ES2291120B2 - SYNTHESIS AND USE OF THE CU-FENANTROLINA-IODOHIPURIC ACID COMPLEX AND RELATED COMPOUNDS AS ANTITUMORAL PHARMACOS. - Google Patents

Abstract

Synthesis and use of the Cu-phenanthroline-iodohipuric acid ternary complex and related compounds as antitumor drugs. The present invention relates to ternary complexes formed by Cu (II), 1,10-phenanthroline or 2,2-bipyridyl and different hippuric acids of general formula (I): [Cu AB {sub, 2}] {sup, + } C nH {sub, 2} O (I) where A is selected from: I-hip, Hip, BGG and B {sup, I} GG; B is selected from: phen and bpy; C is selected from I-hip {sup, -}, Hip {sup, -}, B {sup, I} GG {sup, -}; BGG {sup, -} and I {sup, -}; and n, if it exists, are the crystallization waters that can vary between 1 and 7. Said compounds in solution have great stability in the form of Cu (I) complexes, which act at the DNA level and, therefore, are useful as antitumor agents, particularly in human cancer and especially lung cancer.

Description

Synthesis and use of the ternary complex Cu-phenanthroline-iodohipuric acid and compounds related as antitumor drugs.

Field of the Invention

The present invention relates to complexes ternaries formed by Cu (II), 1,10-phenanthroline or 2,2-bipyridyl and different hippuric acids, to the procedure of their preparation and to their use as antitumor agents, in particularly in human cancer, even more especially in the lung cancer.

Background of the invention

Recently, Cu (II) compounds with 1,10-phenanthroline ( ortho -phenanthroline, phen) have been described which have various clinical activities such as antitumor (Cassiopein), antimycobacterial, antifungicidal and antimicrobial.

In European Patents EP 0434444 and EP 0434445 casiopeins are described which are complex, in which an atom of copper is attached to a single molecule of phenanthroline (with different substituents) and to a form linked amino acid chelator for the N of the amino group and the oxygen of the group carboxylic. Such compounds use free amino acids / peptides with a flat-square coordination, which is very unlikely that the complexes [Cu (N, N-phenanthroline) (N, O-aminoacidate)] they can generate the bisphenantroline copper compound (I) in dissolution, as a minimum, in quantities and favorable kinetics of the present invention.

Regarding the properties antimicobacterial compounds of Cu (II) with 1,10-phenanthroline, see D.K. Saha, U. Sandbhor, K. Shirisha, S. Padhye, D. Deobagkar, C.E. Ansond, A.K. Poweld, Bioorg. Med. Chem. Lett. 14 (2004) 3027-3032.

With regard to antimicrobial properties, see M.A. Zoroddu, S. Zanetti, R. Pogni, R. Basosi, J. Inorg. Biochem 63 (1996) 291-300.

With respect to fungicidal properties, see G. Majella, S. Vivienne, M. Malachy, D. Michael, M. Vickie, Polyhedron 18 (1999) 2931-2939.

The action of compounds derived from phenanthroline as DNA interleavers [K.E. Erkkila, D.T. Odom, J.K. Barton, Chem. Rev. 99 (1999) 2777-2796].

It is also known that some complexes of bisphenantroline-copper have activity of nucleic acid hydrolysis (S. Zhang, Y. Zhu, C. Tu, H. Wei, Z. Yang, L. Lin, J. Ding, J. Zhang, Z. Guo, J. Inorg. Biochem 98 (2004) 2099-2116, and its references, although in all the cases described is necessary for this type of activity the presence of:

to)

thiols and peroxide hydrogen.

b)

reducers and presence of air.

C)

in physiological conditions, the presence of a reducer or irradiation with ultraviolet or visible light.

Without these conditions the formation of the complex estimated as active [Cu (phen) 2 +], as demonstrated by ESI-HRMS from the complex [Cu (gly-L-trp) (phen)] (see, A. García Raso, J.J. Fiol, B. Adrover, V. Moreno, I. Mata, E. Espinosa, E. Molins, J. Inorg. Biochem 95 (2003) 77-86). These references are based on complexes linked to a single phenanthroline molecule and a amino acid / peptide, trying to mimic the structure of Cassiopeins These complexes dissolved in ethanol and without the presence of reducing agent originate copper complexes in state of oxidation (I) [Cu (phen) +], causing the DNA hydrolysis.

Very recently, J. Kang, J. Chen, Y. Shi, J. Jin, Z. Wang, J. Biol. Inorg. Chem. 10 (2005) 190-198, have described the induction of apoptosis in human hematoma cells using phenanthroline in the presence of a  Cu (II) salt due to hypoacetylation of histones (always in the presence of oxygen).

In none of the above documents describe ternary complexes of Cu (II), 1,10-phenanthroline (2,2-bipyridyl) and different hipuric acids that allow to obtain in solution aqueous or ethanolic for a minimum period of 24 hours the species bisfenantroline (I) that is possibly responsible for the DNA hydrolysis and its antitumor effects.

In the document of the present inventors "Study of the interaction of ternary compunds of the type [Cu (o-iodohippurato) (phen) 2] + or [Cu (o-iodohippurato) (bpy) 2+ with DNA "(summary of a poster presented at EUROBIC7 European Biological Inorganic Chemistry Conference in Garmisch-Partenkirchen of 9-29-2004 to 2-9-2004) two are mentioned complexes, whose characterization and method of synthesis are developed in the present invention.

In the document "Synthesis, structure and nuclease properties of several ternary Copper (II) peptide complexes with 1,10-phenantroline" (Journal of Inorganic Biochemistry 95 (2-3): 77-86 (2003) ternary copper complexes are described , phenanthroline and dipeptides, other than those of the invention, that originate copper (I) complexes without the presence of a reducing agent but without claiming that said complex is stable for more than 24 hours, which is one of the basic characteristics of the present invention.

Summary Description of the Invention

The present invention relates to complexes ternaries formed by Cu (II), 1,10-phenanthroline or 2,2-bipyridyl and different hipuric acids.

Another object of the present invention is the procedure for the synthesis of said complexes.

Still another object of the present invention is the use of said complexes as antitumor agents.

Brief description of the figures

Figure 1 shows the ORTEP representation at 50% chance of the complex [Cu (I-hip) (phen) 2] + (I-hip -) • 7 O 2 O.

Figure 2 shows the ORTEP representation of the complex [Cu (I-Hip) (bpy) 2] + (I -) • 1.5H 2 O.

Figure 3 shows the ORTEP representation of the complex [Cu (Hip) (phen) 2] + (Hip -) \ cdot2H2 O.

Figure 4 shows the ORTEP representation of the complex [Cu (B I GG) (bpy) 2] + (I -) • 5 O 2 O.

Figure 5 shows the kinetic study by ESI-HRMS of the aqueous solution generation of the species of copper (I) [Cu (phen) 2] + without the addition of any other agent.

Figure 6 shows the effect of [Cu (phen) 2] + over proliferation of A549 cancer cells.

Figure 7 shows the study of the phase of cell cycle, in which the distribution of cell populations studied by flow cytometry in cultured A549 cells in the absence or presence of the complex [Cu (phen) 2] +, after staining with ethidium bromide.

Figure 8 shows photographs of a) cells treated with the complex [Cu (I-hip) (phen) 2] + (I-hip -) \ cdot7H2 O  at different concentrations, between 0 and 5 micromolar (1st line, 45x; 2nd line 180x) and b) the fragmentation of the PARP obtained by Western blot technique.

Figure 9 shows the determined viability using the trypan blue technique in treated cells during 24 hours with the compounds indicated in the graph at different concentrations.

Detailed description of the invention

The present invention relates to a compound ternary characterized by the general formula (I):

[Cu \ A \ B_2] + C \ cdot nH_ {O}

where

A is selected from: I-hip, Hip, BGG and BI GG;

B is selected from: phen and bpy;

C is selected from I-hip -, Hip -, B I GG -, BGG - and I <->; Y

n, if it exists, are the crystallization waters which may vary between 1 and 7, for use as an agent antitumor

Preferably, said formula excludes ternary compounds [Cu (I-hip) (phen) 2] (I-hip -) \ cdot7H2 O  Y [Cu (I-hip) (bpy) 2] (I-hip -) \ cdot5H2 O.

In said formula Cu represents Cu (II) ions, phen represents 1,10-phenanthroline, bpy represents 2,2-bipyridyl and with respect to the different hippuric acids (amino acids or peptides in which the NH2 group has been protected } terminal by replacing one of the hydrogens with a benzoyl group (or its analogs with substitution of some hydrogen for iodine: ortho- iodobenzoyl, meta- iodobenzoyl or para- iodobenzoyl)), Hip represents benzoylglycinate, BGG represents benzoylglycylglycinate, B ^ {I GG represents ortho-benzoylglycylglycinate, I-hip - represents ortho -iodobenzoylglycinate.

In particular, the present invention relates to [Cu (Hip) (phen) 2] + (Hip -) \ cdot2H2 O, [Cu (BGG) (phen) 2] + (BGG -) • 6H 2 O, [Cu (B I GG) (bpy) 2] + (I -) • 5 O 2 O, [Cu (B I GG) (phen) 2] + (B I GG -) Y [Cu (I-hip) (bpy) 2] + (I-hip) - • 1.5H 2 O.

Another aspect of the present invention relates to to the procedure for the synthesis of ternary complexes of the type copper (II) - hippuric acid-ligand that It comprises the stages of:

a) Preparation of a carbonate suspension basic copper and hippuric acid selected from I-hip, Hip, BGG and BI GG in water;

b) Reflux heating of the suspension ready

c) Addition to the suspension prepared in the stage b) of the ligand selected from 1,10-phenanthroline and 2,2'-bipyridyl;

d) Filtration of the solution formed in step c) and subsequent cooling to obtain a crystalline product
lizado.

They will now be described by way of example. the physicochemical characteristics and the process of synthesis of different compounds of the invention without pretending that limit the scope of the invention.

Physicochemical characterization of the compounds and their synthesis processes

As indicated in each example, the iodide preparations as counterion have been made in order to modify the solubility of the different products and achieve better crystallization (enable resolution of the structure by X-ray diffraction).

The preparations are expressed in quantities molars, the reactions can be scaled if the reactive / solvent ratios.

There may be differences in the amounts of water present between crystalline structures and samples used for the complete characterization of the compounds. In some cases, some samples may be wet (water from hydration), but especially in some cases the samples lose Crystallization waters immediately upon contact with air, the appropriate crystals (X-rays) must be inserted in petroleum jelly to prevent its degradation, this protection being impossible for The other techniques used.

The compounds were characterized by elementary microanalysis with a Carlo Erba model analyzer
1108.

Additionally, the compounds were characterized by monocrystalline X-ray diffraction on a diffractometer Enraf-Nonius CAD4 that produces a radiation Monochrome molybdenum Kα. The index of the parameters of cell was performed with 25 random reflections. The data was collected with the scan mode \ omega-2 \ theta. The Absorption corrections were made following the PSI scan semi-empirical and the empirical DIFABS. The structural resolution is performed using the WINGX program system. The structure is resolved using SIR2002 programs and refinement using the SHELXL97 total matrix method. Not atoms hydrogenoids were refined anisotropically and the atoms of hydrogen were introduced in calculated positions and continued the refinement with its reference atoms.

The compounds obtained are also characterized by high resolution mass spectroscopy with electrospray ionization (ESI-HRMS) from of aqueous or ethanol solutions at concentrations of 0.2 mg / ml The most important result is that in all cases detects the peak corresponding to the copper complex (I) [Cu (phen) 2] + (or the equivalent with bipyridyl).

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Example one

[Cu (I-hip) (phen) 2] + (I-hip) - Obtaining

1 mmol of malachite [basic copper carbonate; Cu (CO 3) • Cu (OH) 2], 3 mmol of ortho- iodideuric acid [I-hipH] and 100 ml of distilled water in a 250 ml frosted round flask. The mixture was heated with stirring at 100 ° C (1 atm pressure) and allowed to reflux (with a refrigerant to prevent evaporation of the solvent) for 2 hours for the reaction to take place.

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After this time, the solution was filtered, 3 mmol of 1,10-phenanthroline was added to the filtrate and allowed to boil under reflux for two more hours. The solution was filtered again hot and allowed to stand at 25 ° C and 1 atm pressure for 2 days to crystallize the desired product. Intense blue crystals were obtained so
Rhombic

X-ray structure

The structure matches the formula [Cu (I-hip) (phen) 2] + (I-hip) - {7} 2 O.

The crystalline structure (figure 1) shows the copper (I) with a distorted octahedron geometry linked to the carboxylate anion with a short distance and a very long distance [distances: Cu-O: O (1), 1,975 (6) and O (2), 2.82 \ ring {A}] and the four nitrogens of the two Phenanthroline molecules [distances: Cu-N: N (1 '), 1,992 (7); N (10 '), 2,206 (7); N (1``), 2,062 (7) and N (10 ''), 1,991 (7) \ ring {A}]. The complex has a positive charge that is compensated with another iodohipurate anion. Seven water molecules per unit formula are present in the asymmetric unit forming a 3D structure through various hydrogen bonds. The structure three-dimensional is formed by alternative planes of positive ions and negatives It is also interesting to observe interactions by stacking between phenanthroline rings (distance, 3.39 \ ring {A}; dihedral angle, 177.5º], and interactions C-I \ cdot \ cdot \ cdotC (ring) similar to C-H \ cdot \ cdot \ cdot \ Pi interactions [distance 3.60 and 3.55 \ ring {A}] between an atom I (7) of a anionic fragment and carbons C (9) -C (10) of a fragment cationic

For the rest of the compounds there is no available definitive refinement, but still no doubt about the environment of coordination.

Next, Table 1 shows a Summary of diffraction parameters for the complex

[Cu (I-hip) (phen) 2] + (I-hip -) \ cdot 7H 2 O

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TABLE 1 Summary of diffraction parameters of [Cu (I-hip) (phen) 2] + (I-hip -) \ cdot7H2 O

one

2

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Elemental analysis

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3

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High resolution mass spectrum (ESI-HRMS)

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4

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Example 2

[Cu (I-hip) (bpy) 2] + Obtaining

1 mmol of malachite [basic copper carbonate; Cu (CO 3) • Cu (OH) 2], 3 mmol of ortho- iodideuric acid [I-hipH] and 100 ml of distilled water in a 250 ml frosted round flask. The mixture was heated with stirring at 100 ° C (1 atm pressure) and allowed to reflux (with a refrigerant to prevent evaporation of the solvent) for 2 hours for the reaction to take place.

After this time, the solution was filtered, 3 mmol of 2,2'-bipyridyl was added to the filtrate and left boiling at reflux for two more hours. Was filtered again the solution was heated and allowed to stand at 25 ° C and 1 atm of pressure for 2 days to crystallize the product wanted.

Elemental analysis

Matches the formula [Cu (I-hip) (bpy) 2] + (I-hip) - {\} \ cdot5H2 O.

5

High resolution mass spectrum (ESI-HRMS)

6

Example 3

[Cu (I-hip) (bpy) 2] + I - Obtaining

The synthesis was performed in the same way as for Example 2, but once the preparation was finished it was added to the Dissolve an excess of potassium iodide KI and re-filter. TO The mixture was then allowed to stand for two days. In this cation product [Cu (I-hip) (bpy) 2] + is identical to the previous one, its solubility is simply modified by changing counterion.

X-ray structure

The structure coincides with the formula [Cu (I-hip) (bpy) 2] + (I -) \ cdot1.5H2 O.

Elemental analysis

7

Next, Table 1 shows a Summary of diffraction parameters for the complex [Cu (I-hip) (bpy) 2] + (I -) • 1.5H 2 O.

TABLE 2 Summary of diffraction parameters of [Cu (I-hip) (bpy) 2] + (I -) \ cdot1.5H2 O

8

Example 4

[Cu (Hip) (phen) 2] + (Hip) Obtaining

1 mmol of malachite [carbonate] basic copper; Cu (CO 3) • Cu (OH) 2], 3 mmol of hippuric acid [HipH] and 100 ml of distilled water in a flask 250 ml frosted round. The mixture was heated with stirring to 100 ° C (1 atm pressure) and allowed to reflux (with a refrigerant to avoid evaporation of the solvent) for 2 hours so that The reaction took place.

After this time, the solution was filtered, 3 mmol of 1,10-phenanthroline was added to the filtrate and left boiling at reflux for two more hours. Turned to heat filter the solution and let stand at 25 ° C and 1 atm pressure for 2 days to crystallize the product wanted.

X-ray structure

The structure coincides with the formula [Cu (Hip) (phen) 2] + (Hip) - • 4,5H 2 O.

Elemental analysis

Loses water and crystallinity in contact with water. Matches the formula [Cu (Hip) (phen) 2] + (Hip) - \ 2d2H2O.

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10

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High resolution mass spectrum (ESI-HRMS)

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eleven

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Example 5

[Cu (B I GG) (phen) 2] + (B I GG) - Obtaining

1 mmol of malachite [basic copper carbonate; Cu (CO 3) • Cu (OH) 2], 3 mmol of ortho- iodobenzoylglyph
cylglycine [BI GGH] and 100 ml of distilled water in a 250 ml frosted round flask. The mixture was heated with stirring at 100 ° C (1 atm pressure) and allowed to reflux (with a refrigerant to prevent evaporation of the solvent) for 2 hours for the reaction to take place.

After this time, the solution was filtered, 3 mmol of 1,10-phenanthroline was added to the filtrate and left boiling at reflux for two more hours. Turned to heat filter the solution and let stand at 25 ° C and 1 atm pressure for 2 days to crystallize the product wanted.

Elemental analysis

It is an oily product, in which two products are apparently present: [Cu (B I GG) (phen) 2] + (B I GG) - and [Cu (B I GG) 2 (phen)].

High resolution mass spectrum (ESI-HRMS)

The two aforementioned products are present, in addition to the Cu (I) [Cu (phen) 2] + complex being detected again.

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12

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Example 6

[Cu (B I GG) (bpy) 2] + I - Obtaining

1 mmol of malachite [basic copper carbonate; Cu (CO 3) • Cu (OH) 2], 3 mmol of ortho- iodobenzoylglyph
cylglycine [BI GGH] and 100 ml of distilled water in a 250 ml frosted round flask. The mixture was heated with stirring at 100 ° C or higher (1 atm pressure) and allowed to reflux (with a refrigerant to prevent evaporation of the solvent) for 2 hours for the reaction to take place.

After this time, the solution was filtered, 3 mmol of 2,2'-bipyridyl was added to the filtrate and it was left boiling at reflux for two more hours. Was added to the solution an excess of potassium iodide KI was filtered again in heat the solution and let stand at 25 ° C and 1 atm pressure for 2 days to crystallize the desired product.

X-ray structure

The structure coincides with the formula [Cu (B I GG) (bpy) 2] + (I -) \ cdot5H 2 O. Nothing else could be done, because it has only given a few crystals and then an oil.

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Example 7

[Cu (BGG) (phen) 2] + (BGG) - Obtaining

1 mmol of malachite [carbonate] basic copper; Cu (CO 3) • Cu (OH) 2], 3 mmol of benzoylglycylglycine [BGGH] and 100 ml of distilled water in a 250 ml frosted round flask. The mixture was heated with stirring at 100 ° C (1 atm pressure) and allowed to reflux (with a refrigerant to avoid solvent evaporation) for 2 hours for the reaction to take place.

After this time, the solution was filtered, 3 mmol of 1,10-phenanthroline was added to the filtrate and left boiling at reflux for two more hours. Turned to heat filter the solution and let stand at 25 ° C and 1 atm pressure for 2 days to crystallize the desired product. Intense blue crystals were obtained in a rhombic way.

Elemental analysis

Matches the formula [Cu (BGG) (phen) 2] + (BGG) - {6} 2 O.

13

High resolution mass spectrum (ESI-HRMS)

14

Kinetic study of copper complex generation (I)

A kinetic study of the generation was carried out of the copper complex (I) from the solutions of the compounds of the invention at certain times up to a maximum of 24 hours (figure 1). In figure 1, all species are indicated detected being of great importance that after 24 hours of dissolution the majority species is the copper complex (I) [Cu (phen) 2] +. This fact is tremendously surprising since the copper (I) complexes are extraordinarily reactive, especially in solution, in a environment where oxygen may be present. Also this copper (I) complex is obtained without adding any other reagent.

Biological effects Antiproliferative effects of the complex [Cu (phen) 2] + (analogues for [Cu (bpy) 2] +)

Cancer is characterized by a proliferation uncontrolled cell phone Numerous antitumor molecules execute its activity through proliferation inhibition mobile.

A study was carried out in culture cells varying the concentrations of the complex [Cu (phen) 2] + (obtained after dissolution of the compounds of the present invention, see above) and a count of the number of cells in a cytometric chamber using the trypan blue exclusion method (figure 6). It was observed that at very low concentrations of [Cu (phen) 2] + was inhibited tumor cell proliferation (in particular, A549 cells of human pulmonary adenocarcinoma). This effect depended on the concentration and administered dose, which rules out possible nonspecific effects of this complex. On the other hand, it could note that this effect showed great power, since it obtained a marked and statistically significant inhibition at nanomolar concentrations.

Pro-apoptic effects of the complex [Cu (phen) 2] + (analogues for [Cu (bpy) 2] +)

Apoptosis, or programmed cell death, is a highly regulated process that eliminates leftover cells in a organism. In human embryos, for example, the cells that form membranes between the fingers, evolutionary waste that do not appear in mature subjects. In adults, they are removed from this way many aged cells, which are renewed, and cells with genetic defects, which can give rise to tumor cells. In many types of cancer, apoptotic processes are altered and cell death does not occur. The complex [Cu (phen) 2] + is capable of inducing Apoptosis in cancer cells. Figure 6 shows the distribution of cells in different phases of the cell cycle in A459 cells in absence or presence of the complex [Cu (phen) 2] +. Said complex induced a dramatic pro-apoptotic effect, since at very low concentrations almost all cells studied had entered apoptosis, characterized by DNA degradation and the appearance of a "sub G0 / G1" peak in flow cytometry studies.

The study of apoptosis was extended through microscopy analysis and quantification of the degradation of the poly-ADP ribose polymerase (PARP). The images of microscopy (figure 8) clearly indicated the reduction of cell proliferation (smaller number of cells), parallel to a increase in apoptotic processes (loss of cellular form, substrate dissociation, apoptotic body formation, etc.). The Apoptosis is a phenomenon that involves the activation of some proteases called caspazas, with the consequent degradation protein One of the first targets attacked by the dandruff is the PARP. This 113 kDa protein initially degrades into two fragments, one of 89 kDa and another of 24 kDa, approximately. In the Figure 8 is seen as incubation in the presence of phen da place for the gradual disappearance of the 113 kDa band (*) and the appearance of the 89 kDa band (**). These data clearly indicate that phen induces apoptosis in tumor cells.

If the cell viability of some of the compounds of the invention is analyzed (Figure 9) it is observed that all products are sufficiently active (at 24 hours) in concentrations between 10 and 50 µM, although [Cu (I- hip)
(bpy) 2] + (I-hip) • 5H 2 O is already active at a concentration of 0.5 µM.

All biological data available indicate that phen and bpy have great power antiproliferative and pro-apoptotic cells Human tumor All this data along with the casualties concentrations at which its activity is carried out, indicate that this complex has a high antitumor activity and therefore It can be used to treat cancer in humans.

Claims (20)

1. Ternary compound characterized by the fact that it presents the general formula (I): [Cu \ A \ B_2] + C \ cdot nH_ {O} where A is selected from: I-hip, Hip, BGG and BI GG; B is selected from: phen and bpy; C is selected from I-hip -, Hip -, B I GG -, BGG - and  I <->; Y n, if it exists, are the crystallization waters which can vary between 1 and 7, and where said compound is different from [Cu (I-hip) (phen) 2] (I-hip -) - 7H 2 O and [Cu (I-hip) (bpy) 2] (I-hip -) - 5H2 O, for use As an antitumor agent. 2. Ternary compound according to claim 1,  in which A is Hip, B is phen, C is Hip - and n is 2, for its use as an antitumor agent. 3. Ternary compound according to claim 1,  where A is BGG, B is phen, C is BGG - and n is 6, for its use as an antitumor agent. 4. Ternary compound according to claim 1,  wherein A is B I GG, B is phen, C is B I GG -, for its use as an antitumor agent. 5. Ternary compound according to claim 1,  where A is I-hip, B is bpy, C is I - and n is 1, 5, for use as an antitumor agent. 6. Ternary compound according to claim 1,  where A is B I GG, B is bpy, C is I - and n is 5, for its use as an antitumor agent. 7. Procedure for preparing a compound ternary according to any of claims 1 to 6, which It comprises the stages of: a) Preparation of a carbonate suspension basic and hippuric acid selected from I-hip, Hip, BGG and BI GG in water. b) Reflux heating of the suspension ready c) Addition to the suspension prepared in the stage b) of the ligand selected from 1,10-phenanthroline and 2,2'-bipyridyl to form a solution. d) Filtration of the solution formed in the stage c) and subsequent cooling to obtain a product crystallized 8. Method according to claim 7, in which is used a proportion of malachite / I-hipH / phen of 1: 3: 3. 9. Method according to claim 7, in which is used a proportion of malachite / I-hipH / bpy of 1: 3: 3 with an excess of KI at the end of stage d). 10. Method according to claim 7, in which is used a proportion of malachite / HipH / phen of 1: 3: 3. 11. Method according to claim 7, in which uses a ratio of malachite / BI GGH / phen of 1: 3: 3 with excess KI in stage d). 12. Method according to claim 7, in which uses a proportion of malachite / BI GGH / bpy of 1: 3: 3. 13. Method according to claim 7, in which is used a proportion of malachite / BGGH / phen of 1: 3: 3. 14. Method according to claim 7, in which steps a) b) c) and d) are carried out at P atmospheric 15. Method according to claim 7, in which step b) is carried out at a temperature of boiling.

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16. Composition comprising between 0.5 and 50 µM of the compound according to any of the claims 1-6, to use as an antitumor agent. 17. Composition according to claim 16, comprising between 0.5 and 50 µM of the compound [Cu (I-hip)
(phen) 2] (I-hip -) • 7 O 2 O, for use as an antitumor agent. 18. Composition according to claim 1-6, which comprises between 10 and 50 µM of compound according to any of the claims 1-6, to use as an antitumor agent. 19. Use of a ternary compound according to any of claims 1-6, for the manufacture of a drug for cancer treatment human. 20. Use according to claim 19 for  the manufacture of a medicine intended for the treatment of lung cancer.