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

Abstract

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

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 ).

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 ).

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 ).

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 ).

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 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 ).

Manganese, on the other hand, is an essential trace element. ( W. Mertz: The Essential Trace Elements, Science 1981, 213, 1332 ).

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).

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 ).

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 ).

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 ).

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.

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.

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 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 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 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.

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.

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.

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:

With:
R = any alkyl or aryl groups
X = halide, pseudohalide

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 .).

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.

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).

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.

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.

The figure shows time- and wavelength-specific UV-Vis spectra to illustrate the light-induced release of carbon monoxide.

• Gesamtausbeute 870 mg = 1,30 mmol = 91% d. Th.
• ¹H-NMR (400.075 MHz, D₂O): δ = 3.34 (t, ³J_H,H = 7.4 Hz, 6H, H¹), 2.80 (t, ³J_H,H = 7.3 Hz, 6H, H²).
• ¹³C{¹H}-NMR (100.599 MHz, D₂O): δ = 220.04 (s, C^Carbonyl), 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%.

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.

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.

QUOTES INCLUDE IN THE DESCRIPTION

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.

Cited patent literature

• WO 98/48848 A1 [0015]
• WO 98/29115 A1 [0016]
• WO 2008/003953 A2 [0017]
• WO 09/066067 A1 [0017]
• WO 95/05814 A1 [0017]
• WO 00/56743 A1 [0017]
• US 7045140 B2 [0017]

Cited non-patent literature

• 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 [0001]
• 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 [0001]
• 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 [0001]
• 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 [0001]
• 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 [0001]
• 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 [0001]
• MA Gonzales, PK Mascharak: Photoactive metal carbonyl complexes as potential agents for targeted CO delivery, Journal of Inorganic Biochemistry 2014, 133, 127-135 [0002]
• 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 [0002]
• 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 [0003]
• 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 [0004]
• LJ Malone, RW Parry, Inorganic Chemistry 1967, 6, 817-822 [0005]
• 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 [0005]
• R. Fischer: Our Organism Requires Boron Complex Compounds - Significance of Boron for All Living Things, SANUM-Post 1989, 8, 29-34 [0006]
• W. Mertz: The Essential Trace Elements, Science 1981, 213, 1332 [0007]
• 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 -5366 [0009]
• P. Govender, S. Pai, U. Schatzschneider, GS Smith: Next generation PhotoCORMs: Polynuclear tricarbonyl manganese (I) - functionalized polypyridyl metallodendrimers, Inorganic Chemistry 2013, 52, 5470-5478 [0009]
• 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 [0010]
• MA Gonzalez, MA Yim, S. Cheng, A. Moyes, AJ Hobbs, PK Mascharak: Manganese Carbonyl Bearing Tripodal Polypyridine Ligands as Photoactive Carbon Monoxide Releasing Molecules, Inorganic Chemistry 2011, 51, 601-608 [0011]
• 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 [0011]
• SJ Carrington, I. Chakraborty, PK Mascharak: Rapid CO release from a Mn (I) carbonyl complex derived from azopyridine upon exposure to visible light and its phototoxicity towards malignant cells, Chemical Communications 2013, 49, 11254-11256 [0011]
• Cremer, Biochemische Zeitschrift 1929, 206, 228 [0012]
• Tomita et al. 1967 [0012]
• 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 [0012]
• J. Koolman, K.-H. Röhm, Pocket Atlas of Biochemistry, 3rd Edition Georg Thieme Verlag, Stuttgart, New York 2003 [0012]
• PM Treichel, PC Nakagaki: New synthetic strategies for organometallic complexes with thiolate ligands, Organometallics 1986, 5, 711-716 [0021]

Claims (9)

Carbon monoxide-releasing molecules according to the general formula I.

with: R = any alkyl or aryl groups X = halide, pseudohalide Process for the preparation of the carbon monoxide-releasing molecules according to Claim 1, characterized by the synthetic route of the general formula II

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. A method according to claim 2, characterized in that the workup is carried out by extraction. A method according to claim 2, characterized in that the work-up is carried out by filtration. A method according to claim 2, characterized in that the workup is carried out by crystallization. A method according to claim 2, characterized in that the workup is carried out by vacuum distillation. A method according to claim 2, characterized in that the workup is carried out by sublimation. A method according to claim 2, characterized in that the work-up is carried out by chromatography. 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.