CZ25727U1 - Salophene iron complexes with heterocyclic N-donor ligands and their use in antitumor therapy - Google Patents

Description

The present invention relates to iron complexes in the oxidation stages +11 or + III of the general formula [Fe (salophen) (L) J, where salophen {2,2 '- ((1', 2-phenylenebis (azanylylidene)) bis (methanylylidene) )) Diphenolate (2-)} acts as a "carrier" chelate ligand and L are complementary A-donor heterocyclic ligands and their use in medical practice as cancer drugs or as part of pharmaceutical compositions for the prevention or treatment of cancer, which contain these complexes as active substance.

BACKGROUND OF THE INVENTION

Cancer has long been ranked second in morbidity and mortality in the World Health Organization (WHO) health statistics, especially in more developed countries. Therefore, the search for new, more effective and safer compounds for use in the therapeutic practice of these diseases is a strong social imperative.

It is generally accepted that the regulation of iron levels in target tissues plays an important role in the metabolic regulation of tumor tissue growth (Zhou, T. et al. Dalton Trans. 41, 2012, 6371-6389; Visca, P. et al. Antimicrob. Agents Chemother., 57, 2013, 2432-2433). Furthermore, it has been found that chelating agents binding non-gelatinized iron to stable complex compounds have an anti-angiogenic effect (Terman, A. and Kurz, T. Antioxid. Redox. Signal. 18, 2013, 888-898), with some low molecular weight iron complexes oxidation stages +11 or + III with ligands derived from Schiff's bases act by another mechanism based on interaction with DNA and other important biomolecules and thus act as highly potent antitumor agents in vitro (Herchel, R. et al. Dalton Trans. 44, 2009 , 9870-9880).

The low-molecular-weight iron complexes in the oxidation stages +11 or + III with suitable ligands therefore constitute a viable alternative to the already used platinum complex compounds, whose still most widely used representatives, for example, the cis-diamindichlorido-platinum complex (cisplatin) of formula A, lack however, deficiencies in the form of resistance to cisplatin derivatives and some adverse effects associated with the therapeutic use of cisplatin derivatives, eg, nausea, nephrotoxicity, ototoxicity and the like.

In recent years, it has been found that aqua-, chloride- and acetate-complexes with carrier chelate ligands of the Schiff base type, in particular salophen of formula B

and its methoxy-, hydroxy-, C 1 -C 4 -alkyl-, C 1 -C 4 -alkoxy- and trihalomethyl derivatives with central iron atoms in oxidation stages +11 or + III show high antitumor activity in vitro and in vivo (WO 2008090081 A1 EP 1949899 A1; US 2009326061 A1; Hille, A. et al. J. Biol, Inorg. Chem. 14, 2009, 711-725; Hille, A. et al. Arch. Pharrn. Chem. Life Sci. 11, 2011, 217-223; Lange, TS et al. Plos ONE 3, 2008, e2303; Lange, TS et al. DrugDes. Dev. Ther. 3,

-1 CZ 25727 Ul

2009, 17-26), which is up to 50 times higher than that of cisplatin under comparable experimental conditions (Hille, A. et al. J. Biol, Inorg. Chem. 14, 2009, 711-725) and mechanisms have been described, how they act on various human tumor cell lines and the mechanisms by which they overcome resistance to cisplatin-derived drugs (Kim, KK et al. Plos ONE 6, 2011, el9049; Alani, MR et al. Russ. J. Phys. Chem. A 84, 2010, 2284-2289, Ansari, K.I., et al., Biomol., Screen 16, 2011, 26-35, Lee, S.Y., et al., Leuk Res. 387-393).

From patent documents (WO 2008/090081 A1; EP 1 949 899 A1; US 2009/326061 A1) and scientific papers (Ross, TM et al. Dalton Trans. 2003, 149-159; Leeuwenkamp, OR et al. Polyhedron 6, 1987, 295-302; Nishida, Y. et al., J. Chem. Soc., Dalton Trans. 1987, 1157-1161; Choudhury, K. and Medhi, OK. Indian J. Chem. SectA-Inorg. Inorg Phys Theor Anal Chem 32A, 1993, 351-354 Hemandez-Molina, R. et al Inorg Chem 37, 1998, 5102-5108, Jana, S. et al Polyhedron 48, 2012 Nichols, PJ et al Inorg Chem 27, 1988, 27952800, Nabei A et al Inorg Chim Acta 361, 2008, 3489-3493, Herchel R. et al Dalton Trans. 40, 2011, 11896-11903) describing the preparation and biological activity of salophene carrier chelate ligand complexes and its methoxy-, hydroxy-, C1-C4-alkyl-, C1-C4-alkoxy- and trihalomethyl derivatives with central iron atoms in oxidation stages +11 or + III and supplementary O-, S-, N- or halogen-Yiganana or a combination thereof It is clear that even a small change in their structure leads to a dramatic change in efficiency, as confirmed by the work of Hille, A. and Gust, R. Eur. J. Med. Chem. 45, 2010, 5486-5492 describing the effect of methoxy substitution on the salophen carrier ligand on the intensity and selectivity of the antitumor effect of the compounds. From the above it is therefore clear why not only suitable substitutions of the basic salophenic skeleton are sought, but also suitable complementary N-donor ligands are sought for the coordination sphere of the iron atom, leading to the formation of complex iron compounds with significantly higher antitumor activity. than is the case with platinum complexes.

It is then evident from the literature review that among the previously known salophene complex iron compounds in the +11 or + III oxidation stages, the complexes with square-pyramidal geometry, containing in their coordination sphere in addition to the salophen derivative also one additional N-donor heterocyclic ligand, are completely absent. The preparation, characterization and detection of significant antitumor effects at the in vitro level is then the subject of the present invention.

The essence of the technical solution

The essence of the invention is based on complex iron compounds in oxidation stages +11 and + III with one salophene ligand {2,2 '- ((1E, 1' £) - (1,2-phenylenebis (azanylylidene)) - bis (methanylylidene)) di-phenolato (2-)} and one additional N-donor heterocyclic ligand and their crystallosolvates, represented by structural formulas I and II

(I), (ID where

-2CZ 25727 Ul

X 1 -X 4 represents a combination of n methanylylidene groups and (4-n) azanylylidene groups, wherein n may be 1 to 2,

R 1 -R 8 represents a hydrogen atom, alkyl, substituted alkyl, alkenyl, aryl and substituted aryl, hydroxy and amino groups, wherein the term:

-alkyl as such or as part of another group represents a branched or unbranched hydrocarbon chain of up to 4, in particular 1 to 2, carbon atoms,

- alkenyl as such or as part of another group represents a branched or unbranched hydrocarbon chain of up to 4 carbon atoms containing at least one carbon-carbon double bond, in particular vinyl and allyl,

-aryl as such or as part of another group represents phenyl

substituted alkyl and aryl as such or as part of other groups represent alkyl and aryl substituted at any position by substituents from the group consisting of alkyl, alkenyl and aryl, or fused with aryl.

Another principle of the present invention is the crystallosolvates of complexes of the general composition [Fe (salophen) (L)] - x 50o / v, where x = 1 to 6 and Solv represents a particular solvent molecule and / or one of the reaction components selected from water, primary alcohol , secondary alcohol, acetone, N, N -dimethylformamide, dimethylsulfoxide, chloroform, dichloromethane, acetonitrile, nitrobenzene, or diethyl ether, either alone or in combination of said solvate molecules.

The use of complexes in medical practice as cancer medicaments or as part of pharmaceutical compositions, with one or more acceptable carriers and excipients for the prevention or treatment of cancer, which contain such complexes as the active ingredient, is also an integral part of the invention.

List of figures attached drawings

Specific embodiments of the invention are illustrated by the accompanying drawings, where

- Figure 1 is the molecular structure of the complex [Fe ⁿ (salophen) (imz)] solved using single crystal X-ray structure analysis,

Fig. 2 is a representation of the spectrum of the [Fe ⁿ (salophen) (imz)] complex measured in the middle infrared region (4000-400 cm ^-1 ) in a KBr tablet identifying all specific vibration of bonds and groups corresponding to the determined composition of the [Fe ⁿ ( salophen) (imz)]

-giant. 3 is a measurement of the temperature dependence of the effective magnetic moment of the complex [Fe ⁿ (salophen) (imz)] on temperature, confirming the presence of the central iron ion in the oxidation stage + II

- Figure 4 is a representation of the Mössbauer spectrum of the [Fe ⁿ (salophen) (imz)] complex at 300 K, with isomeric shift values δ = 0.851 (3) mm / s and quadrupole cleavage Eq = 2.085 (5) mm / s confirming the presence of the central iron ion in the oxidation state + II in the spin state S = 2

- Figure 5 is a representation of the Mössbauer spectrum of the [Fe ¹¹¹ (salophen) (triz)] complex at 300 K, with isomeric shift values δ - 0,3905 (17) mm / s and quadrupole cleavage Eq = 1,2375 (34) mm / s confirm the presence of the central iron ion in the oxidation state + III in the spin state S = 5/2.

-3CZ 25727 Ul

Examples of technical solution

In the following part the technical solution is illustrated, but not limited, by concrete examples of its implementation. The scope of the technical solution is then clearly determined by the protection requirements.

In the examples below, the prepared compounds were characterized by the following physicochemical methods:

- elemental analysis with percentage of elements C, H and N (Thermo Scientific Flash 2000),

- infrared spectroscopy in the 400 to 4000 cm ^{1 range} was performed using KBr tablets (Perkin-Elmer Spectrum One B FT-IR spectrometer),

- single crystal X-ray structure analysis (Xcalibur2, Oxford Diffraction Ltd.),

- Magnetic temperature dependence (5-300 K) and effective magnetic moment at 300 K (SQUID magnetometer model XL-7 from Quantum Design),

- The Mossbauer spectra were measured on a ⁵⁷ Co (Rh) source instrument at 300 K. Isomeric shift values were calibrated against metal α-Fe values.

The technical solution uses μ-oxo-bis (2,2 - ((1 ^ 7,1 ')) - (1,2-phenylenebis (azanylylidene)) bis (methanylylidene)) iron (II) diphenol) complex, [(salophen) Fe-O] -Fe (salophen)], or azido- (2,2 '- ((1 £, 1' £) - (1,2-phenylenebis (azanylylidene)) bis (methanylylidene)) iron (II) diphenol) complex, [Fe (salophen) (N ₃ )], as starting materials for the preparation of the compounds claimed in the protection claims. These starting compounds are not commercially available, but can be prepared by published procedures (Mitchell, PCH and Parker DAJ Chem. Soc., Dalton Trans. 1976, 1821-1824; Jana. S. et al. Polyhedron 48, 2012, 189-198). ).

Example 1: Synthesis of (imidazole-xAU) - {2,2 '- ((1', 1'') - (1,2-phenylenebis (azanylylidene)) bis (methanylylidene)) diphenolate (2 -)} ferrous complex, hereinafter referred to as [Fe (salophen) (imz)]

One molar equivalent of [(salophen) Fe-O-Fe (salophen)] complex (0.1 g; 0.26 mmol) was dissolved in 30 mL of n-butanol and a 40-fold molar excess of imidazole (0.54 g) was added. 8 mmol). The resulting mixture was brought to boiling (about 118 ° C) and 15-20 ml of the original solvent volume was distilled off from the reaction system. By cooling the mixture to 40 ° C, crystals precipitated in n-butanol of an almost insoluble product, which was separated from the excess imidazole dissolved in n-butanol by filtration under reduced pressure. Yield: 0.07 g, i.e. 66% (calculated on Fe). The obtained crystals were suitable for single crystal X-ray structure analysis. The molecular structure of the [Fe (salophen) (imz)] complex is shown in Figure 1.

Percentage of elements C, Η, N in the form: calculated value (found in parentheses) for C ₂₃ H ₇ FeN ₄ O ₂ : C, 63.18 (63.13); H, 3.92 (4.1); N, 12.81 (12.84)%. UV-Vis (vNujol / cm ^-1): 761, 560, 435. IR (vKBr / cm ^-1): 3437, 3134, 3050, 2927, 2856, 1606, 1579, 1536, 1464, 1446, 1381, 1315, 1183, 1149, 1068, 922, 757, 658, 538. The recording of the FT-IR spectrum is presented in Figure 2. Magnetic properties: the effective magnetic moment at room temperature is p _eff / BM = 5.1, which together with the results of temperature dependence measurement p _e ff at temperature (the record presented in Figure 3) and the Mössbauer spectra (the record presented in Figure 4) confirm the presence of the central iron ion in the oxidation stage +11 and the spin state S = 2.

Example 2: Synthesis of (1,2,4-Riazol-1-ido) sesquihydrate - {2,2 '- ((1', 1 '') - (1,2-Phenylenebis (azanylylidene)) - Bis (Methanylylidene) ) Diphenolate (2-) Iron (II) complex, hereinafter [Fe (salophen) (triz)]

One molar equivalent of [(salophen) Fe-O-Fe (salophen)] complex (0.1 g; 0.26 mmol) was slurried in 30 mL of n-butanol and a 40-fold molar excess of 1,2,4- tri-4CZ 25727 U1 azole (0.55 g; 8 mmol). The resulting mixture was brought to boiling (about 118 ° C) and about 18 ml of the original solvent volume was distilled off from the reaction system. By cooling the mixture to 40 ° C, crystals precipitated in n-butanol of an almost insoluble product which was separated from the excess 1,2,4-triazole dissolved in n-butanol by filtration under reduced pressure. Yield: 0.08 g, i.e. 70% (calculated on Fe).

Percentage of elements C, Η, N in the form: calculated value (found in parentheses) for C ₂₂ H ₁₆ FeN ₅ O ₂ : C, 60.29 (59.25); H, 3.68 (3.75); N, 15.98 (15.23)%. UV-Vis (vNujol / cm ¹ ): 761, 560, 435. IR (vKBr / cm ¹ ): 3428,1606,1579,1535,1462,1136,1310,1191,1150, 607, 751, 537. Magnetic Properties The effective magnetic moment at room temperature is μ ^ / Β.Μ. = 5.67, which together with the results of the Mossbauer spectrum measurement (record presented in Figure 5) unambiguously confirms the presence of the central iron ion in the oxidation state + III and the spin state S = 5/2.

Example 3: Synthesis of sesquihydrate (benzo [d [1,2,3] triazole-1-ido) - {2,2 '- ((1', 1 '') - (1,2-phenylenebis (azanylylidene)) - bis (methanylylidene)) diphenol (2 -)} ferric complex, hereinafter referred to as [Fe (salophen) (btriz)]

One molar equivalent of [(salophen) Fe-O-Fe (salophen)] complex (0.1 g; 0.26 mmol) was slurried in 30 mL of n-butanol and a 40-fold molar excess of benzo [</] [ 1,2,3] triazole (0.95 g; 8 mmol). The resulting mixture was brought to boiling (about 118 ° C) and about 18 ml of the original solvent volume was distilled off from the reaction system. By cooling the mixture to 40 ° C, crystals precipitated in n-butanol of an almost insoluble product, which was separated from the excess benzo [d] [1,2,3] triazole dissolved in n-butanol by filtration under reduced pressure. Yield: 0.08 g, i.e. 63% (calculated on Fe).

Percentage of elements C, Η, N in the form: calculated value (found in parentheses) for C ₂₆ H ₂₃ FeN ₅ O ₃ , ₅ : C, 60.60 (60.9); H, 4.11 (3.68); N, 13.59 (15.67)%. UV-Vis (vNujol / cm ^-1): 650, 570, 420. IR (vKBr / cm ^-1): 3047, 1606, 1579.1534, 1489, 1461, 1444, 1381, 1321, 1190, 1150, 1126, 921, 809, 746, 610, 537. Magnetic properties: the effective magnetic moment at room temperature is p _cff / BM = 4.78, which together with the results of the Mössbauer spectra (record presented in Figure 6) indicates the presence of a central iron ion in the oxidation stage +111.

Example 4: Synthesis of (5-Amino-tetrazol-1-ido) - {2,2 '- ((1', 1 ')) - (1,2-phenylenebis (azanylylidene)) bis (methanylylidene)) diphenolate ( 2 -)} ferric complex, hereinafter referred to as [Fe (salophen) (atz) J

One molar equivalent of [(salophen) Fe-O-Fe (salophen)] complex (0.1 g; 0.26 mmol) was slurried in 30 mL of n-butanol and a 40-fold molar excess of 5-aminotetrazole (0, 68 g (8 mmol). The resulting mixture was brought to boiling (about 118 ° C) and about 18 ml of the original solvent volume was distilled off from the reaction system. By cooling the mixture to 40 ° C, crystals precipitated in n-butanol of an almost insoluble product, which was separated from the excess 5 of amino-tetrazole dissolved in n-butanol by filtration under reduced pressure. Yield: 0.08 g, i.e. 68% (calculated on Fe).

Percentage of elements C, Η, N in the form: calculated value (found in parentheses) for C ₂ H ₁₆ FeN ₇ O ₂ : C, 55.53 (54.81); H, 3.55 (3.19); N, 21.58 (21.99)%. UV-Vis (in Nujol / ciri ¹ ): 800, 640, 460. IR (in KBr / cm ¹ ): 1627, 1599, 1542, 1467, 1446, 1341, 1304, 1085, 760, 616, 419. Magnetic properties: effective the magnetic moment at room temperature is p _eff / BM = 5.86, which clearly proves the presence of the central iron ion in the oxidation stage + III and the spin state S = 5/2.

-5GB 25727 Ul

Example 5: Synthesis of (5-phenyl-tetrazol-1-ido) - {2,2 '- ((1', 17 ') - (1,2-phenylenebis (azanylylidene)) bis (methanylylidene)) diphenolato (2-) } ferric complex, hereinafter referred to as [Fe (salophen) (phtz)]

One molar equivalent of [(salophen) Fe-O-Fe (salophen)] complex (0.1 g; 0.26 mmol) was slurried in 30 mL of n-butanol, and a 40-fold molar excess of 5-phenyltetrazole (1, 17 g; 8 mmol). The resulting mixture was brought to boiling (about 118 ° C) and about 18 ml of the original solvent volume was distilled off from the reaction system. By cooling the mixture to 40 ° C, crystals precipitated in n-butanol of an almost insoluble product, which was separated from the excess of 5-phenyl tetrazole dissolved in n-butanol by filtration under reduced pressure. Yield: 0.09 g, i.e. 67% (calculated on Fe).

Percentage of elements C, Η, N in the form: calculated value (found in parentheses) for C ₂₇ H ₁₉ FeN ₆ O ₂ : C, 62.93 (62.78); H, 3.72 (3.65); N, 16.31 (16.38)%. UV-Vis (vNujol / cm ^-1): 670, 450. IR (vKBr / cm ^-1): 3064, 3016, 1605, 1579, 1539, 1463, 1437, 1382, 1313, 1192, 1146, 815, 742, 698, 623, 538. Magnetic properties: effective magnetic moment at room temperature is μ ^ / Β.Μ. = 6.0, which clearly demonstrates the presence of the central iron ion in the oxidation stage + III and the spin state S = 5/2.

Example 6: Synthesis of (5-methyl-tetrazol-1-ido) - {2,2 '- ((1', 1 ')) - (1,2-Phenylenebis (azanylylidene)) bis (methanylylidene)) diphenolato (2 -)} ferric complex, hereinafter referred to as [Fe (salophen) (mtz)]

One molar equivalent of [Fe (salophen) (N ₃ )] (0.5 g, 1.37 mmol) was dissolved in 40 mL acetonitrile and refluxed for 30 hours. Cooling the reaction mixture to room temperature gave (5-methyltetrazol-1-ido) -2,2 '- ((1', 1 ') - (1,2-phenylenebis (azanylidene)) bis (methanylylidene)) ferric diphenol (2-) complex, which was separated from the mixture by filtration under reduced pressure and dried in a desiccator over lump KOH. Yield: 0.4 g, i.e. 72% (calculated on Fe).

Percentage of elements C, Η, N in the form: calculated value (found in parentheses) for C ₂₂ H ₁₇ FeN ₆ O ₂ : C, 58.30 (57.90); H, 3.78 (3.81); N, 18.54 (18.20)%. IR (in KBr / cm @ ^-1 ): 3436, 1606, 1578, 1534, 1461, 1445, 1380, 1316, 1189, 1149, 808, 751, 608, 508. Magnetic properties: the effective magnetic moment at room temperature is p _e ff / BM = 5.89, which clearly demonstrates the presence of the central iron ion in the oxidation stage + III and the spin state S = 5/2.

Example 7: In vitro cytotoxic activity of copper complexes on human tumor lines

The MTT assay was used to determine the cytotoxic activity of the prepared complexes. The method is based on the ability of metabolically active cells to reduce the yellow salt of 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide (MTT) to form a blue formazan dye. Since this conversion occurs only in living cells, the cytotoxicity of various chemicals can be determined in this way. Within the cell, mitochondrial dehydrogenases are responsible for the reduction. The resulting formazan dye is insoluble and is subsequently quantified upon dissolution in DMSO with ammonia using visible spectrophotometry.

In vitro cytotoxic activity assays were performed on seven human tumor cell lines: human osteosarcoma (HOS), human breast adenocarcinoma (MCF-7), human epithelial adenocarcinoma (A549), cervical carcinoma (HeLa), human ovarian carcinoma (A2780), human cisplatin-resistant ovarian carcinoma (A2780cis) and human malignant melanoma (G-361). The lines were maintained in plastic bottles in DMEM medium (5 g / l glucose, 2 mM glutamine, 100 U / ml penicillin, 100 µg / ml streptomycin, 10% fetal calf serum and sodium bicarbonate) for cell cultures.

Cell suspensions (ca 1.25x10 ⁵ cells per ml) were pipetted at 80 μΐ onto 96-well plastic microtiter plates. These were preincubated at 37 ° C in a CO ₂ atmosphere for 24 hours. The iron-cisplatin complexes tested as therapeutic standard were dissolved in Ν, Ν'-dimethylformamide and these served as stock solutions. For the experiment, the stock solutions were diluted 100x in the culture medium (max. Concentration 1.0 µΜ for iron complexes and

The mixture was added to the tumor cells for an incubation period of 24 hours after aspirating the culture medium. MTT analysis was performed spectrophotometrically (TECAN, Schoeller Instruments LLC) at 540 nm. The concentration of test complexes (μΜ) toxic to 50% of tumor cells (IC ₅₀ inhibitory concentration) was calculated from the concentration curves and are presented in Table 1.

Table 1: IC ₅₀ concentrations of in vitro test complexes (IC 50 and standard deviation from three independent measurements (SD), μΜ) toxic to 50% of human tumor cells (osteosarcoma, HOS; breast adenocarcinoma, MCF-7; epithelial adenocarcinoma, A549; cervical carcinoma, HeLa; ovarian carcinoma, A2780; cisplatin-resistant ovarian carcinoma, A21% cis and malignant melanoma, G-361) as compared to cisplatin.

Complex Inhibitory IC concentration (S.D. [μΜ] HOS MCF-7 A549 HeLa A2780 A2780cis G-361 [Fe (salophen) (imz)] 1,8 mm (6) 0.70 (8) 0.57 (25) 0.87 (13) 0,23 mm (7) 0,35 mm (3) 0,32 mm (2) (Fe (salophen)) > 1 0.35 (12) > 1 0.43 (9) 0.29 (7) 0.32 (4) 0.43 (13) [Fe (salophen) (btri2)] 1,8 mm (4) 0.38 (16) 1,9 mm (7) 1.29 (27) 0.352 (5) 0,32 mm (2) 0.42 (10) (Fe (Salophen) (atz) J > 1 0.64 (27) > 1 0.70 (5) 0.31 (13) 0.32 (4) 0.34 (11) (Fe (satophen) (phte)) 2,1 mm (1) 0.70 (26) 1,6 mm (2) 0.74 (25) 0.33 mm (2) 0,35 mm (4) 0.40 (13) (Fe (salophen)) > 1 0.38 (11) 0.47 (6) 0.50 (11) 0.058 (10) 0,30 mm (2) 0.33 (5) cisplatin 34 (6) 20 mm (4) > 50 40 (5) 12 mm (2) 30 mm (6) 7 (2)

PROTECTION REQUIREMENTS

Claims (5)

1. Complex iron compounds in oxidation stages + II and + III with salophen {2,2 '((l.Zi, 170- (1,2-phenylenebis (azanylylidene)) bis (methanylylidene)) diphenolio (2-) ligand} and up to 15 full-length heterocyclic Y-donor ligands and their crystallosolvates, represented by Structural Formulas I and II (I), (II), wherein: X1-X4 represents a combination of n methanylylidene groups and (4-n) azanylylidene groups, where n can be 1 to 2, R 1 -R 8 represents a hydrogen atom, alkyl, substituted alkyl, alkenyl, aryl and substituted aryl, hydroxy and amino groups, wherein the term: -7GB 25727 Ul -alkyl as such or as part of another group represents a branched or unbranched hydrocarbon chain of up to 4, in particular 1 to 2, carbon atoms, - alkenyl as such or as part of another group represents a branched or unbranched hydrocarbon chain of up to 4 carbon atoms containing at least one carbon-carbon double bond, in particular vinyl and allyl, -aryl as such or as part of another group represents phenyl, substituted alkyl and aryl as such or as part of other groups represent alkyl and aryl substituted at any position with substituents from the group consisting of alkyl, alkenyl and aryl, or fused with aryl. Crystallosolvates of complexes according to claim 1, wherein for compounds of the general formula [Fe (salophen) (L)] - xSo / v, where x = 1 to 6 and Solv is a particular solvent molecule and / or one of the reaction components selected from water a primary alcohol, a secondary alcohol, acetone, N, N-dimethylformamide, dimethylsulfoxide, chloroform, dichloromethane, acetonitrile, nitrobenzene, or diethyl ether, either alone or in combination of said solvate molecules. A pharmacological composition comprising a therapeutically effective amount of the iron complexes according to claim 1 and / or a pharmaceutical composition of the iron complexes with one or more active agents, acceptable carriers and excipients. A pharmacological composition according to claim 3 for use in medicine. The pharmacological composition of claim 4 for use as a medicament for the treatment of cancer.