WO 09/066067 A1 . 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. There are no hints on how to get to water-soluble, light-induced CORMs.

Zusammenfassend lässt sich feststellen, dass die bisher hergestellten CORMs, wie bereits genannt, zum Teil Bedenken für ihren Einsatz als Therapeutikum aufweisen. Dies bezieht sich beispielsweise auf die nicht vorhandene Wasserlöslichkeit, auf körperfremde Bestandteile der dargestellten Komplexverbindungen oder auf chelatisierende Ligandensysteme.In summary, it can be stated that the previously produced CORMs, as already mentioned, in part have reservations about their use as therapeutic agents. This relates, for example, to the absence of water solubility, to foreign components of the complexes shown or to chelating ligand systems.

Der Erfindung liegt die Aufgabe zu Grunde, Kohlenstoffmonoxid freisetzende, bioverträgliche und wasserlösliche manganhaltige 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-releasing, biocompatible and water-soluble manganese-containing 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 Kohlenstoffmonoxid freisetzende Manganverbindungen mit der erfindungsgemäßen allgemeinen Formel I vorgeschlagen:

Figure DE102014008537A1_0002
mit:
R = jegliche Alkyl- beziehungsweise Aryl-Gruppen
X = Halogenid, PseudohalogenidCarbon monoxide-releasing manganese compounds having the general formula I according to the invention are proposed:
Figure DE102014008537A1_0002
With:
R = any alkyl or aryl groups
X = halide, pseudohalide

Derartige Komplexe mit einem Mn2S3-Grundkörper sind bisher lediglich als Komplexanionen als Ammoniumsalze bekannt (P. M. Treichel, M. H. Tegen: Synthesis and reactivity of bridging thiolato-manganese carbonyl complexes, Et4N[Mn2(μ-SR)3(CO)6], Journal of Organmetallic Chemistry 1985, 292, 385–394; P. M. Treichel, P. C. Nakagaki: New synthetic strategies for organometallic complexes with thiolate ligands, Organometallics 1986, 5, 711–716 .).Such complexes with an Mn 2 S 3 base are hitherto known only as complex anions as ammonium salts (PM Treichel, MH Tegen: Synthesis and reactivity of bridging thiolato-manganese carbonyl complexes, Et 4 N [Mn 2 (μ-SR) 3 (CO ) 6 ], Journal of Organ Metallic Chemistry 1985, 292, 385-394; PM Treichel, PC Nakagaki: New synthetic strategies for organometallic complexes with thiolate ligands, Organometallics 1986, 5, 711-716 .).

Mit den vorgenannten Verbindungen werden wasserlösliche Mangan(I)-komplexe geschaffen, welche Kohlenstoffmonoxid lichtinduziert oder durch Oxidation abgeben und die entweder ausschließlich körperbekannte Liganden oder solche 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 aforementioned compounds provide water-soluble manganese (I) complexes which light-induce or release carbon monoxide by oxidation and which either exclusively have body-known ligands or those ligands whose pharmacokinetic profile appears harmless for therapeutic uses, so that the CORMs proposed with the general formula I biocompatible and can be used without the known risks as pharmacological agents.

Sie sind verfahrenstechnisch einfach und aufwandgering sowie in sehr guten Ausbeuten (d. h. mehr als 80%) darstellbar (vgl. nachstehende Methode nach Formel II).

Figure DE102014008537A1_0003
They are procedurally simple and aufwandgering and in very good yields (ie more than 80%) can be displayed (see the following method according to formula II).
Figure DE102014008537A1_0003

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 Pentacarbonylmanganhalogenid bzw. Pentacarbonylmanganpseudohalogenid, der entsprechende Ligand und ein geeignetes Lösungsmittel, beispielsweise Tetrahydrofuran, Toluen, Benzen, 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. Only pentacarbonyl manganese halide or pentacarbonyl manganese pseudohalide, the corresponding ligand and a suitable solvent, for example tetrahydrofuran, toluene, benzene, methanol or ethanol, are required.

Die Erfindung soll nachstehend anhand der in Formel III dargestellten speziellen Struktur der Formel I als Ausführungsbeispiel näher erläutert werden.

Figure DE102014008537A1_0004
The invention will be explained in more detail below with reference to the specific structure of the formula I shown in formula III as an exemplary embodiment.
Figure DE102014008537A1_0004

Die Figur zeigt zeit- und wellenlängenspezifische UV-Vis-Spektren zur Verdeutlichung der lichtinduzierten Freisetzung von Kohlenstoffmonoxid.The figure shows time- and wavelength-specific UV-Vis spectra to illustrate the light-induced release of carbon monoxide.

Alle Arbeiten wurden in einer Stickstoffatmosphäre mit Hilfe der Standard-Schlenk-Technik durchgeführt. Zur Synthese der Verbindung wurden 331 mg (4.29 mmol) Cysteamin im Reaktionskolben in 4 mL Tetrahydrofuran (THF) suspendiert. In einem Schlenkgefäß wurden 786 mg (2.86 mmol) Pentacarbonylmanganbromid in 13 mL THF gelöst und in den Reaktionskolben überführt. Das Schlenkgefäß wurde mit weiteren 6 mL THF gewaschen. Die Reaktion wurde für 2 h bei Raumtemperatur (RT) gerührt, wobei eine Gasentwicklung zu beobachten war. Anschließend wurde die Reaktionsmischung für 3 h unter Rückfluss erhitzt. Dabei bildete sich eine ölige Schicht aus. Nach Abkühlung der Reaktionslösung auf RT im Ölbad kristallisierte die ölige Phase über Nacht aus. Die erhaltenen orangefarbenen Kristalle wurden abfiltriert und im Vakuum getrocknet. Zur Entfernung des cokristallisierten THF wurde der komplette Feststoff in 2 mL Wasser gelöst, wieder eingedampft und im Vakuum getrocknet.

  • Gesamtausbeute 870 mg = 1,30 mmol = 91% d. Th.
  • 1H-NMR (400.075 MHz, D2O): δ = 3.34 (t, 3JH,H = 7.4 Hz, 6H, H1), 2.80 (t, 3JH,H = 7.3 Hz, 6H, H2).
  • 13C{1H}-NMR (100.599 MHz, D2O): δ = 220.04 (s, CCarbonyl), 41.94 (s, C1), 29.83 (s, C2).
  • MS (DEI): m/z (%) = 346 [M+ - CO - 3CH2-CH2-NH3] (12), 318 [M+ - 2CO - 3CH2-CH2-NH3] (2), 290 [M+ - 3CO - 3CH2-CH2-NH3] (3), 262 [M+ - 4CO - 3CH2-CH2-NH3] (10), 234 [M+ - 5CO - 3CH2-CH2-NH3] (15), 217 (11), 206 [M+ - 6CO - 3CH2-CH2-NH3] (2), 174 [M+ - 6CO - S - 3CH2-CH2-NH3] (5), 77 [HS-CH2-CH2-NH2] (51), 71 (100), 59 (22), 44 [CH2-CH2-NH2] (31), 42 (99), 30 [CH2-NH2] (100), 28 [CO] (81).
  • IR-Daten (Feststoff, rein): 2873 (m), 1981 (m), 1874 (s), 1581 (m), 1553 (m), 1503 (s), 1483 (s), 1461 (s), 1426 (m), 1384 (w), 1327 (m), 1260 (m), 1228 (w), 1088 (m), 1046 (w), 887 (w), 817 (m), 673 (m), 626 (w), 523 (w), 455 (m).
  • Elementaranalyse: für (CO)6Mn2(μ-S-CH2-CH2-NH3)3]Br2·2.5 THF berechnet: C 31.11%, H 4.86%, N 4.95% gefunden: C 30.80%, H 4.67%, N 4.73%.
All work was done in a nitrogen atmosphere using the standard Schlenk technique. To synthesize the compound, 331 mg (4.29 mmol) of cysteamine were suspended in the reaction flask in 4 mL of tetrahydrofuran (THF). In a Schlenk vessel, 786 mg (2.86 mmol) of pentacarbonyl manganese bromide were dissolved in 13 ml of THF and transferred to the reaction flask. The Schlenk vessel was washed with another 6 mL THF. The reaction was stirred for 2 h at room temperature (RT), with gas evolution observed. Subsequently, the reaction mixture was refluxed for 3 h. This formed an oily layer. After cooling the reaction solution to RT in an oil bath, the oily phase crystallized overnight. The resulting orange crystals were filtered off and dried in vacuo. To remove the cocrystallized THF, the complete solid was dissolved in 2 mL of water, evaporated again and dried in vacuo.
  • Total yield 870 mg = 1.30 mmol = 91% d. Th.
  • 1 H-NMR (400.075 MHz, D 2 O): δ = 3.34 (t, 3 J H, H = 7.4 Hz, 6H, H 1 ), 2.80 (t, 3 J H, H = 7.3 Hz, 6H, H 2 ).
  • 13 C { 1 H} NMR (100.599 MHz, D 2 O): δ = 220.04 (s, C carbonyl ), 41.94 (s, C 1 ), 29.83 (s, C 2 ).
  • MS (DEI): m / z (%) = 346 [M + - CO - 3CH 2 -CH 2 -NH 3 ] (12), 318 [M + - 2CO - 3CH 2 -CH 2 -NH 3 ] (2 ), 290 [M + - 3CO - 3CH 2 -CH 2 -NH 3 ] (3), 262 [M + - 4CO - 3CH 2 -CH 2 -NH 3 ] (10), 234 [M + - 5CO - 3CH 2 -CH 2 -NH 3 ] (15), 217 (11), 206 [M + - 6CO - 3CH 2 -CH 2 -NH 3 ] (2), 174 [M + - 6CO - S - 3CH 2 -CH 2 -NH 3 ] (5), 77 [HS-CH 2 -CH 2 -NH 2 ] (51), 71 (100), 59 (22), 44 [CH 2 -CH 2 -NH 2 ] (31) , 42 (99), 30 [CH 2 -NH 2 ] (100), 28 [CO] (81).
  • IR data (solid, neat): 2873 (m), 1981 (m), 1874 (s), 1581 (m), 1553 (m), 1503 (s), 1483 (s), 1461 (s), 1426 (m), 1384 (w), 1327 (m), 1260 (m), 1228 (w), 1088 (m), 1046 (w), 887 (w), 817 (m), 673 (m), 626 (w), 523 (w), 455 (m).
  • Elemental analysis: for (CO) 6 Mn 2 (μ-S-CH 2 -CH 2 -NH 3 ) 3 ] Br 2 x 2.5 THF calculated: C 31.11%, H 4.86%, N 4.95% Found: C 30.80%, H 4.67%, N 4.73%.

Die Freisetzung von Kohlenstoffmonoxid wurde durch einen auf Myoglobin basierenden Assay (vgl. auch Fig.) verdeutlicht. Dazu wurde von der Verbindung III eine wässrige Phosphatpufferlösung der Konzentration 7 mmol/L hergestellt. 1,5 mL dieser Lösung wurden in einer Küvette mit je 1,5 mL einer Desoxymyoglobinlösung pipettiert. Diese wurde zuvor durch Reduktion von Myoglobinlösung (ca. 47 μmol/L pH 6,8, Phosphatpuffer 0,01 mol/L) mit Natriumdithionit (ca. 1 mg) erhalten. Der Inhalt der Küvette wurde umgehend homogenisiert und durch UV-Vis-Spektroskopie vermessen.The release of carbon monoxide was demonstrated by a myoglobin-based assay (see also Fig.). For this purpose, an aqueous phosphate buffer solution of concentration 7 mmol / L was prepared from compound III. 1.5 mL of this solution was pipetted into a cuvette containing 1.5 mL of a deoxymyoglobin solution. This was previously obtained by reduction of myoglobin solution (about 47 μmol / L pH 6.8, phosphate buffer 0.01 mol / L) with sodium dithionite (about 1 mg). The contents of the cuvette were immediately homogenized and measured by UV-Vis spectroscopy.

Anschließen wurde die Probe bei 365 nm bestrahlt und nach unterschiedlichen Zeiten (t = 0 min, t = 5 min, t = 10 min, t = 20 min und t = 30 min) jeweils ein UV-Vis-Spektrum (Darstellung wellenlängenspezifischer Absorption) aufgenommen. Für die Probe ergab sich dabei im Dunkeln keine signifikante Bildung von Kohlenstoffmonoxid, während durch Bestrahlung eine Myoglobin-CO-Konzentration erhalten wurde. Dies zeigt signifikant die lichtinduzierte Freisetzung von Kohlenstoffmonoxid.Subsequently, the sample was irradiated at 365 nm and, after different times (t = 0 min, t = 5 min, t = 10 min, t = 20 min and t = 30 min), one UV-Vis spectrum each (representation of wavelength-specific absorption) added. For the sample, no significant formation of carbon monoxide was observed in the dark, while irradiation resulted in a myoglobin CO concentration. This significantly indicates the photoinduced 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 98/48848 A1 [0015] WO 98/48848 A1 [0015]
  • WO 98/29115 A1 [0016] WO 98/29115 A1 [0016]
  • WO 2008/003953 A2 [0017] WO 2008/003953 A2 [0017]
  • WO 09/066067 A1 [0017] WO 09/066067 A1 [0017]
  • WO 95/05814 A1 [0017] WO 95/05814 A1 [0017]
  • WO 00/56743 A1 [0017] WO 00/56743 A1 [0017]
  • US 7045140 B2 [0017] US 7045140 B2 [0017]

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Claims (9)

Kohlenstoffmonoxid freisetzende Moleküle gemäß der allgemeinen Formel I
Figure DE102014008537A1_0005
mit: R = jegliche Alkyl- beziehungsweise Aryl-Gruppen X = Halogenid, PseudohalogenidCarbon monoxide-releasing molecules according to the general formula I.
Figure DE102014008537A1_0005
with: R = any alkyl or aryl groups X = halide, pseudohalide Verfahren zur Herstellung der Kohlenstoffmonoxid freisetzenden Moleküle gemäß Anspruch 1, gekennzeichnet durch den Syntheseweg der allgemeinen Formel II
Figure DE102014008537A1_0006
wobei 3 Äquivalente eines Mercaptoalkyl- beziehungsweise Mercaptoarylaminderivates einem geeigneten Lösungsmittel, beispielsweise Tetrahydrofuran (THF), Toluen, Benzen, Ethanol oder Methanol suspendiert oder gelöst und mit 2 Äquivalenten Pentacarbonylmanganhalogenid bzw. Pentacarbonylmanganpseudohalogenid versetzt, bei Temperaturen von 0°C bis 160°C gerührt und nach beendeter Reaktion aufgearbeitet wird.Process for the preparation of the carbon monoxide-releasing molecules according to Claim 1, characterized by the synthetic route of the general formula II
Figure DE102014008537A1_0006
wherein 3 equivalents of a mercaptoalkyl or Mercaptoarylaminderivates a suitable solvent, for example tetrahydrofuran (THF), toluene, benzene, ethanol or methanol suspended or dissolved and mixed with 2 equivalents of Pentacarbonylmanganhalogenid or Pentacarbonylmanganpseudohalogenid, stirred at temperatures of 0 ° C to 160 ° C and is worked up after completion of the reaction. Verfahren gemäß Anspruch 2, dadurch gekennzeichnet, dass die Aufarbeitung durch Extraktion erfolgt.A method according to claim 2, characterized in that the workup is carried out by extraction. Verfahren gemäß Anspruch 2, dadurch gekennzeichnet, dass die Aufarbeitung durch Filtration erfolgt.A method according to claim 2, characterized in that the work-up is carried out by filtration. Verfahren gemäß Anspruch 2, dadurch gekennzeichnet, dass die Aufarbeitung durch Kristallisation erfolgt.A method according to claim 2, characterized in that the workup is carried out by crystallization. Verfahren gemäß Anspruch 2, dadurch gekennzeichnet, dass die Aufarbeitung durch Vakuumdestillation erfolgt.A method according to claim 2, characterized in that the workup is carried out by vacuum distillation. Verfahren gemäß Anspruch 2, dadurch gekennzeichnet, dass die Aufarbeitung durch Sublimation erfolgt.A method according to claim 2, characterized in that the workup is carried out by sublimation. Verfahren gemäß Anspruch 2, dadurch gekennzeichnet, dass die Aufarbeitung durch Chromatographie erfolgt.A method according to claim 2, characterized in that the work-up is carried out by chromatography. Verwendung der Kohlenstoffmonoxid freisetzende Moleküle gemäß Anspruch 1 als pharmakologische Wirkstoffe, insbesondere zur Behandlung jeder Formen von Bluthochdruck, Krebs, Gewebsschädigung durch Bestrahlung, postischämischer 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-releasing molecules according to claim 1 as pharmacological agents, in particular for the treatment of any forms of hypertension, cancer, tissue damage by radiation, postischemic damage, atherosclerosis, sepsis, angina, heart attacks, effects of haemorrhagic shock, cell death, inflammation and associated diseases, and to Vascular dilation, assistive treatment for organ transplantation and stimulation of neurotransmission.
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