ES2912780B2 - IRIDIUM(III) COMPLEXES - Google Patents

Description

DESCRIPTION

IRIDIUM COMPLEXES (MI)

TECHNICAL FIELD OF THE INVENTION

The present invention falls within the field of chemistry of organometallic complexes. Specifically, the invention relates to cationic Iridium(NI) complexes comprising a ligand derived from p-carboline, as well as their compositions, for their use as a medicine, and more particularly for their use as photosensitizers in photodynamic therapy against cancer. In addition, the present invention relates to a particular indoline thiocyanation process that can be carried out in a one-pot manner starting from the corresponding indolines, which comprises the use of said Iridium(III) complexes for the photooxidation of indolines. to obtain the respective indoles and the subsequent regioselective thiocyanation of said indoles to give the indoles functionalized with thiocyanate groups.

BACKGROUND OF THE INVENTION

Today's society demands sustainable chemical compound synthesis procedures, therefore, the elimination of corrosive reagents, such as some oxidants, or the elimination of additional purification steps, are desired objectives in the current chemical industry. In addition, the design of synthetic procedures at room temperature is also a desired objective, allowing savings in energy use, making the procedure more sustainable and more economical, and making the reactions more selective as long as they take place under more favorable conditions. soft that avoid secondary reactions.

Indoles are present in a wide range of natural products such as tryptophan or tryptamines, while the use of some of the natural or synthetic indoles has been approved to treat various pathologies, such as diabetes, hypertension, inflammation, nervous system diseases. central or cancer, and other types of indoles have been found to have antibacterial properties.

On the other hand, cancer continues to be one of the diseases that require the development of new, more effective therapies. In this regard, some authors have described how some Iridium(III) complexes show the ability to induce cell death by autophagy in the dark in various cancer cell lines (He et al., Angewandte Chemie International Edition, 2014, 53, 45, 12137 -12141). Other authors have described complexes of Iridium(NI) that show the ability to induce paraptotic cell death (type of programmed cell death that occurs with cytoplasmic vacuolation) derived from its accumulation in mitochondria, inhibiting the growth of tumors in vivo (Zheng et al., Dalt. Trans., 2018, 47, 6942-6953). However, there is still a need to develop new therapies that allow a more localized treatment, by themselves, or in combination with other existing therapies, and that reduce unwanted side effects in healthy parts of the body.

Indoles can be prepared by several synthetic routes, including the oxidation of indolines in the presence of oxidants and catalysts. However, these procedures often require aggressive conditions (high temperatures, corrosive and toxic oxidants). Oxidative dehydrogenation procedures for CN and CC bonds have also been developed (Haiti et al., Beilstein Journal of Organic Chemistry 2017, 13, 1670-1692) using catalytic amounts of 1,10-phenanthroline-5,6-dione, Znh and pyridinium p-toluenesulfonate (PPTS); or by oxidative aromatization mediated by an oxidizing catalyst formed by [Cu(MeCN) ⁴ ]BF ⁴ and tert-butylperoxy-2-ethylhexyl carbonate (TBPC).

On the other hand, the thiocyanate functional group (-SCN) is found in some bioactive compounds and, more importantly, organic thiocyanates are used as precursors in the synthesis of other sulfur derivatives such as compounds with thiols (R-SH), thioethers (RS-R'), disulfide bonds (RSS-R'), isocyanates (RN=C=S), phosphonothioates (RS-P(O)R ² ), thiocarbamates (RSC(O)NR ² ), sulfonic acids ( RS(O) ² OH), sulfonyl chlorides (RS(O) ² Cl) or sulfonyl cyanides (RS(O) ² CN), as well as in the preparation of heterocycles such as pyridines with thioether groups ortho to nitrogen , or from sulfenyl tetrazoles. Most of the preparation procedures for compounds with the thiocyanato group involve the use of corrosive oxidants such as K ² S ² O ⁸ , Mn(OAc) ³ , ozone, DDQ (2,3-dichloro-5,6-dicyano- 1,4-benzoquinone) or hypervalent iodine reagents, among others, whose use is not easy due to its corrosive nature in many cases and which also generate toxic waste. It has also been possible to develop procedures that make use of O ² as an oxidant, but frequently require the use of high temperatures.

Finally, photocatalytic oxidation has appeared as an attractive option. For example, Fan et al. (Journal of Organic Chemistry 2014, 79, 10588-10592) uses air as the oxidant and Rose Bengal as the photocatalyst. In addition, these authors also describe ruthenium complexes as photocatalysts in the thiocyanation of indoles with good yields.

Finally, in the same work iridium complexes for use as photocatalysts in the thiocyanation of indoles are also described, but the yields obtained are only moderate.

However, a procedure that uses mild oxidants, that does not generate toxic waste, and that allows indoles with a thiocyanate group to be obtained in a regioselective manner, from the corresponding indolines, has not been described.

BRIEF DESCRIPTION OF THE INVENTION

A first aspect of the present invention refers to an Iridium(IM) complex of formula (M ⁺ ) ⁿ X ^n- , where n = 1 to 3, in which X ^n- is an anion and M ⁺ is a complex cation of formula (I), or a stereoisomer thereof:

in which:

- R1 and R2 are independently selected from H and C ¹ -C ⁶ alkyl;

either

- R1 and R2 are joined forming an aromatic ring of 6 carbon atoms to form a group B:

Another aspect of the invention refers to a one-pot process for obtaining a compound of formula (II):

wherein R3, R4, R5, and ^R6 are each independently selected from the group consisting of ^H , halogen, C1-C6 alkyl, and C1- ^{C6 alkoxy} and wherein said process comprises the following steps:

(i) oxidizing a compound of formula (III):

to obtain a first mixture comprising a compound of formula (IV):

Y

(ii) adding to said first mixture a salt of the "SCN" anion;

wherein both stages are carried out at room temperature, irradiating with blue light and in the presence of O ² and an Iridium(III) complex according to the first aspect of the present invention.

Another further aspect relates to the Iridium(NI) complex according to the first aspect of the present invention for use as a medicament and, in particular, for use as a photosensitizer in photodynamic therapy in the treatment of cancer.

Finally, the present invention refers to a pharmaceutical composition comprising an effective amount of an Iridium(III) complex, according to the first aspect of the present invention and, at least, one pharmaceutically acceptable excipient, as well as said pharmaceutical compositions for use as a medicament and in particular for antitumor use in photodynamic therapy.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1: Schematic representation showing the calculated energies (ordinate axis) for the frontier molecular orbitals and the energy intervals between HOMO and LUMO for the reference complex [1]+ ([Ir(ppy) ² (bpy)] ⁺ , where ppy is 2-phenylpyridinate and bpy is bipyridine) and for the complexes of the invention [IrL1]+, [IrL2]+ and [IrL3]+.

Figure 2: Characterization [energy (eV) and A (nm)] of the singlet and triplet states (S ⁱ , S ² , S ³ and T ⁱ , T ² and T ³ respectively) of the reference complex [1]+ y of the complexes of the invention [IrL1]+, [IrL2]+ and [IrL3]+.

Figure 3: Energy diagram showing the difference in energy calculated between the excited state with the lowest triplet energy (T ⁱ ) and the singlet state maintaining the geometry of the respective triplet (S ^o *) for the complexes of the invention [IrL1]+, [IrL2]+ and [IrL3]+ compared to that of the reference complex [1]+.

Figure 4: Phosphorescent emission spectra of the complexes of the invention [IrL1]Cl, [IrL2]Cl and [IrL3]Cl in acetonitrile (10 ^-5 M) at 25 °C.

DESCRIPTION OF THE INVENTION

The present invention relates to an Iridium(III) complex of formula (M ⁺ ) ⁿ X ^n- , where n = 1 to 3, in which X ^n" is an anion and M ⁺ is a cationic complex of formula ( I), or a stereoisomer thereof:

in which:

- R1 and R2 are independently selected from H and C ¹ -C ⁶ alkyl;

either

- R1 and R2 are joined forming an aromatic ring of 6 carbon atoms to form a group B:

(B).

Thus, the present invention refers to iridium(III) complexes in which the iridium atom is coordinated to two 2-phenylpyridinate ligands, through the nitrogen atom of the pyridine ring and one of the carbon atoms of the phenyl group. ; and to a ligand derived from beta-carboline, through two nitrogen atoms.

The 2-phenylpyridinate ligand is abbreviated, for the purposes of this description, as (CAN) indicating the two bond atoms of said ligand to the metal Ir(III), on the one hand, the nitrogen atom (N) of the pyridine and , on the other, a carbon atom (C) of the phenyl group. Similarly, for purposes of this disclosure, the p-carboline-derived ligand is abbreviated as NAN, to indicate that the binding between the ligand and the metal Ir(III) is accomplished, by a On the one hand, by the pyridine nitrogen (N) atom of p-carboline and, on the other, by the nitrogen (N) atom of the thiazolyl group.

For the purposes of the present invention the term stereoisomers is formally defined by IUPAC as compounds, which have identical chemical constitution, but differ with respect to the arrangement or orientation of atoms or groups in space, and are not superimposable, including, for therefore, A/A enantiomers. The mixture of stereoisomers that contains the same proportion of A and A stereoisomers is called a racemic mixture or racemate. In a preferred embodiment, the present invention refers to the cationic complex of formula (I), to a racemate thereof, or to any of the A or A enantiomers thereof, or to a non-racemic mixture of said enantiomers.

For the purposes of the present invention, the Xn" anion can be any anion that forms a stable compound with the cation of formula (I) of the invention. Thus, Xn" anions include, but are not limited to, for example, chloride, bromide, iodide, sulfate, nitrate, phosphate, acetate, trifluoroacetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate, trifluoromethanesulfonate or triflate, p-toluenesulfonyl or tosylate, hexafluorophosphate or tetrafluoroborate. In a preferred embodiment Xn" is selected from the group consisting of Cl, I, CF ³ SO ³ , CH ³ -C ⁶ H ⁴ -SO ³ , PF ⁶ , BF ⁴ ~ and NO ³ .

Example 1 provides details on the preparation of 3 Iridium(III) complexes of the invention, as well as their characterization. In the Iridium(III) complexes of the invention obtained experimentally in Example 1, Xn" is Cl" and, furthermore:

- In a preferred embodiment of the invention, R ¹ and R ² are both H. The synthesis of said complex of the invention, which comprises a cation M+ of formula (la) and is called, for the purposes of the present invention, [IrL1] +, is shown in Example 1.4. Thus, in one embodiment of the Iridium(III) complexes of the invention R ¹ and R ² are both H and M+ is a cationic complex of formula (la), or a stereoisomer thereof:

In another preferred embodiment of the invention, R1 is methyl and R2 is H. The synthesis of said complex of the invention, which comprises a cation M+ of formula (Ib) and is called, for the purposes of the present invention, [IrL2]+, It is shown in Example 1.5. Therefore, in one embodiment of the Iridium(III) complexes of the invention R1 is methyl and R2 is H and, M+ is a cationic complex of formula (Ib), or a stereoisomer thereof:

In another preferred embodiment of the invention, R1 and R2 are joined to form an aromatic ring of 6 carbon atoms. The synthesis of said complex of the invention, which comprises an M+ cation of formula (Ic) and is called, for the purposes of the present invention, [IrL3]+, is shown in example 1.6. Therefore, in one embodiment of the Iridium(III) complexes of the invention R1 and R2 are linked to form an aromatic ring of 6 carbon atoms to form a benzothiazole group (B):

and M+ is a cationic complex of formula (Ic), or a stereoisomer thereof:

The Iridium(IM) complexes of the invention are photocatalysts or photosensitizers, which interact with oxygen in the presence of light. Specifically, these complexes absorb energy from light to access an excited electronic state and are capable of transferring said energy to oxygen, forming reactive species, such as singlet oxygen or superoxide radicals that act as oxidants.

Photocatalytic activity is the result of several factors. Thus, when choosing a photosensitizer, the following characteristics may be relevant:

(1) have good absorption capacity in the visible region, since this allows, on the one hand, the use of conventional light sources, and even sunlight, and, on the other hand, they are light sources with lower energy than ultraviolet light, so they help to minimize the possible formation of secondary products due to the activation of bonds in the substrates or in the resulting products;

(2) be capable of generating the T triplet excited state upon absorbing said visible light; (3) have a high quantum yield of photoluminescence, as evidence of its ability to generate the T ¹ triplet excited state;

(4) be photostable, that is, it does not degrade under irradiation with visible light;

(5) that the half-life of the T ¹ triplet excited state be as long as possible, to allow the transfer of energy to oxygen to occur as efficiently as possible.

Surprisingly, the structural and physicochemical properties of the complexes of the invention give them properties that differentiate them from other complexes known in the state of the art. Thus, as shown in Example 1.7, the molecular structure of the [IrL2]Cl and [IrL3]Cl complexes of the invention shows small torsion angles (C-C-C-N) and (N-C-C-N) (< 4° for [IrL2] + and < 7° for [IrL3]+), in marked contrast to those described for also octahedral complexes of the state of the art, with other azolyl-P-carboline groups, in which larger N-C-C-N angles are observed due to high steric hindrances . Thus, it seems that the presence of the thiazolyl group provides greater stability to the complexes, which also present hydrogen bonds and other weak interactions that stabilize the crystal lattice.

On the other hand, as shown in Example 1.9, in complexes of the type [Ir(CAN) ² (NAN)]+ known in the state of the art, such as the reference complex [Ir(ppy) ² (bpy )]+ (hereinafter, indicated as [1]+) and in the complexes of the invention, the lowest energy unoccupied molecular orbital (LUMO) is predominantly located on the NAN ligands and, consequently, its energy is affected significantly by the identity and electronic properties of said ligand. Thus, the substitution of the bipyridine ligand of the [1]+ complex by a p-carboline ligand of the complexes of the invention significantly stabilizes the LUMO. This can be interpreted based on the higher n -n conjugation of p-carbolines compared to bipyridine.

Finally, as shown in example 1.9, the complexes of the invention show emission energies shifted towards lower energy values (longer wavelengths) compared to those of the reference complex [1]+, in agreement with a value of similar energy of the HOMO orbital in all of them, but a value of higher energy for the LUMO orbital in the reference complex [1]+. Also, as shown in Example 1.8. the complexes of the invention have good photostability under different light sources.

Thus, the Iridium(NI) complexes of the invention present a series of characteristics that differentiate them from the complexes known in the state of the art that make them useful as photocatalysts or photosensitizers, absorbing energy from light and transferring it to oxygen. to form reactive species, such as singlet oxygen or superoxide radicals that act as oxidants. Thanks to these characteristics, they can be used effectively in various applications, both in organic synthesis procedures (photo-oxidation reactions), as photocatalysts, and in therapeutic applications.

Specifically, the substitution of the bipyridine ligand of the complex [1]+ by a p-carboline ligand of the complexes of the invention significantly stabilizes LUMO, based on the higher n -n conjugation of the p-carbolines compared to bipyridine and makes excitation/irradiation with less energetic light (of longer wavelength) possible, which gives the Iridium(III) complexes of the invention certain advantages as photocatalysts and in therapeutic applications:

1) the use of lower energy light implies a lower risk of secondary reactions in photocatalysis and therefore more selective processes; Y

2) the greater penetration capacity of the light of longer wavelength, through the tissues, allows the treatment of internal tissues and organs.

Thus, one aspect described in the present invention refers to a process for obtaining a compound of formula

wherein R3, R4, R5 and R6 are each independently selected from the group consisting of H, halogen, C ¹ -C ⁶ alkyl and C ¹ -C ⁶ alkoxy and wherein said process comprises: (ii) mixing a compound of formula (IV):

with a salt of the -SCN anion, at room temperature, irradiating with blue light and in the presence of O ² and an Iridium(NI) complex according to the invention.

Another additional aspect described in the present invention refers to a process for obtaining a compound of formula (IV):

wherein R3, R4, R5 and R6 are each independently selected from the group consisting of H, halogen, C ¹ -C ⁶ alkyl and C ¹ -C ⁶ alkoxy and wherein said process comprises: (i) oxidizing a compound of formula (III):

at room temperature, irradiating with blue light and in the presence of O ² and an Iridium(III) complex according to the invention.

In addition, the present invention refers to a one-pot process for obtaining a compound of formula (II):

wherein R3, R4, R5, and ^R6 are each independently selected from the group consisting of ^H , halogen, C1-C6 alkyl, and C1- ^{C6 alkoxy} and wherein said process comprises the following steps:

(i) oxidizing a compound of formula (III):

to obtain a first mixture comprising a compound of formula (IV):

Y

(ii) adding to said first mixture a salt of the "SCN" anion;

wherein each of said steps (i) and (ii) are carried out at room temperature, irradiating with blue light and in the presence of O ² and an Iridium(III) complex according to the invention.

For the purposes of the present invention, the term "ambient temperature" refers to the temperature at which the medium in which the reaction is carried out is found without use heat or cooling media. Preferably said ambient temperature is from 15°C to 30°C.

For purposes of the present invention the term "blue light" refers to light of wavelength from 400 nm to 495 nm.

Preferably, each of said stages is carried out in an aprotic organic solvent, at a temperature between 15 °C to 30 °C, irradiating with light with a wavelength of between 400 nm and 495 nm and, in the presence of O ² and an Iridium(III) complex according to the invention. Non-limiting examples of aprotic organic solvents are tetrahydrofuran, acetonitrile, dimethylformamide and acetone among others.

More preferably, each of said steps is carried out in an aprotic organic solvent, at a temperature between 15 °C to 30 °C, irradiating with light of wavelength between 450 nm and 470 nm and, in the presence of O ² and an Iridium(III) complex according to the invention.

Even more preferably, each of said steps is carried out in tetrahydrofuran at a temperature between 15 °C to 30 °C, irradiating with light of wavelength between 450 nm and 470 nm and, in the presence of O ² and an Iridium(III) complex according to the invention. In a preferred embodiment, R3, R4, R5 and R6 are H. In another preferred embodiment of the invention, R3, R4 and R5 are H and R6 is a halogen. In yet another preferred embodiment of the invention, R4, R5 and ^R6 are ^H and R3 is C1-C6 alkyl.

As observed in the results obtained in Example 2, both the onepot process for thiocyanation of indoles from indolines, as well as each of its stages, that is, the process for thiocyanation of indoles and the process for dehydrogenation of indolines, All of them carried out in the presence of the Iridium(III) complexes of the present invention show good yields, both when the substrates comprise electron-donating substituents (eg: alkoxide, alkyl), and substituents that withdraw electrons (electron-withdrawing) (eg: halogen), in several positions (C-1, C-2, C-5 and C-6), showing the great versatility of these procedures.

In addition, the use of the complex of the invention gave a better result in the one-pot process than that of the comparative experiments with eosin Y or with Rose Bengal.

In addition, all the processes and stages can be carried out at room temperature, thus energy costs are significantly reduced, compared to other state-of-the-art procedures that require the use of higher temperatures. Simultaneously, the use of oxygen as an oxidant, in the presence of the Iridium(III) complexes of the present invention, makes it possible to avoid the use of more aggressive oxidants, therefore toxic waste is not generated.

On the other hand, and more preferably, the Iridium(III) complexes of the present invention allow the regioselective thiocyanation of indoles to be carried out, in the C-3 position, from the corresponding indolines, in a one-pot manner. , producing first a dehydrogenation of the indoline and, later, the thiocyanation, in both cases, with the use of oxygen, in the presence of light and with the use of the Iridium(III) complexes of the invention as photocatalysts. Said procedure is of the one-pot type, that is, without the need to isolate the intermediate indole, so it is more economical, since isolation and purification steps of said intermediate products are avoided. Furthermore, thiocyanation is regioselective, ie, it occurs at a specific position on the indole, without significantly giving rise to other products comprising the thiocyanate group at other positions on the indole.

The term "comprises" indicates that it includes a group of certain characteristics (for example, a group of characteristics A, B and C). It is interpreted to mean that it includes those characteristics (A, B and C), but does not exclude the presence of other features (for example, features D or E), as long as they do not make the claim impracticable. Additionally, the terms "contains", "includes", "has" or "encompasses", and the plural forms thereof , are to be taken as synonymous with the term "comprising" for the purposes of the present invention. On the other hand, if the expression "consists of" is used, then no additional characteristics are present in the apparatus/method/product, apart from those that follow said expression. In this sense, for the purposes of the present invention, the term "comprises" may be replaced by any of the terms "consist of" or "consists essentially of". Accordingly, "comprising" may refer to a group of features A, B and C, which may additionally include other features, such as E and D, provided that such features do not render the claim impracticable, but said term "comprising ” also includes the situation where the group of characteristics “consists of” or “consists essentially” of A, B and C.

Another aspect of the present invention refers to a pharmaceutical composition comprising at least one Iridium(NI) complex according to the present invention and at least one pharmaceutically acceptable excipient.

The term "pharmaceutically acceptable" refers, for the purposes of the present invention, to that authorized or authorizable by a regulatory agency of the federal government or a state government or listed in the European Pharmacopoeia, United States or other generally recognized pharmacopoeia for use in animals. , and more particularly in humans. The excipient included in the pharmaceutical compositions described in the present invention refers to an inert component such as, but not limited to, cosolvents, surfactants, oils, humectants, emollients, preservatives, stabilizers, and antioxidants. Any pharmacologically acceptable buffer can be used, such as TRIS or any phosphate buffer.

The person skilled in the art will be able to select one or more pharmaceutically acceptable vehicles or excipients known in the state of the art, in such a way that the pharmaceutical compositions are suitable for administration to both a human subject and an animal. Such administration may be within a treatment of an adult or a pediatric patient.

On the other hand, another aspect of the invention relates to an Iridium(III) complex according to the present invention, or a pharmaceutical composition comprising it, for use as a medicament.

In particular, the present invention relates to an Iridium(III) complex according to the present invention, or a pharmaceutical composition comprising it, for use in the treatment of cancer, and in particular for use as an antitumor in photodynamic therapy. Thus, the present invention relates to an Iridium(III) complex according to the present invention, or a pharmaceutical composition comprising it, for use as a photosensitizer in photodynamic therapy in the treatment of cancer. Preferably, the present invention relates to an Iridium(III) complex according to the present invention, or a pharmaceutical composition comprising the same for use in the treatment of cancer, wherein said Iridium(III) complex of the invention it is administered together with, or before radiation therapy.

For the purposes of the present invention, the term photodynamic therapy refers to a therapeutic treatment using a photosensitizing drug and a specific type of light. By exposing photosensitizing compounds to light irradiation of a particular wavelength, they produce reactive oxygen species that cause nearby cells to die. Thus, since the iridium(III) complexes of the invention are effective photocatalysts and produce reactive oxygen species, they are useful in photodynamic therapy for localized treatment of tumors.

The Iridium(III) complexes of the invention, or pharmaceutical compositions comprising them, may also be administered concurrently, prior to, or subsequent to additional therapy. Preferably, said additional therapy is radiotherapy, immunotherapy or chemotherapy.

A preferred embodiment of the invention refers to an Iridium(III) complex of the invention, or a pharmaceutical composition comprising it, for use in the treatment of cancer, characterized in that said Iridium(III) complex of the invention, or Said pharmaceutical composition comprising it is administered together with, before, or after a radiotherapeutic treatment, a chemotherapeutic treatment, or an immunotherapeutic treatment.

A more preferably embodiment of the invention refers to an Iridium(III) complex of the invention, or a pharmaceutical composition comprising it, for use in the treatment of cancer, characterized in that said Iridium(III) complex of the invention, or said pharmaceutical composition comprising it, is administered together with, or before, the administration of radiotherapy.

One embodiment of the invention relates to the use of an Iridium(III) complex according to the present invention, in the manufacture of a medicament for the treatment of cancer. Preferably, in the preparation of a photodynamic therapy antitumor drug. Another embodiment refers to the use of an Iridium(III) complex according to the present invention, in the preparation of a medicine for the treatment of cancer, in combination with radiotherapy, that is, where said medicine is administered together with, or before the administration of radiotherapy.

Another embodiment of the present invention relates to a method of treating cancer comprising administering an Irido(IN) complex according to the invention, or a pharmaceutical composition comprising it, to a subject in need thereof, together with, or before, the administration of radiotherapy.

An effective amount, or a therapeutically effective amount, for the purposes of the present invention, is understood as that which provides a therapeutic effect without causing unacceptable toxic effects in the patient. The effective amount or dose of the medicament depends on the compound and the condition or disease being treated and, for example, the age, weight and clinical condition of the treated patient, the method of administration, the patient's medical history, the severity of the disease and the potency of the compound administered.

There are multiple types of cancer, among which are, for example, cancer of the oral cavity and pharynx, cancer of other digestive organs, cancer of other respiratory organs, cancer of bone and articular cartilage, melanoma and other malignant neoplasms of the skin, cancer of mesothelial tissues and soft tissues, cancer of the genital organs, cancer of the urinary tract, cancer of the eye, brain and other regions of the nervous system, cancer of the thyroid and other endocrine glands, malignant neuroendocrine tumors, cancer of lymphoid, hematopoietic and related tissues, carcinomas in situ, benign tumors, neoplasms of uncertain behaviour, polycythemia vera and myelodysplastic syndromes, neoplasms of other locations and neoplasms of unspecified behaviour.

Of special interest are pancreatic cancer, bile duct carcinoma, neuroblastoma, colon cancer, breast cancer, myeloma, gastric cancer, liver cancer, glioblastoma, ovarian cancer, colorectal cancer, non-Hodgkin lymphoma, lung cancer, cancer prostate cancer, small cell lung cancer, large cell lung cancer, kidney cancer, esophageal cancer, stomach cancer, cervical cancer, or lymphoma tumors. The lipid modification of the cell membrane can be used as a strategy for the prevention or treatment of multiple types of cancer.

In one embodiment of the invention the cancer is selected from the group consisting of: colon cancer, colorectal carcinoma, colorectal adenocarcinoma, prostate cancer, prostate adenocarcinoma, prostate carcinoma, breast cancer, breast carcinoma, breast adenocarcinoma, triple negative breast cancer, brain cancer, brain adenocarcinoma, brain neuroblastoma, lung cancer, lung adenocarcinoma, carcinoma lung, small cell lung cancer, ovarian cancer, ovarian carcinoma, ovarian adenocarcinoma, uterine cancer, gastroesophageal cancer, renal cell carcinoma, clear cell renal cell carcinoma, endometrial cancer, endometrial carcinoma, sarcoma endometrial stromal cancer, cervical carcinoma, thyroid carcinoma, metastatic papillary thyroid carcinoma, follicular thyroid carcinoma, bladder carcinoma, urinary bladder carcinoma, transitional cell carcinoma of the urinary bladder, liver cancer, metastatic cancer liver, pancreatic cancer, neuroendocrine cancers, squamous cell carcinoma, osteosarcoma, rhabdomyosarcoma, embryonal cancers, glioma, neuroblastoma, medulloblastoma, retinoblastoma, nephroblastoma, hepatoblastoma, melanoma, hematologic malignancies such as leukemias, lymphomas, and myelomas.

In a further embodiment of the present invention, the pharmaceutical compositions disclosed herein comprise at least one additional therapeutic component or active compound. Said additional therapeutic component or active compound provides additive or synergistic biological activities. For the purposes of the present description, the terms "active compound" or "therapeutic component" should be taken as synonymous and mean a chemical or biological entity that exerts therapeutic effects when administered to humans or animals. Said active compound or therapeutic component exerts therapeutic effects when administered to humans or animals, and can be cell therapy, small molecule therapy, immunotherapy, radiotherapy, among others. Preferably said active compound or said therapy is a chemotherapeutic agent, cell therapy or immunotherapeutic agent.

In a preferred embodiment, said pharmaceutical composition further comprises a chemotherapeutic agent selected from the group consisting of platinum-based antineoplastic agents, antimitotic chemotherapeutic agents, a poly adenosine diphosphate ribose polymerase (PARP) inhibitor, type I topoisomerase inhibitors, type II topoisomerase inhibitors, epothilones, skeletal cycle disruptors, alkylating agents, epothilones, histone deacetylase inhibitors, kinase inhibitors, antifolates, kinase inhibitors, peptide antibiotics, retinoids, vinca alkaloids, and thymidylate synthase inhibitors. More preferably, the chemotherapeutic agent is selected from the group consisting of bevacizumab, carmustine, cyclophosphamide, ifosfamide, busulfan, temozolomide, mechlorethamine, chlorambucil, melphalan, dacarbazine, daunorubicin, doxorubicin, daunorubicin, epirubicin, idarubicin, mitoxantrone, valrubicin, paclitaxel, docetaxel, abraxane, taxotere, epothilone, vorinostat, romidepsin, irinotecan, topotecan, camptothecin, exatecan, lurtotecan, etoposide, teniposide, tafluposide, bortezomib, erlotinib, gefitinib, imatinib, vemurafenib, vismodegib, azacitadine, azacitadine, capecitabine cytarabine, cladribine, fludarabine, doxifluridine, fluorouracil, gemcitabine, hydroxyurea, mercaptopurine, methotrexate, pemetrexed, thioguanine, bleomycin, actinomycin, carboplatin, cisplatin, oxaliplatin, tretinoin, alitretinoin, bexarotene, vinblastine, vincristine, vindesine, and vinorelbine.

The compositions of the invention can be included in capsules, tablets, sachets or sachets or any other type of presentation. To make such compositions, conventional techniques for the preparation of pharmaceutical compositions can be used. For example, the compound of interest can be mixed with a vehicle, or diluted in a vehicle, or contained in a vehicle in the form of an ampule, capsule, tablet, sachet, sachet, or other container. When the vehicle serves as a solvent, it can be solid, semi-solid or liquid and act as an excipient or medium for said active compound. The compound of interest can be adsorbed on a solid granular medium. Some examples of suitable vehicles are water, saline solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, lactose, terra alba, sucrose, cyclodextrins, amylose, magnesium stearate, talc, gelatin, agar, pectin , acacia, stearic acid, cellulose alkyl ethers, silicon acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythrol fatty esters, polyethylene, hydroxymethylcellulose and polyvinylpyrrolidone. Likewise, the vehicle or support can include sustained release materials known in the state of the art, such as glyceryl monostearate or distearate alone or mixed with a wax. The formulations may also include wetting agents, emulsifiers, suspending agents, preservatives, sweeteners, or flavors. The compositions can be formulated to provide rapid, sustained or delayed release of the active agent after it is administered to the patient using methods known in the art.

The pharmaceutical compositions can be sterilized and mixed, if desired, with additional agents, emulsifiers, salt to influence osmotic pressure, buffers and/or coloring substances that do not react adversely with the active compounds.

A preferred embodiment disclosed herein relates to the route of administration, which can be any route that efficiently transports the compound. disclosed herein above, to the appropriate or desired site of action, such as oral, nasal, topical, pulmonary, transdermal, or parenteral, eg, rectal, subcutaneous.

For oral administration, both solid and liquid dosage forms can be prepared. To prepare solid compositions such as tablets, the compound of interest is mixed in a formulation with other conventional ingredients such as talc, magnesium stearate, dicalcium phosphate, magnesium aluminum silicate, starch, lactose, acacia, methylcellulose, and functionally similar materials such as carriers and pharmaceutical diluents. Capsules can be prepared by mixing the compound of interest with a pharmaceutically inert solvent and filling the mixture into an appropriately sized hard gelatin. Soft capsules are made by machines for encapsulating suspensions of the compound of interest with an acceptable vegetable oil, light paraffin or inert oil. Liquid dosage forms such as syrups, elixirs and suspensions can also be prepared. The water soluble forms can be dissolved in an aqueous vehicle together with sugar, flavorings, and preservatives to form a syrup. An elixir is prepared using a hydroalcoholic vehicle (eg ethanol) with suitable sweeteners such as sugar or saccharin, together with aromatic flavoring agents. Suspensions can be prepared with an aqueous vehicle and the aid of a suspending agent such as acacia, tragacanth, methylcellulose and the like.

For parenteral application, the use of injectable solutions or suspensions, for intradermal, intramuscular, intravascular and subcutaneous use, are evident to the person skilled in the art. In addition to the compound of interest, the compositions may include other non-toxic pharmaceutically acceptable diluents and excipients, including vehicles commonly used in pharmaceutical compositions commonly used in humans or animals. The diluent is selected so that it does not affect the biological activity of the composition. Examples of diluents used especially in injectable formulations are organic and inorganic saline solutions, Ringer's solution, dextrose solution and Hank's solution. In addition, the compositions can include additives such as other excipients, adjuvant agents, non-therapeutic and non-immunogenic stabilizers, and the like. Examples of excipients that can be included in the formulation include, but are not limited to, cosolvents, surfactants, oils, humectants, emollients, preservatives, stabilizers, and antioxidants. Any physiologically acceptable buffer can be used, such as Tris or phosphate buffers. Effective amounts of diluents or additives or excipients are those that are effective in obtaining a pharmaceutically acceptable formulation in terms of solubility and biological activity.

Another embodiment relates to the dosage regimen. The term "unit dose" refers to physically discrete units suitable as unit doses to a subject wherein each unit contains a predetermined amount of active material calculated to produce the appropriate therapeutic effect in association with the appropriate diluent, carrier, or vehicle.

EXAMPLES

The examples described below are for illustrative purposes and are not intended to limit the scope of the present invention. The materials and methods used in the examples described herein are detailed below.

Materials and methods

All synthetic manipulations were carried out under a dry, oxygen-free atmosphere using standard Schlenk techniques. Solvents were dried and distilled under a nitrogen atmosphere before use. Elemental analyzes were carried out on a Thermo Fisher Scientific Flash 2000 Elemental Microanalyzer. In some cases solvent molecules were introduced into the molecular formula to adjust for values where % carbon differed by more than 0.4%.

UV absorption spectra were measured on a double beam Evolution 300 UV-Vis spectrophotometer (Thermo Scientific). Fluorescence spectra and fluorescence lifetimes were measured with an FLS980 fluorimeter (Edinburg Instruments) with a 450 W Xenon arc lamp and a TCSPC laser, respectively. Quantum yields were determined using the aforementioned FLS980 fluorimeter and a Red PMT integrated sphere as detector. HR-ESI(+) mass spectra (position of peaks in Dalton) were recorded with an Agilent LC-MS system (1260 Infinity LC / 6545 Q-TOF MS mass spectrometer) using DCM/DMSO (4:1) as solvent for the sample and HCOOH/MeOH 0.1% in water as the mobile phase. Experimental m/z values are expressed in Daltons and fit well with calculated m/z values for monoisotopic fragments. NMR samples were prepared by dissolving an appropriate amount of the compound of interest in 0.5 mL of the respective deuterated solvent and spectra were performed at 298 K on a Varian Unity Inova-400 (399.94 MHz for 1H; 376.29 MHz for 19F ; 100.6 MHz for 13C). In general, the 1H NMR spectra were taken with 32 scans in 32k measurements in a spectral width of 16ppm. The ¹ H and ¹³ C{ ¹ H} shifts were internally referenced to TMS taking into account the residual ¹ H and ¹³ C{ ¹ H} signals from DMSO (5 = 2.50 ppm and 5 = 39.52 ppm) and CDCh ( 5 = 7.26 ppm and 5 = 77.16 ppm), according to data published by Fulmer et al, Organometallics 2010, 29, 2176-2179. The values of the chemical shifts (5) were indicated in ppm and the coupling constants (J) in Hertz. The splittings of the proton resonances indicated in the ¹ H NMR data are defined as s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, bs = broad singlet. 2D NMR spectra such as ¹ H- ¹ H gCOSY, ¹ H- ¹ H NOESY, ¹ H- ¹³ C gHSQC and ¹ H-

¹³ C gHMBC were carried out using standard pulse sequences.

The temperature (±1 K) was controlled by a standard unit calibrated with methanol as a reference. All NMR data processing was carried out using the MestReNova version 10.0.2 software program.

Example 1: Synthesis and characterization of the Ir(NI) complexes of the present invention The synthetic procedure for the preparation of p-carbolines was adapted from previously described protocols (Pakhare, DS et al Tetrahedron Lett., 2015, 56, 6012 6015. and Tan, C. et al. J. Med. Chem., 2010, 53, 7613-7624.). Specifically, tryptamine was reacted with the corresponding carboxaldehyde in the presence of MnO ² , using anisole as solvent (Scheme 1). The cationic complexes of Iridium(III) of formula (I) with the ligands L1, L2 and L3, were prepared through a bridge-breaking reaction between the Iridium(III) precursor, rac-[Ir(^-Cl )(ppy) ² ] ² and the respective p-carboline ligand L1 - L3, using a 1:2 molar ratio and a MeOH/CH ² Ch (2:1) solvent mixture at the reflux temperature of the mixture (Scheme one).

Scheme 1: Synthesis and molecular structure of the ligands L1-L3 and the complexes [IrL1]Cl to [IrL3]Cl.

The iridium salt, IrCh XH ² O, was purchased from Johnson Matthey and used as received. Iridium dinuclear precursors [Ir(^-Cl)(ppy > ^2]2 (ppy = 2-phenylpyridinate), were prepared according to the procedure described by S. Sprouse et al., J. Am. Chem. Soc. 1984, 106, 6647-6653.Other reagents such as tryptamine, thiazolyl-2-carboxaldehyde, 4-methyl-2-thiazolylcarbozaldehyde, and benzothiazolyl-2-carboxaldehyde were purchased from Sigma-Aldrich and used without further purification.The deuterated solvents (CDCh and DMSO -d6) were obtained in Eurisotop.

1.1. Synthesis of 1-(thiazol-2-M)-p -carboline (L1):

In a Schlenk flask, a mixture of tryptamine (200 mg, 1.22 mmol) and thiazolyl-2-carboxaldehyde (113 ^L, 1.22 mmol) was heated at 155 °C in dry anisole (50 mL) for 3 h with continuous stirring. Activated MnO ² (20 equiv) was then added and the mixture was refluxed for an additional 21 h. The suspension was filtered hot and the solvent was removed in vacuo to obtain a yellow solid. 227 mg, Yield 74%.

1.2. Synthesis of 1-(5-methMthiazol-2-M)-p-carbolma (L2):

4-methyl-2-thiazolylcarboxaldehyde (145 ^L, 1.35 mmol) at 155 °C in dry anisole (50 mL) for 21 h with continuous stirring. Activated MnO ² (20 equiv) was then added and the mixture was heated under reflux for an additional 21 h. The suspension was filtered hot and the solvent was removed in vacuo to give a yellow solid. 0.198g. Yield 55.34%.

1.3. Synthesis of 1-(benzothiazole-2-M)-p-carbolm (L3):

and benzothiazolyl-2-carboxaldehyde (0.216 g, 1.28 mmol) at 155 °C in dry anisole (50 mL) for 21 h with continuous stirring. Activated MnO ² (20 equiv.) was then added to the mixture and refluxed for an additional 21 h. The suspension was filtered on hot and the solvent was removed in vacuo to give a yellow solid. 0.089g. Yield 58.86%.

1.4. Synthesis of rac-[Ir(ppy)2(L1)]Cl, ([IrL1]Cl):

In a 100 mL Schlenk flask, previously purged with nitrogen, the L1 ligand obtained in example 1.1 was added. (0.05 g, 0.199 mmol) to a solution of [Ir(ppy) ² (^-Cl ^{) ]2} (0.100 g, 0.093 mmol) in a dichloromethane/methanol mixture (25 mL, 2:1). The mixture was stirred overnight at 50 °C under a nitrogen atmosphere. The solvent was removed in vacuo and the solid reaction crude was washed with methyl tert-butyl ether (6 mL). Finally, the product was filtered and dried in vacuo for 5 hours. Orange solid: 0.120 g. Yield 82%.

1.5. Synthesis of rac-[Ir(ppyML2)]Cl, ([IrL2]Cl):

In a 100 mL Schlenk flask, previously purged with nitrogen, the ligand L2 (0.054 g, 0.202 mmol) was added to a solution of [Ir(ppy) ² (^-Cl ^{) ]2} (0.100 g, 0.093 mmol) in a mixture of dichloromethane/methanol (25 mL, 2:1). The mixture was kept stirred under a nitrogen atmosphere overnight at 50 °C. 30 mL of diethyl ether were added to precipitate the product and when the solid was completely formed the ether was filtered off under a nitrogen atmosphere. The solid was washed with an additional 5 mL of Et ² O with stirring (10 min), filtered, and dried in vacuo for 5 hours. Orange solid 0.111 g. Yield: 71.55%.

1.6. Synthesis of rac-[Ir(ppy)2(L3)]Cl, ([IrL3]Cl):

In a 100 mL Schlenk flask, previously purged with nitrogen, the ligand L3 (0.054 g, 0.202 mmol) was added to a solution of [Ir(ppy) ² (^-Cl)] ² (0.116 g, 1.08 mmol) in a dichloromethane/methanol mixture (25 mL, 2:1). The mixture was kept stirred at 50 °C under a nitrogen atmosphere overnight. 30 mL of diethyl ether were added to precipitate the product and when the solid was fully formed, the solvent was filtered off under a nitrogen atmosphere. The solid was washed with an additional 5 mL of Et ² O under stirring (10 min.), filtered, and dried in vacuo for 5 hours. Orange solid 0.102 g. Yield: 57.92%.

The cationic Ir(III) complexes of formula (I) of the invention were obtained as racemates (A and A) as orange or brown solids in acceptable purity and yield. The synthesized Ir(III) complexes of the invention are soluble in common organic solvents such as DMSO, acetone, methanol and dichloromethane, and only slightly soluble in CH ³ CN and water. The synthesized ligands and complexes were characterized by multinuclear NMR, IR spectrophotometry and mass spectrometry and also, by elemental analysis. 1H NMR spectra were carried out in d6-DMSO at 25 °C and show the following distinctive features: (a) two sets of signals for the non-equivalent CAN ligands (16H) consistent with the lack of symmetry of the complexes (Ci symmetry); (b) a broad singlet above 12.2 ppm for the NH group of the coordinated P-carboline ligand, compared to the corresponding resonance below 11.8 ppm for the free ligands; and (c) a singlet at 1.74 (Me) ppm for the [IrL2]Cl complex. The mass spectra (HR ESI(+) MS) of the cationic complexes of formula (I) of the invention show mass/charge ratios and isotopic distributions fully compatible with their molecular structures. Thus, ligands (Ln=L1, L2 or L3) show peaks for [(Ln)+H]+ ions, while complexes show peaks for [Ir(CAN)2(NAN)]+ cations.

1.7. X-ray diffraction characterization

Single crystals of [IrL2]ClCH2Ch and [IrL3]Cl0.5CH3OH0.75H2O suitable for X-ray diffraction were obtained by slow diffusion of dichloromethane in a methanolic solution of [IrL2]Cl and by slow evaporation of a solution of [IrL3]Cl in methanol. Table 1 shows the distances and bond angles with the corresponding standard deviations.

Go(1)-N(1) 2.159(7) Go(1)-N(1) 2.164(8)

Go(1)-N(2) 2.148(8) Go(1)-N(2) 2.172(8)

Go(1)-N(4) 2.042(7) Go(1)-N(4) 1.97(2)

Go(1)-N(5) 2.052(7) Go(1)-N(5) 2.047(9)

Go(1)-C(33) 2.008(10) Go(1)-C(25) 2.039(4)

Go(1)-C(22) 2.020(9) Go(1)-C(36) 2.07(2)

N(2)-Ir(1)-N(1) 76.5(3) N(1)-Ir(1)-N(2) 76.4(3)

C(33)-Ir(1)-N(5) 81.9(4) C(25)-Ir(1)-N(5) 79.9(3)

C(22)-Ir(1)-N(4) 80.8(3) C(36)-Ir(1)-N(4) 82.1(8)

Table 1: Selected bond distances and angles for the [IrL2]Cl and [IrL3]Cl complexes.

The molecular structure of the analyzed complexes has a pseudo-octahedral geometry with a trans-N,N and cis-C,C arrangement for the CAN ligands. In both complexes the distances between the iridium atom and the nitrogen atoms of the P-carboline ligands (2,148(8) Á to 2,172(8) Á) are longer than those of the ligand nitrogen atoms. CAN (2-phenylpyridinate). The torsion angles (CCCN) and (NC-CN) for the CAN ligand and NAN ancillary ligands respectively, are small (<4 Á for [IrL2]+ and <7 Á for [IrL3]+), which confirms the virtual coplanarity of the two aromatic entities that form each ligand. This coplanarity contrasts strongly with the angles described for octahedral complexes with other azolyl-p-carboline ligands, in which larger NCCN angles are observed due to high steric hindrance between the NH or N-Me groups of the p-carboline, and the CH and NH groups on the azolyl ring. For example, for similar Ir(III) complexes NCCN angles of 23.3° and 20.5° have been reported for 1-(quinolin-2-yl)-p-carboline (He L. et al. Chem. Sci ., 2015, 6, 5409-5418.) and 9-methyl-1-(quinolin-2-yl)-p-carboline (He L., et al., Dalt. Trans., 2018, 47, 6942-6953 .), respectively. Thus, we can infer that the substitution of pyridyl or imidazolyl rings by a thiazolyl entity can provide greater stability to the cationic complexes of Ir(III) of formula (I) of the invention. The analysis of the crystal structures of the complexes of the invention also revealed the existence of different hydrogen bonds and n-n interactions that stabilize the crystal lattice.

1.8. Stability of the complexes of the invention

The stability of the complexes in solution (10 ^-2 M, CD ³ CN) was studied in the dark and then under different light sources (sun and blue light), recording their evolution by 1H NMR spectroscopy. Figure 1 shows the photodegradation study carried out for the complex of the invention [IrL2]Cl as a representative example. No degradation symptoms were observed in the absence of light (24h), or under sun exposure (5 days).

1.9. Electrochemical and photophysical properties of the complexes of the invention Theoretical type (DFT) and type (TD-DFT) calculations were carried out for the cationic complexes of formula (I) of the complexes of the invention [IrL1]+ -[ IrL3]+, as well as for the reference complex [Ir(ppy) ² (bpy)]+, [1]+ to better understand the electrochemical and photophysical properties of the complexes of the invention compared to those of the reference complex. Calculations were carried out at the B3LYP/(6-31G(d,p)+LANL2DZ) level (Becke et al., Chem. Phys., 1993, 985648-5652; Lee et al. (Phys. Rev. B. , 1988, 37, 785-789, Hay et al., J. Chem. Phys., 1985, 82, 299-310), and included the effects of solvent (CH ³ CN).

The calculations predict a -pseudo-octahedral structure in its ground electronic state (S ⁰ ), in agreement with the molecular structures determined by X-ray diffraction. The topologies of the frontier molecular orbitals (MOs) from HOMO-2 (HOMO= highest energy occupied molecular orbital) to LUMO+2 (LUMO= lowest energy unoccupied molecular orbital) are similar for the three complexes [IrL1] ⁺ -[IrL3] ⁺ studied. In general, in this type of [Ir(CAN) ² (NAN)] ⁺ complexes, such as the complexes of the invention, or the reference complex [1] ⁺ , the LUMO orbital is located predominantly on the NAN ligands and, consequently, its energy is significantly affected by the identity and electronic properties of said ligand. Thus, in general, the replacement of a bipyridine ligand of the [1] ⁺ complex by a p-carboline ligand of the complexes of the invention significantly stabilizes the LUMO. This can be interpreted on the basis of the higher n conjugation of the p-carbolines compared to bipyridine. This is confirmed by the even higher stability of the LUMO orbital in the [IrL3] ⁺ complex compared to the other complexes of the invention studied, due to the presence of the benzothiazole unit with higher aromaticity. The energy differences between the HOMO-LUMO orbitals calculated for the complexes of the invention [IrL1] ⁺ , [IrL2] ⁺ and [IrL3] ⁺ are smaller than those obtained for the reference complex [1] ⁺ as a consequence of the important stabilization of the LUMO orbital with the ligands derived from p-carboline. Figure 1 shows a schematic representation of the energy values of the frontier molecular orbitals for the reference complex [1] ⁺ and the complexes of the invention [IrL1] ⁺ , [IrL2] ⁺ and [IrL3] ⁺ .

For the 3 complexes of the invention studied in a representative manner, the triplet and singlet excited states were characterized by TD-DFT at the B3LYP/(6-31G**+LANL2DZ) level, as shown in the table of Figure 2. The phosphorescent emission energies (E ^em ) estimated as the vertical energy difference between T ⁱ and S ^or in the minimum energy geometry of the T ⁱ state are included in Table 2 and shown schematically in Figure 3.

Table 2: Differences in energy between states S ^o and T ⁱ and the emission energy for state T ⁱ .

The calculated values listed in Table 2 adequately predict the observed trends for the experimental values determined for the wavelengths of

3 i

issue. Thus, the complexes of the invention show emission energies shifted towards lower energy values (longer wavelengths) compared to those of the reference complex [1]+, in agreement with a similar energy value of the HOMO orbital in all of them. , but a higher energy value for the LUMO orbital of the reference complex [1]+. This result confirms an emission with a marked HOMO^-LUMO nature.

1.10 Emission spectroscopy

The emission spectra for the complexes of the invention [IrL1]Cl, [IrL2]Cl and [IrL3]Cl were determined in deoxygenated acetonitrile (10-5 M) at room temperature and are shown in Figure 4. All complexes show a single unstructured broadband compatible with a dominant charge transfer (CT) for the emitter excited state. The maximum of the emission band (table 3) is observed at 641 nm for the [IrL1]Cl complex, while for the [IrL2]Cl complex the corresponding maximum moves towards blue (605 nm) and in the case of [IrL3]Cl complex (652 nm) toward red. In addition, such complexes have large Stokes shifts (Aem - Aex > 200 nm) which are consistent with a phosphorescence emission mechanism.

Additionally, the half-life times of the excited state (^) of said complexes of the invention in deoxygenated acetonitrile were determined experimentally. The [IrL2]Cl complex shows a lifetime five times longer than the other two complexes, as can be seen in Table 3, probably due to a protective role of the methyl group, which prevents emission quenching processes. ). Once again, these values are compatible with phosphorescence as the emission mechanism.

Table 3: Photophysical properties determined in acetonitrile at 25 °C.

1.11. Electrochemical tests.

The redox potentials of the complexes of the invention [IrL1]Cl, [IrL2]Cl and [IrL3]Cl were determined experimentally in solutions (5x10-4 M) in deoxygenated acetonitrile. with [nBu ⁴ N][PF ⁶ ] (0.1 M) as supporting electrolyte and using a 3-electrode system, including a glassy carbon working electrode. Oxygen was removed using a flow of argon (sparging). The potentials occur in front of the ferricinium/ferrocene pair (Fc+/Fc).

The trends observed for the experimentally determined electrochemical band gaps (AE ¹ / ² ), included in Table 4, roughly match the theoretically determined HOMO-LUMO band gaps. For example, the 3 complexes of the invention [IrL1]Cl, [IrL2]Cl and [IrL3]Cl show lower AE ^1/2 values and HOMO-LUMO band gaps than those described by E. Zysman-Colman et al. (Inorg. Chem. 2011, 50(22), 11514-11526) for the reference complex [1]PF6.

Complex

[b][1]PF6 0.87 (r) -1.78 (r) 2.65

0.64 (go) -1.63 (go)

[IrL1]Cl 2.47

0.84(qr)-2.06(rev)

0.64 (go) -1.65 (go)

[IrL2]Cl 2.51

0.88(qr)-2.07(rev)

0.65 (go) -1.52 (go)

[IrL3]Cl 2.42

0.90(qr)-1.92(rev)

Table 4: Referenced cyclic voltammetry data for FcVFc in 5x10 ^-4 M acetonitrile solution for the [IrL1]Cl, [IrL2]Cl and [IrL3]Cl complexes of the invention. [b] Data published by Zysman-Colman et al., 2011.

Example 2: Photocatalytic activity of the complexes of the invention

2.1. Thiocyanation of 1H-indoles.

First, the activity of the complexes of the invention as photocatalysts in thiocyanation reactions of 1H-indoles was evaluated. For this, 3 equivalents of NH ⁴ SCN, a solution with the corresponding indole indicated in Table 5 in THF (0.5 mmol), and a solution of the corresponding complex of the invention ([IrL1]Cl, [IrL2]Cl and [IrL3]Cl in THF (final mole %) and THF. The tube was sealed with a septum and then filled with a balloon of O ² (1 atm, 10 min) through a needle.The mixture was stirred for 24h under light irradiation (see table 5) at room temperature.After 24h the reaction mixture was diluted with dichloromethane (15 mL) and washed with brine.The combined organic phases were dried over MgSO ⁴ .After removing the solvent under pressure reduced, the reaction crude was purified on a silica gel column chromatography using petroleum ether/ethyl acetate (7:1-2:1).

Scheme 2: Regioselective thiocyanation of indole 2a.

Table 5: conditions of the photocatalytic thiocyanation reactions of 1H-indole, 2a, 0.5 mmol), NH ⁴ SCN (3 equiv), complex of the invention or RB (Rose Bengal) (0.1 or 0.2 mol %), THF ( 5 mL), O ² (1 atm, 10 min), under blue light (LED,Airr = 460 nm, 23 W) or *white light (Compact Fluorescence Lamp, 23 W), room temperature for the specified time. The yields were determined by 1H NMR of the reaction crudes and are expressed as the average of two independent experiments. 1,3,5-Trimethoxybenzene was used as an internal reference for the quantitative determination of 1H NMR.

The results obtained were in most cases much higher than those obtained with the reference complex [1]Cl, and comparable to those obtained with Rose Bengal (Fan et al.). It is noteworthy that the yield was quantitative with the use of 0.1% mol of [IrL2]Cl after 24 hours, while increasing the quantity to 0.2% mol gave a quantitative yield of 97% ( > 99%) at 16 and 20 hours of reaction, respectively. On the other hand, the use of blue light provides better performance than white light. The Thiocyanation is regioselective, since only the thiocyanation product at position C-3 was obtained. The process is also efficient, safe and sustainable since the yield obtained is high, and thanks to the use of visible light and oxygen, without generating toxic waste.

To verify the nature of the reaction mechanism, tests were carried out in the absence of either the complex of the invention (in this case [IrL2]Cl), or light, or NH ⁴ SCN (Table 6). In all cases, zero or very low yields were obtained, proving the photocatalytic nature of the process and demonstrating that both O ² and NH ⁴ SCN actively participate in the reaction. In addition, additional experiments were performed to determine what is the actual or effective oxidizing agent in the reaction. For this, tests were carried out in the presence of TEMPO, since it eliminates or neutralizes superoxides (scavanger) and DABCO, since it is a compound that deactivates (quenches) singlet oxygen (Table 6). In both cases the yield was drastically reduced suggesting that both superoxide and singlet oxygen are involved in the reaction mechanism.

Table 6. General reaction conditions: 1H-indole (2a, 0.5 mmol), NH ⁴ SCN 3 equiv o 0 ^[b] , [IrL2]Cl (0.1 mol %), solvent (5 mL), O ² (1 atm), blue light (LED, A ^exc = 460 nm), room temperature for 24 h. Yields are the average of two independent experiments. 1,3,5-Trimethoxybenzene was used as internal reference for quantitative 1H NMR determinations.

To check the versatility of the procedure depending on the type of starting indole, experiments were also carried out with a variety of indoles (2a to 2h) as substrates, using the representative [IrL2]Cl complex of the invention as photocatalyst. The results are collected in table 7:

Table 7: General reaction conditions: indole (0.5 mmol), NH ⁴ SCN (1.5 mmol, 3 equiv), [Ir2]Cl (0.1 mol %), THF (5 mL), O ² ( 1 atm, 10 min), blue light (LED, Airr = 460 nm, 23 W), room temperature for 24 h. Yields were determined by 1H NMR by analysis of reaction crudes using 1,3,5-trimethoxybenzene as internal reference. Values in parentheses show isolated performance.

The results show very high yields both for indoles with electron-donating substituents (eg: alkoxide, alkyl), and with electron-withdrawing substituents (eg: halogen), in several positions (C1, C-2, C-5 and C- ⁶ ), showing the great versatility of the procedure.

2.2. Indoline dehydrogenation.

Oxidative dehydrogenation experiments of different indolines were also carried out with the use of the complexes of the invention as photocatalysts.

For this, a solution of the corresponding indoline in THF and a solution of [IrL2]Cl in THF were added to a large test tube for catalysis (20 ML) (see table 8 for the specific reaction conditions and quantities). The tubes were sealed with a septum and then filled with an O ² balloon (1 atm) using a needle. The mixture was kept stirring for 24 h under irradiation with blue light (460 nm, 23 W). After 24h the solvent was removed and the yield was estimated by 1H NMR using 1,3,5-trimethoxybenzene as internal reference. The 1H NMR spectrum is consistent with that described in the literature (Ruchun Yang et al., J. Org. Chem 2020, 85 (11), 1-39).

Scheme 3: oxidative dehydrogenation of indoline 1a.

Comparative tests were also carried out with Rose Bengal at different concentrations, obtaining much worse yields than those obtained with the complex of the invention (Table 8).

In addition, to obtain information on the reaction mechanism, assays were carried out in the absence of the complex of the invention (in this case [IrL2]Cl), or light, or NH ⁴ SCN (Table 8). In all cases, zero or very low yields were obtained, proving the photocatalytic nature of the process and demonstrating that both O ² and NH ⁴ SCN actively participate in the reaction.

The control experiments carried out showed (table 8) that the reaction mechanism is photocatalytic since to obtain an adequate yield both the presence of the photocatalyst (complex of the invention) and the presence of light are required.

An experiment with N ² confirmed that the participation of O ² is necessary in the dehydrogenation process, and the experiments with DABCO and TEMPO suggest that the real oxidant is singlet oxygen, although the O ^{2 '} radical also seems to participate in the oxidation.

Table 8: indoline (1a, 0.5 mmol), photocatalyst (0.1 mol%), solvent (5 mL), O ² (1 atm), blue light (LED, Airr = 460 nm, 23 W), temperature environment for 8 or 24 h. Yields were determined by 1H NMR analysis of reaction crudes using 1,3,5-trimethoxybenzene as internal reference.

The reaction conditions were applied to other different indolines, verifying that the complexes of the invention can be successfully used as photocatalysts for the dehydrogenation of indolines with electron-donating (alkyl, for example) or electron-withdrawing (halogen, for example) functional groups. example) in different positions (C-2, C-5).

Table 9: General reaction conditions: indoline (0.5 mmol), [Ir2]Cl (0.1 mol %), THF (5 mL), O ² (1 atm, 10 min), blue light (LED, 460 nm, 23 W), stirring at room temperature for 24 h. Yields were determined by 1H NMR analysis of reaction crudes using 1,3,5-trimethoxybenzene as internal reference. Performance values are the result of two independent experiments.

23. One-pot procedure for the thiocyanation of indoles from the corresponding indoline

Next, different assays were carried out in which indoles with the thiocyanate group were obtained regioselectively in the C-3 position, from the corresponding indolines, in a one-pot manner, that is, without the need to isolate the intermediate indole. Table 10 shows the results obtained taking indoline as a substrate and using [IrL2]Cl as a representative complex of the invention (scheme 4), in comparison with the results obtained with Rose Bengal or with eosin Y.

Scheme 4: Obtaining thiocyanate-indoles from indolines by means of a Onepot process

Table 10. Reaction conditions: indoline (1a, 0.5 mmol), NH ⁴ SCN (1.5 mmol, 3 equiv), catalyst (0.1 mol %), solvent (5 mL), O ² (1 atm ), blue LED light (460 nm) at room temperature for 2 periods of 24 24 h. The % values refer to A=% of the starting indoline 1a at the end of the one-pot process of the present invention; B=% of the indole intermediate 2a at the end of the one-pot process of the present invention; and C=% of the final C-3 thiocyanate-indole 3a after the one-pot process of the present invention.

As can be seen, the use of the complex of the invention provided a much better result than that of the comparative experiments with eosin and Rose Bengal.

The one-pot procedure of the invention was also carried out, taking other indolines as starting substrates, both with electron-donating substituents and with substituents that withdraw electrons in different positions, as shown in Table 11:

Table 11. General reaction conditions: indoline (0.5 mmol), [Ir2]Cl (0.1 mol % or [b] 0.3 mol %), THF (5 mL), O ² (1 atm, 10 min), blue light (LED, 460 nm, 23 W), shaking at room temperature for 2 periods of 24+24 h. Yields were determined by analysis from 1H NMR of reaction crudes using 1,3,5-trimethoxybenzene as internal reference. Performance values are the result of two independent experiments.

Example 3: Iridium(IM) complexes of the invention for antitumor use in photodynamic therapy.

The cytotoxic activity of these same complexes against human prostate cancer cells (PC-3) has been evaluated, both in the dark and after irradiation with light.

To perform this assay, PC-3 cells (commercially obtained from American Type Culture Collection) were seeded in 96-well culture plates at a density of 4000 cells per well. After a 24 h incubation to allow the cells to adhere to the bottom of the wells, two plates were treated in parallel with different concentrations of the [IrL3]Cl complex of the present invention (between 10 and 0.01 mM) dissolved in culture medium. The plates were incubated for 1 h at 37 °C to allow the internalization of the compounds in the cells and then one of the plates was kept in the dark and the other was irradiated with an LED lamp at a wavelength of 450 nm for 60 minutes, applying a light dose of 24 J/cm ² . Both plates were then incubated at 37 °C in a 5% CO ² atmosphere in the dark for 48 h.

To determine cell viability after treatment, an MTT assay was performed, which is based on the metabolic reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazole Bromide (MTT). To do this, the culture medium was removed and the wells were washed with PBS (phosphate-buffered saline solution). 110 ^L of MTT solution was added in a 1:10 ratio with culture medium to each well. The cells were incubated for another 2h. At the end of the incubation period, the medium was removed and the formazan crystals formed from the MTT were dissolved in DMSO (200 ^L per well).

Cell viability was evaluated by determining the absorbance of each well at 570 nm with a spectrophotometer (BioTek, Winooski, USA). IC ⁵⁰ values (concentration of compound required to reduce cell growth by 50 percent) were calculated by a non-linear regression curve fitted to four parameters, using Gen5 Data Analysis software (BioTeck). The phototoxic index (PI) was established by applying the formula: PI — IC ^50darkness / IC ^{50irradiation} ) ^.

Table 12. * Blue LED light (Airr= 460 nm) has been used to irradiate.

Thus, it has been possible to verify how their antiproliferative activity is considerably enhanced after activation with blue light, which allows considering their use as photosensitizers for the treatment of this type of disease through photodynamic therapy.

Claims (20)

1. An Iridium(IM) complex of formula (M+)nXn-, where n = 1 to 3, where Xn- is an anion and M+ is a cationic complex of formula (I), or a stereoisomer thereof:

in which: - R1 and R2 are independently selected from H and C ¹ -C ⁶ alkyl; either - R1 and R2 are joined forming an aromatic ring of 6 carbon atoms to form a group B:

(B). 2. A complex according to claim 1, wherein Xn- is selected from the group consisting of Cl“ I , CF ³ SO ³ , CH ³ -C ⁶ H ⁴ -SO ³ , PF ⁶ _, BF ⁴ ~ and NOT ³ . 3. A complex according to either of claims 1 or 2, wherein R ¹ and R ² are both H and M+ is a cationic complex of formula (Ia), or a stereoisomer thereof:

4. A complex according to any of claims 1 or 2, wherein R1 is methyl and R2 is H and, M+ is a cationic complex of formula (Ib), or a stereoisomer thereof:

5. A complex according to either of claims 1 or 2, wherein R1 and R2 are joined to form a 6 carbon atom aromatic ring to form a benzothiazole group (B):

and M+ is a cationic complex of formula (Ic), or a stereoisomer thereof:

6. Procedure for obtaining a compound of formula (II):

wherein R3, R4, R5 and R6 are each independently selected from the group consisting of H, halogen, C ¹ -C ⁶ alkyl and C ¹ -C ⁶ alkoxy and wherein said process comprises: (ii) mixing a compound of formula (IV):

with a salt of -SCN; carried out at room temperature, irradiating with blue light and in the presence of O ² and an Iridium(NI) complex according to any of claims 1 to 5. 7. Procedure for obtaining a compound of formula (IV):

wherein R3, R4, R5 and R6 are each independently selected from the group consisting of H, halogen, C ¹ -C ⁶ alkyl and C ¹ -C ⁶ alkoxy and wherein said process comprises: (i) oxidizing a compound of formula (III):

at room temperature, irradiating with blue light and in the presence of O ² and an Iridium(III) complex according to any of claims 1 to 5. 8. Procedure for obtaining one-pot of a compound of formula (II):

wherein R3, R4, R5, and ^R6 are each independently selected from the group consisting of ^H , halogen, C1-C6 alkyl, and C1- ^{C6 alkoxy} and wherein said process comprises the following steps: (i) oxidizing a compound of formula (III):

to obtain a first mixture comprising a compound of formula (IV):

Y (ii) adding to said first mixture a salt of "SCN; wherein each of the stages (i) and (ii) are carried out at room temperature, irradiating with blue light and in the presence of O ² and an Iridium(III) complex according to any of claims 1 to 5 . 9. Process according to any of claims 6 to 8, wherein R3, R4, R5 and R6 are H. 10. Process according to any of claims 6 to 8, wherein R3, R4 and R5 are H and R6 is a halogen. 11. Process according to any of claims 6 to ⁸ , wherein R4, R5 and ^R6 are H and R3 is C1-C6 alkyl. An Iridium(III) complex according to any of claims 1 to 5, for use as a medicament. An Iridium(III) complex according to any of claims 1 to 5, for use in the treatment of cancer. An Iridium(III) complex according to any of claims 1 to 5, for antitumor use in photodynamic therapy. An Iridium(III) complex for use according to either of claims 13 or 14, wherein said Iridium(III) complex is administered in conjunction with, or prior to, administration of radiotherapy. 16. Pharmaceutical composition comprising an Iridium(III) complex according to any of claims 1 to 5 and at least one pharmaceutically acceptable excipient. 17. Pharmaceutical composition according to claim 16, for use as a medicament. 18. Pharmaceutical composition according to claim 16, for use in the treatment of cancer. 19. Pharmaceutical composition according to claim 16, for antitumor use in photodynamic therapy. 20. Pharmaceutical composition for use according to either of claims 18 or 19, wherein said Iridium(III) complex is administered in conjunction with, or prior to, administration of radiotherapy.